# ::id a_pmid_2488_5690.10 # ::date 2015-06-08T05:01:37 # ::file a_pmid_2488_5690_10.txt # ::snt Genetic targeting of mutant BRAF resulted in restoration of sensitivity to serum starvation-induced apoptosis and efficiently inhibited cell proliferation in the absence of growth factors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a / and :op1 (r2 / result-01 :ARG1 (t / target-01 :ARG1 (g2 / gene :wiki "BRAF_(gene)" :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (g / gene)) :ARG2 (r / restore-01 :ARG1 (s / sensitive-03 :ARG1 (a2 / apoptosis :ARG2-of (i / induce-01 :ARG0 (s2 / starve-01 :ARG2 (s3 / serum))))))) :op2 (i2 / inhibit-01 :ARG0 t :ARG1 (p / proliferate-01 :ARG0 (c / cell) :condition (a3 / absent-01 :ARG1 (g3 / growth-factor))) :ARG2-of (e / efficient-01) :condition a3)) # ::id a_pmid_2488_5690.11 # ::date 2015-06-08T23:25:37 # ::file a_pmid_2488_5690_11.txt # ::snt Among tested agents, the B-Raf inhibitor dabrafenib was found to induce a strong V600E-dependent shift in cell viability. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (f / find-01 :ARG1 (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "dabrafenib") :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG1-of (i4 / include-01 :ARG2 (a / agent :ARG1-of (t2 / test-01))) :xref (x1 / xref :value "PUBCHEM:44462760" :prob "17.251232")) :ARG2 (s2 / shift-01 :ARG1 (v / viability :mod (c / cell)) :ARG0-of (d / depend-01 :ARG1 (m / mutate-01 :value "V600E")) :mod (s3 / strong)))) # ::id a_pmid_2488_5690.12 # ::date 2015-06-08T23:42:39 # ::file a_pmid_2488_5690_12.txt # ::snt In contrast, no differential sensitizing effect was observed for conventional chemotherapeutic agents (mitomycin C, oxaliplatin, paclitaxel, etoposide, 5-fluorouracil), nor for the targeted agents cetuximab, sorafenib, vemurafenib, RAF265, or for inhibition of PI3 kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (a / affect-01 :polarity "-" :ARG0 (a2 / and :op1 (a3 / agent :mod (c2 / conventional) :mod (c3 / chemotherapy) :ARG1-of (m / mean-01 :ARG2 (a5 / and :op1 (s2 / small-molecule :name (n / name :op1 "mitomycin" :op2 "C") :xref (x4 / xref :value "PUBCHEM:5746" :prob "10.331253")) :op2 (s3 / small-molecule :name (n2 / name :op1 "oxaliplatin") :xref (x3 / xref :value "PUBCHEM:5310940" :prob "10.634277")) :op3 (s4 / small-molecule :name (n3 / name :op1 "paclitaxel") :xref (x8 / xref :value "PUBCHEM:4666" :prob "15.068933")) :op4 (s5 / small-molecule :name (n4 / name :op1 "etoposide") :xref (x7 / xref :value "PUBCHEM:3310" :prob "15.864937")) :op5 (s6 / small-molecule :name (n5 / name :op1 "5-fluorouracil") :xref (x6 / xref :value "PUBCHEM:3385" :prob "10.826826"))))) :op2 (a4 / agent :ARG1-of (t / target-01) :ARG1-of (m2 / mean-01 :ARG2 (a6 / and :op1 (s7 / small-molecule :name (n6 / name :op1 "cetuximab") :xref (x5 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :op2 (s8 / small-molecule :name (n7 / name :op1 "sorafenib") :xref (x2 / xref :value "PUBCHEM:216239" :prob "16.740406")) :op3 (s9 / small-molecule :name (n8 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op4 (s10 / small-molecule :name (n9 / name :op1 "RAF265") :xref (x9 / xref :value "PUBCHEM:11656518" :prob "17.879841"))))) :op3 (i / inhibit-01 :ARG1 (k / kinase :name (n10 / name :op1 "PI3") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "1.002")))) :ARG2 (s / sensitize-01) :ARG1-of (d / differ-02)))) # ::id a_pmid_2488_5690.13 # ::date 2015-06-08T23:54:05 # ::file a_pmid_2488_5690_13.txt # ::snt Treatment with dabrafenib efficiently inhibited phosphorylation of the B-Raf downstream targets Mek 1/2 and Erk 1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / inhibit-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n5 / name :op1 "dabrafenib") :xref (x1 / xref :value "PUBCHEM:44462760" :prob "17.251232"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "Mek1/2")) :op2 (e4 / enzyme :name (n4 / name :op1 "Erk1/2")) :ARG1-of (t2 / target-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :direction (d / downstream))) :ARG2-of (e / efficient-01 :ARG1 t)) # ::id a_pmid_2488_5690.33 # ::date 2015-06-09T00:01:34 # ::file a_pmid_2488_5690_33.txt # ::snt BRAF targeting in RKO # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (t / target-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location (c / cell-line :name (n2 / name :op1 "RKO"))) # ::id a_pmid_2488_5690.34 # ::date 2015-06-09T00:10:23 # ::file a_pmid_2488_5690_34.txt # ::snt It has been shown that B-RafV600E is sufficient to promote proliferation via Erk 1/2 signaling independently of exogenous growth factors and confers mechanisms to evade apoptosis [14-16]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (s / show-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 "14" :op2 "16"))) :ARG1 (a / and :op1 (s2 / suffice-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (p / promote-01 :ARG0 e2 :ARG1 (p2 / proliferate-01 :instrument (s3 / signal-07 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Erk1/2"))) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (g / growth-factor :mod (e4 / exogenous)))))) :op2 (c / confer-02 :ARG0 e2 :ARG1 (m2 / mechanism :purpose (e5 / evade-01 :ARG1 (a2 / apoptosis)))))) # ::id a_pmid_2488_5690.35 # ::date 2015-06-09T00:20:02 # ::file a_pmid_2488_5690_35.txt # ::snt However, these results are primarily based on non-quantitative RNA interference (RNAi) methods which are prone to artifacts in mammalian cells due to nonspecific defense mechanisms [17]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG2 (b / base-02 :ARG1 (t2 / thing :ARG2-of (r / result-01) :mod (t / this)) :ARG2 (m / method :ARG1-of (p / prone-01 :ARG2 (a / artifact) :location (c2 / cell :part-of (a2 / animal :name (n2 / name :op1 "Mammalia"))) :ARG1-of (c3 / cause-01 :ARG0 (m2 / mechanism :purpose (d / defend-01) :ARG1-of (s / specific-02 :polarity "-")))) :mod (q / quantitative :polarity "-") :manner-of (i / interfere-01 :ARG1 (n / nucleic-acid :name (n3 / name :op1 "RNA")))) :manner (p3 / primary)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 "17")))) # ::id a_pmid_2488_5690.36 # ::date 2015-06-09T00:25:38 # ::file a_pmid_2488_5690_36.txt # ::snt In contrast, somatic cell gene targeting enables quantitative knockouts of single alleles (Figure 1A) and the generation of endogenous models featuring well-defined genetic backgrounds [18]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG2 (e / enable-01 :ARG0 (t / target-01 :ARG1 (g / gene :part-of (c2 / cell :mod (s / somatic)))) :ARG1 (a / and :op1 (k / knock-out-03 :ARG1 (a2 / allele :ARG1-of (s2 / single-02)) :mod (q / quantity) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) :op2 (g2 / generate-01 :ARG1 (m / model :mod (e2 / endogenous) :ARG0-of (f2 / feature-01 :ARG1 (b / background :mod (g3 / gene) :ARG1-of (d2 / define-01 :manner (w / well)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 "18")))) # ::id a_pmid_2488_5690.37 # ::date 2015-06-09T00:31:02 # ::file a_pmid_2488_5690_37.txt # ::snt Utilizing this method, we have disrupted BRAF alleles in the colorectal cancer cell line RKO and established syngeneic clones which harbor a single BRAF allele of either wild-type or mutant genotype. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (d2 / disrupt-01 :ARG0 (w2 / we) :ARG1 (a2 / allele :name (n2 / name :op1 "BRAF")) :location (c / cell-line :name (n3 / name :op1 "RKO") :mod (d3 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colorectal" :op2 "cancer")))) :op2 (e / establish-01 :ARG0 w2 :ARG1 (c2 / clone :mod (s / syngeneic) :ARG0-of (h2 / harbor-01 :ARG1 (o / or :op1 (a3 / allele :name (n4 / name :op1 "BRAF") :mod (w3 / wild-type) :ARG1-of (s2 / single-02)) :op2 (a4 / allele :name (n5 / name :op1 "BRAF") :ARG1-of (m / mutate-01) :ARG1-of s2))))) :manner (u / utilize-01 :ARG0 w2 :ARG1 (m2 / method :mod (t / this)))) # ::id a_pmid_2488_5690.38 # ::date 2015-06-09T00:36:59 # ::file a_pmid_2488_5690_38.txt # ::snt Despite its near-diploid karyotype and MSI phenotype, the colorectal cancer cell line RKO carries a stable triplication of the BRAF gene locus (dup (7) (q21q36)) with one wild-type and two mutant alleles present in parental cells [13]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / carry-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "RKO") :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :ARG1 (t / triplicate-00 :ARG1 (l / locus :mod (g / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (l2 / label-01 :ARG2 (s2 / string-entity :value "dup(7)(q21q36)"))) :ARG1-of (s / stable-03) :ARG1-of (m / mean-01 :ARG2 (b / be-located-at-91 :ARG1 (a / and :op1 (a2 / allele :quant "1" :mod (w / wild-type)) :op2 (a3 / allele :quant "2" :ARG1-of (m2 / mutate-01))) :ARG2 (c3 / cell :mod (p / parent))))) :concession (h2 / have-03 :ARG0 c2 :ARG1 (a4 / and :op1 (k / karyotype :ARG1-of (n4 / near-01 :ARG2 (d3 / diploid))) :op2 (p2 / phenotype :name (n5 / name :op1 "microsattelite" :op2 "instability")))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "13")))) # ::id a_pmid_2488_5690.39 # ::date 2015-06-09T00:45:57 # ::file a_pmid_2488_5690_39.txt # ::snt This genotype was verified by DNA sequencing in RKO-E1, a subclone obtained from RKO that was found to be comparable to the parental cell line in terms of morphology and proliferation (Figure 1B and data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (v / verify-01 :ARG1 (g / genotype :mod (t / this)) :location (c / cell-line :name (n2 / name :op1 "RKO-E1") :ARG3-of (s2 / subclone-01 :ARG1-of (o / obtain-01 :ARG2 (c2 / cell-line :name (n3 / name :op1 "RKO"))) :ARG1-of (c3 / compare-01 :ARG2 (c4 / cell-line :mod (p2 / parent)) :ARG1-of (p / possible-01) :topic (a / and :op1 (m / morphology) :op2 (p3 / proliferate-01)) :ARG1-of (f / find-01)))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1B") :op2 (d2 / data :ARG1-of (s / show-01 :polarity "-")))) :manner (s3 / sequence-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))) # ::id a_pmid_2488_5690.40 # ::date 2015-06-09T04:41:16 # ::file a_pmid_2488_5690_40.txt # ::snt In the first targeting round, an oncogenic allele of BRAF exon 15 was recombined and deleted by somatic cell gene targeting to generate the cell clone RBOW (RKO-derived BRAFonc/wt/-). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (r / recombine-01 :ARG1 (a2 / allele :mod (o2 / oncogenic) :mod (e / exon :mod "15" :part-of (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :op2 (d / delete-01 :ARG1 a2) :time (r2 / round-05 :ARG1 (t / target-01) :ord (o / ordinal-entity :value "1")) :instrument (t2 / target-01 :ARG1 (g4 / gene :part-of (c / cell :mod (s / somatic)))) :purpose (g2 / generate-01 :ARG1 (c2 / cell :name (n2 / name :op1 "RBOW") :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :location-of (g3 / gene :name (n3 / name :op1 "BRAF") :ARG1-of (d2 / derive-01 :ARG2 (c3 / cell-line :name (n4 / name :op1 "RKO"))) :ARG1-of (l / label-01 :ARG2 (s2 / string-entity :value "onc/wt/-")) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1-of (c5 / clone-01)))) # ::id a_pmid_2488_5690.41 # ::date 2015-06-09T04:51:08 # ::file a_pmid_2488_5690_41.txt # ::snt Subsequently, either wild-type or V600E-mutant B-Raf was disrupted by targeting a second allele in RBOW, yielding six BRAF-mutant and one wild-type clone from approximately 104 screened colonies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (d / disrupt-01 :ARG1 (o2 / or :op1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :manner (t2 / target-01 :ARG1 (a2 / allele :part-of (c / cell :name (n3 / name :op1 "RBOW")) :mod (o / ordinal-entity :value "2"))) :ARG0-of (y / yield-01 :ARG1 (a3 / and :op1 (c2 / clone :quant "6" :mod (m2 / mutate-01 :ARG1 (g / gene :name (n4 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (c3 / clone :quant "1" :mod w)) :source (c4 / colony :ARG1-of (s2 / screen-01) :quant (a / approximately :op1 "10000"))) :time (s3 / subsequent)) # ::id a_pmid_2488_5690.42 # ::date 2015-06-09T05:02:53 # ::file a_pmid_2488_5690_42.txt # ::snt Out of these double positive clones, BRAF knockout cell lines RBO-1 and RBO-2 (RKO-derived BRAFonc/-/- 1 and 2) as well as RBW-1 (RKO-derived BRAFwt/-/-) were established (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / establish-01 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "RBO-1") :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :mod "1" :location-of (g2 / gene :name (n4 / name :op1 "BRAF") :ARG1-of (d / derive-01 :ARG2 (c4 / cell-line :name (n5 / name :op1 "RKO"))) :ARG2-of (m2 / mutate-01 :mod "−/−") :ARG0-of (c9 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :location-of (k / knock-out-03 :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (c2 / cell-line :name (n2 / name :op1 "RBO-2") :ARG1-of (m3 / mean-01 :ARG2 (c5 / cell-line :mod "2" :location-of g2)) :location-of k) :op3 (c6 / cell-line :name (n6 / name :op1 "RBW-1") :ARG1-of (m4 / mean-01 :ARG2 (c7 / cell-line :location-of (g3 / gene :name (n7 / name :op1 "BRAF") :ARG2-of (m5 / mutate-01 :mod "−/−") :ARG1-of d :mod (w / wild-type) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :source (c8 / clone :mod (p / positive :mod (d2 / double)) :mod (t / this))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id a_pmid_2488_5690.43 # ::date 2015-06-09T05:16:43 # ::file a_pmid_2488_5690_43.txt # ::snt The apparent counterselection against inactivation of B RafV600E might indicate the presence of an oncogene addiction for B-RafV600E as a cancer cell trait in RKO [19]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (p2 / possible-01 :ARG1 (i / indicate-01 :ARG0 (c / counterselect-00 :mod (a / apparent) :ARG0-of (c6 / counter-01 :ARG1 (a3 / activate-01 :polarity "-" :ARG1 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :ARG1 (t / trait :domain (a2 / addict-01 :ARG1 e3 :ARG2 (o / oncogene)) :mod (c2 / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :location (c4 / cell-line :name (n5 / name :op1 "RKO")))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "19")))) # ::id a_pmid_2488_5690.44 # ::date 2015-06-09T05:24:19 # ::file a_pmid_2488_5690_44.txt # ::snt For structural confirmation of the deleted alleles, DNA sequencing was performed and all genotypes were verified (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / and :op1 (p / perform-01 :ARG1 (s / sequence-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA")))) :op2 (v / verify-01 :ARG1 (g / genotype :mod (a2 / all))) :purpose (c / confirm-01 :ARG1 (a3 / allele :ARG1-of (d / delete-01)) :mod (s2 / structure)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id a_pmid_2488_5690.45 # ::date 2015-06-09T05:27:35 # ::file a_pmid_2488_5690_45.txt # ::snt Furthermore, all cells expressed BRAF protein at comparable levels (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (a / and :op2 (p2 / possible-01 :ARG1 (c2 / compare-01 :ARG1 (l / level :quant-of (e / express-03 :ARG2 (e2 / enzyme :wiki "-" :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG3 (c / cell :mod (a2 / all)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2488_5690.46 # ::date 2015-06-09T05:31:04 # ::file a_pmid_2488_5690_46.txt # ::snt While the expression of Mek 1/2 and Erk 1/2 was independent of serum concentration and BRAF status, the phosphorylation of these effector kinases was constantly active in the BRAF-mutant clones but low in BRAF-wild-type cells (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (c3 / contrast-01 :ARG1 (a3 / active :domain (p / phosphorylate-01 :ARG1 "a") :manner (c4 / constant) :location (c5 / clone :location-of (g2 / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (l / low-04 :ARG1 (c6 / cell :location-of (g3 / gene :name (n5 / name :op1 "BRAF") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 p)) :ARG2 (d / depend-01 :polarity "-" :ARG0 (e3 / express-03 :ARG2 (a / and :op1 (k / kinase :name (n / name :op1 "Mek1/2")) :op2 (k2 / kinase :name (n2 / name :op1 "Erk1/2")) :ARG0-of (e / effect-03))) :ARG1 (a2 / and :op1 (c2 / concentrate-02 :ARG1 (s / serum)) :op2 (s2 / status :mod (g / gene :name (n3 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2488_5690.47 # ::date 2015-06-09T05:39:53 # ::file a_pmid_2488_5690_47.txt # ::snt This was found to be independent of the serum concentration, indicating that the phosphorylation status of Mek and Erk is dependent on mutant BRAF in RKO. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (d / depend-01 :polarity "-" :ARG0 (t / this) :ARG1 (c / concentrate-02 :ARG1 (s / serum)) :ARG0-of (i / indicate-01 :ARG1 (d2 / depend-01 :ARG0 (s2 / status :mod (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Mek") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243")) :op2 (e2 / enzyme :name (n2 / name :op1 "Erk") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))))) :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location (c2 / cell-line :name (n4 / name :op1 "RKO")))))) # ::id a_pmid_2488_5690.48 # ::date 2015-06-09T09:55:59 # ::file a_pmid_2488_5690_48.txt # ::snt Cell-biological phenotypes related to mutant BRAF # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (p / phenotype :mod (b / biology :mod (c / cell)) :ARG1-of (r / relate-01 :ARG2 (g / gene :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) # ::id a_pmid_2488_5690.49 # ::date 2015-06-09T09:59:07 # ::file a_pmid_2488_5690_49.txt # ::snt Under standard long-term cell culture conditions no differences in morphology or growth were observed between the cell clones (Figures 1B and 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (o / observe-01 :ARG1 (d / differ-02 :polarity "-" :ARG1 (c2 / cell :ARG1-of (c / clone-01)) :ARG3 (o2 / or :op1 (m / morphology) :op2 (g / grow-01))) :condition (c3 / condition :ARG1-of (s / standard-02) :mod (c4 / culture-01 :ARG1 (c5 / cell) :ARG1-of (l2 / long-03))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "2A")))) # ::id a_pmid_2488_5690.50 # ::date 2015-06-09T10:02:11 # ::file a_pmid_2488_5690_50.txt # ::snt Expectedly, decreased serum concentrations led to lower proliferation rates in these cells, but exponential growth was sustained under all applied conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (c3 / contrast-01 :ARG1 (l2 / lead-03 :ARG0 (c / concentrate-02 :ARG1 (s / serum) :ARG1-of (d / decrease-01)) :ARG2 (p / proliferate-01 :ARG2-of (l / low-04 :ARG1 (c2 / cell :mod (t / this)) :degree (m / more))) :ARG1-of (e2 / expect-01)) :ARG2 (s2 / sustain-01 :ARG1 (g / grow-01 :ARG2 (e / exponential)) :condition (c4 / condition :ARG1-of (a / apply-02) :mod (a2 / all)))) # ::id a_pmid_2488_5690.51 # ::date 2015-06-09T10:05:20 # ::file a_pmid_2488_5690_51.txt # ::snt However, the withdrawal of serum resulted in the inhibition of cell growth of the wild-type cells RBW-1 (Figure 2B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (c / contrast-01 :ARG2 (r / result-01 :ARG1 (w / withdraw-01 :ARG1 (s / serum)) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG0 (c2 / cell-line :name (n / name :op1 "RBW-1") :mod (w2 / wild-type))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2B") :op2 (f2 / figure :mod "2C")))) # ::id a_pmid_2488_5690.52 # ::date 2015-06-09T10:07:28 # ::file a_pmid_2488_5690_52.txt # ::snt It has been shown previously that BRAF wild-type cells require glucose supply for survival whereas BRAF-mutant cell clones maintain proliferation in low-glucose environments [20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / require-01 :ARG0 (c2 / cell :location-of (g / gene :name (n / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG1 (s2 / supply-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "glucose") :xref (x2 / xref :value "PUBCHEM:206" :prob "11.89276"))) :purpose (s4 / survive-01 :ARG0 c2)) :ARG2 (m / maintain-01 :ARG0 (c4 / cell :ARG1-of (c3 / clone-01 :location-of (g2 / gene :name (n3 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1 (p2 / proliferate-01) :location (e / environment :ARG1-of (l / low-04 :ARG2 s3))) :ARG1-of (s / show-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "20")) :time (p / previous))) # ::id a_pmid_2488_5690.53 # ::date 2015-06-09T10:21:30 # ::file a_pmid_2488_5690_53.txt # ::snt Here we show that the V600E mutation of B-Raf also provides independency of serum-derived growth signals in RKO and that targeting of oncogenically mutant BRAF is sufficient to deprive this vital feature of malignancy from the cells, thereby corroborating previous reports [6]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / and :op1 (p / provide-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (d / depend-01 :polarity "-" :ARG1 (s / signal-07 :ARG1 (g / grow-01) :ARG1-of (d2 / derive-01 :ARG2 (s2 / serum)))) :mod (a2 / also) :location (c / cell-line :name (n3 / name :op1 "RKO"))) :op2 (s3 / suffice-01 :ARG0 (t / target-01 :ARG1 (g2 / gene :name (n4 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01 :ARG0-of (c6 / cause-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG1 (d3 / deprive-01 :ARG0 t :ARG1 (f / feature-01 :ARG0 "c2" :ARG1 (m3 / malignancy) :mod (t2 / this) :mod (v / vital)) :ARG2 (c2 / cell))) :ARG1-of (s4 / show-01 :ARG0 (w / we) :location (h / here) :ARG0-of (c3 / cause-01 :ARG1 (c4 / corroborate-01 :ARG1 (r / report :time (p2 / previous) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "6")))))))) # ::id a_pmid_2488_5690.54 # ::date 2015-06-09T10:31:52 # ::file a_pmid_2488_5690_54.txt # ::snt Sustained proliferative signaling is considered one of the major traits of cancer cells and is therefore used as a target mechanism of individualized therapy approaches including anti EGFR therapy strategies in colorectal cancer [21,22]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (c / consider-01 :ARG1 (i / include-01 :ARG1 (s / signal-07 :ARG0-of (p / proliferate-01) :ARG1-of (s2 / sustain-01)) :ARG2 (t / trait :poss (c2 / cell :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :ARG1-of (m / major-02))) :ARG0-of (c4 / cause-01 :ARG1 (u / use-01 :ARG1 s :ARG2 (m2 / mechanism :ARG1-of (t2 / target-01) :poss (a / approach-02 :mod (t3 / therapy :ARG1-of (i2 / individualize-02)) :ARG2-of (i3 / include-91 :ARG1 (s3 / strategy :mod (t4 / therapy :ARG0-of (c7 / counter-01 :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :prep-in (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 "22")))))))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "21")))) # ::id a_pmid_2488_5690.55 # ::date 2015-06-09T23:18:51 # ::file a_pmid_2488_5690_55.txt # ::snt In another context, mutant B-Raf induced cellular senescence rather than proliferation [23,24]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (s / senescence :mod (c / cell) :ARG1-of (i2 / instead-of-91 :ARG2 (p / proliferate-01 :ARG0 c))) :condition (c2 / context :mod (a / another)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 "23" :op2 "24"))))) # ::id a_pmid_2488_5690.56 # ::date 2015-06-09T23:22:38 # ::file a_pmid_2488_5690_56.txt # ::snt However, senescence can be overcome by phosphoinositide 3-kinase (PI3K)/AKT signaling [24] which is hyperactivated in RKO due to a PIK3CA mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (c / contrast-01 :ARG2 (p / possible-01 :ARG1 (o / overcome-01 :ARG0 (s2 / signal-07 :ARG0 (p2 / pathway :name (n2 / name :op1 "phosphoinositide" :op2 "3-kinase" :op3 "AKT")) :ARG1-of (a / activate-01 :degree (h / hyper) :location (c3 / cell-line :name (n3 / name :op1 "RKO")) :ARG1-of (c4 / cause-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))))) :ARG1 (s / senescence)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "24"))))) # ::id a_pmid_2488_5690.57 # ::date 2015-06-09T23:29:10 # ::file a_pmid_2488_5690_57.txt # ::snt By staining of senescence-associated β-galactosidase activity [25] we examined whether the differential proliferation rates observed upon serum deprivation were attributable to cellular senescence. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (p / possible-01 :mode "interrogative" :ARG1 (a / attribute-01 :ARG1 (r / rate :mod (p2 / proliferate-01) :ARG1-of (d / differ-02) :ARG1-of (o / observe-01 :condition (d3 / deprive-01 :ARG1 (s3 / serum)))) :ARG2 (s / senescence :mod (c / cell)))) :manner (s2 / stain-01 :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "senescence-associated" :op2 "β-galactosidase") :xref (x / xref :value "UNIPROT:CLD1_HUMAN" :prob "0.252"))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "25"))))) # ::id a_pmid_2488_5690.58 # ::date 2015-06-09T23:32:53 # ::file a_pmid_2488_5690_58.txt # ::snt Cellular senescence was detected at very low levels in less than 5% of cells (Figure 2D-E), indicating that senescence alone cannot explain the strong reduction in cell growth observed upon withdrawal of serum. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (d / detect-01 :ARG1 (l2 / level :quant-of (s / senescence :mod (c / cell)) :ARG1-of (l3 / low-04 :degree (v / very))) :location (c2 / cell :quant (l / less-than :op1 (p / percentage-entity :value "5"))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :name (n / name :op1 "2D")) :op2 (f2 / figure :name (n2 / name :op1 "2E")))) :ARG0-of (i / indicate-01 :ARG1 (p2 / possible-01 :polarity "-" :ARG1 (e / explain-01 :ARG0 (s2 / senescence :mod (a2 / alone)) :ARG1 (r / reduce-01 :ARG1 (g / grow-01 :ARG1 (c3 / cell)) :ARG2 (s4 / strong) :ARG1-of (o / observe-01 :condition (w / withdraw-01 :ARG1 (s3 / serum)))))))) # ::id a_pmid_2488_5690.59 # ::date 2015-06-09T23:38:16 # ::file a_pmid_2488_5690_59.txt # ::snt Flow cytometry revealed a significant increase of apoptotic cells in wild-type compared to mutant clones upon withdrawal of serum (Figure 2F and G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (r / reveal-01 :ARG0 (t / thing :name (n / name :op1 "flow" :op2 "cytometry")) :ARG1 (i / increase-01 :ARG1 (c / cell :mod (a / apoptosis)) :ARG2 (s / significant-02) :location (c2 / cell :mod (w / wild-type) :compared-to (c3 / clone :ARG2-of (m / mutate-01))) :condition (w2 / withdraw-01 :ARG1 (s2 / serum))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2F") :op2 (f2 / figure :mod "2G")))) # ::id a_pmid_2488_5690.60 # ::date 2015-06-09T23:42:19 # ::file a_pmid_2488_5690_60.txt # ::snt Apoptosis was confirmed by the detection of cleaved caspase 3 at considerable levels in serum-starved RBW-1, while all other samples showed full-length protein only (Figure 2H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c5 / contrast-01 :ARG1 (c / confirm-01 :ARG0 (d / detect-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "caspase" :op2 "3") :ARG1-of (c2 / cleave-01) :xref (x / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.662")) :quant (c3 / considerable)) :location (c4 / cell-line :name (n2 / name :op1 "RBW-1") :ARG1-of (s / starve-01 :ARG2 (s2 / serum)))) :ARG1 (a / apoptosis)) :ARG2 (s3 / show-01 :ARG0 (t / thing :mod (a2 / all) :mod (o / other) :ARG1-of (s4 / sample-01)) :ARG1 (p / protein :ARG1-of (l2 / long-03 :degree (f / full))) :mod (o2 / only)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2H"))) # ::id a_pmid_2488_5690.61 # ::date 2015-06-09T23:49:47 # ::file a_pmid_2488_5690_61.txt # ::snt Consistent with RKO modeling a distinct subpopulation of patients characterized by the presence of certain molecular features and the absence of others [7], no implication of p53 in apoptosis was observed (Figure 2H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 14, 2015 (o / observe-01 :ARG1 (i / implicate-01 :polarity "-" :ARG1 (p / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG2 (a / apoptosis)) :ARG1-of (c / consistent-01 :ARG2 (m / model-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "RKO")) :ARG1 (s / subpopulation :mod (p2 / patient) :mod (d / distinct) :ARG1-of (c3 / characterize-01 :ARG2 (a2 / and :op1 (h / have-03 :ARG0 s :ARG1 (f / feature :mod (m2 / molecule) :mod (c4 / certain))) :op2 (l / lack-01 :ARG0 s :ARG1 (f2 / feature :mod m2 :mod (o2 / other)))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "7"))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "2H"))) # ::id a_pmid_2488_5690.62 # ::date 2015-06-09T23:56:19 # ::file a_pmid_2488_5690_62.txt # ::snt Since serum starvation is often used to model apoptosis mediated via the PUMA pathway [26], we also analyzed PUMA protein levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "PUMA") :xref (x / xref :value "UNIPROT:BBC3B_HUMAN" :prob "1.002"))) :ARG1-of (c / cause-01 :ARG0 (u / use-01 :ARG1 (s / starve-01 :ARG2 (s2 / serum)) :frequency (o / often) :purpose (m / model-01 :ARG0 s :ARG1 (a2 / apoptosis :ARG1-of (m2 / mediate-01 :instrument (p2 / pathway :name (n2 / name :op1 "PUMA"))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "26"))))) :mod (a3 / also)) # ::id a_pmid_2488_5690.63 # ::date 2015-06-10T00:00:07 # ::file a_pmid_2488_5690_63.txt # ::snt PUMA was found to be highly abundant specifically in serum starved RBW-1 (Figure 2H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / abundant :op1 (c / cell-line :name (n2 / name :op1 "RBW-1") :ARG1-of (s / starve-01 :ARG2 (s2 / serum))) :ARG1-of (h / high-02) :domain (p / protein :name (n / name :op1 "PUMA") :xref (x / xref :value "UNIPROT:BBC3B_HUMAN" :prob "1.002")) :ARG1-of (f / find-01) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2H")) :ARG1-of (s3 / specific-02)) # ::id a_pmid_2488_5690.64 # ::date 2015-06-10T00:05:29 # ::file a_pmid_2488_5690_64.txt # ::snt Consistent with data previously shown by others, starvation-induced apoptosis is mediated by PUMA in a p53-independent fashion in our experiments [27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / mediate-01 :ARG0 (p / protein :name (n / name :op1 "PUMA") :xref (x1 / xref :value "UNIPROT:BBC3B_HUMAN" :prob "1.002")) :ARG1 (a / apoptosis :ARG2-of (i / induce-01 :ARG0 (s / starve-01))) :manner (d / depend-01 :polarity "-" :ARG1 (p2 / protein :name (n2 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :time (e / experiment-01 :ARG0 (w / we)) :ARG1-of (c / consistent-01 :ARG2 (d2 / data :ARG1-of (s2 / show-01 :ARG0 (p5 / person :mod (o / other)) :time (p3 / previous)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "27")))))) # ::id a_pmid_2488_5690.65 # ::date 2015-06-10T00:10:01 # ::file a_pmid_2488_5690_65.txt # ::snt Programmed cell death is a key feature of proliferation control in homeostasis and overcoming apoptosis is considered another hallmark of cancer cells [28]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (f / feature :ARG1-of (k / key-02 :ARG2 (d2 / die-01 :ARG1 (c / cell) :ARG1-of (p / program-01))) :part-of (c2 / control-01 :ARG1 (p2 / proliferate-01)) :prep-in (h / homeostasis)) :op2 (c3 / consider-01 :ARG1 (h2 / hallmark :mod (c4 / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :domain (o / overcome-01 :ARG1 (a2 / apoptosis)) :mod (a3 / another)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 "28"))))) # ::id a_pmid_2488_5690.66 # ::date 2015-06-10T00:16:49 # ::file a_pmid_2488_5690_66.txt # ::snt Since virtually all malignant cancer cells show apoptosis resistance, the induction of apoptotic pathways is considered a particularly promising approach for therapeutic strategies [29]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 15, 2016 (c / consider-01 :ARG1 (a / approach-02 :ARG0 (i / induce-01 :ARG2 (p3 / pathway :mod "a4")) :ARG1 (s / strategy :mod (t / therapy)) :ARG2-of (p / promise-01 :degree (p2 / particular))) :ARG1-of (c2 / cause-01 :ARG0 (s2 / show-01 :ARG0 (c3 / cell :mod (a3 / all :degree (v / virtual)) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG2-of (m / malignant-02))) :ARG1 (r / resist-01 :ARG0 c3 :ARG1 (a4 / apoptosis)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "29")))) # ::id a_pmid_2488_5690.67 # ::date 2015-06-10T00:22:21 # ::file a_pmid_2488_5690_67.txt # ::snt Our results show that in RKO this particular cancer cell trait is modulated by and dependent on B-RafV600E and that targeting mutant BRAF is sufficient to restore sensitivity to caspase-dependent apoptosis after serum withdrawal via p53-independent PUMA induction [27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (s / show-01 :ARG0 (t4 / thing :ARG1-of (r / result-01) :poss (w / we)) :ARG1 (a / and :op1 (a2 / and :op1 (m / modulate-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (t / trait :mod (c / cell :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :mod (p / particular) :mod (t3 / this))) :op2 (d2 / depend-01 :ARG0 t :ARG1 e2) :location (c3 / cell-line :name (n4 / name :op1 "RKO"))) :op2 (s2 / suffice-01 :ARG0 (t2 / target-01 :ARG1 (g / gene :name (n5 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x4 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG1 (r2 / restore-01 :ARG0 t2 :ARG1 (s3 / sensitive-03 :ARG1 (a3 / apoptosis :ARG0-of (d3 / depend-01 :ARG1 (p2 / protein :name (n6 / name :op1 "caspase") :xref (x1 / xref :value "UNIPROT:A0A024R3C0_HUMAN" :prob "0.701"))) :time (a4 / after :op1 (w2 / withdraw-01 :ARG1 (s4 / serum))) :instrument (i / induce-01 :ARG2 (p3 / protein :name (n7 / name :op1 "PUMA") :xref (x3 / xref :value "UNIPROT:BBC3B_HUMAN" :prob "1.002")) :ARG0-of (d4 / depend-01 :polarity "-" :ARG1 (p4 / protein :name (n8 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 "27")))))))))) # ::id a_pmid_2488_5690.68 # ::date 2015-06-10T00:40:15 # ::file a_pmid_2488_5690_68.txt # ::snt Complementing and extending previous studies, we thus provide evidence from an endogenous and quantitative genetic model of BRAF-mutant colorectal cancer cells, thereby ruling out the occurrence of artifacts caused by unspecific cellular response or incomplete knockdown in RNAi setups and, likewise, avoiding inter-species bias potentially experienced in mouse models of colorectal cancer [30]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / infer-01 :ARG1 (p / provide-01 :ARG0 (w / we) :ARG1 (e / evidence :source (m2 / model :mod (c / cell :location-of (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :mod (q / quantity) :mod (e2 / endogenous) :mod (g2 / gene))) :ARG0-of (c2 / cause-01 :ARG1 (a / and :op1 (r / rule-out-02 :ARG1 (a2 / artifact :ARG1-of (c3 / cause-01 :ARG0 (o2 / or :op1 (r2 / respond-01 :ARG0 (c4 / cell) :ARG1-of (s / specific-02 :polarity "-")) :op2 (k / knock-down-02 :ARG1-of (c5 / complete-01 :polarity "-") :location (s2 / setup :mod (i3 / interfere-01 :ARG1 (n2 / nucleic-acid :name (n4 / name :op1 "RNA"))))))))) :op2 (a3 / avoid-01 :ARG1 (b / bias-01 :mod (i2 / inter-species) :ARG1-of (e3 / experience-01 :ARG1-of (p2 / possible-01) :location (m3 / model :mod (d2 / disease) :mod (m4 / mouse) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 "30")))))))))) :ARG1-of (c7 / complement-01 :ARG2 (s3 / study-01 :time (p4 / previous))) :ARG0-of (e4 / extend-01 :ARG1 s3)) # ::id bel_pmid_1064_0734.39802 # ::date 2015-04-09T03:22:23 # ::file bel_pmid_1064_0734_39802.txt # ::snt In this paper we demonstrate that expression of CD72 down-modulates both extracellular signal-related kinase (ERK) activation and Ca2+ mobilization induced by BCR ligation in the mouse B lymphoma line K46^mA, whereas BCR-mediated ERK activation was not reduced by the ITIM-mutated form of CD72. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (d2 / downmodulate-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "extracellular" :op2 "signal-related" :op3 "kinase") :ARG1-of (d3 / describe-01 :ARG2 (e3 / enzyme :name (n4 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.393"))) :op2 (m / mobilize-01 :ARG1 (c4 / calcium :ARG1-of (i2 / ionize-01 :value "2+"))) :ARG2-of (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p3 / protein :name (n6 / name :op1 "BCR") :xref (x3 / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004"))) :location (c / cell-line :name (n7 / name :op1 "K46^mA") :mod (m2 / mouse) :consist-of (c3 / cell :name (n / name :op1 "B") :part-of (l2 / lymphoma))))) :ARG2 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "CD72") :xref (x / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003"))) :ARG1-of (c2 / contrast-01 :ARG2 (r / reduce-01 :polarity "-" :ARG0 (p4 / protein :name (n8 / name :op1 "CD72") :ARG2-of (m4 / mutate-01 :ARG0 (p5 / protein-segment :name (n9 / name :op1 "ITIM"))) :xref (x4 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :ARG1 (a3 / activate-01 :ARG1 e3 :ARG1-of (m3 / mediate-01 :ARG0 p3))))) :medium (p / paper :mod (t / this))) # ::id bel_pmid_1064_0734.39804 # ::date 2015-04-09T03:46:19 # ::file bel_pmid_1064_0734_39804.txt # ::snt Results CD72 negatively regulates both ERK activation and Ca2+ mobilization induced by BCR ligation in the K46^mk B lymphoma cells To investigate the signaling function of CD72, we assessed CD72 expression on the surface of B cell lines by flow cytometry. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (t / thing :ARG2-of (r / result-01)) :snt1 (d / downregulate-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op2 (m2 / mobilize-01 :ARG1 (c6 / calcium :ARG1-of (i3 / ionize-01 :value "2+"))) :ARG2-of (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p2 / protein :name (n6 / name :op1 "BCR") :xref (x1 / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004"))))) :ARG2 (p / protein :name (n3 / name :op1 "CD72") :xref (x / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :location (c / cell-line :name (n7 / name :op1 "K46^mk") :consist-of (c5 / cell :name (n9 / name :op1 "B") :part-of (l2 / lymphoma)))) :snt3 (a3 / assess-01 :ARG0 (w / we) :ARG1 (e3 / express-03 :ARG2 (p3 / protein :name (n8 / name :op1 "CD72") :xref (x3 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :location (s2 / surface :part-of (c2 / cell-line :consist-of (c4 / cell :name (n / name :op1 "B"))))) :instrument (c3 / cytometry :mod (f / flow)) :purpose (i2 / investigate-01 :ARG0 w :ARG1 (f2 / function-01 :ARG0 p3 :ARG1 (s3 / signal-07))))) # ::id bel_pmid_1064_0734.39810 # ::date 2015-04-09T04:01:27 # ::file bel_pmid_1064_0734_39810.txt # ::snt However, both of the CD72 transfectants showed reduced phosphorylation of ERK1 and ERK2 compared to that of the parent cells regardless of the duration of Ag stimulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (h / have-concession-91 :ARG1 (s2 / show-01 :ARG0 (m / molecular-physical-entity :mod (b / both) :ARG1-of (t / transfect-01 :ARG2 (p2 / protein :name (n2 / name :op1 "CD72") :xref (x / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")))) :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1-of (r / reduce-01 :compared-to (c3 / cell :mod (p4 / parent)) :ARG1-of (r2 / regardless-91 :ARG2 (d / duration :poss (s / stimulate-01 :ARG2 (a2 / antigen)))))))) # ::id bel_pmid_1064_0734.39812 # ::date 2015-04-09T04:44:25 # ::file bel_pmid_1064_0734_39812.txt # ::snt Taken together, expression of CD72 most probably down-modu-lates phosphorylation of ERK induced by BCR signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-condition-91 :ARG1 (p3 / probable :degree (m / most) :domain (d / downmodulate-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2-of (i / induce-01 :ARG0 (s / signal-07 :ARG0 (p4 / protein :name (n3 / name :op1 "BCR") :xref (x2 / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004"))))) :ARG2 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "CD72") :xref (x / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003"))))) :ARG2 (t / take-01 :mod (t2 / together))) # ::id bel_pmid_1064_0734.39814 # ::date 2015-04-09T04:55:18 # ::file bel_pmid_1064_0734_39814.txt # ::snt Indeed, in vitro kinase assay showed that the activity of ERK2 in Ag-stimulated K46^mA CD72 transfectants was lower than that of Ag-stimulated K46^mA (Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (s / show-01 :ARG0 (a / assay-01 :ARG1 (k / kinase) :manner (i / in-vitro)) :ARG1 (l / low-04 :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :location (m2 / molecular-physical-entity :part-of (c2 / cell-line :name (n4 / name :op1 "K46^mA") :ARG1-of (s2 / stimulate-01 :ARG2 (a4 / antigen))) :ARG1-of (t / transfect-01 :ARG2 (p / protein :name (n3 / name :op1 "CD72") :xref (x1 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003"))))) :degree (m / more) :compared-to (a3 / activity-06 :location c2)) :mod (i2 / indeed) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3"))) # ::id bel_pmid_1064_0734.39818 # ::date 2015-04-09T05:13:20 # ::file bel_pmid_1064_0734_39818.txt # ::snt However, the CD72 transfectants showed less increase in the intracellular Ca2+ concentration than the parent K46^mA cells did. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (h / have-concession-91 :ARG1 (s / show-01 :ARG0 (m / molecular-physical-entity :ARG1-of (t / transfect-01 :ARG2 (p / protein :name (n2 / name :op1 "CD72") :xref (x / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")))) :ARG1 (i / increase-01 :ARG1 (c3 / concentrate-02 :ARG0 (c / calcium :ARG1-of (i3 / ionize-01 :value "2+")) :mod (i2 / intracellular)) :ARG2 (l / less) :compared-to (c4 / cell-line :name (n4 / name :op1 "K46^mA") :mod (p2 / parent))))) # ::id bel_pmid_1064_0734.39820 # ::date 2015-04-09T05:20:31 # ::file bel_pmid_1064_0734_39820.txt # ::snt Thus, expression of CD72 appears to negatively regulate BCR-mediated Ca2+ mobilization in K46^mA cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (i / infer-01 :ARG1 (a / appear-02 :ARG1 (d / downregulate-01 :ARG1 (m / mobilize-01 :ARG1 (c2 / calcium :ARG1-of (i2 / ionize-01 :value "2+")) :ARG1-of (m2 / mediate-01 :ARG0 (p2 / protein :name (n4 / name :op1 "BCR") :xref (x / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004")))) :ARG2 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "CD72") :xref (x1 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003"))) :location (c / cell-line :name (n5 / name :op1 "K46^mA"))))) # ::id bel_pmid_1064_0734.39822 # ::date 2015-04-09T05:27:53 # ::file bel_pmid_1064_0734_39822.txt # ::snt Taken together, CD72 down-modulates both ERK activation and Ca2+ mobilization induced by BCR ligation, strongly suggesting that CD72 negatively regulates BCR signaling in K46^mA cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-condition-91 :ARG1 (d / downmodulate-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op2 (m / mobilize-01 :ARG1 (c2 / calcium :ARG1-of (i2 / ionize-01 :value "2+"))) :ARG2-of (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p2 / protein :name (n5 / name :op1 "BCR") :xref (x / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004"))))) :ARG2 (p / protein :name (n2 / name :op1 "CD72") :xref (x2 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :ARG0-of (s2 / suggest-01 :ARG1 (d2 / downregulate-01 :ARG1 (s4 / signal-07 :ARG0 p2) :ARG2 p :location (c / cell-line :name (n6 / name :op1 "K46^mA"))) :ARG1-of (s3 / strong-02))) :ARG2 (t / take-01 :mod (t2 / together))) # ::id bel_pmid_1064_0734.39824 # ::date 2015-04-09T05:35:11 # ::file bel_pmid_1064_0734_39824.txt # ::snt Western blotting of total cell lysates using anti-phospho-ERK Ab showed that both ERK1 and ERK2 were phosphorylated by either BCR ligation alone or coligation of BCR and CD72 (Fig. 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (i / immunoblot-01 :ARG2 (l / lysate :mod (c / cell) :quant (t2 / total)) :ARG3 (a / antibody :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG2 (o / or :op1 (l2 / ligate-01 :ARG1 (p3 / protein :name (n5 / name :op1 "BCR") :xref (x2 / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004")) :mod (a3 / alone)) :op2 (l3 / ligate-01 :ARG1 p3 :ARG3 (p4 / protein :name (n6 / name :op1 "CD72") :xref (x4 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :mod (t3 / together)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id bel_pmid_1064_0734.39826 # ::date 2015-04-09T05:59:50 # ::file bel_pmid_1064_0734_39826.txt # ::snt However, BCR ligation induced stronger ERK phosphorylation than coligation of CD72 with BCR did, indicating that BCR ligation-induced phosphorylation of ERK is down-modulated when CD72 is coligated with BCR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG1 (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "BCR") :xref (x / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004"))) :ARG2 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (s / strong-02 :degree (m / more) :compared-to (l2 / ligate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "CD72") :xref (x1 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :ARG3 p2 :mod (t / together)))) :ARG0-of (i2 / indicate-01 :ARG1 (d / downmodulate-01 :ARG1 (p4 / phosphorylate-01 :ARG1 e :ARG2-of (i3 / induce-01 :ARG0 l)) :time l2)))) # ::id bel_pmid_1064_0734.39828 # ::date 2015-04-09T06:06:35 # ::file bel_pmid_1064_0734_39828.txt # ::snt Phosphorylation of both ERK1 and ERK2 induced by coligation of BCR and CD72 was weaker than that induced by BCR ligation alone (Fig. 6 C), indicating that coligation with CD72 reduced BCR ligation-mediated phosphorylation of ERK in DBA/2 spleen cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (w / weak-02 :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG2-of (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "BCR") :xref (x / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004")) :ARG3 (p3 / protein :name (n5 / name :op1 "CD72") :xref (x3 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :mod (t / together)))) :degree (m / more) :compared-to (p4 / phosphorylate-01 :ARG2-of (i2 / induce-01 :ARG0 (l2 / ligate-01 :ARG1 p2 :mod (a2 / alone)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C")) :ARG0-of (i3 / indicate-01 :ARG1 (r / reduce-01 :ARG0 l :ARG1 (p5 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x4 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (m2 / mediate-01 :ARG0 l2) :location (c / cell :part-of (s / spleen :source (o / organism :name (n6 / name :op1 "DBA/2" :op2 "mouse")))))))) # ::id bel_pmid_1064_0734.39830 # ::date 2015-04-09T06:20:57 # ::file bel_pmid_1064_0734_39830.txt # ::snt Coligation of CD72 with BCR showed a reduced Ca2+ flux compared to that with BCR ligation alone in spleen B cells (Fig. 6D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (s / show-01 :ARG0 (l / ligate-01 :ARG1 (p / protein :name (n / name :op1 "CD72") :xref (x1 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :ARG3 (p2 / protein :name (n2 / name :op1 "BCR") :xref (x / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004")) :mod (t / together)) :ARG1 (f / flux :quant-of (c3 / calcium :ARG1-of (i / ionize-01 :value "2+")) :ARG1-of (r / reduce-01) :compared-to (f2 / flux :ARG1-of (c / cause-01 :ARG0 (l2 / ligate-01 :ARG1 p2 :mod (a / alone))))) :location (c2 / cell :name (n4 / name :op1 "B") :part-of (s3 / spleen)) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "6D"))) # ::id bel_pmid_1064_0734.39832 # ::date 2015-04-09T06:29:32 # ::file bel_pmid_1064_0734_39832.txt # ::snt Taken together, these results indicate that coligation with CD72 negatively regulates BCR-induced ERK activation and Ca2+ concentration in normal spleen B cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-condition-91 :ARG1 (i / indicate-01 :ARG0 (t / thing :ARG1-of (r / result-01) :mod (t2 / this)) :ARG1 (d / downregulate-01 :ARG1 (a2 / and :op1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n4 / name :op1 "BCR") :xref (x / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004")))) :op2 (c / concentrate-02 :ARG1 (c3 / calcium :ARG1-of (i3 / ionize-01 :value "2+")))) :ARG2 (l / ligate-01 :ARG3 (p / protein :name (n3 / name :op1 "CD72") :xref (x2 / xref :value "UNIPROT:CD72_HUMAN" :prob "1.003")) :mod (t3 / together)) :location (c2 / cell :name (n6 / name :op1 "B") :ARG1-of (n2 / normal-02) :part-of (s2 / spleen)))) :ARG2 (t4 / take-01 :mod t3)) # ::id bel_pmid_1064_4693.7794 # ::date 2015-04-09T06:35:04 # ::file bel_pmid_1064_4693_7794.txt # ::snt Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34(Cdc2)/clb phosphorylation site (p53-phosphor-Ser(315)). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / and :op2 (f / find-01 :ARG1 (d / dephosphorylate-01 :ARG1 (p3 / protein-segment :ARG1-of (p / phosphorylate-01 :ARG2 (e / enzyme :name (n3 / name :op1 "p34Cdc2/clb"))) :ARG1-of (d2 / describe-01 :ARG2 (a2 / amino-acid :mod "315" :name (n4 / name :op1 "serine") :ARG1-of p :part-of "p2" :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :part-of (p2 / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG2 (e2 / enzyme :name (n2 / name :op1 "hCdc14" :op2 "phosphatase")) :manner (s / specific-02)))) # ::id bel_pmid_1064_8414.21216 # ::date 2015-04-09T06:47:05 # ::file bel_pmid_1064_8414_21216.txt # ::snt Overexpression of mutant FGFR3 resulted in IL-6 independence, decreased apoptosis, and an enhanced proliferative response to IL-6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "FGFR3") :ARG1-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:FGFR3_HUMAN" :prob "1.004"))) :ARG2 (a / and :op1 (d / depend-01 :polarity "-" :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op2 (a2 / apoptosis :ARG1-of (d2 / decrease-01)) :op3 (r2 / respond-01 :ARG1 p2 :ARG2 (p3 / proliferate-01) :ARG1-of (e / enhance-01)))) # ::id bel_pmid_1064_8414.21218 # ::date 2015-04-09T06:55:11 # ::file bel_pmid_1064_8414_21218.txt # ::snt B9 clones expressing either wild-type FGFR3 at high levels or mutant FGFR3 displayed increased phosphorylation of STAT3 and higher levels of bcl-x(L) expression than did parental B9 cells after cytokine withdrawal. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (d / display-01 :ARG0 (c3 / clone-01 :ARG1 "c2" :ARG3-of (e / express-03 :ARG2 (o / or :op1 (p2 / protein :name (n2 / name :op1 "FGFR3") :mod (w / wild-type) :degree (l / level :ARG1-of (h2 / high-02)) :xref (x / xref :value "UNIPROT:FGFR3_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n3 / name :op1 "FGFR3") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:FGFR3_HUMAN" :prob "1.004"))))) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "STAT3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (i / increase-01)) :op2 (l2 / level :ARG1-of (h / high-02 :degree (m / more)) :degree-of (e2 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "bcl-xL") :xref (x4 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.231")))) :compared-to (c2 / cell :name (n6 / name :op1 "B9") :mod (p6 / parental) :time (a2 / after :op1 (w2 / withdraw-01 :ARG1 (p7 / protein :name (n7 / name :op1 "cytokine") :xref (x2 / xref :value "UNIPROT:RED_HUMAN" :prob "0.342"))))))) # ::id bel_pmid_1066_0621.6864 # ::date 2015-04-09T07:11:52 # ::file bel_pmid_1066_0621_6864.txt # ::snt Treatment of cells expressing SRC-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. These results identify phosphorylation as a regulatory modification of SRC-1 and provide a basis upon which to identify signaling pathways that regulate SRC-1 function and, consequently, modify steroid/nuclear receptor action. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 17, 2015 (m / multi-sentence :snt1 (e / enhance-01 :ARG0 (t / treat-04 :ARG1 (c / cell :ARG3-of (e2 / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "SRC-1") :xref (x1 / xref :value "UNIPROT:NCOA1_HUMAN" :prob "1.002")))) :ARG2 (p8 / protein :name (n / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703"))) :ARG1 (a2 / activate-01 :ARG1 (g / gene :name (n4 / name :op1 "reporter" :op2 "gene") :ARG1-of (t2 / target-01)) :ARG0-of (d / depend-01 :ARG1 (l / ligand)) :ARG1-of (m2 / mediate-01 :ARG0 (p4 / protein :name (n3 / name :op1 "progesterone" :op2 "receptor") :xref (x / xref :value "UNIPROT:PRGR_HUMAN" :prob "0.702"))))) :snt2 (a3 / and :op1 (i / identify-01 :ARG0 (t3 / thing :ARG1-of (r2 / result-01) :mod (t4 / this)) :ARG1 (p2 / phosphorylate-01) :ARG2 (m3 / modify-01 :ARG1 (p / protein :name (n5 / name :op1 "SRC-1") :xref (x3 / xref :value "UNIPROT:NCOA1_HUMAN" :prob "1.002")) :ARG0-of (r / regulate-01))) :op2 (p5 / provide-01 :ARG0 t3 :ARG1 (b / basis) :purpose (i2 / identify-01 :ARG1 (p6 / pathway :ARG0-of (s2 / signal-07) :ARG0-of (r3 / regulate-01 :ARG1 (f / function-01 :ARG0 p)) :ARG0-of (m4 / modify-01 :ARG1 (a4 / act-01 :ARG0 (p7 / protein :name (n6 / name :op1 "steroid/nuclear" :op2 "receptor"))) :ARG1-of (c2 / cause-01 :ARG0 r3))))))) # ::id bel_pmid_1066_0621.21334 # ::date 2015-04-09T07:31:47 # ::file bel_pmid_1066_0621_21334.txt # ::snt Furthermore, Erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for SRC-1 regulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (a3 / and :op2 (p / phosphorylate-01 :ARG1 (a4 / and :op1 (a / amino-acid :mod "1179" :name (n / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a2 / amino-acid :mod "1185" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op3 (a5 / amino-acid :mod "395" :name (n4 / name :op1 "serine") :degree (e2 / extent :mod (l / less :degree (m / more))) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG2 (e / enzyme :name (n3 / name :op1 "Erk-2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.633")) :manner (i / in-vitro) :ARG0-of (s / suggest-01 :ARG1 (i2 / important :domain (p2 / pathway :mod (t / this)) :purpose (r / regulate-01 :ARG1 (p3 / protein :name (n5 / name :op1 "SRC-1") :xref (x / xref :value "UNIPROT:NCOA1_HUMAN" :prob "1.002"))))))) # ::id bel_pmid_1066_6199.2154 # ::date 2015-04-09T07:44:01 # ::file bel_pmid_1066_6199_2154.txt # ::snt overexpressions of cyclin D1 or bcl-2 inhibited only differentiation or apoptosis, respectively # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (i / inhibit-01 :ARG0 (o3 / overexpress-01 :ARG1 (o4 / or :op1 (p / protein :name (n / name :op1 "cyclin" :op2 "D1") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")) :op2 (p2 / protein :name (n2 / name :op1 "bcl-2") :xref (x / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "1.001")))) :ARG1 (o2 / or :op1 (d / differentiate-01) :op2 (a / apoptosis)) :mod (o / only) :manner (r / respective)) # ::id bel_pmid_1066_6199.28424 # ::date 2015-04-09T07:48:56 # ::file bel_pmid_1066_6199_28424.txt # ::snt Although STAT3 is essential for IL-6-induced macrophage differentiation of M1 cells, GATA-1 had little or no effect on tyrosine phosphorylation, DNA binding, and transcriptional activities of STAT3 in Western blot analysis, electropholic mobility shift assay (EMSA), and luciferase assays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (o2 / or :op1 (a / affect-01 :ARG0 (p2 / protein :name (n / name :op1 "GATA-1") :xref (x / xref :value "UNIPROT:GATA1_HUMAN" :prob "1.003")) :ARG1 (a2 / and :op1 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (b / bind-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n9 / name :op1 "DNA"))) :op3 (a4 / activity-06 :ARG0 (p3 / protein :name (n4 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1 (t / transcribe-01))) :degree (l / little)) :op2 (a6 / affect-01 :polarity "-" :ARG0 p2 :ARG1 a2) :time (a5 / and :op1 (i / immunoblot-01) :op2 (a7 / assay-01 :ARG1 (s / shift-01 :ARG1 (m2 / mobility :mod (e2 / elecropholic)))) :op3 (a8 / assay-01 :ARG1 (l2 / luciferase)))) :ARG2 (e / essential :domain p3 :purpose (d3 / differentiate-01 :ARG1 (c2 / cell :name (n10 / name :op1 "M1")) :ARG2-of (i2 / induce-01 :ARG0 (p4 / protein :name (n11 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :mod (m / macrophage)))) # ::id bel_pmid_1066_6199.38222 # ::date 2015-04-09T08:03:06 # ::file bel_pmid_1066_6199_38222.txt # ::snt During IL-6-induced macrophage differentiation of M1 cells, IL-6 down-regulated cyclin D1 expression and induced p19(INK4D) expression, leading to reduction in cdk4 activities. In contrast, sustained expression of cyclin D1 and a significantly lesser amount of p19(INK4D) induction were observed in IL-6-treated M1 cells overexpressing GATA-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (a / and :op1 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "cyclin" :op2 "D1") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001"))) :ARG2 (p / protein :name (n / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op2 (i / induce-01 :ARG0 p :ARG2 (e2 / express-03 :ARG1 (g / gene :name (n7 / name :op1 "p19(INK4D)")))) :ARG0-of (l / lead-03 :ARG2 (r / reduce-01 :ARG1 (a2 / activity-06 :ARG0 (e3 / enzyme :name (n3 / name :op1 "cdk4") :xref (x2 / xref :value "UNIPROT:CDK4_HUMAN_DNA" :prob "1.001"))))) :time (d2 / differentiate-01 :ARG1 (c / cell :name (n4 / name :op1 "M1")) :ARG2-of (i2 / induce-01 :ARG0 p) :mod (m2 / macrophage))) :snt2 (c3 / contrast-01 :ARG2 (o / observe-01 :ARG1 (a3 / and :op1 (e4 / express-03 :ARG1 (p3 / protein :name (n6 / name :op1 "cyclin" :op2 "D1") :xref (x3 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")) :ARG1-of (s / sustain-01)) :op2 (a4 / amount :mod (l2 / less :degree (s2 / significant) :degree (m3 / more)) :degree-of (i4 / induce-01 :ARG2 (g2 / gene :name (n8 / name :op1 "p19(INK4D)"))))) :location (c4 / cell :name (n9 / name :op1 "M1") :ARG1-of (t / treat-04 :ARG2 (p4 / protein :name (n10 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :location-of (o2 / overexpress-01 :ARG1 (p5 / protein :name (n11 / name :op1 "GATA-1") :xref (x4 / xref :value "UNIPROT:GATA1_HUMAN" :prob "1.003"))))))) # ::id bel_pmid_1067_7502.3614 # ::date 2015-04-09T08:22:18 # ::file bel_pmid_1067_7502_3614.txt # ::snt High concentrations of stauro of up to 1 microM only partially inhibit IL-3-stimulated Bcl2 phosphorylation but completely block PKC-mediated Bcl2 phosphorylation in vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (c2 / concentrate-02 :ARG0 (s / small-molecule :name (n4 / name :op1 "stauro")) :ARG1-of (h / high-02) :quant (u / up-to :op1 (c4 / concentration-quantity :quant "1" :unit (m2 / micromolar)))) :ARG1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "Bcl2") :xref (x1 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.631")) :ARG1-of (s2 / stimulate-01 :ARG0 (p5 / protein :name (n2 / name :op1 "IL-3") :xref (x2 / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003")))) :degree (p2 / part) :mod (o / only)) :ARG2 (b / block-01 :ARG0 c2 :ARG1 (p / phosphorylate-01 :ARG1 p4 :ARG1-of (m / mediate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "PKC") :xref (x / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")))) :ARG1-of (c3 / complete-02) :manner (i2 / in-vitro))) # ::id bel_pmid_1067_7502.21952 # ::date 2015-04-11T01:45:18 # ::file bel_pmid_1067_7502_21952.txt # ::snt p44MAPK/extracellular signal-regulated kinase 1 (ERK1) and p42 MAPK/ERK2 are activated by IL-3, colocalize with mitochondrial Bcl2, and can directly phosphorylate Bcl2 on Ser-70 in a stauro-resistant manner both in vitro and in vivo # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (a2 / activate-01 :ARG0 (p / protein :name (n6 / name :op1 "IL-3") :xref (x6 / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003")) :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "p44MAPK") :ARG1-of (m / mean-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase" :op4 "1") :ARG1-of (d / describe-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))) :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.703"))) :xref (x5 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.693")) :op2 (e4 / enzyme :name (n4 / name :op1 "p42MAPK") :ARG1-of (m2 / mean-01 :ARG2 (e5 / enzyme :name (n5 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.693")))) :op2 (c / colocalize-01 :ARG1 (a6 / and :op1 a3 :op2 (p2 / protein :name (n7 / name :op1 "Bcl2") :part-of (m3 / mitochondrion :xref (x7 / xref :value "GO:0005739" :prob "0.8")) :xref (x4 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.631")))) :op3 (p3 / possible-01 :ARG1 (p4 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "70" :name (n8 / name :op1 "serine") :part-of p2 :xref (x8 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 a3 :manner (r / resist-01 :ARG1 (s / small-molecule :name (n9 / name :op1 "stauro"))) :manner (a5 / and :op1 (i / in-vitro) :op2 (i2 / in-vivo)) :ARG1-of (d2 / direct-02)))) # ::id bel_pmid_1068_1535.5746 # ::date 2015-04-11T02:11:44 # ::file bel_pmid_1068_1535_5746.txt # ::snt We found that TPO stimulation or Ha-Ras G12V expression led to up-regulation of cyclin D1, cyclin D2, and cyclin D3 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (l / lead-03 :ARG0 (o / or :op1 (s / stimulate-01 :ARG1 (p / protein :name (n / name :op1 "TPO") :xref (x4 / xref :value "UNIPROT:TPO_HUMAN" :prob "1.003"))) :op2 (e / express-03 :ARG2 (e5 / enzyme :name (n2 / name :op1 "Ha-Ras") :ARG2-of (m / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))) :ARG2 (u / upregulate-01 :ARG1 (a2 / and :op1 (e2 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D1") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001"))) :op2 (e3 / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "cyclin" :op2 "D2") :xref (x2 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361"))) :op3 (e4 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "cyclin" :op2 "D3") :xref (x3 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361"))))))) # ::id bel_pmid_1068_1535.24496 # ::date 2015-04-11T02:21:10 # ::file bel_pmid_1068_1535_24496.txt # ::snt By using a refined model of megakaryocytic differentiation, we found that either TPO stimulation or Ha-Ras G12V expression could up-regulate the expression of cyclin D1 and cyclin D2 in addition to cyclin D3, and that, when cdc2 activity was suppressed, each of cyclin D1, cyclin D2, and cyclin D3 expression was able to induce megakaryocytic differentiation with a similar efficiency. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p2 / possible-01 :ARG1 (u / upregulate-01 :ARG1 "a3" :ARG2 (o / or :op1 (s / stimulate-01 :ARG1 (p3 / protein :name (n / name :op1 "TPO") :xref (x4 / xref :value "UNIPROT:TPO_HUMAN" :prob "1.003"))) :op2 (e / express-03 :ARG2 (e7 / enzyme :name (n2 / name :op1 "Ha-Ras") :ARG2-of (m / mutate-01 :value "G12V") :xref (x3 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))))) :op2 (p8 / possible-01 :ARG1 (i / induce-01 :ARG0 (a3 / and :op1 (e3 / express-03 :ARG2 (p9 / protein :name (n6 / name :op1 "cyclin" :op2 "D1") :xref (x5 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001"))) :op2 (e4 / express-03 :ARG2 (p10 / protein :name (n7 / name :op1 "cyclin" :op2 "D2") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361"))) :op3 (e5 / express-03 :ARG2 (p11 / protein :name (n8 / name :op1 "cyclin" :op2 "D3") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361"))) :mod (e6 / each)) :ARG2 (d / differentiate-01 :ARG1 (c / cell :name (n10 / name :op1 "megakaryocyte"))) :ARG1-of (e2 / efficient-01 :ARG1-of (r2 / resemble-01))) :time (s2 / suppress-01 :ARG1 (a2 / activity-06 :ARG0 (e8 / enzyme :name (n9 / name :op1 "cdc2") :xref (x2 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")))))) :manner (u2 / use-01 :ARG1 (m3 / model :ARG1-of (r / refine-01) :topic d))) # ::id bel_pmid_1069_9758.15770 # ::date 2015-04-09T09:06:02 # ::file bel_pmid_1069_9758_15770.txt # ::snt which are dual-specificity (serine/threonine and tyrosine) kinases that regulate downstream responses to a broad range of mitogenic, apoptotic, and differentiation-inducing stimuli [368-372]. Interestingly, MEK1 but not MEK2 is stimulated by H2O2 treatment, suggesting that only MEK1 is redox-sensitive [154]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (r / regulate-01 :ARG0 (k / kinase :mod (s7 / specificity :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (s / slash :op1 (a2 / amino-acid :wiki "Serine" :name (n / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :wiki "Threonine" :name (n2 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))) :op2 (a4 / amino-acid :wiki "Tyrosine" :name (n3 / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :mod (d / dual))) :ARG1 (r2 / respond-01 :ARG1 (r4 / range-01 :ARG1 (s5 / stimulus :mod (m3 / mitogenic) :mod (a5 / apoptosis) :ARG0-of (i / induce-01 :ARG2 (d3 / differentiate-01))) :ARG1-of (b / broad-02))) :direction (d2 / downstream) :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 "368" :op2 "372"))))) :snt2 (c2 / contrast-01 :ARG1 (s2 / stimulate-01 :ARG0 (t / treat-04 :ARG2 (s8 / small-molecule :wiki "Hydrogen_peroxide" :name (n6 / name :op1 "H2O2") :xref (x2 / xref :value "PUBCHEM:784" :prob "17.186693"))) :ARG1 (e / enzyme :wiki "MAP2K1" :name (n4 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG2 (s3 / stimulate-01 :polarity "-" :ARG0 t :ARG1 (e2 / enzyme :wiki "MAP2K2" :name (n5 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG2-of (i2 / interest-01) :ARG0-of (s4 / suggest-01 :ARG1 (s6 / sensitive-03 :ARG0 e :ARG1 (r3 / redox) :mod (o / only)) :ARG2-of (i3 / interest-01) :ARG1-of (d5 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "154")))))) # ::id bel_pmid_1069_9758.24188 # ::date 2015-04-11T06:31:13 # ::file bel_pmid_1069_9758_24188.txt # ::snt Additionally, several studies have shown that antioxidant enzymes and mimics also block NF-kB activation by various stimuli. For example, overexpression of peroxiredoxin [247] or thioredoxin [111] blocks NF-kB activation by H2O2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG0 (s2 / study-01 :quant (s3 / several)) :ARG1 (b / block-01 :ARG0 (a7 / and :op1 (e2 / enzyme :mod (a2 / antioxidant)) :op2 (m2 / mimic-01)) :ARG1 (a4 / activate-01 :ARG1 (p / protein :name (n / name :op1 "NF-kB") :xref (x3 / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272"))) :ARG3 (s4 / stimulus :mod (v / various)) :mod (a / also)) :mod (a6 / additional)) :snt2 (b3 / block-01 :ARG0 (o4 / or :op1 (o / overexpress-01 :ARG1 (e4 / enzyme :name (n2 / name :op1 "peroxiredoxin") :xref (x / xref :value "UNIPROT:PRDX1_HUMAN" :prob "0.382")) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "247")))) :op2 (o2 / overexpress-01 :ARG1 (p4 / protein :name (n4 / name :op1 "thioredoxin") :xref (x2 / xref :value "UNIPROT:THIO_HUMAN" :prob "0.703")) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "111"))))) :ARG1 (a5 / activate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "NF-kB") :xref (x1 / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272"))) :ARG3 (s5 / small-molecule :name (n5 / name :op1 "H2O2") :xref (x4 / xref :value "PUBCHEM:784" :prob "17.186693")) :ARG0-of (e / exemplify-01))) # ::id bel_pmid_1069_9758.34686 # ::date 2015-04-11T07:06:57 # ::file bel_pmid_1069_9758_34686.txt # ::snt Furthermore, in many types of cells, antioxidants diminish or completely eliminate NF-kB activation (Table 1). For example, H2O2, UV, and ionizing radiation have all been observed to stimulate degradation of IkB (Table 1). Conversely, antioxidants and reductants such as BHA, NGA, a-tocopherol, NAC, and PDTC decrease NF-kB activity and translocation [12,253]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (m / multi-sentence :snt1 (a / and :op2 (o / or :op1 (d / diminish-01 :ARG0 (a10 / antioxidant) :ARG1 (a2 / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "NF-kB") :xref (x2 / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272")))) :op2 (e2 / eliminate-01 :ARG1 a2 :ARG1-of (c4 / complete-02)) :location (t / type-03 :ARG1 (c / cell) :mod (m3 / many))) :ARG1-of (d2 / describe-01 :ARG0 (t2 / table :mod "1"))) :snt2 (o2 / observe-01 :ARG1 (s / stimulate-01 :ARG0 (a3 / and :op1 (s2 / small-molecule :wiki "Hydrogen_peroxide" :name (n5 / name :op1 "H2O2") :xref (x3 / xref :value "PUBCHEM:784" :prob "17.186693")) :op2 (l / light :mod (u / ultraviolet)) :op3 (r / radiate-01 :ARG0-of (i / ionize-01)) :mod (a11 / all)) :ARG1 (d3 / degrade-01 :ARG1 (p4 / protein :name (n3 / name :op1 "IkB") :xref (x1 / xref :value "UNIPROT:IKKB_HUMAN" :prob "0.382")))) :ARG1-of (d4 / describe-01 :ARG0 (t3 / table :mod "1")) :ARG0-of (e / exemplify-01)) :snt3 (c2 / contrast-01 :ARG2 (d5 / decrease-01 :ARG0 (a12 / and :op1 (a7 / antioxidant :example (a13 / and :op1 (a14 / antioxidant :name (n / name :op1 "BHA")) :op2 (a15 / antioxidant :name (n12 / name :op1 "NGA")))) :op2 (r2 / reductant :example (a6 / and :op1 (r3 / reductant :name (n4 / name :op1 "a-tocopherol")) :op2 (r4 / reductant :name (n6 / name :op1 "NAC")) :op3 (r5 / reductant :name (n7 / name :op1 "PDTC"))))) :ARG1 (a4 / and :op1 (a5 / activity-06 :ARG0 (p2 / protein :name (n11 / name :op1 "NF-kB") :xref (x / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272"))) :op2 (t4 / translocate-01 :ARG1 p2)) :ARG1-of (d7 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a9 / and :op1 "12" :op2 "253"))))))) # ::id bel_pmid_1069_9758.36926 # ::date 2015-04-12T05:16:31 # ::file bel_pmid_1069_9758_36926.txt # ::snt Once activated, Raf-1 phosphorylates serines in the catalytic sites of MKK/MEK [345,367]. MKK1/MEK1 and MKK2/MEK2 activate members of the MAP kinase family (ERK-1/ERK-2), # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "serine") :part-of (p3 / protein-segment :part-of (s2 / slash :op1 (e5 / enzyme :name (n6 / name :op1 "MKK") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.263")) :op2 (e6 / enzyme :name (n7 / name :op1 "MEK") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (c / catalysis)) :xref (x9 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e / enzyme :name (n / name :op1 "Raf-1") :xref (x6 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :time (a2 / activate-01 :ARG1 e) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "345" :op2 "367"))))) :snt2 (a5 / activate-01 :ARG0 (a7 / and :op1 (s3 / slash :op1 (e4 / enzyme :name (n5 / name :op1 "MKK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x5 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (s5 / slash :op1 (e9 / enzyme :name (n10 / name :op1 "MKK2") :xref (x8 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :op2 (e10 / enzyme :name (n11 / name :op1 "MEK2") :xref (x7 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (m2 / member :ARG1-of (m3 / mean-01 :ARG2 (s4 / slash :op1 (e7 / enzyme :name (n8 / name :op1 "ERK-1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e8 / enzyme :name (n9 / name :op1 "ERK-2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :ARG1-of (i / include-91 :ARG2 (p4 / protein-family :name (n4 / name :op1 "MAP" :op2 "kinase")))))) # ::id bel_pmid_1072_9607.86 # ::date 2015-04-13T12:11:45 # ::file bel_pmid_1072_9607_86.txt # ::snt These results are consistent with our previous data showing that PAF is able to translocate PKCa and PKCe from cytosol to plasma membrane # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / consistent-01 :ARG1 (t3 / thing :ARG2-of (r / result-01) :mod (t / this)) :ARG2 (d / data :poss (w / we) :time (p2 / previous)) :ARG0-of (s / show-01 :ARG1 (p / possible-01 :ARG1 (t2 / translocate-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "PAF") :xref (x4 / xref :value "PUBCHEM:124663" :prob "10.878533")) :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "PKCa") :xref (x / xref :value "UNIPROT:KPCA_HUMAN" :prob "0.653")) :op2 (e2 / enzyme :name (n3 / name :op1 "PKCe") :xref (x1 / xref :value "UNIPROT:KPCE_HUMAN" :prob "0.653"))) :ARG2 (m2 / membrane :mod (p3 / plasma) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :ARG3 (c2 / cytosol :xref (x3 / xref :value "GO:0005829" :prob "0.8")))))) # ::id bel_pmid_1072_9607.18666 # ::date 2015-04-13T12:23:45 # ::file bel_pmid_1072_9607_18666.txt # ::snt Eosinophils Human Superoxide production Human Transmigration through epithelial cells Human Transmigration through Matrigel Human CD11b/CD18 (Mac-1) translocation, degranulation Human IL-8 release # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (p / produce-01 :ARG1 (s / superoxide :mod (h / human) :mod (c / cell :name (n / name :op1 "eosinophil")))) :snt2 (t / transmigrate-01 :ARG1 (c2 / cell :mod (e / epithelium)) :mod (h5 / human)) :snt3 (t2 / transmigrate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "Matrigel") :mod (h3 / human) :xref (x3 / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.273")) :mod (h2 / human)) :snt4 (a / and :op1 (t4 / translocate-01 :ARG1 (m2 / macro-molecular-complex :part (p2 / protein :name (n4 / name :op1 "CD11b") :xref (x / xref :value "UNIPROT:ITAM_HUMAN" :prob "1.002")) :part (p3 / protein :name (n5 / name :op1 "CD18") :xref (x1 / xref :value "UNIPROT:ITB2_HUMAN" :prob "1.002")) :ARG1-of (m3 / mean-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Mac-1"))))) :op2 (d / degranulate-00 :ARG1 (r / release-01 :ARG0 (p4 / protein :name (n6 / name :op1 "IL-8") :mod (h4 / human) :xref (x2 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003")))))) # ::id bel_pmid_1072_9607.19486 # ::date 2015-04-13T12:30:20 # ::file bel_pmid_1072_9607_19486.txt # ::snt Activation of tyrosine kinases Fyn and Lyn, but not Lck, also occurred within 2 min after PAF stimulation in the cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c3 / contrast-01 :ARG1 (a3 / activate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "tyrosine" :op2 "kinase" :op3 "Fyn") :xref (x / xref :value "UNIPROT:FER_HUMAN" :prob "0.372")) :op2 (e2 / enzyme :name (n2 / name :op1 "tyrosine" :op2 "kinase" :op3 "Lyn") :xref (x2 / xref :value "UNIPROT:FER_HUMAN" :prob "0.372"))) :time (a6 / after :op1 (s / stimulate-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "PAF") :xref (x3 / xref :value "PUBCHEM:124663" :prob "10.878533")) :location (c2 / cell)) :quant (u / up-to :op1 (t / temporal-quantity :quant "2" :unit (m2 / minute)))) :mod (a2 / also)) :ARG2 (a5 / activate-01 :polarity "-" :ARG1 (e3 / enzyme :name (n3 / name :op1 "Lck") :xref (x1 / xref :value "UNIPROT:LCK_HUMAN" :prob "0.604")))) # ::id bel_pmid_1072_9607.19488 # ::date 2015-04-13T12:41:31 # ::file bel_pmid_1072_9607_19488.txt # ::snt PAFR promoter 2 contained AP-2 and Sp-1 binding sites we demonstrated that PAF activates p44ERK1/p42ERK2 in CHO cells stably expressing PAF receptor # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m3 / multi-sentence :snt1 (c2 / contain-01 :ARG0 (m4 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p6 / protein :name (n5 / name :op1 "PAFR") :xref (x5 / xref :value "UNIPROT:PTAFR_HUMAN" :prob "1.002")))) :ARG1 (b / bind-01 :ARG1 (a2 / and :op1 (p4 / protein-segment :ARG1-of (b2 / bind-01 :ARG2 (p2 / protein :name (n6 / name :op1 "AP-2") :xref (x3 / xref :value "UNIPROT:AP2A_HUMAN" :prob "1.002")))) :op2 (p5 / protein-segment :ARG1-of (b3 / bind-01 :ARG2 (p3 / protein :name (n8 / name :op1 "Sp-1") :xref (x4 / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "0.651"))))))) :snt2 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG0 (p7 / protein :name (n / name :op1 "PAF" :op2 "receptor") :xref (x2 / xref :value "UNIPROT:PTAFR_HUMAN" :prob "0.232")) :ARG1 (m2 / macro-molecular-complex :part (e / enzyme :name (n2 / name :op1 "p44ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.693")) :part (e2 / enzyme :name (n3 / name :op1 "p42ERK2") :xref (x / xref :value "UNIPROT:NUP43_HUMAN" :prob "0.272"))) :location (c / cell-line :name (n4 / name :op1 "CHO") :ARG1-of (e3 / express-03 :ARG2 p7 :ARG1-of (s / stable-03)))))) # ::id bel_pmid_1072_9607.19490 # ::date 2015-04-13T13:35:19 # ::file bel_pmid_1072_9607_19490.txt # ::snt PAF induced tyrosine phosphorylation and activation of focal adhesion kinase (FAK) in human endothelial cells derived from vein umbilical cord # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "PAF") :xref (x1 / xref :value "PUBCHEM:124663" :prob "10.878533")) :ARG2 (a / and :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of "e" :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (a3 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "focal" :op2 "adhesion" :op3 "kinase") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "0.393")))) :location (c / cell :mod (e2 / endothelium) :mod (h / human) :ARG1-of (d / derive-01 :ARG2 (c2 / cord :mod (n4 / navel) :mod (v / vein))))) # ::id bel_pmid_1072_9607.22074 # ::date 2015-04-13T13:49:55 # ::file bel_pmid_1072_9607_22074.txt # ::snt Suppression of the PAF effects by calphostin C, a PKC inhibitor, suggests that PKC is an upstream activator of FAK # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / suggest-01 :ARG0 (s2 / suppress-01 :ARG1 (a / affect-01 :ARG0 (c / calphostin :name (n2 / name :op1 "C") :ARG1-of (m2 / mean-01 :ARG2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")))))) :ARG1 (s3 / small-molecule :name (n / name :op1 "PAF") :xref (x2 / xref :value "PUBCHEM:124663" :prob "10.878533")))) :ARG1 (a2 / activate-01 :ARG0 e2 :ARG1 (e3 / enzyme :name (n4 / name :op1 "FAK") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")) :direction (u / upstream))) # ::id bel_pmid_1072_9607.31242 # ::date 2015-04-13T14:03:47 # ::file bel_pmid_1072_9607_31242.txt # ::snt transforming growth factor-b2 (TGF-b2) was shown to upregulate the transcription rate of PAFR transcript 1 in Ramos human lymphoblastoid cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / show-01 :ARG1 (u / upregulate-01 :ARG1 (r / rate :degree-of (t2 / transcribe-01 :ARG1 (p3 / protein :name (n2 / name :op1 "PAFR" :op2 "transcript" :op3 "1")))) :ARG2 (p2 / protein :name (n3 / name :op1 "transforming" :op2 "growth" :op3 "factor-b2") :ARG1-of (m / mean-01 :ARG2 (p / protein :name (n / name :op1 "TGF-b2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.653"))) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.393")) :location (c / cell :name (n4 / name :op1 "Ramos" :op2 "human" :op3 "lymphoblastoid")))) # ::id bel_pmid_1073_7606.7132 # ::date 2015-04-13T14:43:10 # ::file bel_pmid_1073_7606_7132.txt # ::snt We have further identified, in the GFAP promoter region, a STAT3 site at which nucleotide substitutions almost completely abolished the IL-11-induced GFAP promoter activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / identify-01 :ARG0 (w / we) :ARG1 (p3 / protein-segment :part-of (p / protein :name (n / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :ARG2 (a / abolish-01 :ARG0 (s2 / substitute-01 :ARG2 (n3 / nucleotide)) :ARG1 (a3 / activate-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (p5 / protein :name (n4 / name :op1 "GFAP") :xref (x1 / xref :value "UNIPROT:GFAP_HUMAN" :prob "1.003")))) :ARG2-of (i2 / induce-01 :ARG0 (p6 / protein :name (n5 / name :op1 "IL-11") :xref (x / xref :value "UNIPROT:IL11_HUMAN" :prob "1.003")))) :ARG1-of (c / complete-02 :degree (a2 / almost))) :degree (f / further) :location (r / region :part-of (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 p5)))) # ::id bel_pmid_1073_7606.22816 # ::date 2015-04-14T08:35:13 # ::file bel_pmid_1073_7606_22816.txt # ::snt Activation of the GFAP gene promoter by IL-11 and related cytokines Previous studies have shown that stimulation of gp130 molecules on neuroepithelial cells by LIF, CNTF, or the IL-6/sIL-6R complex induces activation of the GFAP gene promoter (Bonni et al., 1997 ; Nakashima et al., 1999 b ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt2 (s2 / show-01 :ARG0 (s3 / study-01 :time (p9 / previous)) :ARG1 (i / induce-01 :ARG0 (s / stimulate-01 :ARG0 (p5 / protein :name (n5 / name :op1 "gp130") :xref (x7 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")) :ARG1 (c / cell :mod (n6 / neuroepithelium)) :ARG2 (o3 / or :op1 (p4 / protein :name (n4 / name :op1 "LIF") :xref (x6 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n7 / name :op1 "CNTF") :xref (x4 / xref :value "UNIPROT:CNTF_HUMAN" :prob "1.003")) :op3 (m3 / macro-molecular-complex :part (p7 / protein :name (n8 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :part (p8 / protein :name (n9 / name :op1 "sIL-6R") :xref (x8 / xref :value "UNIPROT:IL1R1_HUMAN" :prob "0.222"))))) :ARG2 (a3 / activate-01 :ARG1 (m4 / molecular-physical-entity :ARG0-of (p10 / promote-01 :ARG1 (g2 / gene :name (n10 / name :op1 "GFAP") :xref (x1 / xref :value "UNIPROT:GFAP_HUMAN" :prob "1.003")))))) :ARG1-of (d3 / describe-01 :ARG0 (a7 / and :op1 (p11 / publication-91 :ARG0 (a5 / and :op1 (p12 / person :name (n11 / name :op1 "Bonni")) :op2 (p13 / person :mod (o / other))) :time (d / date-entity :year "1997")) :op2 (p14 / publication-91 :ARG0 (a6 / and :op1 (p15 / person :name (n12 / name :op1 "Nakashima")) :op2 (p16 / person :mod (o2 / other))) :time (d2 / date-entity :year "1999"))))) :snt1 (a2 / activate-01 :ARG0 (a8 / and :op1 (p2 / protein :name (n2 / name :op1 "IL-11") :xref (x2 / xref :value "UNIPROT:IL11_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n3 / name :op1 "cytokine") :ARG1-of (r / relate-01) :xref (x3 / xref :value "UNIPROT:RED_HUMAN" :prob "0.342"))) :ARG1 (m2 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (g / gene :name (n / name :op1 "GFAP") :xref (x / xref :value "UNIPROT:GFAP_HUMAN" :prob "1.003")))))) # ::id bel_pmid_1074_4722.88 # ::date 2015-04-14T09:31:17 # ::file bel_pmid_1074_4722_88.txt # ::snt As shown in Fig. 5B, immediately after -irradiation, the amount of threonine 68- phosphorylated Chk2 increased (lane 2), and prior treatment of cells with caffeine markedly reduced this increase (lane 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Apr 26, 2015 (a5 / and :op1 (i / increase-01 :ARG1 (a3 / amount :quant-of (e / enzyme :name (n2 / name :op1 "Chk2") :part (a / amino-acid :mod "68" :name (n / name :op1 "threonine") :ARG1-of (p / phosphorylate-01) :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :xref (x / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603"))) :ARG1-of (d / describe-01 :ARG2 (l / lane :mod "2")) :time (a4 / after :op1 (i2 / irradiate-01) :mod (i3 / immediate))) :op2 (r / reduce-01 :ARG0 (t / treat-03 :ARG1 (c / cell) :ARG3 (c2 / caffeine) :time (p2 / prior)) :ARG1 i :manner (m2 / marked) :ARG1-of (d2 / describe-01 :ARG2 (l2 / lane :mod "4"))) :ARG1-of (s / show-01) :location (f / figure :mod "5B")) # ::id bel_pmid_1074_4722.15494 # ::date 2015-04-14T09:48:01 # ::file bel_pmid_1074_4722_15494.txt # ::snt As shown in Fig. 3A in normal cells, IR causes activation of Chk2/Cds1 (lane 2), and this activation is inhibited by prior treatment of cells with caffeine (lane 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (c / cause-01 :ARG0 (r / radiate-01 :ARG0-of (i2 / ionize-01)) :ARG1 (a2 / activate-01 :ARG1 (m / macro-molecular-complex :part (e / enzyme :name (n2 / name :op1 "Chk2") :xref (x1 / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603")) :part (e2 / enzyme :name (n3 / name :op1 "Cds1") :xref (x / xref :value "UNIPROT:CDS1_HUMAN" :prob "0.603")))) :ARG1-of (d2 / describe-01 :ARG2 (l / lane :mod "2"))) :op1 (i / inhibit-01 :ARG0 (t2 / treat-03 :ARG1 (c2 / cell) :ARG3 (c3 / caffeine) :time (p / prior)) :ARG1 a2 :ARG1-of (d / describe-01 :ARG2 (l2 / lane :mod "4"))) :ARG1-of (s / show-01 :location (f / figure :mod "3A")) :location (c4 / cell :ARG1-of (n4 / normal-02))) # ::id bel_pmid_1074_4722.15496 # ::date 2015-04-14T10:01:59 # ::file bel_pmid_1074_4722_15496.txt # ::snt Immediately after IR, an increase in serine 216-phosphorylated Cdc25C was observed in the nuclear fraction (Fig. 1B, lane 2), and prior treatment of cells with caffeine inhibited this increase (Fig. 1B, lane 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (o / observe-01 :ARG1 (i / increase-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Cdc25C") :part (a3 / amino-acid :mod "216" :name (n2 / name :op1 "serine") :ARG0-of (p / phosphorylate-01) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :xref (x / xref :value "UNIPROT:MPIP3_HUMAN" :prob "0.653"))) :location (f / fraction-01 :mod (n4 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8"))) :time (a / after :op1 (r / radiate-01 :ARG0-of (i4 / ionize-01)) :mod (i2 / immediate)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "1B") :op2 (l / lane :mod "2")))) :op2 (i3 / inhibit-01 :ARG0 (t2 / treat-03 :ARG1 (c / cell) :ARG3 (c2 / caffeine) :time (p2 / prior)) :ARG1 i :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f3 / figure :mod "1B") :op2 (l2 / lane :mod "4"))))) # ::id bel_pmid_1074_4722.15498 # ::date 2015-04-14T11:11:23 # ::file bel_pmid_1074_4722_15498.txt # ::snt As shown in Fig. 6A, ATM immunoprecipitated from irradiated cells was more active than that from unirradiated cells, and both the basal and radiationinduced ATM activities were inhibited by caffeine with an IC50 at around 200 M. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a2 / and :op1 (a3 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ATM") :ARG1-of (i / immunoprecipitate-01 :ARG2 (c / cell :ARG1-of (i2 / irradiate-01))) :xref (x2 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")) :degree (m2 / more) :compared-to (e2 / enzyme :name (n2 / name :op1 "ATM") :ARG1-of (i3 / immunoprecipitate-01 :ARG2 (c2 / cell :ARG1-of (i8 / irradiate-01 :polarity "-"))) :xref (x / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003"))) :op2 (i5 / inhibit-01 :ARG0 (c3 / caffeine :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (a / around :op1 (c4 / concentration-quantity :quant "200" :unit (m / molar))))) :ARG1 (a5 / and :op1 (a4 / activity-06 :ARG0 (e3 / enzyme :name (n3 / name :op1 "ATM") :xref (x1 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")) :mod (b / basal)) :op2 (a6 / activity-06 :ARG0 e3 :ARG2-of (i6 / induce-01 :ARG0 (r / radiate-01))))) :ARG1-of (s / show-01 :location (f / figure :mod "6A"))) # ::id bel_pmid_1074_4722.15500 # ::date 2015-04-14T11:32:28 # ::file bel_pmid_1074_4722_15500.txt # ::snt However, no such activation was found in A-T cells indicating that caffeine inhibited the ATM-dependent Chk2/Cds1 activation (Fig. 3A, lanes 6 and 8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Apr 14, 2015 (h / have-concession-91 :ARG1 (f / find-01 :ARG1 (a / activate-01 :polarity "-" :mod (s / such)) :location (c / cell :name (n / name :op1 "A-T")) :ARG0-of (i / indicate-01 :ARG1 (i2 / inhibit-01 :ARG0 (c2 / caffeine) :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ATM") :ARG0-of (d / depend-01 :ARG1 (m / macro-molecular-complex :part (e2 / enzyme :name (n3 / name :op1 "Chk2") :xref (x1 / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603")) :part (e3 / enzyme :name (n4 / name :op1 "Cds1") :xref (x / xref :value "UNIPROT:CDS1_HUMAN" :prob "0.603")))) :xref (x2 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "3A") :op2 (a4 / and :op1 (l / lane :op1 "6") :op2 (l2 / lane :mod "8"))))) # ::id bel_pmid_1074_4722.21126 # ::date 2015-04-14T11:42:05 # ::file bel_pmid_1074_4722_21126.txt # ::snt Substitution of threonine 68 by alanine in the full-length kinase-dead Chk2 dramatically reduced but did not abolish the ATM phosphorylation of Chk2/Cds1 in vitro (Fig. 4B; threonine 68 accounts for approximately 70% of the total phosphorylation). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (s / substitute-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "alanine") :xref (x4 / xref :value "PUBCHEM:602" :prob "10.089661")) :ARG2 (a / amino-acid :name (n / name :op1 "threonine") :xref (x6 / xref :value "PUBCHEM:205" :prob "11.848252")) :location (e / enzyme :name (n3 / name :op1 "Chk2") :ARG0-of (f3 / function-01 :polarity "-" :ARG1 (k / kinase :ARG1-of (l / long-03 :degree (f / full)))) :xref (x3 / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603"))) :ARG1 (p3 / phosphorylate-01 :ARG1 (m2 / macro-molecular-complex :part (e2 / enzyme :name (n4 / name :op1 "Chk2") :xref (x2 / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603")) :part (e4 / enzyme :name (n6 / name :op1 "Cds1") :xref (x / xref :value "UNIPROT:CDS1_HUMAN" :prob "0.603"))) :ARG2 (e3 / enzyme :name (n5 / name :op1 "ATM") :xref (x1 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")) :manner (i / in-vitro)) :manner (d2 / dramatic)) :ARG2 (a3 / abolish-01 :ARG0 s :ARG1 p3) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "4B"))) :snt2 (a4 / account-01 :ARG1 (a5 / amino-acid :mod "68" :name (n7 / name :op1 "threonine") :ARG1-of (i2 / include-91 :ARG2 (t / total-01 :ARG1 (p2 / phosphorylate-01)) :ARG3 (a7 / approximately :op1 (p / percentage-entity :value "70"))) :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")))) # ::id bel_pmid_1074_4722.21132 # ::date 2015-04-14T12:32:00 # ::file bel_pmid_1074_4722_21132.txt # ::snt Serine 15 in the N terminus of p53 has been shown to be the preferred ATM phosphorylation site (27, 29, 30). As shown in Fig. 7A, ATM immunoprecipitated from irradiated cells was more active than that from control cells, and both ATM activities were inhibited by caffeine with IC50 at around 200 M. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m2 / multi-sentence :snt1 (s / show-01 :ARG1 (p / protein-segment :ARG1-of (p5 / phosphorylate-01 :ARG2 (e / enzyme :name (n5 / name :op1 "ATM") :xref (x3 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003"))) :ARG1-of (p4 / prefer-01) :domain (a3 / amino-acid :mod "15" :name (n2 / name :op1 "serine") :part-of (p2 / protein-segment :name (n3 / name :op1 "N" :op2 "terminus") :part-of (p3 / protein :name (n4 / name :op1 "p53") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 "27" :op2 "29" :op3 "30"))))) :snt2 (a2 / and :op1 (a7 / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "ATM") :ARG1-of (i / immunoprecipitate-01 :ARG2 (c2 / cell :ARG1-of (i2 / irradiate-01))) :xref (x1 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")) :degree (m3 / more) :compared-to (e3 / enzyme :name (n6 / name :op1 "ATM") :ARG1-of (i3 / immunoprecipitate-01 :ARG2 (c3 / cell :mod (c5 / control-01))) :xref (x / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003"))) :op2 (i4 / inhibit-01 :ARG0 (c4 / caffeine :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (a / around :op1 (c6 / concentration-quantity :quant "200" :unit (m / molar))))) :ARG1 (a5 / activity-06 :ARG0 (a6 / and :op1 e2 :op2 e3))) :ARG1-of (s3 / show-01 :location (f / figure :mod "7A")))) # ::id bel_pmid_1074_4722.21168 # ::date 2015-04-14T13:16:27 # ::file bel_pmid_1074_4722_21168.txt # ::snt Both Chk1 and Chk2/Cds1 have been shown to localize to the nucleus and to phosphorylate serine 216 of Cdc25C in vitro (13, 15) (18–21). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Apr 26, 2015 (s / show-01 :ARG1 (a2 / and :op1 (b / be-located-at-91 :ARG1 (a5 / and :op1 (e / enzyme :name (n2 / name :op1 "Chk1") :xref (x3 / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604")) :op2 (m / macro-molecular-complex :part (e2 / enzyme :name (n3 / name :op1 "Chk2") :xref (x2 / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603")) :part (e3 / enzyme :name (n4 / name :op1 "Cds1") :xref (x1 / xref :value "UNIPROT:CDS1_HUMAN" :prob "0.603")))) :ARG2 (n5 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8"))) :op2 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "216" :name (n / name :op1 "serine") :part-of (e4 / enzyme :name (n6 / name :op1 "Cdc25C") :xref (x / xref :value "UNIPROT:MPIP3_HUMAN" :prob "0.653")) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 a5 :manner (i / in-vitro))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "13" :op2 "15"))) :op2 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 "18" :op2 "21")))))) # ::id bel_pmid_1074_4722.21170 # ::date 2015-04-14T13:31:50 # ::file bel_pmid_1074_4722_21170.txt # ::snt As shown in the Western blot (Fig. 1A, lane 3), the phospho-S216 antibody recognized Cdc25C that was incubated with a wild type Chk2 in the in vitro kinase assay but failed to recognize unphosphorylated Cdc25C, incubated with a kinase-dead mutant (D347A) (Fig. 1A, lane 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (r / recognize-01 :ARG0 (a / antibody :ARG0-of (c2 / counter-01 :ARG1 (a5 / amino-acid :mod "216" :name (n / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :ARG1 (e / enzyme :name (n3 / name :op1 "Cdc25C") :ARG1-of (i / incubate-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Chk2") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603")) :time (a3 / assay-01 :ARG1 (k / kinase) :manner (i2 / in-vitro))) :xref (x2 / xref :value "UNIPROT:MPIP3_HUMAN" :prob "0.653"))) :ARG2 (f2 / fail-01 :ARG1 a :ARG2 (r2 / recognize-01 :ARG0 a :ARG1 (e3 / enzyme :name (n5 / name :op1 "Cdc25C") :ARG3-of (p / phosphorylate-01 :polarity "-") :ARG1-of (i3 / incubate-01 :ARG2 (m2 / molecular-physical-entity :ARG2-of (m / mutate-01 :value "D347A") :ARG0-of (f / function-01 :polarity "-" :ARG1 (k2 / kinase)))) :xref (x / xref :value "UNIPROT:MPIP3_HUMAN" :prob "0.653"))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f3 / figure :mod "1A") :op2 (l / lane :mod "2")))) :ARG1-of (s / show-01 :ARG0 (i4 / immunoblot-01 :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f4 / figure :mod "1A") :op2 (l2 / lane :mod "3")))))) # ::id bel_pmid_1074_7872.20016 # ::date 2015-04-14T14:11:40 # ::file bel_pmid_1074_7872_20016.txt # ::snt We found that STAT3, but not STAT5, was activated in response to IGF-I in 293T cells cotransfected with IGF-IR and STAT expression vectors. Moreover, tyrosine phosphorylation of STAT3, JAK1, and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt2 (a4 / and :op2 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (a5 / and :op1 (a6 / amino-acid :name (n7 / name :op1 "tyrosine") :part-of (p6 / protein :name (n8 / name :op1 "STAT3") :xref (x8 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x13 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a7 / amino-acid :name (n16 / name :op1 "tyrosine") :part-of (e7 / enzyme :name (n9 / name :op1 "JAK1") :xref (x5 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :xref (x12 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op3 (a8 / amino-acid :name (n17 / name :op1 "tyrosine") :part-of (e8 / enzyme :name (n10 / name :op1 "JAK2") :xref (x4 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :xref (x14 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :time (s / stimulate-01 :ARG0 (p9 / protein :name (n11 / name :op1 "IGF-I") :xref (x11 / xref :value "UNIPROT:IGF1_HUMAN" :prob "1.003")) :ARG1 (p8 / protein :name (n12 / name :op1 "IGF-IR") :mod (m2 / monocot) :location (c3 / cell-line :name (n13 / name :op1 "293T") :ARG1-of (t / transfect-01 :ARG2 (o / or :op1 (v3 / vector :ARG1-of (e5 / express-03 :ARG2 (p10 / protein :name (n14 / name :op1 "STAT") :mod (r2 / respective) :xref (x3 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")))) :op2 (v2 / vector :ARG1-of (e4 / express-03 :ARG2 (e6 / enzyme :name (n15 / name :op1 "JAK") :xref (x6 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))))))) :xref (x10 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.313"))))) :snt1 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (a / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG2-of (r / respond-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IGF-I") :location (c2 / cell-line :name (n3 / name :op1 "293T") :ARG1-of (c4 / cotransfect-01 :ARG2 (a2 / and :op1 (p7 / protein :name (n4 / name :op1 "IGF-IR") :xref (x9 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.313")) :op2 (v / vector :ARG1-of (e2 / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "STAT") :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))))))) :xref (x7 / xref :value "UNIPROT:IGF1_HUMAN" :prob "1.003")))) :ARG2 (a3 / activate-01 :polarity "-" :ARG1 (p5 / protein :name (n6 / name :op1 "STAT5") :xref (x2 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :ARG2-of r)))) # ::id bel_pmid_1074_7872.21236 # ::date 2015-04-14T14:46:59 # ::file bel_pmid_1074_7872_21236.txt # ::snt tyrosine phosphorylation of STAT3, JAK1, and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x9 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a3 / amino-acid :name (n10 / name :op1 "tyrosine") :part-of (e6 / enzyme :name (n3 / name :op1 "JAK1") :xref (x3 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :xref (x7 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op3 (a4 / amino-acid :name (n11 / name :op1 "tyrosine") :part-of (e5 / enzyme :name (n9 / name :op1 "JAK2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :xref (x8 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :time (s / stimulate-01 :ARG0 (p4 / protein :name (n4 / name :op1 "IGF-I") :xref (x5 / xref :value "UNIPROT:IGF1_HUMAN" :prob "1.003")) :ARG1 (p3 / protein :name (n5 / name :op1 "IGF-IR") :mod (m / monocot) :location (c / cell-line :name (n6 / name :op1 "293T") :ARG1-of (t / transfect-01 :ARG2 (o / or :op1 (v2 / vector :ARG1-of (e3 / express-03 :ARG2 (p5 / protein :name (n7 / name :op1 "STAT") :mod (r / respective) :xref (x6 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")))) :op2 (v / vector :ARG1-of (e2 / express-03 :ARG2 (e4 / enzyme :name (n8 / name :op1 "JAK") :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))))))) :xref (x4 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.313")))) # ::id bel_pmid_1074_7872.21238 # ::date 2015-04-14T14:54:49 # ::file bel_pmid_1074_7872_21238.txt # ::snt STAT3, but not STAT5, was activated in response to IGF-I in 293T cells cotransfected with IGF-IR and STAT expression vectors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "STAT3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG2-of (r / respond-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-I") :location (c2 / cell-line :name (n3 / name :op1 "293T") :ARG1-of (c3 / cotransfect-01 :ARG2 (a2 / and :op1 (v2 / vector :ARG1-of (e2 / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "IGF-IR") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.313")))) :op2 (v / vector :ARG1-of (e / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "STAT") :xref (x2 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))))))) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "1.003")))) :ARG2 (a3 / activate-01 :polarity "-" :ARG1 (p5 / protein :name (n6 / name :op1 "STAT5") :xref (x3 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :ARG2-of r)) # ::id bel_pmid_1074_7872.21262 # ::date 2015-04-14T14:59:38 # ::file bel_pmid_1074_7872_21262.txt # ::snt Dominant-negative JAK1 or JAK2 was able to block the IGF-IR-mediated tyrosine phosphorylation of STAT3 in 293T cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p3 / possible-01 :ARG1 (b / block-01 :ARG0 (o / or :op1 (e2 / enzyme :name (n / name :op1 "JAK1") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :op2 (e / enzyme :name (n7 / name :op1 "JAK2") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :ARG1 (p2 / phosphorylate-01 :ARG0 (a2 / amino-acid :name (n4 / name :op1 "tyrosine") :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1 (p6 / protein :name (n5 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :location (c / cell-line :name (n6 / name :op1 "293T")) :ARG1-of (m / mediate-01 :ARG0 (p5 / protein :name (n3 / name :op1 "IGF-IR") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.313")))))) # ::id bel_pmid_1077_7583.7596 # ::date 2015-04-16T05:24:23 # ::file bel_pmid_1077_7583_7596.txt # ::snt Inhibition of SHP2 activation leads to increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a reduction of SHP2 phosphorylation after activation of the interleukin-6 signal transduction pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / contrast-01 :ARG1 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (a / activate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "SHP2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673")))) :ARG2 (l2 / level :ARG1-of (i2 / increase-01) :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA") :mod (p / protein :name (n2 / name :op1 "SOCS3") :xref (x2 / xref :value "UNIPROT:SOCS3_HUMAN" :prob "1.004"))))) :ARG2 (r2 / result-01 :ARG1 (e / express-03 :ARG2 p :ARG1-of (i3 / increase-01)) :ARG2 (r3 / reduce-01 :ARG0 e :ARG2 (p3 / phosphorylate-01 :ARG1 e3)) :time (a2 / after :op1 (a3 / activate-01 :ARG1 (p4 / pathway :ARG2-of (t / transduce-01 :ARG1 (s / signal-07 :ARG1 (p2 / protein :name (n4 / name :op1 "interleukin-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))))))))) # ::id bel_pmid_1079_1191.20850 # ::date 2015-04-17T04:02:44 # ::file bel_pmid_1079_1191_20850.txt # ::snt In situ end-labeling detection showed that apoptotic cell death was significantly increased in cells with 5-day treatment of antisense H-ras oligodeoxynucleotide (34.0 +/- 4.5%) in comparing with cells without treatment (2.5 +/- 1.2%, t = 13.434, P < 0.01) or treated with non-specific antisense oligodeoxynucleotide (4.8 +/- 1.4%, t = 12.453, P < 0.01) at the corresponding time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / show-01 :ARG0 (d / detect-01 :ARG2 (l / label-01 :mod (e2 / end)) :mod (i / in-situ)) :ARG1 (i2 / increase-01 :ARG1 (c / cell :mod (a / apoptosis) :ARG0-of (f / function-01 :polarity "-")) :ARG2 (s2 / significant-02) :location (c2 / cell :ARG1-of (t / treat-04 :ARG2 (s7 / small-molecule :name (n / name :op1 "oligodeoxynucleotide") :mod (e / enzyme :name (n2 / name :op1 "H-ras") :mod (a2 / antisense) :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.601")) :quant (c6 / concentration-quantity :quant "34" :unit (m3 / micromolar)) :quant (p2 / percentage-entity :value "4.5") :xref (x1 / xref :value "PUBCHEM:16133903" :prob "7.448343")) :duration (t2 / temporal-quantity :quant "5" :unit (d3 / day)))) :compared-to (o / or :op1 (c3 / cell :ARG1-of (t3 / treat-04 :polarity "-" :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.01"))) :quant (t6 / temperature-quantity :value "13.434") :quant (p4 / percentage-entity :value "1.2")) :op2 (c4 / cell :ARG1-of (t4 / treat-04 :ARG2 (s6 / small-molecule :name (n3 / name :op1 "oligodeoxynucleotide") :mod (a3 / antisense :ARG1-of (s3 / specific-02 :polarity "-")) :quant (p3 / percentage-entity :value "1.4") :quant (c7 / concentration-quantity :quant "12.453" :unit (m4 / micromolar)) :xref (x2 / xref :value "PUBCHEM:16133903" :prob "7.448343")) :ARG1-of (s5 / statistical-test-91 :ARG2 l2))) :time (t5 / time :ARG1-of (c5 / correspond-02))))) # ::id bel_pmid_1084_2184.19138 # ::date 2015-04-16T19:28:31 # ::file bel_pmid_1084_2184_19138.txt # ::snt \"Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha.\" # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / downregulate-01 :ARG1 (m / macro-molecular-complex :part (p / protein :name (n2 / name :op1 "growth" :op2 "hormone" :op3 "receptor") :xref (x2 / xref :value "UNIPROT:GHR_HUMAN" :prob "0.702")) :part (e / enzyme :name (n3 / name :op1 "JAK2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :ARG2 (p3 / protein :name (n / name :op1 "signal" :op2 "regulatory" :op3 "protein" :op4 "alpha") :xref (x / xref :value "UNIPROT:SHPS1_HUMAN" :prob "0.392")) :ARG2-of (c / cite-01)) # ::id bel_pmid_1085_1026.6144 # ::date 2015-04-16T14:12:34 # ::file bel_pmid_1085_1026_6144.txt # ::snt FGFs activate the endogenous FGFRs leading to the formation of a Grb2/FRS2/Shp2 complex and activation of MAP kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "FGF") :xref (x5 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001")) :ARG1 (p2 / protein :name (n2 / name :op1 "FGFR") :mod (m2 / monocot) :ARG0-of (l / lead-03 :ARG2 (a2 / and :op1 (f / form-01 :ARG0 p2 :ARG1 (m / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :part (p4 / protein :name (n4 / name :op1 "FRS2") :xref (x3 / xref :value "UNIPROT:FRS2_HUMAN" :prob "1.004")) :part (e / enzyme :name (n5 / name :op1 "Shp2") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")))) :op2 (a3 / activate-01 :ARG0 p2 :ARG1 (k / kinase :name (n6 / name :op1 "MAP") :xref (x4 / xref :value "UNIPROT:MOTI_HUMAN" :prob "1.002"))))) :xref (x / xref :value "UNIPROT:FGFR1_HUMAN" :prob "0.313"))) # ::id bel_pmid_1085_1026.8692 # ::date 2015-04-16T14:25:22 # ::file bel_pmid_1085_1026_8692.txt # ::snt However, immature osteoblasts respond to FGF treatment with increased proliferation, whereas in differentiating cells FGF does not induce DNA synthesis but causes apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG1 (c2 / contrast-01 :ARG1 (r / respond-01 :ARG0 (o / osteoblast :ARG1-of (m / mature-02 :polarity "-")) :ARG1 (t / treat-04 :ARG1 o :ARG2 (p / protein :name (n / name :op1 "FGF") :xref (x / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001"))) :ARG2 (p2 / proliferate-01 :ARG0 o :ARG1-of (i2 / increase-01))) :ARG2 (c3 / contrast-01 :ARG1 (i / induce-01 :polarity "-" :ARG0 p :ARG2 (s / synthesize-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"))) :time (d2 / differentiate-01 :ARG0 p :ARG1 (c5 / cell))) :ARG2 (c4 / cause-01 :ARG0 p :ARG1 (a / apoptosis))))) # ::id bel_pmid_1085_1026.8694 # ::date 2015-04-16T17:01:37 # ::file bel_pmid_1085_1026_8694.txt # ::snt When either primary or OB1 osteoblasts are induced to differentiate, FGF signaling inhibits expression of alkaline phosphatase, and blocks mineralization. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (i2 / inhibit-01 :ARG0 (p2 / protein :name (n / name :op1 "FGF" :op2 "signaling") :xref (x / xref :value "UNIPROT:FRS3_HUMAN" :prob "0.263")) :ARG1 (e2 / express-03 :ARG1 (e3 / enzyme :name (n3 / name :op1 "alkaline" :op2 "phosphatase") :xref (x1 / xref :value "UNIPROT:A0A024R4A2_HUMAN" :prob "0.701")))) :op2 (b / block-01 :ARG0 p2 :ARG1 (m / mineralize-01)) :time (i / induce-01 :ARG1 (o / or :op1 (o3 / osteoblast :mod (p / primary)) :op2 (o2 / osteoblast :mod (d2 / dna-sequence :name (n2 / name :op1 "OB1"))) :mod (e / either)) :ARG2 (d / differentiate-01 :ARG0 o))) # ::id bel_pmid_1085_1055.19244 # ::date 2015-04-16T17:42:59 # ::file bel_pmid_1085_1055_19244.txt # ::snt IL-2-mediated hetero-dimerization of its receptor triggers a rapid increase in the recruitment of Jak3 and activation of both Jak1 and Jak3 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (t / trigger-01 :ARG0 (h2 / heterodimerize-01 :ARG1 (r3 / receptor :poss "p3") :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n2 / name :op1 "IL-2") :xref (x / xref :value "UNIPROT:IL2_HUMAN" :prob "1.003")))) :ARG1 (i / increase-01 :ARG1 (a / and :op1 (r2 / recruit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Jak3") :xref (x2 / xref :value "UNIPROT:JAK3_HUMAN" :prob "0.604"))) :op2 (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "Jak1") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.604")) :op2 e2))) :manner (r / rapid))) # ::id bel_pmid_1088_0513.7274 # ::date 2015-04-16T13:17:28 # ::file bel_pmid_1088_0513_7274.txt # ::snt We show that IL-6 triggers selective activation of SHP2 and its association with RAFTK in Dex-treated MM cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (t / trigger-01 :ARG0 (p / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (a / and :op1 (a2 / activate-01 :ARG0 p :ARG1 (e / enzyme :name (n / name :op1 "SHP2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673")) :mod (s2 / selective)) :op2 (a3 / associate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n3 / name :op1 "RAFTK") :xref (x2 / xref :value "UNIPROT:FAK2_HUMAN" :prob "1.003")) :location (c / cell :ARG1-of (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "Dex") :xref (x3 / xref :value "PUBCHEM:338" :prob "10.348803"))) :mod (d / disease :name (n5 / name :op1 "multiple" :op2 "myeloma"))))))) # ::id bel_pmid_1088_0513.23686 # ::date 2015-04-16T13:27:35 # ::file bel_pmid_1088_0513_23686.txt # ::snt We and others have shown that IL-6 induces growth in MM cells via the MAPK pathway, which includes activation of protein-tyrosine phosphatase SHP2 (16, 28) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (a2 / and :op1 (w / we) :op2 (p2 / person :mod (o / other))) :ARG1 (i2 / induce-01 :ARG0 (p3 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (g / grow-01 :ARG1 (c2 / cell :mod (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :instrument (p4 / pathway :name (n3 / name :op1 "MAPK") :ARG2-of (i / include-01 :ARG1 (a3 / activate-01 :ARG1 (p6 / protein-tyrosine-phosphatase :name (n6 / name :op1 "SHP2"))))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 "16" :op2 "28"))))) # ::id bio-exp_0001.1 # ::date 2014-09-16T11:13:45 # ::file bio-exp_0001_1.txt # ::snt We next examined the mechanisms accounting for the increase in HER3 by MAPK pathway inhibitors in BRAF mutant thyroid cell lines . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 9, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (m / mechanism :ARG0-of (a / account-01 :ARG1 (i / increase-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / pathway :name (n3 / name :op1 "MAPK")) :location (c / cell-line :source (t / thyroid) :ARG1-of (e3 / encode-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :part (g / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) :ARG1 (e2 / enzyme :name (n2 / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))))) :time (n / next)) # ::id bio-exp_0001.2 # ::date 2014-09-26T12:18:16 # ::file bio-exp_0001_2.txt # ::snt Upregulation of HER3 has been found to mediate resistance to PI3K/AKT ( 26 ) or HER2 ( 27 ) inhibitors in HER2-amplified breast cancer cell lines , which is caused in part through a FoxO3A-dependent induction of HER3 gene transcription . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (m / mediate-01 :ARG0 (u / upregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG1 (r / resist-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (o / or :op1 (p / pathway :name (n2 / name :op1 "PI3K/AKT") :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 "26")))) :op2 (e3 / enzyme :name (n3 / name :op1 "HER2") :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c5 / cite-01 :ARG2 "27"))) :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))) :location (c / cell-line :ARG0-of (a / amplify-01 :ARG1 e3) :source (d4 / disease :wiki "Breast_cancer" :name (n5 / name :op1 "breast" :op2 "cancer")))) :ARG1-of (c3 / cause-01 :ARG0 (i2 / induce-01 :ARG2 (t / transcribe-01 :ARG1 (g / gene :ARG0-of (e2 / encode-01 :ARG1 e))) :ARG0-of (d / depend-01 :ARG1 (p4 / protein :name (n4 / name :op1 "FoxO3A") :xref (x / xref :value "UNIPROT:FOXO3_HUMAN" :prob "0.652")))) :degree (p3 / part)))) # ::id bio-exp_0001.3 # ::date 2014-09-26T12:18:43 # ::file bio-exp_0001_3.txt # ::snt As shown in Fig. 5A, PLX4032 treatment increased HER3 and HER2 mRNAs in all six BRAF-mutant thyroid cancer cell lines tested . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / increase-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "PLX4032") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "18.013371"))) :ARG1 (n8 / nucleic-acid :name (n9 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n2 / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n3 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))) :ARG1-of (s / show-01 :location (f / figure :mod "5A")) :location (c / cell-line :ARG1-of (e2 / encode-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :part (g / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1-of (i2 / include-91 :ARG2 (c3 / cell-line :quant "6" :ARG1-of (t3 / test-01)) :ARG3 (a2 / all)) :source (d / disease :wiki "Thyroid_cancer" :name (n7 / name :op1 "thyroid" :op2 "cancer")))) # ::id bio-exp_0001.4 # ::date 2015-01-23T04:12:10 # ::file bio-exp_0001_4.txt # ::snt Similar results were found following treatment with the MEK inhibitor AZD6244 ( not shown ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01) :ARG1-of (s / show-01 :polarity "-")) :ARG1-of (f2 / follow-01 :ARG2 (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "AZD6244") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056"))))) # ::id bio-exp_0001.5 # ::date 2015-02-07T10:09:52 # ::file bio-exp_0001_5.txt # ::snt The effects of the MEK inhibitor on total HER2 , HER3 protein and on pHER3 were dose dependent , and inversely associated with the degree of inhibition of pERK ( Fig. 5B ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (d / depend-01 :ARG0 (a2 / affect-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))) :ARG1 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "HER2") :mod (t / total) :xref (x3 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "HER3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :op3 (e4 / enzyme :name (n4 / name :op1 "HER3") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")))) :ARG1 (d2 / dose-01)) :op2 (a4 / associate-01 :ARG1 a2 :ARG2 (t2 / thing :degree-of (i2 / inhibit-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK") :ARG3-of p :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :manner (i3 / inverse)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id bio-exp_0001.6 # ::date 2015-02-07T10:17:49 # ::file bio-exp_0001_6.txt # ::snt RAF or MEK inhibitors induced luciferase activity of a HER3 promoter construct spanning ~ 1 kb upstream of the transcriptional start site in 8505C cells . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / induce-01 :ARG0 (o / or :op1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / protein-family :wiki "RAF_kinase" :name (n / name :op1 "RAF")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p4 / protein-family :wiki "Mitogen-activated_protein_kinase_kinase" :name (n2 / name :op1 "MEK"))))) :ARG2 (a / activity-06 :ARG0 (c / construct-01 :ARG0-of (p / promote-01 :ARG1 (e3 / enzyme :wiki "ERBB3" :name (n3 / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG0-of (s / span-01 :ARG1 (r / relative-position :op1 (p2 / protein-segment :location-of (s3 / start-01 :ARG1 (t / transcribe-01))) :direction (u / upstream)) :location (c2 / cell-line :wiki "-" :name (n4 / name :op1 "8505C")) :quant (a2 / approximately :op1 (d / distance-quantity :quant "1" :unit (k / kilo-base-pair))))) :ARG1 (l / luciferase))) # ::id bio-exp_0001.7 # ::date 2015-02-07T10:25:54 # ::file bio-exp_0001_7.txt # ::snt Serial deletions identified a minimal HER3 promoter retaining transcriptional response to vemurafenib and AZD6244 , which was located between -401 and -42 bp ( Fig. 5C ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 4, 2015 (i / identify-01 :ARG0 (d / delete-01 :manner (s2 / serial)) :ARG1 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG1-of (m2 / minimal-02) :ARG0-of (r / retain-01 :ARG1 (t / thing :ARG2-of (r2 / respond-01 :ARG1 (a / and :op1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056"))))) :mod (t2 / transcribe-01)) :location (b / between :op1 (d2 / distance-quantity :quant "-401" :unit (b2 / base-pair)) :op2 (d3 / distance-quantity :quant "-42" :unit (b3 / base-pair)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id bio-exp_0001.8 # ::date 2015-01-28T02:52:22 # ::file bio-exp_0001_8.txt # ::snt This region does not contain any predicted FoxO binding sites . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (c / contain-01 :polarity "-" :ARG0 (r / region :mod (t / this)) :ARG1 (p3 / protein-segment :mod (a / any) :ARG1-of (p / predict-01) :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n / name :op1 "FoxO") :xref (x / xref :value "UNIPROT:FOXO1_HUMAN" :prob "0.232"))))) # ::id bio-exp_0001.9 # ::date 2015-02-07T10:41:21 # ::file bio-exp_0001_9.txt # ::snt Moreover , PLX4032 led to an increase in phosphorylation of FoxO1/3A between 4 – 10 h after addition of compound ( not shown ) , which is known to promote its dissociation from DNA , and likely discards involvement of these factors as transcriptional regulators of HER3 in response to MAPK pathway inhibition . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / and :op2 (l / lead-03 :ARG0 (s / small-molecule :name (n / name :op1 "PLX4032") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "18.013371")) :ARG1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "FoxO1/3A"))) :time (a2 / after :op1 (a3 / add-02 :ARG1 (c / compound)) :quant (b / between :op1 (t / temporal-quantity :quant "4" :unit (h / hour)) :op2 (t2 / temporal-quantity :quant "10" :unit (h2 / hour)))) :ARG1-of (s2 / show-01 :polarity "-") :ARG0-of (p3 / promote-01 :ARG1 (d / dissociate-01 :ARG1 p2 :ARG2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))) :ARG1-of (k / know-01)) :ARG0-of (d3 / discard-01 :ARG1 (i2 / involve-01 :ARG1 (f / factor :mod (t3 / this)) :mod (m / molecular-physical-entity :ARG0-of (r / regulate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG0-of (t4 / transcribe-01))) :ARG1-of (l2 / likely-01) :ARG2-of (r2 / respond-01 :ARG1 (i3 / inhibit-01 :ARG1 (p4 / pathway :name (n4 / name :op1 "MAPK")))))))) # ::id bio-exp_0001.10 # ::date 2015-02-07T10:47:07 # ::file bio-exp_0001_10.txt # ::snt The minimal HER3 promoter region regulated by MAPK inhibitors overlaps with sequences previously described to be immunoprecipitated using antibodies against the ZFN217 transcription factor and CtBP1/CtBP2 corepressors ( 28–30 ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (o / overlap-01 :ARG0 (r / region :part (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x3 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG1-of (m2 / minimal-02)) :ARG1-of (r2 / regulate-01 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "MAPK")))))) :ARG1 (s / sequence :ARG1-of (i2 / immunoprecipitate-01 :ARG2-of (u / use-01 :ARG1 (a / antibody :ARG0-of (o2 / oppose-01 :ARG1 (a2 / and :op1 (f / factor :ARG0-of (t / transcribe-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ZFN217") :xref (x2 / xref :value "UNIPROT:ZFN2A_HUMAN" :prob "0.262")))) :op2 (m4 / molecular-physical-entity :ARG0-of (r3 / repress-01 :ARG1 (o3 / or :op1 (p5 / protein :name (n4 / name :op1 "CtBP1") :xref (x / xref :value "UNIPROT:CTBP1_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n5 / name :op1 "CtBP2") :xref (x1 / xref :value "UNIPROT:CTBP2_HUMAN" :prob "1.003"))))))))) :ARG1-of (d / describe-01 :time (p3 / previous)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 "28" :op2 "30"))))) # ::id bio-exp_0001.11 # ::date 2015-02-07T11:00:42 # ::file bio-exp_0001_11.txt # ::snt CtBPs have also been described to negatively regulate transcriptional activity of the HER3 promoter in breast carcinoma cell lines ( 30 ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (d / describe-01 :ARG1 (p / protein :name (n2 / name :op1 "CtBP") :xref (x1 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652")) :ARG2 (d2 / downregulate-01 :ARG1 (a / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")))) :ARG1 (t / transcribe-01)) :ARG2 p) :location (c / cell-line :mod (m2 / medical-condition :name (n3 / name :op1 "carcinoma") :mod (b / breast))) :mod (a2 / also) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "30")))) # ::id bio-exp_0001.12 # ::date 2015-02-05T12:19:53 # ::file bio-exp_0001_12.txt # ::snt Silencing of CtBP1 , and to a lesser extent CtBP2 , increased basal HER3 in 8505C cells , and markedly potentiated the effects of PLX4032 ( Fig. 5D and 5E ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i / increase-01 :ARG0 (s / silence-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "CtBP1") :xref (x2 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n3 / name :op1 "CtBP2") :degree (l / less :degree (m / more)) :xref (x / xref :value "UNIPROT:CTBP2_HUMAN" :prob "1.003")))) :ARG1 (e / enzyme :name (n / name :op1 "HER3") :mod (b / basal) :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :location (c / cell-line :name (n4 / name :op1 "8505C"))) :op2 (p3 / potentiate-01 :ARG1 (a3 / affect-01 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PLX4032") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "18.013371"))) :ARG2 s :ARG3 (m2 / marked)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "5D") :op2 (f2 / figure :mod "5E")))) # ::id bio-exp_0001.13 # ::date 2015-02-07T09:16:39 # ::file bio-exp_0001_13.txt # ::snt Knockdown of these factors modestly increased basal and PLX4032 - induced HER2 levels , which likely contributes to the remarkable increase in pHER3 we observed ( Fig. 5D and 5E ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (i / increase-01 :ARG0 (k / knock-down-02 :ARG1 (f / factor :mod (t / this))) :ARG1 (a / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "HER2") :mod (b / basal) :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :op2 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "HER2") :ARG2-of (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "PLX4032") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "18.013371"))) :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :degree (m / modest) :ARG0-of (c / contribute-01 :ARG1 (i3 / increase-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "HER3") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :ARG1-of (o / observe-01 :ARG0 (w / we)) :ARG1-of (r / remarkable-02)) :ARG1-of (l3 / likely-01)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "5D") :op2 (f3 / figure :mod "5E")))) # ::id bio-exp_0001.14 # ::date 2015-02-07T11:19:08 # ::file bio-exp_0001_14.txt # ::snt Finally , CtBP1 and CtBP2 chromatin immunoprecipitation assays showed decreased binding to the HER3 promoter after treatment with PLX4032 ( Fig. 5F ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (s / show-01 :li "-1" :ARG0 (a / assay-01 :ARG1 (i / immunoprecipitate-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "CtBP1") :xref (x2 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n3 / name :op1 "CtBP2") :xref (x / xref :value "UNIPROT:CTBP2_HUMAN" :prob "1.003"))) :mod (c / chromatin :xref (x3 / xref :value "GO:0000785" :prob "0.8")))) :ARG1 (b / bind-01 :ARG2 (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")))) :ARG1-of (d / decrease-01 :time (a3 / after :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "PLX4032") :xref (x4 / xref :value "PUBCHEM:42611257" :prob "18.013371")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5F"))) # ::id bio-exp_0001.15 # ::date 2015-02-05T12:14:53 # ::file bio-exp_0001_15.txt # ::snt These findings were confirmed in a second cell line ( Supplementary Fig. S5A ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Feb 8, 2015 (c / confirm-01 :ARG1 (t2 / thing :ARG1-of (f / find-01) :mod (t / this)) :location (c2 / cell-line :ord (o / ordinal-entity :value "2")) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "S5A" :ARG2-of (s / supplement-01)))) # ::id bio-kappa_0001.1 # ::date 2014-09-19T16:48:49 # ::file bio-kappa_0001_1.txt # ::snt Activation of Raf occurs via a complex , yet incompletely understood mechanism requiring membrane translocation , regulatory phosphorylation / dephosphorylation events and , crucially , allosteric activation in the context of a side-to-side dimer comprising two Raf molecules or a Raf and a Ksr molecule . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :manner (m / mechanism :mod (c / complex) :ARG1-of (u / understand-01 :ARG1-of (c2 / complete-02 :polarity "-")) :ARG0-of (r / require-01 :ARG1 (a2 / and :op1 (t / translocate-01 :ARG2 (m2 / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :op2 (p2 / phosphorylate-01 :ARG0-of (r2 / regulate-01)) :op3 (d / dephosphorylate-01 :ARG0-of (r3 / regulate-01)) :op4 (a3 / activate-01 :mod (a4 / allosteric) :mod (c3 / crucial) :condition (h / have-part-91 :ARG1 (d2 / dimer :mod (s / side :prep-to (s2 / side)) :ARG1-of (c5 / comprise-01 :ARG2 (o / or :op1 (m3 / molecule :quant "2" :mod e) :op2 (a5 / and :op1 (m4 / molecule :mod e) :op2 (m5 / molecule :mod (e4 / enzyme :name (n4 / name :op1 "Ksr") :xref (x / xref :value "UNIPROT:KSR1_HUMAN" :prob "0.603"))))))))))))) # ::id bio-kappa_0001.2 # ::date 2014-09-26T12:38:07 # ::file bio-kappa_0001_2.txt # ::snt Of the three Raf kinases , only B-Raf is able to function as an allosteric activator in the context of the Raf heterodimers , a role independent of B-Raf kinase activity . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (k / kinase :name (n / name :op1 "B-Raf") :ARG1-of (i / include-91 :ARG2 (k2 / kinase :quant "3" :name (n2 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :mod (o / only) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :mod (a2 / allosteric) :condition (h2 / have-part-91 :ARG1 (h / heterodimer :part (e / enzyme :name (n3 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG2 k) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a3 / activity-06 :ARG0 k)))) # ::id bio-kappa_0001.3 # ::date 2014-09-27T15:35:13 # ::file bio-kappa_0001_3.txt # ::snt The molecular basis for this has recently been elucidated by the Shaw lab , who has shown that the ability of acting as an activator depends on the presence of negative charges in the Raf N-terminal acidic motif . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (e / elucidate-01 :ARG0 (l / lab :name (n / name :op1 "Shaw") :ARG0-of (s / show-01 :ARG1 (d / depend-01 :ARG0 (p / possible-01 :ARG1 (a / activate-01)) :ARG1 (p2 / present-02 :ARG1 (c / charge :ARG2-of (n2 / negative-06) :location (m3 / motif :mod (a2 / acid) :part-of (p3 / protein-segment :name (n3 / name :op1 "N-terminus") :part-of (e2 / enzyme :name (n4 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))))))) :ARG1 (b / base-02 :ARG1 (t / this) :mod (m2 / molecule)) :time (r / recent)) # ::id bio-kappa_0001.4 # ::date 2015-01-19T06:33:33 # ::file bio-kappa_0001_4.txt # ::snt In B-Raf , this motif is negatively charged due to the constitutive phosphorylation of Ser446 and/or 447 , and to the presence of two aspartates at position 448/9 ( Fig. 2A ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c / charge-03 :ARG1 (m / motif :mod (t / this) :part-of (e2 / enzyme :name (n6 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG2-of (n / negative-06) :ARG1-of (c2 / cause-01 :ARG0 (a / and :op1 (p / phosphorylate-01 :ARG1 (a6 / and-or :op1 (a2 / amino-acid :mod "446" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :mod "447" :name (n3 / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :mod (c3 / constitutive)) :op2 (p4 / present-02 :ARG1 (a4 / amino-acid :quant "2" :name (n4 / name :op1 "aspartate") :xref (x3 / xref :value "PUBCHEM:5960" :prob "13.722911")) :ARG2 (a5 / and :op1 (p2 / protein-segment :mod "448") :op2 (p3 / protein-segment :mod "449"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id bio-kappa_0001.5 # ::date 2015-01-20T00:43:24 # ::file bio-kappa_0001_5.txt # ::snt Allosteric activation by B-Raf induces cis-autophosporylation in the activation loop of the receiver kinase , i.e. C-Raf , and renders it able to phosphorylate Mek . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (a3 / and :op1 (i / induce-01 :ARG0 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :mod (a2 / allosteric)) :ARG2 (p / phosphorylate-01 :ARG1 "k" :ARG2 "k" :subevent-of (l / loop :ARG0-of (a4 / activate-01 :ARG1 (k / kinase :ARG0-of (r2 / receive-01) :ARG1-of (m / mean-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))))))) :op2 (r / render-01 :ARG0 a :ARG1 (p2 / possible-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Mek") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243")) :ARG2 e2)))) # ::id bio-kappa_0001.6 # ::date 2015-01-20T01:34:52 # ::file bio-kappa_0001_6.txt # ::snt Mek , in turn , phosphorylates the N-terminal acidic motif in C-Raf , converting it to an allosteric activator of other Rafs ( Fig. 2B and C ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 27, 2015 (p / phosphorylate-01 :ARG1 (m / motif :mod (a / acid) :part-of (p2 / protein-segment :name (n2 / name :op1 "N-terminus") :part-of (e2 / enzyme :name (n3 / name :op1 "C-Raf") :ARG1-of (c2 / convert-01 :ARG0 "e" :ARG2 (e3 / enzyme :ARG0-of (a2 / activate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "Raf") :mod (o / other) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :mod (a3 / allosteric)))) :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))) :ARG2 (e / enzyme :name (n / name :op1 "Mek") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243")) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2B") :op2 (f2 / figure :mod "2C"))) :mod (i / in-turn)) # ::id bio-kappa_0001.7 # ::date 2015-01-20T01:58:10 # ::file bio-kappa_0001_7.txt # ::snt This model explains why C-Raf mutants devoid of kinase activity cannot function as activators , and why B-Raf can activate Mek directly as a homodimer . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (e / explain-01 :ARG0 (m / model :mod (t3 / this)) :ARG1 (t2 / thing :ARG0-of (c2 / cause-01 :ARG1 (a6 / and :op1 (p / possible-01 :polarity "-" :ARG1 (a2 / activate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "C-Raf") :ARG2-of (m2 / mutate-01) :ARG1-of (v / void-03 :ARG2 (a / activity-06 :ARG0 (k / kinase))) :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))) :op2 (p2 / possible-01 :ARG1 (a4 / activate-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "B-Raf") :ARG0-of (a5 / act-01 :ARG1 (h / homodimer)) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e4 / enzyme :name (n3 / name :op1 "Mek") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243")) :ARG1-of (d / direct-02))))))) # ::id bio-kappa_0001.8 # ::date 2015-01-20T02:34:12 # ::file bio-kappa_0001_8.txt # ::snt Phosphorylated Ksr can also function as a transactivator ; however , since Raf binding to Ksr induces limited kinase activity , in quiescent cells the constitutive association of Ksr with B-Raf may serve to prevent C-Raf binding to B-Raf , safeguarding against undue activation of the pathway . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / possible-01 :ARG1 (t2 / transactivate-01 :ARG2 (e / enzyme :name (n / name :op1 "Ksr") :ARG3-of (p2 / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:KSR1_HUMAN" :prob "0.603")) :mod (a / also) :concession-of (p3 / possible-01 :ARG1 (s / serve-01 :ARG0 (a3 / associate-01 :ARG1 e :ARG2 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :mod (c2 / constitutive)) :ARG1 (p4 / prevent-01 :ARG0 a3 :ARG1 (b / bind-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG2 e3) :ARG0-of (s2 / safeguard-01 :ARG2 (a4 / activate-01 :ARG1 (p5 / pathway) :mod (d / due :polarity "-"))))) :location (c / cell :mod (q / quiescent)) :ARG1-of (c3 / cause-01 :ARG0 (i / induce-01 :ARG0 (b2 / bind-01 :ARG1 (e6 / enzyme :name (n6 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG2 e) :ARG2 (a2 / activity-06 :ARG1 (k / kinase) :ARG1-of (l / limit-01))))))) # ::id bio-kappa_0001.9 # ::date 2015-01-20T03:20:23 # ::file bio-kappa_0001_9.txt # ::snt PSPs dephosphorylate phosphoserine and phosphothreonine residues . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (d / dephosphorylate-01 :ARG1 (a / and :op1 (r / residue :mod (a2 / amino-acid :name (n / name :op1 "serine") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :op2 (r2 / residue :mod (a3 / amino-acid :name (n2 / name :op1 "threonine") :ARG3-of (p4 / phosphorylate-01) :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")))) :ARG2 (s / small-molecule :name (n3 / name :op1 "PSP") :xref (x / xref :value "PUBCHEM:4766" :prob "18.013371"))) # ::id bio-kappa_0001.10 # ::date 2015-01-20T03:41:50 # ::file bio-kappa_0001_10.txt # ::snt One of the most abundantly expressed PSPs , protein phosphatase 2A ( PP2A ) , can regulate the Raf / Mek / Erk pathway both positively and negatively . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (p / possible-01 :ARG1 (a3 / and :op1 (u / upregulate-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "Raf/Mek/Erk")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "protein" :op2 "phosphatase" :op3 "2A") :ARG1-of (i / include-91 :ARG2 (s / small-molecule :name (n / name :op1 "PSP") :ARG2-of (e / express-03 :degree (a / abundant :degree (m2 / most))) :xref (x1 / xref :value "PUBCHEM:4766" :prob "18.013371"))) :xref (x / xref :value "UNIPROT:PPM1A_HUMAN" :prob "0.392"))) :op2 (d / downregulate-01 :ARG1 p3 :ARG2 e2))) # ::id bio-kappa_0001.11 # ::date 2015-01-20T04:54:37 # ::file bio-kappa_0001_11.txt # ::snt As a positive regulator , PP2A associates with C-Raf and Ksr1 and dephosphorylates negative regulatory sites on both proteins , allowing their recruitment to the membrane and leading to Mek and Erk activation . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (a / and :op1 (a7 / associate-01 :ARG1 (e / enzyme :name (n / name :op1 "PP2A") :xref (x4 / xref :value "UNIPROT:PP2AA_HUMAN" :prob "0.372")) :ARG2 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :op2 (e3 / enzyme :name (n3 / name :op1 "Ksr1") :xref (x2 / xref :value "UNIPROT:KSR1_HUMAN" :prob "0.604")))) :op2 (d / dephosphorylate-01 :ARG1 (p2 / protein-segment :ARG0-of (d2 / downregulate-01) :part-of (a3 / and :op1 e2 :op2 e3)) :ARG2 e) :ARG0-of (a4 / allow-01 :ARG1 (r / recruit-01 :ARG1 a2 :destination (m / membrane :xref (x5 / xref :value "GO:0016020" :prob "0.8")))) :ARG0-of (l / lead-03 :ARG2 (a5 / activate-01 :ARG1 (a6 / and :op1 (e4 / enzyme :name (n5 / name :op1 "Mek") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243")) :op2 (e5 / enzyme :name (n6 / name :op1 "Erk") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))))) :condition (u / upregulate-01 :ARG2 e)) # ::id bio-kappa_0001.12 # ::date 2015-01-20T05:30:27 # ::file bio-kappa_0001_12.txt # ::snt A similar role in C-Raf activation has been described for the catalytic subunit of PP1C , which associates with C-Raf in Ras- and growth factor - stimulated cells . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (d / describe-01 :ARG1 (r / role :ARG1-of (r2 / resemble-01) :purpose (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))) :topic (p / protein-segment :ARG0-of (c / catalyze-01) :part-of (e2 / enzyme :name (n2 / name :op1 "PP1C") :xref (x2 / xref :value "UNIPROT:PP12C_HUMAN" :prob "0.312")) :ARG1-of (b / bind-01 :ARG2 e :location (c2 / cell :ARG1-of (s / stimulate-01 :ARG0 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (g / growth-factor))))))) # ::id bio-kappa_0001.13 # ::date 2015-01-20T06:02:25 # ::file bio-kappa_0001_13.txt # ::snt In addition to promoting C-Raf activation , PP2A is also able to dephosphorylate Erk - dependent sites on C-Raf . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 27, 2015 (a / and :op1 (p3 / promote-02 :ARG0 "e" :ARG1 (a2 / activate-01 :ARG1 "e3")) :op2 (p / possible-01 :ARG1 (d / dephosphorylate-01 :ARG1 (p2 / protein-segment :ARG0-of (d2 / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Erk") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))) :part-of (e3 / enzyme :name (n3 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :ARG2 (e / enzyme :name (n / name :op1 "PP2A") :xref (x / xref :value "UNIPROT:PP2AA_HUMAN" :prob "0.372"))) :mod (a3 / also))) # ::id bio-kappa_0001.14 # ::date 2015-01-20T06:22:13 # ::file bio-kappa_0001_14.txt # ::snt Since the sites have been described alternatively as negative regulatory or activating , the significance of these dephosphorylation events for Raf activation is unclear . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (c / clear-06 :polarity "-" :ARG0 (d2 / describe-01 :ARG1 (p / protein-segment) :ARG2 (o / or :op1 (d3 / downregulate-01 :ARG2 p) :op2 (a2 / activate-01 :ARG0 p)) :manner (a / alternative)) :ARG1 (s / significance :topic (a3 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :mod (d / dephosphorylate-01 :mod (t / this)))) # ::id bio-kappa_0001.15 # ::date 2015-01-20T06:38:55 # ::file bio-kappa_0001_15.txt # ::snt As a negative regulator of the pathway , PP2A can dephosphorylate the adapter protein Shc , required downstream of some tyrosine kinase receptors for the activation of the Raf / Mek / Erk module ; and it can dephosphorylate Mek and Erk proteins , thus inhibiting the cascade directly . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (p6 / possible-01 :ARG1 (d / dephosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Shc") :mod (a2 / adapter) :ARG1-of (r / require-01 :ARG0 (a3 / activate-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "Raf/Mek/Erk")) :location (r3 / relative-position :op1 (p / protein :name (n7 / name :op1 "tyrosine" :op2 "kinase" :op3 "receptor") :quant (s / some) :xref (x2 / xref :value "UNIPROT:NTRK1_HUMAN" :prob "0.703")) :direction (d2 / downstream)))) :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG2 (e / enzyme :name (n / name :op1 "PP2A") :xref (x / xref :value "UNIPROT:PP2AA_HUMAN" :prob "0.372")) :condition (d5 / downregulate-01 :ARG1 (p4 / pathway) :ARG2 e))) :op2 (p7 / possible-01 :ARG1 (d4 / dephosphorylate-01 :ARG1 (a4 / and :op1 (p5 / protein-family :name (n4 / name :op1 "Mek")) :op2 (p8 / protein-family :name (n5 / name :op1 "Erk"))) :ARG2 e :ARG0-of (i / inhibit-01 :ARG1 p3 :ARG1-of (d3 / direct-02))))) # ::id bio-kappa_0001.16 # ::date 2015-01-20T07:03:49 # ::file bio-kappa_0001_16.txt # ::snt A further negative regulator of the cascade , at the level of C-Raf , is Protein phosphatase 5 ( PP5 ) , which associates with C-Raf via its N-terminal tetratricopeptide ( TPR ) domain in growth factor stimulated cells . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (d3 / downregulate-01 :ARG0 (e3 / enzyme :name (n / name :op1 "Protein" :op2 "phosphatase" :op3 "5") :ARG1-of (a / associate-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :location (c / cell :ARG1-of (s / stimulate-01 :ARG0 (g / growth-factor))) :instrument (p2 / protein-segment :name (n4 / name :op1 "tetratricopeptide" :op2 "domain") :part-of (p / protein-segment :name (n3 / name :op1 "N-terminal") :part-of e2))) :mod (f / further) :xref (x / xref :value "UNIPROT:PPM1A_HUMAN" :prob "0.392")) :ARG1 (c2 / cascade :location e2)) # ::id bio-kappa_0001.17 # ::date 2015-01-20T07:23:45 # ::file bio-kappa_0001_17.txt # ::snt This interaction leads to the activation of PP5 catalytic activity and to the selective dephosphorylation of the activating serine residue at position 338 , terminating the signal . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (l / lead-03 :ARG0 (i2 / interact-01 :mod (t / this)) :ARG2 (a3 / and :op1 (a / activate-01 :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "PP5") :xref (x / xref :value "UNIPROT:PPP5_HUMAN" :prob "1.002")) :ARG1 (c2 / catalyze-01))) :op2 (d / dephosphorylate-01 :ARG1 (r / residue :mod "338" :mod (a4 / amino-acid :name (n2 / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG0-of (a5 / activate-01)) :mod (s / selective)) :ARG0-of (t2 / terminate-01 :ARG1 (s3 / signal)))) # ::id bio-kappa_0001.18 # ::date 2015-01-20T07:43:07 # ::file bio-kappa_0001_18.txt # ::snt Following ligand binding , Sos is brought from the cytoplasm to the activated receptor in a phosphotyrosine - dependent manner through adapter proteins such as Grb2 . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (b / bring-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Sos") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203")) :ARG2 (r / receptor :ARG1-of (a / activate-01)) :ARG4 (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :manner (d / depend-01 :ARG0 "b" :ARG1 (a2 / amino-acid :name (n / name :op1 "tyrosine") :ARG3-of (p4 / phosphorylate-01) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :instrument (p / protein :example (p2 / protein :name (n2 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :mod (a3 / adapter)) :ARG1-of (f / follow-01 :ARG2 (b2 / bind-01 :ARG1 (l / ligand)))) # ::id bio-kappa_0001.19 # ::date 2015-01-20T08:00:15 # ::file bio-kappa_0001_19.txt # ::snt Grb2 contains SH3 domains that are bound constitutively to a carboxy - terminal proline - rich region of Sos , and the Grb2 '96 Sos complex is recruited to activated receptors by interactions between the SH2 domain of Grb2 and phosphotyrosine residues on the receptor . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jun 13, 2015 (a / and :op1 (c / contain-01 :ARG0 (p / protein :name (n / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG1 (p2 / protein-segment :name (n2 / name :op1 "SH3" :op2 "domain") :ARG1-of (b / bind-01 :ARG2 (r4 / region :mod (r6 / rich :topic (a3 / amino-acid :name (n3 / name :op1 "proline") :xref (x2 / xref :value "PUBCHEM:614" :prob "10.45396"))) :part-of (p5 / protein-segment :name (n4 / name :op1 "carboxy-terminus") :part-of (p6 / protein :name (n5 / name :op1 "Sos") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203")))) :mod (c2 / constitutive)))) :op2 (r5 / recruit-01 :ARG0 (i / interact-01 :ARG0 (a5 / and :op1 (p7 / protein-segment :name (n7 / name :op1 "SH2" :op2 "domain") :part-of p) :op2 (r2 / residue :location (r3 / receptor) :mod (a4 / amino-acid :name (n6 / name :op1 "tyrosine") :ARG3-of (p3 / phosphorylate-01) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :ARG1 (m2 / macro-molecular-complex :part p :part p6) :destination (r / receptor :ARG1-of (a2 / activate-01)))) # ::id bio-kappa_0001.20 # ::date 2015-01-20T08:03:03 # ::file bio-kappa_0001_20.txt # ::snt The guanine nucleotide-binding switch in three dimensions . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 21, 2015 (s / switch :mod (p / protein :name (n / name :op1 "guanine" :op2 "nucleotide-binding") :xref (x / xref :value "UNIPROT:GBP1_HUMAN" :prob "0.372")) :prep-in (d / dimension :quant "3")) # ::id bio-kappa_0001.21 # ::date 2015-01-20T08:10:38 # ::file bio-kappa_0001_21.txt # ::snt Activation requires dissociation of protein - bound GDP , an intrinsically slow process that is accelerated by guanine nucleotide '96 exchange factors ( GEFs ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (r / require-01 :ARG0 (a / activate-01) :ARG1 (d / dissociate-01 :ARG1 (s / small-molecule :name (n / name :op1 "GDP") :ARG1-of (b / bind-01 :ARG2 (p / protein)) :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG1-of (s2 / slow-05 :mod (i / intrinsic)) :ARG1-of (a2 / accelerate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor") :xref (x / xref :value "UNIPROT:PKHG5_HUMAN" :prob "0.393"))))) # ::id bio-kappa_0001.22 # ::date 2015-01-20T08:17:10 # ::file bio-kappa_0001_22.txt # ::snt This switch - ON process involves the exchange of GDP for GTP , and is , at least in principle , reversible . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (a / and :op1 (i2 / involve-01 :ARG0 (p / process-02 :ARG1 (a3 / activate-01) :mod (t / this)) :ARG1 (e / exchange-01 :ARG1 (s / small-molecule :name (n / name :op1 "GDP") :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG3 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645")))) :op2 (p3 / possible-01 :ARG1 (r / reverse-01 :ARG1 p) :mod (i / in-principle :mod (a2 / at-least)))) # ::id bio-kappa_0001.23 # ::date 2015-01-20T08:30:46 # ::file bio-kappa_0001_23.txt # ::snt The switch - OFF process is entirely different and involves hydrolysis of GTP to GDP , the guanosine triphosphatase ( GTPase ) reaction , which is basically irreversible . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (a / and :op1 (d2 / differ-02 :ARG1 (p / process-02 :ARG1 (d / deactivate-01)) :degree (e / entire)) :op2 (i / involve-01 :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG3 (s2 / small-molecule :name (n2 / name :op1 "GDP") :xref (x2 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG2-of (r / react-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "guanosine" :op2 "triphosphatase") :xref (x / xref :value "UNIPROT:ENTP5_HUMAN" :prob "0.332")) :ARG1-of (r2 / reverse-01 :ARG1-of (p2 / possible-01 :polarity "-" :mod (b / basic))))) :ARG2 p)) # ::id bio-kappa_0001.24 # ::date 2015-01-20T08:41:56 # ::file bio-kappa_0001_24.txt # ::snt It is also intrinsically very slow and thus has to be accelerated by GTPase - activating proteins ( GAPs ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s / slow-05 :ARG1 (i / it) :degree (v / very) :mod (i2 / intrinsic) :mod (a4 / also) :ARG0-of (c / cause-01 :ARG1 (o2 / obligate-01 :ARG2 (a / accelerate-01 :ARG0 (p / protein :ARG0-of (a3 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "GTPase") :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")))) :ARG1 i)))) # ::id bio-kappa_0001.25 # ::date 2015-01-20T09:07:33 # ::file bio-kappa_0001_25.txt # ::snt The mechanism of GEF action involves a series of fast reaction steps , which lead from a binary protein - nucleotide complex via a trimeric GNBP - nucleotide - GEF complex to a binary nucleotide - free complex , which is stable in the absence of nucleotide . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (i / involve-01 :ARG1 (s / series :consist-of (s2 / step :ARG1-of (f / fast-02) :mod (r / react-01) :ARG0-of (t3 / turn-02 :ARG2 (c2 / complex :ARG1-of (f2 / free-04 :ARG2 (n3 / nucleotide)) :ARG1-of (s3 / stable-03 :condition (a2 / absent-01 :ARG1 n3))) :ARG3 (m2 / macro-molecular-complex :part (p2 / protein) :part n3 :mod (b2 / binary)) :path (m3 / macro-molecular-complex :mod (t2 / trimeric) :part (p3 / protein :name (n2 / name :op1 "GNBP") :xref (x / xref :value "UNIPROT:GBB1_HUMAN" :prob "0.223")) :part n3 :part "p")))) :ARG2 (m / mechanism :mod (a / act-02 :ARG0 (p / protein :name (n / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002"))))) # ::id bio-kappa_0001.26 # ::date 2015-01-20T09:08:43 # ::file bio-kappa_0001_26.txt # ::snt This series of reactions is reversed by rebinding of nucleotide , predominantly GTP , because of its higher concentration in the cell . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (r / reverse-01 :ARG0 (b / bind-01 :ARG1 (n / nucleotide :ARG1-of (m2 / mean-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645")) :mod (p / predominant :ARG1-of (c / cause-01 :ARG0 (c2 / concentrate-02 :ARG1 s2 :ARG1-of (h / high-02 :degree (m / more)) :location (c3 / cell)))))) :mod (a / again)) :ARG1 (s / series :mod (t / this) :consist-of (r2 / react-01))) # ::id bio-kappa_0001.27 # ::date 2015-01-20T09:16:31 # ::file bio-kappa_0001_27.txt # ::snt In principle , these reactions are fast and fully reversible , so that the GEF merely acts as a catalyst to increase the rate at which equilibrium between the GDP- and GTP - bound forms of the protein is reached . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (a / and :op1 (f / fast-02 :ARG1 (r / react-01 :mod (t / this))) :op2 (p / possible-01 :ARG1 (r2 / reverse-01 :ARG1 r :degree (f2 / full))) :mod (i2 / in-principle) :ARG0-of (c / cause-01 :ARG1 (a2 / act-01 :ARG0 (p3 / protein :name (n / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (c2 / catalyze-01) :degree (m / mere) :purpose (i / increase-01 :ARG0 p3 :ARG1 (r3 / rate :degree-of (r4 / reach-01 :ARG1 (e / equilibrate-01 :ARG1 (a4 / and :op1 (p2 / protein :ARG1-of (b / bind-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "GDP") :xref (x2 / xref :value "PUBCHEM:8977" :prob "14.712257")))) :op2 (p5 / protein :ARG1-of (b2 / bind-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")))))))))))) # ::id bio.bel_0002.1 # ::date 2014-09-29T14:32:03 # ::file bio_bel_0002_1.txt # ::snt Protein kinase A-dependent phosphorylation of serine 43 within the regulatory domain of Raf-1 reciprocally potentiates its interaction with Rheb and decreases its interaction with H-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (a / and :op1 (p / potentiate-01 :ARG1 (i / interact-01 :ARG0 "e2" :ARG1 (p2 / protein :name (n / name :op1 "Rheb") :xref (x / xref :value "UNIPROT:RHEB_HUMAN" :prob "0.603"))) :ARG2 (p3 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "43" :name (n5 / name :op1 "serine") :part-of (d2 / domain :mod (r / regulate-01) :part-of (e2 / enzyme :name (n3 / name :op1 "Raf-1") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG0-of (d3 / depend-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "protein" :op2 "kinase" :op3 "A") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393")))) :mod (r2 / reciprocal)) :op2 (d / decrease-01 :ARG0 p3 :ARG1 (i2 / interact-01 :ARG0 e2 :ARG1 (e / enzyme :name (n2 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) # ::id bio.bel_0002.2 # ::date 2014-09-29T14:54:34 # ::file bio_bel_0002_2.txt # ::snt We show that wild-type B-RAF forms a complex with C-RAF in a RAS-dependent manner, whereas the mutants bind independently of RAS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 9, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (f / form-01 :ARG1 (m / macro-molecular-complex :part (e4 / enzyme :name (n / name :op1 "B-RAF") :mod (w2 / wild-type) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")) :part (e / enzyme :name (n2 / name :op1 "C-RAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.593"))) :ARG0-of (d / depend-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "RAS") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263"))) :ARG1-of (c / contrast-01 :ARG2 (b / bind-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "B-RAF") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")) :ARG2 (e2 / enzyme :name (n5 / name :op1 "C-RAF") :ARG2-of (m3 / mutate-01) :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.593")) :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 e3))))) # ::id bio.bel_0002.3 # ::date 2014-09-29T15:10:36 # ::file bio_bel_0002_3.txt # ::snt Importantly, we show that wild-type B-RAF can also activate C-RAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 10, 2014 (s / show-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "B-RAF") :mod (w2 / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")) :ARG1 (e / enzyme :name (n2 / name :op1 "C-RAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.593")) :mod (a2 / also))) :mod (i / important)) # ::id bio.bel_0002.4 # ::date 2015-02-05T10:13:38 # ::file bio_bel_0002_4.txt # ::snt The homologous site on B-Raf, S445, is constitutively phosphorylated, accounting for the higher basal activity of B-Raf. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "445" :name (n3 / name :op1 "serine") :part-of (e / enzyme :name (n4 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :mod (h2 / homologue) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :mod (c / constitutive) :ARG0-of (a / account-01 :ARG1 (a2 / activity-06 :ARG0 e :mod (b / basal) :ARG1-of (h / high-02 :degree (m / more))))) # ::id bio.bel_0002.5 # ::date 2015-01-23T02:19:50 # ::file bio_bel_0002_5.txt # ::snt In addition, introduction of B-Raf enhances and sustains integrin-mediated activation of ERK in wild-type primary fibroblasts # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (a4 / and :op2 (a / and :op1 (e / enhance-01 :ARG0 (i / introduce-02 :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG1 (a2 / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :location (f / fibroblast :mod (w / wild-type) :mod (p / primary)) :ARG1-of (m / mediate-01 :ARG0 (i2 / integrin)))) :op2 (s / sustain-01 :ARG0 i :ARG1 a2))) # ::id bio.bel_0002.6 # ::date 2015-02-05T10:37:17 # ::file bio_bel_0002_6.txt # ::snt siRNA-mediated depletion of B-Raf reduced cell proliferation by up to 65% through the inhibition of ERK1/2 activation, irrespective of the mutational status of B-Raf. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (r / reduce-01 :ARG0 (d / deplete-01 :ARG1 (e / enzyme :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1-of (m / mediate-01 :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA")))) :ARG1 (p2 / proliferate-01 :ARG0 (c / cell)) :ARG2 (u / up-to :op1 (p / percentage-entity :value "65")) :manner (i / inhibit-01 :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2")))) :ARG1-of (r2 / regardless-91 :ARG2 (s / status :poss e :mod (m2 / mutate-01)))) # ::id bio.bel_0002.7 # ::date 2015-02-05T10:59:48 # ::file bio_bel_0002_7.txt # ::snt Following expression of BRAFV600E in melanocytes, the majority of cells became senescent (Figure 1D and data not shown), consistent with previous studies (Michaloglou et al., 2005) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 9, 2015 (b / become-01 :ARG1 (c / cell :quant (m / majority)) :ARG2 (s / senescent :domain c) :ARG1-of (f / follow-01 :ARG2 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG3 (m3 / melanocyte))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "1D") :op2 (d3 / data :ARG1-of (s2 / show-01 :polarity "-")))) :ARG1-of (c3 / consistent-01 :ARG2 (s3 / study :time (p / previous) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n2 / name :op1 "Michaloglou")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2005")))))) # ::id bio.bel_0002.8 # ::date 2015-01-23T02:59:24 # ::file bio_bel_0002_8.txt # ::snt disruption of the KSR1/CK2 interaction or inhibition of CK2 activity significantly reduces the growth-factor-induced phosphorylation of C-Raf and B-Raf on the activating serine site in the negative-charge regulatory region (N-region). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (r / reduce-01 :ARG0 (o / or :op1 (d / disrupt-01 :ARG1 (i / interact-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "KSR1") :xref (x1 / xref :value "UNIPROT:KSR1_HUMAN" :prob "1.004")) :ARG1 (e4 / enzyme :name (n5 / name :op1 "CK2") :xref (x / xref :value "UNIPROT:CSK22_HUMAN" :prob "0.332")))) :op2 (i2 / inhibit-01 :ARG1 (a3 / activity-06 :ARG0 e4))) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :ARG0-of (a2 / activate-01) :mod (a4 / amino-acid :name (n7 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of (r2 / region :ARG0-of (r3 / regulate-01) :ARG1-of (c / charge-03 :ARG2-of (n3 / negative-06)) :part-of (a / and :op1 (e / enzyme :name (n / name :op1 "C-Raf") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :op2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :ARG2-of (i3 / induce-01 :ARG0 (g / growth-factor))) :ARG2 (s / significant-02)) # ::id bio.bel_0002.9 # ::date 2015-01-23T03:54:56 # ::file bio_bel_0002_9.txt # ::snt Sorafenib is a potent TKI of VEGFR-2, VEGFR-3, B-RAF, and PDGFR-B # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 5, 2015 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "Sorafenib") :xref (x4 / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG1 (a / and :op1 (k / kinase :name (n / name :op1 "VEGFR-2") :xref (x / xref :value "UNIPROT:VGFR2_HUMAN" :prob "1.003")) :op2 (k2 / kinase :name (n3 / name :op1 "VEGFR-3") :xref (x2 / xref :value "UNIPROT:VGFR3_HUMAN" :prob "1.003")) :op3 (k3 / kinase :name (n4 / name :op1 "B-RAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")) :op4 (k4 / kinase :name (n5 / name :op1 "PDGFR-B") :xref (x3 / xref :value "UNIPROT:PGFRB_HUMAN" :prob "0.693"))) :mod (p / potent)) # ::id bio.bel_0002.10 # ::date 2015-01-23T03:55:41 # ::file bio_bel_0002_10.txt # ::snt In addition, we found that Rheb inhibits the association of B-Raf with H-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (a3 / and :op2 (f / find-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "Rheb") :xref (x / xref :value "UNIPROT:RHEB_HUMAN" :prob "0.603")) :ARG1 (a2 / associate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (e3 / enzyme :name (n3 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))))) # ::id bio.bel_0002.11 # ::date 2015-01-23T04:01:28 # ::file bio_bel_0002_11.txt # ::snt hKSR-2 selectively inhibited the Cot-mediated activation of MEK by 60%. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 9, 2015 (i / inhibit-01 :ARG0 (e / enzyme :name (n / name :op1 "hKSR-2") :xref (x / xref :value "UNIPROT:KSR2_HUMAN" :prob "0.682")) :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (m / mediate-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Cot") :xref (x1 / xref :value "UNIPROT:M3K8_HUMAN" :prob "0.602")))) :manner (s / selective) :quant (p / percentage-entity :value "60")) # ::id bio.bel_0002.12 # ::date 2015-02-05T12:05:33 # ::file bio_bel_0002_12.txt # ::snt In contrast, hKSR-2 up-regulated the Rafmediated MEK activation by up to 70%. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 5, 2015 (c / contrast-01 :ARG2 (u / upregulate-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (m / mediate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :ARG2 (e3 / enzyme :name (n3 / name :op1 "hKSR-2") :xref (x1 / xref :value "UNIPROT:KSR2_HUMAN" :prob "0.682")) :quant (u2 / up-to :op1 (p / percentage-entity :value "70")))) # ::id bio.bel_0002.13 # ::date 2015-02-07T09:19:06 # ::file bio_bel_0002_13.txt # ::snt GSK PI3K Phase 2, part 1: List of non-position specific phosphorylation effects on parent protein's activity, derived from existing causal assertions of position-specific phosphorylations on the parent protein activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a4 / and :op1 (e / enzyme :name (n / name :op1 "GSK") :xref (x / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.232")) :op2 (e2 / enzyme :name (n2 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :mod (p8 / phase :mod "2" :part (p9 / part :mod "1" :topic (l / list-01 :ARG1 (a / affect-01 :ARG0 (p / phosphorylate-01 :ARG1-of (s / specific-02 :polarity "-" :ARG2 (p2 / position-01))) :ARG1 (a2 / activity-06 :ARG0 (p3 / protein :mod (p4 / parent)))) :ARG1-of (d / derive-01 :ARG2 (a3 / assert-03 :ARG1 (p5 / phosphorylate-01 :mod (p6 / position :ARG1-of s)) :ARG0-of (c / cause-01) :topic a2 :ARG1-of (e3 / exist-01))))))) # ::id bio.bmtr_0001.1 # ::date 2014-12-03T18:05:22 # ::file bio_bmtr_0001_1.txt # ::snt Sasaki et al., “Ubiquitination of Ras enhances activation and facilitates binding to select downstream effectors” (PMC3437993) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 10, 2014 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Sasaki")) :op2 (p3 / person :mod (o / other))) :ARG1 (a2 / and :op1 (e / enhance-01 :ARG0 (u / ubiquitinate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (a3 / activate-01)) :op2 (f / facilitate-01 :ARG0 u :ARG1 (b / bind-01 :ARG2 (e2 / effector :location (d / downstream) :mod (s2 / select))))) :ARG8 "PMC3437993") # ::id bio.bmtr_0001.2 # ::date 2014-12-03T21:45:59 # ::file bio_bmtr_0001_2.txt # ::snt We utilized an unbiased mass spectrometry-based approach to identify ubiquitination sites of Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 10, 2014 (u / utilize-01 :ARG0 (w / we) :ARG1 (a / approach-02 :ARG1-of (b / base-02 :ARG2 (s / spectrometry :mod (m / mass))) :ARG1-of (b2 / bias-01 :polarity "-")) :purpose (i / identify-01 :ARG0 w :ARG1 (p / protein-segment :part-of (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (u2 / ubiquitinate-01)))) # ::id bio.bmtr_0001.3 # ::date 2014-12-03T21:53:14 # ::file bio_bmtr_0001_3.txt # ::snt His-tagged ubiquitin and Flag-tagged K-Ras4B (K-Ras hereafter) were expressed in HEK293T cells at levels similar to endogenous K-Ras (Fig. 1B) and subjected to sequential affinity chromatography. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 10, 2014 (a3 / and :op1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n2 / name :op1 "ubiquitin") :ARG1-of (t / tag-01 :ARG2 (p3 / protein-segment :part (a2 / amino-acid :name (n5 / name :op1 "histidine") :xref (x / xref :value "PUBCHEM:6274" :prob "11.959939")))) :xref (x3 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :op2 (e5 / enzyme :name (n3 / name :op1 "K-Ras4B") :name (n4 / name :op1 "K-Ras") :ARG1-of (t2 / tag-01 :ARG2 (p4 / protein-segment :name (n6 / name :op1 "Flag"))) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG3 (c / cell-line :name (n / name :op1 "HEK293T")) :degree (l / level :ARG1-of (r / resemble-01 :ARG2 (l2 / level :degree-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n7 / name :op1 "K-Ras") :mod (e2 / endogenous) :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG3 c)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) :op2 (s2 / subject-01 :ARG1 a :ARG2 (c2 / chromatography :mod (a4 / affinity) :mod (s3 / sequence)))) # ::id bio.bmtr_0001.4 # ::date 2014-12-09T14:55:44 # ::file bio_bmtr_0001_4.txt # ::snt His-ubiquitinated proteins were purified by Co2+ metal affinity chromatography in 8M urea denaturing conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (p / purify-01 :ARG1 (p2 / protein :ARG3-of (u / ubiquitinate-01 :mod (a / amino-acid :name (n / name :op1 "histidine") :xref (x / xref :value "PUBCHEM:6274" :prob "11.959939")))) :manner (c / chromatography :mod (a2 / affinity :topic (c3 / copper :ARG1-of (i / ionize-01 :value "2+"))) :condition (d / denature-01 :ARG1 p2 :ARG4 (s / small-molecule :name (n3 / name :op1 "urea") :mod (c2 / concentration-quantity :quant "8" :unit (m2 / molar)) :xref (x1 / xref :value "PUBCHEM:1176" :prob "6.945035"))))) # ::id bio.bmtr_0001.5 # ::date 2014-12-09T22:13:53 # ::file bio_bmtr_0001_5.txt # ::snt His-ubiquitinated K-Ras was subsequently purified with anti-Flag resin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 9, 2014 (p / purify-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01 :mod (a / amino-acid :name (n2 / name :op1 "histidine") :xref (x1 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :time (s / subsequent) :instrument (r / resin :ARG0-of (c / counter-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "Flag"))))) # ::id bio.bmtr_0001.6 # ::date 2014-12-09T22:40:15 # ::file bio_bmtr_0001_6.txt # ::snt Following purification, mono- and di- ubiquitinated K-Ras appeared to be the major ubiquitination forms, which is consistent with the endogenous K-Ras ubiquitination pattern (Fig. 1, A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / appear-02 :ARG1 (f4 / form :mod (u3 / ubiquitinate-01) :mod (m2 / major) :domain (a3 / and :op1 (u4 / ubiquitinate-01 :quant "1" :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (u5 / ubiquitinate-01 :quant "2" :ARG1 e)) :ARG1-of (c / consistent-01 :ARG2 (p2 / pattern :topic (u2 / ubiquitinate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :mod (e3 / endogenous) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1A") :op2 (f3 / figure :mod "1B"))) :ARG1-of (f / follow-01 :ARG2 (p / purify-01 :ARG1 e))) # ::id bio.bmtr_0001.7 # ::date 2014-12-09T22:54:17 # ::file bio_bmtr_0001_7.txt # ::snt H-Ras ubiquitination sites were also determined by the same approach. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (d / determine-01 :ARG1 (p / protein-segment :ARG1-of (u / ubiquitinate-01) :part-of (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :manner (a / approach-02 :ARG1-of (s / same-01)) :mod (a2 / also)) # ::id bio.bmtr_0001.8 # ::date 2014-12-05T20:16:13 # ::file bio_bmtr_0001_8.txt # ::snt Tandem mass spectrometric analysis of tryptic fragments from the bands migrating at the positions expected for mono- and di-ubiquitinated Ras revealed ubiquitination at Lys residues 104 and 147 of K-Ras, and Lys residues 117, 147 and 170 for H-Ras (fig. S1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 5, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (p3 / protein-segment :ARG3-of (h / hydrolyze-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "trypsin") :xref (x3 / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342"))) :source (b / band :ARG0-of (m / migrate-01 :ARG2 (p / position :ARG2-of (b2 / be-located-at-91 :ARG1 (e5 / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant (o / or :op1 "1" :op2 "2")) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (e / expect-01)))))) :manner (s / spectrometry :mod (m2 / mass) :mod (t / tandem))) :ARG1 (u2 / ubiquitinate-01 :ARG1 (a2 / and :op1 (a8 / and :op1 (r2 / residue :mod (a3 / amino-acid :mod "104" :name (n3 / name :op1 "lysine") :xref (x4 / xref :value "PUBCHEM:866" :prob "11.053295"))) :op2 (r3 / residue :mod (a4 / amino-acid :mod "147" :name (n4 / name :op1 "lysine") :xref (x6 / xref :value "PUBCHEM:866" :prob "11.053295"))) :part-of (e4 / enzyme :name (n5 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (a9 / and :op1 (r4 / residue :mod (a5 / amino-acid :mod "117" :name (n6 / name :op1 "lysine") :xref (x5 / xref :value "PUBCHEM:866" :prob "11.053295"))) :op2 (r5 / residue :mod (a6 / amino-acid :mod "147" :name (n7 / name :op1 "lysine") :xref (x8 / xref :value "PUBCHEM:866" :prob "11.053295"))) :op3 (r6 / residue :mod (a7 / amino-acid :mod "170" :name (n8 / name :op1 "lysine") :xref (x7 / xref :value "PUBCHEM:866" :prob "11.053295"))) :part-of (e3 / enzyme :name (n9 / name :op1 "H-Ras") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S1C"))) # ::id bio.bmtr_0001.9 # ::date 2014-12-09T22:57:04 # ::file bio_bmtr_0001_9.txt # ::snt The tryptic peptide with ubiquitination at Lys147 (K147) was the most frequently observed peptide for both K-Ras and H-Ras, while Lys117 appeared as a secondary major ubiquitination site in H-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / contrast-01 :ARG1 (p / peptide :ARG1-of (o / observe-01 :ARG1-of (f / frequent-02 :degree (m / most))) :part-of (e2 / enzyme :mod (o2 / or :op1 (e3 / enzyme :name (n3 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e4 / enzyme :name (n4 / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))) :domain (p2 / peptide :part (a / amino-acid :mod "147" :name (n / name :op1 "lysine") :ARG3-of (u / ubiquitinate-01) :xref (x3 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG3-of (h / hydrolyze-01 :ARG2 (e / enzyme :name (n2 / name :op1 "trypsin") :xref (x2 / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342"))) :part-of e2)) :ARG2 (a3 / appear-01 :ARG1 (p3 / protein-segment :ARG1-of (u2 / ubiquitinate-01) :ARG1-of (m2 / major-02) :mod (s / secondary) :domain (a2 / amino-acid :mod "117" :name (n6 / name :op1 "lysine") :xref (x4 / xref :value "PUBCHEM:866" :prob "11.053295")) :part-of e4))) # ::id bio.bmtr_0001.10 # ::date 2014-12-18T10:39:24 # ::file bio_bmtr_0001_10.txt # ::snt To examine the effect of ubiquitination on GTP loading, we purified wild-type K-Ras, oncogenic G12V-K-Ras mutant or the ubiquitinated subfraction of wild-type K-Ras from 32P-orthophosphate labeled cells and utilized thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) to assess the ratio of 32P-GTP to 32P-GDP that co-purified with each form of K-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a2 / and :op1 (p / purify-01 :ARG0 (w / we) :ARG1 (a / and :op1 (o / or :op1 (e / enzyme :name (n2 / name :op1 "K-Ras") :mod (w2 / wild-type) :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n3 / name :op1 "K-Ras") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))) :ARG2-of (m / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op3 (e3 / enzyme :name (n4 / name :op1 "K-Ras") :mod (w3 / wild-type) :ARG3-of (u / ubiquitinate-01) :mod (s2 / subfraction) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 "s4" :op3 "s5") :source (c3 / cell :ARG1-of (l / label-01 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "orthophosphate") :part (p2 / phosphorus :mod (m2 / molecular-mass :value "32")) :xref (x4 / xref :value "PUBCHEM:1061" :prob "9.399563"))))) :op2 (u2 / utilize-01 :ARG0 w :ARG1 (a5 / and :op1 (c4 / chromatography :mod (l3 / layer :ARG1-of (t / thin-03))) :op2 (c5 / chromatography :mod (l4 / liquid :ARG0-of (p3 / perform-02 :ARG1-of (h / high-02))))) :purpose (a3 / assess-01 :ARG0 w :ARG1 (r / ratio-of :op1 (s4 / small-molecule :name (n6 / name :op1 "GTP") :part (p4 / phosphorus :mod (m3 / molecular-mass :value "32")) :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645")) :op2 (s5 / small-molecule :name (n7 / name :op1 "GDP") :part (p5 / phosphorus :mod (m4 / molecular-mass :value "32")) :xref (x6 / xref :value "PUBCHEM:8977" :prob "14.712257"))))) :purpose (e4 / examine-01 :ARG0 w :ARG1 (a4 / affect-01 :ARG0 (u3 / ubiquitinate-01) :ARG1 (l2 / load-01 :ARG2 (s / small-molecule :name (n / name :op1 "GTP") :xref (x5 / xref :value "PUBCHEM:6830" :prob "15.470645")))))) # ::id bio.bmtr_0001.11 # ::date 2014-12-18T12:35:31 # ::file bio_bmtr_0001_11.txt # ::snt As expected based on previous studies, wild-type K-Ras bound primarily 32P-GDP, while G12V-Ras bound 32P-GTP (Fig.2, A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 22, 2014 (c / contrast-01 :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2 (s / small-molecule :name (n2 / name :op1 "GDP") :part (p / phosphorus :mod (m / molecular-mass :value "32")) :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257")) :mod (p2 / primary)) :ARG2 (b2 / bind-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (s2 / small-molecule :name (n4 / name :op1 "GTP") :part (p3 / phosphorus :mod (m3 / molecular-mass :value "32")) :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B"))) :ARG1-of (e3 / expect-01 :ARG1-of (b3 / base-02 :ARG2 (s4 / study :time (p4 / previous))))) # ::id bio.bmtr_0001.12 # ::date 2014-12-18T17:04:39 # ::file bio_bmtr_0001_12.txt # ::snt Interestingly, the ubiquitinated subfraction of wild-type K-Ras retained a significant amount of 32P-GTP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (r / retain-01 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras") :mod (w / wild-type) :ARG3-of (u / ubiquitinate-01) :mod (s2 / subfraction) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP") :part (p / phosphorus :mod (m / molecular-mass :value "32")) :quant (a / amount :ARG1-of (s3 / significant-02)) :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG2-of (i / interest-01)) # ::id bio.bmtr_0001.13 # ::date 2014-12-18T17:10:57 # ::file bio_bmtr_0001_13.txt # ::snt These results are consistent with a model in which ubiquitination of Lys147 (or Lys117), destabilizes GDP binding, allowing spontaneous GDP/GTP exchange. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / consistent-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (m / model :topic (d / destabilize-01 :ARG0 (u / ubiquitinate-01 :ARG1 (o / or :op1 (a / amino-acid :mod "147" :name (n2 / name :op1 "lysine") :xref (x / xref :value "PUBCHEM:866" :prob "11.053295")) :op2 (a3 / amino-acid :mod "117" :name (n5 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295")))) :ARG1 (b / bind-01 :ARG2 (s / small-molecule :name (n / name :op1 "GDP") :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :ARG0-of (a2 / allow-01 :ARG1 (e / exchange-01 :ARG1 s :ARG3 (s4 / small-molecule :name (n4 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645")) :mod (s2 / spontaneous)))))) # ::id bio.bmtr_0001.14 # ::date 2014-12-22T16:19:51 # ::file bio_bmtr_0001_14.txt # ::snt It could be argued that GTP loading occurs prior to ubiquitination and that the GTP bound form of K-Ras, via interaction with effectors, is preferentially mono-ubiquitinated via a feedback mechanism. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / possible-01 :ARG1 (a / argue-01 :ARG1 (a2 / and :op1 (l / load-01 :ARG2 (s / small-molecule :name (n / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")) :time (p2 / prior :op1 (u / ubiquitinate-01))) :op2 (u2 / ubiquitinate-01 :quant "1" :ARG1 (e / enzyme :name (n2 / name :op1 "K-Ras") :ARG1-of (b / bind-01 :ARG2 s) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1-of (p3 / prefer-01) :manner (i / interact-01 :ARG0 e :ARG1 (e2 / effector)) :manner (f / feedback))))) # ::id bio.bmtr_0001.15 # ::date 2014-12-22T16:27:59 # ::file bio_bmtr_0001_15.txt # ::snt While it is difficult to eliminate this possibility, it is unlikely since, as shown in fig. S1B, the T35 mutant of K-Ras, which fails to interact with downstream effectors (fig. S1B) undergoes comparable monobuiquitination to wild type Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 8, 2015 (c / contrast-01 :ARG1 (d / difficult :domain (e3 / eliminate-01 :ARG1 (t / this :ARG1-of (p / possible-01)))) :ARG2 (l / likely-01 :polarity "-" :ARG1 t :ARG1-of (c2 / cause-01 :ARG0 (u / ubiquitinate-01 :quant "1" :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG2-of (m / mutate-01 :value "T35") :ARG0-of (i / interact-01 :polarity "-" :ARG1 (e4 / effector :location (d2 / downstream)) :ARG1-of (d3 / describe-01 :ARG0 "f")) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "S1B")) :ARG1-of (c3 / comparable-03 :ARG2 (u2 / ubiquitinate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))))) # ::id bio.bmtr_0001.16 # ::date 2014-12-22T16:52:11 # ::file bio_bmtr_0001_16.txt # ::snt These results, along with the crystal structure, support a model in which mono-ubiquitination at a Lys residue directly involved in GDP binding either enhances nucleotide exchange on K-Ras, impairs GTP hydrolysis, or both. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (s3 / support-01 :ARG0 (a / and :op1 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :op2 (s4 / structure :poss (c / crystal))) :ARG1 (m / model :topic (o / or :op1 (e2 / enhance-01 :ARG0 (u / ubiquitinate-01 :quant "1" :ARG1 (r2 / residue :mod (a2 / amino-acid :name (n4 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG1-of (i / involve-01 :ARG2 (b / bind-01 :ARG2 (s / small-molecule :name (n / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :ARG1-of (d / direct-02)))) :ARG1 (e3 / exchange-01 :ARG1 (n5 / nucleotide) :ARG4 (e / enzyme :name (n2 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :op2 (i2 / impair-01 :ARG0 u :ARG1 (h / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :op3 (a3 / and :op1 e2 :op2 i2)))) # ::id bio.bmtr_0001.17 # ::date 2014-12-22T15:12:07 # ::file bio_bmtr_0001_17.txt # ::snt To corroborate this finding, we measure the activity of Ras by the GST-RBD pull-down assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (m / measure-01 :ARG0 (w / we) :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 (a2 / assay-01 :ARG1 (p / pull-down-08 :ARG1 (p2 / protein :name (n2 / name :op1 "GST-RBD") :xref (x / xref :value "UNIPROT:GSTCD_HUMAN" :prob "0.252")))) :purpose (c / corroborate-01 :ARG0 "m" :ARG1 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)))) # ::id bio.bmtr_0001.18 # ::date 2014-12-22T15:16:55 # ::file bio_bmtr_0001_18.txt # ::snt To ensure that ubiquitinated Ras was being detected, the protein pulled down by GST-RBD was subjected to a second affinity purification on a cobalt column to purify the Flag-His-tagged K-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (s / subject-01 :ARG1 (p / protein :ARG1-of (p2 / pull-down-08 :ARG3 (p3 / protein :name (n3 / name :op1 "GST-RBD") :xref (x2 / xref :value "UNIPROT:GSTCD_HUMAN" :prob "0.252")))) :ARG2 (p4 / purify-01 :ARG1 p :ord (o / ordinal-entity :value "2") :mod (a / affinity) :location (c / column :consist-of (c2 / cobalt)) :purpose (p5 / purify-01 :ARG0 p4 :ARG1 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :ARG1-of (t / tag-01 :ARG2 (a2 / and :op1 (p6 / protein-segment :name (n4 / name :op1 "Flag")) :op2 (p7 / protein-segment :part (a3 / amino-acid :name (n5 / name :op1 "histidine") :xref (x3 / xref :value "PUBCHEM:6274" :prob "11.959939"))))) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :purpose (e3 / ensure-01 :ARG0 "s" :ARG1 (d / detect-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) # ::id bio.bmtr_0001.19 # ::date 2014-12-22T15:30:38 # ::file bio_bmtr_0001_19.txt # ::snt As predicted, only a very small fraction of wild-type K-Ras was pulled down by the GST-RBD (Fig. 2C and fig. S1D), consistent with very little wild-type K-Ras being in the GTP state under these conditions (Fig.2, A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / pull-down-08 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :mod (w / wild-type) :quant (f / fraction :mod (s2 / small :degree (v / very)) :mod (o / only)) :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG3 (p2 / protein :name (n3 / name :op1 "GST-RBD") :xref (x1 / xref :value "UNIPROT:GSTCD_HUMAN" :prob "0.252")) :ARG1-of (p3 / predict-01) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "2C") :op2 (f3 / figure :mod "S1D"))) :ARG1-of (c / consistent-01 :ARG2 (b / bind-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "K-Ras") :quant (l / little :degree (v2 / very)) :mod w :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645")) :condition (t / this) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f4 / figure :mod "2A") :op2 (f5 / figure :mod "2B")))))) # ::id bio.bmtr_0001.20 # ::date 2014-12-22T15:36:10 # ::file bio_bmtr_0001_20.txt # ::snt However, a much greater fraction of the ubiquitinated-K-Ras was pulled down by the GST-RBD (Fig. 2C and fig. S1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (c / contrast-01 :ARG2 (p / pull-down-08 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01) :quant (f / fraction :mod (g / great :degree (m / more) :quant (m2 / much))) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG3 (p2 / protein :name (n2 / name :op1 "GST-RBD") :xref (x / xref :value "UNIPROT:GSTCD_HUMAN" :prob "0.252")) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "2C") :op2 (f3 / figure :mod "S1D"))))) # ::id bio.bmtr_0001.21 # ::date 2014-12-22T14:32:40 # ::file bio_bmtr_0001_21.txt # ::snt These results are consistent with a greater fraction of ubiquitinated K-Ras being in the GTP state (Fig. 2, A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 22, 2014 (c / consistent-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01) :degree (f3 / fraction :mod (g / great :degree (m / more))) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B")))) # ::id bio.bmtr_0002.1 # ::date 2014-12-10T12:17:16 # ::file bio_bmtr_0002_1.txt # ::snt Turke et al. “MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors” (PMC3515079) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Turke")) :op2 (p3 / person :mod (o / other))) :ARG1 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2 (a2 / activate-01 :ARG1 (p4 / pathway :name (n3 / name :op1 "PI3K/AKT"))) :manner (r / relieve-01 :ARG0 i :ARG1 (f / feedback :ARG0-of (n4 / negative-03 :ARG1 (r2 / receptor :name (n5 / name :op1 "ERBB")))))) :ARG8 "PMC3515079") # ::id bio.bmtr_0002.2 # ::date 2014-12-14T20:21:31 # ::file bio_bmtr_0002_2.txt # ::snt We hypothesized that the MEK/ERK pathway may suppress trans-phosphorylation of ERBB3 by directly phosphorylating the JM domains of EGFR and HER2, and that this could be a dominant MEK inhibitor-induced feedback leading to AKT activation in these cancers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p / possible-01 :ARG1 (s / suppress-01 :ARG0 (p2 / pathway :name (n / name :op1 "MEK/ERK")) :ARG1 (p3 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERBB3") :xref (x3 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004"))) :manner (p4 / phosphorylate-01 :ARG0 p2 :ARG1 (a2 / and :op1 (p5 / protein-segment :name (n3 / name :op1 "JM" :op2 "domain") :part-of (e2 / enzyme :name (n4 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op2 (p6 / protein-segment :name (n5 / name :op1 "JM" :op2 "domain") :part-of (e3 / enzyme :name (n6 / name :op1 "HER2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :ARG1-of (d / direct-02)))) :op2 (p7 / possible-01 :ARG1 (f / feedback :ARG2-of (i / induce-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p8 / protein-family :name (n7 / name :op1 "MEK"))))) :ARG0-of (d2 / dominate-01) :ARG0-of (l / lead-03 :ARG2 (a3 / activate-01 :ARG1 (e5 / enzyme :name (n8 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :location (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer") :mod (t / this)))) :domain s)))) # ::id bio.bmtr_0002.3 # ::date 2014-12-14T20:37:51 # ::file bio_bmtr_0002_3.txt # ::snt We used tandem mass spectrometry to measure the effects of AZD6244 on phosphorylation of this JM domain threonine residue in both EGFR-mutant and HER2- amplified cancer models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (s / spectrometry :mod (m / mass) :mod (t / tandem)) :ARG2 (m2 / measure-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG1 (p / phosphorylate-01 :ARG1 (r / residue :mod (a2 / amino-acid :name (n2 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (p2 / protein-segment :name (n3 / name :op1 "JM" :op2 "domain")) :mod (t2 / this))) :condition (a4 / and :op1 (m3 / model :topic (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :mod (m4 / mutate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) :op2 (m5 / model :topic (d2 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer") :mod (a3 / amplify-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))))))) # ::id bio.bmtr_0002.4 # ::date 2014-12-14T20:53:57 # ::file bio_bmtr_0002_4.txt # ::snt Targeting both the phosphorylated and non-phosphorylated peptide forms, we detected a 66% average decrease in EGFR T669 phosphorylation and a 75% decrease in HER2 T677 phosphorylation upon treatment with AZD6244 (Figure 5B, Supplemental Figure 8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 15, 2014 (d / detect-01 :ARG0 (w / we) :ARG1 (a / and :op1 (d2 / decrease-01 :ARG1 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "669" :name (n / name :op1 "threonine") :part-of (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252"))) :ARG2 (p2 / percentage-entity :value "66" :ARG2-of (a2 / average-01))) :op2 (d3 / decrease-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "677" :name (n3 / name :op1 "threonine") :part-of (e2 / enzyme :name (n4 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))) :ARG2 (p4 / percentage-entity :value "75"))) :ARG2 (t2 / target-01 :ARG0 w :ARG1 (a6 / and :op1 (p5 / protein-segment :ARG3-of (p7 / phosphorylate-01)) :op2 (p6 / protein-segment :ARG3-of (p8 / phosphorylate-01 :polarity "-")))) :condition (t / treat-04 :ARG2 (s / small-molecule :name (n5 / name :op1 "AZD6244") :xref (x4 / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "5B") :op2 (f2 / figure :mod "8" :ARG2-of (s2 / supplement-01))))) # ::id bio.bmtr_0002.5 # ::date 2014-12-14T21:08:29 # ::file bio_bmtr_0002_5.txt # ::snt Phospho-specific antibodies confirmed that treatment with AZD6244 inhibited phosphorylation of T669 of EGFR and the analogous T677 of HER2 (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (c / confirm-01 :ARG0 (a / antibody :ARG1-of (s / specific-02 :ARG2 (p / phosphorylate-01))) :ARG1 (i / inhibit-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :ARG1 (a3 / and :op1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "669" :name (n2 / name :op1 "threonine") :part-of (e / enzyme :name (n3 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))) :op2 (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "677" :name (n4 / name :op1 "threonine") :mod (a5 / analogous :topic a2) :part-of (e2 / enzyme :name (n5 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id bio.bmtr_0002.6 # ::date 2014-12-14T21:17:43 # ::file bio_bmtr_0002_6.txt # ::snt Together these data indicate that loss of this inhibitory threonine phosphorylation on the JM domains of EGFR and HER2 occurs in cancer cell lines following MEK inhibition, presumably due to differential subcellular localization and/or binding proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / indicate-01 :ARG0 (d / data :mod (t / this) :mod (t2 / together)) :ARG1 (l / lose-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "threonine") :part-of (p2 / protein-segment :name (n2 / name :op1 "JM" :op2 "domain") :part-of (o / or :op1 (e / enzyme :name (n3 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n4 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG0-of (i2 / inhibit-01) :mod (t3 / this)) :location (c / cell-line :mod (d4 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :ARG1-of (f / follow-01 :ARG2 (i3 / inhibit-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG1-of (c3 / cause-01 :ARG0 (a2 / and-or :op1 (l2 / location :location (c4 / cell) :ARG1-of (d2 / differ-02)) :op2 (p4 / protein :ARG1-of (b / bind-01) :ARG1-of (d3 / differ-02))) :ARG1-of (p3 / presume-01)))) # ::id bio.bmtr_0002.7 # ::date 2014-12-15T14:06:48 # ::file bio_bmtr_0002_7.txt # ::snt Mutation of T669 and T677 abrogates MEK inhibitor-induced suppression of ERBB3 Activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / abrogate-01 :ARG0 (m / mutate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "669" :name (n / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a4 / amino-acid :mod "677" :name (n2 / name :op1 "threonine") :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")))) :ARG1 (s / suppress-01 :ARG1 (a5 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERBB3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004"))) :ARG2-of (i / induce-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"))))))) # ::id bio.bmtr_0002.8 # ::date 2014-12-15T14:16:53 # ::file bio_bmtr_0002_8.txt # ::snt We hypothesized that MEK inhibition activates AKT by inhibiting ERK activity, which blocks an inhibitory threonine phosphorylation on the JM domains of EGFR and HER2, thereby increasing ERBB3 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x5 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT") :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :manner (i2 / inhibit-01 :ARG0 i :ARG1 (a2 / activity-06 :ARG0 (e3 / enzyme :name (n3 / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG0-of (b / block-01 :ARG1 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "threonine") :part-of (p2 / protein-segment :name (n5 / name :op1 "JM" :op2 "domain") :part-of (o / or :op1 (e4 / enzyme :name (n6 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e5 / enzyme :name (n7 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :xref (x6 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG0-of (i3 / inhibit-01)) :ARG0-of (i4 / increase-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e6 / enzyme :name (n8 / name :op1 "ERBB3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004")))))))) # ::id bio.bmtr_0002.9 # ::date 2014-12-15T14:52:21 # ::file bio_bmtr_0002_9.txt # ::snt To test this hypothesis, we transiently transfected CHO-KI cells, which do not express ERBB receptors endogenously, with wild-type ERBB3 with either wild-type EGFR or EGFR T669A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (t / transfect-01 :ARG0 (w / we) :ARG1 (c / cell :source (c2 / cell-line :name (n / name :op1 "CHO-KI")) :ARG3-of (e3 / express-03 :polarity "-" :ARG2 (r / receptor :name (n4 / name :op1 "ERBB")) :mod (e4 / endogenous))) :ARG2 (a / and :op1 (e5 / enzyme :name (n5 / name :op1 "ERBB3") :mod (w3 / wild-type) :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004")) :op2 (o / or :op1 (e / enzyme :name (n2 / name :op1 "EGFR") :mod (w2 / wild-type) :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n3 / name :op1 "EGFR") :ARG2-of (m / mutate-01 :value "T669A") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG1-of (t2 / transient-02) :purpose (t3 / test-01 :ARG0 w :ARG1 (t5 / thing :ARG1-of (h / hypothesize-01) :mod (t4 / this)))) # ::id bio.bmtr_0002.10 # ::date 2014-12-15T15:05:31 # ::file bio_bmtr_0002_10.txt # ::snt In cells transfected with wild-type EGFR, MEK inhibition led to feedback activation of phospho-ERBB3 and phosho-EGFR, recapitulating the results we had observed in our panel of cancer cell lines (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2 (a / activate-01 :ARG1 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "ERBB3") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n4 / name :op1 "EGFR") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :subevent-of (f / feedback)) :location (c / cell :ARG1-of (t / transfect-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "EGFR") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG0-of (r / recapitulate-01 :ARG1 (t2 / thing :ARG2-of (r2 / result-01) :ARG1-of (o / observe-01 :ARG0 (w2 / we) :location (p3 / panel :consist-of (c2 / cell-line :mod (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :poss w2)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6A"))) # ::id bio.bmtr_0002.11 # ::date 2014-12-17T01:40:22 # ::file bio_bmtr_0002_11.txt # ::snt In contrast, the EGFR T669A mutant increased both basal EGFR and ERBB3 tyrosine phosphorylation that was not augmented by MEK inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 17, 2014 (c / contrast-01 :ARG2 (i / increase-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "EGFR") :ARG2-of (m / mutate-01 :value "T669A") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n5 / name :op1 "tyrosine") :part-of (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :mod (b / basal)) :op2 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine") :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :part-of (e2 / enzyme :name (n2 / name :op1 "ERBB3") :xref (x3 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004")) :mod b) :ARG1-of (a4 / augment-01 :ARG0 (i2 / inhibit-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :polarity "-")))) # ::id bio.bmtr_0002.12 # ::date 2014-12-15T15:37:12 # ::file bio_bmtr_0002_12.txt # ::snt As a control, we treated CHO-KI cells expressing EGFR T669A with HRG ligand to induce maximal ERBB3 phosphorylation (Figure 6A), indicating that the lack of induction of phospho-ERBB3 in EGFR T669A expressing cells following MEK inhibition was not simply due to the saturation of the system with phospho-ERBB3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (t / treat-04 :ARG0 (w / we) :ARG1 (c / cell :source (c2 / cell-line :name (n / name :op1 "CHO-KI")) :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "EGFR") :ARG2-of (m / mutate-01 :value "T669A") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG2 (l / ligand :name (n3 / name :op1 "HRG")) :purpose (i / induce-01 :ARG0 w :ARG2 (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "ERBB3") :xref (x4 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004")) :degree (m2 / maximum)) :ARG0-of (i2 / indicate-01 :ARG1 (c3 / cause-01 :polarity "-" :ARG0 (l2 / lack-01 :ARG1 (i3 / induce-01 :ARG2 (p3 / phosphorylate-01 :ARG1 e3) :location (c4 / cell :ARG3-of (e5 / express-03 :ARG2 (e6 / enzyme :name (n6 / name :op1 "EGFR") :ARG2-of (m3 / mutate-01 :value "T669A") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG2-of (f2 / follow-01 :ARG1 (i4 / inhibit-01 :ARG1 (e7 / enzyme :name (n7 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))))) :ARG1 (s / saturate-01 :ARG1 (s2 / system) :ARG2 (e4 / enzyme :name (n5 / name :op1 "ERBB3") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004"))) :mod (s3 / simple)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A")) :ARG2-of (c5 / control-01)) # ::id bio.bmtr_0002.13 # ::date 2014-12-15T18:12:14 # ::file bio_bmtr_0002_13.txt # ::snt We observed analogous results in CHO-KI cells expressing wild-type ERBB3 in combination with wild-type or T677A mutant HER2 (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 17, 2014 (o / observe-01 :ARG0 (w / we) :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (c / cell :source (c2 / cell-line :name (n / name :op1 "CHO-KI")) :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "ERBB3") :mod (w2 / wild-type) :accompanier (o2 / or :op1 (e3 / enzyme :name (n3 / name :op1 "HER2") :mod (w3 / wild-type) :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n4 / name :op1 "HER2") :ARG2-of (m / mutate-01 :value "T677A") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004"))))) :mod (a / analogous)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id bio.bmtr_0002.14 # ::date 2014-12-15T18:52:18 # ::file bio_bmtr_0002_14.txt # ::snt Together these results support the hypothesis that inhibition of ERK-mediated phosphorylation of a conserved JM domain threonine residue leads to feedback activation of EGFR, HER2, and ERBB3 (Figure 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 19, 2014 (s / support-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / together) :mod (t3 / this)) :ARG1 (h / hypothesize-01 :ARG1 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (r2 / residue :mod (a3 / amino-acid :name (n5 / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (p2 / protein-segment :name (n6 / name :op1 "JM" :op2 "domain") :ARG1-of (c / conserve-01))) :ARG1-of (m / mediate-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :ARG2 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n2 / name :op1 "HER2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n3 / name :op1 "ERBB3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004"))) :subevent-of (f / feedback)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "7"))) # ::id bio.bmtr_0002.15 # ::date 2015-01-21T16:11:03 # ::file bio_bmtr_0002_15.txt # ::snt To determine if this feedback model explains the activation of PI3K signaling in EGFR-mutant cancers, we used shRNA to knockdown endogenous EGFR (which carries an exon 19 deletion) in the HCC827 NSCLC cell line and replaced with either EGFR (exon 19del) wild-type at T669, or EGFR (exon 19del) carrying a T669A mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (u / use-01 :ARG0 (w / we) :ARG1 (n10 / nucleic-acid :name (n / name :op1 "shRNA")) :ARG2 (k / knock-down-02 :ARG0 w :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR") :mod (e2 / endogenous) :location (c2 / cell-line :name (n3 / name :op1 "HCC827") :mod (d4 / disease :name (n11 / name :op1 "NSCLC"))) :ARG2-of (d / delete-01 :ARG1 (e3 / exon :mod "19")) :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :op2 (r / replace-01 :ARG0 w :ARG1 e :ARG2 (o / or :op1 (e4 / enzyme :name (n4 / name :op1 "EGFR") :mod (w2 / wild-type) :ARG0-of (c / carry-01) :part (a2 / amino-acid :mod "669" :name (n5 / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e5 / enzyme :name (n6 / name :op1 "EGFR") :ARG2-of d :part (m2 / mutate-01 :value "T669A") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :purpose (d2 / determine-01 :ARG0 w :ARG1 (e6 / explain-01 :mode "interrogative" :ARG0 (m3 / model :mod (f / feedback) :mod (t / this)) :ARG1 (a4 / activate-01 :ARG1 (p / pathway :name (n7 / name :op1 "PI3K") :ARG0-of (s / signal-07)) :condition (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer") :mod (m4 / mutate-01 :ARG1 (e7 / enzyme :name (n8 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))))))) # ::id bio.bmtr_0002.16 # ::date 2015-01-21T16:49:26 # ::file bio_bmtr_0002_16.txt # ::snt Of note, this is the same EGFR-mutant cell line in which we observed that EGFR T669 is phosphorylated in MEK-dependent manner (Figure 5, Supplemental Figure 8A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 9, 2015 (n / note-02 :ARG1 (s / same-01 :ARG1 (t / this) :ARG2 (c / cell-line :consist-of (e3 / enzyme :name (n2 / name :op1 "EGFR") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :location-of (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "669" :name (n3 / name :op1 "threonine") :part-of (e / enzyme :name (n4 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1-of (o / observe-01 :ARG0 (w / we)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "5") :op2 (f2 / figure :mod "8A" :ARG2-of (s2 / supplement-01)))))) # ::id bio.bmtr_0002.17 # ::date 2015-01-21T17:03:45 # ::file bio_bmtr_0002_17.txt # ::snt When endogenous EGFR was replaced with EGFR (exon19del) wild-type at T669, MEK inhibition led to significant feedback activation of ERBB3/PI3K/AKT signaling (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 24, 2015 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2 (a / activate-01 :ARG1 (p / pathway :name (n2 / name :op1 "ERBB3/PI3K/AKT") :ARG0-of (s / signal-07)) :subevent-of (f / feedback) :ARG1-of (s2 / significant-02)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6C")) :time (r / replace-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "EGFR") :mod (e4 / endogenous) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG2 (e3 / enzyme :name (n4 / name :op1 "EGFR") :mod (w / wild-type) :ARG2-of (d2 / delete-01 :ARG1 (e5 / exon :mod "19")) :part (a2 / amino-acid :mod "669" :name (n5 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) # ::id bio.bmtr_0002.18 # ::date 2015-01-21T17:32:05 # ::file bio_bmtr_0002_18.txt # ::snt However, replacement with the EGFR (exon19 del) T669A mutant led to increased tyrosine phosphorylation of both EGFR and ERBB3, and activation of PI3K/AKT signaling, mimicking the effect of MEK inhibition (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 5, 2015 (l / lead-03 :ARG0 (r / replace-01 :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :ARG2-of (m / mutate-01 :value "T669A") :ARG2-of (d / delete-01 :ARG1 (e2 / exon :mod "19")) :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG2 (a6 / and :op1 (i / increase-01 :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (e3 / enzyme :name (n3 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (e4 / enzyme :name (n7 / name :op1 "ERBB3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :op2 (a4 / activate-01 :ARG1 (p2 / pathway :name (n5 / name :op1 "PI3K/AKT") :ARG0-of (s / signal-07))) :ARG1-of (m2 / mimic-01 :ARG0 (a5 / affect-01 :ARG0 (i2 / inhibit-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))))) :ARG1-of (h / have-concession-91) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id bio.bmtr_0002.19 # ::date 2015-01-21T17:56:39 # ::file bio_bmtr_0002_19.txt # ::snt As expected, addition of AZD6244 failed to further augment ERBB3 and AKT phosphorylation in cells expressing the 669A mutant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a4 / augment-01 :polarity "-" :ARG0 (a / add-02 :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :ARG1 (p / phosphorylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "ERBB3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n3 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :location (c / cell :ARG3-of (e2 / express-03 :ARG2 (a2 / amino-acid :mod "669" :ARG2-of (m / mutate-01))))) :degree (f2 / further) :ARG1-of (e3 / expect-01)) # ::id bio.bmtr_0002.20 # ::date 2015-01-21T18:15:45 # ::file bio_bmtr_0002_20.txt # ::snt These results demonstrate that EGFR T669 phosphorylation is necessary for MEK/ERK to suppress EGFR-mediated activation of ERBB3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 5, 2015 (d / demonstrate-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG1 (n / need-01 :ARG0 (s / suppress-01 :ARG0 (p2 / pathway :name (n4 / name :op1 "MEK/ERK")) :ARG1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "ERBB3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.004")) :ARG1-of (m / mediate-01 :ARG0 (e3 / enzyme :name (n6 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "669" :name (n2 / name :op1 "threonine") :part-of (e / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))))) # ::id bio.bmtr_0002.21 # ::date 2015-01-21T18:24:17 # ::file bio_bmtr_0002_21.txt # ::snt This supports the hypothesis that a dominant ERK feedback on ERBB3/PI3K/AKT is mediated though phosphorylation of T669 on EGFR (or T677 HER2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 5, 2015 (s / support-01 :ARG0 (t / this) :ARG1 (h / hypothesize-01 :ARG1 (m / mediate-01 :ARG0 (o2 / or :op1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod "669" :name (n3 / name :op1 "threonine") :part-of (e2 / enzyme :name (n4 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))) :op2 (p3 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "677" :name (n5 / name :op1 "threonine") :part-of (e3 / enzyme :name (n6 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")))) :ARG1 (f / feedback :ARG0-of (d / dominate-01) :destination (p / pathway :name (n / name :op1 "ERBB3/PI3K/AKT")) :mod (e / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))) # ::id bio.bmtr_0003.1 # ::date 2015-01-21T23:22:38 # ::file bio_bmtr_0003_1.txt # ::snt Montero-Conde et al. “Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF mutant thyroid carcinomas.” (PMC3651738) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Montero-Conde")) :op2 (p3 / person :mod (o / other))) :ARG1 (a3 / attenuate-01 :ARG0 (r / relieve-01 :ARG1 (i / inhibit-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (a2 / and :op1 (p4 / protein-family :name (n3 / name :op1 "RAF")) :op2 (p5 / protein-family :name (n4 / name :op1 "MEK"))))) :ARG1 (t / transcribe-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :subevent-of (f / feedback))) :ARG1 (a4 / affect-01 :ARG0 m :ARG2 (c / counter-01 :ARG1 (t2 / tumor)) :location (m3 / medical-condition :name (n8 / name :op1 "carcinoma") :mod (t3 / thyroid) :mod (e4 / enzyme :name (n5 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG8 "PMC3651738") # ::id bio.bmtr_0003.2 # ::date 2015-01-23T13:38:34 # ::file bio_bmtr_0003_2.txt # ::snt We next examined the mechanisms accounting for the increase in HER3 by MAPK pathway inhibitors in BRAF mutant thyroid cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 9, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (m / mechanism :ARG0-of (a / account-01 :ARG1 (i / increase-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "MAPK")))) :ARG1 (e2 / enzyme :name (n / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :location (c / cell-line :source (t / thyroid) :ARG1-of (e3 / encode-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :part (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))))) :time (n4 / next)) # ::id bio.bmtr_0003.3 # ::date 2015-01-23T14:45:30 # ::file bio_bmtr_0003_3.txt # ::snt Upregulation of HER3 has been found to mediate resistance to PI3K/AKT (26) or HER2 (27) inhibitors in HER2-amplified breast cancer cell lines, which is caused in part through a FoxO3A-dependent induction of HER3 gene transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (f / find-01 :ARG1 (m / mediate-01 :ARG0 (u / upregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG1 (r / resist-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (o / or :op1 (p / pathway :name (n2 / name :op1 "PI3K/AKT") :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "26")))) :op2 (e2 / enzyme :name (n3 / name :op1 "HER2") :ARG1-of (d2 / describe-01 :ARG1-of (c2 / cite-01 :ARG2 "27")) :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))) :location (c3 / cell-line :mod (a / amplify-01 :ARG0 e2) :source (d4 / disease :wiki "Breast_cancer" :name (n5 / name :op1 "breast" :op2 "cancer")))) :ARG1-of (c5 / cause-01 :ARG0 (i2 / induce-01 :ARG2 (t / transcribe-01 :ARG1 (g / gene :ARG0-of (e3 / encode-01 :ARG1 e))) :ARG0-of (d3 / depend-01 :ARG1 (p3 / protein :name (n4 / name :op1 "FoxO3A") :xref (x1 / xref :value "UNIPROT:FOXO3_HUMAN" :prob "0.652")))) :degree (p4 / part)))) # ::id bio.bmtr_0003.4 # ::date 2015-01-23T15:09:03 # ::file bio_bmtr_0003_4.txt # ::snt As shown in Fig. 5A, PLX4032 treatment increased HER3 and HER2 mRNAs in all six BRAF-mutant thyroid cancer cell lines tested. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (i / increase-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "PLX4032") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "18.013371"))) :ARG1 (n8 / nucleic-acid :name (n9 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))) :location (c / cell-line :quant "6" :source (t2 / thyroid :ARG1-of (e4 / encode-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :part (g / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :mod (a2 / all) :ARG1-of (t3 / test-01) :mod (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "5A"))) # ::id bio.bmtr_0003.5 # ::date 2015-01-25T14:19:38 # ::file bio_bmtr_0003_5.txt # ::snt Similar results were found following treatment with the MEK inhibitor AZD6244 (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :ARG1-of (f2 / follow-01 :ARG2 (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "AZD6244") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"))) :ARG1-of (s2 / show-01 :polarity "-") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056"))))) # ::id bio.bmtr_0003.6 # ::date 2015-01-25T14:28:31 # ::file bio_bmtr_0003_6.txt # ::snt The effects of the MEK inhibitor on total HER2, HER3 protein and on pHER3 were dose dependent, and inversely associated with the degree of inhibition of pERK (Fig. 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (d / depend-01 :ARG0 (a2 / affect-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))) :ARG1 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "HER2") :mod (t / total) :xref (x3 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "HER3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :op3 (e4 / enzyme :name (n4 / name :op1 "HER3") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")))) :ARG1 (d2 / dose-01)) :op2 (a4 / associate-01 :ARG1 a2 :ARG2 (t2 / thing :degree-of (i2 / inhibit-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK") :ARG1-of p :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :mod (i3 / inverse)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id bio.bmtr_0003.7 # ::date 2015-01-25T14:48:37 # ::file bio_bmtr_0003_7.txt # ::snt RAF or MEK inhibitors induced luciferase activity of a HER3 promoter construct spanning ~ 1 kb upstream of the transcriptional start site in 8505C cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / induce-01 :ARG0 (o / or :op1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "RAF")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"))))) :ARG2 (a / activity-06 :ARG0 (c / construct-01 :ARG0-of (p / promote-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG1-of (s / span-01 :location (r / relative-position :op1 (s2 / site :location-of (s3 / start-01 :ARG1 (t / transcribe-01))) :direction (u / upstream)) :quant (a2 / approximately :op1 (d / distance-quantity :quant "1" :unit (k / kilo-base-pair))) :location (c2 / cell-line :name (n5 / name :op1 "8505C")))) :ARG1 (l / luciferase))) # ::id bio.bmtr_0003.8 # ::date 2015-01-25T15:10:43 # ::file bio_bmtr_0003_8.txt # ::snt Serial deletions identified a minimal HER3 promoter retaining transcriptional response to vemurafenib and AZD6244, which was located between -401 and -42 bp (Fig. 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 4, 2015 (i / identify-01 :ARG0 (d / delete-01 :manner (s / serial)) :ARG1 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG1-of (m2 / minimal-02) :ARG0-of (r / retain-01 :ARG1 (t / thing :ARG2-of (r2 / respond-01 :ARG1 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib") :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s3 / small-molecule :name (n3 / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")))) :mod (t2 / transcribe-01))) :location (b / between :op1 (d2 / distance-quantity :quant "-401" :unit (b2 / base-pair)) :op2 (d3 / distance-quantity :quant "-42" :unit (b3 / base-pair)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id bio.bmtr_0003.9 # ::date 2015-01-25T15:28:42 # ::file bio_bmtr_0003_9.txt # ::snt This region does not contain any predicted FoxO binding sites. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 4, 2015 (c / contain-01 :polarity "-" :ARG0 (r / region :mod (t / this)) :ARG1 (p3 / protein-segment :part-of (p / protein :name (n / name :op1 "FoxO") :xref (x / xref :value "UNIPROT:FOXO1_HUMAN" :prob "0.232")) :ARG1-of (b / bind-01) :ARG1-of (p2 / predict-01) :mod (a / any))) # ::id bio.bmtr_0003.10 # ::date 2015-01-25T15:36:32 # ::file bio_bmtr_0003_10.txt # ::snt Moreover, PLX4032 led to an increase in phosphorylation of FoxO1/3A between 4–10h after addition of compound (not shown), which is known to promote its dissociation from DNA, and likely discards involvement of these factors as transcriptional regulators of HER3 in response to MAPK pathway inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / and :op2 (l / lead-03 :ARG0 (s / small-molecule :name (n / name :op1 "PLX4032") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "18.013371")) :ARG1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "FoxO1/3A"))) :time (a2 / after :op1 (a3 / add-02 :ARG1 (c / compound)) :quant (b / between :op1 (t / temporal-quantity :quant "4" :unit (h / hour)) :op2 (t2 / temporal-quantity :quant "10" :unit (h2 / hour)))) :ARG1-of (s2 / show-01 :polarity "-") :ARG0-of (p3 / promote-01 :ARG1 (d / dissociate-01 :ARG1 p2 :ARG2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))) :ARG1-of (k / know-01)) :ARG0-of (d3 / discard-01 :ARG1 (i2 / involve-01 :ARG1 (f / factor :mod (t3 / this)) :mod (m / molecular-physical-entity :ARG0-of (r / regulate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG0-of (t4 / transcribe-01))) :ARG1-of (l2 / likely-01) :ARG2-of (r2 / respond-01 :ARG1 (i3 / inhibit-01 :ARG1 (p4 / pathway :name (n4 / name :op1 "MAPK")))))))) # ::id bio.bmtr_0003.11 # ::date 2015-01-25T15:59:16 # ::file bio_bmtr_0003_11.txt # ::snt The minimal HER3 promoter region regulated by MAPK inhibitors overlaps with sequences previously described to be immunoprecipitated using antibodies against the ZFN217 transcription factor and CtBP1/CtBP2 corepressors (28–30). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (o / overlap-01 :ARG0 (r / region :mod (m2 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x3 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :ARG1-of (m / minimal-02)) :ARG1-of (r2 / regulate-01 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK")))))) :ARG1 (s / sequence :ARG1-of (i2 / immunoprecipitate-01 :ARG2-of (u / use-01 :ARG1 (a / antibody :ARG0-of (o2 / oppose-01 :ARG1 (a2 / and :op1 (f / factor :ARG0-of (t / transcribe-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ZFN217") :xref (x2 / xref :value "UNIPROT:ZFN2A_HUMAN" :prob "0.262")))) :op2 (m4 / molecular-physical-entity :ARG0-of (r3 / repress-01 :ARG1 (o3 / or :op1 (p5 / protein :name (n4 / name :op1 "CtBP1") :xref (x / xref :value "UNIPROT:CTBP1_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n5 / name :op1 "CtBP2") :xref (x1 / xref :value "UNIPROT:CTBP2_HUMAN" :prob "1.003"))))))))) :ARG1-of (d / describe-01 :time (p4 / previous)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 "28" :op2 "30"))))) # ::id bio.bmtr_0003.12 # ::date 2015-01-25T16:16:54 # ::file bio_bmtr_0003_12.txt # ::snt CtBPs have also been described to negatively regulate transcriptional activity of the HER3 promoter in breast carcinoma cell lines (30). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (d / describe-01 :ARG1 (p / protein :name (n / name :op1 "CtBP") :xref (x1 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652")) :ARG2 (d3 / downregulate-01 :ARG0 p :ARG1 (a2 / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")))) :ARG1 (t / transcribe-01)) :location (c / cell-line :mod (m2 / medical-condition :name (n4 / name :op1 "carcinoma") :mod (b / breast)))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "30")))) # ::id bio.bmtr_0003.13 # ::date 2015-01-25T16:25:03 # ::file bio_bmtr_0003_13.txt # ::snt Silencing of CtBP1, and to a lesser extent CtBP2, increased basal HER3 in 8505C cells, and markedly potentiated the effects of PLX4032 (Fig. 5D and 5E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i / increase-01 :ARG0 (s / silence-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "CtBP1") :xref (x2 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "CtBP2") :degree (l / less :degree (m / more)) :xref (x / xref :value "UNIPROT:CTBP2_HUMAN" :prob "1.003")))) :ARG1 (e / enzyme :name (n3 / name :op1 "HER3") :mod (b / basal) :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :location (c / cell-line :name (n4 / name :op1 "8505C"))) :op2 (p3 / potentiate-01 :ARG1 (a3 / affect-01 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PLX4032") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "18.013371"))) :ARG2 s :ARG3 (m2 / marked)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "5D") :op2 (f2 / figure :mod "5E")))) # ::id bio.bmtr_0003.14 # ::date 2015-01-25T16:32:44 # ::file bio_bmtr_0003_14.txt # ::snt Knockdown of these factors modestly increased basal and PLX4032-induced HER2 levels, which likely contributes to the remarkable increase in pHER3 we observed (Fig. 5D and 5E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (i / increase-01 :ARG0 (k / knock-down-02 :ARG1 (f / factor :mod (t / this))) :ARG1 (a / and :op1 (l2 / level :mod (e / enzyme :name (n / name :op1 "HER2") :mod (b / basal) :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :op2 (l3 / level :mod (e2 / enzyme :name (n2 / name :op1 "HER2") :ARG2-of (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "PLX4032") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "18.013371"))) :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :degree (m / modest) :ARG0-of (c / contribute-01 :ARG1 (i3 / increase-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "HER3") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :ARG1-of (r / remarkable-02) :ARG1-of (o / observe-01 :ARG0 (w / we))) :ARG1-of (l / likely-01)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "5D") :op2 (f3 / figure :mod "5E")))) # ::id bio.bmtr_0003.15 # ::date 2015-01-25T16:39:57 # ::file bio_bmtr_0003_15.txt # ::snt Finally, CtBP1 and CtBP2 chromatin immunoprecipitation assays showed decreased binding to the HER3 promoter after treatment with PLX4032 (Fig. 5F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (s / show-01 :li "-1" :ARG0 (a / assay-01 :ARG1 (i / immunoprecipitate-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "CtBP1") :xref (x2 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "CtBP2") :xref (x / xref :value "UNIPROT:CTBP2_HUMAN" :prob "1.003"))) :mod (c / chromatin :xref (x3 / xref :value "GO:0000785" :prob "0.8")))) :ARG1 (b / bind-01 :ARG2 (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (e / enzyme :name (n3 / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")))) :ARG1-of (d / decrease-01 :time (a3 / after :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "PLX4032") :xref (x4 / xref :value "PUBCHEM:42611257" :prob "18.013371")))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5F"))) # ::id bio.bmtr_0003.16 # ::date 2015-01-25T16:48:03 # ::file bio_bmtr_0003_16.txt # ::snt These findings were confirmed in a second cell line (Supplementary Fig. S5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 25, 2015 (c / confirm-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :location (c2 / cell-line :ord (o / ordinal-entity :value "2")) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "S5A" :ARG2-of (s / supplement-01)))) # ::id bio.bmtr_0003.17 # ::date 2015-01-25T16:51:39 # ::file bio_bmtr_0003_17.txt # ::snt The increase in expression of HER3 after MAPK inhibition is due to activation of gene transcription, which was associated with a reduction of binding of the transcriptional repressors CTBP1 and CTBP2 to the HER3 gene promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 4, 2015 (c / cause-01 :ARG0 (a2 / activate-01 :ARG1 (t / transcribe-01 :ARG1 (g / gene)) :ARG1-of (a3 / associate-01 :ARG2 (r / reduce-01 :ARG1 (b / bind-01 :ARG1 (a4 / and :op1 (p3 / protein :name (n3 / name :op1 "CTBP1") :ARG0-of (r2 / repress-01) :xref (x2 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "CTBP2") :ARG0-of r2 :xref (x / xref :value "UNIPROT:CTBP2_HUMAN" :prob "1.003")) :ARG0-of (t2 / transcribe-01)) :ARG2 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (g2 / gene :ARG0-of (e3 / encode-01 :ARG1 "e2")))))))) :ARG1 (i / increase-01 :ARG1 (e / express-03 :ARG1 (e2 / enzyme :name (n / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :time (a / after :op1 (i2 / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "MAPK")))))) # ::id bio.bmtr_0003.18 # ::date 2015-01-25T17:00:21 # ::file bio_bmtr_0003_18.txt # ::snt These corepressors have been previously linked to inhibition of HER3 transcription through promoter regions that show overlapping occupancy with ZNF217, a transcription factor also involved in HER3 regulation (30). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 19, 2015 (l / link-01 :ARG1 (c / corepressor :mod (t / this)) :ARG2 (i / inhibit-01 :ARG1 (t2 / transcribe-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")))) :ARG3 (r / region :ARG0-of (p2 / promote-01) :ARG0-of (s / show-01 :ARG1 (o / occupy-01 :ARG0 (p3 / protein :name (n2 / name :op1 "ZNF217") :mod (f / factor :ARG0-of (t3 / transcribe-01) :ARG1-of (i2 / involve-01 :ARG2 (r2 / regulate-01 :ARG1 e) :mod (a2 / also))) :xref (x / xref :value "UNIPROT:ZN217_HUMAN" :prob "1.002")) :ARG1 r :ARG0-of (o2 / overlap-01)))) :time (p / previous) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "30")))) # ::id bio.bmtr_0003.19 # ::date 2015-01-25T17:07:41 # ::file bio_bmtr_0003_19.txt # ::snt Accordingly, knockdown of CTBPs acutely induced HER3 expression and phosphorylation in thyroid cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / induce-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n / name :op1 "CTBP") :xref (x / xref :value "UNIPROT:CTBP1_HUMAN" :prob "1.002"))) :ARG2 (a2 / and :op1 (e / express-03 :ARG1 (e2 / enzyme :name (n2 / name :op1 "HER3") :xref (x1 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003"))) :op2 (p2 / phosphorylate-01 :ARG1 e2) :location (c / cell :source (t / thyroid) :mod (d / disease :wiki "Thyroid_cancer" :name (n3 / name :op1 "thyroid" :op2 "cancer")))) :manner (a / acute) :manner (a3 / accordingly)) # ::id bio.bmtr_0003.20 # ::date 2015-01-25T17:14:26 # ::file bio_bmtr_0003_20.txt # ::snt MAPK inhibition may dictate a chromatin redistribution of these repressors, and thus activate HER3 transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (d / dictate-01 :ARG0 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG1 (r / redistribute-01 :ARG1 (m / molecular-physical-entity :mod (t / this) :ARG0-of (r2 / repress-01)) :mod (c / chromatin :xref (x2 / xref :value "GO:0000785" :prob "0.8")))) :ARG0-of (c2 / cause-01 :ARG1 (a2 / activate-01 :ARG0 i :ARG1 (t2 / transcribe-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HER3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")))))) # ::id bio.bmtr_0003.21 # ::date 2015-01-25T17:19:05 # ::file bio_bmtr_0003_21.txt # ::snt The biochemical mechanisms involved in delocalization of CtBPs by MAPK inhibition have not been explored, but posttranslational modifications are known to regulate the repressive activity of CtBPs either by translocation to the cytoplasm or by targeting them for degradation (36, 37). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (e / explore-01 :polarity "-" :ARG1 (m / mechanism :mod (b / biochemical) :ARG1-of (i / involve-01 :ARG2 (d / delocalize-01 :ARG0 (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG1 (p2 / protein :name (n2 / name :op1 "CtBP") :xref (x1 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652")))))) :ARG2 (k / know-01 :ARG1 (r / regulate-01 :ARG0 (m2 / modify-01 :time (a3 / after :op1 (t3 / translate-02))) :ARG1 (a / activity-06 :ARG0 p2 :ARG1 (r2 / repress-01)) :manner (o / or :op1 (t / translocate-01 :ARG1 p2 :ARG2 (c2 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8"))) :op2 (t2 / target-01 :ARG1 p2 :purpose (d2 / degrade-01 :ARG1 p2))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 "36" :op2 "37"))))) # ::id bio.bmtr_0004.1 # ::date 2015-01-06T01:27:24 # ::file bio_bmtr_0004_1.txt # ::snt Site-Specific Monoubiquitination Activates Ras by Impeding GTPase Activating Protein (PMC3537887) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (p / publication-91 :ARG1 (a / activate-01 :ARG0 (u / ubiquitinate-01 :quant "1" :ARG1-of (s / specific-02 :ARG2 (p3 / protein-segment))) :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (i / impede-01 :ARG0 u :ARG1 (p2 / protein :name (n2 / name :op1 "GTPase" :op2 "Activating" :op3 "Protein") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.693")))) :ARG8 "PMC3537887") # ::id bio.bmtr_0004.2 # ::date 2015-01-06T08:06:39 # ::file bio_bmtr_0004_2.txt # ::snt Passage 1-1 (Results) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / passage :mod "1-1" :part-of (t / thing :ARG2-of (r / result-01))) # ::id bio.bmtr_0004.3 # ::date 2015-01-06T08:58:49 # ::file bio_bmtr_0004_3.txt # ::snt We next considered the effect of Ras monoubiquitination on GAP-mediated hydrolysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 7, 2015 (c / consider-02 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (u / ubiquitinate-01 :quant "1" :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (h / hydrolyze-01 :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003"))))) :time (n3 / next)) # ::id bio.bmtr_0004.4 # ::date 2015-01-06T09:08:59 # ::file bio_bmtr_0004_4.txt # ::snt To this end we compared the rate of GTP hydrolysis for Ras and mUbRas in the presence of the catalytic domains of two GAPs, NF1 (NF1-333) and p120GAP(GAP-334). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / compare-01 :ARG0 (w / we) :ARG1 (r / rate :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x6 / xref :value "PUBCHEM:6830" :prob "15.470645")) :condition (p / present-02 :ARG1 (a / and :op1 (d2 / domain :name (n10 / name :op1 "NF1-333") :part-of (p4 / protein :name (n12 / name :op1 "NF1") :ARG1-of (i / include-91 :ARG2 (p6 / protein :name (n13 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003"))) :xref (x4 / xref :value "UNIPROT:NF1_HUMAN" :prob "1.004"))) :op2 (d3 / domain :name (n11 / name :op1 "GAP-334") :part-of (p7 / protein :name (n14 / name :op1 "p120GAP") :ARG1-of (i2 / include-91 :ARG2 p6) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003"))) :ARG0-of (c2 / catalyze-01))))) :ARG2 (r2 / rate :degree-of (h2 / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n9 / name :op1 "GTP") :ARG1-of (b2 / bind-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant "1") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x5 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :condition p) :purpose (t / this)) # ::id bio.bmtr_0004.5 # ::date 2015-01-06T10:21:04 # ::file bio_bmtr_0004_5.txt # ::snt At a GAP-to-Ras ratio of 1:500, we observed an order of magnitude increase in the rate of GTP hydrolysis for unmodified Ras relative to the intrinsic rate of GTP hydrolysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 7, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG1 (r / rate :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (m2 / modify-01 :polarity "-") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :ARG4 (p2 / product-of :op1 (a / about :op1 "10") :op2 (r3 / rate :mod (i2 / intrinsic) :degree-of (h2 / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645"))))) :condition (e3 / equal-01 :ARG1 (r4 / ratio-of :op1 (p / protein :name (n3 / name :op1 "GAP") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 "1/500"))) # ::id bio.bmtr_0004.6 # ::date 2015-01-06T10:36:40 # ::file bio_bmtr_0004_6.txt # ::snt No increase in the rate of GTP hydrolysis was observed for mUbRas in the presence of the same GAP-to Ras ratio (Fig. 5b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (o / observe-01 :ARG1 (i / increase-01 :polarity "-" :ARG1 (r / rate :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n4 / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant "1") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :condition (p / present-02 :ARG1 (r2 / ratio-of :op1 (p2 / protein :name (n2 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (s2 / same-01)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5b"))) # ::id bio.bmtr_0004.7 # ::date 2015-01-06T10:42:11 # ::file bio_bmtr_0004_7.txt # ::snt Therefore, mUbRas is insensitive to GAP-mediated regulation, similar to an oncogenic Ras-G12V mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (c / cause-01 :ARG1 (s / sensitive-03 :polarity "-" :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant "1") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (r / regulate-01 :ARG1 e :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))) :ARG1-of (r2 / resemble-01 :ARG2 (m2 / mutate-01 :value "G12V" :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))))) # ::id bio.bmtr_0004.8 # ::date 2015-01-06T11:02:39 # ::file bio_bmtr_0004_8.txt # ::snt We obtained similar results using K-Ras (Supplementary Figure 6), indicating that the effects of monoubiquitination on Ras are not isoform-specific. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (o / obtain-01 :ARG0 (w / we) :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6" :ARG2-of (s / supplement-01))) :ARG0-of (i / indicate-01 :ARG1 (s2 / specific-02 :polarity "-" :ARG1 (a / affect-01 :ARG0 (u2 / ubiquitinate-01 :quant "1") :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 (i2 / isoform)))) :manner (u / use-01 :ARG0 w :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) # ::id bio.bmtr_0004.9 # ::date 2015-01-06T11:13:11 # ::file bio_bmtr_0004_9.txt # ::snt To verify that the differences between the enzymatic and chemical ubiquitination linkers (seven bonds and five bonds, respectively) do not alter GAP-responsiveness, we placed an additional cysteine at the c-terminus of Ubiquitin (Ubiquitin-C77), thereby creating a linker one bond longer than the native linker. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (p / place-01 :ARG0 (w / we) :ARG1 (a / amino-acid :name (n / name :op1 "cysteine") :mod (a2 / additional) :xref (x3 / xref :value "PUBCHEM:594" :prob "11.272514")) :ARG2 (p2 / protein-segment :name (n2 / name :op1 "C-terminus") :part-of (p3 / protein :name (n3 / name :op1 "ubiquitin") :xref (x / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702"))) :manner-of (b4 / become-01 :ARG1 a :ARG2 (a5 / amino-acid :mod "77" :name (n4 / name :op1 "cysteine") :part-of p3 :xref (x2 / xref :value "PUBCHEM:594" :prob "11.272514"))) :ARG0-of (c / create-01 :ARG1 (p6 / protein-segment :ARG1-of (l / long-03 :ARG2 (b / bond :quant "1") :degree (m2 / more) :compared-to (p7 / protein-segment :mod (n7 / native) :ARG0-of (l3 / link-01))) :ARG0-of (l2 / link-01))) :purpose (v / verify-01 :ARG0 w :ARG1 (a4 / alter-01 :polarity "-" :ARG0 (d / differ-02 :ARG1 (p8 / protein-segment :consist-of (b2 / bond :quant "7") :ARG0-of (l4 / link-01) :location-of (u2 / ubiquitinate-01 :mod (e / enzyme))) :ARG2 (p9 / protein-segment :location-of (u / ubiquitinate-01 :mod (c2 / chemical)) :consist-of (b3 / bond :quant "5") :ARG0-of (l5 / link-01))) :ARG1 (r / respond-01 :ARG0 (p5 / protein :name (n5 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))))) # ::id bio.bmtr_0004.10 # ::date 2015-01-06T11:14:24 # ::file bio_bmtr_0004_10.txt # ::snt We measured the rate of GAP-mediated GTP hydrolysis and observed that the response of Ras ligated to Ubiquitin-C77 was identical to Ras ligated to Ubiquitin-G76C (Fig. 5b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (a / and :op1 (m / measure-01 :ARG0 (w / we) :ARG1 (r / rate :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x7 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG1-of (m2 / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))))) :op2 (o / observe-01 :ARG0 w :ARG1 (i / identical-01 :ARG1 (t / thing :ARG2-of (r2 / respond-01 :ARG0 (e / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (l / ligate-01 :ARG3 (a2 / amino-acid :mod "77" :name (n7 / name :op1 "cysteine") :part-of (p4 / protein :name (n8 / name :op1 "ubiquitin") :xref (x3 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :xref (x6 / xref :value "PUBCHEM:594" :prob "11.272514"))) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (t2 / thing :ARG2-of (r3 / respond-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (l2 / ligate-01 :ARG3 (a3 / amino-acid :mod "76" :name (n3 / name :op1 "cysteine") :part-of (p2 / protein :name (n9 / name :op1 "ubiquitin") :ARG3-of (m3 / mutate-01 :value "G76C") :xref (x1 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :xref (x5 / xref :value "PUBCHEM:594" :prob "11.272514"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5b"))))) # ::id bio.bmtr_0004.11 # ::date 2015-01-06T12:31:02 # ::file bio_bmtr_0004_11.txt # ::snt These results indicate that variations in the linker length on this scale (1-2 bonds) do not influence the sensitivity of mUbRas to GAP downregulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (i2 / influence-01 :polarity "-" :ARG0 (v2 / vary-01 :ARG1 (p2 / protein-segment :ARG0-of (l2 / link-01)) :ARG2 (o / or :op1 (b / bond :quant "1") :op2 (b2 / bond :quant "2")) :ARG5 (l / length)) :ARG1 (s / sensitive-03 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant "1") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (d / downregulate-01 :ARG1 e :ARG2 (p / protein :name (n2 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))))) # ::id bio.bmtr_0004.12 # ::date 2015-01-06T12:43:54 # ::file bio_bmtr_0004_12.txt # ::snt To validate the use of an in vitro system to dissect the mechanism of Ras regulation, we measured the sensitivity of mUbRas to GAP-mediated hydrolysis in a cellular reconstitution system. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / measure-01 :ARG0 (w / we) :ARG1 (s / sensitive-03 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant "1") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (h / hydrolyze-01 :ARG1-of (m2 / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))) :location (s2 / system :ARG0-of (r / reconstitute-01 :ARG1 (c / cell)))) :purpose (v / validate-01 :ARG0 w :ARG1 (u2 / use-01 :ARG0 w :ARG1 (s3 / system :mod (i / in-vitro)) :ARG2 (d / dissect-01 :ARG0 w :ARG1 (m3 / mechanism :instrument-of (r2 / regulate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))))) # ::id bio.bmtr_0004.13 # ::date 2015-01-06T12:53:31 # ::file bio_bmtr_0004_13.txt # ::snt We immunoprecipitated Ras from HEK293T cells and compared the sensitivity of the monoubiquitinated and unmodified fractions of Ras to regulation by GAP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (a / and :op1 (i / immunoprecipitate-01 :ARG0 (w / we) :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (c / cell-line :name (n2 / name :op1 "HEK293T"))) :op2 (c2 / compare-01 :ARG0 w :ARG1 (s / sensitive-03 :ARG0 (f / fraction :part-of e :ARG1-of (u / ubiquitinate-01 :quant "1")) :ARG1 (r / regulate-01 :ARG0 (p / protein :name (n3 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :ARG1 f)) :ARG2 (s2 / sensitive-03 :ARG0 (f2 / fraction :part-of e :ARG1-of (m / modify-01 :polarity "-")) :ARG1 (r2 / regulate-01 :ARG0 p :ARG1 f2)))) # ::id bio.bmtr_0004.14 # ::date 2015-01-06T13:00:57 # ::file bio_bmtr_0004_14.txt # ::snt As seen in Figure 5c, monoubiquitinated K-Ras is less sensitive than the unmodified protein to GAP-mediated GTP hydrolysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (s / sensitive-03 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras") :ARG1-of (u / ubiquitinate-01 :quant "1") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1 (h / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG1-of (m2 / mediate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))) :degree (l / less) :compared-to (e2 / enzyme :name (n4 / name :op1 "K-Ras") :ARG1-of (m / modify-01 :polarity "-") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1-of (s3 / see-01 :medium (f / figure :mod "5c"))) # ::id bio.bmtr_0004.15 # ::date 2015-01-06T13:05:57 # ::file bio_bmtr_0004_15.txt # ::snt These data support our in vitro findings that monoubiquitination increases the population of active, GTP-bound Ras through a defect in sensitivity to GAP-mediated regulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (s / support-01 :ARG0 (d / data :mod (t / this)) :ARG1 (f / find-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG0 (u / ubiquitinate-01 :quant "1") :ARG1 (p / population :consist-of (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (a / activity-06) :ARG2-of (b / bind-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :manner (d2 / defect :topic (s3 / sensitive-03 :ARG1 (r / regulate-01 :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003"))))))) :manner (i2 / in-vitro))) # ::id bio.bmtr_0004.16 # ::date 2015-01-06T13:16:30 # ::file bio_bmtr_0004_16.txt # ::snt Passage 1-2 (Discussion/Conclusion) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / passage :mod "1-2" :part-of (s / slash :op1 (t / thing :ARG1-of (d / discuss-01)) :op2 (t2 / thing :ARG1-of (c / conclude-01)))) # ::id bio.bmtr_0004.17 # ::date 2015-01-06T13:19:56 # ::file bio_bmtr_0004_17.txt # ::snt It was established recently that monoubiquitination increases the proportion of Ras that is in the activated (GTP-bound) state, that monoubiquitination enhances association with the downstream effectors Raf and PI3-Kinase, and that mutation of the primary site of monoubiquitination impairs oncogenic Ras-mediated tumorigenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (e / establish-01 :ARG1 (a / and :op1 (i / increase-01 :ARG0 (u / ubiquitinate-01 :quant "1") :ARG1 (p / proportion :quant-of (e2 / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (a2 / activate-01) :ARG1-of (b / bind-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645"))))) :op2 (e3 / enhance-01 :ARG0 u :ARG1 (a3 / associate-01 :ARG2 (a4 / and :op1 (e4 / effector :mod (d / downstream) :mod (e7 / enzyme :name (n3 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :op2 (e5 / effector :mod (e8 / enzyme :name (n4 / name :op1 "PI3-Kinase") :xref (x / xref :value "UNIPROT:PK3C3_HUMAN" :prob "0.303")))))) :op3 (i2 / impair-01 :ARG0 (m2 / mutate-01 :ARG1 (p3 / protein-segment :mod (p2 / primary) :part-of u)) :ARG1 (c3 / create-01 :ARG1 (t / tumor) :ARG1-of (m3 / mediate-01 :ARG0 (e6 / enzyme :name (n5 / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :time (r / recent)) # ::id bio.bmtr_0004.18 # ::date 2015-01-06T13:33:35 # ::file bio_bmtr_0004_18.txt # ::snt Here we show that monoubiquitination decreases the sensitivity of Ras to GAP-mediated hydrolysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 6, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (d / decrease-01 :ARG0 (u / ubiquitinate-01 :quant "1") :ARG1 (s2 / sensitive-03 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (h / hydrolyze-01 :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))))) :location (h2 / here)) # ::id bio.bmtr_0004.19 # ::date 2015-01-06T13:36:10 # ::file bio_bmtr_0004_19.txt # ::snt A major advance was our ability to easily generate mUbRas, modified at a single site, in a form suitable for detailed biophysical studies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / advance-01 :ARG1 (c / capable-01 :ARG1 (w / we) :ARG2 (g / generate-01 :ARG0 w :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant "1") :ARG1-of (m2 / modify-01 :location (p / protein-segment :ARG1-of (s2 / single-02))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG4 (f / form :ARG1-of (s / suitable-04 :ARG2 (s4 / study-01 :ARG1 (b / biophysical) :ARG1-of (d / detail-01))))) :ARG1-of (e2 / easy-05)) :ARG2 (m / major-02)) # ::id bio.bmtr_0004.20 # ::date 2015-01-06T13:41:51 # ::file bio_bmtr_0004_20.txt # ::snt This chemical ligation strategy will likely be useful for the study of other monoubiquitinated proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (l / likely-01 :ARG1 (u / useful-05 :ARG1 (s / strategy :mod (l2 / ligate-01 :mod (c / chemical)) :mod (t / this)) :ARG2 (s2 / study-01 :ARG1 (p / protein :ARG1-of (u2 / ubiquitinate-01 :quant "1") :mod (o / other))))) # ::id bio.bmtr_0004.21 # ::date 2015-01-06T02:02:31 # ::file bio_bmtr_0004_21.txt # ::snt Surprisingly, monoubiquitination did not alter the intrinsic activity of Ras, despite the size of the modification. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (s / surprise-01 :ARG0 (a / alter-01 :polarity "-" :ARG0 (u / ubiquitinate-01 :quant "1") :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :mod (i / intrinsic))) :concession (t / thing :ARG2-of (s2 / size-01 :ARG1 (m / modify-01)))) # ::id bio.bmtr_0004.22 # ::date 2015-01-06T02:13:25 # ::file bio_bmtr_0004_22.txt # ::snt Our modeling and NMR analyses indicated that Ubiquitin dynamically samples a broad surface area of Ras that alters switch region dynamics. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (i / indicate-01 :ARG0 (a / and :op1 (m / model-01 :ARG0 (w / we)) :op2 (a2 / analyze-01 :ARG0 w :manner (r2 / resonate-01 :ARG1 (n / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :mod (m2 / magnet)))) :ARG1 (s / sample-01 :ARG0 (p / protein :name (n2 / name :op1 "ubiquitin") :xref (x1 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :ARG1 (a3 / area :mod (s2 / surface :ARG1-of (b / broad-02)) :part-of (e / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :manner (d / dynamic) :ARG0-of (a4 / alter-01 :ARG1 (d2 / dynamic :location (r / region :mod (s3 / switch-01)))))) # ::id bio.bmtr_0004.23 # ::date 2015-01-06T02:48:52 # ::file bio_bmtr_0004_23.txt # ::snt These results led us to examine the effect of monoubiquitination on the interaction of Ras with its cognate GEF and GAPs, which also target the switch domains. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (l / lead-03 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (w / we) :ARG2 (e / examine-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (u / ubiquitinate-01 :quant "1") :ARG1 (i / interact-01 :ARG0 (e2 / enzyme :name (n / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n3 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :mod (c / cognate :prep-with e2) :ARG0-of (t3 / target-01 :ARG1 (d / domain :mod (s / switch-01)) :mod (a3 / also))))))) # ::id bio.bmtr_0004.24 # ::date 2015-01-06T03:38:45 # ::file bio_bmtr_0004_24.txt # ::snt The analysis revealed that monoubiquitination abrogates GAP-mediated GTP hydrolysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 6, 2015 (r / reveal-01 :ARG0 (a / analyze-01) :ARG1 (a2 / abrogate-01 :ARG0 (u / ubiquitinate-01 :quant "1") :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))))) # ::id bio.bmtr_0004.25 # ::date 2015-01-06T03:44:41 # ::file bio_bmtr_0004_25.txt # ::snt All other activities, including the ability to bind regulators, were largely preserved and our kinetic modeling suggests that the GAP defect will dominate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (a3 / and :op1 (p / preserve-01 :ARG1 (a / act-02 :mod (a2 / all) :mod (o / other) :ARG2-of (i / include-01 :ARG1 (p2 / possible-01 :ARG1 (b / bind-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (r / regulate-01)))))) :mod (l / large)) :op2 (s / suggest-01 :ARG0 (m / model-01 :ARG0 (w / we) :mod (k / kinetic)) :ARG1 (d / dominate-01 :ARG1 (d2 / defect :mod (p3 / protein :name (n / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))))) # ::id bio.bmtr_0004.26 # ::date 2015-01-06T06:25:29 # ::file bio_bmtr_0004_26.txt # ::snt Furthermore, this outcome was specific to monoubiquitination at position 147. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / and :op2 (s / specific-02 :ARG1 (o / outcome :mod (t / this)) :ARG2 (u / ubiquitinate-01 :quant "1" :ARG1 (a2 / amino-acid :mod "147")))) # ::id bio.bmtr_0004.27 # ::date 2015-01-06T07:18:02 # ::file bio_bmtr_0004_27.txt # ::snt Thus our work establishes an entirely new mode of Ras activation in which signaling is sustained even in the absence of hormone stimulus or oncogene mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (e / establish-01 :ARG0 (w / work-01 :ARG0 (w2 / we)) :ARG1 (m / mode :ARG1-of (n / new-01 :degree (e2 / entire)) :mod (a / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG0-of (s / sustain-01 :ARG1 (s2 / signal-07) :concession (a2 / absent-01 :ARG1 (o / or :op1 (s3 / stimulus :mod (h / hormone)) :op2 (m2 / mutate-01 :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))))))) # ::id bio.bmtr_0005.1 # ::date 2015-01-06T07:32:43 # ::file bio_bmtr_0005_1.txt # ::snt Phosphorylation of ASPP2 by RAS/MAPK Pathway Is Critical for Its Full Pro-Apoptotic Function (PMC3847091) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (p5 / publication-91 :ARG1 (c / critical-02 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :ARG2 (p3 / pathway :name (n2 / name :op1 "RAS/MAPK"))) :ARG2 (f / function-01 :ARG0 p2 :ARG1 (a / apoptosis :ARG1-of (f3 / favor-01)) :mod (f2 / full))) :ARG8 "PMC3847091") # ::id bio.bmtr_0005.2 # ::date 2015-01-06T07:47:04 # ::file bio_bmtr_0005_2.txt # ::snt Passage 1-1 (Results) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / passage :mod "1-1" :part-of (t / thing :ARG2-of (r / result-01))) # ::id bio.bmtr_0005.3 # ::date 2015-01-06T07:52:16 # ::file bio_bmtr_0005_3.txt # ::snt It has recently been shown that oncogenic RAS can enhance the apoptotic function of p53 via ASPP1 and ASPP2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (s / show-01 :ARG1 (p / possible-01 :ARG1 (e / enhance-01 :ARG0 (e2 / enzyme :name (n / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (f / function-01 :ARG0 (p2 / protein :name (n2 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1 (a / apoptosis)) :instrument (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "ASPP1") :xref (x2 / xref :value "UNIPROT:ASPP1_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))))) :time (r / recent)) # ::id bio.bmtr_0005.4 # ::date 2015-01-06T08:05:46 # ::file bio_bmtr_0005_4.txt # ::snt Mechanistically ASPP1 and ASPP2 bind RAS-GTP and potentiates RAS signalling to enhance p53 mediated apoptosis [2]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (b / bind-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "ASPP1") :xref (x3 / xref :value "UNIPROT:ASPP1_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))) :ARG2 (m3 / macro-molecular-complex :part (e / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part (s / small-molecule :name (n4 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :manner (m / mechanistic) :ARG2-of (p3 / potentiate-01 :ARG1 (s2 / signal-07 :ARG0 e) :purpose (e2 / enhance-01 :ARG0 "b" :ARG1 (a / apoptosis :ARG1-of (m2 / mediate-01 :ARG0 (p4 / protein :name (n5 / name :op1 "p53") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "2")))) # ::id bio.bmtr_0005.5 # ::date 2015-01-07T00:52:41 # ::file bio_bmtr_0005_5.txt # ::snt As RAS is upstream of several signalling cascades [13], we queried whether the activity of ASPP2 is regulated by the activation of a RAS-mediated signalling pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (q / query-01 :ARG0 (w / we) :ARG2 (r / regulate-01 :ARG0 (a / activate-01 :ARG0 (p / pathway :ARG0-of (s / signal-07 :ARG1-of (m / mediate-01 :ARG0 "e")))) :ARG1 (a2 / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")))) :ARG1-of (c / cause-01 :ARG0 (b / be-located-at-91 :ARG1 (e / enzyme :name (n / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :ARG2 (r2 / relative-position :op1 (c2 / cascade :subevent (s2 / signal-07) :quant (s3 / several)) :direction (u / upstream)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG0-of (c3 / cite-01 :ARG2 "13")))))) # ::id bio.bmtr_0005.6 # ::date 2015-01-07T01:51:47 # ::file bio_bmtr_0005_6.txt # ::snt One of the most studied downstream pathways of RAS signalling is the Raf-MAPK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 7, 2015 (i / include-91 :ARG1 (p / pathway :name (n / name :op1 "Raf-MAPK")) :ARG2 (p2 / pathway :ARG1-of (s / study-01 :degree (m / most)) :mod (d / downstream) :location-of (s2 / signal-07 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) # ::id bio.bmtr_0005.7 # ::date 2015-01-07T02:19:05 # ::file bio_bmtr_0005_7.txt # ::snt Interestingly, we observed two conserved putative MAPK phosphorylation sites in ASPP1 and ASPP2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (o / observe-01 :ARG0 (w2 / we) :ARG1 (a / and :op1 (p3 / protein-segment :quant "2" :ARG1-of (c / conserve-01) :ARG1-of (p2 / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2-of (t / think-01)) :part-of (a2 / and :op1 (p5 / protein :name (n2 / name :op1 "ASPP1") :xref (x1 / xref :value "UNIPROT:ASPP1_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n3 / name :op1 "ASPP2") :xref (x2 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))))) :ARG2-of (i / interest-01 :ARG1 w2)) # ::id bio.bmtr_0005.8 # ::date 2015-01-07T02:54:52 # ::file bio_bmtr_0005_8.txt # ::snt The ASPP1 sites are at residues 671 and 746, and the ASPP2 sites are at residues 698 and 827 (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (a4 / and :op1 (b / be-located-at-91 :ARG1 (p / protein-segment :part-of (p2 / protein :name (n / name :op1 "ASPP1") :xref (x / xref :value "UNIPROT:ASPP1_HUMAN" :prob "1.003"))) :ARG2 (a2 / and :op1 (r / residue :mod (a / amino-acid :mod "671")) :op2 (r2 / residue :mod (a3 / amino-acid :mod "746")))) :op2 (b2 / be-located-at-91 :ARG1 (p3 / protein-segment :part-of (p4 / protein :name (n2 / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))) :ARG2 (a5 / and :op1 (r3 / residue :mod (a6 / amino-acid :mod "698")) :op2 (r4 / residue :mod (a7 / amino-acid :mod "827")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id bio.bmtr_0005.9 # ::date 2015-01-07T01:10:14 # ::file bio_bmtr_0005_9.txt # ::snt We thus tested whether RAS activation may regulate ASPP2 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 7, 2015 (c / cause-01 :ARG1 (t / test-01 :ARG0 (w / we) :ARG1 (p / possible-01 :mode "interrogative" :ARG1 (r / regulate-01 :ARG0 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "RAS") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))))))) # ::id bio.bmtr_0005.10 # ::date 2015-01-07T01:19:03 # ::file bio_bmtr_0005_10.txt # ::snt An in vitro phophorylation assay was performed with a purified C-terminus fragment of ASPP2 (693-1128) containing both MAPK putative phosphorylation sites. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (a / assay-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :part-of (p3 / protein-segment :name (n / name :op1 "C-terminus") :part-of (p4 / protein :name (n2 / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))) :ARG1-of (p5 / purify-01) :mod (b / between :op1 (a2 / amino-acid :mod "693") :op2 (a3 / amino-acid :mod "1128")) :ARG0-of (c / contain-01 :ARG1 (p6 / protein-segment :ARG1-of (p7 / phosphorylate-01 :ARG2 (e / enzyme :name (n4 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1-of (t / think-01)) :mod (b2 / both)))) :manner (i / in-vitro))) # ::id bio.bmtr_0005.11 # ::date 2015-01-07T01:50:22 # ::file bio_bmtr_0005_11.txt # ::snt When compared to p38 SAPK, MAPK1 was clearly able to phosphorylate the ASPP2 fragment in vitro (Figure 1B, left and middle panels). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (p / possible-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein-segment :part-of (p4 / protein :name (n2 / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))) :ARG2 (e / enzyme :name (n / name :op1 "MAPK1") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :manner (i / in-vitro)) :ARG1-of (c / clear-06) :compared-to (p5 / possible-01 :ARG1 (p6 / phosphorylate-01 :ARG1 p3 :ARG2 (e2 / enzyme :name (n3 / name :op1 "p38" :op2 "SAPK") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203")))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (p7 / panel :ARG1-of (l / left-20)) :op2 (p8 / panel :location (m / middle)) :part-of (f / figure :mod "1B")))) # ::id bio.bmtr_0005.12 # ::date 2015-01-07T02:20:07 # ::file bio_bmtr_0005_12.txt # ::snt As shown in Figure S1, histone 2B phosphorylated by p38 SAPK had high levels of incorporated 32P, suggesting that p38 SAPK was active; while under the same conditions, ASPP2 (693-1128) fragment phosphorylated by p38 SAPK had very low levels of incorporated 32P, indicating that p38 SAPK is not an efficient kinase for ASPP2 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (s / show-01 :ARG0 (f / figure :mod "S1") :ARG1 (c / contrast-01 :ARG1 (h / have-part-91 :ARG1 (p8 / protein :name (n / name :op1 "Histone" :op2 "2B") :ARG3-of (p2 / phosphorylate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "p38" :op2 "SAPK") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203"))) :xref (x1 / xref :value "UNIPROT:A0A024QZZ7_HUMAN" :prob "0.381")) :ARG2 (p / phosphorus :mod (m / molecular-mass :value "32") :quant (l / level :ARG1-of (h2 / high-02)) :ARG1-of (i / incorporate-02 :ARG2 p8)) :ARG0-of (s2 / suggest-01 :ARG1 (a / activity-06 :ARG0 e))) :ARG2 (h4 / have-part-91 :ARG1 (p3 / protein-segment :mod (b / between :op1 (a2 / amino-acid :mod "693") :op2 (a3 / amino-acid :mod "1128")) :part (p5 / protein :name (n3 / name :op1 "ASPP2") :xref (x2 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :ARG3-of (p6 / phosphorylate-01 :ARG2 e)) :ARG2 (p4 / phosphorus :mod (m2 / molecular-mass :value "32") :quant (l2 / level :ARG1-of (l3 / low-04 :degree (v / very))) :ARG1-of (i2 / incorporate-02 :ARG2 p3)) :ARG0-of (i3 / indicate-01 :ARG1 (e2 / efficient-01 :polarity "-" :ARG1 e :ARG2 (p7 / phosphorylate-01 :ARG1 p5 :ARG2 e))) :condition (t / thing :ARG1-of (s3 / same-01 :ARG2 (t2 / thing :condition-of h)))))) # ::id bio.bmtr_0005.13 # ::date 2015-01-07T02:45:06 # ::file bio_bmtr_0005_13.txt # ::snt The phosphorylated ASPP2 fragment by MAPK1 was digested by trypsin and fractioned on a high performance liquid chromatography (HPLC). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / and :op1 (d / digest-01 :ARG0 (e / enzyme :name (n / name :op1 "trypsin") :xref (x1 / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342")) :ARG1 (p / protein-segment :part-of (p2 / protein :name (n2 / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :ARG3-of (p3 / phosphorylate-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "MAPK1") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))))) :op2 (f / fraction-01 :ARG1 p :manner (c / chromatography :mod (l / liquid :ARG0-of (p4 / perform-02 :ARG1-of (h / high-02)))))) # ::id bio.bmtr_0005.14 # ::date 2015-01-07T02:59:19 # ::file bio_bmtr_0005_14.txt # ::snt Each eluted fraction was measured for its radioactivity content (Figure 1B, right panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (m / measure-01 :ARG1 (f / fraction :ARG1-of (e / elute-01) :mod (e2 / each)) :purpose (t / thing :mod (r2 / radioactive) :ARG1-of (c / contain-01 :ARG0 f)) :ARG1-of (d / describe-01 :ARG0 (p / panel :ARG1-of (r / right-04) :part-of (f2 / figure :mod "1B")))) # ::id bio.bmtr_0005.15 # ::date 2015-01-07T03:12:21 # ::file bio_bmtr_0005_15.txt # ::snt The fractions representing these radioactive peaks were analysed by mass spectrometry. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 7, 2015 (a / analyze-01 :ARG1 (f / fraction :ARG0-of (r / represent-01 :ARG1 (p / peak :mod (r2 / radioactive) :mod (t / this)))) :manner (s / spectrometry :mod (m / mass))) # ::id bio.bmtr_0005.16 # ::date 2015-01-07T03:17:37 # ::file bio_bmtr_0005_16.txt # ::snt Of the two radioactive peaks, one represented the linker region between the GST and our ASPP2 fragment and the other corresponded to a fragment of the same mass as that containing the second putative phosphorylation site, serine 827. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (r / represent-01 :ARG0 (p / peak :ARG1-of (i / include-91 :ARG2 (p2 / peak :quant "2" :mod (r2 / radioactive)))) :ARG1 (r4 / region :ARG3-of (l / link-01 :ARG1 (e / enzyme :name (n / name :op1 "GST") :xref (x / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :ARG2 (p3 / protein-segment :part-of (p4 / protein :name (n2 / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :poss (w / we))))) :op2 (c / correspond-02 :ARG1 (p5 / peak :mod (o / other) :ARG1-of (i2 / include-91 :ARG2 p2)) :ARG2 (p6 / protein-segment :ARG0-of (h / have-03 :ARG1 (m / mass :ARG1-of (s / same-01 :ARG2 (m2 / mass :poss (p7 / protein-segment :ARG1-of (p8 / phosphorylate-01) :ord (o2 / ordinal-entity :value "2") :ARG1-of (e2 / equal-01 :ARG2 (a3 / amino-acid :mod "827" :name (n3 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (t / think-01)))))))))) # ::id bio.bmtr_0005.17 # ::date 2015-01-07T04:57:02 # ::file bio_bmtr_0005_17.txt # ::snt Hence ASPP2 can be phosphorylated at serine 827 by MAPK1 in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 7, 2015 (c / cause-01 :ARG1 (p / possible-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "serine") :mod "827" :part-of (p3 / protein :name (n2 / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e / enzyme :name (n3 / name :op1 "MAPK1") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :manner (i / in-vitro)))) # ::id bio.bmtr_0005.18 # ::date 2015-01-07T05:01:25 # ::file bio_bmtr_0005_18.txt # ::snt Passage 1-2 (Discussion/Conclusion) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / passage :mod "1-2" :part-of (s / slash :op1 (t2 / thing :ARG1-of (d / discuss-01)) :op2 (t / thing :ARG1-of (c / conclude-01)))) # ::id bio.bmtr_0005.19 # ::date 2015-01-07T05:12:17 # ::file bio_bmtr_0005_19.txt # ::snt We and others have recently shown that ASPP2 can potentiate RAS signaling by binding directly via the ASPP2 N-terminus [2,6]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (s / show-01 :ARG0 (a / and :op1 (w / we) :op2 (p / person :mod (o / other))) :ARG1 (p2 / possible-01 :ARG1 (p3 / potentiate-01 :ARG1 (s2 / signal-07 :ARG0 (e / enzyme :name (n2 / name :op1 "RAS") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263"))) :ARG2 (p4 / protein :name (n / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :manner (b / bind-01 :ARG1 e :ARG2 (p5 / protein-segment :name (n3 / name :op1 "N-terminus") :part-of p4) :ARG1-of (d / direct-02)))) :time (r / recent) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 "2" :op2 "6"))))) # ::id bio.bmtr_0005.20 # ::date 2015-01-07T05:23:11 # ::file bio_bmtr_0005_20.txt # ::snt Moreover, the RAS-ASPP interaction enhances the transcription function of p53 in cancer cells [2]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / and :op2 (e / enhance-01 :ARG0 (i / interact-01 :ARG0 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "RAS") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op2 (p / protein :name (n2 / name :op1 "ASPP") :xref (x1 / xref :value "UNIPROT:A1CF_HUMAN" :prob "0.342")))) :ARG1 (f / function-01 :ARG0 (p2 / protein :name (n3 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1 (t / transcribe-01) :location (c2 / cell :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "2"))))) # ::id bio.bmtr_0005.21 # ::date 2015-01-07T05:39:33 # ::file bio_bmtr_0005_21.txt # ::snt Until now, it has been unclear how RAS could affect ASPP2 to enhance p53 function. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (c / clear-06 :polarity "-" :ARG1 (t / thing :manner-of (p / possible-01 :ARG1 (a / affect-01 :ARG0 (e / enzyme :name (n / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :ARG1 (p2 / protein :name (n3 / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :ARG2 (e2 / enhance-01 :ARG1 (f / function-01 :ARG0 (p3 / protein :name (n4 / name :op1 "p53") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))))))) :time (u / until :op1 (n2 / now))) # ::id bio.bmtr_0005.22 # ::date 2015-01-07T05:10:22 # ::file bio_bmtr_0005_22.txt # ::snt We show here that ASPP2 is phosphorylated by the RAS/Raf/MAPK pathway and that this phosphorylation leads to its increased translocation to the cytosol/nucleus and increased binding to p53, providing an explanation of how RAS can activate p53 pro-apoptotic functions (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :ARG2 (p2 / pathway :name (n / name :op1 "RAS/Raf/MAPK")) :ARG0-of (l / lead-03 :ARG2 (a / and :op1 (i / increase-01 :ARG1 (t / translocate-01 :ARG1 p3 :ARG2 (s2 / slash :op1 (c / cytosol :xref (x3 / xref :value "GO:0005829" :prob "0.8")) :op2 (n3 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8"))))) :op2 (i2 / increase-01 :ARG1 (b / bind-01 :ARG1 p3 :ARG2 (p4 / protein :name (n4 / name :op1 "p53") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))))) :ARG0-of (e2 / explain-01 :ARG1 (p5 / possible-01 :ARG1 (a2 / activate-01 :ARG0 (e / enzyme :name (n5 / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :ARG1 (f / function-01 :ARG0 p4 :ARG1 (a3 / apoptosis :ARG1-of (f2 / favor-01)))))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "5"))) :location (h / here)) # ::id bio.bmtr_0005.23 # ::date 2015-01-07T05:40:37 # ::file bio_bmtr_0005_23.txt # ::snt Additionally, RAS/Raf/MAPK pathway activation stabilizes ASPP2 protein, although the underlying mechanism remains to be investigated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 8, 2015 (a / and :op2 (s / stabilize-01 :ARG0 (a2 / activate-01 :ARG1 (p / pathway :name (n / name :op1 "RAS/Raf/MAPK"))) :ARG1 (p2 / protein :name (n2 / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :concession (r / remain-01 :ARG1 (m / mechanism :ARG0-of (u / underlie-01 :ARG1 s)) :ARG3 (i / investigate-01 :ARG1 m)))) # ::id bio.chicago_2015.17089 # ::date 2015-10-25T12:26:35 # ::file bio_chicago_2015_17089.txt # ::snt The analogous result for PKC interaction with Par6 in the lower panel shows that, similarly to p62, Par6b binds to PKC only when the PKC OPCA motif is not mutated and the back of Par6b has the wild-type Lys 20. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (a / analogous) :topic (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "PKC") :xref (x2 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :ARG1 (p2 / protein :name (n2 / name :op1 "Par6b") :xref (x / xref :value "UNIPROT:PAR6B_HUMAN" :prob "0.603"))) :location (p3 / panel :ARG1-of (l / low-04 :degree (m / more)))) :ARG1 (b / bind-01 :ARG0 p2 :ARG1 e :condition (a2 / and :op1 (m2 / mutate-01 :polarity "-" :ARG1 (m3 / motif :mod (p4 / protein-segment :name (n3 / name :op1 "OPCA") :part-of e))) :op2 (h / have-03 :ARG0 (b2 / back :poss p2) :ARG1 (a3 / amino-acid :mod "20" :name (n7 / name :op1 "lysine") :mod (w / wild-type) :xref (x3 / xref :value "PUBCHEM:866" :prob "11.053295")))) :mod (o / only) :ARG1-of (r2 / resemble-01 :ARG2 (p6 / protein :name (n6 / name :op1 "p62") :xref (x1 / xref :value "UNIPROT:MCAF1_HUMAN" :prob "0.222"))))) # ::id bio.chicago_2015.17091 # ::date 2015-10-25T12:49:36 # ::file bio_chicago_2015_17091.txt # ::snt A model is proposed in which endosomal Sca and Gp150 promote Notch activation in response to Delta, by regulating acquisition of insensitivity to Delta in a subset of cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / propose-01 :ARG1 (m / model :topic (p2 / promote-02 :ARG0 (a / and :op1 (p3 / protein :name (n / name :op1 "Sca") :xref (x1 / xref :value "UNIPROT:SPTN2_HUMAN" :prob "0.203")) :op2 (p4 / protein :name (n2 / name :op1 "Gp150") :xref (x / xref :value "UNIPROT:AMPN_HUMAN" :prob "0.702")) :mod (e / endosomal)) :ARG1 (a2 / activate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "Notch") :xref (x2 / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.323")) :ARG2-of (r / respond-01 :ARG1 (p6 / protein :name (n4 / name :op1 "Delta") :xref (x3 / xref :value "UNIPROT:DLL3_HUMAN" :prob "0.333")))) :manner (r2 / regulate-01 :ARG1 (a3 / acquire-01 :ARG1 (s / sensitive-03 :polarity "-" :ARG0 p5 :ARG1 p6)) :location (s2 / subset :consist-of (c / cell)))))) # ::id bio.chicago_2015.17114 # ::date 2015-10-25T12:59:51 # ::file bio_chicago_2015_17114.txt # ::snt Because PLD activates PKC through the formation of diacylglycerol in VSMCs,47 PLD also may contribute to this suppression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (a / activate-01 :ARG0 (e3 / enzyme :name (n / name :op1 "PLD") :xref (x1 / xref :value "UNIPROT:PLD1_HUMAN" :prob "0.263")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "PKC") :xref (x2 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :manner (f / form-01 :ARG1 (e / enzyme :name (n3 / name :op1 "diacylglycerol") :xref (x / xref :value "UNIPROT:A0A024R495_HUMAN" :prob "0.351")) :location (c2 / cell :name (n4 / name :op1 "VSMC"))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "47")))) :ARG1 (p3 / possible-01 :ARG1 (c3 / contribute-01 :ARG0 e3 :ARG1 (s / suppress-01 :mod (t / this))) :mod (a2 / also))) # ::id bio.chicago_2015.17152 # ::date 2015-10-25T13:07:12 # ::file bio_chicago_2015_17152.txt # ::snt Whether PKC regulation of DAT and other neurotransmitter transporters is due to direct phosphorylation of the transporter remains unclear. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / remain-01 :ARG1 (c2 / cause-01 :mode "interrogative" :ARG0 (p / phosphorylate-01 :ARG1 (m / molecular-physical-entity :ARG0-of (t2 / transport-01)) :ARG1-of (d / direct-02)) :ARG1 (r2 / regulate-01 :ARG0 (e / enzyme :name (n / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "DAT") :xref (x / xref :value "UNIPROT:SC6A3_HUMAN" :prob "1.002")) :op2 (p4 / protein-family :name (n3 / name :op1 "neurotransmitter" :op2 "transporter") :mod (o / other))))) :ARG3 (c / clear-06 :polarity "-" :ARG1 c2)) # ::id bio.chicago_2015.17165 # ::date 2015-10-25T13:24:48 # ::file bio_chicago_2015_17165.txt # ::snt Venable et al. ( 66) also described an inhibition by ceramide of PLD stimulation by PKC, but ascribed this to an upstream effect on PKC rather than a decrease in the translocation to membranes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / contrast-01 :ARG1 (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Venable")) :op1 (p3 / person :mod (o / other))) :ARG1-of (c / cite-01 :ARG2 "66")) :ARG1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "ceramide") :xref (x3 / xref :value "PUBCHEM:2498" :prob "8.570734")) :ARG1 (s / stimulate-01 :ARG0 (e / enzyme :name (n4 / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :ARG1 (e2 / enzyme :name (n3 / name :op1 "PLD") :xref (x / xref :value "UNIPROT:PLD1_HUMAN" :prob "0.263")))) :mod (a4 / also)) :ARG2 (a2 / ascribe-01 :ARG0 p :ARG1 i :ARG2 (a3 / affect-01 :ARG1 e :mod (u / upstream) :ARG1-of (i2 / instead-of-91 :ARG2 (d2 / decrease-01 :ARG1 (t2 / translocate-01 :ARG2 (m / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8")))))))) # ::id bio.chicago_2015.17176 # ::date 2015-10-27T05:34:49 # ::file bio_chicago_2015_17176.txt # ::snt dSir2 Interacts Genetically with Hairy Embryos derived from mothers transheterozygous for hairy and dSir2 mated to wild-type males exhibit moderate # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 14, 2015 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "dSir2")) :ARG1 (e / embryo :mod (p3 / protein :name (n2 / name :op1 "hairy") :xref (x / xref :value "UNIPROT:HAIR_HUMAN" :prob "0.232")) :ARG1-of (d / derive-01 :ARG2 (p2 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (m / mother)) :mod (t / transheterozygous :topic (a / and :op1 p3 :op2 p)) :ARG1-of (m2 / mate-02 :ARG2 (m3 / male :mod (w / wild-type))) :ARG0-of (e2 / exhibit-01 :ARG1 (t2 / thing :ARG1-of (m4 / moderate-01)))))) :manner (g / genetic)) # ::id bio.chicago_2015.17177 # ::date 2015-10-27T05:36:13 # ::file bio_chicago_2015_17177.txt # ::snt We now report that, although PS1 mutations augment gamma-secretase cleavage at residue 42, they in fact suppress both S3-cleavage of Notch and epsilon-cleavage of APP near residue 50. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r3 / report-01 :ARG0 (w / we) :ARG1 (s / suppress-01 :ARG0 "m" :ARG1 (a / and :op1 (c / cleave-01 :ARG1 (p3 / protein-segment :name (n / name :op1 "S3") :part-of (p / protein :name (n2 / name :op1 "Notch") :xref (x3 / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.323")) :ARG1-of (n5 / near-02 :ARG2 (r / residue :mod (a2 / amino-acid :mod "50"))))) :op2 (c2 / cleave-01 :ARG1 (p4 / protein-segment :name (n4 / name :op1 "epsilon") :part-of (p2 / protein :name (n3 / name :op1 "APP") :xref (x / xref :value "UNIPROT:A4_HUMAN" :prob "1.002")) :ARG1-of n5))) :mod (i / in-fact) :concession (a3 / augment-01 :ARG0 (m / mutate-01 :ARG1 (p5 / protein :name (n6 / name :op1 "PS1") :xref (x2 / xref :value "UNIPROT:PSN1_HUMAN" :prob "1.002"))) :ARG1 (c3 / cleave-01 :ARG1 (r2 / residue :mod (a4 / amino-acid :mod "42" :part-of (e3 / enzyme :name (n7 / name :op1 "gamma-secretase") :xref (x1 / xref :value "UNIPROT:APH1A_HUMAN" :prob "0.302"))))))) :time (n8 / now)) # ::id bio.chicago_2015.17180 # ::date 2015-10-27T07:35:52 # ::file bio_chicago_2015_17180.txt # ::snt At the nucleus, PKC betaII mediates direct phosphorylation of the nuclear envelope polypeptide lamin B on sites involved in mitotic nuclear lamina disassembly ( 12, 13, 15). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 14, 2015 (m / mediate-01 :ARG0 (e / enzyme :name (n / name :op1 "PKC" :op2 "betaII") :xref (x / xref :value "UNIPROT:KPCB_HUMAN" :prob "0.313")) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "lamin" :op2 "B") :part-of (e2 / envelope :part-of "n3")) :ARG1-of (d / direct-02) :location (s / site :ARG1-of (i / involve-01 :ARG2 (a / assemble-01 :polarity "-" :ARG1 (l / lamina :mod (m2 / mitosis) :part-of "n3"))))) :location (n3 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 "12" :op2 "13" :op3 "15"))))) # ::id bio.chicago_2015.17227 # ::date 2015-10-27T08:07:18 # ::file bio_chicago_2015_17227.txt # ::snt At the nucleus, PKC betaII directly phosphorylates the nuclear envelope polypeptide lamin B at sites involved in mitotic nuclear lamina disassembly ( 8-10). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "lamin" :op2 "B") :part-of (e2 / envelope :part-of "n2")) :ARG2 (e / enzyme :name (n / name :op1 "PKC" :op2 "betaII") :xref (x / xref :value "UNIPROT:KPCB_HUMAN" :prob "0.313")) :manner (d / direct) :location (n2 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :location (s / site :ARG1-of (i / involve-01 :ARG2 (a / assemble-01 :polarity "-" :ARG1 (l / lamina :part-of n2 :mod (m / mitosis))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 "8" :op2 "10"))))) # ::id bio.chicago_2015.17275 # ::date 2015-10-27T08:19:07 # ::file bio_chicago_2015_17275.txt # ::snt To determine whether in vitro phosphorylation of fascin with PKC occurs at the same sites as observed in vivo, two-dimensional phosphopeptide mapping was performed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p2 / perform-02 :ARG1 (m / map-02 :ARG1 (s4 / small-molecule :name (n / name :op1 "phosphopeptide")) :manner (d / dimension :quant "2")) :purpose (d2 / determine-01 :ARG1 (p4 / phosphorylate-01 :mode "interrogative" :ARG1 (p5 / protein :name (n2 / name :op1 "fascin") :xref (x1 / xref :value "UNIPROT:FSCN1_HUMAN" :prob "0.702")) :ARG2 (e / enzyme :name (n3 / name :op1 "PKC") :xref (x / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :manner (i / in-vitro) :location (s / site :ARG1-of (s2 / same-01 :ARG2 (s3 / site :location-of p4 :ARG1-of (o2 / observe-01 :manner (i2 / in-vivo)))))))) # ::id bio.chicago_2015.17347 # ::date 2015-10-27T08:45:34 # ::file bio_chicago_2015_17347.txt # ::snt Dl then activates Notch (N) in the R4 precursor ( Cooper and Bray, 1999; Fanto and Mlodzik, 1999; Tomlinson and Struhl, 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 14, 2015 (a / activate-01 :ARG0 (p11 / protein :name (n9 / name :op1 "Dl") :xref (x1 / xref :value "UNIPROT:EDAR_HUMAN" :prob "0.602")) :ARG1 (p / protein :name (n / name :op1 "Notch") :xref (x / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.323")) :location (c / cell :name (n2 / name :op1 "R4" :op2 "precursor")) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p2 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n3 / name :op1 "Cooper")) :op2 (p4 / person :name (n4 / name :op1 "Bray"))) :time (d4 / date-entity :year "1999")) :op2 (p5 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :name (n6 / name :op1 "Fanto")) :op2 (p6 / person :name (n5 / name :op1 "Mlodzik"))) :time d4) :op3 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n7 / name :op1 "Tomlinson")) :op2 (p10 / person :name (n8 / name :op1 "Struhl"))) :time d4))) :time (t / then)) # ::id bio.chicago_2015.17446 # ::date 2015-10-27T09:03:36 # ::file bio_chicago_2015_17446.txt # ::snt to prevent the additional stabilization of U2AF65 binding conferred by the interaction between U2AF35 and the AG dinucleotide. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (h / have-purpose-91 :ARG2 (p / prevent-01 :ARG1 (s / stabilize-01 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "U2AF65") :xref (x / xref :value "UNIPROT:U2AF2_HUMAN" :prob "1.002")) :ARG1-of (c / confer-02 :ARG0 (i / interact-01 :ARG0 (p3 / protein :name (n2 / name :op1 "U2AF35") :xref (x1 / xref :value "UNIPROT:U2AF1_HUMAN" :prob "1.002")) :ARG1 (d / dinucleotide :name (n3 / name :op1 "AG"))))) :mod (a / additional)))) # ::id bio.chicago_2015.17480 # ::date 2015-10-27T09:19:04 # ::file bio_chicago_2015_17480.txt # ::snt Axin mutants with C-terminal truncations lacked the ability to inhibit Lef-1 reporter activity, even though they bound GSK-3beta and beta-catenin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 14, 2015 (l / lack-01 :ARG0 (p2 / protein :name (n / name :op1 "Axin") :ARG2-of (m / mutate-01) :ARG0-of (h / have-03 :ARG1 (t / truncate-01 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "C-terminus")))) :xref (x / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1 (c / capable-01 :ARG1 p2 :ARG2 (i / inhibit-01 :ARG0 p2 :ARG1 (a / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (r2 / report-01 :ARG1 (p / protein :name (n3 / name :op1 "Lef-1") :xref (x3 / xref :value "UNIPROT:LEF1_HUMAN" :prob "0.632"))))))) :concession (b / bind-01 :ARG1 p2 :ARG2 (a2 / and :op1 (e / enzyme :name (n4 / name :op1 "GSK-3beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :op2 (p4 / protein :name (n5 / name :op1 "beta-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))))) # ::id bio.chicago_2015.17550 # ::date 2015-10-27T14:46:47 # ::file bio_chicago_2015_17550.txt # ::snt In vivo binding of GSK-3beta with Axin or beta-catenin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "GSK-3beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :ARG2 (o / or :op1 (p / protein :name (n2 / name :op1 "Axin") :xref (x2 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :op2 (p2 / protein :name (n3 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))) :manner (i / in-vivo)) # ::id bio.chicago_2015.17615 # ::date 2015-10-27T14:48:22 # ::file bio_chicago_2015_17615.txt # ::snt For some of these transcription factors, the domain that interacts with Groucho is mapped to a short peptide motif. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 14, 2015 (m / map-02 :ARG1 (d / domain :ARG0-of (i / interact-01 :ARG1 (p / protein :name (n / name :op1 "Groucho") :xref (x / xref :value "UNIPROT:TLE4_HUMAN" :prob "0.212"))) :part-of "f") :ARG2 (m2 / motif :part-of (p2 / peptide :ARG1-of (s / short-07))) :beneficiary (f / factor :ARG0-of (t / transcribe-01) :quant (s2 / some) :mod (t2 / this))) # ::id bio.chicago_2015.17655 # ::date 2015-10-27T15:27:57 # ::file bio_chicago_2015_17655.txt # ::snt We may conclude that GAGA factor binds to ( CT) n repeats independently of TBP binding and facilitates binding of the latter directly or indirectly. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 14, 2015 (p / possible-01 :ARG1 (c / conclude-01 :ARG0 (w / we) :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "GAGA" :op2 "factor")) :ARG2 (p3 / protein :name (n2 / name :op1 "(CT)n" :op2 "repeat")) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (b2 / bind-01 :ARG1 (p4 / protein :name (n3 / name :op1 "TBP") :xref (x / xref :value "UNIPROT:TBP_HUMAN" :prob "1.003"))))) :op2 (f / facilitate-01 :ARG0 p2 :ARG1 (b3 / bind-01 :ARG1 p4 :ARG1-of (d2 / direct-02) :ARG1-of (d3 / direct-02 :polarity "-")))))) # ::id bio.chicago_2015.17666 # ::date 2015-10-27T15:29:09 # ::file bio_chicago_2015_17666.txt # ::snt As - catenin interacts with transcription factors of the LEF/ TCF family to regulate target gene expression, this raises the possibility that nuclear events of Wnt/ - catenin signaling are involved in regulating convergent extension. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG1 (f / factor :ARG0-of (t / transcribe-01) :part-of (p2 / protein-family :name (n2 / name :op1 "LEF" :op2 "TCF"))) :ARG2 (r / regulate-01 :ARG0 p :ARG1 (e / express-03 :ARG1 (g / gene :ARG1-of (t2 / target-01)))) :ARG0-of (r2 / raise-01 :ARG1 (p3 / possible-01 :ARG1 (i2 / involve-01 :ARG1 (e2 / event :location (n3 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (c / cause-01 :ARG0 (s / signal-07 :ARG0 (p4 / pathway :name (n4 / name :op1 "Wnt/beta-catenin"))))) :ARG2 (r3 / regulate-01 :ARG0 e2 :ARG1 (e3 / extend-01 :ARG0-of (c2 / converge-01))))))) # ::id bio.chicago_2015.17703 # ::date 2015-10-27T15:29:27 # ::file bio_chicago_2015_17703.txt # ::snt We believe that it represents an unlikely scenario as we have shown that a PS1 allele defective in beta-catenin binding, while retaining full Notch processing activity, cannot suppress the elevated beta-catenin signaling caused by PS1 deficiency (Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (b / believe-01 :ARG0 (w2 / we) :ARG1 (r / represent-01 :ARG1 (i / it) :ARG2 (s / scenario :ARG1-of (l / likely-01 :polarity "-"))) :ARG1-of (c / cause-01 :ARG0 (s2 / show-01 :ARG0 w2 :ARG1 (p / possible-01 :polarity "-" :ARG1 (s3 / suppress-01 :ARG0 (p5 / protein :name (n / name :op1 "PS1") :mod (d / defective) :ARG1-of (b2 / bind-01 :ARG2 (p2 / protein :name (n2 / name :op1 "beta-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))) :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:PSN1_HUMAN" :prob "1.002")) :ARG1 (s4 / signal-07 :ARG0 p2 :ARG1-of (e / elevate-01) :ARG1-of (c2 / cause-01 :ARG0 (l2 / lack-01 :ARG1 p5))) :concession (r2 / retain-01 :ARG0 p5 :ARG1 (a2 / activity-06 :ARG1 (p3 / process-01 :ARG0 p5 :ARG1 (p4 / protein :name (n3 / name :op1 "Notch") :xref (x / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.323"))) :mod (f / full))))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4"))) # ::id bio.chicago_2015.17707 # ::date 2015-10-27T15:29:36 # ::file bio_chicago_2015_17707.txt # ::snt CKI did not phosphorylate GSK3beta, B56alpha, or beta-TrCP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (p / phosphorylate-01 :polarity "-" :ARG1 (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "GSK3beta") :xref (x2 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.672")) :op2 (e3 / enzyme :name (n3 / name :op1 "B56alpha")) :op2 (p2 / protein :name (n4 / name :op1 "beta-TrCP") :xref (x / xref :value "UNIPROT:COPB_HUMAN" :prob "0.262"))) :ARG2 (e / enzyme :name (n / name :op1 "CKI") :xref (x1 / xref :value "UNIPROT:CHKA_HUMAN" :prob "1.002"))) # ::id bio.chicago_2015.17718 # ::date 2015-10-28T00:35:29 # ::file bio_chicago_2015_17718.txt # ::snt Because the mutations in PS1 apparently inhibit transcriptional activity of beta-catenin downstream of GSK 3beta, we hypothesized that PS1 may be interacting with the binding partner of beta-catenin, namely hTcf-4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 14, 2015 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (p4 / protein :name (n / name :op1 "PS1") :xref (x2 / xref :value "UNIPROT:PSN1_HUMAN" :prob "1.002")) :ARG1 (p2 / partner :ARG1-of (b / bind-01 :ARG2 (p3 / protein :name (n2 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))) :ARG1-of (m / mean-01 :ARG2 (p5 / protein :name (n3 / name :op1 "hTcf-4") :xref (x3 / xref :value "UNIPROT:TF7L2_HUMAN" :prob "0.652")))))) :ARG1-of (c / cause-01 :ARG0 (i2 / inhibit-01 :ARG0 (m2 / mutate-01 :ARG1 p4) :ARG1 (a3 / activity-06 :ARG0 p3 :ARG1 (t2 / transcribe-01) :location (r / relative-position :op1 (e / enzyme :name (n5 / name :op1 "GSK3" :op2 "beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :direction (d2 / downstream))) :ARG1-of (a / appear-02)))) # ::id bio.chicago_2015.17743 # ::date 2015-10-28T00:41:06 # ::file bio_chicago_2015_17743.txt # ::snt Currently, a link between MAPK activation and the phosphorylation and activation of transcription factors involved in proliferation and cell growth is established by the finding that MAPK activates p90 ribosomal S6 kinase (p90RSK; De Cesare et al., 1998 ; Frodin and Gammeltoft, 1999 ; Smith et al. 1999 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / establish-01 :ARG0 (f / find-01 :ARG1 (a / activate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1 (e3 / enzyme :name (n3 / name :op1 "p90" :op2 "ribosomal" :op3 "S6" :op4 "kinase")))) :ARG1 (l / link-01 :ARG1 (a2 / activate-01 :ARG0 e2) :ARG2 (a3 / and :op1 (p3 / phosphorylate-01 :ARG1 (f2 / factor :ARG0-of (t / transcribe-01) :ARG1-of (i / involve-01 :ARG2 (a5 / and :op1 (p4 / proliferate-01) :op2 (g / grow-01 :ARG1 (c / cell)))))) :op2 (a4 / activate-01 :ARG1 f2))) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and :op1 (p5 / publication-91 :ARG0 (a7 / and :op1 (p6 / person :name (n4 / name :op1 "De" :op2 "Cesare")) :op2 (p7 / person :mod (o / other))) :time (d4 / date-entity :year "1998")) :op2 (p8 / publication-91 :ARG0 (a8 / and :op1 (p9 / person :name (n5 / name :op1 "Frodin")) :op2 (p10 / person :name (n6 / name :op1 "Gammeltoft"))) :time (d5 / date-entity :year "1999")) :op3 (p11 / publication-91 :ARG0 (a9 / and :op1 (p12 / person :name (n7 / name :op1 "Smith")) :op2 (p13 / person :mod (o2 / other))) :time d5))) :time (c2 / current)) # ::id bio.chicago_2015.17757 # ::date 2015-10-28T01:04:42 # ::file bio_chicago_2015_17757.txt # ::snt These results suggest that CBP can bind to various transcription factors of the ATF/ CREB family through the b-ZIP domain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t3 / this)) :ARG1 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "CBP") :xref (x / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :ARG2 (f / factor :ARG0-of (t2 / transcribe-01) :part-of (p3 / protein-family :name (n2 / name :op1 "ATF" :op2 "CREB")) :mod (v / various)) :instrument (p4 / protein-segment :name (n3 / name :op1 "b-ZIP"))))) # ::id bio.chicago_2015.17801 # ::date 2015-10-28T01:30:03 # ::file bio_chicago_2015_17801.txt # ::snt GSK-3beta, glycogen synthase kinase 3beta; EC, embryonal carcinoma; RA, retinoic acid; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; CM, conditioned medium; PBS, phosphate-buffered saline; RT, reverse transcriptase; PMSF, phenylmethylsulfonyl fluoride; MAP2, microtubule-associated protein 2; GFP, green fluorescence protein; EGFP, enhanced GFP; CMV, cytomegalovirus; Dox, doxycycline; Tcf/ LEF, T cell factor/ lymphoid enhancer factor; CKI, casein kinase I; dpc, days post-coitum; rtTA, reverse tetracycline controlled transactivator; ICAT, inhibitor of beta-catenin and Tcf-4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (n19 / name :op1 "GSK-3beta" :ARG2-of (l / label-01 :ARG1 (e / enzyme :name (n / name :op1 "glycogen" :op2 "synthase" :op3 "kinase3" :op4 "beta") :xref (x8 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")))) :op2 (n20 / name :op1 "EC" :ARG2-of (l2 / label-01 :ARG1 (m / medical-condition :name (n2 / name :op1 "carcinoma") :location (e4 / embryo)))) :op3 (n21 / name :op1 "RA" :ARG2-of (l3 / label-01 :ARG1 (p / protein :name (n17 / name :op1 "retinoic" :op2 "acid") :xref (x2 / xref :value "UNIPROT:CCD26_HUMAN" :prob "0.312")))) :op4 (n22 / name :op1 "DMEM" :ARG2-of (l4 / label-01 :ARG1 (m21 / medium :poss (p3 / person :name (n3 / name :op1 "Eagle")) :ARG1-of (m22 / modify-01) :poss (p4 / person :name (n4 / name :op1 "Dulbecco"))))) :op5 (n23 / name :op1 "FBS" :ARG2-of (l5 / label-01 :ARG1 (s / serum :source (f2 / fetus :mod (b2 / bovine))))) :op6 (n24 / name :op1 "CM" :ARG2-of (l6 / label-01 :ARG1 (m23 / medium :ARG1-of (c4 / condition-01)))) :op7 (n25 / name :op1 "PBS" :ARG2-of (l7 / label-01 :ARG1 (s2 / saline :ARG1-of (b / buffer-01 :ARG0 (p5 / phosphate))))) :op8 (n26 / name :op1 "RT" :ARG2-of (l8 / label-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "reverse" :op2 "transcriptase") :xref (x3 / xref :value "UNIPROT:POK10_HUMAN" :prob "0.702")))) :op9 (n27 / name :op1 "PMSF" :ARG2-of (l9 / label-01 :ARG1 (s4 / small-molecule :name (n7 / name :op1 "phenylmethylsulfonyl" :op2 "fluoride") :xref (x10 / xref :value "PUBCHEM:4784" :prob "13.388928")))) :op10 (n28 / name :op1 "MAP2" :ARG2-of (l10 / label-01 :ARG1 (p6 / protein :name (n8 / name :op1 "microtubule-associated" :op2 "protein" :op3 "2") :xref (x5 / xref :value "UNIPROT:MTAP2_HUMAN" :prob "0.702")))) :op11 (n29 / name :op1 "GFP" :ARG2-of (l11 / label-01 :ARG1 (p7 / protein :name (n9 / name :op1 "green" :op2 "fluorescence" :op3 "protein") :xref (x6 / xref :value "UNIPROT:BLVRB_HUMAN" :prob "0.232")))) :op12 (n30 / name :op1 "EGFP" :ARG2-of (l12 / label-01 :ARG1 (p8 / protein :name (n10 / name :op1 "GFP") :ARG1-of (e7 / enhance-01) :xref (x7 / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")))) :op13 (n31 / name :op1 "CMV" :ARG2-of (l13 / label-01 :ARG1 (c / cytomegalovirus))) :op14 (n32 / name :op1 "Dox" :ARG2-of (l14 / label-01 :ARG1 (s3 / small-molecule :name (n14 / name :op1 "doxycycline") :xref (x9 / xref :value "PUBCHEM:54671203" :prob "15.91623")))) :op15 (n33 / name :op1 "TcfLEF" :ARG2-of (l15 / label-01 :ARG1 (p9 / protein-family :name (n12 / name :op1 "T" :op2 "cell" :op3 "factor/" :op4 "lymphoid" :op5 "enhancer" :op6 "factor")))) :op16 (n34 / name :op1 "CKI" :ARG2-of (l16 / label-01 :ARG1 (e6 / enzyme :name (n13 / name :op1 "casein" :op2 "kinase" :op3 "I") :xref (x4 / xref :value "UNIPROT:KC1A_HUMAN" :prob "0.292")))) :op17 (n35 / name :op1 "dpc" :ARG2-of (l17 / label-01 :ARG1 (m2 / multiple :op1 (t / temporal-quantity :quant "1" :unit (d / day)) :time (a3 / after :op1 (c5 / coitus))))) :op18 (n18 / name :op1 "rtTA" :ARG2-of (l18 / label-01 :ARG1 (p11 / protein :name (n15 / name :op1 "reverse" :op2 "tetracycline" :op3 "controlled" :op4 "transactivator")))) :op19 (n11 / name :op1 "ICAT" :ARG2-of (l19 / label-01 :ARG1 (m26 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (a2 / and :op1 (p12 / protein :name (n5 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :op2 (p13 / protein :name (n16 / name :op1 "Tcf-4") :xref (x1 / xref :value "UNIPROT:ITF2_HUMAN" :prob "0.632")))))))) # ::id bio.chicago_2015.17831 # ::date 2015-10-28T02:37:03 # ::file bio_chicago_2015_17831.txt # ::snt The ability to form H-DNA cannot substitute for GAGA factor binding to the ( CT)n sequence. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (p / possible-01 :polarity "-" :ARG1 (s / substitute-01 :ARG1 (c / capable-01 :ARG2 (f / form-01 :ARG1 (n / nucleic-acid :name (n2 / name :op1 "H-DNA")))) :ARG2 (b / bind-01 :ARG1 (p2 / protein :name (n3 / name :op1 "GAGA" :op2 "factor")) :ARG2 (p3 / protein-segment :name (n4 / name :op1 "(CT)n" :op2 "sequence"))))) # ::id bio.chicago_2015.17892 # ::date 2015-10-28T02:49:19 # ::file bio_chicago_2015_17892.txt # ::snt Identification of the pathway directing TCF-1 import will be an important step in determining whether different mechanisms of LEF-1 and TCF-1 nuclear transport promote different LEF-1, TCF-1, and beta-catenin function. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (s / step-01 :ARG1 (i2 / identify-01 :ARG1 (p / pathway :ARG0-of (d4 / direct-01 :ARG1 (i3 / import-01 :ARG1 (p2 / protein :name (n / name :op1 "TCF-1") :xref (x / xref :value "UNIPROT:HNF1A_HUMAN" :prob "1.002")))))) :ARG2 (d / determine-01 :ARG1 (p3 / promote-01 :mode "interrogative" :ARG0 (m / mechanism :ARG1-of (d2 / differ-02) :instrument-of (t / transport-01 :ARG1 (a / and :op1 (p4 / protein :name (n3 / name :op1 "LEF-1") :xref (x2 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :op2 p2) :ARG4 (n2 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")))) :ARG1 (f / function-01 :ARG0 (a2 / and :op1 p4 :op2 p2 :op3 (p5 / protein :name (n4 / name :op1 "beta-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))) :ARG1-of d2))) :mod (i / important)) # ::id bio.chicago_2015.17923 # ::date 2015-10-28T03:02:13 # ::file bio_chicago_2015_17923.txt # ::snt The role of other transcription factors that are regulated by PKA and that bind to the CRE of the fibronectin promoter, such as ATF-1 and ATF-2, may also be relevant to TGF-beta stimulation of fibronectin gene transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (r / relevant-01 :ARG1 (r2 / role :poss (f / factor :ARG0-of (t / transcribe-01) :ARG1-of (r3 / regulate-01 :ARG0 (e / enzyme :name (n / name :op1 "PKA") :xref (x4 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG1-of (b / bind-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "CRE") :part-of (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n3 / name :op1 "fibronectin") :xref (x3 / xref :value "UNIPROT:FINC_HUMAN" :prob "0.703"))) :example (a / and :op1 (p4 / protein :name (n4 / name :op1 "ATF-1") :xref (x5 / xref :value "UNIPROT:ATF1_HUMAN" :prob "0.672")) :op2 (p5 / protein :name (n5 / name :op1 "ATF-2") :xref (x / xref :value "UNIPROT:ATF2_HUMAN" :prob "0.672")))) :xref (x2 / xref :value "UNIPROT:CREG1_HUMAN" :prob "0.262"))) :mod (o / other))) :ARG2 (s / stimulate-01 :ARG0 (p6 / protein :name (n6 / name :op1 "TGF-beta") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.373")) :ARG1 (t2 / transcribe-01 :ARG1 (g / gene :ARG0-of (e2 / encode-01 :ARG1 p3)))) :mod (a2 / also))) # ::id bio.chicago_2015.18003 # ::date 2015-10-28T03:20:35 # ::file bio_chicago_2015_18003.txt # ::snt LiCl Activates a Prosurvival Pathway through GSK-3beta Inhibition and Activation of beta-Catenincf-mediated Transcription-- To determine whether LiCl had an effect on GSK-3-mediated beta-catenin signaling, we used the pTopflash or pFopflash luciferase reporter plasmids. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt1 (a / activate-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "LiCl") :xref (x3 / xref :value "PUBCHEM:433294" :prob "18.167522")) :ARG1 (p2 / pathway :ARG0-of (f / favor-01 :ARG1 (s2 / survive-01))) :manner (a2 / and :op1 (i / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "GSK-3beta") :xref (x2 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692"))) :op2 (a3 / activate-01 :ARG1 (t / transcribe-01 :ARG1-of (m3 / mediate-01 :ARG0 (p3 / protein-family :name (n4 / name :op1 "beta-catenin/Tcf"))))))) :snt2 (u / use-01 :ARG0 (w / we) :ARG1 (o / or :op1 (d / dna-sequence :name (n5 / name :op1 "pTopflash" :op2 "plasmid") :ARG0-of (r2 / report-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "luciferase")))) :op2 (d2 / dna-sequence :name (n6 / name :op1 "pFopflash" :op2 "plasmid") :ARG0-of r2)) :purpose (d3 / determine-01 :mode "interrogative" :ARG0 w :ARG1 (s4 / small-molecule :name (n8 / name :op1 "LiCl") :ARG0-of (a4 / affect-01 :ARG1 (s / signal-07 :ARG0 (p4 / protein :name (n9 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG1-of (m5 / mediate-01 :ARG0 (e3 / enzyme :name (n10 / name :op1 "GSK-3") :xref (x1 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.262"))))) :xref (x4 / xref :value "PUBCHEM:433294" :prob "18.167522"))))) # ::id bio.chicago_2015.18005 # ::date 2015-10-28T03:44:52 # ::file bio_chicago_2015_18005.txt # ::snt ILK also appears to regulate muscle differentiation by activating Erk, which suppresses transcription factors required for myogenic differentiation ( Huang et al., 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / appear-02 :ARG1 (r / regulate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "ILK") :xref (x / xref :value "UNIPROT:ILK_HUMAN" :prob "1.004")) :ARG1 (d2 / differentiate-01 :ARG1 (m / muscle)) :manner (a2 / activate-01 :ARG0 p2 :ARG1 (e / enzyme :name (n4 / name :op1 "Erk") :ARG0-of (s / suppress-01 :ARG1 (f / factor :ARG0-of (t / transcribe-01) :ARG1-of (r2 / require-01 :ARG0 (d3 / differentiate-01 :mod (m2 / myogenic))))) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n3 / name :op1 "Huang")) :op2 (p5 / person :mod (o / other))) :time (d5 / date-entity :year "2000"))) :mod (a4 / also)) # ::id bio.chicago_2015.18031 # ::date 2015-10-28T03:57:48 # ::file bio_chicago_2015_18031.txt # ::snt This observation suggested that the 60-residue linker region may assist Ldb binding by LIM B in the 1m construct. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 26, 2015 (s / suggest-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (a / assist-01 :ARG0 (r / region :ARG3-of (l / link-01 :ARG1 (r2 / residue :mod "60"))) :ARG1 (b / bind-01 :ARG1 (p3 / protein :name (n2 / name :op1 "LIM" :op2 "B") :xref (x / xref :value "UNIPROT:Q4W5K9_HUMAN" :prob "0.251")) :ARG2 (p2 / protein :name (n / name :op1 "Ldb") :xref (x1 / xref :value "UNIPROT:LDB1_HUMAN" :prob "0.202")) :location (c / construct :ARG1-of (l2 / label-01 :ARG2 (n3 / name :op1 "1m"))))))) # ::id bio.chicago_2015.18065 # ::date 2015-10-28T04:11:05 # ::file bio_chicago_2015_18065.txt # ::snt Again, Ser 5 phosphorylation of the CTD is seen at the promoter (Fig. 3, CTD-S5-P), whereas phosphorylation at Ser 2 increases as Pol II passes through the coding region (Fig. 3, CTD-S2-P). As seen with the ADH1 gene, levels of Ser 2 phosphorylation in coding regions increased in the fcp1 mutants. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 26, 2015 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (s / see-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod "5" :name (n / name :op1 "serine") :part-of (p3 / protein-segment :name (n2 / name :op1 "CTD")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (l2 / label-01 :ARG2 (n8 / name :op1 "CTD-S5-P"))) :location (m3 / molecular-physical-entity :ARG0-of (p4 / promote-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3"))) :ARG2 (i / increase-01 :ARG1 (p5 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "2" :name (n3 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (l3 / label-01 :ARG2 (n9 / name :op1 "CTD-S2-P"))) :time (p6 / pass-08 :ARG0 (e / enzyme :name (n4 / name :op1 "Pol" :op2 "II") :xref (x2 / xref :value "UNIPROT:POLI_HUMAN" :prob "0.262")) :ARG1 (r / region :location-of (c3 / code-01))) :ARG1-of (d2 / describe-01 :ARG0 f)) :mod (a6 / again)) :snt2 (i2 / increase-01 :ARG1 (l / level :degree-of (p7 / phosphorylate-01 :ARG1 (a5 / amino-acid :mod "2" :name (n5 / name :op1 "serine") :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :location (r2 / region :location-of (c5 / code-01)))) :location (g / gene :name (n6 / name :op1 "fcp1") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:CTDP1_HUMAN" :prob "0.602")) :ARG1-of (s2 / see-01 :topic (g2 / gene :name (n7 / name :op1 "ADH1") :xref (x / xref :value "UNIPROT:ADH1A_HUMAN" :prob "1.002"))))) # ::id bio.chicago_2015.18079 # ::date 2015-10-28T04:55:26 # ::file bio_chicago_2015_18079.txt # ::snt Thus, these results suggest that endogenous bHLH proteins bind to the E1 E-box and consequently activate GAP-43 promoter activity, an activity that is affected by the action of Id2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (i / infer-01 :ARG1 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "bHLH") :mod (e / endogenous) :xref (x2 / xref :value "UNIPROT:MAX_HUMAN" :prob "0.283")) :ARG2 (d / dna-sequence :name (n2 / name :op1 "E1" :op2 "E-box"))) :op2 (a2 / activate-01 :ARG0 p :ARG1 (a3 / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n3 / name :op1 "GAP-43") :xref (x / xref :value "UNIPROT:NEUM_HUMAN" :prob "0.683")))) :ARG1-of (a4 / affect-01 :ARG0 (a5 / act-02 :ARG0 (p4 / protein :name (n4 / name :op1 "Id2") :xref (x1 / xref :value "UNIPROT:ID2_HUMAN" :prob "0.623"))))))))) # ::id bio.chicago_2015.18091 # ::date 2015-10-28T05:17:13 # ::file bio_chicago_2015_18091.txt # ::snt Inhibition of GSK-3beta-dependent phosphorylation of Axin by Dvl. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (i / inhibit-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (p / protein :name (n2 / name :op1 "Axin") :xref (x2 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG2 (p3 / protein :name (n3 / name :op1 "Dvl") :xref (x / xref :value "UNIPROT:DVLP1_HUMAN" :prob "0.602")) :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n / name :op1 "GSK-3beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692"))))) # ::id bio.chicago_2015.18127 # ::date 2015-10-28T05:25:16 # ::file bio_chicago_2015_18127.txt # ::snt Axin also blocks beta-catenin-mediated transcription in colon cancer cells that have a mutation in the adenomatous polyposis coli gene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (b / block-01 :ARG0 (p / protein :name (n / name :op1 "Axin") :xref (x2 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1 (t / transcribe-01 :ARG1-of (m2 / mediate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")))) :location (c / cell :poss-of (t2 / thing) :source (d / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colon" :op2 "cancer")) :ARG2-of (m / mutate-01 :location (g / gene :name (n3 / name :op1 "adenomatous" :op2 "polyposis" :op3 "coli") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "0.383")))) :mod (a / also)) # ::id bio.chicago_2015.18130 # ::date 2015-10-20T03:27:20 # ::file bio_chicago_2015_18130.txt # ::snt Hemin treatment caused no reduction in cellular glutathione concentrations, indicating that the increased TRX expression was not due to oxidative stress. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (c / cause-01 :polarity "-" :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "hemin") :xref (x2 / xref :value "PUBCHEM:455658" :prob "17.656696"))) :ARG1 (r / reduce-01 :ARG1 (c2 / concentrate-02 :ARG1 (e / enzyme :name (n2 / name :op1 "glutathione") :xref (x / xref :value "UNIPROT:GSHB_HUMAN" :prob "0.333")) :mod (c3 / cell))) :ARG0-of (i / indicate-01 :ARG1 (c4 / cause-01 :polarity "-" :ARG0 (s / stress :mod (o / oxidative)) :ARG1 (e2 / express-03 :ARG1 (p / protein :name (n3 / name :op1 "TRX") :xref (x1 / xref :value "UNIPROT:THIO_HUMAN" :prob "1.003")) :ARG1-of (i2 / increase-01))))) # ::id bio.chicago_2015.18156 # ::date 2015-10-20T09:26:53 # ::file bio_chicago_2015_18156.txt # ::snt Upon CTD phosphorylation by TFIIH, RNA pol II dissociates from the initiation complex and leaves the promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (a / and :op1 (d / dissociate-01 :ARG1 (e / enzyme :name (n / name :op1 "RNA" :op2 "pol" :op3 "II") :xref (x1 / xref :value "UNIPROT:RNC_HUMAN" :prob "0.222")) :ARG2 (c / complex :mod (i / initiate-01))) :op2 (l / leave-05 :ARG0 e :ARG1 (m / molecular-physical-entity :ARG0-of (p2 / promote-01))) :condition (p / phosphorylate-01 :ARG1 (p4 / protein-segment :name (n3 / name :op1 "C-terminus")) :ARG2 (p3 / protein :name (n2 / name :op1 "TFIIH") :xref (x / xref :value "UNIPROT:TCEA3_HUMAN" :prob "0.332")))) # ::id bio.chicago_2015.18159 # ::date 2015-10-20T09:28:01 # ::file bio_chicago_2015_18159.txt # ::snt This is supported by the in vitro observations that Dvl inhibits GSK-3beta-dependent phosphorylation of Axin, APC, and beta-catenin in the Axin complex, although the bindings of GSK-3beta, beta-catenin, and APC to Axin are not changed, and that Dvl does not affect GSK-3beta activity to phosphorylate the peptide substrate ( 22, 26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (s / support-01 :ARG0 (o / observe-01 :ARG1 (a / and :op1 (h / have-concession-91 :ARG1 (i / inhibit-01 :ARG0 (p2 / protein :name (n / name :op1 "Dvl") :xref (x / xref :value "UNIPROT:DVLP1_HUMAN" :prob "0.602")) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "Axin") :xref (x1 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :op2 (p4 / protein :name (n4 / name :op1 "APC") :xref (x3 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")) :op3 (p5 / protein :name (n5 / name :op1 "beta-catenin") :xref (x4 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :location (c2 / complex :mod p3)) :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n3 / name :op1 "GSK-3beta") :xref (x2 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692"))))) :ARG2 (c / change-01 :polarity "-" :ARG1 (b / bind-01 :ARG1 (a3 / and :op1 e :op2 p5 :op3 p4) :ARG2 p3))) :op2 (a4 / affect-01 :polarity "-" :ARG0 p2 :ARG1 (a5 / activity-06 :ARG0 e :ARG1 (p6 / phosphorylate-01 :ARG1 (s2 / substrate :mod (p7 / peptide)) :ARG2 e)))) :manner (i2 / in-vitro)) :ARG1 (t / this) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 "22" :op2 "26"))))) # ::id bio.chicago_2015.18163 # ::date 2015-10-21T09:20:17 # ::file bio_chicago_2015_18163.txt # ::snt As demonstrated in Figure 5, B and C, in the absence of neurotrophins, DRG neurons derived from NF1-deficient embryos exhibit elevated erk phosphorylation levels that are comparable to wild-type neurons in the presence of NGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / exhibit-01 :ARG0 (n8 / neuron :ARG1-of (d / derive-01 :ARG2 (e2 / embryo :ARG0-of (l / lack-01 :ARG1 (p3 / protein :name (n3 / name :op1 "NF1") :xref (x2 / xref :value "UNIPROT:NF1_HUMAN" :prob "1.004"))))) :source (g / ganglion :mod (r / root) :mod (d3 / dorsal))) :ARG1 (l2 / level :degree-of (p4 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (e3 / elevate-01) :ARG1-of (c / comparable-03 :ARG2 (n4 / neuron :mod (w / wild-type) :condition (p5 / present-02 :ARG1 (p6 / protein :name (n5 / name :op1 "NGF") :xref (x3 / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")))))) :condition (a / absent-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "neurotrophin") :xref (x / xref :value "UNIPROT:NTF3_HUMAN" :prob "0.383"))) :ARG1-of (d2 / demonstrate-01 :ARG0 (a2 / and :op1 (f / figure :mod "B") :op2 (f2 / figure :mod "C") :part-of (f3 / figure :mod "5")))) # ::id bio.chicago_2015.18186 # ::date 2015-10-21T09:35:41 # ::file bio_chicago_2015_18186.txt # ::snt This result suggests that Axin binding to both GSK-3beta and beta-catenin is necessary for inhibition of Lef-1 reporter gene transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 22, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r2 / result-01) :mod (t2 / this)) :ARG1 (n2 / need-01 :ARG0 (i / inhibit-01 :ARG1 (t3 / transcribe-01 :ARG1 (g / gene :name (n / name :op1 "Lef-1") :ARG0-of (r / report-01) :xref (x2 / xref :value "UNIPROT:LEF1_HUMAN" :prob "0.632")))) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Axin") :xref (x / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG2 (a / and :op1 (e / enzyme :name (n4 / name :op1 "GSK-3beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :op2 (p4 / protein :name (n5 / name :op1 "beta-catenin") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")))))) # ::id bio.chicago_2015.18196 # ::date 2015-10-21T09:43:28 # ::file bio_chicago_2015_18196.txt # ::snt The major region of phosphorylation of beta-catenin by CK2 is the central armadillo repeat domain, where carrier proteins like axin and the adenomatous polyposis coli gene product APC interact with beta-catenin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (r2 / region :ARG1-of (m / major-02) :location-of (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG2 (e / enzyme :name (n2 / name :op1 "CK2") :xref (x1 / xref :value "UNIPROT:CSK22_HUMAN" :prob "0.332"))) :domain (p6 / protein-segment :name (n5 / name :op1 "central" :op2 "armadillo" :op3 "repeat") :location-of (i / interact-01 :ARG0 (p3 / protein :example (a2 / and :op1 (p4 / protein :name (n3 / name :op1 "axin") :xref (x3 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :op2 (p5 / protein :name (n6 / name :op1 "APC") :ARG1-of (e2 / encode-01 :ARG0 (g / gene :name (n4 / name :op1 "adenomatous" :op2 "polyposis" :op3 "coli") :xref (x2 / xref :value "UNIPROT:APC_HUMAN" :prob "0.383"))) :xref (x4 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004"))) :mod (c / carrier)) :ARG1 p2))) # ::id bio.chicago_2015.18258 # ::date 2015-10-21T09:55:48 # ::file bio_chicago_2015_18258.txt # ::snt In contrast, the ATP binding-deficient, dominant-negative HA-MEKK1-K1255M reduced Axin activation of JNK by 3-fold, suggesting that MEKK1 acts in the same signaling pathway in Axin-mediated activation of JNK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / contrast-01 :ARG2 (r / reduce-01 :ARG0 (e / enzyme :name (n / name :op1 "HA-MEKK1-K1255M") :ARG2-of (m2 / mutate-01 :mod "-/-" :ARG0-of (d / dominate-01)) :ARG0-of (l / lack-01 :ARG1 (b / bind-01 :ARG1 e :ARG2 (s / small-molecule :name (n5 / name :op1 "ATP") :xref (x3 / xref :value "PUBCHEM:5957" :prob "14.368295"))))) :ARG1 (a / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "Axin") :xref (x2 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :ARG2 (p2 / product-of :op1 "3") :ARG0-of (s4 / suggest-01 :ARG1 (a2 / act-02 :ARG0 (e2 / enzyme :name (n6 / name :op1 "MEKK1") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :location (p3 / pathway :ARG0-of (s2 / signal-07) :ARG1-of (s3 / same-01)) :topic (a3 / activate-01 :ARG1 e3 :ARG1-of (m / mediate-01 :ARG0 p)))))) # ::id bio.chicago_2015.18265 # ::date 2015-10-21T10:13:09 # ::file bio_chicago_2015_18265.txt # ::snt First, PR facilitates binding of NF1 by an ATP-dependent process that results in marked reduction of the linking number of chromosomal DNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / facilitate-01 :ARG0 (e / enzyme :name (n / name :op1 "PR") :xref (x1 / xref :value "UNIPROT:CCGL_HUMAN" :prob "1.002")) :ARG1 (b / bind-01 :ARG0 (p3 / process-02 :ARG0-of (d / depend-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP") :xref (x3 / xref :value "PUBCHEM:5957" :prob "14.368295"))) :ARG1-of (r / result-01 :ARG2 (r2 / reduce-01 :ARG1 (n4 / number :mod (l / link-01) :quant-of (n5 / nucleic-acid :name (n6 / name :op1 "DNA") :mod (c / chromosome :xref (x2 / xref :value "GO:0005694" :prob "0.8")))) :ARG2 (m / mark-01)))) :ARG1 (p2 / protein :name (n2 / name :op1 "NF1") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "1.004"))) :time (f2 / first)) # ::id bio.chicago_2015.18319 # ::date 2015-10-21T10:22:56 # ::file bio_chicago_2015_18319.txt # ::snt Axin is also phosphorylated by GSK-3beta and stabilized by its phosphorylation in contrast to beta-catenin ( 22), and the phosphorylation increases the binding of Axin to beta-catenin ( 23, 24). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (a / and :op1 (a2 / and :op1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "Axin") :xref (x / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG2 (e / enzyme :name (n2 / name :op1 "GSK-3beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692"))) :op2 (s / stabilize-01 :ARG0 (p / phosphorylate-01 :ARG1 p3) :ARG1 p3) :mod (a3 / also) :ARG1-of (c / contrast-01 :ARG2 (p4 / protein :name (n3 / name :op1 "beta-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "22"))))) :op2 (i / increase-01 :ARG0 p2 :ARG1 (b / bind-01 :ARG1 p3 :ARG2 p4) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 "23" :op2 "24")))))) # ::id bio.chicago_2015.18396 # ::date 2015-10-21T10:35:19 # ::file bio_chicago_2015_18396.txt # ::snt Axin enhances the phosphorylation of beta-catenin by GSK-3beta by positioning GSK-3beta close to beta-catenin, resulting in the inhibition of the Wnt signaling pathway ( 32). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 21, 2015 (e / enhance-01 :ARG0 (p2 / protein :name (n / name :op1 "Axin") :xref (x / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "beta-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG2 (e2 / enzyme :name (n3 / name :op1 "GSK-3beta") :xref (x2 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692"))) :manner (p5 / position-01 :ARG0 p2 :ARG1 e2 :ARG2 (c / close-10 :ARG1 e2 :ARG2 n2)) :ARG1-of (r / result-01 :ARG2 (i / inhibit-01 :ARG1 (p / pathway :name (n4 / name :op1 "Wnt") :ARG0-of (s / signal-07))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "32"))))) # ::id bio.chicago_2015.18464 # ::date 2015-10-21T10:41:59 # ::file bio_chicago_2015_18464.txt # ::snt ( c) Axin inhibits secondary axis formation induced by CKI . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :li "c" :ARG0 (p / protein :name (n / name :op1 "Axin") :xref (x1 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1 (f / form-01 :ARG1 (a / axis :mod (s / secondary)) :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "CKI") :xref (x / xref :value "UNIPROT:CHKA_HUMAN" :prob "1.002"))))) # ::id bio.chicago_2015.18510 # ::date 2015-10-21T10:44:36 # ::file bio_chicago_2015_18510.txt # ::snt Full-length Axin did not activate TCF-dependent transcription, but unexpectedly, the introduction of L521P into full-length Myc- or Flag-tagged murine Axin [mFlagAx-(1-956)] transformed it into a transcriptional activator (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (c / contrast-01 :ARG1 (a2 / activate-01 :polarity "-" :ARG0 (p / protein :name (n / name :op1 "Axin") :ARG1-of (l / long-03 :ARG1-of (f / full-09)) :xref (x4 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1 (t2 / transcribe-01 :ARG0-of (d / depend-01 :ARG1 (p2 / protein :name (n2 / name :op1 "TCF") :xref (x1 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.263"))))) :ARG2 (t3 / transform-01 :ARG0 (i / introduce-02 :ARG1 (m / mutate-01 :ARG1 p :ARG2 (p3 / protein :name (n3 / name :op1 "L521P"))) :ARG2 (o / or :op1 (p4 / protein :name (n4 / name :op1 "Axin") :mod (m2 / murine) :ARG1-of (t4 / tag-01 :ARG0 (p7 / protein :name (n6 / name :op1 "Myc") :xref (x / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604"))) :ARG1-of l :xref (x2 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :op2 (p5 / protein :name (n5 / name :op1 "Axin") :ARG1-of (t5 / tag-01 :ARG0 (p6 / protein-segment :name (n7 / name :op1 "Flag"))) :mod m2 :ARG1-of l :xref (x3 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")))) :ARG1 p :ARG2 (m3 / molecular-physical-entity :ARG0-of (a5 / activate-01 :ARG1 (t7 / transcribe-01))) :ARG1-of (e / expect-01 :polarity "-")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5D"))) # ::id bio.chicago_2015.18552 # ::date 2015-10-21T12:34:15 # ::file bio_chicago_2015_18552.txt # ::snt These interactions are specific, because an E1A polypeptide that binds to the ASH1 binding region in dCBP blocks the GST-ASH1(47-456)- dCBP interaction more efficiently than an E1A-RG2 polypeptide that carries a mutation that reduces E1A binding to dCBP (Fig. 7E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / specific-02 :ARG1 (i / interact-01 :mod (t / this)) :ARG1-of (c / cause-01 :ARG0 (b2 / block-01 :ARG0 (p / polypeptide :mod (p2 / protein :name (n / name :op1 "E1A") :xref (x2 / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.262")) :ARG1-of (b3 / bind-01 :ARG2 (r / region :location-of (b4 / bind-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ASH1") :xref (x3 / xref :value "UNIPROT:ASCL1_HUMAN" :prob "1.002"))) :location (p3 / protein :name (n3 / name :op1 "dCBP"))))) :ARG1 (i2 / interact-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "GST") :xref (x1 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :ARG1 (a / and :op1 (a2 / amino-acid :mod (v2 / value-interval :op1 "47" :op2 "456") :part-of e) :op2 p3)) :ARG1-of (e3 / efficient-01 :degree (m / more) :compared-to (p5 / polypeptide :mod (p6 / protein :name (n6 / name :op1 "E1A-RG2") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.212")) :ARG0-of (c2 / carry-01 :ARG1 (m2 / mutate-01 :ARG0-of (r2 / reduce-01 :ARG1 (b5 / bind-01 :ARG1 p2 :ARG2 p3)))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7E"))) # ::id bio.chicago_2015.18587 # ::date 2015-10-21T12:48:06 # ::file bio_chicago_2015_18587.txt # ::snt The copurification suggested that BMP-1 and BMP-2 might physically interact, leading to the idea that Tolloid might increase DPP activity by proteolytically processing DPP precursors (Shimell et al., 1991 ; Childs and O'Connor, 1994 ; Finelli et al., 1994 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (s / suggest-01 :ARG0 (c / copurify-00) :ARG1 (p2 / possible-01 :ARG1 (i / interact-01 :ARG0 (p3 / protein :name (n / name :op1 "BMP-1") :xref (x1 / xref :value "UNIPROT:BMP1_HUMAN" :prob "1.003")) :ARG1 (p4 / protein :name (n2 / name :op1 "BMP-2") :xref (x3 / xref :value "UNIPROT:BMP2_HUMAN" :prob "1.003")) :manner (p5 / physical))) :ARG0-of (l / lead-03 :ARG2 (i2 / idea :topic (p6 / possible-01 :ARG1 (i3 / increase-01 :ARG0 (p7 / protein :name (n3 / name :op1 "Tolloid") :xref (x2 / xref :value "UNIPROT:TLL1_HUMAN" :prob "0.243")) :ARG1 (a / activity-06 :ARG0 (p19 / protein :name (n4 / name :op1 "DPP") :xref (x / xref :value "UNIPROT:DSPP_HUMAN" :prob "1.002"))) :manner (p8 / process-01 :ARG1 (p10 / precursor :mod p19) :manner (p9 / proteolytical)))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p11 / publication-91 :ARG0 (a3 / and :op1 (p12 / person :name (n5 / name :op1 "Shimell")) :op2 (p13 / person :mod (o / other))) :time (d / date-entity :year "1991")) :op2 (p14 / publication-91 :ARG0 (a4 / and :op1 (p15 / person :name (n6 / name :op1 "Childs")) :op2 (p16 / person :name (n7 / name :op1 "O'Connor"))) :time (d2 / date-entity :year "1994")) :op3 (p / publication-91 :ARG0 (a5 / and :op1 (p17 / person :name (n8 / name :op1 "Finelli")) :op2 (p18 / person :mod (o2 / other))) :time d2)))) # ::id bio.chicago_2015.18599 # ::date 2015-10-21T13:03:50 # ::file bio_chicago_2015_18599.txt # ::snt Moreover ectopic expression of cyclin E does not activate E2F in the absence of cdk4 and cdk6 activity (Lukas et al., 1997 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (a2 / and :op2 (a / activate-01 :polarity "-" :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "cyclin" :op2 "E") :xref (x3 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")) :mod (e2 / ectopic)) :ARG1 (p5 / protein :name (n2 / name :op1 "E2F") :xref (x2 / xref :value "UNIPROT:E2F1_HUMAN" :prob "0.262")) :condition (a3 / absent-01 :ARG1 (a4 / activity-06 :ARG0 (a5 / and :op1 (e3 / enzyme :name (n3 / name :op1 "cdk4") :xref (x1 / xref :value "UNIPROT:CDK4_HUMAN_DNA" :prob "1.001")) :op2 (e4 / enzyme :name (n4 / name :op1 "cdk6") :xref (x / xref :value "UNIPROT:CDK6_HUMAN" :prob "0.603")))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a6 / and :op1 (p3 / person :name (n5 / name :op1 "Lukas")) :op1 (p4 / person :mod (o / other))) :time (d / date-entity :year "1997")))) # ::id bio.chicago_2015.18617 # ::date 2015-10-21T13:09:51 # ::file bio_chicago_2015_18617.txt # ::snt DLT Interacts with CRB and NRX IV # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "DLT") :xref (x2 / xref :value "UNIPROT:ODP2_HUMAN" :prob "0.262")) :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "CRB") :xref (x / xref :value "UNIPROT:CRUM1_HUMAN" :prob "0.262")) :op2 (p3 / protein :name (n3 / name :op1 "NRX" :op2 "IV") :xref (x1 / xref :value "UNIPROT:NXN_HUMAN" :prob "0.212")))) # ::id bio.chicago_2015.18666 # ::date 2015-10-20T09:27:46 # ::file bio_chicago_2015_18666.txt # ::snt The negative regulation of brinker expression by Dpp signaling illustrates a significant element of regulatory versatility afforded by the use of a Type II, as compared with a Type I, switch mechanism. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / illustrate-01 :ARG0 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "brinker"))) :ARG2 (s / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "Dpp")))) :ARG1 (e2 / element :ARG1-of (s2 / significant-02) :part-of (v / versatility :ARG0-of (r2 / regulate-01) :ARG1-of (a / afford-02 :ARG0 (u / use-01 :ARG1 (m / mechanism :mod (s3 / switch-01) :ARG1-of (t / type-03 :ARG2 (s4 / string-entity :value "II")) :compared-to (m2 / mechanism :mod s3 :ARG1-of (t2 / type-03 :ARG2 (s5 / string-entity :value "I"))))))))) # ::id bio.chicago_2015.18675 # ::date 2015-10-21T13:22:15 # ::file bio_chicago_2015_18675.txt # ::snt Unlike known E2Fs, these E2F-like proteins efficiently bind E2F sites in the monomeric form but not as a heterodimer with DP proteins and repress E2F-regulated promoters. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (a / and :op1 (b / bind-01 :ARG1 (p / protein :ARG1-of (r2 / resemble-01 :ARG2 (p4 / protein-family :name (n / name :op1 "E2F"))) :ARG1-of (r5 / resemble-01 :polarity "-" :ARG2 (p5 / protein-family :name (n3 / name :op1 "E2F") :ARG1-of (k / know-01))) :mod (t2 / this)) :ARG2 (s / site :mod p4) :ARG1-of (e / efficient-01) :condition (c / contrast-01 :ARG1 (f / form :mod (m / monomer)) :ARG2 (h / heterodimer :polarity "-" :prep-with (p2 / protein :name (n2 / name :op1 "DP") :xref (x / xref :value "UNIPROT:DESP_HUMAN" :prob "1.002"))))) :op2 (r3 / repress-01 :ARG0 p :ARG1 (m2 / molecular-physical-entity :ARG0-of (p3 / promote-01) :ARG1-of (r4 / regulate-01 :ARG0 p4)))) # ::id bio.chicago_2015.18689 # ::date 2015-10-21T13:36:50 # ::file bio_chicago_2015_18689.txt # ::snt By definition, PLD catalyzes the hydrolysis of PC to PA and choline. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (c / catalyze-01 :ARG0 (e / enzyme :name (n / name :op1 "PLD") :xref (x / xref :value "UNIPROT:PLD1_HUMAN" :prob "0.263")) :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "PC") :xref (x2 / xref :value "PUBCHEM:3338" :prob "1.522007")) :ARG3 (a / and :op1 (s2 / small-molecule :name (n3 / name :op1 "PA") :xref (x3 / xref :value "PUBCHEM:985" :prob "7.888558")) :op2 (s3 / small-molecule :name (n4 / name :op1 "choline") :xref (x1 / xref :value "PUBCHEM:305" :prob "13.349933")))) :ARG1-of (d / define-01)) # ::id bio.chicago_2015.18690 # ::date 2015-10-21T13:45:39 # ::file bio_chicago_2015_18690.txt # ::snt Dephosphorylation of cyclin E by Cdc14 reverses the effects of the mitotic kinases and promotes cyclin E - Cdk2 binding to chromatin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (a2 / and :op1 (r / reverse-01 :ARG0 (d / dephosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "cyclin" :op2 "E") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")) :ARG2 (p / protein :name (n / name :op1 "Cdc14") :xref (x2 / xref :value "UNIPROT:CC14A_HUMAN" :prob "0.252"))) :ARG1 (a / affect-01 :ARG0 (k / kinase :mod (m / mitosis)))) :op2 (p3 / promote-01 :ARG0 d :ARG1 (b / bind-01 :ARG1 (m2 / macro-molecular-complex :part p2 :part (e / enzyme :name (n3 / name :op1 "Cdk2") :xref (x1 / xref :value "UNIPROT:CDK2_HUMAN" :prob "0.603"))) :ARG2 (m3 / macro-molecular-complex :name (n4 / name :op1 "chromatin"))))) # ::id bio.chicago_2015.18717 # ::date 2015-10-22T08:52:41 # ::file bio_chicago_2015_18717.txt # ::snt Our results demonstrate that the chromosome condensation defect caused by perturbed ISWI function is mediated through the NURF complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 22, 2015 (d / demonstrate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (m / mediate-01 :ARG0 (m2 / macro-molecular-complex :name (n2 / name :op1 "NURF")) :ARG1 (d2 / defect :mod (c / condense-01 :ARG1 (c2 / chromosome :xref (x / xref :value "GO:0005694" :prob "0.8"))) :ARG1-of (c3 / cause-01 :ARG0 (f / function-01 :ARG0 (p / protein :name (n / name :op1 "ISWI")) :ARG1-of (p2 / perturb-01)))))) # ::id bio.chicago_2015.18724 # ::date 2015-10-22T09:11:09 # ::file bio_chicago_2015_18724.txt # ::snt The Essential Activity of DSmurf Is Limited to the DPP Signaling Pathway # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (l / limit-01 :ARG1 (a / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "DSmurf")) :mod (e / essential)) :ARG2 (p / pathway :name (n2 / name :op1 "DPP") :ARG0-of (s / signal-07))) # ::id bio.chicago_2015.18744 # ::date 2015-10-22T09:17:29 # ::file bio_chicago_2015_18744.txt # ::snt Alternatively, auxilin might bind much more weakly to Hsc70 in ADP than ATP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 22, 2015 (p2 / possible-01 :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "auxilin") :xref (x1 / xref :value "UNIPROT:AUXI_HUMAN" :prob "0.212")) :ARG2 (p3 / protein :name (n2 / name :op1 "Hsc70") :xref (x / xref :value "UNIPROT:HSP7C_HUMAN" :prob "0.633")) :ARG1-of (w / weak-02 :degree (m / more :quant (m2 / much))) :location (s / small-molecule :name (n3 / name :op1 "ADP") :xref (x3 / xref :value "PUBCHEM:6022" :prob "14.621743")) :compared-to (b2 / bind-01 :ARG1 e :ARG2 p3 :location (s2 / small-molecule :name (n4 / name :op1 "ATP") :xref (x2 / xref :value "PUBCHEM:5957" :prob "14.368295")))) :manner (a / alternative)) # ::id bio.chicago_2015.18747 # ::date 2015-10-22T09:22:43 # ::file bio_chicago_2015_18747.txt # ::snt Regulation of Dpp Targets by brinker. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (r / regulate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "brinker")) :ARG1 (m / molecular-physical-entity :ARG1-of (t / target-01 :ARG0 (p / protein :name (n / name :op1 "Dpp") :xref (x / xref :value "UNIPROT:DSPP_HUMAN" :prob "0.602"))))) # ::id bio.chicago_2015.18750 # ::date 2015-10-22T09:25:20 # ::file bio_chicago_2015_18750.txt # ::snt The only other known zinc finger-homeodomain cooperation is in Drosophila, where it was recently shown that the orphan nuclear receptor alphaFtz-F1 is a cofactor for the homeodomain protein Ftz (Guichet et al., 1997; Yu et al., 1997); in this case, the physical association between alphaFtz-F1 and Ftz is thought to enhance the binding of the Ftz to its lower-affinity target sequences (Guichet et al., 1997; Yu et al., 1997), much in the same way that Extradenticle and Pbx modulate the DNA binding activity of Hox proteins (Phelan et al., 1995; Lu and Kamps, 1996 ; Peltenburg and Murre, 1997 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (m / multi-sentence :snt1 (o / organism :wiki "Drosophila" :name (n / name :op1 "Drosophila") :location-of (c / cooperate-01 :ARG0 (p / protein :name (n2 / name :op1 "zinc" :op2 "finger") :xref (x1 / xref :value "UNIPROT:CHD3_HUMAN" :prob "0.302")) :ARG1 (p23 / protein :name (n3 / name :op1 "homeodomain") :xref (x2 / xref :value "UNIPROT:HOP_HUMAN" :prob "0.312")) :ARG1-of (k / know-01) :mod (o2 / other) :mod (o3 / only)) :location-of (s / show-01 :ARG1 (c2 / cofactor :domain (r / receptor :name (n4 / name :op1 "alphaFtz-F1") :mod (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :mod (o4 / orphan)) :beneficiary (p4 / protein :name (n6 / name :op1 "Ftz") :mod p23)) :time (r2 / recent) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (p2 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n7 / name :op1 "Guichet")) :op2 (p6 / person :mod (o5 / other))) :time (d / date-entity :year "1997")) :op2 (p7 / publication-91 :ARG0 (a3 / and :op1 (p8 / person :name (n8 / name :op1 "Yu")) :op2 (p9 / person :mod (o6 / other))) :time d))))) :snt2 (t / think-01 :ARG1 (e / enhance-01 :ARG0 (a5 / associate-01 :ARG1 (r4 / receptor :name (n17 / name :op1 "alphaFtz-F1")) :ARG2 (p3 / protein :name (n18 / name :op1 "Ftz")) :mod (p10 / physical)) :ARG1 (b / bind-01 :ARG1 p3 :ARG2 (s2 / sequence :ARG1-of (t2 / target-01) :mod (a6 / affinity :ARG1-of (l / low-04 :degree (m2 / more))) :poss p3)) :ARG1-of (r3 / resemble-01 :ARG2 (m4 / modulate-01 :ARG0 (a7 / and :op1 (p11 / protein :name (n9 / name :op1 "Extradenticle")) :op2 (p12 / protein :name (n10 / name :op1 "Pbx") :xref (x / xref :value "UNIPROT:PBX1_HUMAN" :prob "0.202"))) :ARG1 (a8 / activity-06 :ARG0 (p13 / protein-family :name (n11 / name :op1 "Hox")) :ARG1 (b2 / bind-01 :ARG2 (n21 / nucleic-acid :name (n22 / name :op1 "DNA")))) :ARG1-of (d8 / describe-01 :ARG0 (a9 / and :op1 (p14 / publication-91 :ARG0 (a10 / and :op1 (p15 / person :name (n12 / name :op1 "Phelan")) :op2 (p16 / person :mod (o7 / other))) :time (d9 / date-entity :year "1995")) :op2 (p17 / publication-91 :ARG0 (a11 / and :op1 (p18 / person :name (n13 / name :op1 "Lu")) :op2 (p19 / person :name (n14 / name :op1 "Kamps"))) :time (d10 / date-entity :year "1996")) :op3 (p20 / publication-91 :ARG0 (a12 / and :op1 (p21 / person :name (n15 / name :op1 "Peltenburg")) :op2 (p22 / person :name (n16 / name :op1 "Murre"))) :time (d11 / date-entity :year "1997"))))) :degree (m3 / much))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (p24 / publication-91 :ARG0 (a13 / and :op1 (p26 / person :name (n19 / name :op1 "Guichet")) :op2 (p29 / person :mod (o8 / other))) :time d11) :op2 (p25 / publication-91 :ARG0 (a14 / and :op1 (p27 / person :name (n20 / name :op1 "Yu")) :op2 (p28 / person :mod (o9 / other))) :time d11))) :mod (c3 / case-04 :ARG1 (t3 / this)))) # ::id bio.chicago_2015.18761 # ::date 2015-10-22T09:59:43 # ::file bio_chicago_2015_18761.txt # ::snt During gastrulation, DLT may first form a complex with CRB to target it to the apical domain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (p / possible-01 :ARG1 (f / form-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n / name :op1 "DLT") :xref (x / xref :value "UNIPROT:ODP2_HUMAN" :prob "0.262")) :op2 (p3 / protein :name (n2 / name :op1 "CRB") :xref (x1 / xref :value "UNIPROT:CRUM1_HUMAN" :prob "0.262"))) :ARG1 (m / macro-molecular-complex) :purpose (t / target-01 :ARG0 p2 :ARG1 (d2 / domain :mod (a / apical)) :ARG2 p3) :time (f2 / first)) :time (g / gastrulate-00)) # ::id bio.chicago_2015.18776 # ::date 2015-10-22T10:03:55 # ::file bio_chicago_2015_18776.txt # ::snt We compared cdc25A induction to that of cyclin E, which is regulated by E2F and Rb family members ( 4, 20, 45). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / compare-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG2 (e / enzyme :name (n / name :op1 "cdc25A") :xref (x1 / xref :value "UNIPROT:MPIP1_HUMAN" :prob "0.652"))) :ARG2 (i2 / induce-01 :ARG2 (p2 / protein :name (n2 / name :op1 "cyclin" :op2 "E") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")) :ARG1-of (r / regulate-01 :ARG0 (a / and :op1 (m / member :part-of (p3 / protein-family :name (n3 / name :op1 "E2F"))) :op2 (m2 / member :part-of (p4 / protein-family :name (n4 / name :op1 "Rb")))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "4" :op2 "20" :op3 "45"))))) # ::id bio.chicago_2015.18798 # ::date 2015-10-22T10:18:54 # ::file bio_chicago_2015_18798.txt # ::snt Furthermore, during early gastrulation, DLT normally colocalizes with CRB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op2 (c / colocalize-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "DLT") :xref (x1 / xref :value "UNIPROT:ODP2_HUMAN" :prob "0.262")) :op2 (p2 / protein :name (n2 / name :op1 "CRB") :xref (x / xref :value "UNIPROT:CRUM1_HUMAN" :prob "0.262"))) :ARG1-of (n3 / normal-02) :time (g / gastrulate-00 :mod (e / early)))) # ::id bio.chicago_2015.18911 # ::date 2015-10-22T10:26:00 # ::file bio_chicago_2015_18911.txt # ::snt However, caldesmon together with TM completely inhibits actin binding of human fascin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / contrast-01 :ARG2 (i / inhibit-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "caldesmon") :xref (x3 / xref :value "UNIPROT:CALD1_HUMAN" :prob "0.702")) :op2 (p2 / protein :name (n2 / name :op1 "TM") :xref (x / xref :value "UNIPROT:ENR1_HUMAN" :prob "1.002"))) :ARG1 (b / bind-01 :ARG1 (p3 / protein :name (n3 / name :op1 "actin") :xref (x2 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG2 (p4 / protein :name (n4 / name :op1 "fascin") :mod (h / human) :xref (x1 / xref :value "UNIPROT:FSCN1_HUMAN" :prob "0.702"))) :ARG1-of (c2 / complete-02))) # ::id bio.chicago_2015.18974 # ::date 2015-10-22T11:18:19 # ::file bio_chicago_2015_18974.txt # ::snt Binding of filamin to actin bundles was determined in the absence of another ABP (curve 1, A,B) or in the presence of saturating quantities of calponin (curve 2, A) or - actinin (curve 2, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (d / determine-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "filamin") :xref (x4 / xref :value "UNIPROT:FLNA_HUMAN" :prob "0.343")) :ARG2 (b2 / bundle :mod (p2 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :condition (o / or :op1 (a / absent-01 :ARG1 (p3 / protein :name (n3 / name :op1 "ABP") :mod (a2 / another) :xref (x1 / xref :value "UNIPROT:SHBG_HUMAN" :prob "1.002")) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "A") :op2 (f2 / figure :mod "B") :part-of (f3 / figure :mod (c / curve :mod "1"))))) :op2 (p4 / present-02 :ARG1 (q / quantity :ARG0-of (s / saturate-01 :ARG2 (o2 / or :op1 (p5 / protein :name (n4 / name :op1 "calponin") :ARG1-of (d3 / describe-01 :ARG0 (f4 / figure :mod "A" :part-of (f5 / figure :mod (c2 / curve :mod "2")))) :xref (x3 / xref :value "UNIPROT:A0A087X1X5_HUMAN" :prob "0.701")) :op2 (p6 / protein :name (n5 / name :op1 "actinin") :ARG1-of (d4 / describe-01 :ARG0 (f6 / figure :mod "B" :part-of f5)) :xref (x2 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))))))) # ::id bio.chicago_2015.18987 # ::date 2015-10-22T11:30:05 # ::file bio_chicago_2015_18987.txt # ::snt During cell morphogenesis and motility, cells undergo extensive remodeling of the actin cytoskeleton, a phenomenon that is mediated by various actin-binding proteins ( 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (u / undergo-28 :ARG1 (c / cell) :ARG2 (r / remodel-01 :ARG1 (c2 / cytoskeleton :mod (p / protein :name (n / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :xref (x1 / xref :value "GO:0005856" :prob "0.8")) :ARG1-of (e / extensive-03)) :time (a / and :op1 (m / motility :mod (c3 / cell)) :op2 (m2 / morphogenesis :mod c3)) :ARG1-of (m3 / mediate-01 :ARG0 (p3 / protein :ARG0-of (b / bind-01 :ARG1 p) :mod (v / various))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "1")))) # ::id bio.chicago_2015.19008 # ::date 2015-10-22T11:34:00 # ::file bio_chicago_2015_19008.txt # ::snt For instance, the proposed role of Grb2 in clathrin-independent endocytosis of EGFR (Yamazaki et al., 2002 ) may be related to the ability of Grb2 to mediate EGFR signaling to actin cytoskeleton # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (p / possible-01 :ARG1 (r / relate-01 :ARG1 (r2 / role :ARG1-of (p2 / propose-01 :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a / and :op1 (p6 / person :name (n5 / name :op1 "Yamazaki")) :op2 (p7 / person :mod (o / other))) :time (d5 / date-entity :year "2002")))) :mod (p3 / protein :name (n2 / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :topic (e3 / endocytosis :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 (p4 / protein :name (n3 / name :op1 "clathrin") :xref (x / xref :value "UNIPROT:A0A087WVQ6_HUMAN" :prob "0.291"))) :mod (e4 / enzyme :name (n4 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG2 (c / capable-01 :ARG1 p3 :ARG2 (m / mediate-01 :ARG0 p3 :ARG1 (s / signal-07 :ARG1 e4 :ARG2 (c2 / cytoskeleton :mod (p8 / protein :name (n / name :op1 "actin") :xref (x3 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :xref (x4 / xref :value "GO:0005856" :prob "0.8")))))) :ARG0-of (e / exemplify-01)) # ::id bio.chicago_2015.19022 # ::date 2015-10-22T11:45:49 # ::file bio_chicago_2015_19022.txt # ::snt We found that the overexpression of SH3PX1 alone did not significantly affect the EGF receptor levels through a 60-min exposure to EGF (Fig. 6, lanes 9-12, upper panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (a / affect-01 :polarity "-" :ARG1 (o / overexpress-01 :ARG1 (g / gene :name (n / name :op1 "SH3PX1") :xref (x1 / xref :value "UNIPROT:SNX9_HUMAN" :prob "1.002")) :mod (a2 / alone)) :ARG2 (l / level :quant-of (e2 / enzyme :name (n3 / name :op1 "EGF" :op2 "receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.213"))) :ARG1-of (s / significant-02) :time (e / expose-01 :ARG2 (r / receptor) :duration (t / temporal-quantity :quant "60" :unit (m / minute)))) :ARG1-of (d / describe-01 :ARG0 (l2 / lane :value (v / value-interval :op1 "9" :op2 "12") :part-of (f2 / figure :mod "6") :location (p / panel :ARG1-of (u / up-02 :degree (m2 / more)))))) # ::id bio.chicago_2015.19058 # ::date 2015-10-20T05:40:46 # ::file bio_chicago_2015_19058.txt # ::snt Overexpression of cdc5delta N induces a disturbance in septin ring structures and Cdc5 interacts with two septins, Cdc11 and Cdc12, in a polo-box - dependent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / and :op1 (i / induce-01 :ARG0 (o / overexpress-01 :ARG1 (p3 / protein :name (n6 / name :op1 "cdc5" :op2 "delta" :op3 "N"))) :ARG2 (d / disturb-01 :ARG1 (s / structure-01 :ARG1 (r / ring :mod (p / protein-family :name (n2 / name :op1 "septin")))))) :op2 (i2 / interact-01 :ARG0 (p4 / protein :name (n3 / name :op1 "Cdc5") :xref (x / xref :value "UNIPROT:RGRF1_HUMAN" :prob "0.233")) :ARG1 (a2 / and :op1 (s2 / septin :name (n4 / name :op1 "Cdc11")) :op2 (s3 / septin :name (n5 / name :op1 "Cdc12"))) :ARG0-of (d3 / depend-01 :ARG1 (p2 / polo-box)))) # ::id bio.chicago_2015.19083 # ::date 2015-10-20T06:32:06 # ::file bio_chicago_2015_19083.txt # ::snt How the interactions of filamin with actin and transmembrane proteins are regulated is largely unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (k / know-01 :polarity "-" :ARG1 (t2 / thing :manner-of (r / regulate-01 :ARG1 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "filamin") :xref (x1 / xref :value "UNIPROT:FLNA_HUMAN" :prob "0.343")) :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :op2 (p3 / protein :mod (t / transmembrane)))))) :degree (l / large)) # ::id bio.chicago_2015.19095 # ::date 2015-10-20T11:08:30 # ::file bio_chicago_2015_19095.txt # ::snt P-TEFb may alter the role of Spt proteins either by phosphorylation of Pol II or Spt5 (Ivanov et al. 2000 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 20, 2015 (p / possible-01 :ARG1 (a / alter-01 :ARG0 (p2 / protein :name (n / name :op1 "P-TEFb") :xref (x / xref :value "UNIPROT:ACOT4_HUMAN" :prob "0.232")) :ARG1 (r / role :poss (p3 / protein :name (n2 / name :op1 "Spt") :xref (x2 / xref :value "UNIPROT:SPYA_HUMAN" :prob "0.602"))) :manner (p4 / phosphorylate-01 :ARG1 (o / or :op1 (e / enzyme :name (n3 / name :op1 "Pol" :op2 "II") :xref (x1 / xref :value "UNIPROT:POLI_HUMAN" :prob "0.262")) :op2 (p5 / protein :name (n4 / name :op1 "SPT5") :xref (x3 / xref :value "UNIPROT:SPT5H_HUMAN" :prob "1.002"))))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a2 / and :op1 (p7 / person :name (n5 / name :op1 "Ivanov")) :op2 (p8 / person :mod (o2 / other))) :time (d2 / date-entity :year "2000")))) # ::id bio.chicago_2015.19112 # ::date 2015-10-20T11:57:48 # ::file bio_chicago_2015_19112.txt # ::snt Site II seems to be generally less well conserved (for example, Arp1 and beta- and gamma-tubulin), and this may explain why these target proteins bind less well to prefoldin than actin and alpha-tubulin (see Fig. 4; the fragments of Arp1 and beta- and gamma-tubulin also show binding to CCT, whereas actin and alpha-tubulin do not). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (s / seem-01 :ARG1 (c / conserve-01 :ARG1 (s2 / site :mod "2" :example (a4 / and :op1 (p / protein :name (n / name :op1 "Arp1") :xref (x4 / xref :value "UNIPROT:ACTZ_HUMAN" :prob "0.602")) :op2 (a5 / and :op1 (p7 / protein :name (n5 / name :op1 "beta-tubulin") :xref (x1 / xref :value "UNIPROT:TBCD_HUMAN" :prob "0.302")) :op2 (p8 / protein-family :name (n6 / name :op1 "gamma-tubulin"))))) :mod (w / well :degree (l / less)) :ARG1-of (g / general-02))) :op2 (p2 / possible-01 :ARG1 (e / explain-01 :ARG0 s :ARG1 (t4 / thing :ARG0-of (c2 / cause-01 :ARG1 (b / bind-01 :ARG1 (p3 / protein :ARG0-of (t / target-01) :mod (t2 / this)) :ARG2 (p4 / protein-family :name (n2 / name :op1 "prefoldin")) :mod (w2 / well :degree (l2 / less) :compared-to (a3 / and :op1 (p5 / protein :name (n3 / name :op1 "actin") :xref (x2 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :op2 (p6 / protein :name (n4 / name :op1 "alpha-tubulin") :xref (x3 / xref :value "UNIPROT:TBA4A_HUMAN" :prob "0.393"))))))))) :ARG1-of (d / describe-01 :ARG2 (f / figure :mod "4" :ARG0-of (e2 / explain-01 :ARG1 (s3 / show-01 :ARG0 (f2 / fragment :part-of (a6 / and :op1 p :op2 a5)) :ARG1 (b2 / bind-01 :ARG1 (a7 / and :op1 p :op2 a5) :ARG2 (p9 / protein :name (n7 / name :op1 "CCT") :xref (x / xref :value "UNIPROT:FLVC2_HUMAN" :prob "1.002"))) :ARG1-of (c3 / contrast-01 :ARG2 (s4 / show-01 :polarity "-" :ARG0 (a8 / and :op1 p5 :op2 p6) :ARG1 b2)) :mod (a / also))) :ARG1-of (s5 / see-01 :mode "imperative" :ARG0 (y / you))))) # ::id bio.chicago_2015.19139 # ::date 2015-10-20T14:25:08 # ::file bio_chicago_2015_19139.txt # ::snt These functions of cadherin require intracellular attachment of cadherin to the actin cytoskeleton that is dependent on binding of cadherin to catenins (Hirano et al., 1987 ; Nagafuchi and Takeichi, 1988 ; Ozawa et al., 1990 ); beta-catenin mediates the linkage of cadherins to alpha-catenin, which in turn interacts with the actin cytoskeleton (Aberle et al., 1994 ; Hulsken et al., 1994 ; Jou et al., 1995 ; Rimm et al., 1995 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (r / require-01 :ARG0 (f / function-01 :ARG0 (p / protein-family :name (n / name :op1 "cadherin")) :mod (t / this)) :ARG1 (a / attach-01 :ARG1 p :ARG2 (c / cytoskeleton :mod (p2 / protein :name (n2 / name :op1 "actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG0-of (d / depend-01 :ARG1 (b / bind-01 :ARG1 p :ARG2 (p3 / protein-family :name (n3 / name :op1 "catenin")))) :xref (x3 / xref :value "GO:0005856" :prob "0.8")) :mod (i3 / intracellular)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n4 / name :op1 "Hirano")) :op2 (p6 / person :mod (o / other))) :time (d3 / date-entity :year "1987")) :op2 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n5 / name :op1 "Nagafuchi")) :op2 (p9 / person :name (n6 / name :op1 "Takeichi"))) :time (d4 / date-entity :year "1988")) :op3 (p10 / publication-91 :ARG0 (a5 / and :op1 (p11 / person :name (n7 / name :op1 "Ozawa")) :op2 (p12 / person :mod (o2 / other))) :time (d5 / date-entity :year "1990"))))) :snt2 (m2 / mediate-01 :ARG0 (p13 / protein :name (n8 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG1 (l / link-01 :ARG1 (p14 / protein-family :name (n9 / name :op1 "cadherin")) :ARG2 (p15 / protein :name (n10 / name :op1 "alpha-catenin") :ARG0-of (i / interact-01 :ARG1 c :mod (i2 / in-turn)) :xref (x2 / xref :value "UNIPROT:CTNA3_HUMAN" :prob "0.392"))) :ARG1-of (d6 / describe-01 :ARG0 (a6 / and :op1 (p16 / publication-91 :ARG0 (a7 / and :op1 (p17 / person :name (n11 / name :op1 "Aberle")) :op2 (p18 / person :mod (o3 / other))) :time "d7") :op2 (p19 / publication-91 :ARG0 (a8 / and :op1 (p20 / person :name (n12 / name :op1 "Hulsken")) :op2 (p21 / person :mod (o4 / other))) :time (d7 / date-entity :year "1994")) :op3 (p22 / publication-91 :ARG0 (a9 / and :op1 (p23 / person :name (n13 / name :op1 "Jou")) :op2 (p24 / person :mod (o5 / other))) :time (d8 / date-entity :year "1995")) :op4 (p25 / publication-91 :ARG0 (a10 / and :op1 (p26 / person :name (n14 / name :op1 "Rimm")) :op2 (p27 / person :mod (o6 / other))) :time d8))))) # ::id bio.chicago_2015.19160 # ::date 2015-10-20T15:07:36 # ::file bio_chicago_2015_19160.txt # ::snt Other possibilities would be that actin promotes interaction of the BR particle with a fibrous network in the nucleoplasm, allows binding to export receptors (cf. ref. 52), or is involved in the dramatic conformational change of the particle upon translocation through the nuclear pore. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (p / possible-01 :ARG1 (o2 / or :op1 (p2 / promote-02 :ARG0 (p3 / protein :name (n / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG1 (i / interact-01 :ARG0 (p4 / particle :name (n2 / name :op1 "BR")) :ARG1 (n3 / network :mod (f / fibrous)) :location (n4 / nucleoplasm :xref (x1 / xref :value "GO:0005654" :prob "0.8")))) :op2 (a2 / allow-01 :ARG0 p3 :ARG1 (b / bind-01 :ARG2 (r / receptor :ARG0-of (e / export-01))) :ARG1-of (c / compare-01 :ARG2 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "52")))) :op3 (i2 / involve-01 :ARG1 p3 :ARG2 (c3 / change-01 :ARG1 p4 :degree (d / dramatic) :mod (c4 / conformational) :condition (t / translocate-01 :ARG1 p4 :path (p6 / pore :mod (n5 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8"))))))) :mod (o / other)) # ::id bio.chicago_2015.19248 # ::date 2015-10-21T00:52:45 # ::file bio_chicago_2015_19248.txt # ::snt 1) the MLC-pep blocks an interaction between vMLC-1 and actin, which releases a tethering effect that leads to the inotropic effect; 2) the MLC-pep blocks a site on myosin to which the vMLC-1 binds that disrupts myosin binding to actin; and 3) the MLC-pep exerts a direct effect on the actin-myosin interaction or actin-actin interactions in the presence of regulatory proteins and Ca2+, such that it cooperatively stimulates the entire thin filament. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (b / block-01 :li "1" :ARG0 (s / small-molecule :name (n / name :op1 "MLC-pep")) :ARG1 (i / interact-01 :ARG0 (p / protein :name (n2 / name :op1 "vMLC-1")) :ARG1 (p2 / protein :name (n3 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :ARG0-of (r / release-01 :ARG1 (a2 / affect-01 :ARG0-of (t / tether-01) :ARG0-of (l / lead-03 :ARG2 (a3 / affect-01 :mod (i2 / inotropic)))))) :op2 (b2 / block-01 :li "2" :ARG0 s :ARG1 (s2 / site :part-of (p3 / protein :name (n4 / name :op1 "myosin") :xref (x1 / xref :value "UNIPROT:MYH1_HUMAN" :prob "0.322")) :ARG2-of (b3 / bind-01 :ARG1 p)) :ARG0-of (d / disrupt-01 :ARG1 (b4 / bind-01 :ARG1 p3 :ARG2 p2))) :op3 (e / exert-01 :li "3" :ARG0 s :ARG1 (a4 / affect-01 :ARG1-of (d2 / direct-02)) :ARG2 (o / or :op1 (i3 / interact-01 :ARG0 p2 :ARG1 p3) :op2 (i4 / interact-01 :ARG0 p2 :ARG1 p2)) :condition (p4 / present-02 :ARG1 (a5 / and :op1 (p5 / protein :ARG0-of (r2 / regulate-01)) :op2 (s3 / small-molecule :name (n5 / name :op1 "calcium") :ARG0-of r2 :ARG1-of (i5 / ionize-01 :value "2+") :xref (x2 / xref :value "PUBCHEM:5460341" :prob "10.601383")))) :ARG0-of (c2 / cause-01 :ARG1 (s4 / stimulate-01 :ARG0 s :ARG1 (f / filament :mod (e2 / entire) :ARG1-of (t2 / thin-03)) :ARG2-of (c / cooperate-01))))) # ::id bio.chicago_2015.19251 # ::date 2015-10-21T01:50:29 # ::file bio_chicago_2015_19251.txt # ::snt In addition, in co-transfection experiments, Rlf (Zwartkruis et al., 1998 ), but apparently not RalGDS (Urano et al., 1996 ), can mediate Rap1- and C3G-induced Ral activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (a / and :op2 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (m / mediate-01 :ARG0 (e / enzyme :name (n / name :op1 "Rlf") :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n2 / name :op1 "Zwartkruis")) :op2 (p4 / person :mod (o / other))) :time (d4 / date-entity :year "1998"))) :xref (x2 / xref :value "UNIPROT:RLF_HUMAN" :prob "0.603")) :ARG1 (a3 / activate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "Ral") :xref (x3 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.603")) :ARG2-of (i / induce-01 :ARG0 (a4 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Rap1") :xref (x1 / xref :value "UNIPROT:RABX5_HUMAN" :prob "0.603")) :op2 (s / small-molecule :name (n5 / name :op1 "C3G")))))) :time (e3 / experiment-01 :ARG2 (c2 / cotransfect-01))) :ARG2 (p6 / possible-01 :polarity "-" :ARG1 (m2 / mediate-01 :ARG0 (p7 / protein :name (n6 / name :op1 "RalGDS") :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n7 / name :op1 "Urano")) :op2 (p10 / person :mod (o2 / other))) :time (d3 / date-entity :year "1996"))) :xref (x / xref :value "UNIPROT:GNDS_HUMAN" :prob "1.003")) :ARG1 a3 :time e3) :ARG1-of (a6 / appear-02)))) # ::id bio.chicago_2015.19256 # ::date 2015-10-21T02:14:06 # ::file bio_chicago_2015_19256.txt # ::snt Towards the center of the gradient, high levels of Dpp signaling strongly repress brk transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / repress-01 :ARG0 (l / level :ARG1-of (h / high-02) :degree-of (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Dpp")))) :ARG1 (t / transcribe-01 :ARG0 (p2 / protein :name (n2 / name :op1 "brk") :xref (x / xref :value "UNIPROT:PTK6_HUMAN" :prob "0.602"))) :direction (c / center :part-of (g2 / gradient)) :ARG1-of (s2 / strong-02)) # ::id bio.chicago_2015.19269 # ::date 2015-10-21T02:29:26 # ::file bio_chicago_2015_19269.txt # ::snt high amounts of Dpp signaling abolish brk transcription completely, intermediate amounts of Dpp only partially repress brk transcription, while the absence of Dpp results in high levels of brk transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (a / and :op1 (a2 / abolish-01 :ARG0 (a3 / amount :degree-of (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Dpp"))) :ARG1-of (h3 / high-02)) :ARG1 (t / transcribe-01 :ARG0 (p3 / protein :name (n2 / name :op1 "brk") :xref (x / xref :value "UNIPROT:PTK6_HUMAN" :prob "0.602"))) :ARG1-of (c2 / complete-02)) :op2 (r / repress-01 :ARG0 (a4 / amount :degree (i / intermediate) :quant-of p) :ARG1 t :degree (p4 / part :mod (o / only)))) :ARG2 (r2 / result-01 :ARG1 (a5 / absent-01 :ARG1 p) :ARG2 (l / level :quant-of t :ARG1-of h3))) # ::id bio.chicago_2015.19306 # ::date 2015-10-21T03:50:36 # ::file bio_chicago_2015_19306.txt # ::snt Dissected wing imaginal discs stained with antibodies against the beta-galactosidase and Engrailed proteins showing the induction and suppression of induction of Engrailed expression; anterior upward, wing pouch to the left. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (d3 / disc :ARG1-of (s / stain-01 :ARG2 (a2 / antibody :ARG0-of (o / oppose-01 :ARG1 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "beta-galactosidase") :xref (x / xref :value "UNIPROT:BGAL_HUMAN" :prob "0.702")) :op2 (p2 / protein :name (n3 / name :op1 "Engrailed")))))) :ARG0-of (s2 / show-01 :ARG1 (a4 / and :op1 (i / induce-01 :ARG2 (e / express-03 :ARG2 p2)) :op2 (s3 / suppress-01 :ARG1 i))) :ARG1-of (d2 / describe-01 :medium (p / pouch :ARG1-of (l / left-20) :mod (a5 / anterior :direction (u / upward)) :mod (w2 / wing))) :mod (w / wing) :ARG1-of (d / dissect-01) :mod (i2 / imaginal)) # ::id bio.chicago_2015.19311 # ::date 2015-10-21T13:44:06 # ::file bio_chicago_2015_19311.txt # ::snt To identify the site(s) on the cytoplasmic domain of the EGFR that mediates its recruitment of PI3K-C2beta, a panel of receptor point mutations was expressed in HEK293 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (e / express-03 :ARG2 (p / panel :consist-of (m / mutate-01 :ARG1 (p2 / point :mod (r / receptor)))) :ARG3 (c / cell :name (n / name :op1 "HEK293")) :purpose (i / identify-01 :ARG1 (s / site :location (d / domain :mod (c2 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :part-of (e2 / enzyme :name (n2 / name :op1 "EGFR") :ARG0-of (m2 / mediate-01 :ARG1 (r2 / recruit-01 :ARG0 e2 :ARG1 (e3 / enzyme :name (n3 / name :op1 "PI3K-C2beta") :xref (x / xref :value "UNIPROT:P3C2B_HUMAN" :prob "0.693")))) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))))) # ::id bio.chicago_2015.19345 # ::date 2015-10-21T14:06:37 # ::file bio_chicago_2015_19345.txt # ::snt Formation of sharp borders of Iro-C gene expression in response to localized EGFR signaling The lateral border delimiting Iro-C expression in the wing disc is relatively straight and sharp (e.g. Fig. 1B, Fig. 4C), raising the question of how such a well-defined border can be established and maintained in response to EGFR signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (m / multi-sentence :snt1 (f / form-01 :ARG1 (b / border :ARG1-of (s / sharp-02) :poss (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Iro-C")))) :ARG2-of (r / respond-01 :ARG1 (s2 / signal-07 :ARG0 (e2 / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (l / local-02)))) :snt2 (a / and :op1 (s3 / straight-04 :ARG1 (b2 / border :mod (l2 / lateral) :ARG1-of (d / delimit-01 :ARG2 (e4 / express-03 :ARG1 (g2 / gene :name (n3 / name :op1 "Iro-C"))) :location (d2 / disc :topic (w / wing)))) :ARG2-of (r2 / relative-05)) :op2 (s4 / sharp-02 :ARG1 b2 :degree r2) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1B") :op2 (f3 / figure :mod "4C"))) :ARG0-of (r3 / raise-01 :ARG1 (q / question-01 :ARG1 (t / thing :manner-of (e3 / establish-01 :ARG1 (b3 / border :ARG1-of (d4 / define-01 :manner (w2 / well) :mod (s6 / such))) :ARG2-of (r4 / respond-01 :ARG1 (s5 / signal-07 :ARG0 (e5 / enzyme :name (n4 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG1-of (p / possible-01)) :ARG0-of (m2 / maintain-01 :ARG1 b3 :ARG2-of r4)))))) # ::id bio.chicago_2015.19362 # ::date 2015-10-21T14:50:57 # ::file bio_chicago_2015_19362.txt # ::snt Ectopic Gem or Rad expression inhibits ROK-dependent functions such as formation of stress fibers and focal adhesions, neurite retraction, and Rho-dependent transformation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (i / inhibit-01 :ARG0 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "Gem") :xref (x2 / xref :value "UNIPROT:GEM_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n2 / name :op1 "Rad") :xref (x / xref :value "UNIPROT:RAD_HUMAN" :prob "0.603")) :mod (e2 / ectopic))) :ARG1 (f / function-01 :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n3 / name :op1 "ROK") :xref (x1 / xref :value "UNIPROT:DDX52_HUMAN" :prob "0.262"))) :example (a2 / and :op1 (f2 / form-01 :ARG1 (a3 / and :op1 (f3 / fiber :mod (s / stress)) :op2 (a4 / adhere-01 :mod (f4 / focal)))) :op2 (r / retract-01 :ARG1 (c / cell :name (n4 / name :op1 "neurite"))) :op3 (t / transform-01 :ARG0-of (d2 / depend-01 :ARG1 (p4 / protein-family :name (n5 / name :op1 "Rho"))))))) # ::id bio.mskcc_0001.1 # ::date 2014-11-03T12:55:43 # ::file bio_mskcc_0001_1.txt # ::snt We identify four S/TP sites of B-Raf phosphorylated by activated ERK and find that feedback phosphorylation of B-Raf inhibits binding to activated Ras and disrupts heterodimerization with C-Raf, which is dependent on the B-Raf pS729/14-3-3 binding site. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 10, 2014 (a / and :op1 (i / identify-01 :ARG0 (w / we) :ARG1 (p / protein-segment :quant "4" :part (a5 / amino-acid :ARG3-of (p2 / phosphorylate-01 :ARG2 (e / enzyme :name (n3 / name :op1 "ERK") :ARG1-of (a2 / activate-01) :xref (x4 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :subevent-of (f2 / feedback)) :mod (o / or :op1 (a6 / amino-acid :name (n / name :op1 "serine") :xref (x7 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a7 / amino-acid :name (n9 / name :op1 "threonine") :xref (x6 / xref :value "PUBCHEM:205" :prob "11.848252")))) :part-of (e4 / enzyme :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :op2 (f / find-01 :ARG0 w :ARG1 (a3 / and :op1 (i2 / inhibit-01 :ARG0 p2 :ARG1 (b / bind-01 :ARG1 e4 :ARG2 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (a4 / activate-01) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (d / disrupt-01 :ARG0 p2 :ARG1 (h / heterodimerize-01 :ARG1 e4 :ARG2 (e2 / enzyme :name (n5 / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG0-of (d2 / depend-01 :ARG1 (a8 / amino-acid :mod "729" :name (n10 / name :op1 "serine") :ARG3-of (p4 / phosphorylate-01) :ARG1-of (b2 / bind-01 :ARG2 (p3 / protein :name (n6 / name :op1 "14-3-3") :xref (x3 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :part-of e4 :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")))))))) # ::id bio.mskcc_0001.2 # ::date 2014-11-03T19:18:55 # ::file bio_mskcc_0001_2.txt # ::snt 14-3-3 dimers bind to phosphorylation sites present in both the N- and C-terminal regions and stabilize the autoinhibited state (22). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (b / bind-01 :ARG1 (d / dimer :part (p5 / protein :name (n / name :op1 "14-3-3") :xref (x / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :ARG2 (p9 / protein-segment :ARG1-of (p / phosphorylate-01) :ARG1-of (p11 / present-02 :ARG2 (p2 / protein-segment :name (n2 / name :op1 "N-terminus"))))) :op2 (b2 / bind-01 :ARG1 d :ARG2 (p10 / protein-segment :ARG1-of (p3 / phosphorylate-01) :ARG1-of (p12 / present-02 :ARG2 (p4 / protein-segment :name (n3 / name :op1 "C-terminus"))))) :op3 (s3 / stabilize-01 :ARG0 d :ARG1 (i / inhibit-01 :ARG0 p5 :ARG1 p5)) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c / cite-01 :ARG2 "22")))) # ::id bio.mskcc_0001.3 # ::date 2014-11-03T19:35:08 # ::file bio_mskcc_0001_3.txt # ::snt To activate the Raf proteins, autoinhibition mediated by the N terminus must be relieved and the kinase domain must adopt the active catalytic conformation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (r / require-01 :ARG0 (a / activate-01 :ARG1 (p / protein-family :name (n / name :op1 "Raf"))) :ARG1 (a2 / and :op1 (o / obligate-01 :ARG2 (r2 / relieve-01 :ARG1 (i / inhibit-01 :ARG0 (p2 / protein-segment :part-of p) :ARG1 (p3 / protein-segment :part-of p) :ARG1-of (m / mediate-01 :ARG0 (p5 / protein-segment :name (n2 / name :op1 "N-terminus") :part-of p))))) :op2 (o2 / obligate-01 :ARG2 (a3 / activate-01 :ARG1 (d / domain :mod (k / kinase) :part-of p :ARG0-of (c / catalyze-01)))))) # ::id bio.mskcc_0001.4 # ::date 2014-11-03T20:16:00 # ::file bio_mskcc_0001_4.txt # ::snt Under normal signaling conditions, Ras activation helps mediate these events by recruiting the Raf proteins to the plasma membrane, which induces the release of 14-3-3 from the N-terminal binding site and facilitates phosphorylation of the Raf kinase domain (19). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (h / help-01 :ARG0 (a / activate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (m / mediate-01 :ARG0 a :ARG1 (e / event :mod (t / this))) :manner (r / recruit-01 :ARG0 a :ARG1 (e2 / enzyme :name (n6 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :destination (m2 / membrane :mod (p2 / plasma) :xref (x3 / xref :value "GO:0016020" :prob "0.8")) :ARG0-of (i / induce-01 :ARG2 (r2 / release-01 :ARG1 (p3 / protein :name (n2 / name :op1 "14-3-3") :xref (x2 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572")) :ARG2 (p8 / protein-segment :part-of (p4 / protein-segment :name (n3 / name :op1 "N-terminus")) :ARG1-of (b / bind-01)))) :ARG0-of (f / facilitate-01 :ARG1 (p5 / phosphorylate-01 :ARG1 (d / domain :mod (k / kinase) :part-of e2)))) :condition (n4 / normal-02 :ARG1 (s2 / signal-07 :ARG0 e3)) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 "19")))) # ::id bio.mskcc_0001.5 # ::date 2014-11-03T20:23:34 # ::file bio_mskcc_0001_5.txt # ::snt Once activated, either by upstream signaling or by mutational events, all Raf proteins are capable of initiating the phosphorylation cascade that results in the sequential activation of MEK and ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / capable-01 :ARG1 (p / protein-family :name (n / name :op1 "Raf") :mod (a / all)) :ARG2 (i / initiate-01 :ARG0 p :ARG1 (c2 / cascade :subevent (p3 / phosphorylate-01) :ARG1-of (r / result-01 :ARG2 (a3 / and :op1 (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op2 (a4 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2-of (f / follow-01 :ARG1 a2)))))) :time (a6 / activate-01 :ARG0 (o / or :op1 (s / signal-07 :source (u / upstream)) :op2 (m / mutate-01)) :ARG1 p)) # ::id bio.mskcc_0001.6 # ::date 2014-11-03T20:34:01 # ::file bio_mskcc_0001_6.txt # ::snt Strikingly, the Raf proteins themselves are also substrates of activated ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / catalyze-01 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1 (p / protein-family :name (n2 / name :op1 "Raf") :mod (a2 / also)) :ARG1-of (s / strike-04)) # ::id bio.mskcc_0001.7 # ::date 2014-11-05T22:08:42 # ::file bio_mskcc_0001_7.txt # ::snt In regard to C-Raf, ERK-dependent feedback phosphorylation has been shown to instigate a regulatory cycle whereby phosphorylation of the feedback sites down-modulates C-Raf signaling, after which the hyperphosphorylated C-Raf protein is dephosphorylated and returned to a signaling-competent state through dephosphorylation events involving protein phosphatase 2A (PP2A) and the Pin1 prolyl-isomerase (8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (s / show-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "8")) :ARG1 (i / instigate-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :part-of (e / enzyme :name (n / name :op1 "C-Raf") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :destination-of (f / feedback)) :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (c / cycle-02 :ARG1-of (r / regulate-01) :subevent (d2 / downmodulate-01 :ARG1 (s2 / signal-07 :ARG0 e) :ARG2 p :op1-of (a / after :time-of (d3 / dephosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "C-Raf") :ARG3-of (h / hyperphosphorylate-01) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG0-of (a2 / activate-01 :ARG1 s2) :ARG1-of (i2 / involve-01 :ARG2 (a3 / and :op1 (e4 / enzyme :name (n4 / name :op1 "protein" :op2 "phosphatase" :op3 "2A") :xref (x / xref :value "UNIPROT:PPM1A_HUMAN" :prob "0.392")) :op2 (p4 / prolyl-isomerase :name (n5 / name :op1 "Pin1")))))))))) # ::id bio.mskcc_0001.8 # ::date 2014-11-06T21:40:56 # ::file bio_mskcc_0001_8.txt # ::snt For B-Raf, two ERK-dependent feedback sites, S750 and T753, have been identified, and phosphorylation of these sites has been reported to have a negative regulatory effect # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 28, 2015 (a / and :op1 (i / identify-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "750" :name (n4 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "753" :name (n3 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :destination-of (f / feedback :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))) :op2 (r / report-01 :ARG1 (a5 / affect-01 :ARG0 (p / phosphorylate-01 :ARG1 a2) :ARG2 (d2 / downregulate-01)))) # ::id bio.mskcc_0001.9 # ::date 2014-11-06T21:57:03 # ::file bio_mskcc_0001_9.txt # ::snt Here we find that both normal and oncogenic B-Raf proteins are phosphorylated on four S/TP sites (S151, T401, S750, and T753) by activated ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "151" :name (n / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :mod "401" :name (n2 / name :op1 "threonine") :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :op3 (a4 / amino-acid :mod "750" :name (n3 / name :op1 "serine") :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op4 (a5 / amino-acid :mod "753" :name (n4 / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (e / enzyme :name (n5 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG2 (e2 / enzyme :name (n7 / name :op1 "ERK") :ARG1-of (a6 / activate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :condition (o / or :op1 (n6 / normal-02 :ARG1 e) :op2 (c / cause-01 :ARG0 e :ARG1 (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))))) :medium (h / here)) # ::id bio.mskcc_0001.10 # ::date 2014-11-06T22:59:41 # ::file bio_mskcc_0001_10.txt # ::snt Previously, we found that in response to growth factor treatment, signaling from C-Raf is downregulated by ERK-dependent feedback phosphorylation on S/TP sites and that C-Raf is subsequently dephosphorylated and returned to a signaling-competent state through the activities of PP2A and the Pin1 prolyl-isomerase (8) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (f2 / find-01 :ARG0 (w / we) :ARG1 (a / and :op1 (d2 / downregulate-01 :ARG0 (p / phosphorylate-01 :ARG1 (a4 / amino-acid :mod (o / or :op1 (a6 / amino-acid :name (n7 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a7 / amino-acid :name (n8 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))) :part-of (e / enzyme :name (n / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :destination-of (f / feedback)) :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (s2 / signal-07 :ARG0 e)) :op2 (a8 / and :op1 (d3 / dephosphorylate-01 :ARG1 e) :op2 (r / return-03 :ARG1 e :ARG2 (s3 / state :mod s2)) :manner (a9 / activity-06 :ARG0 (a3 / and :op1 (e4 / enzyme :name (n4 / name :op1 "PP2A") :xref (x / xref :value "UNIPROT:PP2AA_HUMAN" :prob "0.372")) :op2 (p4 / prolyl-isomerase :name (n5 / name :op1 "Pin1")))) :time (a5 / after :op1 d2)) :ARG0-of (r2 / respond-01 :ARG1 (t / treat-04 :ARG2 (g / growth-factor)))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "8"))) :time (p2 / previous)) # ::id bio.mskcc_0001.11 # ::date 2014-11-09T19:29:37 # ::file bio_mskcc_0001_11.txt # ::snt The Pin1 prolyl-isomerase binds specifically to phosphorylated S/TP (pS/TP) motifs (33), and isomerization of the pS/TP bond is required for PP2A to efficiently dephosphorylate certain proteins, such as cdc25C, Myc, and C-Raf (16). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (b / bind-01 :ARG1 (p7 / prolyl-isomerase :name (n / name :op1 "Pin1")) :ARG2 (p / protein-segment :ARG3-of (p2 / phosphorylate-01) :mod (s2 / slash :op1 (a3 / amino-acid :name (n6 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :name (n7 / name :op1 "threonine") :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")))) :ARG1-of (s / specific-02) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "33")))) :op2 (r / require-01 :ARG0 (d2 / dephosphorylate-01 :ARG1 (p4 / protein :example (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "cdc25C") :xref (x2 / xref :value "UNIPROT:MPIP3_HUMAN" :prob "0.653")) :op2 (p5 / protein :name (n4 / name :op1 "Myc") :xref (x3 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")) :op3 (e4 / enzyme :name (n5 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :mod (c3 / certain)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "PP2A") :xref (x / xref :value "UNIPROT:PP2AA_HUMAN" :prob "0.372")) :ARG2-of (e5 / efficient-01 :ARG1 e2)) :ARG1 (i / isomerize-01 :ARG1 (b2 / bond :part-of p)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "16"))))) # ::id bio.mskcc_0001.12 # ::date 2014-11-09T20:58:01 # ::file bio_mskcc_0001_12.txt # ::snt Complex formation between B-Raf and Pin1 correlated with the phosphorylation of B-Raf on S/TP sites (Fig. 1C) and this interaction could be blocked when the MEK inhibitor U0126 was used to prevent ERK activation and the S/TP phosphorylation of B-Raf (Fig. 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (c / correlate-01 :ARG1 (f / form-01 :ARG1 (m / macro-molecular-complex) :ARG2 (a2 / and :op1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "Pin1") :xref (x1 / xref :value "UNIPROT:PIN1_HUMAN" :prob "0.603")))) :ARG2 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :part-of e :mod (s2 / slash :op1 (a5 / amino-acid :name (n6 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a6 / amino-acid :name (n7 / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1C"))) :op2 (p3 / possible-01 :ARG1 (b / block-01 :ARG1 f) :condition (u / use-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (p6 / protein-family :name (n4 / name :op1 "MEK"))) :xref (x5 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG2 (p4 / prevent-01 :ARG0 s :ARG1 (a3 / and :op1 (a4 / activate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op2 (p5 / phosphorylate-01 :ARG1 p2)))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "1D")))) # ::id bio.mskcc_0001.13 # ::date 2014-11-16T16:37:31 # ::file bio_mskcc_0001_13.txt # ::snt Together, these findings indicate that Pin1 is needed for the efficient dephosphorylation of B-Raf and are consistent with the model that S/TP phosphorylation inhibits Raf signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (i / indicate-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t3 / this)) :ARG1 (n4 / need-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Pin1") :xref (x2 / xref :value "UNIPROT:PIN1_HUMAN" :prob "0.603")) :purpose (d / dephosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2-of (e3 / efficient-01)))) :op2 (c / consistent-01 :ARG1 t :ARG2 (m / model :topic (i2 / inhibit-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :mod (s2 / slash :op1 (a2 / amino-acid :name (n5 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :name (n6 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))))) :ARG1 (s / signal-07 :ARG0 (e4 / enzyme :name (n3 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))))) :mod (t2 / together)) # ::id bio.mskcc_0001.14 # ::date 2014-11-16T16:54:17 # ::file bio_mskcc_0001_14.txt # ::snt Eluting in HPLC fractions 78 to 79 was a peptide phosphorylated on S750 and T753, the previously identified ERK sites, and eluting in fractions 26 and 58 to 59 were peptides phosphorylated at S151 and T401, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (e / elute-01 :ARG1 (p / peptide :part (a2 / amino-acid :mod "750" :name (n / name :op1 "serine") :part-of (p4 / protein-segment :part-of (e2 / enzyme :name (n3 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (i / identify-01 :time (p5 / previous))) :ARG3-of "p2" :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part (a3 / amino-acid :mod "753" :name (n2 / name :op1 "threonine") :ARG3-of (p2 / phosphorylate-01) :part-of p4 :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252"))) :ARG2 (f / fraction :mod (b / between :op1 "78" :op2 "79") :mod (c / chromatography :mod (l / liquid :ARG1-of (p10 / perform-02 :ARG1-of (h / high-02)))))) :op2 (e3 / elute-01 :ARG1 (p6 / peptide :part (a5 / amino-acid :mod "151" :name (n4 / name :op1 "serine") :ARG3-of p2 :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG2 (f3 / fraction :mod "26")) :op3 (e4 / elute-01 :ARG1 (p9 / peptide :part (a6 / amino-acid :mod "401" :name (n5 / name :op1 "threonine") :ARG3-of p2 :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252"))) :ARG2 (f4 / fraction :mod (b2 / between :op1 "58" :op2 "59")))) # ::id bio.mskcc_0001.15 # ::date 2014-11-16T17:31:43 # ::file bio_mskcc_0001_15.txt # ::snt All four of these identified sites are followed by a proline residue, and their phosphorylation could be blocked by pretreating cells with the MEK inhibitor U0126 (Fig. 2A), suggesting that these residues are feedback targets of the proline-directed kinase, ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (f / follow-01 :ARG1 (r / residue :mod (a3 / amino-acid :name (n / name :op1 "proline") :xref (x1 / xref :value "PUBCHEM:614" :prob "10.45396"))) :ARG2 (p / protein-segment :quant "4" :mod (a2 / all) :mod (t / this) :ARG1-of (i2 / identify-01))) :op2 (p2 / possible-01 :ARG1 (b / block-01 :ARG0 (t2 / treat-04 :ARG1 (c / cell) :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK"))) :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :time (b2 / before)) :ARG1 (p3 / phosphorylate-01 :ARG1 p)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2A"))) :ARG0-of (s2 / suggest-01 :ARG1 (f3 / feedback :destination r :source (k / kinase :name (n4 / name :op1 "ERK") :ARG1-of (d2 / direct-01 :ARG2 p) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) # ::id bio.mskcc_0001.16 # ::date 2014-11-16T17:46:13 # ::file bio_mskcc_0001_16.txt # ::snt Consistent with this model, we found that when purified activated ERK was incubated with kinase-dead B-Raf(K375M) in vitro, ERK strongly phosphorylated B-Raf on the S151, S750, and T753 sites, with phosphorylation of T401 also observed (Fig. 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (a6 / and :op1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "151" :name (n4 / name :op1 "serine") :part-of "e2" :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "750" :name (n5 / name :op1 "serine") :part-of "e2" :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op3 (a5 / amino-acid :mod "753" :name (n6 / name :op1 "threonine") :part-of "e2" :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))) :ARG2 (e / enzyme :name (n / name :op1 "ERK") :ARG1-of (a / activate-01) :ARG1-of (p2 / purify-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (s / strong-02)) :op2 (p3 / phosphorylate-01 :ARG1 (a7 / amino-acid :mod "401" :name (n7 / name :op1 "threonine") :part-of "e2" :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 e :ARG1-of (o / observe-01 :mod (a8 / also))) :condition (i / incubate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "K375M") :ARG0-of (f2 / function-01 :polarity "-" :ARG1 (k / kinase)) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :manner (i2 / in-vitro)) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "2B"))) :ARG1-of (c / consistent-01 :ARG2 (m / model :mod (t / this)))) # ::id bio.mskcc_0001.17 # ::date 2014-11-16T18:19:06 # ::file bio_mskcc_0001_17.txt # ::snt These findings are similar to what has been observed for C-Raf (8) and suggest that feedback phosphorylation is a conserved mechanism used to disrupt the Ras/Raf interaction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jun 13, 2015 (a / and :op1 (r / resemble-01 :ARG1 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG2 (t3 / thing :ARG1-of (o / observe-01) :topic (e / enzyme :name (n / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "8")))) :op2 (s / suggest-01 :ARG0 t :ARG1 (m / mechanism :ARG1-of (c2 / conserve-01) :ARG1-of (u / use-01 :ARG2 (d2 / disrupt-01 :ARG0 m :ARG1 (i / interact-01 :ARG0 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))))) :domain (p3 / phosphorylate-01 :subevent-of (f2 / feedback))))) # ::id bio.mskcc_0001.18 # ::date 2014-11-16T20:11:46 # ::file bio_mskcc_0001_18.txt # ::snt Consistent with these data, we found that B-Raf interacted with C-Raf in an inducible and transient manner following growth factor treatment (Fig. 3B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG2-of (i2 / induce-01) :ARG1-of (t2 / transient-02) :ARG2-of (f4 / follow-01 :ARG1 (t3 / treat-04 :ARG2 (g / growth-factor)))) :ARG1-of (c / consistent-01 :ARG2 (d / data :mod (t / this))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "3B") :op2 (f3 / figure :mod "3C")))) # ::id bio.mskcc_0001.19 # ::date 2014-11-21T12:13:54 # ::file bio_mskcc_0001_19.txt # ::snt In addition, when B-Raf feedback phosphorylation was prevented, either by U0126 treatment or by mutation of all the feedback sites, an increase in the basal level of heterodimerization with C-Raf was observed, and heterodimerization in response to growth factor treatment was increased and prolonged (Fig. 3B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a2 / and :op2 (a / and :op1 (o / observe-01 :ARG1 (i / increase-01 :ARG1 (l / level :mod (b / basal) :degree-of (h / heterodimerize-01 :ARG1 "e" :ARG2 (e2 / enzyme :name (n3 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))))) :op2 (i2 / increase-01 :ARG1 (h2 / heterodimerize-01 :ARG2-of (r / respond-01 :ARG1 (t2 / treat-04 :ARG2 (g / growth-factor))))) :op3 (p / prolong-01 :ARG1 h2) :condition (p2 / prevent-01 :ARG0 (o2 / or :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :op2 (m / mutate-01 :ARG1 (p4 / protein-segment :part-of "e" :destination-of "f" :mod (a3 / all)))) :ARG1 (p3 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :subevent-of (f / feedback))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "3B") :op2 (f3 / figure :mod "3C"))))) # ::id bio.mskcc_0001.20 # ::date 2014-11-21T12:36:32 # ::file bio_mskcc_0001_20.txt # ::snt These findings support a model whereby feedback phosphorylation disrupts Raf heterodimerization. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 24, 2014 (s / support-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (m / model :topic (d / disrupt-01 :ARG0 (p / phosphorylate-01 :ARG1 "e" :subevent-of (f2 / feedback)) :ARG1 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))))) # ::id bio.mskcc_0001.21 # ::date 2014-11-21T12:49:56 # ::file bio_mskcc_0001_21.txt # ::snt Unlike WT B-Raf, oncogenic B-Raf proteins have been shown to heterodimerize constitutively with C-Raf in a Ras-independent manner (11). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (c5 / contrast-01 :ARG1 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :mod (c3 / constitutive) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (e4 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (s / show-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 "11")))) :ARG2 (h2 / heterodimerize-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "B-Raf") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 e2 :mod (c6 / constitutive :polarity "-"))) # ::id bio.mskcc_0001.22 # ::date 2014-11-28T17:28:12 # ::file bio_mskcc_0001_22.txt # ::snt When we next examined the effect of feedback phosphorylation on the ability of oncogenic B-Raf to form heterodimers with C-Raf, we found that the levels of endogenous C-Raf associating with B-Raf proteins of high (V600E), intermediate (G466A), and impaired (D594G) kinase activities all increased when the feedback sites were mutated, indicating that feedback phosphorylation also inhibits the heterodimerization of oncogenic B-Raf proteins (Fig. 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG1 (a / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "C-Raf") :ARG1-of (a2 / associate-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E") :ARG0-of (a3 / act-01 :ARG1 (k / kinase) :ARG1-of (h / high-02)) :xref (x7 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :mod (e7 / endogenous) :xref (x8 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :op2 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "C-Raf") :ARG1-of (a5 / associate-01 :ARG2 (e5 / enzyme :name (n5 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "G466A") :ARG0-of (a4 / act-01 :ARG1 (k2 / kinase) :degree (i2 / intermediate)) :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :mod (e8 / endogenous) :xref (x6 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :op3 (l3 / level :quant-of (e4 / enzyme :name (n4 / name :op1 "C-Raf") :ARG1-of (a6 / associate-01 :ARG2 (e6 / enzyme :name (n6 / name :op1 "B-Raf") :ARG2-of (m3 / mutate-01 :value "D594G") :ARG0-of (a7 / activity-06 :ARG1-of (i3 / impair-01)) :xref (x5 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :mod (e9 / endogenous) :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))) :condition (m4 / mutate-01 :ARG1 (p / protein-segment :part-of (e10 / enzyme :name (n7 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :destination-of (f2 / feedback))) :ARG0-of (i4 / indicate-01 :ARG1 (i5 / inhibit-01 :ARG0 "p2" :ARG1 (h3 / heterodimerize-01 :ARG1 "e12" :ARG2 "e13") :mod (a9 / also))) :ARG1-of (d / describe-01 :ARG0 (f4 / figure :mod "3D"))) :manner (e11 / examine-01 :ARG0 w :ARG1 (a8 / affect-01 :ARG0 (p2 / phosphorylate-01 :subevent-of (f3 / feedback)) :ARG1 (p3 / possible-01 :ARG1 (h2 / heterodimerize-01 :ARG1 (e12 / enzyme :name (n9 / name :op1 "B-Raf") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n11 / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (e13 / enzyme :name (n10 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))))) :time (n8 / next))) # ::id bio.mskcc_0001.23 # ::date 2014-11-28T18:08:23 # ::file bio_mskcc_0001_23.txt # ::snt Previous studies have shown that, for both normal and oncogenic B-Raf proteins to heterodimerize with C-Raf, the C-terminal 14-3-3 binding site of C-Raf (S621) must be intact (11, 27) (Fig. 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (s / show-01 :ARG0 (s2 / study :time (p / previous) :ARG1-of (c / cite-01 :ARG2 (a / and :op1 "11" :op2 "27"))) :ARG1 (a2 / and :op1 (r / require-01 :ARG0 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))) :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :ARG1 (i / intact :domain (a3 / amino-acid :mod "621" :name (n3 / name :op1 "serine") :part-of (p2 / protein-segment :name (n4 / name :op1 "C-terminus") :part-of e2) :ARG1-of (b / bind-01 :ARG2 (p3 / protein :name (n5 / name :op1 "14-3-3") :xref (x2 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :op2 (r2 / require-01 :ARG0 (h2 / heterodimerize-01 :ARG1 (e3 / enzyme :name (n6 / name :op1 "B-Raf") :ARG1-of (n7 / normal-02) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 e2) :ARG1 i) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3E")))) # ::id bio.mskcc_0001.24 # ::date 2014-11-29T14:06:52 # ::file bio_mskcc_0001_24.txt # ::snt To determine whether binding of 14-3-3 to B-Raf is also required for heterodimerization, B-Raf proteins containing lanine substitutions in the two 14-3-3 binding sites, S365 and S729 (2), were examined for their abilities to heterodimerize with C-Raf in response to growth factor treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (e / examine-01 :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (h / heterodimerize-01 :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf") :part (a / amino-acid :name (n2 / name :op1 "alanine") :ARG1-of (s / substitute-01 :ARG3 (a2 / amino-acid :mod "365" :name (n3 / name :op1 "serine") :ARG1-of (b / bind-01 :ARG2 (p / protein :name (n6 / name :op1 "14-3-3") :xref (x3 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :xref (x4 / xref :value "PUBCHEM:602" :prob "10.089661")) :part (a3 / amino-acid :name (n4 / name :op1 "alanine") :ARG1-of (s2 / substitute-01 :ARG2 (a4 / amino-acid :mod "729" :name (n5 / name :op1 "serine") :ARG1-of (b2 / bind-01 :ARG2 p) :xref (x7 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :xref (x5 / xref :value "PUBCHEM:602" :prob "10.089661")) :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (e3 / enzyme :name (n7 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG2-of (r / respond-01 :ARG1 (t / treat-04 :ARG2 (g / growth-factor))))) :purpose (d / determine-01 :ARG1 (r2 / require-01 :mode "interrogative" :ARG0 (h2 / heterodimerize-01 :ARG1 "e4" :ARG2 e3) :ARG1 (b3 / bind-01 :ARG1 p :ARG2 (e4 / enzyme :name (n9 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :mod (a5 / also)))) # ::id bio.mskcc_0001.25 # ::date 2014-11-29T21:20:25 # ::file bio_mskcc_0001_25.txt # ::snt Not surprisingly, given that mutation of the S365 14-3-3 binding site enhances the membrane localization of B-Raf (2), increased heterodimerization with C-Raf was observed for S365A B-Raf compared to WT B-Raf (Fig. 3F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 29, 2014 (o / observe-01 :ARG1 (i / increase-01 :ARG1 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "S365A") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :compared-to (h2 / heterodimerize-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 e2) :ARG1-of (c / cause-01 :ARG0 (e4 / enhance-01 :ARG0 (m2 / mutate-01 :ARG1 (a / amino-acid :mod "365" :name (n4 / name :op1 "serine") :ARG1-of (b / bind-01 :ARG2 (p / protein :name (n5 / name :op1 "14-3-3") :xref (x3 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (b2 / be-located-at-91 :ARG1 e2 :ARG2 (m3 / membrane :xref (x4 / xref :value "GO:0016020" :prob "0.8"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "2"))))) :ARG0-of (s / surprise-01 :polarity "-") :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3F")))) # ::id bio.mskcc_0001.26 # ::date 2014-11-29T21:32:40 # ::file bio_mskcc_0001_26.txt # ::snt In contrast, S729A B-Raf failed to heterodimerize with C-Raf in response to growth factor treatment, and mutation of this site disrupted the constitutive interaction of oncogenic B-Raf proteins and C-Raf (Fig. 3F), indicating that heterodimerization with C-Raf is dependent on the C-terminal S729 14-3-3 binding site of B-Raf. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (c / contrast-01 :ARG2 (a / and :op1 (f / fail-01 :ARG1 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "S729A") :xref (x4 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG0-of (r / respond-01 :ARG1 (t / treat-04 :ARG2 (g / growth-factor))))) :op2 (d / disrupt-01 :ARG0 m :ARG1 (i / interact-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "B-Raf") :ARG0-of (c2 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer"))) :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 e2 :mod (c4 / constitutive))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3F")) :ARG0-of (i2 / indicate-01 :ARG1 (d3 / depend-01 :ARG0 (h2 / heterodimerize-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 e2) :ARG1 (a2 / amino-acid :mod "729" :name (n6 / name :op1 "serine") :part-of (p / protein-segment :name (n7 / name :op1 "C-terminus") :part-of e4) :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n8 / name :op1 "14-3-3") :xref (x2 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")))))) # ::id bio.mskcc_0001.27 # ::date 2015-01-19T22:53:44 # ::file bio_mskcc_0001_27.txt # ::snt Previous studies have found that all oncogenic B-Raf proteins can activate C-Raf and that heterodimerization with C-Raf is required for kinase-impaired oncogenic B-Raf proteins to mediate ERK activation in vivo (31). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (f / find-01 :ARG0 (s / study :time (p / previous)) :ARG1 (a / and :op1 (p2 / possible-01 :ARG1 (a2 / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :mod (a3 / all) :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))) :op2 (r / require-01 :ARG0 (m / mediate-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG0-of c :ARG0-of (a5 / activate-01 :ARG1 e2 :ARG1-of (i / impair-01)) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (a4 / activate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :manner (i2 / in-vivo))) :ARG1 (h / heterodimerize-01 :ARG1 e :ARG2 e2))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "31")))) # ::id bio.mskcc_0001.28 # ::date 2015-01-20T11:13:17 # ::file bio_mskcc_0001_28.txt # ::snt Therefore, to further investigate both the impact of feedback phosphorylation and the contribution of heterodimerization to oncogenic B-Raf function, we examined the transformation potential of oncogenic B-Raf proteins containing mutations in either the feedback phosphorylation sites (which exhibit increased heterodimerization) or the S729 14-3-3 binding site (which are unable to heterodimerize). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (i / infer-01 :ARG1 (e / examine-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (t / transform-01 :ARG0 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :ARG2-of (m / mutate-01 :ARG1 (o / or :op1 (p2 / protein-segment :ARG1-of (p3 / phosphorylate-01 :subevent-of (f / feedback)) :ARG0-of (e3 / exhibit-01 :ARG1 (h / heterodimerize-01 :ARG1-of (i2 / increase-01)))) :op2 (a / amino-acid :mod "729" :name (n4 / name :op1 "serine") :ARG1-of (b / bind-01 :ARG2 (p4 / protein :name (n2 / name :op1 "14-3-3") :xref (x1 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :ARG0-of (h2 / heterodimerize-01 :ARG1-of (p5 / possible-01 :polarity "-")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :purpose (i3 / investigate-01 :ARG0 w :ARG1 (a2 / and :op1 (i4 / impact-01 :ARG0 (p6 / phosphorylate-01 :subevent-of (f3 / feedback)) :ARG1 "f4") :op2 (c4 / contribute-01 :ARG0 (h3 / heterodimerize-01) :ARG2 (f4 / function-01 :ARG0 e2))) :degree (f2 / further)))) # ::id bio.mskcc_0001.29 # ::date 2015-01-20T12:45:00 # ::file bio_mskcc_0001_29.txt # ::snt For these studies, FBm or S729A mutations were incorporated into a number of oncogenic B-Raf proteins that exhibit various levels of kinase activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (i / incorporate-02 :ARG1 (o / or :op1 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m / mutate-01) :ARG1-of (h / have-part-91 :polarity "-" :ARG2 (p / protein-segment :destination-of (f / feedback))) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e4 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "S729A") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG2 (e / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :quant (n2 / number) :ARG0-of (e2 / exhibit-01 :ARG1 (l / level :mod (v / various) :degree-of (a / activity-06 :ARG0 (k / kinase)))) :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :purpose (s / study :mod (t / this))) # ::id bio.mskcc_0001.30 # ::date 2015-01-20T14:21:50 # ::file bio_mskcc_0001_30.txt # ::snt The proteins were then expressed in NIH 3T3 cells and examined for their abilities to alter cell morphology and induce focus formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (a / and :op1 (e / express-03 :ARG2 (p / protein) :ARG3 (c / cell-line :name (n / name :op1 "NIH" :op2 "3T3"))) :op2 (e2 / examine-01 :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (a2 / and :op1 (a3 / alter-01 :ARG0 p :ARG1 (m / morphology :mod (c2 / cell))) :op2 (i / induce-01 :ARG0 p :ARG2 (f / form-01 :ARG1 (f2 / focus)))))) :time (t / then)) # ::id bio.mskcc_0001.31 # ::date 2015-01-20T14:44:20 # ::file bio_mskcc_0001_31.txt # ::snt As shown in Fig. 4A, the FBm or S729A mutation had no effect on transformation induced by the V600E or G469A B-Raf protein, both of which possess high kinase activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a2 / affect-01 :polarity "-" :ARG0 (o / or :op1 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG1-of (h2 / have-part-91 :polarity "-" :ARG2 (p / protein-segment :destination-of (f2 / feedback))) :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :op2 (m3 / mutate-01 :value "S729A")) :ARG1 (t / transform-01 :ARG2-of (i / induce-01 :ARG0 (o2 / or :op1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m4 / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m5 / mutate-01 :value "G469A") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG0-of (a / activity-06 :ARG1-of (h / high-02))))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "4A"))) # ::id bio.mskcc_0001.32 # ::date 2015-01-20T15:12:00 # ::file bio_mskcc_0001_32.txt # ::snt However, mutation of the feedback sites significantly increased the transforming activities of B-Raf proteins with intermediate or impaired kinase activity (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG2 (i / increase-01 :ARG0 (m / mutate-01 :ARG1 (p / protein-segment :destination-of (f / feedback))) :ARG1 (o / or :op1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (k / kinase) :degree (i3 / intermediate)) :op2 (a2 / activity-06 :ARG0 e :ARG1 k :ARG1-of (i2 / impair-01)) :ARG0-of (t / transform-01)) :ARG2 (s / significant-02) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4A")))) # ::id bio.mskcc_0001.33 # ::date 2015-01-20T22:53:13 # ::file bio_mskcc_0001_33.txt # ::snt The total number of foci observed and, often, the sizes of the foci were increased, and cells within the foci exhibited a more transformed appearance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 5, 2015 (a / and :op1 (i / increase-01 :ARG1 (a3 / and :op1 (n / number :ARG2-of (t / total-01 :ARG1 (f / focus :ARG1-of (o / observe-01)))) :op2 (s / size :poss f)) :frequency (o2 / often)) :op3 (e / exhibit-01 :ARG0 (c / cell :location f) :ARG1 (a2 / appear-02 :ARG1 c :ARG1-of (t2 / transform-01 :degree (m / more))))) # ::id bio.mskcc_0001.34 # ::date 2015-01-21T02:29:01 # ::file bio_mskcc_0001_34.txt # ::snt In contrast, the S729A mutation reduced the transforming activities of the oncogenic proteins with intermediate or impaired kinase activity, causing a reduction in focus number and a flatter cell morphology (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / contrast-01 :ARG2 (r / reduce-01 :ARG0 (m / mutate-01 :value "S729A") :ARG1 (o2 / or :op1 (a / activity-06 :ARG0 (p / protein :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))) :ARG1 (k / kinase) :degree (i / intermediate)) :op2 (a2 / activity-06 :ARG0 (p2 / protein :ARG0-of c2) :ARG1 k :ARG1-of (i2 / impair-01)) :ARG0-of (t / transform-01)) :ARG0-of (c4 / cause-01 :ARG1 (a4 / and :op1 (r2 / reduce-01 :ARG1 (n / number :quant-of (f / focus))) :op2 (m2 / morphology :mod (c5 / cell) :ARG1-of (f2 / flat-06 :degree (m3 / more))))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "4A")))) # ::id bio.mskcc_0001.35 # ::date 2015-01-21T03:05:03 # ::file bio_mskcc_0001_35.txt # ::snt Examination of activated phospho-MEK levels revealed that the FBm and S729 mutations had no effect on MEK activation induced by the high-activity V600E B-Raf protein; however, the FBm and S729A mutations increased and decreased, respectively, the abilities of the intermediate G466A and kinase-impaired D594G B-Raf proteins to activate MEK (Fig. 4B), indicating a correlation between the transformation potential of these proteins and their ability to activate ERK cascade signaling in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (r2 / reveal-01 :ARG0 (e / examine-01 :ARG1 (l / level :degree-of (e2 / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :ARG1-of (a / activate-01) :xref (x5 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG1 (c / contrast-01 :ARG1 (a2 / affect-01 :polarity "-" :ARG0 (a3 / and :op1 (m7 / mutate-01 :ARG1 (e9 / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (h2 / have-part-91 :polarity "-" :ARG2 (p5 / protein-segment :destination-of (f2 / feedback))) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :op2 (m / mutate-01 :ARG1 (a11 / amino-acid :mod "729" :name (n9 / name :op1 "serine") :xref (x7 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :ARG1 (a4 / activate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG2-of (i / induce-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of (m3 / mutate-01 :value "V600E") :ARG0-of (a5 / activity-06 :ARG1-of (h / high-02)) :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :ARG2 (a6 / and :op1 (i2 / increase-01 :ARG0 (a7 / and :op1 m7 :op2 (m4 / mutate-01 :value "S729A")) :ARG1 (p2 / possible-01 :ARG1 (a8 / activate-01 :ARG0 (a9 / and :op1 (e5 / enzyme :name (n5 / name :op1 "B-Raf") :ARG2-of (m5 / mutate-01 :value "G466A" :degree (i3 / intermediate)) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e6 / enzyme :name (n6 / name :op1 "B-Raf") :ARG2-of (m6 / mutate-01 :value "D594G") :mod (i4 / impair-01 :ARG1 (k / kinase)) :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG1 e3))) :op2 (d / decrease-01 :ARG0 a7) :mod (r / respective) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B")) :ARG0-of (i5 / indicate-01 :ARG1 (c2 / correlate-01 :ARG1 (p3 / possible-01 :ARG1 (t / transform-01 :ARG0 a9)) :ARG2 (p4 / possible-01 :ARG1 (a10 / activate-01 :ARG0 a9 :ARG1 (s / signal-07 :ARG0 (e8 / enzyme :name (n8 / name :op1 "ERK") :xref (x6 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :manner (i6 / in-vivo) :subevent-of (c3 / cascade))))))))) # ::id bio.mskcc_0001.36 # ::date 2015-01-21T05:10:00 # ::file bio_mskcc_0001_36.txt # ::snt Not unexpectedly, for all of the oncogenic B-Raf proteins, the S729A mutation, which disrupts heterodimerization with C-Raf, caused a >90% decrease in C-Raf activity levels (Fig. 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (c / cause-01 :ARG0 (m / mutate-01 :value "S729A" :ARG2 (e / enzyme :name (n / name :op1 "B-Raf") :mod (a / all) :ARG0-of (c2 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG0-of (d / disrupt-01 :ARG1 (h / heterodimerize-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))))) :ARG1 (d2 / decrease-01 :ARG1 (l / level :degree-of (a2 / activity-06 :ARG0 e2)) :ARG2 (m2 / more-than :op1 (p / percentage-entity :value "90"))) :ARG1-of (e3 / expect-01) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id bio.mskcc_0001.37 # ::date 2015-01-21T07:29:54 # ::file bio_mskcc_0001_37.txt # ::snt Together, these findings indicate a correlation between the changes in the transformation potentials of the intermediate and impaired oncogenic B-Raf proteins and their abilities to heterodimerize and activate C-Raf. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / indicate-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (c / correlate-01 :ARG1 (c2 / change-01 :ARG1 (p / possible-01 :ARG1 (t4 / transform-01 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "B-Raf") :mod (i2 / intermediate) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (i3 / impair-01) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))))) :ARG2 (c5 / capable-01 :ARG1 a :ARG2 (a2 / and :op1 (h / heterodimerize-01 :ARG1 a :ARG2 (e3 / enzyme :name (n3 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :op2 (a3 / activate-01 :ARG0 a :ARG1 e3)))) :mod (t3 / together)) # ::id bio.mskcc_0001.38 # ::date 2015-01-21T09:11:56 # ::file bio_mskcc_0001_38.txt # ::snt To investigate the contributions of the various feedback sites to the overall effect of feedback phosphorylation on B-Raf function, we generated a panel of mutants in which specific feedback phosphorylation sites were incorporated into either WT B-Raf or the intermediate-activity G466A B-Raf protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (g / generate-01 :ARG0 (w / we) :ARG1 (p / panel :consist-of (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :ARG1-of (c2 / cause-01 :ARG0 (i / incorporate-02 :ARG1 (p2 / protein-segment :part-of e :ARG1-of (p3 / phosphorylate-01 :subevent-of (f / feedback) :ARG1-of (s / specific-02))) :ARG2 (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :mod (w2 / wild-type) :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "G466A") :ARG0-of (a / activity-06 :degree (i2 / intermediate)) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))))) :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :purpose (i3 / investigate-01 :ARG0 w :ARG1 (t / thing :ARG1-of (c / contribute-01 :ARG0 (p4 / protein-segment :mod (v / various) :destination-of f) :ARG2 (a2 / affect-01 :ARG0 p3 :ARG1 (f2 / function-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :mod (o2 / overall)))))) # ::id bio.mskcc_0001.39 # ::date 2015-01-21T12:14:33 # ::file bio_mskcc_0001_39.txt # ::snt The mutant proteins were then examined for their abilities to heterodimerize with C-Raf and to bind activated Ras under conditions where feedback phosphorylation was induced (in cycling cells for the G466A mutants and in cells treated with PDGF for 30 min for the WT B-Raf mutants). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / examine-01 :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (a / and :op1 (h / heterodimerize-01 :ARG1 (p / protein :ARG2-of (m / mutate-01) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (e4 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m3 / mutate-01 :value "G466A") :location (c / cell :ARG1-of (c2 / cycle-02)) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e5 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of m :mod (w / wild-type) :location (c3 / cell :ARG1-of (t2 / treat-04 :ARG2 (p4 / protein :name (n5 / name :op1 "PDGF") :xref (x4 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :duration (t3 / temporal-quantity :quant "30" :unit (m4 / minute)))) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :ARG2 (e2 / enzyme :name (n / name :op1 "C-Raf") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :op2 (b / bind-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (a2 / activate-01) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :condition (i / induce-01 :ARG2 (p3 / phosphorylate-01 :subevent-of (f / feedback))))) :time (t / then)) # ::id bio.mskcc_0001.40 # ::date 2015-01-21T13:09:21 # ::file bio_mskcc_0001_40.txt # ::snt As shown in Fig. 6A, only mutation of the S151 feedback site, which is in close proximity to the Ras binding domain (residues 155 to 227), was found to significantly increase binding to activated Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (f / find-01 :ARG1 (i / increase-01 :ARG0 (m / mutate-01 :ARG1 (a / amino-acid :mod "151" :name (n / name :op1 "serine") :part-of (p / protein-segment :destination-of (f2 / feedback) :ARG1-of (c / close-10 :ARG2 (d / domain :ARG2-of (b / bind-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (m2 / mean-01 :ARG2 (v / value-interval :op1 (r / residue :mod (a3 / amino-acid :value "155")) :op2 (r2 / residue :mod (a4 / amino-acid :value "227"))))))) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :mod (o / only)) :ARG1 (b3 / bind-01 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 (s / significant-02)) :ARG1-of (s2 / show-01 :ARG0 (f3 / figure :mod "6A"))) # ::id bio.mskcc_0001.41 # ::date 2015-01-21T14:06:45 # ::file bio_mskcc_0001_41.txt # ::snt In contrast, mutation of S151A, T401A, and S750A T753A were all found to increase C-Raf binding (Fig. 6A), a finding consistent with peptide studies suggesting that there are multiple points of contact between heterodimerized B- and C-Raf proteins (27). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (c / contrast-01 :ARG2 (f / find-01 :ARG1 (i / increase-01 :ARG0 (a / and :op1 (m / mutate-01 :value "S151A") :op2 (m2 / mutate-01 :value "T401A") :op3 (m3 / mutate-01 :value "S750A") :op4 (m4 / mutate-01 :value "T753A")) :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n5 / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6A"))) :ARG1-of (c2 / consistent-01 :ARG2 (s / study-01 :ARG1 (p / peptide) :ARG0-of (s2 / suggest-01 :ARG1 (c3 / contact-01 :ARG0 (e2 / enzyme :name (n6 / name :op1 "B-Raf") :ARG1-of (h / heterodimerize-01) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e3 / enzyme :name (n7 / name :op1 "C-Raf") :ARG1-of h :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :quant (m5 / multiple))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 "27"))))))) # ::id bio.mskcc_0001.42 # ::date 2015-01-21T14:42:13 # ::file bio_mskcc_0001_42.txt # ::snt Interestingly, when the S729A mutation was introduced into the FBm mutant, binding to C-Raf was abolished (Fig. 6A), indicating that the increased heterodimerization observed when the feedback sites are mutated is still dependent on 14-3-3 binding. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 9, 2015 (a / abolish-01 :ARG1 (b / bind-01 :ARG2 (e / enzyme :wiki "C-Raf" :name (n / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A")) :time (i / introduce-02 :ARG1 (m / mutate-01 :value "S729A") :ARG2 (e2 / enzyme :wiki "-" :name (n3 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01) :ARG1-of (h2 / have-part-91 :polarity "-" :ARG2 (p / protein-segment :destination-of (f3 / feedback))) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :manner (i2 / interesting) :ARG0-of (i3 / indicate-01 :ARG1 (d2 / depend-01 :ARG0 (h / heterodimerize-01 :ARG1-of (i4 / increase-01) :ARG1-of (o / observe-01 :time (m3 / mutate-01 :ARG1 (p2 / protein-segment :destination-of (f2 / feedback))))) :ARG1 (b2 / bind-01 :ARG2 (p3 / protein :wiki "14-3-3_protein" :name (n4 / name :op1 "14-3-3") :xref (x1 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :mod (s / still)))) # ::id bio.mskcc_0001.43 # ::date 2014-11-21T12:50:26 # ::file bio_mskcc_0001_43.txt # ::snt Given that oncogenic B-Raf proteins are targets of feedback phosphorylation, we next examined whether they might also be dephosphorylated and recycled in a manner involving the PP2A phosphatase and the Pin1 prolyl-isomerase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (a / and :op1 (d / dephosphorylate-01 :ARG1 "e2") :op2 (r / recycle-01 :ARG1 "e2") :mod (a2 / also) :manner (i / involve-01 :ARG1 (a3 / and :op1 (p4 / phosphatase :name (n2 / name :op1 "PP2A")) :op2 (p3 / prolyl-isomerase :name (n3 / name :op1 "Pin1"))) :ARG2 a))) :ARG1-of (c / cause-01 :ARG0 (t / target-01 :ARG0 (p / phosphorylate-01 :subevent-of (f / feedback)) :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :time (n4 / next)) # ::id bio.mskcc_0001.44 # ::date 2014-11-21T13:03:30 # ::file bio_mskcc_0001_44.txt # ::snt As indicated in Fig. 7A, when PP2A was inhibited with okadaic acid treatment, slower-migrating forms of the V600E, G466A, and D594G B-Raf proteins were found to accumulate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (f / find-01 :ARG1 (a / accumulate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e3 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of (m4 / mutate-01 :value "G466A") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op3 (e4 / enzyme :name (n5 / name :op1 "B-Raf") :ARG2-of (m5 / mutate-01 :value "D594G") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG0-of (m2 / migrate-01 :ARG1-of (s / slow-05 :degree (m3 / more)))) :condition (i / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "PP2A") :xref (x3 / xref :value "UNIPROT:PP2AA_HUMAN" :prob "0.372")) :instrument (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "okadaic" :op2 "acid") :xref (x4 / xref :value "PUBCHEM:4584" :prob "10.68039"))))) :ARG1-of (i2 / indicate-01 :ARG0 (f2 / figure :mod "7A"))) # ::id bio.mskcc_0001.45 # ::date 2014-11-21T13:16:55 # ::file bio_mskcc_0001_45.txt # ::snt Moreover, given their constitutive phosphorylation on S/TP sites (Fig. 3D), these oncogenic B-Raf mutants were found to interact constitutively with Pin1 (Fig. 7B), indicating that oncogenic B-Raf proteins are dephosphorylated and recycled. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op2 (f / find-01 :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01) :ARG0-of (c3 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :mod (t / this) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Pin1") :xref (x / xref :value "UNIPROT:PIN1_HUMAN" :prob "0.603")) :mod (c5 / constitutive) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "7B")) :ARG0-of (i2 / indicate-01 :ARG1 (a2 / and :op1 (d3 / dephosphorylate-01 :ARG1 e) :op2 (r / recycle-01 :ARG1 e))) :ARG1-of (c / cause-01 :ARG0 (p / phosphorylate-01 :ARG2 (p2 / protein-segment :part-of e :mod (s / slash :op1 (a3 / amino-acid :name (n4 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :name (n5 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")))) :mod (c2 / constitutive) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3D"))))))) # ::id bio.mskcc_0001.46 # ::date 2014-11-21T15:05:26 # ::file bio_mskcc_0001_46.txt # ::snt Consistent with the model that Pin1 influences B-Raf signaling by facilitating the dephosphorylation of the feedback sites, overexpression of the Pin1 proteins had no effect on the transformation potential of G466A FBm-B-Raf, which lacks the sites of feedback phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / affect-01 :polarity "-" :ARG0 (o / overexpress-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Pin1") :xref (x2 / xref :value "UNIPROT:PIN1_HUMAN" :prob "0.603"))) :ARG1 (p / possible-01 :ARG1 (t2 / transform-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "G466A") :ARG1-of (h / have-part-91 :polarity "-" :ARG2 (p2 / protein-segment :ARG1-of (p3 / phosphorylate-01 :subevent (f / feedback)))) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :ARG1-of (c / consistent-01 :ARG2 (m2 / model :topic (i / influence-01 :ARG0 e2 :ARG1 (s / signal-07 :ARG0 (e5 / enzyme :name (n4 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :manner (f2 / facilitate-01 :ARG0 (e4 / enzyme) :ARG1 (d / dephosphorylate-01 :ARG1 (p4 / protein-segment :part-of e5 :destination-of (f3 / feedback)))))))) # ::id bio.mskcc_0001.47 # ::date 2014-11-22T17:41:50 # ::file bio_mskcc_0001_47.txt # ::snt Previous studies have found that both the C-Raf and B-Raf proteins are targets of ERK-dependent feedback phosphorylation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 22, 2014 (f / find-01 :ARG0 (s / study :time (p / previous)) :ARG1 (t / target-01 :ARG0 (p2 / phosphorylate-01 :subevent-of (f2 / feedback) :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :op2 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) # ::id bio.mskcc_0001.48 # ::date 2014-11-22T19:04:35 # ::file bio_mskcc_0001_48.txt # ::snt In the case of C-Raf, six sites of feedback phosphorylation have been identified, five of which are direct targets of activated ERK (8) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (i / identify-01 :ARG1 (p / protein-segment :quant "6" :part-of (e / enzyme :name (n / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG1-of (p2 / phosphorylate-01 :subevent-of (f / feedback)) :ARG2-of (i2 / include-91 :ARG1 (p3 / protein-segment :quant "5" :ARG1-of (t / target-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG1-of (a / activate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (d / direct-02))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "8")))) # ::id bio.mskcc_0001.49 # ::date 2014-11-22T19:09:15 # ::file bio_mskcc_0001_49.txt # ::snt For B-Raf, previous work by Brummer et al. (3) identified the C-terminal S750 and T753 residues as sites phosphorylated by activated ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (i / identify-01 :ARG0 (p / publication :ARG1-of (w / work-12 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Brummer")) :op2 (p3 / person :mod (o / other))) :time (p6 / previous)) :ARG1-of (c / cite-01 :ARG2 "3")) :ARG1 (a2 / and :op1 (r / residue :mod (a3 / amino-acid :mod "750" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of (p4 / protein-segment :name (n4 / name :op1 "C-terminus") :part-of (e2 / enzyme :name (n6 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :op2 (r2 / residue :mod (a4 / amino-acid :mod "753" :name (n3 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of p4)) :ARG2 (p5 / phosphorylate-01 :ARG1 a2 :ARG2 (e / enzyme :name (n5 / name :op1 "ERK") :ARG1-of (a5 / activate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) # ::id bio.mskcc_0001.50 # ::date 2014-11-22T19:21:02 # ::file bio_mskcc_0001_50.txt # ::snt Through metabolic labeling experiments, we find here that in addition to the S750 and T753 sites, B-Raf is feedback phosphorylated on two other sites, S151 and T401. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 26, 2014 (f / find-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "750" :name (n / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :mod "753" :name (n2 / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :op3 (a4 / amino-acid :mod "151" :name (n3 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op4 (a5 / amino-acid :mod "401" :name (n4 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (e2 / enzyme :name (n5 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :subevent-of (f2 / feedback)) :medium (h / here) :manner (e / experiment-01 :ARG2 (l / label-01 :mod (m / metabolism)))) # ::id bio.mskcc_0001.51 # ::date 2014-11-22T19:29:50 # ::file bio_mskcc_0001_51.txt # ::snt These residues are phosphorylated by activated ERK in vitro, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 22, 2014 (p / phosphorylate-01 :ARG1 (r / residue :mod (t / this)) :ARG2 (e / enzyme :name (n / name :op1 "ERK") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :manner (i / in-vitro)) # ::id bio.mskcc_0001.52 # ::date 2014-11-22T19:31:23 # ::file bio_mskcc_0001_52.txt # ::snt As has been observed for C-Raf, we find that the hyperphosphorylated B-Raf protein is subsequently dephosphorylated in a manner requiring the activities of the PP2A phosphatase and Pin1 prolyl-isomerase, indicating that the feedback phosphorylation/dephosphorylation cycle is a conserved regulatory mechanism for the Raf proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (d / dephosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG3-of (h / hyperphosphorylate-01) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1-of (r / resemble-01 :ARG2 (d2 / dephosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :ARG3-of (h2 / hyperphosphorylate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG1-of (o / observe-01))) :manner (r2 / require-01 :ARG0 d :ARG1 (a2 / and :op1 (a / act-02 :ARG0 (p / phosphatase :name (n3 / name :op1 "PP2A"))) :op2 (a4 / act-02 :ARG0 (p2 / prolyl-isomerase :name (n4 / name :op1 "Pin1"))))) :ARG0-of (i / indicate-01 :ARG1 (m / mechanism :ARG0-of (r3 / regulate-01 :ARG1 (p4 / protein-family :name (n5 / name :op1 "Raf"))) :ARG1-of (c / conserve-01) :domain (c2 / cycle-02 :subevent (p3 / phosphorylate-01) :subevent (d3 / dephosphorylate-01) :mod (f3 / feedback)))) :time (a3 / after :op1 h))) # ::id bio.mskcc_0001.53 # ::date 2015-01-21T14:48:03 # ::file bio_mskcc_0001_53.txt # ::snt Through mutational analysis, we find that feedback phosphorylation disrupts the abilities of B-Raf to bind activated Ras and to heterodimerize with C-Raf. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 21, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (d / disrupt-01 :ARG0 (p / phosphorylate-01 :subevent-of (f2 / feedback)) :ARG1 (c / capable-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG2 (a2 / and :op1 (b / bind-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (a / activate-01) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (h / heterodimerize-01 :ARG1 e :ARG2 (e3 / enzyme :name (n3 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))))) :manner (a3 / analyze-01 :ARG0 w :ARG1 (m / mutate-01))) # ::id bio.mskcc_0001.54 # ::date 2015-01-21T15:23:22 # ::file bio_mskcc_0001_54.txt # ::snt Although phosphorylation of the S151 site appears to have the greatest effect on Ras binding, our results indicate that phosphorylation of all the feedback sites contributes to the inhibition of C-Raf binding. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 5, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (c / contribute-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :mod (a / all) :destination-of (f / feedback))) :ARG2 (i2 / inhibit-01 :ARG1 (b / bind-01 :ARG2 (e / enzyme :name (n / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))))) :concession (a2 / appear-02 :ARG1 (a3 / affect-01 :ARG0 (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "151" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (b2 / bind-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :mod (g / great :degree (m / most))))) # ::id bio.mskcc_0001.55 # ::date 2015-01-21T15:38:56 # ::file bio_mskcc_0001_55.txt # ::snt This finding is consistent with those of peptide binding studies conducted by Rushworth et al. (27) indicating that there are multiple points of contact between heterodimerized B-Raf and C-Raf proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 21, 2015 (c / consistent-01 :ARG1 (t / thing :mod (t2 / this) :ARG1-of (f / find-01) :ARG0-of (i / indicate-01 :ARG1 (c4 / contact-01 :ARG0 (e / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (h / heterodimerize-01) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e2 / enzyme :name (n3 / name :op1 "C-Raf") :ARG1-of h :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :quant (m / multiple)))) :ARG2 (t3 / thing :ARG1-of (f2 / find-01 :ARG0 (s / study-01 :ARG1 (b / bind-01 :ARG1 (p / peptide)) :ARG1-of (c2 / conduct-01 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Rushworth")) :op2 (p3 / person :mod (o / other)))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "27"))))) # ::id bio.mskcc_0001.56 # ::date 2015-01-21T15:50:56 # ::file bio_mskcc_0001_56.txt # ::snt Interestingly, these peptide binding studies also indicate that homodimerized B-Raf and C-Raf proteins have multiple contact points (27), suggesting that feedback phosphorylation of the Raf proteins may disrupt Raf homodimers as well # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (s / study-01 :ARG1 (b / bind-01 :ARG1 (p / peptide)) :mod (t / this)) :ARG1 (c / contact-01 :ARG0 (a2 / and :op1 (e / enzyme :wiki "-" :name (n / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :wiki "C-Raf" :name (n2 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG3-of (h / homodimerize-01)) :quant (m / multiple)) :manner (i2 / interesting) :mod (a / also) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "27"))) :ARG0-of (s2 / suggest-01 :ARG1 (p3 / possible-01 :ARG1 (d2 / disrupt-01 :ARG0 (p4 / phosphorylate-01 :ARG1 (p5 / protein-family :wiki "RAF_kinase" :name (n3 / name :op1 "Raf")) :subevent-of (f / feedback)) :ARG1 (h2 / homodimer :part p5) :mod (a3 / as-well))))) # ::id bio.mskcc_0001.57 # ::date 2014-11-24T15:21:00 # ::file bio_mskcc_0001_57.txt # ::snt Taken together, these findings suggest a model whereby the binding of a 14-3-3 dimer to the C-terminal pS621 site of C-Raf and the C-terminal pS729 site of B-Raf provides the stable docking event that then allows the two proteins to make additional contacts (Fig. 9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (s / suggest-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this) :ARG1-of (t3 / take-01 :mod (t4 / together))) :ARG1 (m / model :topic (p / provide-01 :ARG0 (a / and :op1 (b / bind-01 :ARG1 (d / dimer :mod (p6 / protein :name (n / name :op1 "14-3-3") :xref (x2 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :ARG2 (a2 / amino-acid :mod "621" :name (n2 / name :op1 "serine") :ARG3-of (p2 / phosphorylate-01) :part-of (p3 / protein-segment :name (n3 / name :op1 "C-terminus") :part-of (e / enzyme :name (n4 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :op2 (b3 / bind-01 :ARG1 d :ARG2 (a3 / amino-acid :mod "729" :name (n5 / name :op1 "serine") :ARG3-of (p4 / phosphorylate-01) :part-of (p5 / protein-segment :name (n6 / name :op1 "C-terminus") :part-of (e2 / enzyme :name (n7 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :ARG1 (d2 / dock-01 :ARG0-of (a4 / allow-01 :ARG1 (c / contact-01 :ARG0 e :ARG1 e2 :mod (a5 / additional) :time (a6 / after :op1 a))) :ARG1-of (s2 / stable-03)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "9"))) # ::id bio.ras_0001.1 # ::date 2014-08-13T14:22:25 # ::file bio_ras_0001_1.txt # ::snt The most frequently mutated oncogenes in the deadliest cancers responsible for human mortality are KRAS , PIK3CA and BRAF . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (o / oncogene :domain (a / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op3 (g3 / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG1-of (m2 / mutate-01 :ARG1-of (f / frequent-02 :degree (m3 / most))) :location (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :ARG0-of (k / kill-01 :ARG1 (h / human) :degree (m / most)))) # ::id bio.ras_0001.2 # ::date 2014-08-13T16:12:45 # ::file bio_ras_0001_2.txt # ::snt Importantly the signaling enzymes encoded by PIK3CA and BRAF are , in part , regulated by direct binding to activated forms of the Ras proteins suggesting that dysregulation of this key step in signaling is critical for tumor formation . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / regulate-01 :ARG0 (b / bind-01 :ARG1 "e" :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG1-of (a2 / activate-01) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (d / direct-02)) :ARG1 (e / enzyme :ARG0-of (s / signal-07) :ARG1-of (e2 / encode-01 :ARG0 (a / and :op1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :degree (p / part) :mod (i / important) :ARG0-of (s2 / suggest-01 :ARG1 (c / critical-02 :ARG1 (i2 / impair-01 :ARG1 "r") :ARG2 (f / form-01 :ARG1 (t / tumor))))) # ::id bio.ras_0001.3 # ::date 2014-08-13T16:08:20 # ::file bio_ras_0001_3.txt # ::snt Ras acts as a molecular switch that is activated upon GTP loading and deactivated upon hydrolysis of GTP to GDP . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 10, 2014 (s / switch :domain (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (a / activate-01 :ARG0 (l / load-01 :ARG1 e :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :ARG1-of (d / deactivate-01 :ARG0 (h / hydrolyze-01 :ARG1 s2 :ARG3 (s3 / small-molecule :name (n3 / name :op1 "GDP") :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257")))) :mod (m / molecule)) # ::id bio.ras_0001.4 # ::date 2014-08-13T17:11:08 # ::file bio_ras_0001_4.txt # ::snt This switch mechanism is common to a wide variety of GTP - binding proteins and is mediated by a conserved structure called the G - domain that consists of five conserved G boxes . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (s / share-01 :ARG0 (p / protein :ARG2-of (b / bind-01 :ARG1 (s4 / small-molecule :name (n / name :op1 "GTP") :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645"))) :mod (v / various :ARG1-of (w / wide-02))) :ARG1 (m / mechanism :topic (s2 / switch) :mod (t / this)) :manner (p2 / protein-segment :name (n2 / name :op1 "G-domain") :ARG1-of (c2 / conserve-01) :part (p3 / protein-segment :quant "5" :name (n3 / name :op1 "G" :op2 "box") :ARG1-of (c3 / conserve-01)))) # ::id bio.ras_0001.5 # ::date 2014-08-13T18:43:18 # ::file bio_ras_0001_5.txt # ::snt Under physiological conditions , the rate of GDP or GTP release from the G - domain is slow . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 25, 2014 (s / slow-05 :ARG1 (r / release-01 :ARG1 (o / or :op1 (s2 / small-molecule :name (n / name :op1 "GDP") :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257")) :op2 (s3 / small-molecule :name (n2 / name :op1 "GTP") :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG2 (p3 / protein-segment :name (n3 / name :op1 "G-domain"))) :condition (p2 / physiology)) # ::id bio.ras_0001.6 # ::date 2014-08-13T16:59:02 # ::file bio_ras_0001_6.txt # ::snt As a consequence the GDP produced by GTP hydrolysis on Ras is trapped and the bulk of cellular Ras accumulates in the GDP - bound ‘off’ state , despite the high GTP / GDP ratio in the cytosol ( 1 – 3 ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (c / cause-01 :ARG1 (a / and :op1 (t / trap-01 :ARG1 (s / small-molecule :name (n / name :op1 "GDP") :ARG3-of (h / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "GTP") :ARG1-of (b3 / bind-01 :ARG2 (e / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x5 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :op2 (a2 / accumulate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (i / include-91 :ARG2 (e2 / enzyme :name (n5 / name :op1 "Ras") :location (c5 / cell) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG3 (b / bulk)) :ARG1-of (d / deactivate-01) :ARG2-of (b2 / bind-01 :ARG1 s) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :concession (h2 / high-02 :ARG1 (r / ratio-of :op1 s2 :op2 s :location (c6 / cytosol :xref (x3 / xref :value "GO:0005829" :prob "0.8")))))) :ARG1-of (a3 / attest-01 :ARG0 (p4 / publication :ARG1-of (c7 / cite-01 :ARG2 (v / value-interval :op1 "1" :op2 "3"))))) # ::id bio.ras_0001.7 # ::date 2014-08-13T18:57:28 # ::file bio_ras_0001_7.txt # ::snt Growth factors can turn on Ras by activating Guanine nucleotide Exchange Factors ( GEFs ) or by inhibiting the GTPase Activating Proteins ( GAPs ) or by both mechanisms . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (p5 / possible-01 :ARG1 (t / turn-on-13 :ARG0 (g / growth-factor) :ARG1 (e2 / enzyme :name (n / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (o / or :op1 (a / activate-01 :ARG0 g :ARG1 (p2 / protein :name (n2 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor") :xref (x / xref :value "UNIPROT:PKHG5_HUMAN" :prob "0.393"))) :op2 (i / inhibit-01 :ARG0 g :ARG1 (p3 / protein :ARG0-of (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "GTPase") :xref (x1 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312"))))) :op3 (a3 / and :op1 a :op2 i)))) # ::id bio.ras_0001.8 # ::date 2014-08-13T19:05:56 # ::file bio_ras_0001_8.txt # ::snt RasGEFs bind to Ras and lower the transition energy for the nucleotide exchange of the bound GDP for the more abundant cytosolic GTP , whereas RasGAPs bind to Ras and catalyze GTP hydrolysis . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / contrast-01 :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "RasGEF") :xref (x2 / xref :value "UNIPROT:VKIND_HUMAN" :prob "0.282")) :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (l / lower-05 :ARG0 p :ARG1 (e / energy :mod (t / transition-01) :poss (e2 / exchange-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "GDP") :ARG1-of (b2 / bind-01 :ARG2 e3) :xref (x4 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG3 (s / small-molecule :name (n5 / name :op1 "GTP") :mod (a2 / abundant :degree (m / more) :compared-to s2) :location (c3 / cytosol :xref (x3 / xref :value "GO:0005829" :prob "0.8")) :xref (x5 / xref :value "PUBCHEM:6830" :prob "15.470645")))))) :ARG2 (a3 / and :op1 (b3 / bind-01 :ARG1 (p5 / protein :name (n3 / name :op1 "RasGAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :ARG2 e3) :op2 (c2 / catalyze-01 :ARG0 p5 :ARG1 (h / hydrolyze-01 :ARG1 s)))) # ::id bio.ras_0001.9 # ::date 2014-08-13T20:35:42 # ::file bio_ras_0001_9.txt # ::snt The most prevalent oncogenic mutations in Ras ( Gly12 and Gly13 in the G1 box , and Gln61 in the G3 box ) preserve the GTP bound state by inhibiting intrinsic GTPase activity and by interfering with the ability of GAPs . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (p / preserve-01 :ARG0 (m / mutation :ARG1-of (p2 / prevail-02 :degree (m2 / most) :compared-to (e / enzyme :name (n / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n10 / name :op1 "cancer"))) :location (a / and :op1 (p4 / protein-segment :name (n2 / name :op1 "Gly12") :location (p7 / protein-segment :name (n5 / name :op1 "G1" :op2 "box") :location e)) :op2 (p5 / protein-segment :name (n3 / name :op1 "Gly13") :location p7) :op3 (p6 / protein-segment :name (n4 / name :op1 "Gln61") :location (p8 / protein-segment :name (n6 / name :op1 "G3" :op2 "box") :location e)))) :ARG1 (b / bind-01 :ARG1 (s / small-molecule :name (n7 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG2 e) :manner (a2 / and :op1 (i / inhibit-01 :ARG0 m :ARG1 (a3 / activity-06 :ARG0 (e2 / enzyme :name (n8 / name :op1 "GTPase") :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :mod (i3 / intrinsic))) :op2 (i2 / interfere-01 :ARG0 m :ARG1 (c4 / capable-01 :ARG1 (p10 / protein :name (n9 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))))) # ::id bio.ras_0001.10 # ::date 2014-08-13T21:50:34 # ::file bio_ras_0001_10.txt # ::snt Other less frequently observed mutations , such as those found in the G4 and G5 boxes , increase the rate of nucleotide exchange , thereby mimicking the GEFs and increasing the GTP - bound state ( 1 – 7 ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (i / increase-01 :ARG0 (m / mutation :ARG1-of (o / observe-01 :ARG1-of (f / frequent-02 :degree (l / less))) :mod (o2 / other) :example (m2 / mutation :location (o3 / or :op1 (p / protein-segment :name (n / name :op1 "G4" :op2 "box")) :op2 (p2 / protein-segment :name (n2 / name :op1 "G5" :op2 "box"))))) :ARG1 (r / rate :degree-of (e / exchange-01 :ARG1 (n3 / nucleotide))) :manner-of (m3 / mimic-01 :ARG0 m :ARG1 (p3 / protein :name (n4 / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002"))) :ARG0-of (c / cause-01 :ARG1 (i2 / increase-01 :ARG1 (n7 / number :quant-of (e2 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (b / bind-01 :ARG1 (s / small-molecule :name (n6 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1-of (a / attest-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 "1" :op2 "7"))))) # ::id bio.ras_0002.1 # ::date 2015-01-13T21:00:03 # ::file bio_ras_0002_1.txt # ::snt Activated Ras controls diverse signaling pathways that ultimately determine Ras - induced cellular responses such as cell proliferation , survival , differentiation and motility . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (c / control-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (p / pathway :mod (d / diverse) :ARG0-of (s / signal-07) :ARG0-of (d2 / determine-01 :ARG1 (r / respond-01 :ARG0 (c2 / cell) :ARG2 (a2 / and :op1 (p2 / proliferate-01 :ARG0 c2) :op2 (s2 / survive-01 :ARG0 c2) :op3 (d3 / differentiate-01 :ARG1 c2) :op4 (m / motility :mod c2)) :ARG2-of (i / induce-01 :ARG0 e)) :time (u / ultimate)))) # ::id bio.ras_0002.2 # ::date 2015-01-13T20:53:19 # ::file bio_ras_0002_2.txt # ::snt These multiple Ras functions depend on its binding to a range of functionally diverse effector molecules such as Raf , PI3K , AF6 and RASSFs ( 1 ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 5, 2015 (d / depend-01 :ARG0 (t3 / thing :quant (m / multiple) :mod (t / this) :ARG1-of (f / function-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1 (b / bind-01 :ARG1 e :ARG2 (m2 / molecule :mod (e3 / effector) :example (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n3 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op3 (e5 / enzyme :name (n4 / name :op1 "AF6") :xref (x / xref :value "UNIPROT:AFAD_HUMAN" :prob "1.002")) :op4 (p / protein :name (n5 / name :op1 "RASSF") :xref (x4 / xref :value "UNIPROT:RIN2_HUMAN" :prob "0.333"))) :quant (r / range) :ARG0-of (f2 / function-01 :mod (d2 / diverse)))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "1")))) # ::id bio.ras_0002.3 # ::date 2015-01-14T04:48:20 # ::file bio_ras_0002_3.txt # ::snt The enhancement of specific effector pathways plays a critical role in maintaining an appropriate biological response ( 8 ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / play-02 :ARG0 (e / enhance-01 :ARG1 (p2 / pathway :mod (e2 / effector) :ARG1-of (s / specific-02))) :ARG1 (r / role :ARG1-of (c / critical-02 :ARG2 (m / maintain-01 :ARG0 e :ARG1 (t / thing :ARG2-of (r2 / respond-01) :mod (b / biology) :ARG1-of (a / appropriate-02))))) :ARG1-of (d / describe-01 :ARG2 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "8")))) # ::id bio.ras_0002.4 # ::date 2015-01-14T06:53:00 # ::file bio_ras_0002_4.txt # ::snt The specificity in Ras - induced signaling is primarily determined by the balance between Ras affinity for each of its effectors and the local concentrations of those effectors . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (d / determine-01 :ARG0 (b / balance-01 :ARG1 (a / affinity :poss (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :topic (e2 / effector :mod (e3 / each) :poss e)) :ARG2 (c / concentrate-02 :ARG1 e2 :ARG1-of (l / local-02))) :ARG1 (s / specificity :mod (s2 / signal-07 :ARG2-of (i / induce-01 :ARG0 e))) :mod (p / primary)) # ::id bio.ras_0002.5 # ::date 2015-01-14T07:23:18 # ::file bio_ras_0002_5.txt # ::snt In addition , scaffold proteins have been shown to guide activation of specific effector pathway(s) . For example , SHOC2 / Sur-8 bridges Ras and Raf to specifically enhance the Raf / MEK / ERK pathway without enhancing PI3K / AKT signaling ( 9 , 10 ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (m / multi-sentence :snt1 (a4 / and :op2 (s / show-01 :ARG1 (g / guide-01 :ARG0 (p / protein :mod (s5 / scaffold)) :ARG1 (a / activate-01 :ARG1 (p2 / pathway :mod (e5 / effector) :mod (s2 / specific)))))) :snt2 (e8 / exemplify-01 :ARG0 (b / bridge-01 :ARG0 (m2 / macro-molecular-complex :part (e3 / enzyme :name (n3 / name :op1 "SHOC2") :xref (x1 / xref :value "UNIPROT:SHOC2_HUMAN" :prob "1.003")) :part (e4 / enzyme :name (n4 / name :op1 "Sur-8") :xref (x / xref :value "UNIPROT:ABCC8_HUMAN" :prob "0.202"))) :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :purpose (e6 / enhance-01 :ARG0 m2 :ARG1 (p4 / pathway :name (n7 / name :op1 "Raf/MEK/ERK")) :ARG1-of (s3 / specific-02)) :manner (e7 / enhance-01 :polarity "-" :ARG0 m2 :ARG1 (s4 / signal-07 :ARG0 (p5 / pathway :name (n8 / name :op1 "PI3K/AKT")))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "9" :op2 "10"))))))) # ::id bio.ras_0003.1 # ::date 2015-01-19T01:16:07 # ::file bio_ras_0003_1.txt # ::snt We utilized an unbiased mass spectrometry - based approach to identify ubiquitination sites of Ras . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 19, 2015 (u / utilize-01 :ARG0 (w / we) :ARG1 (a / approach-02 :ARG1-of (b / bias-01 :polarity "-") :ARG1-of (b2 / base-02 :ARG2 (s / spectrometry :mod (m / mass)))) :purpose (i / identify-01 :ARG0 w :ARG1 (p / protein-segment :part-of (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (u2 / ubiquitinate-01)))) # ::id bio.ras_0003.2 # ::date 2015-01-19T01:53:15 # ::file bio_ras_0003_2.txt # ::snt His - tagged ubiquitin and Flag - tagged K-Ras4B ( K-Ras hereafter ) were expressed in HEK293T cells at levels similar to endogenous K-Ras ( Fig. 1B ) and subjected to sequential affinity chromatography . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (a3 / and :op1 (e2 / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "ubiquitin") :ARG1-of (t / tag-01 :ARG2 (a2 / amino-acid :name (n3 / name :op1 "histidine") :xref (x1 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :xref (x3 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :op2 (e / enzyme :name (n2 / name :op1 "K-Ras4B") :name (n7 / name :op1 "K-Ras") :ARG1-of (t2 / tag-01 :ARG2 (p2 / protein-segment :name (n4 / name :op1 "Flag"))) :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG3 (c / cell-line :name (n5 / name :op1 "HEK293T")) :degree (l / level :ARG1-of (r / resemble-01 :ARG2 (l2 / level :degree-of (e4 / express-03 :ARG2 (e3 / enzyme :name (n6 / name :op1 "K-Ras") :mod (e5 / endogenous) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) :op2 (s / subject-01 :ARG1 a :ARG2 (c2 / chromatography :mod (a4 / affinity) :mod (s2 / sequence)))) # ::id bio.ras_0003.3 # ::date 2015-01-19T02:56:52 # ::file bio_ras_0003_3.txt # ::snt His - ubiquitinated proteins were purified by Co2+ metal affinity chromatography in 8M urea denaturing conditions . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (p / purify-01 :ARG1 (p2 / protein :ARG3-of (u / ubiquitinate-01 :mod (a / amino-acid :name (n / name :op1 "histidine") :xref (x / xref :value "PUBCHEM:6274" :prob "11.959939")))) :manner (c / chromatography :mod (a2 / affinity :topic (c3 / copper :ARG1-of (i / ionize-01 :value "2+"))) :condition (d2 / denature-01 :ARG1 p2 :ARG4 (s / small-molecule :name (n3 / name :op1 "urea") :mod (c2 / concentration-quantity :quant "8" :unit (m / molar)) :xref (x1 / xref :value "PUBCHEM:1176" :prob "6.945035"))))) # ::id bio.ras_0003.4 # ::date 2015-01-19T05:25:54 # ::file bio_ras_0003_4.txt # ::snt His - ubiquitinated K-Ras was subsequently purified with anti - Flag resin . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 19, 2015 (p / purify-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01 :mod (a / amino-acid :name (n2 / name :op1 "histidine") :xref (x1 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :time (s / subsequent) :instrument (r / resin :ARG0-of (c / counter-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "Flag"))))) # ::id bio.ras_0003.5 # ::date 2015-01-19T05:43:28 # ::file bio_ras_0003_5.txt # ::snt Following purification , mono- and di- ubiquitinated K-Ras appeared to be the major ubiquitination forms , which is consistent with the endogenous K-Ras ubiquitination pattern ( Fig. 1 , A and B ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (a / appear-02 :ARG1 (f2 / form :mod (u2 / ubiquitinate-01) :ARG1-of (m / major-02) :domain (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01 :quant (o / or :op1 "1" :op2 "2")) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG1-of (f / follow-01 :ARG2 (p / purify-01 :ARG1 e)) :ARG1-of (c / consistent-01 :ARG2 (p2 / pattern :topic (u3 / ubiquitinate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :mod (e3 / endogenous) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f3 / figure :mod "1A") :op2 (f4 / figure :mod "1B")))) # ::id bio.ras_0003.6 # ::date 2015-01-19T06:56:05 # ::file bio_ras_0003_6.txt # ::snt H-Ras ubiquitination sites were also determined by the same approach . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 6, 2015 (d / determine-01 :ARG1 (p / protein-segment :ARG1-of (u / ubiquitinate-01) :part-of (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :mod (a / also) :manner (a2 / approach-02 :ARG1-of (s / same-01))) # ::id bio.ras_0003.7 # ::date 2015-01-19T07:05:34 # ::file bio_ras_0003_7.txt # ::snt Tandem mass spectrometric analysis of tryptic fragments from the bands migrating at the positions expected for mono- and di- ubiquitinated Ras revealed ubiquitination at Lys residues 104 and 147 of K-Ras , and Lys residues 117 , 147 and 170 for H-Ras ( fig. S1C ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 5, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (f / fragment :source (b / band :ARG0-of (m / migrate-01 :ARG2 (p / position :ARG2-of (b2 / be-located-at-91 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant (o / or :op1 "1" :op2 "2")) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (e4 / expect-01))))) :mod (e5 / enzyme :name (n9 / name :op1 "trypsin") :xref (x / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342"))) :manner (s / spectrometry :mod (m2 / mass) :mod (t2 / tandem))) :ARG1 (u2 / ubiquitinate-01 :ARG1 (a2 / and :op1 (a3 / and :op1 (r2 / residue :mod (a4 / amino-acid :mod "104" :name (n4 / name :op1 "lysine") :xref (x6 / xref :value "PUBCHEM:866" :prob "11.053295"))) :op2 (r3 / residue :mod (a5 / amino-acid :mod "147" :name (n5 / name :op1 "lysine") :xref (x5 / xref :value "PUBCHEM:866" :prob "11.053295"))) :part-of (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (a6 / and :op1 (r4 / residue :mod (a7 / amino-acid :mod "117" :name (n6 / name :op1 "lysine") :xref (x7 / xref :value "PUBCHEM:866" :prob "11.053295"))) :op2 (r5 / residue :mod (a8 / amino-acid :mod "147" :name (n7 / name :op1 "lysine") :xref (x8 / xref :value "PUBCHEM:866" :prob "11.053295"))) :op3 (r6 / residue :mod (a9 / amino-acid :mod "170" :name (n8 / name :op1 "lysine") :xref (x4 / xref :value "PUBCHEM:866" :prob "11.053295"))) :part-of (e3 / enzyme :name (n3 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "S1C"))) # ::id bio.ras_0003.8 # ::date 2015-01-19T07:59:53 # ::file bio_ras_0003_8.txt # ::snt The tryptic peptide with ubiquitination at Lys147 ( K147 ) was the most frequently observed peptide for both K-Ras and H-Ras , while Lys117 appeared as a secondary major ubiquitination site in H-Ras . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / contrast-01 :ARG1 (p / peptide :part-of (a / and :op1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :domain (p2 / peptide :ARG3-of (h / hydrolyze-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "trypsin") :xref (x / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342"))) :part (a2 / amino-acid :mod "147" :name (n4 / name :op1 "lysine") :ARG1-of (u / ubiquitinate-01) :xref (x3 / xref :value "PUBCHEM:866" :prob "11.053295"))) :ARG1-of (o / observe-01 :ARG1-of (f / frequent-02 :degree (m / most)))) :ARG2 (a3 / appear-01 :ARG1 (p3 / protein-segment :ARG1-of (m2 / major-02) :ARG1-of (u2 / ubiquitinate-01) :mod (s / secondary) :domain (a4 / amino-acid :mod "117" :name (n5 / name :op1 "lysine") :xref (x4 / xref :value "PUBCHEM:866" :prob "11.053295")) :part-of e2))) # ::id bmtr_0006.1 # ::date 2015-02-25T09:09:15 # ::file bmtr_0006_1.txt # ::snt A New Dimension to Ras Function: A Novel Role for Nucleotide-Free Ras in Class II Phosphatidylinositol 3-Kinase Beta (PI3KC2β) Regulation (PMC3441633) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (d3 / dimension :ARG1-of (n2 / new-01) :topic (f / function-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG0-of (m2 / mean-01 :ARG1 (r / role :mod (n3 / novel) :mod (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (f2 / free-04 :ARG2 (n5 / nucleotide)) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :purpose (r2 / regulate-01 :ARG0 e2 :ARG1 (e3 / enzyme :name (n6 / name :op1 "Phosphatidylinositol" :op2 "3-Kinase" :op3 "Beta") :mod (c / class :ord (o / ordinal-entity :value "2")) :xref (x1 / xref :value "UNIPROT:PI4KB_HUMAN" :prob "0.392"))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG8 "PMC3441633"))) # ::id bmtr_0006.2 # ::date 2015-02-25T09:23:27 # ::file bmtr_0006_2.txt # ::snt Ras, like all GTPases, cycles between an inactive GDP-bound state and an active GTP-bound state. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / cycle-02 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (s / same-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "GTPase") :mod (a / all) :xref (x3 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG3 (e5 / enzyme :name (n5 / name :op1 "Ras") :ARG0-of (a2 / activity-06 :polarity "-") :ARG1-of (b2 / bind-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "GDP") :xref (x4 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG4 (e4 / enzyme :name (n6 / name :op1 "Ras") :ARG0-of (a3 / activity-06) :ARG1-of (b3 / bind-01 :ARG2 (s5 / small-molecule :name (n4 / name :op1 "GTP") :xref (x5 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) # ::id bmtr_0006.3 # ::date 2015-02-25T09:34:42 # ::file bmtr_0006_3.txt # ::snt The transition from the inactive to active state requires formation of nucleotide-free Ras through the action of exchange factors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (r / require-01 :ARG0 (t / transition-01 :ARG2 (s2 / state :ARG0-of (a2 / activity-06)) :ARG3 (s / state :ARG0-of (a / activity-06 :polarity "-"))) :ARG1 (f / form-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (f2 / free-04 :ARG2 (n2 / nucleotide)) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (a3 / act-01 :ARG0 (f3 / factor :ARG0-of (e2 / exchange-01))))) # ::id bmtr_0006.4 # ::date 2015-02-25T09:44:18 # ::file bmtr_0006_4.txt # ::snt This state is considered to be a short-lived transition state intermediate in vivo [36] based on the relatively high GTP: GDP ratio in vivo [37], the ability of GTP to dissociate the GEF-Ras complex in vitro [31], and the assumption that there are no proteins in vivo that might stabilize nucleotide-free Ras and prevent GTP loading. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / consider-01 :ARG1 (s3 / state :ARG1-of (t / transition-01) :ARG0-of (l / live-01 :ARG1-of (s4 / short-07)) :mod (i / intermediate :manner (i2 / in-vivo)) :ARG1-of (b / base-02 :ARG2 (a / and :op1 (r / ratio-of :op1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645")) :op2 (s2 / small-molecule :wiki "Guanosine_diphosphate" :name (n2 / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257")) :manner i2 :ARG1-of (h / high-02 :ARG2-of (r2 / relative-05)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 "37")))) :op2 (c5 / capable-01 :ARG1 s :ARG2 (d / dissociate-01 :ARG0 s :ARG1 (m / macro-molecular-complex :part (p3 / protein :name (n4 / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :part (e / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :manner (i3 / in-vitro)) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 "31")))) :op3 (a2 / assume-02 :ARG1 (p4 / protein :polarity "-" :manner i2 :ARG0-of (s5 / stabilize-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n6 / nucleotide)) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (p5 / possible-01)) :ARG0-of (p6 / prevent-01 :ARG1 (l2 / load-01 :ARG2 s) :ARG1-of p5))))) :ARG1-of (d4 / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "36"))) :mod (t2 / this))) # ::id bmtr_0006.5 # ::date 2015-02-25T10:26:21 # ::file bmtr_0006_5.txt # ::snt However, our results provide the first direct evidence for a protein that may stabilize nucleotide-free Ras in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (c / contrast-01 :ARG2 (p / provide-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (e2 / evidence :ARG1-of (d / direct-02) :ord (o2 / ordinal-entity :value "1") :topic (p2 / protein :ARG0-of (s / stabilize-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n2 / nucleotide)) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (p3 / possible-01) :manner (i / in-vivo)))))) # ::id bmtr_0006.6 # ::date 2015-02-25T10:37:26 # ::file bmtr_0006_6.txt # ::snt We demonstrate that the RBD of PI3KC2β binds nucleotide-free Ras in vitro (Fig. 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (b / bind-01 :ARG1 (p / protein-segment :name (n2 / name :op1 "RBD") :part-of (e2 / enzyme :name (n3 / name :op1 "PI3KC2β") :xref (x1 / xref :value "UNIPROT:P3C2B_HUMAN" :prob "0.263"))) :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n4 / nucleotide)) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (i / in-vitro)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5"))) # ::id bmtr_0006.7 # ::date 2015-02-25T10:43:42 # ::file bmtr_0006_7.txt # ::snt In contrast to the GEF-Ras complex, which is disrupted by addition of guanine nucleotides, the PI3KC2β RBD-Ras complex is stable even in the presence of high concentrations of GTP or GDP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s3 / stable-03 :ARG1 (m / macro-molecular-complex :part (p2 / protein-segment :name (n3 / name :op1 "RBD") :part-of (e / enzyme :name (n4 / name :op1 "PI3KC2β") :xref (x2 / xref :value "UNIPROT:P3C2B_HUMAN" :prob "0.263"))) :part (e2 / enzyme :name (n5 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (c2 / contrast-01 :ARG2 (m2 / macro-molecular-complex :part (p3 / protein :name (n6 / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :part e2 :ARG1-of (d2 / disrupt-01 :ARG0 (a / add-02 :ARG1 (n7 / nucleotide :mod (g2 / guanine)) :ARG2 m2)))) :condition (p / present-02 :ARG1 (c / concentrate-02 :ARG0 (o / or :op1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645")) :op2 (s2 / small-molecule :wiki "Guanosine_diphosphate" :name (n2 / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :ARG1-of (h / high-02)) :mod (e3 / even))) # ::id bmtr_0006.8 # ::date 2015-02-25T10:59:27 # ::file bmtr_0006_8.txt # ::snt These data suggest that PI3KC2β binding to nucleotide-free Ras in vivo may prevent loading of nucleotides onto Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (s / suggest-01 :ARG0 (d2 / data :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (p2 / prevent-01 :ARG0 (b / bind-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "PI3KC2β") :xref (x1 / xref :value "UNIPROT:P3C2B_HUMAN" :prob "0.263")) :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n3 / nucleotide)) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (i / in-vivo)) :ARG1 (l / load-01 :ARG1 e :ARG2 (n4 / nucleotide))))) # ::id bmtr_0006.9 # ::date 2015-02-25T12:27:05 # ::file bmtr_0006_9.txt # ::snt Although current methods do not allow for detection of nucleotide-free GTPases in vivo, our BiFC results provide additional support for our model. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / provide-01 :ARG0 (t / thing :ARG2-of (r / result-01 :ARG1 (c2 / complement-01 :manner (f2 / fluorescence :mod (b / biomolecular)))) :poss "w") :ARG1 (s / support-01 :ARG1-of (a / add-02)) :ARG2 (m / model :poss (w / we)) :concession (a2 / allow-01 :polarity "-" :ARG0 (m2 / method :time (c / current)) :ARG1 (d / detect-01 :ARG1 (e / enzyme :name (n / name :op1 "GTPase") :ARG1-of (f / free-04 :ARG2 (n2 / nucleotide)) :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :manner (i / in-vivo)))) # ::id bmtr_0006.10 # ::date 2015-02-25T12:36:53 # ::file bmtr_0006_10.txt # ::snt PI3KC2β preferentially interacts with Ras17N, which has a 30-fold lower affinity for nucleotide compared to wild type Ras and therefore should exist for longer periods in the nucleotide-free state. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (i / interact-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PI3KC2β") :xref (x1 / xref :value "UNIPROT:P3C2B_HUMAN" :prob "0.263")) :ARG1 (e / enzyme :name (n / name :op1 "Ras17N") :ARG0-of (h / have-03 :ARG1 (a / affinity :ARG1-of (l / low-04 :degree (m / more) :compared-to (e4 / enzyme :name (n5 / name :op1 "Ras") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :quant (p3 / product-of :op1 "30")) :topic (n4 / nucleotide)) :ARG0-of (c / cause-01 :ARG1 (r / recommend-01 :ARG1 (e6 / exist-01 :ARG1 e :ARG2 (s / state :ARG1-of (f / free-04 :ARG2 n4)) :ARG1-of (l2 / long-03 :degree (m3 / more)))))) :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.213")) :ARG1-of (p / prefer-01)) # ::id bmtr_0006.11 # ::date 2015-02-26T00:19:31 # ::file bmtr_0006_11.txt # ::snt As a result, BiFC traps this form of Ras resulting in greater fluorescence complementation for Ras17N (and Ras17N/69N) compared to wild type or constitutively activated Ras (61L or 12V). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (t / trap-01 :ARG0 (c2 / complement-01 :ARG1 (f3 / fluoresce-01 :mod (b2 / biomolecular))) :ARG1 (f / form :mod (e / enzyme :name (n / name :op1 "Ras") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :mod (t2 / this)) :ARG1-of (r / result-01 :ARG2 (c / complement-01 :ARG2 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "Ras17N") :xref (x3 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n3 / name :op1 "Ras17N/69N"))) :mod (f2 / fluorescence) :mod (g2 / great :degree (m2 / more) :compared-to (o / or :op1 (e4 / enzyme :name (n4 / name :op1 "Ras") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e5 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "61L") :ARG1-of "a" :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op3 (e6 / enzyme :name (n6 / name :op1 "Ras") :ARG1-of (a / activate-01 :manner (c3 / constitutive)) :ARG2-of (m3 / mutate-01 :value "12V") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) # ::id bmtr_0007.1 # ::date 2015-02-26T00:31:54 # ::file bmtr_0007_1.txt # ::snt Phosphorylation of ASPP2 by RAS/MAPK Pathway Is Critical for Its Full Pro-Apoptotic Function (PMC3847091) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / critical-02 :ARG1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :ARG2 (p2 / pathway :name (n2 / name :op1 "RAS/MAPK"))) :ARG3 (f / function-01 :ARG0 p4 :ARG1 (a / apoptosis :ARG1-of (f2 / favor-01 :ARG0 p4)) :degree (f3 / full)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMC3847091"))) # ::id bmtr_0007.2 # ::date 2015-02-26T00:42:26 # ::file bmtr_0007_2.txt # ::snt A synthetic peptide encoding amino acids 824-832, with a phosphoserine at residue 827, was used to raise antibodies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (u / use-01 :ARG1 (p / peptide :mod (s / synthetic) :ARG0-of (e / encode-01 :ARG1 (a / amino-acid :quant (b2 / between :op1 "824" :op2 "832") :ARG2-of (i / include-01 :ARG1 (r3 / residue :location "827" :ARG3-of (p2 / phosphorylate-01) :mod (a3 / amino-acid :name (n / name :op1 "serine") :xref (x / xref :value "PUBCHEM:5951" :prob "11.218784"))))))) :ARG2 (r2 / raise-01 :ARG1 (a2 / antibody))) # ::id bmtr_0007.3 # ::date 2015-02-26T00:55:09 # ::file bmtr_0007_3.txt # ::snt A polyclonal antibody NGH.S4 was purified by affinity column purification. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 9, 2015 (p / purify-01 :ARG0 (p3 / purify-01 :mod (a2 / affinity) :instrument (c / column)) :ARG1 (a3 / antibody :name (n / name :op1 "NGH.S4") :mod (p2 / polyclonal))) # ::id bmtr_0007.4 # ::date 2015-02-26T01:00:24 # ::file bmtr_0007_4.txt # ::snt To test the efficacy of the purified phospho-specific # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (t / test-01 :ARG1 (e / efficacy :poss (a / antibody :ARG1-of (p / purify-01) :ARG1-of (s / specific-02 :ARG2 (p2 / phosphorylate-01))))) # ::id bmtr_0007.5 # ::date 2015-02-26T01:01:36 # ::file bmtr_0007_5.txt # ::snt antibody, a non-radioactive in vitro phosphorylation assay was performed on the purified GST-ASPP2 fragment (693-1128) with recombinant MAPK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (p2 / perform-02 :ARG1 (a / assay-01 :ARG1 (p / phosphorylate-01 :manner (i / in-vitro) :mod (r / radioactive :polarity "-")) :instrument (e / enzyme :name (n2 / name :op1 "MAPK1") :ARG0-of (r2 / recombine-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :location (p4 / protein-segment :part-of (p3 / protein :name (n / name :op1 "GST-ASPP2") :xref (x / xref :value "UNIPROT:CHST2_HUMAN" :prob "0.252")) :quant (b / between :op1 "693" :op2 "1128") :ARG1-of (p5 / purify-01))) # ::id bmtr_0007.6 # ::date 2015-02-26T01:02:48 # ::file bmtr_0007_6.txt # ::snt Figure 1C shows that the phosphospecific antibody is specific for the ASPP2 fragment phosphorylated in vitro by MAPK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (f / figure :mod "1C") :ARG1 (s2 / specific-02 :ARG1 (a / antibody :ARG1-of (s3 / specific-02 :ARG2 (p2 / phosphorylate-01))) :ARG2 (p4 / protein-segment :part-of (p5 / protein :name (n2 / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :ARG1-of (p3 / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :manner (i / in-vitro))))) # ::id bmtr_0007.7 # ::date 2015-02-26T01:08:16 # ::file bmtr_0007_7.txt # ::snt To test whether endogenous ASPP2 could be phosphorylated in cells, Saos2 cells were grown in low serum for 50 hours to remove all background stimulation of RAS, after which the cells were stimulated with EGF and 20% fetal calf serum (FCS). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (g / grow-03 :ARG1 (c / cell-line :name (n2 / name :op1 "Saos2")) :location (s / serum :ARG1-of (l / low-04)) :duration (t2 / temporal-quantity :quant "50" :unit (h2 / hour)) :purpose (r / remove-01 :ARG1 (s2 / stimulate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (b / background) :mod (a / all))) :purpose (t / test-01 :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (p4 / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "ASPP2") :mod (e3 / endogenous) :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :location (c2 / cell)))) :op1-of (a2 / after :time-of (s3 / stimulate-01 :ARG1 c :ARG2 (a3 / and :op1 (p5 / protein :name (n4 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (s5 / serum :source (f / fetus :mod (c3 / calf)) :quant (p / percentage-entity :value "20")))))) # ::id bmtr_0007.8 # ::date 2015-02-26T01:28:20 # ::file bmtr_0007_8.txt # ::snt Phosphorylated endogenous ASPP2 was detected by the phospho-specific antibody 30 minutes after RAS stimulation (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (d / detect-01 :ARG0 (a / antibody :ARG1-of (s / specific-02 :ARG2 "p")) :ARG1 (p2 / protein :name (n2 / name :op1 "ASPP2") :mod (e3 / endogenous) :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :time (a2 / after :op1 (s2 / stimulate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :quant (t / temporal-quantity :quant "30" :unit (m / minute))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1D"))) # ::id bmtr_0007.9 # ::date 2015-02-26T01:32:43 # ::file bmtr_0007_9.txt # ::snt ASPP2 phosphorylation was rapid and transient as 3 hours after EGF stimulation phosphorylated ASPP2 was barely detectable. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (r / rapid :domain "p2") :op2 (t2 / transient-02 :ARG1 (p2 / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")))) :ARG1-of (i / infer-01 :ARG2 (p3 / possible-01 :ARG1 (d / detect-01 :ARG1 (p5 / protein :name (n3 / name :op1 "ASPP2") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :degree (b / bare)) :time (a2 / after :op1 (s / stimulate-01 :ARG2 (p6 / protein :name (n2 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :quant (t / temporal-quantity :quant "3" :unit (h / hour)))))) # ::id bmtr_0007.10 # ::date 2015-02-26T01:39:26 # ::file bmtr_0007_10.txt # ::snt Moreover, with another different phospho-ASPP2 antibody, ES1, ASPP2 phosphorylation was also observed in a human colon cancer cell line HKe3 ER:HRASV12 cells, in which RAS activation is induced upon the addition of 4-hydroxytamoxifen (4-OHT) [2,10,11] (Figure 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a2 / and :op2 (o / observe-01 :ARG1 (p / phosphorylate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "ASPP2") :xref (x2 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))) :mod (a / also) :location (c2 / cell-line :name (n4 / name :op1 "HKe3" :op2 "ER") :location-of (i / induce-01 :ARG0 (a6 / add-02 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "4-hydroxytamoxifen") :xref (x3 / xref :value "PUBCHEM:449459" :prob "11.717745"))) :ARG2 (a5 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG0-of (m2 / mean-01 :ARG1 (c4 / cell :name (n8 / name :op1 "HRASV12"))) :mod (h / human) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colon" :op2 "cancer"))) :instrument (a3 / antibody :name (n7 / name :op1 "ES1") :ARG1-of (d2 / differ-02) :mod (a4 / another) :ARG1-of (s / specific-02 :ARG2 (p4 / protein :name (n6 / name :op1 "ASPP2") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))))) :ARG1-of (d3 / describe-01 :ARG0 (a7 / and :op1 (f / figure :mod "1E") :op2 (p3 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a8 / and :op1 "2" :op2 "10" :op3 "11")))))) # ::id bmtr_0007.11 # ::date 2015-02-26T02:06:09 # ::file bmtr_0007_11.txt # ::snt The phospho-specific antibody for ASPP2 is specific as knockdown of ASPP2 resulted in a lack of detection of phospho-ASPP2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / specific-02 :ARG1 (a / antibody :ARG1-of (s2 / specific-02 :ARG2 "p")) :ARG1-of (i / infer-01 :ARG2 (r / result-01 :ARG1 (k / knock-down-02 :ARG1 (p3 / protein :name (n / name :op1 "ASPP2") :xref (x / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))) :ARG2 (l / lack-01 :ARG1 (d / detect-01 :ARG1 (p / protein :name (n2 / name :op1 "ASPP2") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003"))))))) # ::id bmtr_0007.12 # ::date 2015-02-26T02:12:13 # ::file bmtr_0007_12.txt # ::snt All these demonstrate that ASPP2 is a novel substrate of MAPK and Ser827 of ASPP2 can be phosphorylated by RAS/MAPK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (d / demonstrate-01 :ARG0 (t / this :mod (a / all)) :ARG1 (a2 / and :op1 (c / catalyze-01 :ARG0 (e / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1 (p5 / protein :name (n3 / name :op1 "ASPP2") :xref (x1 / xref :value "UNIPROT:ASPP2_HUMAN" :prob "1.003")) :mod (n6 / novel)) :op2 (p2 / possible-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "827" :name (n4 / name :op1 "serine") :part-of p5 :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (p4 / pathway :name (n5 / name :op1 "RAS/MAPK")))))) # ::id pmid_1528_0923.1 # ::date 2015-06-18T01:10:09 # ::file pmid_1528_0923_1.txt # ::snt Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells (PMID:15280923) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (p2 / potentiate-01 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (c / cell :source (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))) :ARG2 (b / blockade-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK1/2")))) :mod (d2 / dual)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG8 "PMID15280923"))) # ::id pmid_1528_0923.66 # ::date 2015-06-18T02:16:52 # ::file pmid_1528_0923_66.txt # ::snt RESULTS # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1528_0923.67 # ::date 2015-06-18T03:17:13 # ::file pmid_1528_0923_67.txt # ::snt Differences in activity of ERK1/2 in the breast cancer cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (d / differ-02 :ARG3 (a / act-02 :ARG0 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (c / cell-line :source (d2 / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer"))))) # ::id pmid_1528_0923.68 # ::date 2015-06-18T03:20:56 # ::file pmid_1528_0923_68.txt # ::snt Immunoblotting revealed differences in basal levels of ERK1/2 phosphorylation in different breast cancer cell lines, while the expression of ERK1/2 protein, normalised to actin expression, was relatively consistent (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (c / contrast-01 :ARG1 (r / reveal-01 :ARG0 (i / immunoblot-01) :ARG1 (d2 / differ-02 :ARG1 (l / level :mod (b / basal) :quant-of (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")) :location (c2 / cell-line :source (d4 / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")) :ARG1-of (d3 / differ-02)))))) :ARG2 (c4 / consistent-01 :ARG1 (e2 / express-03 :ARG2 e :ARG1-of (n3 / normalize-01) :destination (e3 / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :ARG2-of (r2 / relative-05)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1528_0923.69 # ::date 2015-06-18T04:12:42 # ::file pmid_1528_0923_69.txt # ::snt To test whether the ERK1/2 activity was only a tissue culture phenomenon, selected cell lines were injected into the mammary fatpads of nude mice, and protein lysates were prepared from the tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (i / inject-01 :ARG1 (c / cell-line :ARG1-of (s / select-01)) :ARG2 (f / fatpad :source (b / breast) :part-of (m / mouse :mod (n / nude)))) :op2 (p / prepare-01 :ARG1 (l / lysate :mod (p2 / protein)) :ARG2 (t / tumor)) :purpose (t2 / test-01 :ARG1 (p3 / phenomenon :mod (c2 / culture-01 :ARG1 (t3 / tissue)) :mod (o / only) :domain (a2 / activity-06 :mode "interrogative" :ARG0 (e / enzyme :name (n2 / name :op1 "ERK1/2")))))) # ::id pmid_1528_0923.70 # ::date 2015-06-18T05:40:38 # ::file pmid_1528_0923_70.txt # ::snt Taking into account the fact that lysates were of a mixture of tumour cells and surrounding stromal and infiltrating host cells, the immunoblotting of the tumour-derived proteins showed similar results to those obtained using lysates of cultured cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (c / consider-02 :ARG1 (l / lysate :source (m / mix-01 :ARG1 (c2 / cell :mod (t / tumor)) :ARG2 (a / and :op1 (c3 / cell :mod (s / stroma) :ARG1-of (s2 / surround-01)) :op2 (c4 / cell :mod (h / host) :ARG0-of (i / infiltrate-01))))) :ARG2 (s3 / show-01 :ARG0 (i2 / immunoblot-01 :ARG1 (p / protein :ARG1-of (d / derive-01 :ARG2 t))) :ARG1 (t2 / thing :ARG1-of (r3 / resemble-01 :ARG2 (t3 / thing :ARG1-of (o / obtain-01 :ARG2 (l2 / lysate :source (c5 / cell :ARG1-of (c6 / culture-01)))) :ARG2-of (r2 / result-01))) :ARG2-of (r / result-01)))) # ::id pmid_1528_0923.71 # ::date 2015-06-18T06:26:09 # ::file pmid_1528_0923_71.txt # ::snt MDA-MB-231 and MDA-MB-435 tumour lysates showed high levels of p-ERK1/2 in comparison to MDA-MB-468 and GI101A tumours (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (l / lysate :source (a / and :op1 (c / cell-line :name (n / name :op1 "MDA-MB-231")) :op2 (c2 / cell-line :name (n2 / name :op1 "MDA-MB-435")) :mod (t / tumor))) :ARG1 (l2 / level :ARG1-of (h / high-02) :quant-of (e / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (c3 / compare-01 :ARG2 (a2 / and :op1 (c4 / cell-line :name (n4 / name :op1 "MDA-MB-468")) :op2 (c5 / cell-line :name (n5 / name :op1 "GI101A")) :mod (t2 / tumor)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id pmid_1528_0923.72 # ::date 2015-06-18T06:52:55 # ::file pmid_1528_0923_72.txt # ::snt Elevated ERK activity does not necessarily correlate with the status of EGFR and HER2 in breast cancer cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / correlate-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n6 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (e5 / elevate-01)) :ARG2 (s / status :poss (a2 / and :op1 (e6 / enzyme :name (n7 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e7 / enzyme :name (n8 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :location (c2 / cell :source (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))) :ARG1-of (n5 / need-01 :polarity "-")) # ::id pmid_1528_0923.73 # ::date 2015-06-18T07:16:08 # ::file pmid_1528_0923_73.txt # ::snt Since ERK1/2 can be activated via EGFR and HER2 signalling, relative expression levels of these growth factor receptors were measured in the panel of cell lines, to test if there was a correlation between ERK activation and receptor expression levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (c / cause-01 :ARG0 (p / possible-01 :ARG1 (a / activate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK1/2")) :manner (s2 / signal-07 :ARG0 (a2 / and :op1 (e5 / enzyme :name (n6 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e6 / enzyme :name (n7 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))))) :ARG1 (m / measure-01 :ARG1 (l / level :degree-of (e7 / express-03 :ARG2 (r2 / receptor :mod (g / growth-factor))) :ARG1-of (r / relative-05)) :location (p2 / panel :consist-of (c2 / cell-line)) :purpose (t / test-01 :ARG2 (c3 / correlate-01 :mode "interrogative" :ARG1 (l3 / level :degree-of (a3 / activate-01 :ARG1 (e / enzyme :name (n9 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG2 (l2 / level :degree-of e7))))) # ::id pmid_1528_0923.74 # ::date 2015-06-18T08:10:43 # ::file pmid_1528_0923_74.txt # ::snt As expected from the heterogeneity seen in clinical specimens of breast cancer, there was variability in expression of EGFR, from high expression in MDA-MB-468 and minimal expression in MDA-MB-435 cells (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (v / vary-01 :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG3 (e4 / express-03 :ARG3 (c / cell-line :name (n4 / name :op1 "MDA-MB-468")) :ARG1-of (h / high-02)) :ARG4 (e5 / express-03 :ARG3 (c2 / cell-line :name (n5 / name :op1 "MDA-MB-435")) :ARG1-of (m / minimal-02)) :ARG1-of (e6 / expect-01 :source (h2 / heterogenous :ARG1-of (s / see-01 :location (s2 / specimen :mod (c3 / clinic) :source (d2 / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1528_0923.75 # ::date 2015-06-19T00:21:32 # ::file pmid_1528_0923_75.txt # ::snt Comparing these results with the level of pERK1/2 indicated that there was no direct correlation between levels of these growth factor receptors and basal levels of ERK1/2 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (c / compare-01 :ARG1 (t3 / thing :mod (t / this) :ARG2-of (r / result-01)) :ARG2 (l / level :quant-of (e / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :ARG0-of (i / indicate-01 :ARG1 (c2 / correlate-01 :polarity "-" :ARG1 (l2 / level :quant-of (r2 / receptor :mod (g / growth-factor) :mod (t2 / this))) :ARG2 (l3 / level :mod (b / basal) :quant-of (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")))) :ARG1-of (d / direct-02)))) # ::id pmid_1528_0923.76 # ::date 2015-06-19T00:35:28 # ::file pmid_1528_0923_76.txt # ::snt Thus, while the MDA-MB-231 cell line with highly activated ERK1/2 expressed a relatively high level of EGFR, other combinations occur. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / cause-01 :ARG1 (c2 / contrast-01 :ARG1 (e2 / express-03 :ARG1 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (h / high-02 :ARG2-of (r / relative-05))) :ARG3 (c3 / cell-line :name (n2 / name :op1 "MDA-MB-231") :mod (e4 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG1-of (a / activate-01 :ARG1-of (h2 / high-02))))) :ARG2 (c5 / combine-01 :mod (o / other)))) # ::id pmid_1528_0923.77 # ::date 2015-06-19T00:53:23 # ::file pmid_1528_0923_77.txt # ::snt High pERK1/2 levels were detected in MDA-MB-435 cells, which have very little EGFR, in contrast to the SUM149 cells with high EGFR expression and low ERK1/2 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / detect-01 :ARG1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (h / high-02)) :location (c / cell-line :name (n3 / name :op1 "MDA-MB-435") :ARG0-of (h2 / have-03 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR") :quant (l3 / little :degree (v / very)) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (c2 / contrast-01 :ARG2 (c3 / cell-line :name (n5 / name :op1 "SUM149") :poss (a / and :op1 (e4 / express-03 :ARG2 e3 :ARG1-of h) :op2 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ERK1/2")) :ARG1-of (l2 / low-04)))))))) # ::id pmid_1528_0923.78 # ::date 2015-06-21T05:31:55 # ::file pmid_1528_0923_78.txt # ::snt Similarly, no correlation was found between the expression of HER2 receptor and the status of pERK (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (c / correlate-01 :polarity "-" :ARG1 (e2 / express-03 :ARG2 (r2 / receptor :mod (e3 / enzyme :name (n2 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :ARG2 (s / status :poss (e / enzyme :name (n3 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1-of (r / resemble-01) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1A"))) # ::id pmid_1528_0923.79 # ::date 2015-06-21T05:42:15 # ::file pmid_1528_0923_79.txt # ::snt PKI166 inhibition of breast cancer cell proliferation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "PKI166") :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (p / proliferate-01 :ARG0 (c / cell :source (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))) # ::id pmid_1528_0923.80 # ::date 2015-06-21T05:55:48 # ::file pmid_1528_0923_80.txt # ::snt Six cell lines with different levels of EGFR expression were selected for treatment with PKI166. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (s / select-01 :ARG1 (c / cell-line :quant "6") :ARG3 (t / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PKI166") :xref (x1 / xref :value "PUBCHEM:6918403" :prob "18.86067"))) :poss-of (l / level :ARG1-of (d / differ-02) :quant-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) # ::id pmid_1528_0923.81 # ::date 2015-06-21T06:17:25 # ::file pmid_1528_0923_81.txt # ::snt Initial studies used a dose range of 0.1–5.0 μM (data not shown), and the results of treating cells with 0.5 and 5.0 μM are shown in Table 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / and :op1 (u / use-01 :ARG0 (s / study-01 :mod (i / initial)) :ARG1 (r / range-01 :ARG1 (d / dose) :ARG3 (c / concentration-quantity :quant "0.1" :unit (m / micromolar)) :ARG4 (c2 / concentration-quantity :quant "5.0" :unit m)) :ARG1-of (s2 / show-01 :polarity "-" :ARG0 (d2 / data))) :op2 (s3 / show-01 :ARG1 (t3 / thing :ARG2-of (r2 / result-01 :ARG1 (t / treat-04 :ARG1 (c3 / cell) :ARG2 (a2 / and :op1 (c4 / concentration-quantity :quant "0.5" :unit m) :op2 c2)))) :location (t2 / table :mod "1"))) # ::id pmid_1528_0923.82 # ::date 2015-06-21T07:44:10 # ::file pmid_1528_0923_82.txt # ::snt Growth inhibition was determined from the results of MTT assays, comparing PKI166 treated cells with cells exposed to medium with 0.1% DMSO. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (d / determine-01 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01)) :ARG2 (t4 / thing :ARG2-of (r / result-01 :ARG1 (a / assay-01 :instrument (s3 / small-molecule :name (n / name :op1 "MTT") :xref (x1 / xref :value "PUBCHEM:64965" :prob "17.320225"))))) :manner (c / compare-01 :ARG1 (c2 / cell :ARG1-of (t2 / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "PKI166") :xref (x2 / xref :value "PUBCHEM:6918403" :prob "18.86067")))) :ARG2 (c3 / cell :ARG1-of (e / expose-01 :ARG2 (m / medium :ARG0-of (h / have-03 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "DMSO") :quant (p2 / percentage-entity :value "0.1") :xref (x / xref :value "PUBCHEM:679" :prob "16.740406")))))))) # ::id pmid_1528_0923.83 # ::date 2015-06-21T08:19:01 # ::file pmid_1528_0923_83.txt # ::snt Treatment with 0.5 μM PKI166, a concentration less than plasma and tumour concentrations achieved in preclinical models from oral administration of the drug, and the higher dose of 5.0 μM, produced different levels of growth inhibition in different cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (p / produce-01 :ARG0 (a / and :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "PKI166") :mod (c / concentration-quantity :quant "0.5" :unit (m / micromolar) :mod (l2 / less) :compared-to (c4 / concentration :poss (a2 / and :op1 (p2 / plasma) :op2 (t2 / tumor)) :ARG1-of (a3 / achieve-01 :location (m4 / model :mod (p3 / preclinical) :source (a4 / administer-01 :ARG1 s :path (m5 / mouth)))))) :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067"))) :op2 (d / dose :mod (c2 / concentration-quantity :quant "5.0" :unit (m2 / micromolar)) :ARG1-of (h / high-02 :degree (m3 / more)))) :ARG1 (l / level :ARG1-of (d2 / differ-02) :quant-of (i / inhibit-01 :ARG1 (g / grow-01))) :location (c3 / cell-line :ARG1-of d2)) # ::id pmid_1528_0923.84 # ::date 2015-06-21T09:11:05 # ::file pmid_1528_0923_84.txt # ::snt As expected, cells expressing low levels of EGFR and HER2, GI101A, MDA-MB-435 showed least growth inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (s / show-01 :ARG0 (c / cell :ARG3-of (e3 / express-03 :ARG2 (l / level :ARG1-of (l2 / low-04) :quant-of (a / and :op1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n2 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "GI101A")) :op2 (c3 / cell-line :name (n4 / name :op1 "MDA-MB-435"))))) :ARG1 (i / inhibit-01 :ARG1 (g / grow-01) :degree (l3 / least)) :ARG1-of (e4 / expect-01)) # ::id pmid_1528_0923.85 # ::date 2015-06-21T09:24:57 # ::file pmid_1528_0923_85.txt # ::snt However, not all of the high EGFR-expressing lines were sensitive to PKI166. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG2 (s / sensitive-03 :ARG0 (l / line :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (h / high-02)) :mod (a / all :polarity "-")) :ARG1 (s2 / small-molecule :name (n2 / name :op1 "PKI166") :xref (x1 / xref :value "PUBCHEM:6918403" :prob "18.86067")))) # ::id pmid_1528_0923.86 # ::date 2015-06-21T09:55:03 # ::file pmid_1528_0923_86.txt # ::snt The lower dose produced 46 and 21% growth inhibition of SUM149 and MDA-MB-468 cells, respectively, but had little effect (3.3% inhibition) on the growth of MDA-MB-231 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (p3 / produce-01 :ARG0 (d / dose :ARG1-of (l / low-04 :degree (m2 / more))) :ARG1 (a / and :op1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (c2 / cell-line :name (n / name :op1 "SUM149"))) :quant (p4 / percentage-entity :value "46")) :op2 (i2 / inhibit-01 :ARG1 (g2 / grow-01 :ARG1 (c3 / cell-line :name (n2 / name :op1 "MDA-MB-468"))) :quant (p5 / percentage-entity :value "21"))) :mod (r / respective)) :ARG2 (a2 / affect-01 :ARG0 d :ARG1 (g3 / grow-01 :ARG1 (c4 / cell-line :name (n3 / name :op1 "MDA-MB-231"))) :degree (l3 / little) :ARG1-of (m3 / mean-01 :ARG2 (i3 / inhibit-01 :quant (p6 / percentage-entity :value "3.3"))))) # ::id pmid_1528_0923.87 # ::date 2015-06-21T10:26:54 # ::file pmid_1528_0923_87.txt # ::snt The SKBR3 cells, expressing EGFR and also high levels of HER2, were most sensitive, showing 55% growth inhibition with 0.5 μM and 76% inhibition with 5.0 μM PKI166. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (l / level :ARG1-of (h / high-02) :quant-of (e3 / enzyme :name (n3 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :ARG3 (c / cell-line :name (n / name :op1 "SKBR3") :ARG0-of (s / sensitive-03 :degree (m / most))) :manner (s2 / show-01 :ARG0 c :ARG1 (a2 / and :op1 (i / inhibit-01 :ARG0 (s3 / small-molecule :name (n4 / name :op1 "PKI166") :mod (c2 / concentration-quantity :quant "0.5" :unit (m2 / micromolar)) :xref (x2 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (g / grow-01) :quant (p / percentage-entity :value "55")) :op2 (i2 / inhibit-01 :ARG0 (s4 / small-molecule :name (n5 / name :op1 "PKI166") :mod (c3 / concentration-quantity :quant "5.0" :unit m2) :xref (x3 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :quant (p2 / percentage-entity :value "76"))))) # ::id pmid_1528_0923.88 # ::date 2015-06-21T10:57:30 # ::file pmid_1528_0923_88.txt # ::snt PKI166 inhibits phosphorylation of EGFR and HER2 in breast cancer cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "PKI166") :xref (x2 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n5 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n6 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :location (c / cell :source (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))) # ::id pmid_1528_0923.89 # ::date 2015-06-21T11:00:46 # ::file pmid_1528_0923_89.txt # ::snt To demonstrate inhibition of EGFR and HER2 phosphorylation by the concentrations of PKI166 used for the growth inhibition assays, cell lysates were prepared from MDA-MB-231, MDA-MB-468, SUM149 and SKBR3 cells after treatment with PKI166 and stimulation with EGF, and phosphorylation of the receptors assessed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (p2 / prepare-01 :ARG1 (l / lysate :mod (c / cell)) :ARG2 (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "MDA-MB-231")) :op2 (c3 / cell-line :name (n4 / name :op1 "MDA-MB-468")) :op3 (c4 / cell-line :name (n5 / name :op1 "SUM149")) :op4 (c5 / cell-line :name (n6 / name :op1 "SKBR3"))) :time (a3 / after :op1 (a4 / and :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n7 / name :op1 "PKI166") :xref (x4 / xref :value "PUBCHEM:6918403" :prob "18.86067"))) :op2 (s2 / stimulate-01 :ARG2 (p / protein :name (n8 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))))) :op2 (a5 / assess-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (r / receptor))) :purpose (d / demonstrate-01 :ARG1 (i / inhibit-01 :ARG0 (s4 / small-molecule :name (n / name :op1 "PKI166") :ARG1-of (c6 / concentrate-02 :ARG1-of (u / use-01 :ARG2 (a7 / assay-01 :ARG1 (i2 / inhibit-01 :ARG1 (g / grow-01))))) :xref (x3 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (p4 / phosphorylate-01 :ARG1 (a6 / and :op1 (e3 / enzyme :name (n9 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n10 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))))) # ::id pmid_1528_0923.90 # ::date 2015-06-21T11:17:53 # ::file pmid_1528_0923_90.txt # ::snt PKI166 inhibited ligand-induced EGFR phosphorylation in a dose dependent manner in these four cell lines, and also phosphorylation of HER2 in SKBR3 cells, in the absence or presence of 50 ng ml−1 EGF (Figure 2) (data for other cell lines not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "PKI166") :xref (x3 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG2-of (i3 / induce-01 :ARG0 (l / ligand))) :ARG0-of (d / depend-01 :ARG1 (d2 / dose)) :location (c2 / cell-line :quant "4" :mod (t / this))) :op2 (i2 / inhibit-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :location (c3 / cell-line :name (n6 / name :op1 "SKBR3"))) :condition (o / or :op1 (p / protein :name (n7 / name :op1 "EGF") :quant (c5 / concentration-quantity :quant "50" :unit (n8 / nanogram-per-milliliter)) :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (a2 / absent-01 :ARG1 p))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2")) :ARG1-of (s3 / show-01 :polarity "-" :ARG0 (d4 / data :topic (c4 / cell-line :mod (o2 / other))))) # ::id pmid_1528_0923.91 # ::date 2015-06-21T12:11:40 # ::file pmid_1528_0923_91.txt # ::snt Constitutive ERK1/2 phosphorylation as a potential escape mechanism from inhibition by PKI166 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (p / provide-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :mod (c / constitutive)) :ARG1 (m / mechanism :mod (p3 / potential) :purpose (e2 / escape-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "PKI166") :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")))))) # ::id pmid_1528_0923.92 # ::date 2015-06-21T12:18:34 # ::file pmid_1528_0923_92.txt # ::snt Inhibition of growth by PKI166 was most effective in cells with high levels of EGFR and nonactivated ERK1/2 (SUM149, MDA-MB-468) when compared with cells with high EGFR and high basal level of phosphorylated ERK1/2 (MDA-MB-231). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (e2 / effective-04 :ARG0 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "PKI166") :xref (x1 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (g / grow-01)) :degree (m / most) :location (c / cell :ARG0-of (h / have-03 :ARG1 (l / level :ARG1-of (h2 / high-02) :quant-of (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG1-of (a2 / activate-01 :polarity "-"))))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (c2 / cell-line :name (n5 / name :op1 "SUM149")) :op2 (c3 / cell-line :name (n6 / name :op1 "MDA-MB-468"))))) :compared-to (c4 / cell :ARG0-of (h3 / have-03 :ARG1 (a4 / and :op1 (l3 / level :ARG1-of (h6 / high-02) :quant-of e3) :op2 (l2 / level :mod (b / basal) :quant-of (e6 / enzyme :name (n8 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (h5 / high-02)))) :ARG1-of (m3 / mean-01 :ARG2 (c5 / cell-line :name (n9 / name :op1 "MDA-MB-231"))))) # ::id pmid_1528_0923.93 # ::date 2015-06-21T13:04:23 # ::file pmid_1528_0923_93.txt # ::snt To test whether the basal ERK1/2 activity was providing an escape mechanism from inhibition by PKI166, cells were treated with a combination of PKI166 and UO126, an inhibitor of MEK (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (t2 / treat-04 :ARG1 (c / cell) :ARG2 (c2 / combine-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "PKI166") :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "UO126") :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))))) :purpose (t3 / test-01 :ARG1 (p / provide-01 :mode "interrogative" :ARG0 (a / activity-06 :ARG0 (e3 / enzyme :name (n5 / name :op1 "ERK1/2") :mod (b / basal))) :ARG1 (m2 / mechanism :purpose (e4 / escape-01 :ARG1 (i3 / inhibit-01 :ARG0 s))))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "1"))) # ::id pmid_1528_0923.94 # ::date 2015-06-15T12:42:09 # ::file pmid_1528_0923_94.txt # ::snt GI101A cells, with low EGFR and nonactivated ERK1/2, showed modest growth inhibition when treated with an individual inhibitor and no significant difference with the combination of the two. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (s2 / show-01 :ARG0 (c / cell-line :name (n2 / name :op1 "GI101A") :ARG0-of (h / have-03 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n3 / name :op1 "EGFR") :ARG1-of (l / low-04) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG1-of (a3 / activate-01 :polarity "-"))))) :ARG1 (a4 / and :op1 (i2 / inhibit-01 :ARG1 (g / grow-01) :time (t2 / treat-04 :ARG1 c :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (i3 / individual))) :mod (m / modest)) :op2 (d / differ-02 :ARG1 c :ARG2 (c2 / combine-01 :ARG1 (t / thing :quant "2")) :ARG1-of (s / significant-02 :polarity "-")))) # ::id pmid_1528_0923.95 # ::date 2015-06-15T13:48:11 # ::file pmid_1528_0923_95.txt # ::snt MDA-MB-435 cells were significantly inhibited by U0126 alone, and the addition of PKI166 made no difference. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (a / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "U0126") :mod (a2 / alone) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1 (c / cell-line :name (n2 / name :op1 "MDA-MB-435")) :ARG1-of (s2 / significant-02)) :op2 (m / make-01 :polarity "-" :ARG0 (a3 / add-02 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "PKI166") :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067"))) :ARG1 (d / differ-02))) # ::id pmid_1528_0923.96 # ::date 2015-06-15T13:52:51 # ::file pmid_1528_0923_96.txt # ::snt The combination of agents significantly increased the antiproliferative action of PKI166 at the 0.5 and 5.0 μM doses in cells expressing higher levels of EGFR or HER2 (SUM149, MDA-MB-468, SKBR3), including MDA-MB-231 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / increase-01 :ARG0 (c / combine-01 :ARG1 (a / agent)) :ARG1 (a2 / act-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "PKI166") :ARG2-of (d3 / dose-01 :quant (a4 / and :op1 (c2 / concentration-quantity :quant "0.5" :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant "5" :unit (m2 / micromolar)))) :xref (x2 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG0-of (c9 / counter-01 :ARG1 (p / proliferate-01))) :ARG1-of (s / significant-02) :location (c4 / cell :ARG3-of (e / express-03 :ARG2 (o / or :op1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (h / high-02 :degree (m3 / more))) :op2 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :ARG1-of h))) :ARG1-of (m4 / mean-01 :ARG2 (a5 / and :op1 (c5 / cell-line :name (n4 / name :op1 "SUM149")) :op2 (c6 / cell-line :name (n5 / name :op1 "MDA-MB-468")) :op3 (c7 / cell-line :name (n6 / name :op1 "SKBR3")))) :ARG2-of (i2 / include-01 :ARG1 (c8 / cell-line :name (n7 / name :op1 "MDA-MB-231"))))) # ::id pmid_1528_0923.97 # ::date 2015-06-15T14:09:53 # ::file pmid_1528_0923_97.txt # ::snt Treating the MDA-MB-231 cells with U0126 alone produced 8.5% inhibition, which was not significantly different from control values. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (p2 / produce-01 :ARG0 (t / treat-04 :ARG1 (c / cell-line :name (n2 / name :op1 "MDA-MB-231")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "U0126") :mod (a / alone) :xref (x / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 (i / inhibit-01 :quant (p / percentage-entity :value "8.5")) :ARG1-of (d / differ-02 :polarity "-" :ARG2 (v / value :mod (c2 / control)) :ARG1-of (s / significant-02))) # ::id pmid_1528_0923.98 # ::date 2015-06-15T14:13:28 # ::file pmid_1528_0923_98.txt # ::snt The addition of U0126 to 0.5 or 5.0 μM PKI166 significantly increased the growth inhibition produced by the receptor tyrosine kinase inhibitor alone (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (i / increase-01 :ARG0 (a / add-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG2 (o / or :op1 (s3 / small-molecule :name (n2 / name :op1 "PKI166") :quant (c / concentration-quantity :quant "0.5" :unit (m / micromolar)) :xref (x1 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :op2 (s4 / small-molecule :name (n3 / name :op1 "PKI166") :quant (c2 / concentration-quantity :quant "5" :unit (m3 / micromolar)) :xref (x3 / xref :value "PUBCHEM:6918403" :prob "18.86067")))) :ARG1 (i2 / inhibit-01 :ARG1 (g / grow-01) :ARG1-of (p / produce-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :xref (x / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392"))) :mod (a2 / alone)))) :ARG2 (s / significant-02) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "1"))) # ::id pmid_1528_0923.99 # ::date 2015-06-15T14:19:24 # ::file pmid_1528_0923_99.txt # ::snt Apoptosis induced by PKI166 and U0126 was assessed by measuring DNA fragmentation by propidium iodide staining and FACS analysis, and determining the proportions of hypodiploid cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (a8 / assess-01 :ARG0 (a7 / and :op1 (m / measure-01 :ARG1 (f / fragment-01 :ARG0 (a5 / and :op1 (s4 / stain-01 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "propidium" :op2 "iodide") :xref (x / xref :value "PUBCHEM:104981" :prob "12.372932"))) :op2 (a6 / analyze-01 :mod (t / thing :name (n5 / name :op1 "FACS")))) :ARG1 (n6 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA") :name (n3 / name :op1 "DNA")))) :op2 (d2 / determine-01 :ARG1 (p / proportion-01 :ARG1 (c / cell :mod (h / hypodiploid))))) :ARG1 (a3 / apoptosis :ARG2-of (i / induce-01 :ARG0 (a4 / and :op1 (s2 / small-molecule :name (n2 / name :op1 "PKI166") :xref (x1 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :op2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696")))))) # ::id pmid_1528_0923.100 # ::date 2015-06-15T14:29:24 # ::file pmid_1528_0923_100.txt # ::snt This showed that PKI166 alone or in combination with U0126 induced apoptosis in the EGFR or HER2 expressing cell lines MDA-MB-231, MDA-MB-468, SKBR3 and SUM149 cells (Figure 3), although the proportions of hypodiploid cells varied between the different lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s2 / show-01 :ARG0 (t / this) :ARG1 (i / induce-01 :ARG0 (o / or :op1 (s3 / small-molecule :name (n4 / name :op1 "PKI166") :mod (a / alone) :xref (x2 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :op2 (s4 / small-molecule :name (n9 / name :op1 "PKI166") :ARG1-of (c / combine-01 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x4 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :xref (x3 / xref :value "PUBCHEM:6918403" :prob "18.86067"))) :ARG2 (a2 / apoptosis) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3")) :concession (v / vary-01 :ARG1 (p / proportion-01 :ARG1 (c6 / cell :mod (h2 / hypodiploid))) :location (l / line :ARG1-of (d2 / differ-02))) :location (a3 / and :op1 (c2 / cell-line :name (n5 / name :op1 "MDA-MB-231")) :op2 (c3 / cell-line :name (n6 / name :op1 "MDA-MB-468")) :op3 (c4 / cell-line :name (n7 / name :op1 "SKBR3")) :op4 (c5 / cell-line :name (n8 / name :op1 "SUM149")) :ARG3-of (e3 / express-03 :ARG2 (o2 / or :op1 (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n3 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))))) # ::id pmid_1528_0923.101 # ::date 2015-06-15T14:47:46 # ::file pmid_1528_0923_101.txt # ::snt Similar to the MTT results in Table 1, SKBR3 and SUM 149 cells were most sensitive to treatment with the inhibitors, while the proportions of hypodiploid MDA-MB-231 cells were lower. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / contrast-01 :ARG1 (s / sensitive-03 :ARG0 (a / and :op1 (c2 / cell-line :name (n / name :op1 "SKBR3")) :op2 (c3 / cell-line :name (n2 / name :op1 "SUM149"))) :ARG1 (t2 / treat-04 :ARG1 a :ARG2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01))) :degree (m2 / most)) :ARG2 (l / low-04 :ARG1 (p / proportion-01 :ARG1 (c4 / cell-line :name (n3 / name :op1 "MDA-MB-231") :mod (h / hypodiploid))) :degree (m / more)) :ARG1-of (r / resemble-01 :ARG2 (t4 / thing :ARG2-of (r2 / result-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "MTT") :xref (x / xref :value "PUBCHEM:64965" :prob "17.320225"))) :location (t3 / table :mod "1")))) # ::id pmid_1528_0923.102 # ::date 2015-06-16T10:36:10 # ::file pmid_1528_0923_102.txt # ::snt Treatment with U0126 alone significantly increased the numbers of MDA-MB-231 in the G1 phase of the cell cycle (89–93% compared with 70–72% of control or PKI 166 treated cells, P<0.001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / increase-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :mod (a / alone) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 (n2 / number-01 :ARG1 (c / cell-line :name (n3 / name :op1 "MDA-MB-231"))) :ARG2 (v / value-interval :op1 (p4 / percentage-entity :value "89") :op2 (p / percentage-entity :value "93")) :ARG1-of (s2 / significant-02) :time (e / event :name (n5 / name :op1 "G1" :op2 "phase") :part-of (c2 / cycle-02 :ARG1 (c3 / cell))) :compared-to (v2 / value-interval :op1 (p5 / percentage-entity :value "70") :op2 (p2 / percentage-entity :value "72") :quant-of (o / or :op1 (c4 / cell :mod (c5 / control)) :op2 (c6 / cell :ARG1-of (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "PKI166") :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")))))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) # ::id pmid_1528_0923.103 # ::date 2015-06-16T10:44:12 # ::file pmid_1528_0923_103.txt # ::snt The proportion of SUM149 cells in G1 was significantly increased by treatment with either inhibitor alone and the combination, while apoptosis was significantly increased in cells exposed to PKI166, with or without U0126. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (i2 / increase-01 :ARG0 (t2 / treat-04 :ARG2 (a / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (a2 / alone)) :op2 (m2 / molecular-physical-entity :ARG0-of (i4 / inhibit-01) :ARG1-of (c3 / combine-01)))) :ARG1 (p / proportion-01 :ARG1 (c2 / cell-line :name (n2 / name :op1 "SUM149")) :time (e2 / event :name (n4 / name :op1 "G1"))) :ARG2 (s2 / significant-02)) :ARG2 (i3 / increase-01 :ARG1 (a3 / apoptosis) :location (c4 / cell :ARG1-of (e / expose-01 :ARG2 (o / or :op1 (a4 / and :op1 (s4 / small-molecule :name (n3 / name :op1 "PKI166") :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")) :op2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :op2 s4))) :ARG1-of s2)) # ::id pmid_1528_0923.104 # ::date 2015-06-16T10:52:27 # ::file pmid_1528_0923_104.txt # ::snt Induction of the cyclin-dependent kinase inhibitor p27KIP1 generally corresponded with increases in the proportion of cells in G1, as shown for MDA-MB-231 and SUM149 (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (c / correspond-02 :ARG1 (i2 / induce-01 :ARG2 (p2 / protein :name (n4 / name :op1 "p27KIP1") :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "cyclin-dependent" :op2 "kinase"))) :xref (x / xref :value "UNIPROT:CDN1B_HUMAN" :prob "0.663"))) :ARG2 (i3 / increase-01 :ARG1 (p / proportion-01 :ARG1 (c2 / cell) :time (e2 / event :name (n5 / name :op1 "G1")))) :ARG1-of (g / general-02) :ARG1-of (s / show-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n2 / name :op1 "MDA-MB-231")) :op2 (c4 / cell-line :name (n3 / name :op1 "SUM149")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4"))) # ::id pmid_1528_0923.105 # ::date 2015-06-16T11:00:05 # ::file pmid_1528_0923_105.txt # ::snt Differential effect of PKI166 on ERK1/2 phosphorylation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "PKI166") :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2"))) :ARG1-of (d / differ-02)) # ::id pmid_1528_0923.106 # ::date 2015-06-16T11:03:57 # ::file pmid_1528_0923_106.txt # ::snt To evaluate whether the antiproliferative effects of EGFR inhibition involve ERK1/2 activation, the status of pERK1/2 was determined in cells exposed to the same concentrations of PKI166 used for the growth inhibition assays, in the presence and absence of U0126 (10 μM) (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (d / determine-01 :ARG1 (s2 / status :poss-of (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :location (c / cell :ARG1-of (e3 / expose-01 :ARG2 (c2 / concentrate-02 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "PKI166") :ARG1-of (u / use-01 :ARG2 (a / assay-01 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01)))) :xref (x1 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1-of (s4 / same-01)) :manner (a2 / and :op1 (p2 / present-02 :ARG1 (s / small-molecule :name (n2 / name :op1 "U0126") :quant (c3 / concentration-quantity :quant "10" :unit (m / micromolar)) :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :op2 (a3 / absent-01 :ARG1 s)))) :purpose (e4 / evaluate-01 :ARG1 (i3 / involve-01 :mode "interrogative" :ARG0 (a4 / affect-01 :ARG0 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG0-of (c4 / counter-01 :ARG1 (p3 / proliferate-01))) :ARG1 (a5 / activate-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK1/2"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5"))) # ::id pmid_1528_0923.107 # ::date 2015-06-16T11:29:16 # ::file pmid_1528_0923_107.txt # ::snt U1026 alone inhibited ERK1/2 phosphorylation in MDA-MB-435 cells, with PKI 166 having no effect, as expected from minimal expression of EGFR in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (a / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "U1026") :mod (a2 / alone)) :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"))) :location (c / cell-line :name (n4 / name :op1 "MDA-MB-435"))) :op2 (a3 / affect-01 :polarity "-" :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PKI166") :xref (x1 / xref :value "PUBCHEM:6918403" :prob "18.86067"))) :ARG1-of (e3 / expect-01 :source (e4 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG3 c :ARG1-of (m / minimal-02)))) # ::id pmid_1528_0923.108 # ::date 2015-06-16T11:44:35 # ::file pmid_1528_0923_108.txt # ::snt PKI166 inhibited ERK1/2 phosphorylation in SUM149 cells, as did U0126 alone, and further inhibition by the combination of drugs was barely discernible. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (a / and :op1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "PKI166") :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2"))) :location (c / cell-line :name (n4 / name :op1 "SUM149")) :ARG1-of (r / resemble-01 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :mod (a2 / alone) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")))) :op2 (d / discern-01 :ARG1 (i2 / inhibit-01 :ARG0 (c2 / combine-01 :ARG1 (d2 / drug)) :time (f / further)) :degree (b / bare) :ARG1-of (p2 / possible-01))) # ::id pmid_1528_0923.109 # ::date 2015-06-16T11:50:30 # ::file pmid_1528_0923_109.txt # ::snt Treatment of MDA-MB-468 with either drug resulted in similar inhibition of ERK1/2 phosphorylation, with almost complete elimination of phosphorylated proteins by the combination. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (r2 / result-01 :ARG1 (t / treat-04 :ARG1 (c / cell-line :name (n / name :op1 "MDA-MB-468")) :ARG2 (d / drug :mod (e / either))) :ARG2 (a / and :op1 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))) :ARG1-of (r / resemble-01)) :op2 (e3 / eliminate-01 :ARG0 (c3 / combine-01) :ARG1 (p2 / protein :ARG3-of (p3 / phosphorylate-01)) :ARG1-of (c2 / complete-01 :mod (a2 / almost))))) # ::id pmid_1528_0923.110 # ::date 2015-06-16T11:55:33 # ::file pmid_1528_0923_110.txt # ::snt PKI166 alone minimally altered the ERK1/2 status in the MDA-MB-231 cells, and U0126 produced some inhibition, while the combination resulted in a substantial reduction, reflecting the effect on cell proliferation and apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (c / contrast-01 :ARG1 (a / and :op1 (a2 / alter-01 :ARG0 (s2 / small-molecule :wiki "-" :name (n2 / name :op1 "PKI166") :mod (a3 / alone) :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")) :ARG1 (s3 / status :mod (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n3 / name :op1 "ERK1/2"))) :ARG1-of (m / minimal-02) :location (c2 / cell-line :wiki "-" :name (n4 / name :op1 "MDA-MB-231"))) :op2 (p / produce-01 :ARG0 (s4 / small-molecule :wiki "U0126" :name (n5 / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1 (i / inhibit-01 :mod (s5 / some)))) :ARG2 (r / result-01 :ARG1 (c3 / combine-01) :ARG2 (r2 / reduce-01 :ARG1 s3 :degree (s6 / substantial)) :ARG1-of (r3 / reflect-01 :ARG2 (a4 / affect-01 :ARG1 (a5 / and :op1 (p2 / proliferate-01 :ARG0 (c4 / cell)) :op2 (a6 / apoptosis)))))) # ::id pmid_1528_0923.111 # ::date 2015-06-16T12:02:26 # ::file pmid_1528_0923_111.txt # ::snt For SUM149 and MDA-MB-468 cells the combination of the inhibitors almost completely eliminated ERK1/2 phosphorylation after 1 h incubation, although growth inhibition over 72 h was 54–63% with 0.5 μM PKI166 plus 10 μM U0126, and 63–81% with 5.0 μM PKI166 plus 10 μM U0126 (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (e / eliminate-01 :ARG0 (c / combine-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01))) :ARG1 (p3 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2"))) :ARG2 (a3 / and :op1 (c3 / cell-line :name (n2 / name :op1 "SUM149")) :op2 (c4 / cell-line :name (n3 / name :op1 "MDA-MB-468"))) :ARG1-of (c2 / complete-01 :mod (a / almost)) :time (a2 / after :op1 (i2 / incubate-01) :quant (t / temporal-quantity :quant "1" :unit (h / hour))) :concession (a5 / and :op1 (i3 / inhibit-01 :ARG0 (a4 / and :op1 (s2 / small-molecule :name (n4 / name :op1 "PKI166") :quant (c5 / concentration-quantity :quant "0.5" :unit (m2 / micromolar)) :xref (x1 / xref :value "PUBCHEM:6918403" :prob "18.86067")) :op2 (s / small-molecule :name (n5 / name :op1 "U0126") :quant (c6 / concentration-quantity :quant "10" :unit (m3 / micromolar)) :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 (g / grow-01) :quant (v / value-interval :op1 (p4 / percentage-entity :value "54") :op2 (p / percentage-entity :value "63")) :duration (o2 / over :op1 (t2 / temporal-quantity :quant "72" :unit (h3 / hour)))) :op2 (i4 / inhibit-01 :ARG0 (a6 / and :op1 (s3 / small-molecule :name (n6 / name :op1 "PKI166") :quant (c7 / concentration-quantity :quant "5" :unit (m4 / micromolar)) :xref (x / xref :value "PUBCHEM:6918403" :prob "18.86067")) :op2 s) :ARG1 (g2 / grow-01) :quant (v2 / value-interval :op1 (p5 / percentage-entity :value "63") :op2 (p2 / percentage-entity :value "81")) :duration o2)) :ARG1-of (d / describe-01 :ARG0 (t3 / table :mod "1"))) # ::id pmid_1528_0923.112 # ::date 2015-06-16T12:21:26 # ::file pmid_1528_0923_112.txt # ::snt Recovery of ERK1/2 phosphorylation in the U0126-treated cells over the period of the growth inhibition assays was not investigated, but the data may also suggest that other signal pathways were contributing to the growth and survival of the cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG1 (i / investigate-01 :polarity "-" :ARG1 (r / recover-02 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (c2 / cell :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126") :xref (x / xref :value "PUBCHEM:3006531" :prob "17.656696"))))) :time (a / assay-01 :ARG1 (i2 / inhibit-01 :ARG1 (g / grow-01))))) :ARG2 (p3 / possible-01 :ARG1 (s2 / suggest-01 :ARG0 (d / data) :ARG1 (c3 / contribute-01 :ARG0 (p4 / pathway :ARG0-of (s3 / signal-07) :mod (o2 / other)) :ARG2 (a3 / and :op1 (g2 / grow-01 :ARG1 (c4 / cell)) :op2 (s4 / survive-01 :ARG0 c4))) :mod (a2 / also)))) # ::id pmid_1528_0923.113 # ::date 2015-06-16T12:35:01 # ::file pmid_1528_0923_113.txt # ::snt The effects of the inhibitors were not related to downregulation of total ERK1/2 proteins, as the levels did not decrease with treatment (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (r2 / relate-01 :polarity "-" :ARG1 (a / affect-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01))) :ARG2 (d / downregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :mod (t2 / total))) :ARG1-of (c / cause-01 :ARG0 (d2 / decrease-01 :polarity "-" :ARG0 (t3 / treat-04) :ARG1 (l / level))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5"))) # ::id a_pmid_2234_3622.60 # ::date 2015-05-28T07:09:27 # ::file a_pmid_2234_3622_60.txt # ::snt Combined treatment of selumetinib and standard of care agents results in enhanced anti-tumour efficacy # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (r / result-01 :ARG1 (a / and :op1 (t / treat-04 :ARG2 (a3 / and :op1 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op2 (s / standard :mod (a2 / agent :mod (c / care-03)))) :ARG3-of (c2 / combine-01))) :ARG2 (e / efficacy :ARG1-of (e2 / enhance-01) :mod (c3 / counter-01 :ARG1 (t2 / tumor)))) # ::id a_pmid_2234_3622.61 # ::date 2015-05-28T15:47:00 # ::file a_pmid_2234_3622_61.txt # ::snt Mechanistic biomarker studies of the effects of selumetinib in human tumour xenograft models have shown that, in addition to pERK1/2 downregulation, a sustained exposure to the agent results in an increase in downstream apoptotic signalling and a decrease in cell cycle progression (Davies et al, 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (s2 / study-01 :ARG1 (a / affect-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1 (m2 / model :mod (x / xenograft :mod (t / tumor)) :mod (h / human))) :mod (b / biomarker :mod (m / mechanistic))) :ARG1 (r / result-01 :ARG1 (e / expose-01 :ARG2 s3 :ARG1-of (s4 / sustain-01)) :ARG2 (a7 / and :op1 (d2 / downregulate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :op2 (i / increase-01 :ARG1 (s5 / signal-07 :mod (a5 / apoptosis) :location (d4 / downstream))) :op3 (d3 / decrease-01 :ARG1 (p2 / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)))))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n2 / name :op1 "Davies")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2007")))) # ::id a_pmid_2234_3622.62 # ::date 2015-05-29T11:36:12 # ::file a_pmid_2234_3622_62.txt # ::snt Furthermore, a chronic dosing schedule of selumetinib (25 mg kg–1 per bid for 14 doses) in HCT-116 xenografts increased the levels of the pro-apoptotic BH3 protein Bim-EL (∼4-fold increase) compared with no change with the level of this protein following a shorter dosing period (three doses) (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op2 (i / increase-01 :ARG0 (s / schedule-01 :ARG1 (d2 / dose-01 :quant "14" :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :quant (c4 / concentration-quantity :quant "25" :unit (m / milligram-per-kilogram)) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :mod (c / chronic) :frequency (r / rate-entity-91 :ARG1 "2" :ARG2 (t / temporal-quantity :quant "1" :unit (d5 / day))))) :ARG1 (l / level :quant-of (p / protein :name (n2 / name :op1 "Bim-EL") :ARG0-of (f / favor-01 :ARG1 (a2 / apoptosis)) :ARG1-of (i2 / include-91 :ARG2 (p4 / protein-family :name (n3 / name :op1 "BH3"))))) :ARG4 (p2 / product-of :op1 "4") :compared-to (c2 / change-01 :polarity "-" :ARG1 (l2 / level :quant-of p) :ARG1-of (f3 / follow-01 :ARG2 (p3 / period :time-of (d3 / dose-01) :ARG1-of (s3 / short-07 :degree (m2 / more)) :ARG1-of (m3 / mean-01 :ARG3 (d4 / dose-01 :quant "3"))))) :location (x / xenograft :mod (c3 / cell-line :name (n / name :op1 "HCT-116")))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1"))) # ::id a_pmid_2234_3622.63 # ::date 2015-05-28T15:50:33 # ::file a_pmid_2234_3622_63.txt # ::snt In order to exploit the apoptotic threshold of selumetinib, we wanted to study the effects of combining it with agents known to induce the apoptotic cascade to drive tumour growth inhibition and/or cell death. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (w / want-01 :ARG0 (w2 / we) :ARG1 (s / study-01 :ARG0 w2 :ARG1 (a / affect-01 :ARG0 (c / combine-01 :ARG1 "s2" :ARG2 (a2 / agent :ARG0-of (i / induce-01 :ARG2 (c2 / cascade :mod "a3") :purpose (d / drive-02 :ARG0 a2 :ARG1 (a4 / and-or :op1 (i2 / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t2 / tumor))) :op2 (d2 / die-01 :ARG1 (c3 / cell)))) :ARG1-of (k / know-01)))))) :purpose (e / exploit-01 :ARG0 w2 :ARG1 (t / threshold :poss (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :mod (a3 / apoptosis)))) # ::id a_pmid_2234_3622.64 # ::date 2015-05-28T15:56:00 # ::file a_pmid_2234_3622_64.txt # ::snt The effects of selumetinib in combination with a number of key standard of care agents were tested pre-clinically in human tumour xenograft models and resulted in enhanced anti-tumour activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (t / test-01 :ARG1 (a2 / affect-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1-of (c / combine-01 :ARG2 (s2 / standard :ARG1-of (k / key-02) :mod (a4 / agent :mod (c3 / care-03) :quant (n / number))))) :time (b / before :op1 (c2 / clinic)) :location (m / model :mod (x / xenograft :mod (t2 / tumor)) :mod (h / human))) :op2 (r / result-01 :ARG1 a2 :ARG2 (a3 / activity-06 :ARG1-of (e / enhance-01) :ARG0-of (c4 / counter-01 :ARG1 t2)))) # ::id a_pmid_2234_3622.65 # ::date 2015-05-28T15:59:44 # ::file a_pmid_2234_3622_65.txt # ::snt A number of compounds including the DNA-alkylating agent TMZ and the anti-mitotic drug docetaxel resulted in a greatly enhanced tumour growth inhibition compared with monotherapies (Table 1 and supplementary Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (r / result-01 :ARG1 (c2 / compound :ARG2-of (i3 / include-91 :ARG1 (a3 / and :op1 (a4 / agent :ARG0-of (a / alkylate-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))) :ARG1-of (m3 / mean-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "TMZ") :xref (x / xref :value "PUBCHEM:444209" :prob "18.572987")))) :op2 (s2 / small-molecule :name (n4 / name :op1 "docetaxel") :ARG0-of (c3 / counter-01 :ARG1 (m2 / mitosis)) :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744")))) :quant (n2 / number)) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :ARG1-of (e / enhance-01 :ARG3 (g2 / great) :compared-to (m / monotherapy))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (t2 / table :mod "1") :op2 (t3 / table :mod "1" :ARG2-of (s / supplement-01))))) # ::id a_pmid_2234_3622.66 # ::date 2015-05-28T15:47:43 # ::file a_pmid_2234_3622_66.txt # ::snt However, combining selumetinib with gemcitabine did not enhance the anti-tumour activity of the individual agents (supplementary Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG2 (e / enhance-01 :polarity "-" :ARG0 (c2 / combine-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "gemcitabine") :xref (x / xref :value "PUBCHEM:60750" :prob "16.027456"))) :ARG1 (a / activity-06 :ARG0 (a2 / agent :mod (i / individual)) :ARG0-of (c3 / counter-01 :ARG1 (t2 / tumor)))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "1" :ARG2-of (s / supplement-01)))) # ::id a_pmid_2234_3622.67 # ::date 2015-05-28T15:50:05 # ::file a_pmid_2234_3622_67.txt # ::snt The data presented here suggests that when selumetinib is combined, with either TMZ or docetaxel, the resulting anti-tumour phenotypes maybe due to mechanistic interactions between the two compounds. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / suggest-01 :ARG0 (d / data :ARG1-of (p2 / present-01 :medium (h / here))) :ARG1 (p3 / possible-01 :ARG1 (c2 / cause-01 :ARG0 (i / interact-01 :ARG0 "s2" :ARG1 "o" :ARG2 (m / mechanistic)) :ARG1 (p / phenotype :ARG2-of (r / result-01) :ARG0-of (c3 / counter-01 :ARG1 (t2 / tumor)))) :time (c / combine-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 (o / or :op1 (s4 / small-molecule :name (n3 / name :op1 "TMZ") :xref (x1 / xref :value "PUBCHEM:444209" :prob "18.572987")) :op2 (s3 / small-molecule :name (n / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744")))))) # ::id a_pmid_2234_3622.68 # ::date 2015-05-28T16:03:06 # ::file a_pmid_2234_3622_68.txt # ::snt Selumetinib in combination with TMZ enhances DNA damage # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (e / enhance-01 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TMZ") :xref (x / xref :value "PUBCHEM:444209" :prob "18.572987"))) :ARG1 (d / damage-01 :ARG0 c :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))) # ::id a_pmid_2234_3622.69 # ::date 2015-05-28T16:04:17 # ::file a_pmid_2234_3622_69.txt # ::snt The combination of selumetinib and TMZ in the SW-620 human tumour xenograft model resulted in a significantly enhanced anti-tumour efficacy (103.5% inhibition; P<0.0005), compared with selumetinib (52% inhibition; P<0.0005) and TMZ (88% inhibition; P<0.0005) alone (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / result-01 :ARG1 (c2 / combine-01 :ARG1 "s2" :ARG2 "s3" :location (c3 / cell-line :name (n / name :op1 "SW-620") :mod (x / xenograft :mod (t3 / tumor :mod (h / human))))) :ARG2 (e / efficacy :ARG0-of (c / counter-01 :ARG1 t3) :ARG1-of (e2 / enhance-01 :ARG1-of (s / significant-02)) :ARG1-of (m5 / mean-01 :ARG2 (a3 / and :op1 (i3 / inhibit-01 :degree (p / percentage-entity :value "103.5")) :op2 (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0005"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A")) :compared-to (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :ARG0-of (i / inhibit-01 :degree (p2 / percentage-entity :value "52")) :mod s4 :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op2 (s3 / small-molecule :name (n3 / name :op1 "TMZ") :ARG0-of (i2 / inhibit-01 :degree (p3 / percentage-entity :value "88")) :mod s4 :xref (x1 / xref :value "PUBCHEM:444209" :prob "18.572987")) :mod (a2 / alone))) # ::id a_pmid_2234_3622.70 # ::date 2015-05-29T11:05:55 # ::file a_pmid_2234_3622_70.txt # ::snt At the end of the dosing period, the monotherapy and combination treatment groups were left to observe the growth rate following the cessation of dosing (animals in the control group had to be killed due to tumour size). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (l / leave-17 :ARG1 (a / and :op1 (g / group :ARG1-of (t / treat-04 :ARG2 (m / monotherapy))) :op2 (g2 / group :mod (t2 / treat-04 :ARG1-of (c / combine-01)))) :time (e / end-01 :ARG1 (p / period :time-of (d / dose-01))) :purpose (o / observe-01 :ARG1 (r / rate :mod (g3 / grow-01) :ARG1-of (f / follow-01 :ARG2 (c2 / cease-01 :ARG1 d :ARG1-of (m2 / mean-01 :ARG2 (o2 / obligate-01 :ARG1 (k / kill-01 :ARG1 (a2 / animal :part-of (g4 / group :mod (c4 / control)))) :ARG1-of (c3 / cause-01 :ARG0 (s / size :poss (t3 / tumor)))))))))) # ::id a_pmid_2234_3622.71 # ::date 2015-05-28T22:00:08 # ::file a_pmid_2234_3622_71.txt # ::snt In the selumetinib and TMZ monotherapy-treated groups, tumour growth progressed rapidly once compound treatment had been removed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (p / progress-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :manner (r / rapid) :ARG1-of (c / cause-01 :ARG0 (r2 / remove-01 :ARG1 (t2 / treat-04 :ARG2 (c2 / compound)))) :location (a / and :op1 (g2 / group :ARG1-of (t3 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :mod (m2 / monotherapy) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :op2 (g3 / group :ARG1-of (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TMZ") :mod m2 :xref (x / xref :value "PUBCHEM:444209" :prob "18.572987")))))) # ::id a_pmid_2234_3622.72 # ::date 2015-05-28T22:03:28 # ::file a_pmid_2234_3622_72.txt # ::snt In contrast, the start of tumour growth in the combination group was delayed for approximately 24 days from the start of the experiment compared with 15 days in the TMZ alone group. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (c / contrast-01 :ARG2 (d3 / delay-01 :ARG1 (s / start-01 :ARG1 (g / grow-01 :ARG1 (t3 / tumor) :location (g2 / group :mod (c2 / combine-01)))) :ARG2 (a / approximately :op1 (t / temporal-quantity :quant "24" :unit (d / day))) :compared-to (d4 / delay-01 :ARG2 (t2 / temporal-quantity :quant "15" :unit (d2 / day)) :location (g4 / group :mod (s5 / small-molecule :name (n / name :op1 "TMZ") :mod (a2 / alone) :xref (x / xref :value "PUBCHEM:444209" :prob "18.572987")))) :time (s4 / start-01 :ARG1 (e / experiment-01)))) # ::id a_pmid_2234_3622.73 # ::date 2015-05-29T11:48:06 # ::file a_pmid_2234_3622_73.txt # ::snt In order to investigate potential mechanisms, to explain the enhanced combination effect with TMZ, we used the growth inhibition data generated from our anti-tumour studies to guide our pharmacodynamic sampling times (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (d / data :topic (i / inhibit-01 :ARG1 (g / grow-01)) :ARG1-of (g2 / generate-01 :ARG2 (s / study-01 :ARG0 w :ARG0-of (c2 / counter-01 :ARG1 (t3 / tumor))))) :ARG2 (g3 / guide-01 :ARG0 d :ARG1 (t / time :time-of (s2 / sample-01 :ARG0 w :mod (p / pharmacodynamic)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A")) :purpose (a / and :op1 (i2 / investigate-01 :ARG0 w :ARG1 (m / mechanism :mod (p2 / potential))) :op2 (e / explain-01 :ARG0 w :ARG1 (a2 / affect-01 :ARG0 (c / combine-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "TMZ") :xref (x / xref :value "PUBCHEM:444209" :prob "18.572987"))) :ARG1-of (e2 / enhance-01))))) # ::id a_pmid_2234_3622.74 # ::date 2015-05-29T11:56:18 # ::file a_pmid_2234_3622_74.txt # ::snt Samples were collected at the end of the TMZ dosing (PD1), when the TMZ and combination groups growth rate started to diverge (PD2), at the end of selumetinib dosing (PD3) and at the end of the re-growth period (PD4) (Figure 2A; white arrows on graph). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / collect-01 :ARG1 (t5 / thing :ARG1-of (s / sample-01)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2A") :op2 (a2 / arrow :ARG1-of (w / white-03) :location (g2 / graph)))) :time (a6 / and :op1 (e / end-01 :ARG1 (d / dose-01 :ARG2 (s4 / small-molecule :name (n6 / name :op1 "TMZ") :xref (x1 / xref :value "PUBCHEM:444209" :prob "18.572987"))) :ARG1-of (l / label-01 :ARG2 (t2 / thing :name (n / name :op1 "PD1")))) :op2 (s2 / start-01 :ARG1 (d4 / diverge-01 :ARG0 (r / rate :mod (g6 / grow-01 :ARG1 (g / group :mod s4))) :ARG1 (r2 / rate :mod (g7 / grow-01 :ARG1 (g8 / group :mod (c2 / combine-01))))) :ARG1-of (l2 / label-01 :ARG2 (t3 / thing :name (n4 / name :op1 "PD2")))) :op3 (e2 / end-01 :ARG1 (d3 / dose-01 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1-of (l3 / label-01 :ARG2 (t4 / thing :name (n3 / name :op1 "PD3")))) :op4 (e3 / end-01 :ARG1 (g3 / grow-01 :mod (a4 / again)) :ARG1-of (l4 / label-01 :ARG2 (t / thing :name (n2 / name :op1 "PD4")))))) # ::id a_pmid_2234_3622.75 # ::date 2015-05-29T12:07:22 # ::file a_pmid_2234_3622_75.txt # ::snt IHC analysis and histological scoring was performed on all the tissues collected to examine, selumetinib effects (pERK1/2), DNA damage (γH2A.X), apoptosis (cleaved caspase 3) and the cell cycle (pHH3) (scoring data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG1 (a5 / and :op1 (a6 / analyze-01 :mod (i / immunohistochemistry)) :op2 (s2 / score-01 :ARG3 (h / histology))) :location (t / tissue :mod (a7 / all) :ARG1-of (c3 / collect-01 :purpose (a4 / and :op1 (e / examine-01 :ARG1 (a3 / affect-01 :ARG0 (s / small-molecule :name (n5 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)))) :op2 (e3 / examine-01 :ARG1 (d / damage-01 :ARG1 (n7 / nucleic-acid :wiki "DNA" :name (n8 / name :op1 "DNA"))) :instrument (p5 / protein :name (n2 / name :op1 "γH2A.X") :xref (x1 / xref :value "UNIPROT:A0N6L7_HUMAN" :prob "0.691"))) :op3 (e4 / examine-01 :ARG1 (a2 / apoptosis) :instrument (p6 / protein :name (n3 / name :op1 "Cleaved" :op2 "Caspase" :op3 "3"))) :op4 (e5 / examine-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :instrument (p4 / protein :name (n4 / name :op1 "HH3") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:HRH3_HUMAN" :prob "0.262")))))) :ARG1-of (s3 / show-01 :polarity "-" :ARG0 (d3 / data :mod (s4 / score-01)))) # ::id a_pmid_2234_3622.76 # ::date 2015-05-29T13:21:18 # ::file a_pmid_2234_3622_76.txt # ::snt The sampling timepoint, which gave us the greatest insight into the mechanistic effects of these agents was that taken when we started to see the TMZ and combination groups diverge (PD2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (t3 / timepoint :mod (t5 / thing :name (n / name :op1 "PD2")) :ARG1-of (t4 / take-01 :ARG0 "w" :time (s3 / start-01 :ARG0 "w" :ARG1 (s2 / see-01 :ARG0 "w" :ARG1 (d / diverge-01 :ARG0 (g4 / group :mod (s4 / small-molecule :name (n2 / name :op1 "TMZ") :xref (x / xref :value "PUBCHEM:444209" :prob "18.572987"))) :ARG1 (g3 / group :mod (c / combine-01) :ARG1-of (m3 / mean-01)))))) :domain (t / timepoint :time-of (s / sample-01) :ARG0-of (g2 / give-01 :ARG1 (i / insight :mod (g / great :degree (m / most)) :topic (a / affect-01 :ARG0 (a2 / agent :mod (t2 / this)) :mod (m2 / mechanistic))) :ARG2 (w / we)))) # ::id a_pmid_2234_3622.77 # ::date 2015-05-29T13:30:43 # ::file a_pmid_2234_3622_77.txt # ::snt As expected, in response to selumetinib or TMZ alone we saw changes in the mechanistic biomarkers pERK1/2 (decrease) and γH2A.X (increase), respectively, and a reduction in mitotic cells as shown by pHH3 in the selumetinib group compared with an increase in the TMZ tissues (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (r2 / respond-01 :ARG1 (o / or :op1 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op2 (s4 / small-molecule :name (n5 / name :op1 "TMZ") :xref (x3 / xref :value "PUBCHEM:444209" :prob "18.572987")) :mod (a / alone)) :ARG2 (s3 / see-01 :ARG0 "w" :ARG1 (a3 / and :op1 (c / change-01 :ARG1 (b2 / biomarker :mod (m3 / mechanistic) :ARG1-of (m5 / mean-01 :ARG2 (a4 / and :op1 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG1-of (d / decrease-01) :ARG3-of "p2") :op2 (p3 / protein :name (n2 / name :op1 "γH2A.X") :mod m3 :ARG1-of (i / increase-01) :xref (x / xref :value "UNIPROT:A0N6L7_HUMAN" :prob "0.691")))))) :op2 (r / reduce-01 :ARG1 (c2 / cell :mod (m4 / mitosis)) :ARG1-of (s / show-01 :ARG0 (p / protein :name (n3 / name :op1 "HH3") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:HRH3_HUMAN" :prob "0.262")) :location (g / group :mod s2)) :compared-to (i2 / increase-01 :ARG1 (t2 / tissue :mod s4)))) :ARG1-of (e / expect-01 :ARG0 (w / we)))) # ::id a_pmid_2234_3622.78 # ::date 2015-05-28T22:04:00 # ::file a_pmid_2234_3622_78.txt # ::snt Level of the apoptotic marker, cleaved caspase 3, was comparable in the combination group compared with the TMZ monotherapy (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (p / possible-01 :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B")) :ARG1 (c / compare-01 :ARG1 (l / level :degree-of (m / marker :name (n / name :op1 "cleaved" :op2 "caspase" :op3 "3") :mod (a / apoptosis)) :location (g / group :mod (c2 / combine-01))) :ARG2 (m2 / monotherapy :mod (s / small-molecule :name (n2 / name :op1 "TMZ") :xref (x / xref :value "PUBCHEM:444209" :prob "18.572987"))))) # ::id a_pmid_2234_3622.79 # ::date 2015-05-28T22:07:33 # ::file a_pmid_2234_3622_79.txt # ::snt However, in the combination group we observed a greatly enhanced upregulation of γH2A.X compared with the TMZ group alone, suggesting that when selumetinib and TMZ are combined DNA damage is enhanced (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (c / contrast-01 :ARG2 (o / observe-01 :ARG0 (w / we) :ARG1 (u / upregulate-01 :ARG1 (p / protein :name (n / name :op1 "γH2A.X") :xref (x / xref :value "UNIPROT:A0N6L7_HUMAN" :prob "0.691")) :location (g / group :mod (c2 / combine-01)) :ARG1-of (e / enhance-01 :ARG3 (g2 / great) :compared-to (g3 / group :mod (s3 / small-molecule :name (n3 / name :op1 "TMZ") :mod (a2 / alone) :xref (x1 / xref :value "PUBCHEM:444209" :prob "18.572987")))) :ARG0-of (s / suggest-01 :ARG1 (e2 / enhance-01 :ARG1 (d / damage-01 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))) :time (c3 / combine-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 s3))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id a_pmid_2234_3622.80 # ::date 2015-05-29T08:39:59 # ::file a_pmid_2234_3622_80.txt # ::snt Selumetinib is efficacious in combination with docetaxel when dosed concurrently or following docetaxel # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (e / efficacious :time (o / or :op1 (d / dose-01 :ARG1 (a / and :op1 "s3" :op2 "s2") :ARG1-of (c2 / concurrent-02)) :op2 (f / follow-01 :ARG1 "s3" :ARG2 "s2")) :domain (s3 / small-molecule :name (n2 / name :op1 "selumetinib") :ARG1-of (c / combine-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "docetaxel") :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744"))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) # ::id a_pmid_2234_3622.81 # ::date 2015-05-29T08:46:53 # ::file a_pmid_2234_3622_81.txt # ::snt Continuous, concurrent combinations of selumetinib and docetaxel resulted in significant anti-tumour effects in several models (Table 1 and Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (r / result-01 :ARG1 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 (s4 / small-molecule :name (n2 / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744")) :ARG1-of (c2 / concurrent-02) :ARG1-of (c3 / continue-01)) :ARG2 (a / affect-01 :ARG2 (c4 / counter-01 :ARG0 (t / tumor)) :location (m / model :quant (s2 / several)) :ARG1-of (s3 / significant-02)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (t2 / table :mod "1") :op2 (f / figure :mod "3A")))) # ::id a_pmid_2234_3622.82 # ::date 2015-05-29T08:54:24 # ::file a_pmid_2234_3622_82.txt # ::snt However, we were interested to explore the effect of dose sequencing on the anti-tumour efficacy of these two agents as administration of selumetinib and docetaxel as monotherapies results in distinct cell cycle phenotypes; a G1 or mitotic arrest, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / contrast-01 :ARG2 (c2 / cause-01 :ARG0 (r / result-01 :ARG1 (a3 / administer-01 :ARG1 (a4 / and :op1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op2 (s3 / small-molecule :name (n3 / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744"))) :manner (m / monotherapy)) :ARG2 (p / phenotype :mod (c4 / cycle-02 :ARG1 (c5 / cell) :mod (d2 / distinct)) :ARG1-of (m5 / mean-01 :ARG2 (a5 / and :op2 (a6 / arrest-02 :time (e3 / event :name (n / name :op1 "G1"))) :op3 (a7 / arrest-02 :time (m2 / mitosis)))))) :ARG1 (i / interest-01 :ARG1 (w / we) :ARG2 (e / explore-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (s / sequence-01 :ARG1 (d / dose-01)) :ARG1 (e2 / efficacy :poss (a2 / agent :quant "2" :mod (t2 / this) :ARG1-of (m4 / mean-01 :ARG2 a4) :ARG0-of (c3 / counter-01 :ARG1 (t / tumor))))))))) # ::id a_pmid_2234_3622.83 # ::date 2015-05-29T11:05:20 # ::file a_pmid_2234_3622_83.txt # ::snt Two schedules were designed in which mice bearing HCT-116 CRC tumours were treated with either a single dose of docetaxel (15 mg kg–1) followed 24 h later by selumetinib (25 mg kg–1 per bid) for 7 days (schedule 1) or selumetinib was administered as above for 7 days followed 24 h later with docetaxel (schedule 2) (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d2 / design-01 :ARG1 (s / schedule :quant "2") :ARG3 (o / or :op1 (t2 / treat-04 :ARG1 (m2 / mouse :ARG0-of (b / bear-01 :ARG1 (t3 / tumor :mod (c / cell-line :name (n / name :op1 "HCT-116") :mod (d4 / disease :name (n4 / name :op1 "CRC")))))) :ARG2 (s5 / small-molecule :name (n3 / name :op1 "docetaxel") :ARG2-of (d5 / dose-01 :ARG1-of (s2 / single-02)) :ARG2-of (f2 / follow-01 :ARG1 (d6 / dose-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "selumetinib") :quant (c3 / concentration-quantity :quant "25" :unit "m3") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :duration (t / temporal-quantity :quant "7" :unit (d / day)) :frequency (r / rate-entity-91 :ARG1 "2" :ARG2 (t5 / temporal-quantity :quant "1" :unit d))) :time (l / late :op1 (t4 / temporal-quantity :quant "24" :unit (h / hour)) :degree (m / more))) :quant (c2 / concentration-quantity :quant "15" :unit (m3 / milligram-per-kilogram)) :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744"))) :op2 (a / administer-01 :ARG1 s3 :duration t :ARG2-of (f3 / follow-01 :ARG1 (a3 / administer-01 :ARG1 s5) :time l) :mod t2)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id a_pmid_2234_3622.84 # ::date 2015-05-29T12:36:05 # ::file a_pmid_2234_3622_84.txt # ::snt As monotherapies, docetaxel and selumetinib resulted in 77% (P<0.0005) and 50% (P<0.005) tumour growth inhibition, respectively (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / result-01 :ARG1 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744")) :op2 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :mod (m / monotherapy)) :ARG2 (a2 / and :op1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor) :mod (p / percentage-entity :value "77")) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0005"))) :op2 (i2 / inhibit-01 :ARG1 (g2 / grow-01 :ARG1 t :mod (p2 / percentage-entity :value "50")) :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.005")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3C"))) # ::id a_pmid_2234_3622.85 # ::date 2015-05-29T12:40:17 # ::file a_pmid_2234_3622_85.txt # ::snt Interestingly, in the two combination schedules docetaxel administered before selumetinib (schedule 1) resulted in a 110% (P<0.0005) compared with 61% (P<0.005) tumour growth inhibition when docetaxel was administered after selumetinib (schedule 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / result-01 :ARG1 (a / administer-01 :ARG1 (s5 / small-molecule :name (n / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744")) :time (b / before :op1 (a2 / administer-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1-of (m / mean-01 :ARG2 (s3 / schedule :mod "1")))) :ARG2 (i3 / inhibit-01 :degree (p / percentage-entity :value "110") :compared-to (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :degree (p2 / percentage-entity :value "61") :time (a3 / administer-01 :ARG1 s5 :time (a4 / after :op1 s) :ARG1-of (m4 / mean-01 :ARG2 (s4 / schedule :mod "2")))) :ARG1-of (s6 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.0005"))) :ARG0-of (i2 / interest-01) :condition (s2 / schedule :quant "2" :mod (c / combine-01))) # ::id a_pmid_2234_3622.86 # ::date 2015-05-28T22:12:42 # ::file a_pmid_2234_3622_86.txt # ::snt These results suggest that selumetinib could enhance the efficacy of docetaxel when administered in the sequence of docetaxel followed by selumetinib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p / possible-01 :ARG1 (e / enhance-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1 (e2 / efficacy :poss (s4 / small-molecule :name (n / name :op1 "docetaxel") :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744"))) :condition (a / administrate-01 :manner (s2 / sequence :poss s4 :mod (f / follow-01 :ARG1 s3 :ARG2 s4)))))) # ::id a_pmid_2234_3622.87 # ::date 2015-05-28T22:16:07 # ::file a_pmid_2234_3622_87.txt # ::snt The sequence dependency of selumetinib when combined with docetaxel enhances apoptotic cell death # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (e / enhance-01 :ARG0 (d / depend-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "selumetinib") :ARG1-of (c / combine-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744"))) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1 (s / sequence)) :ARG1 (d2 / die-01 :ARG1 (c2 / cell) :mod (a / apoptosis))) # ::id a_pmid_2234_3622.88 # ::date 2015-05-29T08:38:19 # ::file a_pmid_2234_3622_88.txt # ::snt In order to determine the mechanism of action in the scheduling studies with docetaxel, a series of tumour tissue samples were taken at different time points following exposure to the two dosing regimens (Figure 4Ai and Bi). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (s / sample-01 :ARG1 (t2 / tissue :mod (t3 / tumor)) :time (p / point :mod (t / time) :ARG1-of (d4 / differ-02)) :ARG1-of (f / follow-01 :ARG2 (e / expose-01 :ARG2 (r2 / regimen :quant "2" :ARG0-of (d / dose-01)))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "4Ai") :op2 (f3 / figure :mod "4Bi"))) :quant (s2 / series) :purpose (d3 / determine-01 :ARG1 (m / mechanism :mod (a2 / act-02) :purpose (s3 / study-01 :ARG1 (s5 / small-molecule :name (n / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744")) :ARG1-of (s4 / schedule-01))))) # ::id a_pmid_2234_3622.89 # ::date 2015-05-29T09:40:00 # ::file a_pmid_2234_3622_89.txt # ::snt To assess the cell cycle mechanistic effects the mitotic marker pHH3 was quantitated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (q / quantitate-01 :ARG1 (m / marker :mod (m2 / mitosis) :ARG1-of (m4 / mean-01 :ARG2 (p / protein :name (n / name :op1 "HH3") :ARG1-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:HRH3_HUMAN" :prob "0.262")))) :purpose (a / assess-01 :ARG1 (a2 / affect-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :mod (m3 / mechanistic)))) # ::id a_pmid_2234_3622.90 # ::date 2015-05-29T09:44:56 # ::file a_pmid_2234_3622_90.txt # ::snt In the sequence when docetaxel was administered before selumetinib, increased levels of pHH3 were observed at the early timepoints (PD1 & PD2) (2.7- and 2.3-fold change, respectively; P<0.0005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (o / observe-01 :ARG1 (l / level :ARG1-of (i / increase-01 :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.0005"))) :quant-of (p4 / protein :name (n / name :op1 "HH3") :ARG3-of (p5 / phosphorylate-01) :xref (x / xref :value "UNIPROT:HRH3_HUMAN" :prob "0.262"))) :time (t / timepoint :mod (e / early)) :location (s / sequence :mod (a / administer-01 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "docetaxel") :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744")) :time (b2 / before :op1 (a2 / administer-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")))))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (t2 / thing :name (n2 / name :op1 "PD1")) :op2 (t3 / thing :name (n3 / name :op1 "PD2")))) :ARG1-of (m3 / mean-01 :ARG2 (a5 / and :op1 (c / change-01 :ARG2 (p2 / product-of :op1 "2.7")) :op2 (c2 / change-01 :ARG2 (p3 / product-of :op1 "2.3"))))) # ::id a_pmid_2234_3622.91 # ::date 2015-05-29T12:26:53 # ::file a_pmid_2234_3622_91.txt # ::snt In schedule 2, pHH3 levels were seen to increase following docetaxel (PD7) (3.4-fold; P<0.0005) (Figure 4Aii and 4Bii). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / see-01 :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (p3 / protein :name (n2 / name :op1 "HH3") :ARG3-of (p4 / phosphorylate-01) :xref (x / xref :value "UNIPROT:HRH3_HUMAN" :prob "0.262"))) :ARG2 (p / product-of :op1 "3.4") :ARG1-of (f / follow-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "docetaxel") :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744"))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.0005"))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "4Aii") :op2 (f3 / figure :mod "4Bii"))) :condition (s3 / schedule :mod "2") :ARG1-of (m3 / mean-01 :ARG2 (t / thing :name (n / name :op1 "PD7")))) # ::id a_pmid_2234_3622.92 # ::date 2015-05-29T12:35:08 # ::file a_pmid_2234_3622_92.txt # ::snt When selumetinib was administered alone levels of pHH3 decreased at several measurement points compared with controls (PD2 P<0.0005; PD4 P<0.005; PD5 P<0.0005; PD6 P<0.0005) consistent with the inhibition of the MEK/ERK pathway resulting in a G1/S arrest. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / decrease-01 :ARG1 (l / level :quant-of (p7 / protein :name (n3 / name :op1 "HH3") :ARG3-of (p8 / phosphorylate-01) :xref (x / xref :value "UNIPROT:HRH3_HUMAN" :prob "0.262"))) :time (a / administer-01 :ARG1 (s / small-molecule :name (n8 / name :op1 "selumetinib") :mod (a3 / alone) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :time (p2 / point :quant (s2 / several) :mod (m3 / measure-01) :ARG1-of (m4 / mean-01 :ARG2 (a4 / and :op1 (t / thing :name (n4 / name :op1 "PD2")) :op2 (t2 / thing :name (n5 / name :op1 "PD4")) :op3 (t4 / thing :name (n6 / name :op1 "PD5")) :op4 (t5 / thing :name (n7 / name :op1 "PD6"))))) :compared-to (c / control) :ARG1-of (c2 / consistent-01 :ARG2 (i / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "MEK/ERK")) :ARG1-of (r / result-01 :ARG2 (a2 / arrest-02 :time (e / event :name (n2 / name :op1 "G1/S")))))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.0005"))) # ::id a_pmid_2234_3622.93 # ::date 2015-05-29T13:41:36 # ::file a_pmid_2234_3622_93.txt # ::snt Interestingly, in both sequences in the combination there is a reduction in pHH3 compared with the docetaxel alone group at that timepoint (PD2 and PD7) (3.8- and 2.5-fold change, respectively; P<0.0005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / reduce-01 :ARG1 (p4 / protein :name (n / name :op1 "HH3") :ARG3-of (p5 / phosphorylate-01) :xref (x / xref :value "UNIPROT:HRH3_HUMAN" :prob "0.262")) :ARG0-of (i / interest-01) :location (s / sequence :mod (b / both) :mod (c / combine-01)) :compared-to (g / group :mod (s2 / small-molecule :name (n4 / name :op1 "docetaxel") :mod (a / alone) :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744"))) :time (t / timepoint :mod (t2 / that) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (t3 / thing :name (n2 / name :op1 "PD2")) :op2 (t4 / thing :name (n3 / name :op1 "PD7"))))) :ARG1-of (m5 / mean-01 :ARG2 (a3 / and :op1 (c2 / change-01 :ARG2 (p / product-of :op1 "3.8")) :op2 (c3 / change-01 :ARG2 (p2 / product-of :op1 "2.5")))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0005"))) # ::id a_pmid_2234_3622.94 # ::date 2015-05-29T14:26:40 # ::file a_pmid_2234_3622_94.txt # ::snt Levels of the apoptotic marker cleaved caspase 3, in tumour tissue taken from the docetaxel followed by selumetinib group, increased in this combination group (16.8-fold change from the control; P<0.0005) compared with the single agents alone (3.5- and 2.4-fold change for docetaxel and selumetinib, respectively) (Figure 4Aiii PD2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / increase-01 :ARG1 (l / level :quant-of (m / marker :name (n / name :op1 "cleaved" :op2 "caspase" :op3 "3") :mod (a3 / apoptosis) :location (t / tissue :source (t2 / tumor) :ARG1-of (t3 / take-01 :ARG2 (g / group :mod (s3 / small-molecule :name (n2 / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744")) :ARG2-of (f2 / follow-01 :ARG1 (g2 / group :mod (s2 / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386"))))))))) :ARG4 (a4 / and :op1 (c / change-01 :ARG1 (c2 / control) :ARG2 (p2 / product-of :op1 "16.8"))) :compared-to (a / agent :ARG1-of (s / single-02) :mod (a2 / alone) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (c3 / change-01 :ARG0 s3 :ARG2 (p3 / product-of :op1 "3.5")) :op2 (c4 / change-01 :ARG0 s2 :ARG2 (p4 / product-of :op1 "2.4"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4AiiiPD2")) :location g :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.0005"))) # ::id a_pmid_2234_3622.95 # ::date 2015-05-29T12:08:32 # ::file a_pmid_2234_3622_95.txt # ::snt In comparison, tumour tissue analysed in the same study after the chronic dosing schedule of selumetinib did not demonstrate an increase in cleaved caspase 3 levels in the combination group when compared with the single agents alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / compare-01 :ARG1 (d / demonstrate-01 :polarity "-" :ARG0 (t / tissue :source (t2 / tumor) :ARG1-of (a3 / analyze-01 :ARG0 (s2 / study-01 :ARG1-of (s3 / same-01) :time (a4 / after :op1 (s4 / schedule-01 :ARG1 (d2 / dose-01 :ARG2 (s5 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :mod (c4 / chronic))))))) :ARG1 (i / increase-01 :ARG1 (l / level :location (g / group :mod (c2 / combine-01)) :quant-of (p / protein :name (n / name :op1 "cleaved" :op2 "caspase" :op3 "3")))) :time (c3 / compare-01 :ARG2 (a / agent :ARG1-of (s / single-02)) :mod (a2 / alone)))) # ::id a_pmid_2234_3622.96 # ::date 2015-05-29T09:45:32 # ::file a_pmid_2234_3622_96.txt # ::snt When selumetinib was dosed before docetaxel an increase in cleaved caspase 3 was not observed in the combination group at any of the sampling timepoints compared with at least one of the monotherapies (Figure 4Biii). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (o / observe-01 :polarity "-" :ARG1 (i / increase-01 :ARG1 (p / protein :name (n / name :op1 "cleaved" :op2 "caspase" :op3 "3")) :compared-to (m2 / monotherapy :quant (a / at-least :op1 "1") :ARG1-of (i2 / include-91 :ARG2 (m3 / monotherapy)))) :time (d / dose-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :time (b / before :op1 (d2 / dose-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "docetaxel") :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744"))))) :location (g / group :mod (c / combine-01)) :time (t / timepoint :time-of (s2 / sample-01)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "4Biii"))) # ::id a_pmid_2234_3622.97 # ::date 2015-06-02T09:01:36 # ::file a_pmid_2234_3622_97.txt # ::snt Representative IHC images from PD2 highlights the increase in pHH3 following docetaxel exposure and the increase in cleaved caspase 3 in the docetaxel followed by selumetinib group (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / highlight-01 :ARG0 (i / image :ARG0-of (r / represent-01) :source (t2 / thing :name (n7 / name :op1 "PD2")) :mod (i4 / immunohistochemistry)) :ARG1 (a / and :op1 (i2 / increase-01 :ARG1 (p / protein :name (n2 / name :op1 "HH3") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:HRH3_HUMAN" :prob "0.262")) :ARG1-of (f / follow-01 :ARG2 (e / expose-01 :ARG1 p :ARG2 (s / small-molecule :name (n3 / name :op1 "docetaxel") :xref (x4 / xref :value "PUBCHEM:148124" :prob "15.881744"))))) :op2 (i3 / increase-01 :ARG1 (p2 / protein :name (n4 / name :op1 "caspase" :op2 "3") :ARG1-of (c / cleave-01) :xref (x / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.662")) :location (g / group :mod (s2 / small-molecule :name (n5 / name :op1 "docetaxel") :ARG2-of (f3 / follow-01 :ARG1 (s3 / small-molecule :name (n6 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :xref (x3 / xref :value "PUBCHEM:148124" :prob "15.881744"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4C"))) # ::id a_pmid_2234_3622.98 # ::date 2015-06-02T09:44:05 # ::file a_pmid_2234_3622_98.txt # ::snt The data presented here suggests that the combination efficacy effect seen when docetaxel was dosed before selumetinib was due to an increase in apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 11, 2015 (s / suggest-01 :ARG0 (d / data :ARG1-of (p / present-01 :location (h / here))) :ARG1 (c / cause-01 :ARG0 (i / increase-01 :ARG1 (a / apoptosis)) :ARG1 (a2 / affect-01 :ARG0 (e / efficient-01 :ARG1 (c2 / combine-01)) :ARG1-of (s2 / see-01 :time (d2 / dose-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "docetaxel") :xref (x / xref :value "PUBCHEM:148124" :prob "15.881744")) :time (b / before :op1 (d3 / dose-01 :ARG2 (s4 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386"))))))))) # ::id a_pmid_2234_3622.99 # ::date 2015-06-02T10:16:19 # ::file a_pmid_2234_3622_99.txt # ::snt Sequence scheduling of selumetinib and the Aurora B kinase inhibitor, barasertib (AZD1152), results in tumour regression and increased cell death # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (r / result-01 :ARG1 (s / schedule-01 :ARG1 (a2 / and :op1 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op2 (s3 / small-molecule :name (n2 / name :op1 "barasertib") :ARG0-of (i2 / inhibit-01 :ARG1 (k / kinase :name (n3 / name :op1 "Aurora" :op2 "B") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342"))) :xref (x1 / xref :value "PUBCHEM:11497983" :prob "17.394333"))) :manner (s4 / sequence)) :ARG2 (a / and :op1 (r2 / regress-01 :ARG1 (t / tumor)) :op2 (d / die-01 :ARG1 (c / cell) :ARG1-of (i / increase-01)))) # ::id a_pmid_2234_3622.100 # ::date 2015-06-02T10:32:21 # ::file a_pmid_2234_3622_100.txt # ::snt The dose-scheduling effects of combining selumetinib and docetaxel lead us to investigate the sequence dependency of selumetinib combined with another mitotic targeting agent, the Aurora B kinase inhibitor, barasertib (AZD1152) (16). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (l / lead-03 :ARG0 (a / affect-01 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x4 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "docetaxel") :xref (x2 / xref :value "PUBCHEM:148124" :prob "15.881744"))) :ARG1 (s6 / schedule-01 :ARG1 (d2 / dose-01))) :ARG1 (w / we) :ARG2 (i / investigate-01 :ARG0 w :ARG1 (d / depend-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "selumetinib") :ARG1-of (c2 / combine-01 :ARG2 (a2 / agent :ARG0-of (t / target-01 :ARG1 (m / mitosis)) :ARG1-of (m2 / mean-01 :ARG2 (s5 / small-molecule :name (n5 / name :op1 "barasertib") :ARG0-of (i3 / inhibit-01 :ARG1 (k / kinase :name (n4 / name :op1 "Aurora" :op2 "B") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342"))) :xref (x3 / xref :value "PUBCHEM:11497983" :prob "17.394333"))) :mod (a3 / another))) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1 (s4 / sequence))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 "16")))) # ::id a_pmid_2234_3622.101 # ::date 2015-06-02T10:49:07 # ::file a_pmid_2234_3622_101.txt # ::snt We designed two regimes in which barasertib was dosed at 150 mg kg–1 per qd for 2 consecutive days through a mini-pump (MP) with a 24 h gap followed by selumetinib 25 mg kg–1 per bid for 14 consecutive days (schedule 1) or the reverse of this schedule where barasertib was dosed following selumetinib treatment (schedule 2) (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (d7 / design-01 :ARG0 (w / we) :ARG1 (r4 / regime :quant "2" :consist-of (o / or :op1 (d / dose-01 :ARG2 (a / and :op1 (s / small-molecule :quant "150" :name (n / name :op1 "barasertib") :quant (c2 / concentration-quantity :quant "150" :ARG1-of (r / rate-entity-91 :ARG2 (t / temporal-quantity :quant "24" :unit (h / hour))) :unit (m2 / milligram-per-kilogram)) :xref (x3 / xref :value "PUBCHEM:11497983" :prob "17.394333"))) :duration (t2 / temporal-quantity :quant "2" :unit (d3 / day :mod (c / consecutive))) :instrument (p / pump :mod (m3 / mini)) :manner (g / gap :duration (t3 / temporal-quantity :quant "24" :unit h)) :ARG2-of (f / follow-01 :ARG1 (d5 / dose-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :quant (c3 / concentration-quantity :quant "25" :ARG1-of (r2 / rate-entity-91 :ARG2 (t4 / temporal-quantity :quant "12" :unit h)) :unit (m / milligram-per-kilogram)) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :duration (t5 / temporal-quantity :quant "14" :unit d3))) :ARG1-of (m9 / mean-01 :ARG2 (s5 / schedule :mod "1"))) :op2 (d6 / dose-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "barasertib") :xref (x / xref :value "PUBCHEM:11497983" :prob "17.394333")) :ARG2-of (f2 / follow-01 :ARG1 (t6 / treat-03 :ARG3 (s4 / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :ARG1-of (d8 / describe-01 :ARG0 (f3 / figure :mod "5A")) :ARG1-of (m10 / mean-01 :ARG2 (s6 / schedule :mod "2")) :ARG1-of (r3 / reverse-01 :ARG2 d))))) # ::id a_pmid_2234_3622.102 # ::date 2015-06-02T14:53:51 # ::file a_pmid_2234_3622_102.txt # ::snt The CaLu-6 NSCLC human tumour xenograft model was used in this study as previous experience with both agents allowed us to select appropriate dose levels in order to investigate these schedules (Davies et al, 2007; Wilkinson et al, 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (u / use-01 :ARG1 (m / model :mod (x2 / xenograft :name (n / name :op1 "CaLu-6") :mod (t / tumor :mod (h / human) :mod (d / disease :name (n2 / name :op1 "NSCLC"))))) :ARG2 (t2 / thing :ARG1-of (s / study-01) :mod (t3 / this)) :ARG1-of (c2 / cause-01 :ARG0 (a / allow-01 :ARG0 (e / experience-01 :ARG0 "w" :ARG1 (a2 / agent :mod (b / both)) :time (p7 / previous)) :ARG1 (s2 / select-01 :ARG0 (w / we) :ARG1 (l / level :quant-of (d2 / dose-01 :ARG1-of (a3 / appropriate-02))) :ARG3 (i / investigate-01 :ARG0 w :ARG1 (s3 / schedule :mod t3))))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p / publication-91 :ARG0 (a5 / and :op1 (p2 / person :name (n3 / name :op1 "Davies")) :op2 (p3 / person :mod (o / other))) :time (d4 / date-entity :year "2007")) :op2 (p4 / publication-91 :ARG0 (a6 / and :op1 (p5 / person :name (n4 / name :op1 "Wilkinson")) :op2 p3) :time d4)))) # ::id a_pmid_2234_3622.103 # ::date 2015-06-02T15:30:10 # ::file a_pmid_2234_3622_103.txt # ::snt Selumetinib and barasertib alone resulted in 57% (P<0.005) and 95% (P<0.0005) tumour growth inhibition compared with the vehicle-treated controls at day 21 after the start of dosing. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a3 / and :op1 (r / result-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :mod (a / alone) :ARG1-of (c / compare-01 :ARG2 (c3 / control :ARG1-of (t2 / treat-04 :ARG2 (v / vehicle)))) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :quant (p / percentage-entity :value "57") :time (a2 / after :op1 (s2 / start-01 :ARG1 (d / dose-01)) :quant (t3 / temporal-quantity :quant "21" :unit (d2 / day))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.005")))) :op2 (r2 / result-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "barasertib") :mod a :ARG1-of c :xref (x / xref :value "PUBCHEM:11497983" :prob "17.394333")) :ARG2 (i2 / inhibit-01 :ARG1 g :quant (p2 / percentage-entity :value "95") :time a2 :ARG1-of (s5 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.0005"))))) # ::id a_pmid_2234_3622.104 # ::date 2015-06-02T15:31:49 # ::file a_pmid_2234_3622_104.txt # ::snt In comparison when selumetinib was dosed before barasertib the anti-tumour efficacy was 74% (P<0.0005) in contrast to 106% (P<0.0005) observed when selumetinib was dosed following barasertib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (e3 / efficient-01 :ARG1 (d / dose-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :time (b / before :op1 (d2 / dose-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "barasertib") :xref (x / xref :value "PUBCHEM:11497983" :prob "17.394333"))))) :ARG2 (o / oppose-01 :ARG1 (t / tumor)) :ARG1-of (c / contrast-01 :ARG2 (e2 / efficient-01 :quant (p3 / percentage-entity :value "106") :ARG1-of (o2 / observe-01 :time (d3 / dose-01 :ARG1 s :ARG1-of (f / follow-01 :ARG2 s2))) :ARG1-of (s4 / statistical-test-91 :ARG2 "l"))) :ARG1-of (c2 / compare-01) :quant (p / percentage-entity :value "74") :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0005"))) # ::id a_pmid_2234_3622.105 # ::date 2015-06-02T15:34:02 # ::file a_pmid_2234_3622_105.txt # ::snt At 21 days after the start of dosing the control, animals had to be culled due to tumour size; however, the monotherapy and combination-treated groups were kept on study for a further 14 days. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (o / obligate-01 :ARG2 (c / cull-01 :ARG1 (a / animal) :ARG1-of (c2 / cause-01 :ARG0 (s / size-01 :ARG1 (t / tumor))) :time (a2 / after :op1 (s2 / start-01 :ARG1 (d / dose-01 :ARG1 (c3 / control))) :quant (t2 / temporal-quantity :quant "21" :unit (d2 / day))))) :snt2 (h / have-concession-91 :ARG2 (k / keep-01 :ARG1 (a3 / and :op1 (g / group :mod (m2 / monotherapy)) :op2 (g2 / group :ARG1-of (t3 / treat-04 :ARG2 (c5 / combine-01))) :ARG1-of (s3 / study-01)) :duration (t5 / temporal-quantity :quant "14" :mod (f / further) :unit d2)))) # ::id a_pmid_2234_3622.106 # ::date 2015-06-02T16:10:24 # ::file a_pmid_2234_3622_106.txt # ::snt During this time, the tumours in the monotherapy and schedule 2 groups started to re-grow. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 11, 2015 (s / start-01 :ARG0 (t / tumor :source (a / and :op1 (g / group :mod (m / monotherapy)) :op2 (g2 / group :mod (s2 / schedule :mod "2")))) :ARG1 (g3 / grow-01 :ARG1 t :mod (a2 / again)) :time (t3 / time :mod (t4 / this))) # ::id a_pmid_2234_3622.107 # ::date 2015-06-03T13:18:28 # ::file a_pmid_2234_3622_107.txt # ::snt Interestingly, the tumours in the group where barasertib was administered before selumetinib (schedule 1) tumour re-growth was delayed (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 11, 2015 (d / delay-01 :ARG1 (g / grow-01 :ARG1 (t / tumor :source (g2 / group :ARG2-of (a / administer-01 :ARG1 (s / small-molecule :name (n / name :op1 "barasertib") :xref (x1 / xref :value "PUBCHEM:11497983" :prob "17.394333")) :time (b / before :op1 (a2 / administer-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :ARG2-of (m / mean-01 :ARG1 (s3 / schedule :mod "1")))))) :mod (i / interesting) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id a_pmid_2234_3622.108 # ::date 2015-06-03T13:52:34 # ::file a_pmid_2234_3622_108.txt # ::snt In order to investigate this further, we performed pharmacodynamic analysis on tumour tissue. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (p / perform-02 :ARG0 (w / we) :ARG1 (a / analyze-01 :ARG0 w :ARG1 (t / tissue :mod (t2 / tumor)) :mod (p2 / pharmacodynamic)) :purpose (i / investigate-01 :ARG0 w :ARG1 (t3 / this) :degree (f / further))) # ::id a_pmid_2234_3622.109 # ::date 2015-06-03T14:03:40 # ::file a_pmid_2234_3622_109.txt # ::snt In schedule 1 we analysed tumour tissue at 24 h after the end of the barasertib infusion (PD1) and at the end of the selumetinib-dosing period (PD2) (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (t / tissue :mod (t2 / tumor)) :time (a2 / after :op1 (e / end-01 :ARG1 (i / infuse-01 :ARG1 (s / small-molecule :name (n / name :op1 "barasertib") :xref (x2 / xref :value "PUBCHEM:11497983" :prob "17.394333")))) :quant (t3 / temporal-quantity :quant "24" :unit (h / hour))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5A")) :location (s3 / schedule :mod "1") :time (a5 / and :op1 (a3 / after :op1 (e3 / end-01 :ARG1 (p2 / period :duration-of (i2 / infuse-01 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "barasertib") :xref (x1 / xref :value "PUBCHEM:11497983" :prob "17.394333")) :ARG1-of (d3 / describe-01 :ARG2 (s5 / string-entity :value "PD1")))))) :op2 (a4 / after :op1 (e2 / end-01 :ARG1 (p / period :duration-of (d / dose-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1-of (d4 / describe-01 :ARG2 (s6 / string-entity :value "PD2"))))))) # ::id a_pmid_2234_3622.110 # ::date 2015-06-03T14:17:55 # ::file a_pmid_2234_3622_110.txt # ::snt In schedule 2, tumours were harvested 24 h after the end of the barasertib infusion at the end of the study (PD3) (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (h / harvest-01 :ARG1 (t / tumor) :time (a / and :op1 (a2 / after :op1 (e / end-01 :ARG1 (i / infuse-01 :ARG1 (s / small-molecule :name (n / name :op1 "barasertib") :xref (x / xref :value "PUBCHEM:11497983" :prob "17.394333"))))) :op2 (a3 / after :op1 (e2 / end-01 :ARG1 (t2 / thing :ARG1-of (s2 / study-01)))) :quant (t3 / temporal-quantity :quant "24" :unit (h2 / hour))) :location (s3 / schedule :mod "2") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A")) :ARG1-of (d2 / describe-01 :ARG2 (s4 / string-entity :value "PD3"))) # ::id a_pmid_2234_3622.111 # ::date 2015-06-03T14:23:05 # ::file a_pmid_2234_3622_111.txt # ::snt Using flow cytometry we assessed tissues for polyploidy and demonstrated that compared with the vehicle-treated control group, barasertib-treated tumours resulted in increased polyploidy (1.7-fold change; P<0.05) in the PD1 samples consistent with the mechanism of this agent (Figure 5C) (Wilkinson et al, 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (a2 / assess-01 :ARG0 (w / we) :ARG1 (t / tissue) :ARG2 (p / polyploidy)) :op2 (d / demonstrate-01 :ARG0 w :ARG1 (r / result-01 :ARG1 (t2 / tumor :ARG1-of (t3 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "barasertib") :xref (x / xref :value "PUBCHEM:11497983" :prob "17.394333"))) :ARG1-of (c3 / compare-01 :ARG2 (g / group :ARG0-of (c4 / control-01) :ARG1-of (t6 / treat-03 :ARG2 (v / vehicle))))) :ARG2 (p2 / polyploidy :ARG1-of (i / increase-01 :ARG2 (p3 / product-of :op1 "1.7") :ARG2-of (m / mean-01 :ARG1 (c / change-01 :ARG1 p2)) :source (s2 / sample-01 :ARG2 (t4 / thing :name (n2 / name :op1 "PD1"))) :ARG1-of (c2 / consistent-01 :ARG2 (m2 / mechanism :poss (a3 / agent :mod (t5 / this)))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05")))))) :ARG2-of (u / use-01 :ARG0 w :ARG1 (c5 / cytometry :mod (f / flow))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5C")) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and :op1 (p5 / person :name (n3 / name :op1 "Wilkinson")) :op2 (p6 / person :mod (o / other))) :time (d4 / date-entity :year "2007")))) # ::id a_pmid_2234_3622.112 # ::date 2015-06-03T15:03:40 # ::file a_pmid_2234_3622_112.txt # ::snt In the same experiment, we monitored the population of sub G1 cells in these groups. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (m / monitor-01 :ARG0 (w / we) :ARG1 (p / population :consist-of (c / cell-line :name (n / name :op1 "sub" :op2 "G1"))) :location (g / group :mod (t / this)) :medium (e / experiment-01 :ARG1-of (s / same-01))) # ::id a_pmid_2234_3622.113 # ::date 2015-06-03T15:23:12 # ::file a_pmid_2234_3622_113.txt # ::snt At the end of the dosing period in schedule 1 (PD2), there was a significant increase (3.5-fold change; P<0.0005) in the sub G1 population in the combination compared with the vehicle-treated controls and selumetinib monotherapy (Figure 5Cii). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / increase-01 :ARG1 (p / population :consist-of (c / cell-line :name (n / name :op1 "sub" :op2 "G1")) :ARG1-of (c3 / combine-01)) :ARG2 (p2 / product-of :op1 "3.5" :ARG2-of (c2 / change-01)) :ARG1-of (s / significant-02) :ARG2-of (m / mean-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5Cii")) :ARG1-of (c4 / compare-01 :ARG2 (a / and :op1 (c5 / control :ARG1-of (t / treat-04 :ARG2 (v / vehicle))) :op2 (m2 / monotherapy :mod (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :time (a2 / after :op1 (e / end-01 :ARG1 (p4 / period :duration-of (d2 / dose-01) :ARG1-of (d3 / describe-01 :ARG2 (s5 / string-entity :value "PD2")) :time (s3 / schedule :mod "1")))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0005"))) # ::id a_pmid_2234_3622.114 # ::date 2015-06-03T15:48:09 # ::file a_pmid_2234_3622_114.txt # ::snt In comparison, the sub G1 populations in schedule 2 (PD3) were increased ∼2-fold in both the monotherapy and combination groups (Figure 5Dii). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / increase-01 :ARG1 (p / population :consist-of (c2 / cell-line :name (n / name :op1 "sub" :op2 "G1"))) :ARG2 (a2 / approximately :op1 (p2 / product-of :op1 "2")) :time (s / schedule :mod "2" :ARG1-of (d2 / describe-01 :ARG2 (s2 / string-entity :value "PD3"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5Dii")) :ARG1-of (c / compare-01) :location (a / and :op1 (g / group :mod (m / monotherapy)) :op2 (g2 / group :ARG3-of (c3 / combine-01)))) # ::id a_pmid_2234_3622.115 # ::date 2015-06-03T16:00:12 # ::file a_pmid_2234_3622_115.txt # ::snt These results suggest that the sustained anti-tumour effect and regression observed when barasertib is scheduled before selumetinib is likely to be due to an avoidance of cell cycle-mediated antagonism which allowed an increase in cell death. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (l / likely-01 :ARG1 (c / cause-01 :ARG0 (a / avoid-01 :ARG1 (a2 / antagonize-02 :ARG1-of (m / mediate-01 :ARG0 (c2 / cycle-02 :ARG1 (c3 / cell))) :ARG0-of (a3 / allow-01 :ARG1 (i / increase-01 :ARG1 (d / die-01 :ARG1 (c4 / cell)))))) :ARG1 (a4 / and :op1 (a5 / affect-01 :ARG2 (o / oppose-01 :ARG1 (t3 / tumor)) :ARG1-of (s6 / sustain-01)) :op2 (r2 / regress-01) :ARG1-of (o2 / observe-01 :time (s2 / schedule-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "barasertib") :xref (x / xref :value "PUBCHEM:11497983" :prob "17.394333")) :ARG3 (b / before :op1 (s4 / schedule-01 :ARG1 (s5 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")))))))))) # ::id bel_pmid_1002_9589.23800 # ::date 2015-04-02T02:24:15 # ::file bel_pmid_1002_9589_23800.txt # ::snt We present a model in which activation of the MAPK cascade signals via c-fos/c-jun family members to activate alpha 2 integrin gene expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p2 / present-01 :ARG0 (w / we) :ARG1 (m / model :location-of (s / signal-07 :ARG0 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK"))) :instrument (m2 / member :ARG1-of (i / include-91 :ARG2 (a2 / and :op1 (p3 / protein-family :name (n2 / name :op1 "c-fos")) :op2 (p4 / protein-family :name (n3 / name :op1 "c-jun"))))) :purpose (a3 / activate-01 :ARG0 a :ARG1 (e / express-03 :ARG1 (g / gene :name (n4 / name :op1 "alpha" :op2 "2" :op3 "integrin") :xref (x / xref :value "UNIPROT:AINX_HUMAN" :prob "0.272"))))))) # ::id bel_pmid_1002_9589.23888 # ::date 2015-04-02T02:33:06 # ::file bel_pmid_1002_9589_23888.txt # ::snt In addition, constitutive activation of the pathway via expression of the constitutively active mutants of MAPKK1 or MAPKK2 induced the expression of the platelet/megakaryocytic-specific genes alpha IIb and eta 3 . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a / and :op2 (i / induce-01 :ARG0 (a2 / activate-01 :ARG1 (p / pathway) :mod (c / constitutive) :manner (e / express-03 :ARG2 (o / or :op1 (e2 / enzyme :name (n / name :op1 "MAPKK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.693")) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPKK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.693")) :ARG1-of (m2 / mutate-01) :ARG0-of (a3 / activity-06 :mod c)))) :ARG2 (e4 / express-03 :ARG1 (a5 / and :op1 (g / gene :name (n3 / name :op1 "alpha" :op2 "IIb") :xref (x3 / xref :value "UNIPROT:AFAM_HUMAN" :prob "0.262")) :op2 (g2 / gene :name (n4 / name :op1 "beta3") :xref (x1 / xref :value "UNIPROT:B3GL1_HUMAN" :prob "0.292")) :ARG1-of (s / specific-02 :ARG2 (c3 / cell :name (n5 / name :op1 "platelet") :source (c4 / cell :name (n6 / name :op1 "megakaryocyte")))))))) # ::id bel_pmid_1008_0909.21272 # ::date 2015-04-02T02:47:09 # ::file bel_pmid_1008_0909_21272.txt # ::snt Using these methods, we found that JAK2 was essential for signal transduction but that loss of TYK2 made no appreciable difference in tyrosine phosphorylation of downstream molecules, including Mpl, STAT3, and Shc (33).....In fact, tyrosine phosphorylation of STATs and DNA binding assays seem to be almost interchangeable measures of transcriptional activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (e / essential :domain (e2 / enzyme :name (n / name :op1 "JAK2") :xref (x3 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :purpose (t / transduce-01 :ARG1 (s / signal-07))) :ARG2 (m2 / make-01 :ARG0 (l / lose-02 :ARG1 (e3 / enzyme :name (n2 / name :op1 "TYK2") :xref (x2 / xref :value "UNIPROT:TYK2_HUMAN" :prob "1.003"))) :ARG1 (d / difference :ARG1-of (a / appreciate-03 :ARG1-of (p9 / possible-01 :polarity "-"))) :ARG3 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (m5 / molecule :location (d2 / downstream) :ARG2-of (i / include-01 :ARG1 (a3 / and :op1 (p2 / protein :name (n4 / name :op1 "Mpl") :xref (x1 / xref :value "UNIPROT:TPOR_HUMAN" :prob "0.602")) :op2 (p3 / protein :name (n5 / name :op1 "STAT3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op3 (p4 / protein :name (n6 / name :op1 "Shc") :xref (x5 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))) :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "33"))) :manner (u / use-01 :ARG1 (m3 / method :mod (t2 / this)))) :snt2 (s3 / seem-01 :ARG1 (a4 / and :op1 (p6 / phosphorylate-01 :ARG1 (a5 / amino-acid :name (n7 / name :op1 "tyrosine") :part-of (p7 / protein :name (n8 / name :op1 "STAT") :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")) :xref (x7 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (a6 / assay-01 :ARG1 (b / bind-01 :ARG1 (n9 / nucleic-acid :wiki "DNA" :name (n10 / name :op1 "DNA")))) :ARG2-of (m4 / measure-01 :ARG1 (a7 / activity-06 :ARG1 (t3 / transcribe-01)) :ARG1-of (i3 / interchange-01 :mod (a8 / almost) :ARG1-of (p8 / possible-01)))) :mod (i2 / in-fact))) # ::id bel_pmid_1008_0909.24618 # ::date 2015-04-02T03:25:22 # ::file bel_pmid_1008_0909_24618.txt # ::snt It has been difficult to interpret the physiologic role of STAT signaling in megakaryocyte development. In multiple cell lines it was reported that TPO induced activation of both STAT3 and STAT5 (5A and 5B) (26, 28?30, 37, 38)....However, when purified murine megakaryocyte extracts were examined, we found that STAT3 was much more pronounced in both tyrosine phosphorylation and DNA binding activity than STAT5 (32) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (d / difficult :domain (i / interpret-01 :ARG1 (r / role :mod (p2 / physiologic) :poss (s / signal-07 :ARG0 (p3 / protein :name (n / name :op1 "STAT") :xref (x3 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))) :purpose (d2 / develop-02 :ARG1 (c / cell :name (n2 / name :op1 "megakaryocyte")))))) :snt2 (r2 / report-01 :ARG1 (i2 / induce-01 :ARG0 (p4 / protein :name (n3 / name :op1 "TPO") :xref (x / xref :value "UNIPROT:TPO_HUMAN" :prob "1.003")) :ARG2 (a / activate-01 :ARG1 (a2 / and :op1 (p5 / protein :name (n4 / name :op1 "STAT3") :xref (x5 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (p6 / protein :name (n5 / name :op1 "STAT5") :xref (x4 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :mod (b / both)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "5A") :op2 (f2 / figure :mod "5B") :op3 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 "26" :op2 "28" :op3 "30" :op4 "37" :op5 "38"))))) :location (c5 / cell-line :quant (m5 / multiple))) :snt3 (c6 / contrast-01 :ARG2 (f3 / find-01 :ARG0 (w / we) :ARG1 (p / pronounced-02 :ARG1 (p9 / protein :name (n6 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :degree (m2 / more :quant (m3 / much)) :condition (a5 / and :op1 (p10 / phosphorylate-01 :ARG1 (a6 / amino-acid :name (n7 / name :op1 "tyrosine") :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (a7 / activity-06 :ARG1 (b2 / bind-01 :ARG1 (n9 / nucleic-acid :wiki "DNA" :name (n10 / name :op1 "DNA")))) :mod (b3 / both)) :compared-to (p11 / protein :name (n8 / name :op1 "STAT5") :xref (x2 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003"))) :time (e / examine-01 :ARG1 (t / thing :ARG1-of (e2 / extract-01 :ARG2 (m6 / megakaryocyte :mod (m4 / murine)) :ARG1-of (p13 / purify-01))))) :ARG1-of (d5 / describe-01 :ARG0 (p12 / publication :ARG1-of (c3 / cite-01 :ARG2 "32"))))) # ::id bel_pmid_1008_5062.23884 # ::date 2015-04-02T03:42:42 # ::file bel_pmid_1008_5062_23884.txt # ::snt Activation of MEK1 and MEK2 involves phosphorylation upon conserved serine residues (Ser-218 and Ser-222 on MEK1, Ser-222 and Ser-226 on MEK2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Apr 21, 2015 (i / involve-01 :ARG0 (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (p2 / phosphorylate-01 :ARG1 (r / residue :mod (a4 / amino-acid :name (n4 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (c / conserve-01) :ARG1-of (m / mean-01 :ARG2 (a5 / and :op1 (a6 / and :op1 (a7 / amino-acid :mod "218" :name (n5 / name :op1 "serine") :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a8 / amino-acid :mod "222" :name (n6 / name :op1 "serine") :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of e) :op2 (a9 / and :op1 (a10 / amino-acid :mod "222" :name (n7 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a11 / amino-acid :mod "226" :name (n8 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of e2)))))) # ::id bel_pmid_1019_4465.17324 # ::date 2015-04-02T03:29:34 # ::file bel_pmid_1019_4465_17324.txt # ::snt c-Cbl is tyrosine-phosphorylated, binds to Fyn upon insulin stimulation, and is translocated to small invaginations of the plasma membrane, called caveolae, after insulin stimulation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (p3 / protein :name (n / name :op1 "c-Cbl") :xref (x / xref :value "UNIPROT:Q6LB30_HUMAN" :prob "0.601")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (b / bind-01 :ARG1 p3 :ARG2 (e / enzyme :name (n3 / name :op1 "Fyn") :xref (x1 / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604")) :condition (s / stimulate-01 :ARG2 (p4 / protein :name (n4 / name :op1 "insulin") :xref (x2 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")))) :op3 (t / translocate-01 :ARG1 p3 :ARG2 (i / invaginate-01 :ARG1 (m / membrane :mod (p2 / plasma) :ARG1-of (c / call-01 :ARG2 (c2 / caveolae)) :xref (x3 / xref :value "GO:0016020" :prob "0.8")) :mod (s2 / small)) :time (a3 / after :op1 s))) # ::id bel_pmid_1019_4465.17346 # ::date 2015-04-02T05:27:43 # ::file bel_pmid_1019_4465_17346.txt # ::snt Insulin and IGF-1 stimulation also promote association between IRS-1 and aVb3 integrin (vitronectin receptor) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / promote-01 :ARG0 (s / stimulate-01 :ARG1 (a2 / and :op1 (p6 / protein :name (n5 / name :op1 "insulin") :xref (x2 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :op2 (p3 / protein :name (n2 / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))) :ARG1 (a3 / associate-01 :ARG0 a2 :ARG1 (p2 / protein :name (n3 / name :op1 "IRS-1") :xref (x / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")) :ARG2 (p5 / protein :name (n6 / name :op1 "aVb3" :op2 "integrin") :ARG1-of (d / describe-01 :ARG2 (r / receptor :mod (p4 / protein :name (n / name :op1 "vitronectin") :xref (x3 / xref :value "UNIPROT:VTNC_HUMAN" :prob "0.703")))))) :mod (a / also)) # ::id bel_pmid_1019_4465.17828 # ::date 2015-04-02T05:34:18 # ::file bel_pmid_1019_4465_17828.txt # ::snt Thiazolidinediones (TZDs), the class of insulin sensitizers that act through the nuclear receptor PPAR-g, increase CAP expression levels and c-Cbl phosphorylation significantly in adipocytes (54), possibly contributing to their insulin sensitizing effect # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / increase-01 :ARG0 (t / thiazolidinedione :mod (c / class :mod (m / molecular-physical-entity :ARG0-of (s / sensitize-01 :ARG1 (p2 / protein :name (n3 / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :ARG0-of (a / act-01 :instrument (r / receptor :name (n2 / name :op1 "PPAR-g") :mod (n / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8"))))))) :ARG1 (a2 / and :op1 (l / level :degree-of (e / express-03 :ARG2 (p5 / protein :name (n6 / name :op1 "CAP") :xref (x1 / xref :value "UNIPROT:CAP1_HUMAN" :prob "1.002")))) :op2 (p3 / phosphorylate-01 :ARG1 (p6 / protein :name (n4 / name :op1 "c-Cbl") :xref (x2 / xref :value "UNIPROT:Q6LB30_HUMAN" :prob "0.601")))) :ARG2 (s2 / significant-02) :location (c2 / cell :name (n5 / name :op1 "adipocyte")) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "54"))) :ARG0-of (c3 / contribute-01 :ARG1 (a3 / affect-01 :ARG2 (s3 / sensitize-01 :ARG0 t :ARG1 p2)) :ARG1-of (p / possible-01))) # ::id bel_pmid_1019_4465.19902 # ::date 2015-04-02T06:43:55 # ::file bel_pmid_1019_4465_19902.txt # ::snt Interestingly, this NPXY sequence is also a receptor internalization motif found in many members of the tyrosine kinase receptor family, the low-density lipoprotein receptor (11-13), and the transferrin receptor (14), all of which are internalized in a ligand-dependent fashion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / motif :ARG0-of (i / internalize-01 :ARG1 (r / receptor)) :domain (d / dna-sequence :name (n / name :op1 "NPXY") :mod (t / this)) :ARG1-of (f2 / find-01 :location (m2 / member :quant (m3 / many) :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n2 / name :op1 "tyrosine" :op2 "kinase" :op3 "receptor"))) :ARG1-of (i4 / internalize-01 :manner (d4 / depend-01 :ARG1 (l / ligand))) :example (a / and :op1 (p2 / protein :name (n3 / name :op1 "low-density" :op2 "lipoprotein" :op3 "receptor") :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 "11" :op2 "13")))) :xref (x / xref :value "UNIPROT:LDLR_HUMAN" :prob "0.702")) :op2 (p4 / protein :name (n4 / name :op1 "transferrin" :op2 "receptor") :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "14"))) :xref (x1 / xref :value "UNIPROT:TFR1_HUMAN" :prob "0.362"))))) :ARG2-of (i3 / interest-01) :mod (a2 / also)) # ::id bel_pmid_1019_4465.19968 # ::date 2015-04-02T07:41:15 # ::file bel_pmid_1019_4465_19968.txt # ::snt Csk has been reported to associate with IRS-1 through its SH2 domain and promote dephosphorylation of the focal adhesion kinase (FAK) in an insulin-dependent manner (56). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / report-01 :ARG1 (a / and :op1 (a2 / associate-01 :ARG1 (p6 / protein-segment :name (n6 / name :op1 "SH2" :op2 "domain") :part-of (p / protein :name (n / name :op1 "Csk") :xref (x2 / xref :value "UNIPROT:CSK_HUMAN" :prob "0.603"))) :ARG2 (p2 / protein :name (n2 / name :op1 "IRS-1") :xref (x / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003"))) :op2 (p3 / promote-01 :ARG0 p :ARG1 (d2 / dephosphorylate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "focal" :op2 "adhesion" :op3 "kinase") :xref (x3 / xref :value "UNIPROT:FAK1_HUMAN" :prob "0.393")) :manner (d4 / depend-01 :ARG1 (p7 / protein :name (n3 / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")))))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "56")))) # ::id bel_pmid_1019_4465.20030 # ::date 2015-04-02T08:15:35 # ::file bel_pmid_1019_4465_20030.txt # ::snt In smooth muscle cells, blocking ligand occupancy of aVb3 integrin reduces IGF-1-induced IRS-1 phosphorylation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / reduce-01 :ARG0 (b / block-01 :ARG1 (o / occupy-01 :ARG0 (l / ligand) :ARG1 (i2 / integrin :name (n / name :op1 "aVb3")))) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IRS-1") :xref (x / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")) :ARG2-of (i / induce-01 :ARG0 (p3 / protein :name (n3 / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))) :location (c / cell :mod (m / muscle :ARG1-of (s / smooth-06)))) # ::id bel_pmid_1019_4465.20066 # ::date 2015-04-02T08:27:14 # ::file bel_pmid_1019_4465_20066.txt # ::snt Nck associates with IRS-1 (45), many different tyrosine kinases, several serine/threonine kinases through its SH2 domain, as well as Sos through its SH3 domains # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / associate-01 :ARG0 (p3 / protein-segment :name (n8 / name :op1 "SH2" :op2 "domain") :part-of (p / protein :name (n / name :op1 "Nck") :xref (x / xref :value "UNIPROT:NCK1_HUMAN" :prob "0.603"))) :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "tyrosine" :op2 "kinase") :quant (m / many) :ARG1-of (d / differ-02) :xref (x4 / xref :value "UNIPROT:FER_HUMAN" :prob "0.392")) :op2 (o / or :op1 (e2 / enzyme :name (n3 / name :op1 "serine" :op2 "kinase") :xref (x2 / xref :value "UNIPROT:SRR_HUMAN" :prob "0.282")) :op2 (e3 / enzyme :name (n4 / name :op1 "threonine" :op2 "kinase") :xref (x1 / xref :value "UNIPROT:TASP1_HUMAN" :prob "0.272")) :quant (s / several)) :op3 (p4 / protein-segment :name (n9 / name :op1 "SH3" :op2 "domain") :part-of (p2 / protein :name (n6 / name :op1 "Sos") :xref (x3 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203")))) :ARG2 (p5 / protein :name (n5 / name :op1 "IRS-1") :xref (x5 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 "45")))) # ::id bel_pmid_1019_4465.21192 # ::date 2015-04-02T14:26:15 # ::file bel_pmid_1019_4465_21192.txt # ::snt Gab-1 is heavily phosphorylated by the epidermal growth factor receptor, but poorly by the insulin receptor # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "Gab-1") :xref (x1 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.593")) :ARG2 (e / enzyme :name (n / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.703")) :degree (h2 / heavy)) :ARG2 (p2 / phosphorylate-01 :ARG1 p4 :ARG2 (r / receptor :mod (p5 / protein :name (n3 / name :op1 "insulin") :xref (x2 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :degree (p3 / poor))) # ::id bel_pmid_1019_4465.21226 # ::date 2015-04-08T00:00:00 # ::file bel_pmid_1019_4465_21226.txt # ::snt Recently, it was shown that Fyn is one of the kinases responsible for the phosphorylation of caveolin # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (s / show-01 :ARG1 (e / enzyme :name (n / name :op1 "Fyn") :ARG1-of (i / include-91 :ARG2 (k / kinase :ARG0-of (r / responsible-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "caveolin") :xref (x / xref :value "UNIPROT:A0A024R2D8_HUMAN" :prob "0.701")))))) :xref (x1 / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604")) :time (r2 / recent)) # ::id bel_pmid_1019_4465.21256 # ::date 2015-04-13T13:37:33 # ::file bel_pmid_1019_4465_21256.txt # ::snt It also contains an additional binding site located in the phosphorylated kinase activation loop of the insulin receptor but is only very slightly phosphorylated by insulin receptor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (h / have-concession-91 :ARG1 (c / contain-01 :ARG0 (i / it) :ARG1 (p3 / protein-segment :location (l2 / loop :ARG0-of (a / activate-01 :ARG1 (k / kinase :ARG3-of (p / phosphorylate-01))) :poss (r2 / receptor :mod (p4 / protein :name (n / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")))) :mod (a2 / additional) :ARG1-of (b / bind-01)) :mod (a3 / also)) :ARG2 (p2 / phosphorylate-01 :ARG1 i :ARG2 r2 :degree (s2 / slight :degree (v / very) :mod (o / only)))) # ::id bel_pmid_1019_4465.22614 # ::date 2015-04-04T09:13:52 # ::file bel_pmid_1019_4465_22614.txt # ::snt Crk has been reported to associate with tyrosine-phosphorylated proteins, such as p130Cas and paxillin (42, 43), involved in the rearrangement of cytoskeletal components, through its SH2 domain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (r / report-01 :ARG1 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "Crk") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.604")) :ARG2 (p2 / protein :example (a3 / and :op1 (p4 / protein :name (n3 / name :op1 "p130Cas") :xref (x / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.683")) :op2 (p5 / protein :name (n4 / name :op1 "paxillin") :xref (x1 / xref :value "UNIPROT:PAXI_HUMAN" :prob "0.703")) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 "42" :op2 "43"))))) :part (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (p3 / phosphorylate-01) :ARG1-of (i / involve-01 :ARG2 (r2 / rearrange-01 :ARG1 (c2 / component :part-of (c3 / cytoskeleton :xref (x3 / xref :value "GO:0005856" :prob "0.8")))) :instrument (p7 / protein-segment :name (n5 / name :op1 "SH2" :op2 "domain") :part-of p))))) # ::id bel_pmid_1019_4465.22706 # ::date 2015-04-04T09:27:39 # ::file bel_pmid_1019_4465_22706.txt # ::snt c-Cbl associated protein (CAP) that has three sequential SH3 domains is specifically expressed in insulin-responsive cell types and associates with both c- Cbl and the insulin receptor # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "c-Cbl" :op2 "associated" :op3 "protein") :ARG0-of (h / have-03 :ARG1 (p2 / protein-segment :quant "3" :name (n2 / name :op1 "SH3" :op2 "domain") :mod (s / sequential))) :xref (x2 / xref :value "UNIPROT:SRBS1_HUMAN" :prob "0.692")) :ARG3 (t / type-03 :ARG1 (c / cell :ARG0-of (r / responsive-02 :ARG1 (p4 / protein :name (n4 / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))))) :ARG1-of (s2 / specific-02)) :op2 (a2 / associate-01 :ARG1 p :ARG2 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "c-Cbl") :xref (x / xref :value "UNIPROT:Q6LB30_HUMAN" :prob "0.601")) :op2 (r2 / receptor :mod p4)))) # ::id bel_pmid_1019_4465.22914 # ::date 2015-04-04T09:38:05 # ::file bel_pmid_1019_4465_22914.txt # ::snt Recently, phosphorylated p62dok was demonstrated to associate with the GTPase-activating protein (GAP) for Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (d / demonstrate-01 :ARG1 (a / associate-01 :ARG1 (p / protein :name (n2 / name :op1 "p62dok") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:DOK1_HUMAN" :prob "0.653")) :ARG2 (p3 / protein :name (n3 / name :op1 "GTPase-activating" :op2 "protein") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :beneficiary (p4 / protein-family :name (n / name :op1 "Ras"))) :time (r / recent)) # ::id bel_pmid_1019_4465.23034 # ::date 2015-04-04T09:42:59 # ::file bel_pmid_1019_4465_23034.txt # ::snt In the case of insulin, it is unclear whether SHIP associates with IRS proteins or the insulin receptor, although a recent report has demonstrated SHIP association with IRS-2 in response to erythropoietin # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (h / have-concession-91 :ARG1 (e / exemplify-01 :ARG0 (p4 / protein :name (n / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :ARG1 (c / clear-06 :polarity "-" :ARG1 (a / associate-01 :mode "interrogative" :ARG1 (p2 / protein :name (n3 / name :op1 "SHIP") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003")) :ARG2 (o / or :op1 (p / protein :name (n2 / name :op1 "IRS") :xref (x3 / xref :value "UNIPROT:SYIC_HUMAN" :prob "1.002")) :op2 (r / receptor :mod p4))))) :ARG2 (d / demonstrate-01 :ARG0 (r2 / report :time (r3 / recent)) :ARG1 (a2 / associate-01 :ARG1 p :ARG2 (p3 / protein :name (n4 / name :op1 "IRS-2") :xref (x2 / xref :value "UNIPROT:IRS2_HUMAN" :prob "1.003")) :ARG2-of (r4 / respond-01 :ARG1 (e2 / erythropoietin))))) # ::id bel_pmid_1019_4465.23202 # ::date 2015-04-04T09:50:58 # ::file bel_pmid_1019_4465_23202.txt # ::snt The SH2 domain of the adaptor protein Grb- 2 and the SH2 domain of the phosphotyrosine phosphatase SHP-2 bind other sequences, including pYVNI, pYIDL, and pYASI sequences (1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 16, 2015 (b / bind-01 :ARG1 (a / and :op1 (p7 / protein-segment :name (n8 / name :op1 "SH2" :op2 "domain") :part-of (p / protein :name (n2 / name :op1 "Grb2") :mod (a2 / adaptor) :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :op2 (p8 / protein-segment :name (n / name :op1 "SH2" :op2 "domain") :part-of (p2 / protein :name (n4 / name :op1 "phosphotyrosine" :op2 "phosphatase" :op3 "SHP-2") :xref (x / xref :value "UNIPROT:SERB_HUMAN" :prob "0.292")))) :ARG2 (s / sequence :ARG2-of (i / include-91 :ARG1 (a3 / and :op1 (p3 / protein-segment :name (n5 / name :op1 "pYVNI")) :op2 (p4 / protein-segment :name (n6 / name :op1 "pYIDL")) :op2 (p5 / protein-segment :name (n7 / name :op1 "pYASI")))) :mod (o / other)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 "1")))) # ::id bel_pmid_1019_4465.23382 # ::date 2015-04-05T02:57:06 # ::file bel_pmid_1019_4465_23382.txt # ::snt Since an inhibitor against SERCA induces apoptosis in some cell lines (76), the IRS/SERCA complex might be involved in an insulin and IGF-1-dependent antiapoptotic effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / cause-01 :ARG0 (i2 / induce-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein :name (n / name :op1 "SERCA") :xref (x / xref :value "UNIPROT:AT2A1_HUMAN" :prob "0.332")))) :ARG2 (a / apoptosis) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "76"))) :location (c3 / cell-line :mod (s / some))) :ARG1 (p / possible-01 :ARG1 (i3 / involve-01 :ARG1 (m / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "IRS") :xref (x2 / xref :value "UNIPROT:SYIC_HUMAN" :prob "1.002")) :part p2) :ARG2 (a2 / affect-01 :ARG2 (c2 / counter-01 :ARG1 (a5 / apoptosis)) :ARG0-of (d2 / depend-01 :ARG1 (a4 / and :op1 (p5 / protein :name (n3 / name :op1 "insulin") :xref (x3 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :op2 (p6 / protein :name (n5 / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))))))) # ::id bel_pmid_1019_4465.23752 # ::date 2015-04-05T03:09:42 # ::file bel_pmid_1019_4465_23752.txt # ::snt Grb-IR is a recently discovered SH2 domain protein that may translocate from the cytosol to the plasma membrane and bind directly to the tyrosine-phosphorylated insulin receptor # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p6 / protein :part (p5 / protein-segment :name (n2 / name :op1 "SH2" :op2 "domain")) :ARG1-of (d2 / discover-01 :time (r / recent)) :domain (p2 / protein :name (n / name :op1 "Grb-IR") :xref (x / xref :value "UNIPROT:GRB10_HUMAN" :prob "0.622")) :ARG1-of (t / translocate-01 :ARG2 (m / membrane :mod (p3 / plasma) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :ARG3 (c / cytosol :xref (x1 / xref :value "GO:0005829" :prob "0.8")) :ARG1-of (p / possible-01)) :ARG1-of (b / bind-01 :ARG2 (r2 / receptor :mod (i / insulin :ARG1-of (p4 / phosphorylate-01)) :part (a2 / amino-acid :name (n4 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (d / direct-02) :ARG1-of p)) # ::id bel_pmid_1019_4465.23766 # ::date 2015-04-05T03:17:58 # ::file bel_pmid_1019_4465_23766.txt # ::snt The physiological substrates for SHP- 2 are not known, but overexpression of SHP-2 modulates cell adhesion and migration, as well as insulin activation of the Ras/MAP-kinase pathway Several isoforms of 14-3-3 proteins (b, e, and z) have also been shown to associate with IRS-1, presumably through one of the several RXRXXpS motifs of IRS-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (m3 / multi-sentence :snt1 (c / contrast-01 :ARG1 (k / know-01 :polarity "-" :ARG1 (s / substrate :mod (p2 / physiology) :topic (p3 / protein :name (n2 / name :op1 "SHP-2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")))) :ARG2 (a / and :op1 (m / modulate-01 :ARG0 (o / overexpress-01 :ARG1 p3) :ARG1 (a4 / and :op1 (a2 / and :op1 (a3 / adhere-01 :ARG1 (c2 / cell)) :op2 (m2 / migrate-01 :ARG0 c2)) :op2 (a5 / activate-01 :ARG0 (i3 / insulin) :ARG1 (p4 / pathway :name (n3 / name :op1 "Ras/MAP-kinase"))))))) :snt2 (s2 / show-01 :ARG1 (a8 / associate-01 :ARG1 (i / isoform :mod (p / protein :name (n / name :op1 "14-3-3") :xref (x4 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572")) :ARG1-of (d / describe-01 :ARG2 (a7 / and :op1 (p5 / protein :name (n4 / name :op1 "14-3-3β") :xref (x3 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572")) :op2 (p8 / protein :name (n5 / name :op1 "14-3-3ε") :xref (x5 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572")) :op3 (p9 / protein :name (n8 / name :op1 "14-3-3ζ") :xref (x / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572")))) :quant (s3 / several)) :ARG2 (p6 / protein :name (n6 / name :op1 "IRS-1") :xref (x2 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")) :instrument (m5 / motif :ARG1-of (i2 / include-91 :ARG2 (m4 / motif :name (n7 / name :op1 "RXRXXpS") :part-of p6)) :ARG1-of (p7 / presume-01))) :mod (a6 / also))) # ::id bel_pmid_1019_4465.23768 # ::date 2015-04-05T03:52:27 # ::file bel_pmid_1019_4465_23768.txt # ::snt TNF-a appears to impair insulin signaling by increasing serine phosphorylation of IRS-1. Serine-phosphorylated IRS-1 inhibits insulin receptor tyrosine kinase activity, which leads to impaired downstream signaling # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / multi-sentence :snt1 (a2 / appear-02 :ARG1 (i / impair-01 :ARG0 (p2 / protein :name (n2 / name :op1 "TNF-a") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG1 (s / signal-07 :ARG1 (i5 / insulin)) :manner (i2 / increase-01 :ARG0 p2 :ARG1 (p3 / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "serine") :part-of (p4 / protein :name (n4 / name :op1 "IRS-1") :xref (x2 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")))))) :snt2 (i3 / inhibit-01 :ARG0 (p6 / phosphorylate-01 :ARG1 (a4 / amino-acid :name (n6 / name :op1 "serine") :part-of (p5 / protein :name (n3 / name :op1 "IRS-1") :xref (x3 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (a3 / activity-06 :ARG0 (e / enzyme :name (n5 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :mod (i6 / insulin) :xref (x / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392"))) :ARG0-of (l / lead-03 :ARG2 (s2 / signal-07 :location (d / downstream) :ARG1-of (i4 / impair-01))))) # ::id bel_pmid_1019_4465.23770 # ::date 2015-04-05T04:01:19 # ::file bel_pmid_1019_4465_23770.txt # ::snt other SH2 proteins, such as Crk (adaptor), Nck (adaptor), Fyn (tyrosine kinase), and Csk (tyrosine kinase), bind to tyrosine residues on IRS proteins through their specific SH2 domains. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (b / bind-01 :ARG1 (p / protein-segment :name (n / name :op1 "SH2" :op2 "domain") :example (a / and :op1 (p2 / protein :name (n2 / name :op1 "Crk") :ARG1-of (d / describe-01 :ARG2 (a2 / adaptor)) :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n3 / name :op1 "Nck") :ARG1-of (d2 / describe-01 :ARG2 a2) :xref (x3 / xref :value "UNIPROT:NCK1_HUMAN" :prob "0.603")) :op3 (e2 / enzyme :name (n4 / name :op1 "Fyn") :ARG1-of (d3 / describe-01 :ARG2 (e / enzyme :name (n6 / name :op1 "tyrosine" :op2 "kinase") :xref (x4 / xref :value "UNIPROT:FER_HUMAN" :prob "0.392"))) :xref (x2 / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604")) :op4 (p5 / protein :name (n5 / name :op1 "Csk") :ARG1-of (d4 / describe-01 :ARG2 e) :xref (x5 / xref :value "UNIPROT:CSK_HUMAN" :prob "0.603"))) :mod (o / other)) :ARG2 (r / residue :mod (a4 / amino-acid :name (n7 / name :op1 "tyrosine") :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481")) :part-of (p7 / protein-segment :name (n9 / name :op1 "SH2" :op2 "domain") :part-of (p6 / protein :name (n8 / name :op1 "IRS") :xref (x1 / xref :value "UNIPROT:SYIC_HUMAN" :prob "1.002")) :ARG1-of (s / specific-02)))) # ::id bel_pmid_1019_4465.23772 # ::date 2015-04-05T04:07:46 # ::file bel_pmid_1019_4465_23772.txt # ::snt Fyn is not activated directly by the insulin receptor, but rather by interaction with IRS-1 (49) and another insulin receptor substrate, c-Cbl (50). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (a / activate-01 :polarity "-" :ARG0 (r / receptor :mod (i / insulin)) :ARG1 (e / enzyme :name (n2 / name :op1 "Fyn") :xref (x1 / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604")) :ARG1-of (d / direct-02)) :ARG2 (a2 / activate-01 :ARG0 (i2 / interact-01 :ARG0 e :ARG1 (a3 / and :op1 (p2 / protein :name (n3 / name :op1 "IRS-1") :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "49"))) :xref (x / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")) :op2 (s / substrate :mod (r2 / receptor :mod i) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "50"))) :ARG0-of (m / mean-01 :ARG1 (p5 / protein :name (n / name :op1 "c-Cbl") :xref (x2 / xref :value "UNIPROT:Q6LB30_HUMAN" :prob "0.601"))) :mod (a4 / another)))) :ARG1 e)) # ::id bel_pmid_1019_4465.23788 # ::date 2015-04-05T04:16:53 # ::file bel_pmid_1019_4465_23788.txt # ::snt Recently, b1 integrins have also been reported to enhance IRS-1 phosphorylation and interaction, but not glucose transport, with downstream molecules such as PI3-kinase and Akt (74). These results suggest that integrins and insulin/IGF-1 receptor signaling pathways converge at an early point in the signaling cascade around the IRS proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (r / report-01 :ARG1 (c / contrast-01 :ARG1 (e / enhance-01 :ARG0 (p12 / protein :name (n / name :op1 "b1" :op2 "integrin")) :ARG1 (a / and :op1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "IRS-1") :xref (x3 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003"))) :op2 (i / interact-01 :ARG0 p4 :ARG1 (m2 / molecule :mod (d / downstream) :example (a2 / and :op1 (e3 / enzyme :name (n4 / name :op1 "PI3-kinase") :xref (x2 / xref :value "UNIPROT:PK3C3_HUMAN" :prob "0.323")) :op2 (e5 / enzyme :name (n5 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))))))) :ARG2 (e2 / enhance-01 :polarity "-" :ARG0 (t2 / transport-01 :ARG1 (s4 / small-molecule :name (n3 / name :op1 "glucose") :xref (x5 / xref :value "PUBCHEM:206" :prob "11.89276"))) :ARG1 a)) :time (r2 / recent) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "74"))) :mod (a5 / also)) :snt2 (s / suggest-01 :ARG0 (t3 / thing :ARG2-of (r3 / result-01) :mod (t / this)) :ARG1 (c3 / converge-01 :ARG0 (p10 / protein :name (n8 / name :op1 "integrin") :xref (x / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")) :ARG1 (p9 / pathway :name (n6 / name :op1 "insulin/IGF-1" :op2 "receptor") :ARG0-of (s3 / signal-07 :mod (r5 / receptor))) :time (p7 / point :mod (e4 / early) :subevent-of (c4 / cascade :subevent (s2 / signal-07) :location (a4 / around :op1 (p8 / protein :name (n7 / name :op1 "IRS") :xref (x4 / xref :value "UNIPROT:SYIC_HUMAN" :prob "1.002")))))))) # ::id bel_pmid_1019_4465.24722 # ::date 2015-04-05T17:29:49 # ::file bel_pmid_1019_4465_24722.txt # ::snt PC-1 is a membrane glycoprotein with ectonucleotide pyrophosphatase activity that seems to act as an intrinsic inhibitor of insulin receptor tyrosine kinase activity # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (g / glycoprotein :mod (m / membrane :xref (x3 / xref :value "GO:0016020" :prob "0.8")) :ARG0-of (h2 / have-03 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n3 / name :op1 "ectonucleotide" :op2 "pyrophosphatase") :xref (x1 / xref :value "UNIPROT:ENPP1_HUMAN" :prob "0.292")))) :ARG0-of (a2 / act-01 :ARG1 (i2 / inhibit-01 :ARG0 "p2" :ARG1 (a3 / activity-06 :ARG0 (e2 / enzyme :name (n4 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :mod (i / insulin) :xref (x2 / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392"))) :mod (i3 / intrinsic)) :ARG1-of (s / seem-01)) :domain (p2 / protein :name (n2 / name :op1 "PC-1") :xref (x / xref :value "UNIPROT:ENPP1_HUMAN" :prob "0.652"))) # ::id bel_pmid_1019_4465.24724 # ::date 2015-04-06T06:56:01 # ::file bel_pmid_1019_4465_24724.txt # ::snt It has been reported that PC-1 overexpression in skeletal muscle of obese subjects explains downregulation of insulin receptor tyrosine phosphorylation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (r / report-01 :ARG1 (e / explain-01 :ARG0 (o / overexpress-01 :ARG1 (p3 / protein :name (n / name :op1 "PC-1") :xref (x1 / xref :value "UNIPROT:ENPP1_HUMAN" :prob "0.652")) :location (m / muscle :mod (s / skeletal) :part-of (s2 / subject :mod (o2 / obese)))) :ARG1 (d / downregulate-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "insulin" :op2 "receptor" :op3 "tyrosine") :xref (x / xref :value "UNIPROT:BI2L1_HUMAN" :prob "0.352")))))) # ::id bel_pmid_1022_8560.5928 # ::date 2015-04-06T07:02:33 # ::file bel_pmid_1022_8560_5928.txt # ::snt Inhibition of MEK1 also led to reduced expression of alpha-enolase, phosphoglycerate kinase, elongation factor 2 and heterogeneous nuclear ribonucleoprotein A3, the latter two being detected as truncated proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG2 (e2 / express-03 :ARG1 (a / and :op1 (e3 / enzyme :name (n2 / name :op1 "alpha-enolase") :xref (x4 / xref :value "UNIPROT:ENOA_HUMAN" :prob "0.702")) :op2 (e4 / enzyme :name (n3 / name :op1 "phosphoglycerate" :op2 "kinase") :xref (x3 / xref :value "UNIPROT:B4DHB3_HUMAN" :prob "0.701")) :op3 (p / protein :name (n4 / name :op1 "elongation" :op2 "factor" :op3 "2") :ARG0-of (d / detect-01 :ARG1 (p3 / protein :ARG1-of (t / truncate-01)) :ord (o / ordinal-entity :value "-2")) :xref (x1 / xref :value "UNIPROT:EF2_HUMAN" :prob "0.702")) :op4 (p2 / protein :name (n5 / name :op1 "heterogeneous" :op2 "nuclear" :op3 "ribonucleoprotein" :op4 "A3") :ARG0-of d :xref (x2 / xref :value "UNIPROT:ROA3_HUMAN" :prob "0.702"))) :ARG1-of (r / reduce-01)) :mod (a2 / also)) # ::id bel_pmid_1023_2608.5936 # ::date 2015-04-06T07:17:40 # ::file bel_pmid_1023_2608_5936.txt # ::snt In support of these data, we also show that MEK1 is highly phosphorylated in vivo on Ser 217/221 in MLK3-transformed fibroblasts # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (s2 / slash :op1 (a / amino-acid :mod "217" :name (n2 / name :op1 "serine") :part-of (e / enzyme :name (n5 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :mod "221" :name (n4 / name :op1 "serine") :part-of e :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1-of (h / high-02) :manner (i / in-vivo) :location (f / fibroblast :ARG1-of (t / transform-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "MLK3") :xref (x1 / xref :value "UNIPROT:M3K11_HUMAN" :prob "1.002"))))) :purpose (s3 / support-01 :ARG1 (d / data :mod (t2 / this))) :mod (a2 / also)) # ::id bel_pmid_1023_2608.16572 # ::date 2015-04-06T07:26:22 # ::file bel_pmid_1023_2608_16572.txt # ::snt expression of MLK3 strongly activated SAPK? to the same extent seen with the established JNK/SAPK activator arsenite (45) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG0 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MLK3") :xref (x1 / xref :value "UNIPROT:M3K11_HUMAN" :prob "1.002"))) :ARG1 (e4 / enzyme :name (n2 / name :op1 "SAPK") :xref (x / xref :value "UNIPROT:MK08_HUMAN" :prob "0.313")) :ARG1-of (s / strong-02) :extent (s2 / see-01 :ARG1 (a2 / arsenite :ARG0-of (a3 / activate-01 :ARG1 (p2 / pathway :name (n3 / name :op1 "JNK/SAPK"))) :ARG1-of (e3 / establish-01)) :ARG1-of (s3 / same-01)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "45")))) # ::id bel_pmid_1023_2608.23890 # ::date 2015-04-06T07:38:05 # ::file bel_pmid_1023_2608_23890.txt # ::snt Using a coupled assay, we were able to show that MLK3-mediated phosphorylation of SEK1 resulted in activation because GST-SEK1 is able to phosphorylate recombinant SAPK? (Fig. 5D) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (s / show-01 :ARG0 (w / we) :ARG1 (r / result-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "SEK1") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003")) :ARG1-of (m / mediate-01 :ARG0 (e / enzyme :name (n2 / name :op1 "MLK3") :xref (x2 / xref :value "UNIPROT:M3K11_HUMAN" :prob "1.002")))) :ARG2 (a / activate-01) :ARG1-of (c / cause-01 :ARG0 (p5 / possible-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "SAPK") :ARG3-of (r2 / recombine-01) :xref (x / xref :value "UNIPROT:MK08_HUMAN" :prob "0.313")) :ARG2 (p7 / protein :name (n4 / name :op1 "GST-SEK1") :xref (x3 / xref :value "UNIPROT:GSTK1_HUMAN" :prob "0.242"))))))) :manner (u / use-01 :ARG0 w :ARG1 (a2 / assay-01 :ARG1-of (c2 / couple-01))) :ARG1-of (d / describe-01 :ARG2 (f / figure :mod "5D"))) # ::id bel_pmid_1023_2608.23894 # ::date 2015-04-05T06:03:51 # ::file bel_pmid_1023_2608_23894.txt # ::snt Wild type, but not KD, MLK3 was able to phosphorylate His-MEK1 (Fig. 5A) ? and GST-SEK1 (Fig. 5B) ? in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n / name :op1 "His" :op2 "MEK1") :ARG1-of (d / describe-01 :ARG2 (f / figure :mod "5A")) :xref (x1 / xref :value "UNIPROT:HIS3_HUMAN" :prob "0.202")) :op2 (p4 / protein :name (n2 / name :op1 "GST-SEK1") :ARG1-of (d2 / describe-01 :ARG2 (f2 / figure :mod "5B")) :xref (x3 / xref :value "UNIPROT:GSTK1_HUMAN" :prob "0.242"))) :ARG2 (e / enzyme :name (n3 / name :op1 "MLK3") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:M3K11_HUMAN" :prob "1.002")) :manner (i / in-vitro))) :ARG2 (p5 / possible-01 :polarity "-" :ARG1 (p6 / phosphorylate-01 :ARG1 a2 :ARG2 (e2 / enzyme :name (n5 / name :op1 "MLK3") :ARG0-of (f3 / function-01 :polarity "-" :ARG1 (k / kinase)) :xref (x / xref :value "UNIPROT:M3K11_HUMAN" :prob "1.002"))))) # ::id bel_pmid_1034_3541.46 # ::date 2015-04-03T11:38:00 # ::file bel_pmid_1034_3541_46.txt # ::snt Thrombin receptor mediated signal transduction could induce the expressions of IL6 and G-CSF, and increase inflammatory events in the cavum articulare via NF-kappa B activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (p / possible-01 :ARG1 (a / and :op1 (i / induce-01 :ARG0 (t / transduce-01 :ARG1 (s / signal-07) :ARG1-of (m / mediate-01 :ARG0 (r / receptor :name (n / name :op1 "thrombin")))) :ARG2 (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "IL6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n3 / name :op1 "G-CSF") :xref (x1 / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.002"))))) :op2 (i2 / increase-01 :ARG0 t :ARG1 (e2 / event :mod (i3 / inflame-01)) :location (c / cavum :mod (a3 / articulare)) :manner (a4 / activate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "NF-kappa-B") :xref (x2 / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.392")))))) # ::id bel_pmid_1034_3541.18504 # ::date 2015-04-03T12:30:58 # ::file bel_pmid_1034_3541_18504.txt # ::snt Thrombin receptor mediated signal transduction could induce the expressions of IL6 and G-CSF, and increase inflammatory events in the cavum articulare via NF-êB activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (p / possible-01 :ARG1 (a / and :op1 (i / induce-01 :ARG0 (t / transduce-01 :ARG1 (s / signal-07) :ARG1-of (m / mediate-01 :ARG0 (r / receptor :name (n / name :op1 "thrombin")))) :ARG2 (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "IL6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n3 / name :op1 "G-CSF") :xref (x1 / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.002"))))) :op2 (i2 / increase-01 :ARG0 t :ARG1 (e2 / event :mod (i3 / inflame-01)) :location (c / cavum :mod (a3 / articulare)) :manner (a4 / activate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "NF-κB")))))) # ::id bel_pmid_1034_3541.23056 # ::date 2015-04-05T13:16:12 # ::file bel_pmid_1034_3541_23056.txt # ::snt The levels of IL6 and of G-CSF mRNAs showed a time dependent increase during two to eight hours after thrombin stimulation....Cytokines were measured by enzyme linked immunosorbent assay (ELISA) in the supernatants of cultured rheumatoid synovial fibroblasts stimulated by thrombin # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (s / show-01 :ARG0 (a / and :op1 (l / level :quant-of (n9 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004"))))) :op2 (l2 / level :quant-of (n10 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "G-CSF") :xref (x1 / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.002")))))) :ARG1 (i / increase-01 :ARG0-of (d / depend-01 :ARG1 (t / time)) :time (a2 / after :op1 (s2 / stimulate-01 :ARG1 (e / enzyme :name (n5 / name :op1 "thrombin") :xref (x3 / xref :value "UNIPROT:THRB_HUMAN" :prob "0.292"))) :quant (b / between :op1 (t2 / temporal-quantity :quant "2" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "8" :unit h))))) :snt2 (m2 / measure-01 :ARG1 (p / protein :name (n8 / name :op1 "cytokine") :xref (x / xref :value "UNIPROT:RED_HUMAN" :prob "0.342")) :location (s3 / supernatant :part-of (c2 / culture-01 :ARG1 (f / fibroblast :location (s4 / synovia) :mod (r3 / rheumatoid))) :ARG1-of (s5 / stimulate-01 :ARG0 e)) :manner (a3 / assay-01 :instrument (i2 / immunosorbent :ARG1-of (l3 / link-01 :ARG2 (e2 / enzyme)))))) # ::id bel_pmid_1034_3541.35586 # ::date 2015-04-05T14:44:10 # ::file bel_pmid_1034_3541_35586.txt # ::snt Thrombin receptor mediated signal transduction could induce the expressions of IL6 and G-CSF, and increase inflammatory events in the cavum articulare via NF-êB activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (p / possible-01 :ARG1 (a / and :op1 (i / induce-01 :ARG0 (t / transduce-01 :ARG1 (s / signal-07) :ARG1-of (m / mediate-01 :ARG0 (r / receptor :name (n / name :op1 "thrombin")))) :ARG2 (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "IL6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n3 / name :op1 "G-CSF") :xref (x1 / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.002"))))) :op2 (i2 / increase-01 :ARG0 t :ARG1 (e2 / event :mod (i3 / inflame-01)) :location (c / cavum :mod (a3 / articulare)) :manner (a4 / activate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "NF-κB")))))) # ::id bel_pmid_1034_7197.8888 # ::date 2015-04-05T14:56:34 # ::file bel_pmid_1034_7197_8888.txt # ::snt Induction of the urokinase promoter by HGF/SF via the Met receptor was blocked by co-expression of a dominant-negative Grb2 and Sos1 expression construct. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (b / block-01 :ARG0 (c / coexpress-01 :ARG2 (c2 / construct-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "Grb2") :ARG2-of (m / mutate-01 :mod "-/-") :ARG0-of (d / dominate-01) :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Sos1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.604")))))) :ARG1 (i / induce-01 :ARG0 (p3 / protein :name (n3 / name :op1 "HGF/SF")) :ARG2 (m2 / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "urokinase") :xref (x2 / xref :value "UNIPROT:HUTU_HUMAN" :prob "0.292")))) :medium (r / receptor :name (n5 / name :op1 "Met")))) # ::id bel_pmid_1034_7197.20912 # ::date 2015-04-06T05:19:24 # ::file bel_pmid_1034_7197_20912.txt # ::snt Further, the expression of the catalytically inactive mutants of Ha-Ras, RhoA, c-Raf, and Erk2 or addition of the Mek1-specific inhibitor PD 098059 abrogated the stimulation of the urokinase promoter by HGF/SF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op2 (a2 / abrogate-01 :ARG1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "HGF/SF")) :ARG1 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n2 / name :op1 "urokinase") :xref (x4 / xref :value "UNIPROT:HUTU_HUMAN" :prob "0.292"))))) :ARG2 (o / or :op1 (e2 / express-03 :ARG2 (m2 / mutate-01 :ARG1 (a3 / and :op1 (e6 / enzyme :name (n3 / name :op1 "Ha-Ras") :xref (x2 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "RhoA") :xref (x5 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :op3 (e3 / enzyme :name (n5 / name :op1 "c-Raf") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :op3 (e4 / enzyme :name (n6 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :ARG1-of (a4 / activate-01 :polarity "-" :manner (c / catalytic)))) :op2 (a5 / add-02 :ARG1 (m3 / molecular-physical-entity :name (n7 / name :op1 "PD-098059") :ARG0-of (i / inhibit-01 :ARG1-of (s2 / specific-02 :ARG2 (e5 / enzyme :name (n8 / name :op1 "Mek1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.603")))) :xref (x6 / xref :value "PUBCHEM:4713" :prob "19.972591")))))) # ::id bel_pmid_1035_9574.24516 # ::date 2015-04-06T07:13:26 # ::file bel_pmid_1035_9574_24516.txt # ::snt c-Raf-1 kinase was identified as an intracellular target of a signal transduction cascade initiated by binding of TNF-alpha to TNFR-I. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (i / identify-01 :ARG1 (e / enzyme :name (n / name :op1 "c-Raf-1" :op2 "kinase")) :ARG2 (t / target-01 :ARG0 (c / cascade-01 :ARG2-of (t2 / transduce-01 :ARG1 (s / signal-07)) :ARG1-of (i2 / initiate-01 :ARG2 (b / bind-01 :ARG1 (p / protein :name (n2 / name :op1 "TNF-alpha") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n3 / name :op1 "TNFR-I") :xref (x / xref :value "UNIPROT:TNR1A_HUMAN" :prob "1.002"))))) :ARG1 e :location (i3 / intracellular))) # ::id bel_pmid_1036_2260.5288 # ::date 2015-04-06T08:02:50 # ::file bel_pmid_1036_2260_5288.txt # ::snt Gadd45 was also able to physically interact with Cdc2, but not Cyclin B1. Addition of Gadd45 to immunoprecipitated Cdc2/Cyclin B1 in vitro led to a dissociation of this complex, and thus may represent a new checkpoint mechanism whereby Cdc2/Cyclin B1 can be inhibited. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "Gadd45") :xref (x2 / xref :value "UNIPROT:GA45A_HUMAN" :prob "0.622")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Cdc2") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :manner (p3 / physical)) :mod (a / also)) :ARG2 (p4 / possible-01 :ARG1 (i2 / interact-01 :polarity "-" :ARG0 p2 :ARG1 (p5 / protein :name (n3 / name :op1 "Cyclin-B1") :xref (x5 / xref :value "UNIPROT:CCNA1_HUMAN" :prob "0.362")) :ARG2 p3))) :snt2 (l / lead-03 :ARG0 (a2 / add-02 :ARG1 (p6 / protein :name (n4 / name :op1 "Gadd45") :xref (x3 / xref :value "UNIPROT:GA45A_HUMAN" :prob "0.622")) :ARG2 (m3 / macro-molecular-complex :part (e / enzyme :name (n5 / name :op1 "Cdc2") :xref (x / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :part (p7 / protein :name (n6 / name :op1 "Cyclin-B1") :xref (x4 / xref :value "UNIPROT:CCNA1_HUMAN" :prob "0.362")) :ARG1-of (i3 / immunoprecipitate-01)) :manner (i4 / in-vitro)) :ARG2 (d / dissociate-01 :ARG0 a2 :ARG1 (c2 / complex :mod (t / this))) :ARG0-of (c3 / cause-01 :ARG1 (p8 / possible-01 :ARG1 (r / represent-01 :ARG0 (m5 / mechanism :mod (c4 / checkpoint) :ARG1-of (n7 / new-01) :instrument-of (p9 / possible-01 :ARG1 (i5 / inhibit-01 :ARG1 m3))) :ARG1 a2))))) # ::id bel_pmid_1036_2713.15636 # ::date 2015-04-06T09:17:54 # ::file bel_pmid_1036_2713_15636.txt # ::snt Treatment with TNF-a significantly decreased the intracellular GSH content of HS-24 cells. Pretreatment of this culture with DMSO recovered the TNF-a-induced decrease in GSH (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (d / decrease-01 :ARG0 (t / treat-04 :ARG2 (p / protein :name (n / name :op1 "TNF-α") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642"))) :ARG1 (s3 / small-molecule :name (n2 / name :op1 "GSH") :ARG1-of (c / contain-01 :ARG0 (c2 / cell :name (n3 / name :op1 "HS-24")) :location (i / intracellular)) :xref (x2 / xref :value "PUBCHEM:124886" :prob "15.988989")) :ARG2 (s / significant-02)) :snt2 (r / recover-02 :ARG0 (p2 / pretreat-01 :ARG1 (c3 / culture :mod (t2 / this)) :ARG3 (s2 / small-molecule :name (n4 / name :op1 "DMSO") :xref (x3 / xref :value "PUBCHEM:679" :prob "16.740406"))) :ARG1 (d2 / decrease-01 :ARG1 (s4 / small-molecule :name (n5 / name :op1 "GSH") :xref (x4 / xref :value "PUBCHEM:124886" :prob "15.988989")) :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n6 / name :op1 "TNF-α") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")))) :ARG1-of (d3 / describe-01 :ARG0 (t3 / table :mod "1")))) # ::id bel_pmid_1036_2713.15640 # ::date 2015-04-06T10:08:11 # ::file bel_pmid_1036_2713_15640.txt # ::snt TNF-a (200 U/ml) significantly increased the levels of IL-6 mRNA in HS-24 cells and DMSO (1.0%) markedly reduced those induced with the cytokine (Fig. 5E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "TNF-α") :quant (c / concentration-quantity :quant "200" :unit (u / unit-per-milliliter)) :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :ARG1 (l / level :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :ARG2 (s / significant-02) :location (c2 / cell :name (n3 / name :op1 "HS-24"))) :op2 (r2 / reduce-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "DMSO") :quant (p2 / percentage-entity :quant "1.0") :xref (x3 / xref :value "PUBCHEM:679" :prob "16.740406")) :ARG1 (l2 / level :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n6 / name :op1 "cytokine") :xref (x / xref :value "UNIPROT:RED_HUMAN" :prob "0.342"))) :quant-of n7) :manner (m2 / marked)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5E"))) # ::id bel_pmid_1036_2713.18726 # ::date 2015-04-06T10:58:45 # ::file bel_pmid_1036_2713_18726.txt # ::snt An XO enzyme activity of 5.0 mU/ml led to a twofold increase in IL-6 secretion in NHBE cells. And incubation of HS-24 cells with XO (20 mU/ml) induced a 1.8-fold increase in IL-6 production # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (l / lead-03 :ARG0 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "XO") :quant (c / concentration-quantity :quant "5.0" :unit (m2 / milliunit-per-milliliter)) :xref (x1 / xref :value "UNIPROT:XDH_HUMAN" :prob "1.002"))) :ARG2 (i / increase-01 :ARG0 a :ARG1 (s / secrete-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (p2 / product-of :op1 "2") :location (c2 / cell :name (n3 / name :op1 "NHBE")))) :snt2 (a2 / and :op2 (i2 / induce-01 :ARG0 (i3 / incubate-01 :ARG1 (c3 / cell :name (n4 / name :op1 "HS-24")) :ARG2 (e2 / enzyme :name (n5 / name :op1 "XO") :quant (c4 / concentration-quantity :quant "20" :unit (m3 / milliunit-per-milliliter)) :xref (x / xref :value "UNIPROT:XDH_HUMAN" :prob "1.002"))) :ARG2 (i4 / increase-01 :ARG0 i3 :ARG1 (p3 / produce-01 :ARG1 (p4 / protein :name (n6 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (p5 / product-of :op1 "1.8"))))) # ::id bel_pmid_1036_2713.24360 # ::date 2015-04-06T11:37:34 # ::file bel_pmid_1036_2713_24360.txt # ::snt SOD (250 U/ml) significantly suppressed the IL-6 production and IL-6 mRNA expression induced by XO, whereas catalase (500 U/ml) did not modulate the IL-6 response to XO (Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (s / suppress-01 :ARG0 (e / enzyme :name (n / name :op1 "SOD") :quant (c2 / concentration-quantity :quant "250" :unit (u / unit-per-milliliter)) :xref (x3 / xref :value "UNIPROT:BAG4_HUMAN" :prob "0.342")) :ARG1 (a / and :op1 (p / produce-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op2 (e2 / express-03 :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e5 / encode-01 :ARG1 p2))) :ARG2-of (i / induce-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "XO") :xref (x2 / xref :value "UNIPROT:XDH_HUMAN" :prob "1.002")))) :ARG1-of (s2 / significant-02)) :ARG2 (m / modulate-01 :polarity "-" :ARG0 (e4 / enzyme :name (n6 / name :op1 "catalase") :quant (c3 / concentration-quantity :quant "500" :unit u) :xref (x1 / xref :value "UNIPROT:CATA_HUMAN" :prob "0.702")) :ARG1 (r2 / respond-01 :ARG0 p2 :ARG1 e3)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4"))) # ::id bel_pmid_1036_2713.24536 # ::date 2015-04-06T12:03:56 # ::file bel_pmid_1036_2713_24536.txt # ::snt TNF-a significantly increased the production of IL-6 in WI-38-40 cells. However, DMSO was not able to inhibit the TNF-a-induced IL-6 enhancement in both protein and mRNA levels (Fig. 7). These results suggest that ROIs may not be involved in the production of IL-6 in human lung fibroblasts # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "TNF-α") :xref (x4 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :ARG1 (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (s / significant-02) :location (c / cell :name (n3 / name :op1 "WI-38-40"))) :snt2 (h / have-concession-91 :ARG1 (p4 / possible-01 :polarity "-" :ARG1 (i2 / inhibit-01 :ARG0 (s3 / small-molecule :name (n4 / name :op1 "DMSO") :xref (x5 / xref :value "PUBCHEM:679" :prob "16.740406")) :ARG1 (e / enhance-01 :ARG1 (p5 / protein :name (n5 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2-of (i3 / induce-01 :ARG0 (p6 / protein :name (n6 / name :op1 "TNF-α") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642"))) :location (a / and :op1 (l / level :mod (p7 / protein)) :op2 (l2 / level :mod (n10 / nucleic-acid :name (n7 / name :op1 "mRNA"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7"))) :snt3 (s2 / suggest-01 :ARG0 (t / thing :ARG2-of (r2 / result-01) :mod (t2 / this)) :ARG1 (p8 / possible-01 :polarity "-" :ARG1 (i4 / involve-01 :ARG1 (s4 / small-molecule :name (n8 / name :op1 "ROI")) :ARG2 (p9 / produce-01 :ARG1 (p10 / protein :name (n9 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (f2 / fibroblast :part-of (l3 / lung :part-of (h2 / human)))))))) # ::id bel_pmid_1036_2713.24538 # ::date 2015-04-06T12:36:29 # ::file bel_pmid_1036_2713_24538.txt # ::snt TNF-a was dose dependently capable of inducing IL-6 release from NHBE and HS-24 cells (Fig. 5, A and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p / possible-01 :ARG1 (i / induce-01 :ARG0 (p2 / protein :name (n / name :op1 "TNF-α") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :ARG2 (r / release-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (a / and :op1 (c / cell :name (n3 / name :op1 "NHBE")) :op2 (c2 / cell :name (n4 / name :op1 "HS-24"))))) :manner (d / depend-01 :ARG0 p2 :ARG1 (d2 / dose)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "5A") :op2 (f2 / figure :mod "5C")))) # ::id bel_pmid_1036_2713.24690 # ::date 2015-04-06T13:06:00 # ::file bel_pmid_1036_2713_24690.txt # ::snt As shown in Fig. 3A, stimulation with XO resulted in a significant increase in the levels of IL-6 at 12 and 24 h compared with those with 0.7 mM X alone (P , 0.0001). Consistent with these protein data, stimulation of HS-24 cells with XO caused the maximum elevation in IL-6 mRNAlevels at 6 h, whereas XO did not modulate control GAPDH transcript levels (Fig. 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (m / multi-sentence :snt1 (r / result-01 :ARG1 (s / stimulate-01 :ARG2 (e / enzyme :name (n / name :op1 "XO") :xref (x4 / xref :value "UNIPROT:XDH_HUMAN" :prob "1.002")) :ARG1-of (c / compare-01 :ARG2 (s2 / stimulate-01 :ARG2 (e6 / enzyme :name (n2 / name :op1 "XO") :quant (c2 / concentration-quantity :quant "0.7" :unit (m3 / millimolar)) :mod (a / alone) :xref (x3 / xref :value "UNIPROT:XDH_HUMAN" :prob "1.002")) :mod (t / that))) :ARG1-of (s6 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001"))) :ARG2 (i / increase-01 :ARG1 (l2 / level :quant-of (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (s3 / significant-02) :time (a2 / and :op1 (t2 / temporal-quantity :quant "12" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "24" :unit h))) :ARG1-of (s4 / show-01 :ARG0 (f / figure :mod "3A"))) :snt2 (c3 / contrast-01 :ARG1 (c4 / cause-01 :ARG0 (s5 / stimulate-01 :ARG1 (c5 / cell :name (n4 / name :op1 "HS-24")) :ARG2 (e2 / enzyme :name (n5 / name :op1 "XO") :xref (x1 / xref :value "UNIPROT:XDH_HUMAN" :prob "1.002"))) :ARG1 (e3 / elevate-01 :ARG1 (l3 / level :mod (n9 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e5 / encode-01 :ARG1 (p4 / protein :name (n7 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :degree (m4 / maximum) :quant (t4 / temporal-quantity :quant "6" :unit (h2 / hour)))) :ARG2 (m5 / modulate-01 :polarity "-" :ARG0 e2 :ARG1 (l4 / level :quant-of (e4 / enzyme :name (n8 / name :op1 "GAPDH") :ARG1-of (t5 / transcribe-01) :ARG0-of (c6 / control-01) :xref (x / xref :value "UNIPROT:G3P_HUMAN" :prob "1.002")))) :ARG1-of (c7 / consistent-01 :ARG2 (d / data :mod (p3 / protein) :mod (t6 / this))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3B")))) # ::id bel_pmid_1036_2713.39152 # ::date 2015-04-06T15:20:44 # ::file bel_pmid_1036_2713_39152.txt # ::snt TNF-a significantly increased the production of IL-6 in WI-38-40 cells. However, DMSO was not able to inhibit the TNF-a-induced IL-6 enhancement in both protein and mRNA levels (Fig. 7). These results suggest that ROIs may not be involved in the production of IL-6 in human lung fibroblasts # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "TNF-α") :xref (x4 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :ARG1 (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (s / significant-02) :location (c / cell :name (n3 / name :op1 "WI-38-40"))) :snt2 (h / have-concession-91 :ARG1 (p4 / possible-01 :polarity "-" :ARG1 (i2 / inhibit-01 :ARG0 (s3 / small-molecule :name (n4 / name :op1 "DMSO") :xref (x5 / xref :value "PUBCHEM:679" :prob "16.740406")) :ARG1 (e / enhance-01 :ARG1 (p5 / protein :name (n5 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2-of (i3 / induce-01 :ARG0 (p6 / protein :name (n6 / name :op1 "TNF-α") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642"))) :location (a / and :op1 (l / level :quant-of (p7 / protein)) :op2 (l2 / level :quant-of (n10 / nucleic-acid :name (n7 / name :op1 "mRNA"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7"))) :snt3 (s2 / suggest-01 :ARG0 (t / thing :ARG2-of (r2 / result-01) :mod (t2 / this)) :ARG1 (p8 / possible-01 :polarity "-" :ARG1 (i4 / involve-01 :ARG1 (s4 / small-molecule :name (n8 / name :op1 "ROI")) :ARG2 (p9 / produce-01 :ARG1 (p10 / protein :name (n9 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (f2 / fibroblast :part-of (l3 / lung :part-of (h2 / human)))))))) # ::id bel_pmid_1036_2713.39154 # ::date 2015-04-06T15:34:35 # ::file bel_pmid_1036_2713_39154.txt # ::snt TNF-a was dose dependently capable of inducing IL-6 release from NHBE and HS-24 cells (Fig. 5, A and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p / possible-01 :ARG1 (i / induce-01 :ARG0 (p2 / protein :name (n / name :op1 "TNF-α") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :ARG2 (r / release-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (a / and :op1 (c / cell :name (n3 / name :op1 "NHBE")) :op2 (c2 / cell :name (n4 / name :op1 "HS-24"))))) :manner (d / depend-01 :ARG0 p2 :ARG1 (d2 / dose)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "5A") :op2 (f2 / figure :mod "5C")))) # ::id bel_pmid_1037_5612.23694 # ::date 2015-04-06T15:41:28 # ::file bel_pmid_1037_5612_23694.txt # ::snt Northern blot analysis documented that two transcription factor genes chosen for further study, c-myc promoter-binding protein (MBP-1) and X-box binding protein 1 (XBP-1), were up-regulated in U266 cells about 3-fold relative to the cell cycle-dependent beta-actin gene 12 h after IL-6 treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (d / document-01 :ARG0 (a / analyze-01 :instrument (t / thing :name (n / name :op1 "northern" :op2 "blot"))) :ARG1 (u / upregulate-01 :ARG1 (g / gene :quant "2" :name (n2 / name :op1 "transcription" :op2 "factor") :ARG1-of (c / choose-01 :ARG4 (s / study-01 :degree (f / further))) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (p / protein :ARG0-of (b / bind-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of (p8 / promote-01 :ARG1 (p2 / protein :name (n3 / name :op1 "c-myc") :xref (x / xref :value "UNIPROT:Q16158_HUMAN" :prob "1.001"))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / protein :name (n4 / name :op1 "MBP-1") :xref (x3 / xref :value "UNIPROT:ENOA_HUMAN" :prob "1.002")))) :op2 (p9 / protein :name (n11 / name :op1 "X-box" :op2 "binding" :op3 "protein" :op4 "1") :ARG1-of (d3 / describe-01 :ARG0 (p5 / protein :name (n7 / name :op1 "XBP-1") :xref (x1 / xref :value "UNIPROT:XBP1_HUMAN" :prob "1.002"))) :xref (x6 / xref :value "UNIPROT:XBP1_HUMAN" :prob "0.692")))) :xref (x5 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.393")) :location (c2 / cell :name (n8 / name :op1 "U266")) :degree (p6 / product-of :op1 "3" :mod (a3 / about)) :time (a4 / after :op1 (t2 / treat-04 :ARG2 (p7 / protein :name (n9 / name :op1 "IL-6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :quant (t3 / temporal-quantity :quant "12" :unit (h / hour))) :ARG2-of (r / relative-05 :ARG3 (g2 / gene :name (n10 / name :op1 "beta-actin") :ARG0-of (d4 / depend-01 :ARG1 (c3 / cycle-02 :ARG1 (c4 / cell))) :xref (x2 / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702"))))) # ::id bel_pmid_1040_9724.52 # ::date 2015-04-07T03:14:02 # ::file bel_pmid_1040_9724_52.txt # ::snt Signaling by the IL-6 receptor is mediated through the signal transducing subunit gp130 and involves the activation of Janus-associated kinases (JAKs), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein (MAP) kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / and :op1 (m / mediate-01 :ARG1 (s / signal-07 :ARG0 (r / receptor :name (n / name :op1 "IL-6"))) :medium (p / protein :name (n2 / name :op1 "gp130") :mod (s2 / subunit :ARG2-of (t / transduce-01 :ARG1 (s3 / signal-07))) :xref (x6 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))) :op2 (i / involve-01 :ARG1 (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "Janus-associated" :op2 "kinase") :ARG1-of (d / describe-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "JAK") :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))) :xref (x5 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.253")) :op2 (p2 / protein :name (n5 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription-3") :ARG1-of (d2 / describe-01 :ARG0 (p3 / protein :name (n6 / name :op1 "STAT3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.693")) :op3 (e3 / enzyme :name (n7 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase") :ARG1-of (d3 / describe-01 :ARG0 (e4 / enzyme :name (n8 / name :op1 "MAP") :xref (x / xref :value "UNIPROT:MOTI_HUMAN" :prob "1.002"))) :xref (x1 / xref :value "UNIPROT:A0A024QZ12_HUMAN" :prob "0.701")))) :ARG2 s)) # ::id bel_pmid_1040_9724.18580 # ::date 2015-04-07T04:04:47 # ::file bel_pmid_1040_9724_18580.txt # ::snt Signaling by the IL-6 receptor is mediated through the signal transducing subunit gp130 and involves the activation of Janus-associated kinases (JAKs), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein (MAP) kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / and :op1 (m / mediate-01 :ARG1 (s / signal-07 :ARG0 (r / receptor :name (n / name :op1 "IL-6"))) :medium (p / protein :name (n2 / name :op1 "gp130") :mod (s2 / subunit :ARG2-of (t / transduce-01 :ARG1 (s3 / signal-07))) :xref (x6 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))) :op2 (i / involve-01 :ARG1 (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "Janus-associated" :op2 "kinase") :ARG1-of (d / describe-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "JAK") :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))) :xref (x5 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.253")) :op2 (p2 / protein :name (n5 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription-3") :ARG1-of (d2 / describe-01 :ARG0 (p3 / protein :name (n6 / name :op1 "STAT3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.693")) :op3 (e3 / enzyme :name (n7 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase") :ARG1-of (d3 / describe-01 :ARG0 (e4 / enzyme :name (n8 / name :op1 "MAP") :xref (x / xref :value "UNIPROT:MOTI_HUMAN" :prob "1.002"))) :xref (x1 / xref :value "UNIPROT:A0A024QZ12_HUMAN" :prob "0.701")))) :ARG2 s)) # ::id bel_pmid_1040_9724.23704 # ::date 2015-04-07T04:16:59 # ::file bel_pmid_1040_9724_23704.txt # ::snt This study shows that in hepatoma cells, the recruitment and tyrosine phosphorylation of SHP-2, but not SHC, is the primary signaling event associated with the activation of MAP kinases (ERK1/2) by gp130. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (s2 / study-01 :mod (t / this)) :ARG1 (e / event :ARG0-of (s3 / signal-07) :mod (p / primary) :domain (a / and :op1 (r / recruit-01 :ARG1 (p2 / protein :name (n / name :op1 "SHP-2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003"))) :op2 (p3 / phosphorylate-01 :ARG1 p2 :ARG2 (t2 / tyrosine)) :ARG1-of (c / contrast-01 :ARG2 (a2 / and :op1 (r2 / recruit-01 :polarity "-" :ARG1 (p4 / protein :name (n2 / name :op1 "SHC") :xref (x2 / xref :value "UNIPROT:SHC1_HUMAN" :prob "1.003"))) :op2 (p5 / phosphorylate-01 :polarity "-" :ARG1 p4 :ARG2 t2)))) :ARG1-of (a3 / associate-01 :ARG2 (a4 / activate-01 :ARG0 (p6 / protein :name (n3 / name :op1 "gp130") :xref (x1 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")) :ARG1 (p7 / protein-family :name (n4 / name :op1 "MAP" :op2 "kinase"))) :location (c2 / cell :mod (m / medical-condition :name (n6 / name :op1 "hepatoma")))))) # ::id bel_pmid_1043_6166.3510 # ::date 2015-04-03T06:52:44 # ::file bel_pmid_1043_6166_3510.txt # ::snt NO modulation of the signaling pathway was shown by its inhibitory effect on shear stress-induced ERK1/ERK2 phosphorylation and activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (s / show-01 :ARG0 (a3 / affect-01 :ARG0 "m2" :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (s3 / slash :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG2-of (i2 / induce-01 :ARG0 (s4 / stress-02 :mod (s5 / shear-01))))) :op2 (a2 / activity-06 :ARG0 s3)) :ARG2 (i / inhibit-01 :ARG1 p)) :ARG1 (m2 / modulate-01 :ARG0 (n / name :op1 "NO") :ARG1 (p2 / pathway :ARG0-of (s2 / signal-07)))) # ::id bel_pmid_1043_6166.18636 # ::date 2015-04-03T14:02:25 # ::file bel_pmid_1043_6166_18636.txt # ::snt Treatment of ECs with an NO donor, S-nitroso-N-acetylpenicillamine (SNAP) or 3-morpholinosydnonimine (SIN-1), inhibited this shear stress-induced Egr-1 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i3 / inhibit-01 :ARG0 (t / treat-04 :ARG1 (c / cell :name (n / name :op1 "EC")) :ARG2 (s3 / small-molecule :name (n8 / name :op1 "nitric" :op2 "oxide") :ARG0-of (d / donate-01) :example (o / or :op1 (s4 / small-molecule :name (n3 / name :op1 "S-nitroso-N-acetylpenicillamine") :ARG1-of (m / mean-01 :ARG2 (n4 / name :op1 "SNAP")) :xref (x3 / xref :value "PUBCHEM:5231" :prob "19.143221")) :op2 (s5 / small-molecule :name (n5 / name :op1 "3-morpholinosydnonimine") :ARG1-of (m2 / mean-01 :ARG2 (n6 / name :op1 "SIN-1")) :xref (x2 / xref :value "PUBCHEM:9859122" :prob "12.458405"))) :xref (x1 / xref :value "PUBCHEM:145068" :prob "9.213943"))) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n7 / name :op1 "Egr-1") :ARG2-of (i2 / induce-01 :ARG0 (s / stress-02 :mod (s2 / shear-01))) :xref (x / xref :value "UNIPROT:A0A089VKS7_HUMAN" :prob "1.001")) :mod (t2 / this))) # ::id bel_pmid_1044_6041.18010 # ::date 2015-04-05T09:32:37 # ::file bel_pmid_1044_6041_18010.txt # ::snt The FAK and Fyn/Shc pathways. Integrins activate various protein tyrosine kinases, including focal adhesion kinase (FAK), Srcfamily kinases, and Abl, and a serine-threonine kinase, integrin-linked kinase (ILK) (4, 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (m / multi-sentence :snt1 (a / and :op1 (p / pathway :name (n / name :op1 "FAK")) :op2 (p2 / pathway :name (n2 / name :op1 "Fyn/Shc"))) :snt2 (a2 / activate-01 :ARG0 (p7 / protein :name (n3 / name :op1 "integrin") :xref (x4 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")) :ARG1 (a3 / and :op1 (e3 / enzyme :name (n10 / name :op1 "protein" :op2 "tyrosine" :op3 "kinase") :ARG2-of (i2 / include-91 :ARG1 (a4 / and :op1 (e2 / enzyme :name (n4 / name :op1 "focal" :op2 "adhesion" :op3 "kinase") :ARG1-of (m2 / mean-01 :ARG2 (n5 / name :op1 "FAK")) :xref (x2 / xref :value "UNIPROT:FAK1_HUMAN" :prob "0.393")) :op2 (p3 / protein-family :name (n9 / name :op1 "Src")) :op3 (p4 / protein :name (n6 / name :op1 "Abl") :xref (x5 / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603")))) :mod (v2 / various) :xref (x1 / xref :value "UNIPROT:LTK_HUMAN" :prob "0.392")) :op2 (e / enzyme :name (n7 / name :op1 "serine-threonine" :op2 "kinase") :ARG1-of (m5 / mean-01 :ARG2 (e4 / enzyme :name (n8 / name :op1 "integrin-linked" :op2 "kinase") :xref (x / xref :value "UNIPROT:ILK_HUMAN" :prob "0.373"))) :xref (x3 / xref :value "UNIPROT:ERN1_HUMAN" :prob "0.353"))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a5 / and :op1 "4" :op2 "7")))))) # ::id bel_pmid_1044_6041.18016 # ::date 2015-04-05T10:20:04 # ::file bel_pmid_1044_6041_18016.txt # ::snt (38). Integrins also stimulate the p70 S6- kinase, which may promote cyclin D1 translation (39). Finally, anchorage to the ECM is necessary for the down-regulation of the Cdk 2 inhibitors p21 and p27 and, thus, the activation of cyclin E-Cdk 2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "38"))) :snt2 (s / stimulate-01 :ARG0 (p8 / protein :name (n10 / name :op1 "integrin") :xref (x6 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")) :ARG2 (e / enzyme :name (n2 / name :op1 "p70" :op2 "S6" :op3 "kinase") :xref (x3 / xref :value "UNIPROT:KS6B2_HUMAN" :prob "0.362")) :mod (a / also) :ARG0-of (p2 / promote-01 :ARG1 (t2 / translate-01 :ARG2 (p4 / protein :name (n3 / name :op1 "cyclin" :op2 "D1") :xref (x5 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001"))) :ARG1-of (p3 / possible-01)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "39")))) :snt3 (n / need-01 :li "-1" :ARG0 (d4 / downregulate-01 :ARG1 (a3 / and :op1 (p6 / protein :name (n6 / name :op1 "p21") :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "Cdk" :op2 "2") :xref (x2 / xref :value "UNIPROT:CDK2_HUMAN" :prob "0.592"))) :xref (x / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")) :op2 (p7 / protein :name (n8 / name :op1 "p27") :ARG0-of (i3 / inhibit-01 :ARG1 e2) :xref (x4 / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003")))) :ARG1 (a2 / anchor-01 :ARG1 (m2 / matrix :mod (e4 / extracellular))) :ARG0-of (c3 / cause-01 :ARG1 (a4 / activate-01 :ARG1 (e3 / enzyme :name (n9 / name :op1 "cyclin" :op2 "E-Cdk" :op3 "2") :xref (x1 / xref :value "UNIPROT:CCNC_HUMAN" :prob "0.262")))))) # ::id bel_pmid_1044_6041.18018 # ::date 2015-04-05T11:10:55 # ::file bel_pmid_1044_6041_18018.txt # ::snt PTP-PEST has a COOH-terminal extension that anchors it to the cytosolic aspect of the endoplasmic reticulum. Integrin-mediated adhesion activates calpain, a protease that cleaves this extension and allows the phosphatase to relocate to focal adhesions (21). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (m / multi-sentence :snt1 (h / have-03 :ARG0 (e4 / enzyme :name (n / name :op1 "PTP-PEST") :xref (x / xref :value "UNIPROT:PTN12_HUMAN" :prob "1.002")) :ARG1 (e / extend-01 :mod (p2 / protein-segment :name (n2 / name :op1 "COOH-terminus")) :ARG0-of (a / anchor-01 :ARG1 e4 :location (a2 / aspect :mod (c / cytosol :xref (x3 / xref :value "GO:0005829" :prob "0.8")) :part-of (r / reticulum :mod (e2 / endoplasm) :xref (x4 / xref :value "GO:0005783" :prob "0.8")))))) :snt2 (a3 / activate-01 :ARG0 (a4 / adhere-01 :ARG1-of (m2 / mediate-01 :ARG0 (p3 / protein :name (n5 / name :op1 "integrin") :xref (x2 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")))) :ARG1 (p / protease :name (n6 / name :op1 "calpain") :ARG0-of (c2 / cleave-01 :ARG1 (e5 / extend-01 :mod (t / this))) :ARG0-of (a5 / allow-01 :ARG1 (r2 / relocate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "phosphatase") :xref (x1 / xref :value "UNIPROT:Q59GM9_HUMAN" :prob "0.291")) :ARG2 (a6 / adhere-01 :mod (f / focal))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "21"))))) # ::id bel_pmid_1044_6041.18060 # ::date 2015-04-05T12:28:37 # ::file bel_pmid_1044_6041_18060.txt # ::snt Whereas FAK is phosphorylated on tyrosine upon assembly of focal adhesions, it becomes phosphorylated on serine and disassociates from Src and p130CAS during mitosis (14). These events may loosen cell-substrate contacts and allow cells to divide and move apart. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n2 / name :op1 "FAK") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :time (a3 / assemble-02 :ARG1 (a4 / adhere-01 :mod (f / focal)))) :ARG2 (a6 / and :op1 (b / become-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "serine") :part-of e2 :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :op2 (d2 / disassociate-01 :ARG1 e2 :ARG2 (a5 / and :op1 (p4 / protein :name (n4 / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :op2 (p5 / protein :name (n5 / name :op1 "p130CAS") :xref (x2 / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.633"))) :time (m2 / mitosis))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "14")))) :snt2 (a7 / and :op1 (p7 / possible-01 :ARG1 (l / loosen-01 :ARG0 (e / event :mod (t / this)) :ARG1 (c3 / contact-01 :ARG0 (c4 / cell) :ARG1 (s / substrate)))) :op2 (a8 / allow-01 :ARG0 e :ARG1 (a9 / and :op1 (d4 / divide-02 :ARG0 (c5 / cell) :ARG1 c5) :op2 (m3 / move-01 :ARG1 c5 :mod (a10 / apart)))))) # ::id bel_pmid_1044_6041.18334 # ::date 2015-04-05T14:31:28 # ::file bel_pmid_1044_6041_18334.txt # ::snt Certain integrins may regulate proliferation by additional mechanisms. For example, the a6b1 integrin may in part promote exit from the cell cycle in myoblasts, because the cytoplasmic domain of a6 inhibits paxillin signaling (44). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt2 (c2 / cause-01 :ARG0 (i3 / inhibit-01 :ARG0 (d2 / domain :mod (c5 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :part-of "p6") :ARG1 (s / signal-07 :ARG0 (p5 / protein :name (n3 / name :op1 "paxillin") :xref (x / xref :value "UNIPROT:PAXI_HUMAN" :prob "0.703")))) :ARG1 (p / possible-01 :ARG1 (p3 / promote-01 :ARG0 (p6 / protein :name (n2 / name :op1 "a6b1" :op2 "integrin")) :ARG1 (e2 / exit-01 :ARG1 (c3 / cycle-02 :ARG1 (c4 / cell) :location (m3 / myoblast))) :degree (p4 / part))) :ARG0-of (e / exemplify-01) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c6 / cite-01 :ARG2 "44")))) :snt1 (p8 / possible-01 :ARG1 (r / regulate-01 :ARG0 (p9 / protein :name (n / name :op1 "integrin") :mod (c / certain) :xref (x1 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")) :ARG1 (p2 / proliferate-01) :instrument (m2 / mechanism :mod (a / additional))))) # ::id bel_pmid_1044_6041.18348 # ::date 2015-04-05T14:32:02 # ::file bel_pmid_1044_6041_18348.txt # ::snt For example, avb3 associates with the PDGF receptor, and fibroblasts show greater proliferation in response to PDGFb when adhering to the avb3 ligand vitronectin than when they adhere to the b1 integrin ligand collagen (26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (a2 / associate-01 :ARG1 (p4 / protein :name (n9 / name :op1 "avb3")) :ARG2 (p8 / protein :name (n5 / name :op1 "PDGF" :op2 "receptor") :xref (x3 / xref :value "UNIPROT:PDGFC_HUMAN" :prob "0.273"))) :op2 (s / show-01 :ARG0 (c / cell :name (n2 / name :op1 "fibroblast")) :ARG1 (p / proliferate-01 :mod (g2 / great :degree (m / more))) :ARG2-of (r2 / respond-01 :ARG1 (p2 / protein :name (n3 / name :op1 "PDGFb") :xref (x1 / xref :value "UNIPROT:PDGFB_HUMAN" :prob "0.664"))) :time (a4 / adhere-01 :ARG1 p2 :ARG2 (p7 / protein :name (n6 / name :op1 "vitronectin") :ARG1-of (b2 / bind-01 :ARG2 p4) :xref (x / xref :value "UNIPROT:VTNC_HUMAN" :prob "0.703")) :compared-to (a5 / adhere-01 :ARG1 p2 :ARG2 (p5 / protein :name (n4 / name :op1 "collagen") :ARG1-of (b / bind-01 :ARG2 (p3 / protein :name (n8 / name :op1 "b1" :op2 "integrin"))) :xref (x2 / xref :value "UNIPROT:COLLAGEN_I_HUMAN" :prob "1.002"))))) :ARG0-of (e / exemplify-01) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "26")))) # ::id bel_pmid_1044_6041.18586 # ::date 2015-04-05T14:32:31 # ::file bel_pmid_1044_6041_18586.txt # ::snt In addition to activating FAK, some b1 and av integrins also activate the tyrosine kinase Fyn and, through it, the adapter protein Shc (4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "FAK") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003"))) :op2 (a3 / and :op1 (a4 / activate-01 :ARG0 (p4 / protein :name (n6 / name :op1 "b1" :op2 "integrin") :quant (s / some)) :ARG1 (e / enzyme :name (n3 / name :op1 "tyrosine" :op2 "kinase" :op3 "Fyn") :xref (x2 / xref :value "UNIPROT:FER_HUMAN" :prob "0.372")) :mod (a5 / also)) :op2 (a6 / activate-01 :ARG0 (p5 / protein :name (n2 / name :op1 "b1" :op2 "integrin") :quant s) :ARG1 e :mod a5) :ARG0-of (a7 / activate-01 :ARG1 (p2 / protein :name (n5 / name :op1 "Shc") :mod (a8 / adapter) :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "4")))) # ::id bel_pmid_1044_6041.20870 # ::date 2015-04-05T14:32:53 # ::file bel_pmid_1044_6041_20870.txt # ::snt Rac promotes cell cycle progression, an effect that correlates with its ability to organize the cytoskeleton and promote spreading, rather than with its ability to activate MAP kinases (63). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / promote-01 :ARG0 (e / enzyme :name (n / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1 (p2 / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell))) :ARG2-of (a / affect-01 :ARG1-of (c3 / correlate-01 :ARG2 (c6 / capable-01 :ARG1 e :ARG2 (a4 / and :op1 (o / organize-01 :ARG0 e :ARG1 (c4 / cytoskeleton :xref (x1 / xref :value "GO:0005856" :prob "0.8"))) :op2 (p3 / promote-01 :ARG1 (s / spread-02))) :ARG1-of (i / instead-of-91 :ARG2 (c7 / capable-01 :ARG1 e :ARG2 (a3 / activate-01 :ARG0 e :ARG1 (p4 / protein-family :name (n2 / name :op1 "MAP" :op2 "kinase")))))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c5 / cite-01 :ARG2 "63")))) # ::id bel_pmid_1044_6041.21282 # ::date 2015-04-05T14:33:17 # ::file bel_pmid_1044_6041_21282.txt # ::snt Yes and Lck are known to be enriched in rafts and may mediate the activation of Shc when Fyn is not expressed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Apr 11, 2015 (a2 / and :op1 (k / know-01 :ARG1 (e3 / enrich-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Yes") :xref (x1 / xref :value "UNIPROT:YES_HUMAN" :prob "0.604")) :op2 (e2 / enzyme :name (n2 / name :op1 "Lck") :xref (x3 / xref :value "UNIPROT:LCK_HUMAN" :prob "0.604"))) :ARG2 (r / raft))) :op2 (p / possible-01 :ARG1 (m / mediate-01 :ARG0 a :ARG1 (a3 / activate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :time (e4 / express-03 :polarity "-" :ARG2 (e5 / enzyme :name (n4 / name :op1 "Fyn") :xref (x2 / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604")))))) # ::id bel_pmid_1044_6041.21342 # ::date 2015-04-05T14:33:38 # ::file bel_pmid_1044_6041_21342.txt # ::snt Integrin signaling may be needed for the transcription of cyclin D1, because the cyclin D1 promoter is coordinately regulated by JNK and ERK (37) (Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / cause-01 :ARG0 (r / regulate-01 :ARG0 (a / and :op1 (e2 / enzyme :name (n4 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1 (p2 / promote-01 :ARG1 "p") :manner (c2 / coordinate-01)) :ARG1 (p4 / possible-01 :ARG1 (n2 / need-01 :ARG0 (t / transcribe-01 :ARG1 (p / protein :name (n3 / name :op1 "cyclin" :op2 "D1") :xref (x3 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001"))) :ARG1 (s / signal-07 :ARG0 (p5 / protein :name (n / name :op1 "integrin") :xref (x2 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311"))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "37"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4"))) # ::id bel_pmid_1044_6041.21364 # ::date 2015-04-06T09:25:09 # ::file bel_pmid_1044_6041_21364.txt # ::snt Activated JNK enters the nucleus and phosphorylates the transcription factor c-Jun, which combines with c-Fos to form the AP-1 transcription factor complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / and :op1 (e / enter-01 :ARG0 (e2 / enzyme :name (n / name :op1 "JNK") :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG1 (n2 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8"))) :op2 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "c-Jun") :ARG0-of (t / transcribe-01) :mod (f / factor) :ARG1-of (c / combine-01 :ARG2 (p3 / protein :name (n4 / name :op1 "c-Fos")) :ARG3 (c2 / complex :mod (f2 / factor) :mod (p4 / protein :name (n5 / name :op1 "AP-1") :ARG0-of (t2 / transcribe-01) :xref (x / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))))) :ARG2 e2)) # ::id bel_pmid_1044_6041.22694 # ::date 2015-04-06T09:36:21 # ::file bel_pmid_1044_6041_22694.txt # ::snt Several integrins have been found to associate laterally with the oligomeric membrane protein caveolin-1, at least in primary cells (4, 5). Although the biochemical nature of this interaction is not known, inhibiting caveolin expression suppresses the formation of focal adhesions and integrin signaling (4, 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (m / multi-sentence :snt1 (f / find-01 :ARG1 (a2 / associate-01 :ARG1 (p6 / protein :name (n3 / name :op1 "integrin") :quant (s4 / several) :xref (x1 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")) :ARG2 (p / protein :name (n / name :op1 "caveolin-1") :mod (m2 / membrane :mod (o / oligomer) :xref (x4 / xref :value "GO:0016020" :prob "0.8")) :xref (x3 / xref :value "UNIPROT:CAV1_HUMAN" :prob "0.702")) :manner (l / lateral) :location (c / cell :mod (p2 / primary) :mod (a / at-least))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "4" :op2 "5"))))) :snt2 (h / have-concession-91 :ARG1 (i3 / inhibit-01 :ARG1 (e / express-03 :ARG2 (p5 / protein :name (n4 / name :op1 "caveolin") :xref (x2 / xref :value "UNIPROT:A0A024R2D8_HUMAN" :prob "0.701"))) :ARG0-of (s2 / suppress-01 :ARG1 (f2 / form-01 :ARG1 (a4 / and :op1 (a5 / adhere-01 :mod (f3 / focal)) :op2 (s3 / signal-07 :ARG0 (p7 / protein :name (n6 / name :op1 "integrin") :xref (x / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311"))))))) :ARG2 (k / know-01 :polarity "-" :ARG1 (n2 / nature :mod (b / biochemistry) :poss (i2 / interact-01 :mod (t / this)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 "4" :op2 "5")))))) # ::id bel_pmid_1044_6041.24492 # ::date 2015-04-06T09:55:30 # ::file bel_pmid_1044_6041_24492.txt # ::snt IAP, an immunoglobulin superfamily transmembrane protein, cooperates with b3 integrins in binding thrombospondin to cells, and it also activates an inhibitory trimeric guanine nucleotide- binding protein (29). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (c / cooperate-01 :ARG0 (p / protein :name (n / name :op1 "IAP") :ARG1-of (i4 / include-91 :ARG2 (p2 / protein-family :name (n6 / name :op1 "immunoglobulin"))) :mod (t / transmembrane) :xref (x2 / xref :value "UNIPROT:CD47_HUMAN" :prob "1.002")) :ARG1 (p7 / protein :name (n5 / name :op1 "b3" :op2 "integrin")) :ARG2 (b / bind-01 :ARG1 (p3 / protein :name (n2 / name :op1 "thrombospondin") :xref (x / xref :value "UNIPROT:TSP1_HUMAN" :prob "0.392")) :ARG2 (c2 / cell))) :op2 (a2 / activate-01 :ARG0 p :ARG1 (p4 / protein :name (n4 / name :op1 "guanine" :op2 "nucleotide-binding") :mod (t2 / trimeric) :ARG0-of (i3 / inhibit-01) :xref (x1 / xref :value "UNIPROT:GBP1_HUMAN" :prob "0.372")) :mod (a3 / also)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "29")))) # ::id bel_pmid_1044_6041.24730 # ::date 2015-04-06T09:58:56 # ::file bel_pmid_1044_6041_24730.txt # ::snt The FAK and Shc pathways are regulated both positively and negatively by tyrosine phosphatases. Integrin-mediated activation of ERK is suppressed in cells that lack the re- ceptor-type protein tyrosine phosphatase a or the cytosolic phosphatase SHP-2 (19). These enzymes dephosphorylate the negative regulatory site in Src-family kinases and thus, presumably, amplify both FAK and Shc signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt2 (s / suppress-01 :ARG1 (a3 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (m2 / mediate-01 :ARG0 (p8 / protein :name (n5 / name :op1 "integrin") :xref (x2 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")))) :location (c / cell :ARG0-of (l / lack-01 :ARG1 (o / or :op1 (e5 / enzyme :name (n8 / name :op1 "protein" :op2 "tyrosine" :op3 "phosphatase" :op4 "a") :ARG1-of (t / type-03 :ARG2 (r2 / receptor))) :op2 (p9 / phosphatase :name (n7 / name :op1 "SHP-2") :mod (c2 / cytosol :xref (x3 / xref :value "GO:0005829" :prob "0.8")))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "19")))) :snt3 (d2 / dephosphorylate-01 :ARG1 (s2 / site :ARG1-of (d3 / downregulate-01)) :ARG2 (e3 / enzyme :mod (t2 / this)) :ARG3 (k / kinase :ARG1-of (i / include-91 :ARG2 (p3 / protein-family :name (n6 / name :op1 "Src")))) :ARG0-of (c4 / cause-01 :ARG1 (a4 / amplify-01 :ARG1 (a2 / and :op1 (s3 / signal-07 :ARG0 (p6 / pathway :name (n9 / name :op1 "FAK"))) :op2 (s4 / signal-07 :ARG0 (p7 / pathway :name (n10 / name :op1 "Shc"))))) :ARG1-of (p5 / presume-01))) :snt1 (a6 / and :op1 (u / upregulate-01 :ARG1 (a / and :op1 (p / pathway :name (n2 / name :op1 "FAK")) :op2 (p2 / pathway :name (n3 / name :op1 "Shc"))) :ARG2 (e2 / enzyme :name (n4 / name :op1 "tyrosine" :op2 "phosphatase") :xref (x / xref :value "UNIPROT:UBS3B_HUMAN" :prob "0.302"))) :op2 (d4 / downregulate-01 :ARG1 a :ARG2 e2))) # ::id bel_pmid_1044_6041.39480 # ::date 2015-04-06T12:33:09 # ::file bel_pmid_1044_6041_39480.txt # ::snt Two cytoplasmic protein tyrosine phosphatases, PTP-PEST and PTP-1B, target p130CAS and may specifically inhibit some of the signals downstream of FAK (20). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (t / target-01 :ARG0 (e / enzyme :quant "2" :name (n / name :op1 "protein" :op2 "tyrosine" :op3 "phosphatase") :mod (c / cytoplasm :xref (x4 / xref :value "GO:0005737" :prob "0.8")) :example (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "PTP-PEST") :xref (x1 / xref :value "UNIPROT:PTN12_HUMAN" :prob "1.002")) :op2 (e3 / enzyme :name (n3 / name :op1 "PTP-1B") :xref (x / xref :value "UNIPROT:PTN1_HUMAN" :prob "1.003"))) :xref (x2 / xref :value "UNIPROT:A0A024R963_HUMAN" :prob "0.691")) :ARG1 (p / protein :name (n4 / name :op1 "p130CAS") :xref (x3 / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.633"))) :op2 (p2 / possible-01 :ARG1 (i / inhibit-01 :ARG1 (s / signal-07 :ARG2-of (i2 / include-91 :ARG3 (s2 / some)) :location (r / relative-position :op1 (p3 / pathway :name (n5 / name :op1 "FAK")) :direction (d2 / downstream))) :ARG1-of (s3 / specific-02))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "20")))) # ::id bel_pmid_1044_6219.2808 # ::date 2015-04-06T12:56:39 # ::file bel_pmid_1044_6219_2808.txt # ::snt Stat3 is activated by phosphorylation on Tyr-705, which leads to dimer formation, nuclear translocation, and regulation of gene expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (a / activate-01 :ARG0 (p3 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "705" :name (n2 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1 (p2 / protein :name (n / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG0-of (l / lead-03 :ARG2 (a3 / and :op1 (f / form-01 :ARG1 (m / macro-molecular-complex :name (n3 / name :op1 "dimer"))) :op2 (t / translocate-01 :ARG2 (n4 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8"))) :op3 (r / regulate-01 :ARG1 (e / express-03 :ARG2 (g / gene)))))) # ::id bel_pmid_1044_6219.5996 # ::date 2015-04-06T13:15:53 # ::file bel_pmid_1044_6219_5996.txt # ::snt Here, we report that Stat3 was specifically associated with PKC delta in vivo in an IL-6-dependent manner in several cell types. Furthermore, Stat3 was phosphorylated by PKC delta in vivo on Ser-727, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (r / report-01 :ARG0 (w / we) :ARG1 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "Stat3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKC" :op2 "delta") :xref (x2 / xref :value "UNIPROT:KPCB_HUMAN" :prob "0.253")) :ARG1-of (s / specific-02) :manner (i / in-vivo) :location (t / type-03 :ARG1 (c / cell) :quant (s2 / several)) :manner (d / depend-01 :ARG1 (p4 / protein :name (n6 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :location (h / here)) :snt2 (a3 / and :op2 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "727" :name (n5 / name :op1 "serine") :part-of (p3 / protein :name (n3 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e2 / enzyme :name (n4 / name :op1 "PKA" :op2 "delta") :manner (i2 / in-vivo) :xref (x / xref :value "UNIPROT:KAPCB_HUMAN" :prob "0.263"))))) # ::id bel_pmid_1044_6219.5998 # ::date 2015-04-06T13:58:27 # ::file bel_pmid_1044_6219_5998.txt # ::snt Finally, we showed that the phosphorylation of Stat3 by PKC delta led to a negative regulation of Stat3 DNA binding and transcriptional activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (s / show-01 :li "-1" :ARG0 (w / we) :ARG1 (l / lead-03 :ARG0 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKC" :op2 "delta") :xref (x1 / xref :value "UNIPROT:KPCB_HUMAN" :prob "0.253"))) :ARG2 (a / and :op1 (d / downregulate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "Stat3") :ARG0-of (b / bind-01 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :op2 (a2 / activity-06 :ARG0 p3 :ARG1 (t / transcribe-01))))) # ::id bel_pmid_1044_6219.7272 # ::date 2015-04-06T14:12:34 # ::file bel_pmid_1044_6219_7272.txt # ::snt Here, we report that Stat3 was specifically associated with PKC delta in vivo in an IL-6-dependent manner in several cell types. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / report-01 :ARG0 (w / we) :ARG1 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "Stat3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKC" :op2 "delta") :xref (x1 / xref :value "UNIPROT:KPCB_HUMAN" :prob "0.253")) :manner (i / in-vivo) :ARG1-of (s / specific-02) :location (t / type-03 :ARG1 (c / cell :quant (s2 / several))) :manner (d / depend-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :location (h / here)) # ::id bio.chicago_2015.55 # ::date 2015-10-20T04:45:05 # ::file bio_chicago_2015_55.txt # ::snt Binding of armadillo to dTCF has been shown to reduce the ability of CBP to catalyze this reaction, perhaps by steric interference [ 97]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG1 (r / reduce-01 :ARG0 (b / bind-01 :ARG1 (p3 / protein :name (n3 / name :op1 "armadillo") :xref (x / xref :value "UNIPROT:ARM10_HUMAN" :prob "0.202")) :ARG2 (p5 / protein :name (n / name :op1 "dTCF"))) :ARG1 (c / capable-01 :ARG1 (p4 / protein :name (n2 / name :op1 "CBP") :xref (x1 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :ARG2 (c2 / catalyze-01 :ARG0 p4 :ARG1 (t / thing :ARG2-of (r2 / react-01) :mod (t2 / this)) :instrument (i / interfere-01 :mod (s4 / steric) :ARG1-of (p / possible-01))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "97")))) # ::id bio.chicago_2015.119 # ::date 2015-10-20T04:50:31 # ::file bio_chicago_2015_119.txt # ::snt In particular, the dCtBP corepressor may interact with Ttk69 to form a repressive complex for transcriptional repression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (c / corepressor :name (n / name :op1 "dCtBP")) :ARG1 (p4 / protein :name (n2 / name :op1 "Ttk69")) :purpose (f / form-01 :ARG0 c :ARG1 (c2 / complex :ARG0-of (r / repress-01 :ARG1 (t2 / transcribe-01))))) :mod (p2 / particular)) # ::id bio.chicago_2015.125 # ::date 2015-10-20T04:55:23 # ::file bio_chicago_2015_125.txt # ::snt The N-termini of XTcf-3 and LEF-1 interact with the Armadillo repeat region of beta-catenin (Behrens et al., 1996 ; Huber et al., 1996 ; Molenaar et al., 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (i / interact-01 :ARG0 (a / and :op1 (p / protein-segment :name (n / name :op1 "N-terminus") :part-of (p13 / protein :name (n2 / name :op1 "XTcf-3"))) :op2 (p2 / protein-segment :name (n3 / name :op1 "N-terminus") :part-of (p14 / protein :name (n4 / name :op1 "LEF-1") :xref (x / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")))) :ARG1 (p9 / protein-segment :name (n5 / name :op1 "Armadillo" :op2 "repeat") :part-of (p3 / protein :name (n6 / name :op1 "beta-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p4 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n7 / name :op1 "Behrens")) :op2 (p6 / person :mod (o / other))) :time (d3 / date-entity :year "1996")) :op2 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n8 / name :op1 "Huber")) :op2 p6) :time d3) :op3 (p10 / publication-91 :ARG0 (a5 / and :op1 (p11 / person :name (n9 / name :op1 "Molenaar")) :op2 p6) :time d3)))) # ::id bio.chicago_2015.129 # ::date 2015-10-20T05:07:01 # ::file bio_chicago_2015_129.txt # ::snt Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (a / activate-01 :ARG0 (a2 / acetylate-01 :ARG1 (p3 / protein-segment :name (n / name :op1 "C-terminus" :op2 "domain") :part-of (p2 / protein :name (n3 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :ARG1 (b / bind-01 :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "DNA") :ARG1-of (s / specific-02 :ARG2 (s2 / sequence :part-of p2))))) # ::id bio.chicago_2015.132 # ::date 2015-10-20T21:07:56 # ::file bio_chicago_2015_132.txt # ::snt The nonmodular activation regions contain a TFIID interaction domain that binds specifically to TAFII110 and TAFII250. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / contain-01 :ARG0 (r / region :mod (n / nonmodular) :mod (a / activate-01)) :ARG1 (d / domain :location-of (i / interact-01 :ARG0 (p / protein :name (n2 / name :op1 "TFIID") :xref (x2 / xref :value "UNIPROT:TBP_HUMAN" :prob "1.002"))) :ARG1-of (b / bind-01 :ARG2 (a2 / and :op1 (p2 / protein :name (n3 / name :op1 "TAFII110") :xref (x / xref :value "UNIPROT:TAF1C_HUMAN" :prob "0.392")) :op2 (p3 / protein :name (n4 / name :op1 "TAFII250") :xref (x1 / xref :value "UNIPROT:TAF1_HUMAN" :prob "1.002"))) :ARG1-of (s / specific-02)))) # ::id bio.chicago_2015.139 # ::date 2015-10-20T21:14:38 # ::file bio_chicago_2015_139.txt # ::snt (E) The TALE motif does not prevent PBX binding to CBP, but changing an arginine to lysine within HD helix 3 increases CBP binding to PBX. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / contrast-01 :ARG1 (p / prevent-01 :polarity "-" :ARG0 (m / motif :name (n2 / name :op1 "TALE")) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n3 / name :op1 "PBX") :xref (x / xref :value "UNIPROT:PBX1_HUMAN" :prob "0.262")) :ARG2 (p3 / protein :name (n4 / name :op1 "CBP") :xref (x1 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")))) :ARG2 (i / increase-01 :ARG0 (c2 / change-01 :ARG1 (a2 / amino-acid :name (n5 / name :op1 "arginine") :xref (x4 / xref :value "PUBCHEM:232" :prob "11.348415")) :ARG2 (a3 / amino-acid :name (n6 / name :op1 "lysine") :xref (x3 / xref :value "PUBCHEM:866" :prob "11.053295")) :location (p4 / protein-segment :name (n / name :op1 "helix" :op2 "3") :part-of (p5 / protein :name (n7 / name :op1 "HD") :xref (x2 / xref :value "UNIPROT:HD_HUMAN" :prob "1.003")))) :ARG1 (b2 / bind-01 :ARG1 p3 :ARG2 p2)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "E"))) # ::id bio.chicago_2015.157 # ::date 2015-10-20T21:28:13 # ::file bio_chicago_2015_157.txt # ::snt Given that p53 interacts with p300/CBP ( 3, 26, 51), the same membrane was then probed with polyclonal anti-CBP antibodies, which detect both p300 and CBP ( 4, 56). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 20, 2015 (c / cause-01 :ARG0 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "p53") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1 (s / slash :op1 (p2 / protein :name (n2 / name :op1 "p300") :xref (x / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")) :op2 (p3 / protein :name (n3 / name :op1 "CBP") :xref (x1 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")))) :ARG1 (p5 / probe-01 :ARG0 (a2 / antibody :ARG0-of (o / oppose-01 :ARG1 p3) :mod (p7 / polyclonal) :ARG0-of (d2 / detect-01 :ARG1 (a3 / and :op1 p2 :op2 p3) :ARG1-of (d3 / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 "4" :op2 "56")))))) :ARG1 (m / membrane :ARG1-of (s2 / same-01) :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "3" :op2 "26" :op3 "51"))))) # ::id bio.chicago_2015.177 # ::date 2015-10-20T22:19:22 # ::file bio_chicago_2015_177.txt # ::snt Huckebein, Hairy, Goosecoid, and Engrailed are among the repressors that interact with Groucho (Paroush et al. 1994 ; Goldstein et al. 1999 ), whereas Kruppel, Knirps, and Snail interact with dCtBP (Nibu et al. 1998a ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / contrast-01 :ARG1 (i2 / include-91 :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "Huckebein") :xref (x1 / xref :value "UNIPROT:FCN2_HUMAN" :prob "0.242")) :op2 (p4 / protein :name (n3 / name :op1 "Hairy") :xref (x2 / xref :value "UNIPROT:HES1_HUMAN" :prob "0.242")) :op3 (p18 / protein :name (n12 / name :op1 "Goosecoid")) :op4 (p5 / protein :name (n4 / name :op1 "Engrailed"))) :ARG2 (p / protein :ARG0-of (r / repress-01) :ARG0-of (i / interact-01 :ARG1 (p2 / protein :name (n / name :op1 "Groucho") :xref (x / xref :value "UNIPROT:TLE4_HUMAN" :prob "0.212")))) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and :op1 (p6 / publication-91 :ARG0 (a2 / and :op1 (p7 / person :name (n5 / name :op1 "Paroush")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "1994")) :op2 (p9 / publication-91 :ARG0 (a4 / and :op1 (p10 / person :name (n6 / name :op1 "Goldstein")) :op2 p8) :time (d2 / date-entity :year "1999"))))) :ARG2 (i3 / interact-01 :ARG0 (a5 / and :op1 (p12 / protein :name (n7 / name :op1 "Kruppel")) :op2 (p13 / protein :name (n8 / name :op1 "Knirps")) :op3 (p14 / protein :name (n9 / name :op1 "Snail") :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1 (p19 / protein :name (n10 / name :op1 "dCtBP")) :ARG1-of (d5 / describe-01 :ARG0 (p15 / publication-91 :ARG0 (a6 / and :op1 (p16 / person :name (n11 / name :op1 "Nibu")) :op2 p8) :time (d3 / date-entity :year "1998"))))) # ::id bio.chicago_2015.218 # ::date 2015-10-21T01:38:43 # ::file bio_chicago_2015_218.txt # ::snt For example, abd-A depends on exd for the regulation of wg, but not for the regulation of dpp [14] . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e2 / exemplify-01 :ARG0 (c / contrast-01 :ARG1 (d / depend-01 :ARG0 (p2 / protein :name (n / name :op1 "abd-A")) :ARG1 (p3 / protein :name (n2 / name :op1 "exd") :xref (x / xref :value "UNIPROT:EXD1_HUMAN" :prob "0.202")) :purpose (r / regulate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "wg")))) :ARG2 (d2 / depend-01 :polarity "-" :ARG0 p2 :ARG1 p3 :purpose (r2 / regulate-01 :ARG1 (p5 / protein :name (n4 / name :op1 "dpp") :xref (x1 / xref :value "UNIPROT:DSPP_HUMAN" :prob "0.602"))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "14")))) # ::id bio.chicago_2015.232 # ::date 2015-10-21T01:44:49 # ::file bio_chicago_2015_232.txt # ::snt This suggests that Exd is required to release the transcriptional activation function of Dfd independently of Exd enhancement of Dfd-binding affinity on the composite site. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (s / suggest-01 :ARG0 (t / this) :ARG1 (r / require-01 :ARG0 (r2 / release-01 :ARG0 "p" :ARG1 (f / function-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Dfd")) :ARG1 (a / activate-01) :ARG0-of (t3 / transcribe-01))) :ARG1 (p / protein :name (n / name :op1 "Exd") :xref (x / xref :value "UNIPROT:EXD1_HUMAN" :prob "0.202")) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (e2 / enhance-01 :ARG0 p :ARG1 (a2 / affinity :mod (b / bind-01 :ARG2 p2)) :location (s2 / site :mod (c / composite)))))) # ::id bio.chicago_2015.289 # ::date 2015-10-21T02:13:12 # ::file bio_chicago_2015_289.txt # ::snt Ttk activates ftz transcription in yeast cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "Ttk") :xref (x / xref :value "UNIPROT:TTK_HUMAN" :prob "0.603")) :ARG1 (t / transcribe-01 :ARG1 (p / protein :name (n2 / name :op1 "Ftz"))) :location (c / cell :mod (y / yeast))) # ::id bio.chicago_2015.325 # ::date 2015-10-21T02:15:20 # ::file bio_chicago_2015_325.txt # ::snt In summary, the genetic analysis of dCtBP mutants suggests that Kruppel, Knirps and Snail depend on dCtBP+ activity, while Hairy and Dorsal continue to function as repressors in the absence of the dCtBP co-repressor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s2 / summarize-01 :ARG2 (c / contrast-01 :ARG1 (s3 / suggest-01 :ARG0 (a / analyze-01 :ARG1 (p7 / protein :name (n / name :op1 "dCtBP") :ARG2-of (m / mutate-01)) :mod (g / genetic)) :ARG1 (d / depend-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Kruppel")) :op2 (p3 / protein :name (n3 / name :op1 "Knirps")) :op3 (p4 / protein :name (n4 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1 (a3 / activity-06 :ARG0 (p8 / protein :name (n5 / name :op1 "dCtBP") :mod (w / wild-type))))) :ARG2 (c2 / continue-01 :ARG1 (f / function-01 :ARG0 (a4 / and :op1 (p5 / protein :name (n6 / name :op1 "Hairy") :xref (x1 / xref :value "UNIPROT:HES1_HUMAN" :prob "0.242")) :op2 (p6 / protein :name (n7 / name :op1 "Dorsal"))) :ARG1 (m2 / molecular-physical-entity :ARG0-of (r / repress-01))) :condition (a5 / absent-01 :ARG1 (p / protein :name (n8 / name :op1 "dCtBP") :ARG0-of (c3 / corepress-00)))))) # ::id bio.chicago_2015.328 # ::date 2015-10-21T02:25:13 # ::file bio_chicago_2015_328.txt # ::snt Unilateral photoactivation of UBX repressed ANTP expression on one side of the embryo, indicating that the photo-induced UBX was functional (Fig. 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (r / repress-01 :ARG0 (a / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "UBX") :xref (x / xref :value "UNIPROT:UBX10_HUMAN" :prob "0.232")) :mod (p / photo) :mod (u / unilateral)) :ARG1 (e / express-03 :ARG2 (p5 / protein :name (n2 / name :op1 "ANTP") :xref (x1 / xref :value "UNIPROT:S35F6_HUMAN" :prob "0.282")) :ARG3 (s / side :quant "1" :part-of (e3 / embryo))) :ARG0-of (i / indicate-01 :ARG1 (f / function-01 :ARG0 (p3 / protein :name n :ARG2-of (i2 / induce-01 :ARG0 (p4 / photo)) :xref (x2 / xref :value "UNIPROT:UBX10_HUMAN" :prob "0.232")))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3C"))) # ::id bio.chicago_2015.340 # ::date 2015-10-21T02:31:39 # ::file bio_chicago_2015_340.txt # ::snt Binding of PC and TRX to Ubx, abd-A and Abd-B promoters during different embryonic stages. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "PC") :xref (x1 / xref :value "UNIPROT:PODXL_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "TRX") :xref (x / xref :value "UNIPROT:THIO_HUMAN" :prob "1.003"))) :ARG2 (a2 / and :op1 (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (p4 / protein :name (n3 / name :op1 "Ubx")))) :op2 (m2 / molecular-physical-entity :ARG0-of (p5 / promote-01 :ARG1 (p6 / protein :name (n4 / name :op1 "abd-A")))) :op3 (m3 / molecular-physical-entity :ARG0-of (p7 / promote-01 :ARG1 (p8 / protein :name (n5 / name :op1 "Abd-B"))))) :time (s / stage :mod (e / embryo) :ARG1-of (d / differ-02))) # ::id bio.chicago_2015.366 # ::date 2015-10-21T02:36:03 # ::file bio_chicago_2015_366.txt # ::snt Su(fu) regulates Ci via two distinct mechanisms # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 21, 2015 (r / regulate-01 :ARG0 (p / protein :name (n / name :op1 "Su(fu)")) :ARG1 (p2 / protein :name (n2 / name :op1 "Ci")) :manner (m / mechanism :quant "2" :mod (d / distinct))) # ::id bio.chicago_2015.376 # ::date 2015-10-21T03:04:11 # ::file bio_chicago_2015_376.txt # ::snt Thus, the difference between Knirps and other short-range transcriptional repressors may indicate that the mechanism of repression is not identical between these proteins, even though Giant, Knirps, and Kruppel all interact with the CtBP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c / cause-01 :ARG1 (p3 / possible-01 :ARG1 (i / indicate-01 :ARG0 (d / differ-02 :ARG1 (p2 / protein :name (n / name :op1 "Knirps")) :ARG2 (p / protein :ARG0-of (r / repress-01 :ARG1 (t / transcribe-01)) :mod (o / other) :mod (r2 / range :ARG1-of (s / short-07)))) :ARG1 (i2 / identical-01 :polarity "-" :ARG1 (m / mechanism :mod r :poss p2) :ARG2 (m2 / mechanism :mod r :poss p) :concession (i3 / interact-01 :ARG0 (a / and :op1 (p4 / protein :name (n2 / name :op1 "Giant") :xref (x / xref :value "UNIPROT:GOGB1_HUMAN" :prob "0.312")) :op2 p2 :op3 (p6 / protein :name (n4 / name :op1 "Kruppel")) :mod (a2 / all)) :ARG1 (p7 / protein :name (n5 / name :op1 "CtBP") :xref (x1 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652"))))))) # ::id bio.chicago_2015.381 # ::date 2015-10-21T03:34:03 # ::file bio_chicago_2015_381.txt # ::snt B-C, dCtBP and Groucho can bind Hairy simultaneously in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 21, 2015 (p / possible-01 :ARG1 (b / bind-01 :ARG0 (a / and :op1 (p2 / protein :name (n / name :op1 "B-C")) :op2 (p3 / protein :name (n2 / name :op1 "dCtBP")) :op3 (p4 / protein :name (n3 / name :op1 "Groucho") :xref (x / xref :value "UNIPROT:TLE4_HUMAN" :prob "0.212"))) :ARG1 (p5 / protein :name (n4 / name :op1 "Hairy") :xref (x1 / xref :value "UNIPROT:HES1_HUMAN" :prob "0.242")) :mod (s / simultaneous) :manner (i / in-vitro))) # ::id bio.chicago_2015.465 # ::date 2015-10-21T03:35:58 # ::file bio_chicago_2015_465.txt # ::snt Repression of hth by Antp is cell autonomous. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (r / repress-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Antp") :xref (x / xref :value "UNIPROT:S35F6_HUMAN" :prob "0.212")) :ARG1 (p / protein :name (n / name :op1 "Hth") :xref (x1 / xref :value "UNIPROT:THAP9_HUMAN" :prob "0.202")) :mod (a / autonomous :mod (c / cell))) # ::id bio.chicago_2015.503 # ::date 2015-10-21T03:37:46 # ::file bio_chicago_2015_503.txt # ::snt Whereas, 24B=> Ubx represses both Scr and Antp, leaving abd-A unaffected ( Fig. 4E-H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (r / repress-01 :ARG0 (a3 / and :op1 (p2 / protein :name (n6 / name :op1 "24B")) :op2 (p / protein :name (n / name :op1 "Ubx")) :ARG0-of (l / leave-02 :ARG1 (a2 / affect-01 :polarity "-" :ARG1 (p5 / protein :name (n4 / name :op1 "abd-A"))))) :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "Scr") :xref (x1 / xref :value "UNIPROT:RBMS1_HUMAN" :prob "0.202")) :op2 (p4 / protein :name (n3 / name :op1 "Antp") :xref (x / xref :value "UNIPROT:S35F6_HUMAN" :prob "0.212")))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4H")))) # ::id bio.chicago_2015.568 # ::date 2015-10-21T03:41:32 # ::file bio_chicago_2015_568.txt # ::snt The Ras signaling cascade leads to activation of the inductive transcription factor, Pnt, and inactivation of the Yan repressor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 21, 2015 (l / lead-03 :ARG0 (c / cascade-01 :ARG1 (s / signal-07 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (a2 / and :op1 (a / activate-01 :ARG1 (f / factor :name (n3 / name :op1 "Pnt") :ARG0-of (t / transcribe-01) :ARG0-of (i / induce-01))) :op2 (a3 / activate-01 :polarity "-" :ARG1 (p3 / protein :ARG0-of (r / repress-01 :ARG1 (p4 / protein :name (n4 / name :op1 "Yan"))))))) # ::id bio.chicago_2015.588 # ::date 2015-10-21T03:45:04 # ::file bio_chicago_2015_588.txt # ::snt H3 was strongly acetylated in the active Abd-B and RpII140 promoters ( Fig. 1a, g; p10, p10b, pol2), whereas the inactive loci ( iab-4, abd-A, Ubx, en, ems and bw) showed a decrease (5 - 10 times lessR than the H3 signal in the active Abd-B and RpII140 promoters) or absence of acetylation both at the core promoters as well as downstream of the initiator ( Fig. 1b - f, h). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 26, 2016 (c / contrast-01 :ARG1 (a / acetylate-01 :ARG1 (p5 / protein :name (n / name :op1 "H3")) :ARG1-of (s2 / strong-02) :location (m2 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p6 / protein :name (n2 / name :op1 "Abd-B") :ARG0-of (a10 / activity-06))) :ARG1-of (l8 / label-01 :ARG2 (a11 / and :op1 (n10 / name :op1 "p10") :op2 (n11 / name :op1 "p10b") :op3 (n12 / name :op1 "pol2")))) :location (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p7 / protein :name (n3 / name :op1 "RpII140")))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1a") :op2 (f2 / figure :mod "1g")))) :ARG2 (s3 / show-01 :ARG1 (o / or :op1 (d2 / decrease-01 :ARG1 (a4 / and :op1 (l / locus :ARG0-of (a3 / activity-06 :polarity "-") :mod (e / enzyme :name (n4 / name :op1 "iab-4"))) :op2 (l2 / locus :ARG0-of a3 :mod (p9 / protein :name (n5 / name :op1 "abd-A"))) :op3 (l3 / locus :ARG0-of a3 :mod (p10 / protein :name (n6 / name :op1 "Ubx"))) :op4 (l4 / locus :ARG0-of a3 :mod (p11 / protein :name (n7 / name :op1 "en"))) :op5 (l5 / locus :ARG0-of a3 :mod (p12 / protein :name (n8 / name :op1 "ems") :xref (x / xref :value "UNIPROT:SRC8_HUMAN" :prob "0.202"))) :op6 (l6 / locus :ARG0-of a3 :mod (p13 / protein :name (n9 / name :op1 "bw")))) :ARG2 (l7 / less-than :op1 (p3 / product-of :op1 (b / between :op1 "5" :op2 "10") :op2 (s4 / signal-07 :ARG0 p5 :location (a5 / and :op1 m2 :op2 m))))) :op2 (a6 / absent-01 :ARG1 (a7 / acetylate-01) :ARG2 (a8 / and :op1 (m3 / molecular-physical-entity :ARG0-of (p4 / promote-01) :mod (c2 / core)) :op2 (r / relative-position :op1 (m4 / molecular-physical-entity :ARG0-of (i / initiate-01)) :direction (d3 / downstream))))) :ARG1-of (d4 / describe-01 :ARG0 (a9 / and :op1 (f5 / figure :mod "1b") :op2 (f6 / figure :mod "1f") :op3 (f3 / figure :mod "1g") :op4 (f4 / figure :mod "1h"))))) # ::id bio.chicago_2015.592 # ::date 2015-10-21T04:01:03 # ::file bio_chicago_2015_592.txt # ::snt Since Phyl and Sina associate with the Ttk complex without reducing its apparent size, it indicates that Sina and Phyl bind to Ttk without altering its ability to multimerize. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (a / associate-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "Phyl") :xref (x2 / xref :value "UNIPROT:PAHX_HUMAN" :prob "0.222")) :op2 (p2 / protein :name (n2 / name :op1 "Sina") :xref (x / xref :value "UNIPROT:SIN3A_HUMAN" :prob "0.232"))) :ARG2 (e / enzyme :name (n3 / name :op1 "Ttk") :xref (x1 / xref :value "UNIPROT:TTK_HUMAN" :prob "0.603")) :manner (r / reduce-01 :polarity "-" :ARG1 (s / size :poss e :ARG1-of (a3 / appear-02)))) :ARG1 (i / indicate-01 :ARG0 a :ARG1 (b / bind-01 :ARG1 a2 :ARG2 e :manner (a4 / alter-01 :polarity "-" :ARG1 (c3 / capable-01 :ARG1 e :ARG2 (m / multimerize)))))) # ::id bio.chicago_2015.596 # ::date 2015-10-21T04:19:47 # ::file bio_chicago_2015_596.txt # ::snt In summary, transgenic embryos for wg-Gal4/UAS-GFP or ems-Gal4/UAS-GFP accurately reproduce the expression of wg or ems that depends on AbdA or AbdB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s2 / summarize-01 :ARG2 (r / reproduce-01 :ARG0 (e / embryo :mod (t2 / transgenic) :poss (o / or :op1 (o4 / organism :name (n / name :op1 "wg-Gal4/UAS-GFP")) :op2 (o5 / organism :name (n2 / name :op1 "ems-Gal4/UAS-GFP")))) :ARG1 (e4 / express-03 :ARG2 (o2 / or :op1 (p3 / protein :name (n3 / name :op1 "wg")) :op2 (p4 / protein :name (n4 / name :op1 "ems") :xref (x / xref :value "UNIPROT:SRC8_HUMAN" :prob "0.202"))) :ARG0-of (d / depend-01 :ARG1 (o3 / or :op1 (p / protein :name (n5 / name :op1 "AbdA")) :op2 (p2 / protein :name (n6 / name :op1 "AbdB"))))) :mod (a / accurate))) # ::id bio.chicago_2015.627 # ::date 2015-10-21T04:24:52 # ::file bio_chicago_2015_627.txt # ::snt Table I dCtBP specifically interacts with Hairy and E( spl)mdelta bHLH family members in directed yeast two-hybrid assays (beta-galactosidase activity in diploid yeast strains) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (i / interact-01 :ARG0 (p3 / protein :name (n / name :op1 "dCtBP") :ARG1-of (d / describe-01 :ARG0 (t / table :mod "I"))) :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "Hairy") :xref (x1 / xref :value "UNIPROT:HES1_HUMAN" :prob "0.242")) :op2 (m / member :ARG1-of (i2 / include-91 :ARG2 (p2 / protein-family :name (n3 / name :op1 "E(spl)mdelta-bHLH"))))) :ARG1-of (s / specific-02) :location (a2 / assay-01 :mod (h / hybrid :quant "2") :mod (y / yeast) :ARG1-of (d3 / direct-01)) :ARG1-of (m2 / mean-01 :ARG2 (a3 / activity-06 :ARG0 (e / enzyme :name (n4 / name :op1 "beta-galactosidase") :xref (x / xref :value "UNIPROT:BGAL_HUMAN" :prob "0.702")) :location (s3 / strain :mod (d2 / diploid) :mod y)))) # ::id bio.chicago_2015.634 # ::date 2015-10-21T04:55:19 # ::file bio_chicago_2015_634.txt # ::snt dCtBP was identified in interaction studies with Knirps, Snail, and Hairy (Nibu et al., 1998b ; Poortinga et al., 1998 ) These repressor proteins interact with dCtBP through CtBP binding motifs located within the repressor domains located near their C-terminal ends. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (m / multi-sentence :snt1 (i / identify-01 :ARG1 (p13 / protein :name (n / name :op1 "dCtBP")) :location (s2 / study-01 :ARG1 (i2 / interact-01 :ARG0 (a / and :op1 (p2 / protein :name (n2 / name :op1 "Knirps")) :op2 (p3 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op3 (p4 / protein :name (n4 / name :op1 "Hairy") :xref (x1 / xref :value "UNIPROT:HES1_HUMAN" :prob "0.242"))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n5 / name :op1 "Nibu")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "1998")) :op2 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n6 / name :op1 "Poortinga")) :op2 p7) :time d)))) :snt2 (i3 / interact-01 :ARG0 (p / protein :ARG0-of (r / repress-01) :mod (t / this)) :ARG1 p13 :instrument (m2 / motif :mod (b / bind-01 :ARG1 (p12 / protein :name (n8 / name :op1 "CtBP") :xref (x2 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652"))) :location (d4 / domain :ARG1-of (n9 / near-02 :ARG2 (e / end :poss m2 :mod (p10 / protein-segment :name (n10 / name :op1 "C-terminus")))) :part-of p)))) # ::id bio.chicago_2015.635 # ::date 2015-10-21T05:03:40 # ::file bio_chicago_2015_635.txt # ::snt (E) Association of Sina with HA-tagged Ttk is specifically enhanced by Phyl. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / enhance-01 :ARG0 (p / protein :name (n3 / name :op1 "Phyl") :xref (x2 / xref :value "UNIPROT:PAHX_HUMAN" :prob "0.222")) :ARG1 (a / associate-01 :ARG1 (p2 / protein :name (n / name :op1 "Sina") :xref (x / xref :value "UNIPROT:SIN3A_HUMAN" :prob "0.232")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ttk") :ARG1-of (t / tag-01 :ARG2 (p4 / protein :name (n4 / name :op1 "HA") :xref (x1 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :xref (x3 / xref :value "UNIPROT:TTK_HUMAN" :prob "0.603"))) :ARG1-of (s / specific-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "E"))) # ::id bio.chicago_2015.679 # ::date 2015-10-21T05:09:44 # ::file bio_chicago_2015_679.txt # ::snt In the bug Oncopeltus fasciatus, Dfd cannot activate pb because pb is not even present in the maxillae ( 30). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p2 / possible-01 :polarity "-" :ARG1 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "Dfd")) :ARG1 (e / enzyme :name (n2 / name :op1 "pb") :xref (x / xref :value "UNIPROT:HIS3_HUMAN" :prob "0.602"))) :ARG1-of (c / cause-01 :ARG0 (p3 / present-02 :polarity "-" :ARG1 e :ARG2 (m / maxilla) :mod (e2 / even))) :location (o / organism :name (n3 / name :op1 "Oncopeltus" :op2 "fasciatus") :mod (b / bug))) # ::id bio.chicago_2015.705 # ::date 2015-10-21T05:13:57 # ::file bio_chicago_2015_705.txt # ::snt We have also tested if Trl and PcG genes interact to silence the endogenous Ubx gene and MCP reporter constructs in double heterozygous animals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (i / interact-01 :mode "interrogative" :ARG0 (g / gene :name (n / name :op1 "Trl")) :ARG1 (g2 / gene :name (n2 / name :op1 "PcG")) :purpose (s / silence-01 :ARG0 (a / and :op1 g :op2 g2) :ARG1 (a2 / and :op1 (c / construct-01 :ARG1 (g3 / gene :name (n3 / name :op1 "Ubx") :mod (e / endogenous))) :op2 (c2 / construct-01 :ARG1 (g4 / gene :name (n4 / name :op1 "MCP") :ARG0-of (r / report-01) :xref (x / xref :value "UNIPROT:MCP_HUMAN" :prob "1.003")))) :location (a3 / animal :mod (h2 / heterozygous :mod (d / double))))) :mod (a4 / also)) # ::id bio.chicago_2015.708 # ::date 2015-10-21T05:20:35 # ::file bio_chicago_2015_708.txt # ::snt In these studies, Gro was found to interact specifically with Hairy and Hairy-related proteins, and maternally expressed Gro was shown to be required for the transcriptional repression of genes that direct Drosophila segmentation, neurogenesis, and sex-determination -- three processes known to be regulated by Hairy family repressors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a2 / and :op1 (f / find-01 :ARG1 (i / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "Gro") :xref (x / xref :value "UNIPROT:GROA_HUMAN" :prob "0.602")) :ARG1 (a / and :op1 (p3 / protein-family :name (n2 / name :op1 "Hairy")) :op2 (p4 / protein :ARG1-of (r2 / relate-01 :ARG2 p3))) :ARG1-of (s / specific-02)) :location (s2 / study :mod (t / this))) :op2 (s3 / show-01 :ARG1 (r3 / require-01 :ARG0 (r / repress-01 :ARG1 (g / gene :ARG0-of (d / direct-01 :ARG1 (a3 / and :op1 (s4 / segment-01 :ARG1 (o / organism :name (n3 / name :op1 "Drosophila"))) :op2 (n4 / neurogenesis) :op3 (d2 / determine-01 :ARG1 (s5 / sex)) :ARG1-of (m / mean-01 :ARG2 (p6 / process :quant "3" :ARG1-of (k / know-02 :ARG3 (r4 / regulate-01 :ARG0 (p7 / protein-family :name (n5 / name :op1 "Hairy") :ARG0-of (r5 / repress-01)) :ARG1 p6))))))) :ARG0-of (t2 / transcribe-01)) :ARG1 (p / protein :name (n6 / name :op1 "Gro") :ARG2-of (e / express-03 :ARG3 (o2 / organism :ARG0-of (h / have-rel-role-91 :ARG2 (m2 / mother)))) :xref (x1 / xref :value "UNIPROT:GROA_HUMAN" :prob "0.602"))))) # ::id bio.chicago_2015.710 # ::date 2015-10-21T05:28:37 # ::file bio_chicago_2015_710.txt # ::snt Recent studies have demonstrated that the Sina and Phyl proteins form a ternary complex with Ttk and promote ubiquitination and rapid degradation of Ttk through the proteasome pathway ( 14, 22). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (d / demonstrate-01 :ARG0 (s / study :time (r / recent)) :ARG1 (a2 / and :op1 (f / form-01 :ARG1 (c / complex :mod (t / ternary)) :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "Sina") :xref (x2 / xref :value "UNIPROT:SIN3A_HUMAN" :prob "0.232")) :op2 (p2 / protein :name (n2 / name :op1 "Phyl") :xref (x / xref :value "UNIPROT:PAHX_HUMAN" :prob "0.222")) :op3 (e / enzyme :name (n3 / name :op1 "Ttk") :xref (x1 / xref :value "UNIPROT:TTK_HUMAN" :prob "0.603")))) :op2 (p3 / promote-01 :ARG0 (a4 / and :op1 p :op2 p2) :ARG1 (a3 / and :op1 (u / ubiquitinate-01 :ARG1 e) :op2 (d2 / degrade-01 :ARG1 e :mod (r2 / rapid)))) :instrument (p4 / pathway :name (n4 / name :op1 "proteasome"))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 "14" :op2 "22"))))) # ::id bio.chicago_2015.717 # ::date 2015-10-21T05:33:10 # ::file bio_chicago_2015_717.txt # ::snt If this model is correct, iab-4 mutations must therefore affect abd-A expression in a specific subset of mesodermal cells which they were not able to identify. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o2 / obligate-01 :ARG2 (a / affect-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "iab-4") :ARG2-of (m2 / mutate-01)) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "abd-A")) :ARG3 (s / subset :ARG1-of (s2 / specific-02) :consist-of (c / cell :mod (m / mesodermal) :ARG1-of (i / identify-01 :ARG0 (t / they) :ARG1-of (p / possible-01 :polarity "-"))))) :ARG1-of (c3 / cause-01)) :condition (c2 / correct-02 :ARG1 (m3 / model :mod (t2 / this)))) # ::id bio.chicago_2015.725 # ::date 2015-10-21T05:45:14 # ::file bio_chicago_2015_725.txt # ::snt Dm-Ftz generated strong segmentation phenotypes and interacted strongly with Ftz-F1, Tc-Ftz caused moderate phenotypes and interacted with Ftz-F1 to a lesser extent than Dm-Ftz, while Sg-Ftz generated extremly weak phenotypes and only interacted marginally with Ftz-F1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c2 / contrast-01 :ARG1 (a2 / and :op1 (a / and :op1 (g / generate-01 :ARG0 (g2 / gene :name (n / name :op1 "Dm-Ftz")) :ARG1 (p / phenotype :mod (s / segment-01 :ARG1-of (s2 / strong-02)))) :op2 (i / interact-01 :ARG0 g2 :ARG1 (g3 / gene :name (n2 / name :op1 "Ftz-F1") :xref (x / xref :value "UNIPROT:STF1_HUMAN" :prob "0.622")) :ARG1-of s2)) :op2 (a3 / and :op1 (c / cause-01 :ARG0 (g4 / gene :name (n3 / name :op1 "Tc-Ftz")) :ARG1 (p2 / phenotype :ARG1-of (m / moderate-03))) :op2 (i2 / interact-01 :ARG0 g4 :ARG1 g3 :extent (l / less) :compared-to g2))) :ARG2 (a4 / and :op1 (g5 / generate-01 :ARG0 (g6 / gene :name (n4 / name :op1 "Sg-Ftz")) :ARG1 (p3 / phenotype :ARG1-of (w / weak-02 :degree (e / extreme)))) :op2 (i3 / interact-01 :ARG0 g6 :ARG1 g3 :ARG1-of (m2 / marginal-02 :mod (o / only))))) # ::id bio.chicago_2015.734 # ::date 2015-10-21T05:55:13 # ::file bio_chicago_2015_734.txt # ::snt Regulation of pb expression by Dfd and Scr # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (r / regulate-01 :ARG0 (a / and :op1 (p / protein :name (n2 / name :op1 "Dfd")) :op2 (p2 / protein :name (n3 / name :op1 "Scr") :xref (x / xref :value "UNIPROT:RBMS1_HUMAN" :prob "0.202"))) :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "pb") :xref (x1 / xref :value "UNIPROT:HIS3_HUMAN" :prob "0.602")))) # ::id bio.chicago_2015.746 # ::date 2015-10-21T05:56:36 # ::file bio_chicago_2015_746.txt # ::snt While iab-2, iab-3 and iab-4 regulate abd-A in PS7, PS8 and PS9 respectively, iab-5, iab-6, iab-7 and iab-8 regulate Abd-B expression in PS10, PS11, PS12 and PS13. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (c / contrast-01 :ARG1 (r / regulate-01 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "iab-2")) :op2 (e2 / enzyme :name (n2 / name :op1 "iab-3")) :op3 (e3 / enzyme :name (n3 / name :op1 "iab-4"))) :ARG1 (p / protein :name (n11 / name :op1 "abd-A")) :location (a2 / and :op1 (t / thing :name (n4 / name :op1 "PS7")) :op2 (t2 / thing :name (n5 / name :op1 "PS8")) :op3 (t3 / thing :name (n6 / name :op1 "PS9")))) :ARG2 (r2 / regulate-01 :ARG0 (a3 / and :op1 (e4 / enzyme :name (n7 / name :op1 "iab-5")) :op2 (e5 / enzyme :name (n8 / name :op1 "iab-6")) :op3 (e6 / enzyme :name (n9 / name :op1 "iab-7")) :op4 (e7 / enzyme :name (n10 / name :op1 "iab-8"))) :ARG1 (e9 / express-03 :ARG2 (p2 / protein :name (n12 / name :op1 "Abd-B"))) :location (a4 / and :op1 (t4 / thing :name (n13 / name :op1 "PS10")) :op2 (t5 / thing :name (n14 / name :op1 "PS11")) :op3 (t6 / thing :name (n15 / name :op1 "PS12")) :op4 (t7 / thing :name (n16 / name :op1 "PS13"))))) # ::id bio.chicago_2015.756 # ::date 2015-10-21T06:06:53 # ::file bio_chicago_2015_756.txt # ::snt In fact, all PRD=>Hox combinations, except Lab (data not shown) and Dfd ( Fig. 3D), negatively regulate mesodermal pb expression (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (d4 / downregulate-01 :ARG0 (c / combine-01 :ARG1 (p / protein :name (n / name :op1 "PRD") :xref (x3 / xref :value "UNIPROT:PEPD_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n2 / name :op1 "Hox") :xref (x1 / xref :value "UNIPROT:HXD1_HUMAN" :prob "0.202")) :mod (a / all :ARG2-of (e / except-01 :ARG1 (a2 / and :op1 (p4 / protein :name (n3 / name :op1 "Lab") :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s / show-01 :polarity "-"))) :xref (x2 / xref :value "UNIPROT:NTAL_HUMAN" :prob "0.603")) :op2 (p3 / protein :name (n4 / name :op1 "Dfd") :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3D"))))))) :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n5 / name :op1 "pb") :xref (x / xref :value "UNIPROT:HIS3_HUMAN" :prob "0.602")) :mod (m / mesodermal) :ARG1-of d) :mod (i / in-fact)) # ::id bio.chicago_2015.761 # ::date 2015-10-21T06:12:01 # ::file bio_chicago_2015_761.txt # ::snt Mutations in dTCF and expression of a dominant-negative dTCF transgene cause a segment polarity phenotype and affect expression of the Wingless target genes engrailed and Ultrabithorax. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a2 / and :op1 (c / cause-01 :ARG0 (a / and :op1 (m / mutate-01 :ARG1 (p / protein :name (n / name :op1 "dTCF"))) :op2 (e / express-03 :ARG1 (t / transgene :name (n4 / name :op1 "dTCF") :ARG0-of (d / dominate-01) :ARG2-of (m2 / mutate-01 :mod "-/-")))) :ARG1 (p2 / phenotype :mod (s / segment) :mod (p3 / polarity))) :op2 (a3 / affect-01 :ARG0 a :ARG1 (e2 / express-03 :ARG1 (a4 / and :op1 (g2 / gene :name (n3 / name :op1 "Wingless") :ARG1-of (t2 / target-01)) :op2 (g3 / gene :name (n6 / name :op1 "Engrailed")) :op3 (g / gene :name (n5 / name :op1 "Ultrabithorax")))))) # ::id bio.chicago_2015.772 # ::date 2015-10-21T06:16:31 # ::file bio_chicago_2015_772.txt # ::snt Treatment with either of the PI 3-kinase inhibitors, wortmannin or LY294002, or the MEK inhibitor PD 098059, which prevents MAPK signaling, attenuated the dexamethasone stimulation of TER without affecting apical junction remodeling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / attenuate-01 :ARG0 (t2 / treat-04 :ARG2 (o2 / or :op1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (k / kinase :name (n3 / name :op1 "PI3") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "1.002"))) :ARG1-of (m2 / mean-01 :ARG2 (o / or :op1 (s3 / small-molecule :name (n4 / name :op1 "wortmannin") :xref (x2 / xref :value "PUBCHEM:312145" :prob "18.013371")) :op2 (s4 / small-molecule :name (n5 / name :op1 "LY294002") :xref (x4 / xref :value "PUBCHEM:3973" :prob "18.86067")))) :mod (e5 / either)) :op2 (s6 / small-molecule :name (n / name :op1 "PD098059") :ARG0-of (i3 / inhibit-01 :ARG1 (p / protein-family :name (n6 / name :op1 "MEK"))))) :ARG0-of (p4 / prevent-01 :ARG1 (s / signal-07 :ARG0 (p2 / pathway :name (n2 / name :op1 "MAPK"))))) :ARG1 (s2 / stimulate-01 :ARG0 (s5 / small-molecule :name (n8 / name :op1 "dexamethasone") :xref (x3 / xref :value "PUBCHEM:5743" :prob "14.701785")) :ARG1 (e4 / enzyme :name (n7 / name :op1 "TER") :xref (x / xref :value "UNIPROT:TECR_HUMAN" :prob "1.002")) :manner (a2 / affect-01 :polarity "-" :ARG1 (r / remodel-01 :ARG1 (j / junction :mod (a3 / apical)))))) # ::id bio.chicago_2015.777 # ::date 2015-10-21T04:41:36 # ::file bio_chicago_2015_777.txt # ::snt The recent finding that the dCtBP protein interacts with the repressors Knirps and Snail ( 14) and Hairy ( 17) supports this notion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (s / support-01 :ARG0 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "dCtBP")) :ARG1 (a / and :op1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Knirps")) :op2 (p3 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "14")))) :op2 (p5 / protein :name (n4 / name :op1 "Hairy") :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "17"))) :xref (x1 / xref :value "UNIPROT:HES1_HUMAN" :prob "0.242")) :ARG0-of (r / repress-01)) :ARG1-of (f / find-01 :time (r2 / recent))) :ARG1 (n5 / notion :mod (t / this))) # ::id bio.chicago_2015.798 # ::date 2015-10-21T05:00:17 # ::file bio_chicago_2015_798.txt # ::snt Later in development, the transcription patterns in Mcp mutant and yw67 embryos are indistinguishable, suggesting that the Mcp deletion disrupts iab4 transcription only early in development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (d / distinguish-01 :polarity "-" :ARG1 (p / pattern-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "Mcp") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:MCP_HUMAN" :prob "0.603")) :op2 (e / embryo :name (n2 / name :op1 "yw67"))) :mod (t / transcribe-01)) :ARG0-of (s / suggest-01 :ARG1 (d2 / disrupt-01 :ARG0 (d3 / delete-01 :ARG1 p2) :ARG1 (t2 / transcribe-01 :ARG1 (g / gene :name (n3 / name :op1 "iab4"))) :time (e2 / early :op1 (d4 / develop-01) :mod (o / only)))) :time (l / late :op1 (d5 / develop-01) :degree (m2 / more))) # ::id bio.chicago_2015.807 # ::date 2015-10-21T05:12:25 # ::file bio_chicago_2015_807.txt # ::snt We present evidence that Apterous activity depends on the formation of a LIM homeodomain dimer bridged by a dimer of cofactor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (p / present-01 :ARG0 (w / we) :ARG1 (t / thing :ARG0-of (e / evidence-01 :ARG1 (d / depend-01 :ARG0 (a / activity-06 :ARG0 (g / gene :name (n / name :op1 "Apterous"))) :ARG1 (f / form-01 :ARG1 (d2 / dimer :mod (p2 / protein-segment :name (n2 / name :op1 "LIM" :op2 "homeodomain")) :ARG1-of (b / bridge-01 :ARG2 (d3 / dimer :mod (c / cofactor))))))))) # ::id bio.chicago_2015.830 # ::date 2015-10-21T06:54:05 # ::file bio_chicago_2015_830.txt # ::snt Brinker is an antagonist of the Dpp-signaling because it prevents the transcription of a subset of Mad activated genes (Kirkpatrick et al., 2001 ; Rushlow et al., 2001 ; Saller and Bienz, 2001 ), but Brinker is itself a Dpp target (Minami et al., 1999 ) because Mad and Schnurri heterodimers can block brk transcription in dpp-responsive cells (Marty et al., 2000 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (c2 / cause-01 :ARG0 (p / prevent-01 :ARG0 (p2 / protein :name (n / name :op1 "brinker")) :ARG1 (t / transcribe-01 :ARG1 (s / subset :ARG2-of (i / include-91 :ARG1 (g / gene :ARG1-of (a / activate-01 :ARG0 (p3 / protein :name (n2 / name :op1 "Mad") :xref (x / xref :value "UNIPROT:MAD1_HUMAN" :prob "0.602")))))))) :ARG1 (a2 / antagonist :domain p2 :topic (s2 / signal-07 :ARG0 (p4 / pathway :name (n3 / name :op1 "Dpp")))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n4 / name :op1 "Kirkpatrick")) :op2 (p7 / person :mod (o / other))) :time (d2 / date-entity :year "2001")) :op2 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n5 / name :op1 "Rushlow")) :op2 p7) :time d2) :op3 (p10 / publication-91 :ARG0 (a6 / and :op1 (p11 / person :name (n6 / name :op1 "Saller")) :op2 (p12 / person :name (n7 / name :op1 "Bienz"))) :time d2)))) :ARG2 (c3 / cause-01 :ARG0 (p13 / possible-01 :ARG1 (b / block-01 :ARG0 (a7 / and :op1 p3 :op2 (p14 / protein :name (n8 / name :op1 "Schnurri")) :mod (h / heterodimer)) :ARG1 (t2 / transcribe-01 :ARG1 p2)) :location (c4 / cell :ARG0-of (r / responsive-02 :ARG1 p4)) :ARG1-of (d3 / describe-01 :ARG0 (p15 / publication-91 :ARG0 (a8 / and :op1 (p16 / person :name (n9 / name :op1 "Marty")) :op2 p7) :time (d4 / date-entity :year "2000")))) :ARG1 (t3 / target-01 :ARG0 p4 :ARG1 p2 :ARG1-of (d5 / describe-01 :ARG0 (p17 / publication-91 :ARG0 (a9 / and :op1 (p18 / person :name (n10 / name :op1 "Minami")) :op2 p7) :time (d6 / date-entity :year "1999")))))) # ::id bio.chicago_2015.858 # ::date 2015-10-21T17:35:21 # ::file bio_chicago_2015_858.txt # ::snt CtBP and Giant exhibited repression activity similar to the Knirps repression domains. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 22, 2015 (e / exhibit-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "CtBP") :xref (x1 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652")) :op2 (p2 / protein :name (n2 / name :op1 "Giant") :xref (x / xref :value "UNIPROT:GOGB1_HUMAN" :prob "0.312"))) :ARG1 (a2 / activity-06 :ARG0 a :ARG1 (r / repress-01 :ARG0 a) :ARG1-of (r2 / resemble-01 :ARG2 (d / domain :ARG0-of (r3 / repress-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Knirps"))))))) # ::id bio.chicago_2015.867 # ::date 2015-10-22T02:02:54 # ::file bio_chicago_2015_867.txt # ::snt Pan is bound and its transcriptional activity inhibited by dCBP ( 33). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (a / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Pan") :xref (x / xref :value "UNIPROT:SPI2_HUMAN" :prob "0.272")) :ARG2 (p2 / protein :name (n2 / name :op1 "dCBP"))) :op2 (i / inhibit-01 :ARG0 p2 :ARG1 (a2 / activity-06 :ARG0 p :ARG1 (t / transcribe-01 :ARG0 p))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG1-of (c / cite-01 :ARG2 "33")))) # ::id bio.chicago_2015.875 # ::date 2015-10-22T02:27:19 # ::file bio_chicago_2015_875.txt # ::snt Similarly, ectopic Scr and Dfd proteins have no effect on lab gene expression while we find positive regulation of pb by Dfd and Scr as discussed above. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (a / affect-01 :polarity "-" :ARG0 (a2 / and :op1 (p / protein :name (n / name :op1 "Scr") :xref (x / xref :value "UNIPROT:RBMS1_HUMAN" :prob "0.202")) :op2 (p2 / protein :name (n2 / name :op1 "Dfd")) :mod (e / ectopic)) :ARG1 (e2 / express-03 :ARG1 (g / gene :mod (l / lab)))) :ARG2 (f / find-01 :ARG0 (w / we) :ARG1 (u / upregulate-01 :ARG0 a2 :ARG1 (e3 / enzyme :name (n3 / name :op1 "pb") :xref (x1 / xref :value "UNIPROT:HIS3_HUMAN" :prob "0.602"))) :ARG1-of (d / discuss-01 :location (a3 / above))) :ARG1-of (r / resemble-01)) # ::id bio.chicago_2015.887 # ::date 2015-10-22T02:44:41 # ::file bio_chicago_2015_887.txt # ::snt Impact of CSN-specific phosphorylation on degradation of p53wt and p53 mutants by the Ub - 26S proteasome system Ub - 26S proteasome-dependent degradation of p53 was studied in reticulocyte lysate containing an intact Ub - 26S proteasome system and the CSN complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (m / multi-sentence :snt1 (i / impact-01 :ARG0 (p / phosphorylate-01 :ARG1-of (s / specific-02 :ARG2 (m2 / macro-molecular-complex :name (n / name :op1 "CSN")))) :ARG1 (d / degrade-01 :ARG0 (s2 / system :mod (p2 / proteasome :name (n2 / name :op1 "Ub-26S") :xref (x3 / xref :value "GO:0000502" :prob "0.8"))) :ARG1 (a / and :op1 (p3 / protein :name (n3 / name :op1 "p53") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :op2 (p4 / protein :name (n4 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG2-of (m3 / mutate-01)))) :snt2 (s3 / study-01 :ARG1 (d2 / degrade-01 :ARG1 (p5 / protein :name (n5 / name :op1 "p53") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG0-of (d3 / depend-01 :ARG1 (p6 / proteasome :name (n6 / name :op1 "Ub-26S") :xref (x4 / xref :value "GO:0000502" :prob "0.8")))) :location (l / lysate :mod (r / reticulocyte) :ARG0-of (c4 / contain-01 :ARG1 (a2 / and :op1 (s4 / system :mod p6 :mod (i2 / intact)) :op2 (m4 / macro-molecular-complex :name (n7 / name :op1 "CSN"))))))) # ::id bio.chicago_2015.894 # ::date 2015-10-22T03:21:11 # ::file bio_chicago_2015_894.txt # ::snt E6 promotes the ubiquitin-mediated degradation of p53 by the proteasome. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (p / promote-01 :ARG0 (p2 / protein :name (n / name :op1 "E6") :xref (x / xref :value "UNIPROT:Q8V9K8_HUMAN" :prob "1.001")) :ARG1 (d / degrade-01 :ARG0 p2 :ARG1 (p3 / protein :name (n2 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG2 (m2 / macro-molecular-complex :name (n4 / name :op1 "proteasome")) :ARG1-of (m / mediate-01 :ARG0 (p5 / protein :name (n3 / name :op1 "ubiquitin") :xref (x2 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702"))))) # ::id bio.chicago_2015.900 # ::date 2015-10-22T03:32:21 # ::file bio_chicago_2015_900.txt # ::snt The exception to this hierarchy is seen for pb where we find that ectopic epidermal expression of Scr and Dfd actually activate epidermal pb expression ( Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :ARG1 (e / except-01 :ARG1 (e7 / enzyme :name (n / name :op1 "pb") :xref (x1 / xref :value "UNIPROT:HIS3_HUMAN" :prob "0.602")) :ARG2 (h / hierarchy :mod (t / this)) :location-of (f / find-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG0 (e2 / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Scr") :xref (x / xref :value "UNIPROT:RBMS1_HUMAN" :prob "0.202")) :op2 (p3 / protein :name (n3 / name :op1 "Dfd"))) :ARG3 (e3 / epidermis :mod (e4 / ectopic))) :ARG1 (e5 / express-03 :ARG2 e7 :ARG3 (e6 / epidermis)) :ARG1-of (a3 / actual-02)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3"))) # ::id bio.chicago_2015.901 # ::date 2015-10-22T05:48:28 # ::file bio_chicago_2015_901.txt # ::snt beta-catenin contains amino- and carboxy-terminal transcriptional activation domains and a covalent fusion of either domain with the amino terminus of LEF-1 generates a fusion protein that functions constitutively and activates transcription independently of a Wnt signal ( 19). . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (a / and :op1 (c / contain-01 :ARG0 (p / protein :name (n / name :op1 "beta-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG1 (a2 / and :op1 (p2 / protein-segment :name (n2 / name :op1 "amino-terminus")) :op2 (p3 / protein-segment :name (n3 / name :op1 "carboxy-terminus")) :ARG0-of (a3 / activate-01 :ARG1 (t / transcribe-01)))) :op2 (g / generate-01 :ARG0 (f / fuse-01 :ARG1 (o / or :op1 p2 :op2 p3) :ARG2 (p4 / protein-segment :name (n4 / name :op1 "amino-terminus") :part-of (p5 / protein :name (n5 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002"))) :mod (c2 / covalent)) :ARG1 (p6 / protein :ARG3-of (f2 / fuse-01) :ARG0-of (f3 / function-01 :manner (c3 / constitutive)) :ARG0-of (a4 / activate-01 :ARG1 t :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 (s / signal-07 :ARG0 (p7 / protein :name (n6 / name :op1 "Wnt") :xref (x / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202"))))))) :ARG1-of (d3 / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "19")))) # ::id bio.chicago_2015.936 # ::date 2015-10-22T18:25:38 # ::file bio_chicago_2015_936.txt # ::snt Binding to Mdm2 inhibits the transcriptional activity of p53 (Momand et al., 1992 ; Oliner et al., 1993 ) and promotes the degradation of p53 by the 26S proteasome (Haupt et al., 1997 ; Kubbutat et al., 1997 ; Honda et al., 1997 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (a / and :op1 (i / inhibit-01 :ARG0 (b / bind-01 :ARG2 (p / protein :name (n / name :op1 "Mdm2") :xref (x1 / xref :value "UNIPROT:A7UKX7_HUMAN" :prob "0.701"))) :ARG1 (a2 / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1 (t / transcribe-01)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (p3 / publication-91 :ARG0 (a4 / and :op1 (p4 / person :name (n3 / name :op1 "Momand")) :op2 (p5 / person :mod (o / other))) :time (d2 / date-entity :year "1992")) :op2 (p6 / publication-91 :ARG0 (a5 / and :op1 (p7 / person :name (n4 / name :op1 "Oliner")) :op2 p5) :time (d3 / date-entity :year "1993"))))) :op2 (p8 / promote-01 :ARG0 b :ARG1 (d4 / degrade-01 :ARG0 (p9 / proteasome :name (n5 / name :op1 "26S") :xref (x2 / xref :value "GO:0000502" :prob "0.8")) :ARG1 p2) :ARG1-of (d5 / describe-01 :ARG0 (a6 / and :op1 (p10 / publication-91 :ARG0 (a7 / and :op1 (p11 / person :name (n6 / name :op1 "Haupt")) :op2 p5) :time (d6 / date-entity :year "1997")) :op2 (p12 / publication-91 :ARG0 (a8 / and :op1 (p13 / person :name (n7 / name :op1 "Kubbutat")) :op2 p5) :time d6) :op3 (p14 / publication-91 :ARG0 (a9 / and :op1 (p15 / person :name (n8 / name :op1 "Honda")) :op2 p5) :time d6))))) # ::id bio.chicago_2015.970 # ::date 2015-10-22T18:45:03 # ::file bio_chicago_2015_970.txt # ::snt Functionally, CBP and p300 enhance CREB-mediated transcription upon PKA activation [1,2,4] . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (e / enhance-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "CBP") :xref (x2 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "p300") :xref (x / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702"))) :ARG1 (t / transcribe-01 :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "CREB") :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")))) :time (a2 / activate-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "PKA") :xref (x3 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 "1" :op2 "2" :op3 "4"))))) :ARG1-of (f / function-01)) # ::id bio.chicago_2015.1058 # ::date 2015-10-22T18:56:38 # ::file bio_chicago_2015_1058.txt # ::snt Purified CREB and CREMalpha proteins were then phosphorylated with PKA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 22, 2015 (p / phosphorylate-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "CREB") :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :op2 (p3 / protein :name (n2 / name :op1 "CREMalpha") :xref (x2 / xref :value "UNIPROT:CREM_HUMAN" :prob "0.232")) :ARG1-of (p4 / purify-01)) :ARG2 (e / enzyme :name (n3 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :time (t / then)) # ::id bio.chicago_2015.1064 # ::date 2015-10-22T18:59:54 # ::file bio_chicago_2015_1064.txt # ::snt Although a mammalian homologue of STE5 has not yet been identified, two proteins, MP1 and JIP-1, have been suggested to function as a scaffold for MAPK modules that leads to specific activation of ERK and JNK ( 41, 52). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / suggest-01 :ARG1 (f / function-01 :ARG0 (p / protein :quant "2" :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (p2 / protein :name (n / name :op1 "MP1") :xref (x / xref :value "UNIPROT:PREP_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n2 / name :op1 "JIP-1") :xref (x2 / xref :value "UNIPROT:JIP1_HUMAN" :prob "1.002"))))) :ARG1 (s2 / scaffold :ARG0-of (l / lead-03 :ARG2 (a2 / activate-01 :ARG0 f :ARG1 (a3 / and :op1 (e / enzyme :name (n4 / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :ARG1-of (s3 / specific-02)))) :beneficiary (m2 / module :mod (p4 / pathway :name (n3 / name :op1 "MAPK")))) :concession (i / identify-01 :polarity "-" :ARG1 (h / homologue :mod (m3 / mammal) :mod (p5 / protein :name (n6 / name :op1 "STE5") :xref (x4 / xref :value "UNIPROT:ST1E1_HUMAN" :prob "0.262"))) :time (y / yet)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 "41" :op2 "52"))))) # ::id bio.chicago_2015.1117 # ::date 2015-10-25T19:10:17 # ::file bio_chicago_2015_1117.txt # ::snt Since the Asp replacement at Ser greatly decreases, but does not completely block, the activation of CREB by PKA, it is possible that the effect of this mutation is a quantitative rather than a complete block of CREB binding to CBP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (c / cause-01 :ARG0 (c2 / contrast-01 :ARG1 (d / decrease-01 :ARG0 (r / replace-01 :ARG1 (a / amino-acid :name (n / name :op1 "aspartic" :op2 "acid") :xref (x4 / xref :value "PUBCHEM:424" :prob "7.741247")) :location (a2 / amino-acid :name (n2 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 "a3" :ARG2 (g / great)) :ARG2 (b / block-01 :polarity "-" :ARG0 r :ARG1 (a3 / activate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1 (p / protein :name (n4 / name :op1 "CREB") :xref (x2 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))) :ARG1-of (c3 / complete-01))) :ARG1 (p2 / possible-01 :ARG1 (i / instead-of-91 :ARG1 (b2 / block-01 :mod (q / quantitative) :ARG2-of (a4 / affect-01 :ARG0 r)) :ARG2 (b3 / block-01 :ARG1 (b4 / bind-01 :ARG1 p :ARG2 (p3 / protein :name (n5 / name :op1 "CBP") :xref (x / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003"))) :ARG1-of c3)))) # ::id bio.chicago_2015.1141 # ::date 2015-10-26T17:37:11 # ::file bio_chicago_2015_1141.txt # ::snt p300/CBP interacts with CREB, E1A, PCAF, c-jun, c-fos, c-Myb, MyoD, and TFIIB # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (i / interact-01 :ARG0 (p / protein-family :name (n / name :op1 "p300/CBP")) :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "CREB") :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :op2 (p3 / protein :name (n3 / name :op1 "E1A") :xref (x4 / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.262")) :op3 (p4 / protein :name (n4 / name :op1 "PCAF") :xref (x3 / xref :value "UNIPROT:KAT2B_HUMAN" :prob "1.002")) :op4 (p5 / protein :name (n5 / name :op1 "c-jun")) :op5 (p6 / protein :name (n6 / name :op1 "c-fos")) :op6 (p7 / protein :name (n7 / name :op1 "c-Myb") :xref (x2 / xref :value "UNIPROT:Q708E1_HUMAN" :prob "0.661")) :op7 (p8 / protein :name (n8 / name :op1 "MyoD") :xref (x5 / xref :value "UNIPROT:MYOD1_HUMAN" :prob "0.602")) :op8 (p9 / protein :name (n9 / name :op1 "TFIIB") :xref (x1 / xref :value "UNIPROT:TF2B_HUMAN" :prob "1.002")))) # ::id bio.chicago_2015.1157 # ::date 2015-10-26T17:55:24 # ::file bio_chicago_2015_1157.txt # ::snt Somatostatin exerts its antiproliferative effect inhibiting more upstream the TSH stimulation of PKA and PI 3-kinase, interfering with the TSH-mediated increases of intracellular cAMP levels by inactivation of adenylyl cyclase activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (e / exert-01 :ARG0 (s / small-molecule :name (n / name :op1 "Somatostatin") :xref (x5 / xref :value "PUBCHEM:16129681" :prob "15.061441")) :ARG1 (a / affect-01 :ARG0 s :ARG0-of (c / counter-01 :ARG1 (p / proliferate-01))) :manner (i / inhibit-01 :ARG0 s :ARG1 (s2 / stimulate-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TSH") :xref (x3 / xref :value "PUBCHEM:15303" :prob "10.703792")) :ARG1 (a2 / and :op1 (e2 / enzyme :name (n3 / name :op1 "PKA") :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :op2 (e3 / enzyme :name (n4 / name :op1 "PI3-kinase") :xref (x1 / xref :value "UNIPROT:PK3C3_HUMAN" :prob "0.323")))) :location (u / upstream :degree (m / more)) :manner (i2 / interfere-01 :ARG0 s :ARG1 (i3 / increase-01 :ARG1 (l / level :quant-of (s4 / small-molecule :name (n5 / name :op1 "cAMP") :xref (x4 / xref :value "PUBCHEM:6076" :prob "15.374314")) :mod (i4 / intracellular)) :ARG1-of (m2 / mediate-01 :ARG0 s3)) :manner (a3 / activate-01 :polarity "-" :ARG0 s :ARG1 (a4 / activity-06 :ARG0 (e4 / enzyme :name (n6 / name :op1 "adenylyl" :op2 "cyclase") :xref (x / xref :value "UNIPROT:ADCY1_HUMAN" :prob "0.392"))))))) # ::id bio.chicago_2015.1195 # ::date 2015-10-27T18:57:02 # ::file bio_chicago_2015_1195.txt # ::snt We have previously shown that when the four consensus PKA sites are mutated, CI is no longer proteolyzed, regulated by PKA, or regulated by hedgehog signaling to activate wg ( 7, 8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (o / or :op1 (p / proteolyze-00 :polarity "-" :ARG1 (p2 / protein :name (n / name :op1 "CI"))) :op2 (r / regulate-01 :polarity "-" :ARG0 (e / enzyme :name (n2 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1 p2) :op3 (r2 / regulate-01 :ARG0 (s2 / signal-07 :ARG0 (p3 / protein :name (n3 / name :op1 "hedgehog") :xref (x / xref :value "UNIPROT:B2R8G3_HUMAN" :prob "0.281"))) :ARG1 p2) :purpose (a / activate-01 :ARG0 p2 :ARG1 (p4 / protein :name (n4 / name :op1 "wg"))) :time (m2 / mutate-01 :ARG1 (s3 / site-01 :quant "4" :ARG1 e :mod (c / consensus))) :ARG1-of (l / long-03 :degree (m / more))) :time (p5 / previous) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "7" :op2 "8"))))) # ::id bio.chicago_2015.1205 # ::date 2015-10-28T04:26:45 # ::file bio_chicago_2015_1205.txt # ::snt PKA and MAPK lead to the activation of CREB and to the induction of immediate-early genes, one of which--the ubiquitin hydrolase--is neuron specific. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (l / lead-03 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "PKA") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :op2 (e2 / enzyme :name (n2 / name :op1 "MAPK") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG2 (a2 / and :op1 (a3 / activate-01 :ARG0 a :ARG1 (p / protein :name (n3 / name :op1 "CREB") :xref (x2 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))) :op2 (i / induce-01 :ARG0 a :ARG2 (g / gene :mod (e3 / early :mod (i2 / immediate)) :ARG2-of (i3 / include-91 :ARG1 (g2 / gene :quant "1" :name (n4 / name :op1 "ubiquitin" :op2 "hydrolase") :ARG1-of (s / specific-02 :ARG2 (n5 / neuron)) :xref (x1 / xref :value "UNIPROT:D6RBV3_HUMAN" :prob "0.361"))))))) # ::id bio.chicago_2015.1221 # ::date 2015-10-28T04:43:16 # ::file bio_chicago_2015_1221.txt # ::snt Coexpressing axin inhibited the Lef-1 reporter activation induced by CKI (Fig. 3 b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "axin") :ARG2-of (c / coexpress-01) :xref (x2 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1 (a / activate-01 :ARG0 (e / enzyme :name (n2 / name :op1 "CKI") :xref (x1 / xref :value "UNIPROT:CHKA_HUMAN" :prob "1.002")) :ARG1 (p3 / protein :name (n3 / name :op1 "Lef-1") :ARG0-of (r / report-01) :xref (x / xref :value "UNIPROT:LEF1_HUMAN" :prob "0.632")) :ARG2-of (i2 / induce-01 :ARG0 e)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id bio.chicago_2015.1253 # ::date 2015-10-28T05:08:47 # ::file bio_chicago_2015_1253.txt # ::snt Activation of alpha 1A Adrenergic Receptors in Rat1 Cells Does Not Activate MAPK and RSK2-- Other investigators have reported that activation of MAPK (ERK1 and ERK2) by growth factors such as epidermal growth factor can lead to CREB phosphorylation and stimulation of gene expression via CRE elements ( 17). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (a / activate-01 :polarity "-" :ARG0 (a2 / activate-01 :ARG1 (p / protein-family :name (n / name :op1 "alpha" :op2 "1A" :op3 "adrenergic" :op4 "receptor")) :location (c / cell :name (n2 / name :op1 "Rat1"))) :ARG1 (a3 / and :op1 (p8 / protein-family :name (n3 / name :op1 "MAPK")) :op2 (e2 / enzyme :name (n4 / name :op1 "RSK2") :xref (x3 / xref :value "UNIPROT:KS6A3_HUMAN" :prob "1.002")))) :snt2 (r / report-01 :ARG0 (p2 / person :ARG0-of (i / investigate-01) :mod (o / other)) :ARG1 (p3 / possible-01 :ARG1 (l / lead-03 :ARG0 (a4 / activate-01 :ARG0 (f / factor :ARG0-of (g / grow-01) :example (p4 / protein :name (n5 / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x5 / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703"))) :ARG1 (p9 / protein-family :name (n6 / name :op1 "MAPK") :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (e4 / enzyme :name (n7 / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n8 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))))) :ARG2 (a6 / and :op1 (p5 / phosphorylate-01 :ARG1 (p6 / protein :name (n9 / name :op1 "CREB") :xref (x4 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :ARG2 p9) :op2 (s / stimulate-01 :ARG0 a4 :ARG1 (e6 / express-03 :ARG1 (g2 / gene)))) :instrument (e7 / element :mod (e8 / enzyme :name (n10 / name :op1 "CRE") :xref (x / xref :value "UNIPROT:CREG1_HUMAN" :prob "0.262"))))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 "17"))))) # ::id bio.chicago_2015.1255 # ::date 2015-10-28T07:39:52 # ::file bio_chicago_2015_1255.txt # ::snt These findings indicate that a PKA-dependent event other than CREB Ser133 phosphorylation is required for Ca2+ induction of CaRE-dependent transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i / indicate-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (r / require-01 :ARG0 (i2 / induce-01 :ARG0 (s / small-molecule :name (n6 / name :op1 "calcium") :ARG1-of (i3 / ionize-01 :value "2+") :xref (x4 / xref :value "PUBCHEM:5460341" :prob "10.601383")) :ARG2 (t3 / transcribe-01 :ARG0-of (d2 / depend-01 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "CaRE") :xref (x2 / xref :value "PUBCHEM:1176" :prob "10.82514"))))) :ARG1 (e / event :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG2-of (e3 / except-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "133" :name (n2 / name :op1 "serine") :part-of (p2 / protein :name (n3 / name :op1 "CREB") :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :mod (o / other)))) # ::id pmid_1592_8660.1 # ::date 2015-06-30T06:29:45 # ::file pmid_1592_8660_1.txt # ::snt Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS (PMID:15928660) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (e / event :mod (c / common) :location (m / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal)) :domain (a / activate-01 :ARG1 (p / pathway :name (n2 / name :op1 "MAPK")))) :ARG2 (m2 / mutate-01 :ARG1 (o2 / or :op1 (g / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n4 / name :op1 "RAS") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263"))) :manner-of e :ARG1-of (r / rare-02)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID15928660"))) # ::id pmid_1592_8660.81 # ::date 2015-06-30T08:42:48 # ::file pmid_1592_8660_81.txt # ::snt RESULTS # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 21, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1592_8660.82 # ::date 2015-06-30T09:29:29 # ::file pmid_1592_8660_82.txt # ::snt Mutation analysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (a / analyze-01 :ARG1 (m / mutate-01)) # ::id pmid_1592_8660.83 # ::date 2015-06-30T09:31:21 # ::file pmid_1592_8660_83.txt # ::snt Of the 11 uveal melanoma cell lines under study, only one cell line (Ocm 1) carried a BRAF mutation, the common V599E (also described by Calipel et al and Kilic et al). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / include-91 :ARG1 (c2 / cell-line :quant "1" :name (n3 / name :op1 "Ocm" :op2 "1") :mod (o / only) :ARG0-of (c3 / carry-01 :ARG1 (m / mutate-01 :value "V599E" :ARG1 (g / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (p / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n4 / name :op1 "Calipel")) :op2 (p3 / person :mod (o2 / other)))) :op2 (p6 / publication-91 :ARG0 (a4 / and :op1 (p4 / person :name (n5 / name :op1 "Kilic")) :op2 p3))) :mod (a / also)) :mod (c4 / common)))) :ARG2 (c / cell-line :quant "11" :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal)) :ARG1-of (s / study-01))) # ::id pmid_1592_8660.84 # ::date 2015-06-30T10:14:11 # ::file pmid_1592_8660_84.txt # ::snt All primary tumour specimens were wild type for BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (w / wild-type :domain (s / specimen :mod (t / tumor) :mod (a / all) :mod (p / primary)) :prep-for (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id pmid_1592_8660.85 # ::date 2015-06-30T10:36:01 # ::file pmid_1592_8660_85.txt # ::snt No mutations were found in the NRAS, HRAS or KRAS genes, in both the cell lines and primary tissue. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (f / find-01 :polarity "-" :ARG1 (m / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "HRAS") :location "a2" :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :op3 (g3 / gene :name (n3 / name :op1 "KRAS") :location "a2" :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :location (a2 / and :op1 (c / cell-line) :op2 (t / tissue :mod (p / primary)))) # ::id pmid_1592_8660.86 # ::date 2015-06-30T10:50:20 # ::file pmid_1592_8660_86.txt # ::snt Western blotting # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / immunoblot-01) # ::id pmid_1592_8660.87 # ::date 2015-06-30T10:56:22 # ::file pmid_1592_8660_87.txt # ::snt In order to assess the level of expression and the activation (by phosphorylation) of members of the MAPK pathway downstream of RAS and BRAF, Western blot analysis was performed on uveal melanoma cell lines (Table 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p3 / perform-01 :ARG1 (i2 / immunoblot-01 :ARG2 (c / cell-line :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma") :mod (u / uveal))) :purpose (a2 / assess-01 :ARG1 (a3 / and :op1 (l / level :degree-of (e / express-03 :ARG2 (m / member :ARG1-of (i / include-91 :ARG2 (p2 / pathway :name (n3 / name :op1 "MAPK")))) :location (r / relative-position :op1 (g / gene :name (n4 / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op2 (g2 / gene :name (n5 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :direction (d2 / downstream)))) :op2 (a4 / activate-01 :ARG0 (p / phosphorylate-01) :ARG1 m :location r))) :ARG1-of (d3 / describe-01 :ARG0 (t2 / table :mod "2A")))) # ::id pmid_1592_8660.88 # ::date 2015-06-30T12:14:56 # ::file pmid_1592_8660_88.txt # ::snt The expression levels of the downstream members of RAS and BRAF are presented in Figure 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / present-01 :ARG1 (l / level :degree-of (e / express-03 :ARG2 (m / member :ARG1-of (i / include-91 :ARG2 (a / and :op1 (p2 / protein-family :name (n / name :op1 "RAS")) :op2 (e3 / enzyme :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :mod (d / downstream)))) :location (f / figure :mod "3")) # ::id pmid_1592_8660.89 # ::date 2015-06-30T12:39:19 # ::file pmid_1592_8660_89.txt # ::snt In response to the constitutively activating BRAF mutation in Ocm 1, downstream members of the MAPK pathway show activation (phosphorylated MEK, ERK and ELK). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / show-01 :ARG0 (m / member :ARG1-of (i / include-91 :ARG2 (p / pathway :name (n / name :op1 "MAPK"))) :mod (d / downstream)) :ARG1 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK") :ARG3-of p2 :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n4 / name :op1 "ELK") :ARG3-of p2 :xref (x / xref :value "UNIPROT:EPHB1_HUMAN" :prob "1.003")))) :ARG2-of (r / respond-01 :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n5 / name :op1 "BRAF") :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (a3 / activate-01 :manner (c / constitutive)) :location (c2 / cell-line :name (n6 / name :op1 "Ocm" :op2 "1"))))) # ::id pmid_1592_8660.90 # ::date 2015-06-30T13:10:18 # ::file pmid_1592_8660_90.txt # ::snt Levels of expression of the downstream members were not different in the two cell lines derived from the same primary tumour (92.1 and 92.2), except for phosphorylated MEK, indicating that there had been little clonal divergence between the cell populations during in vitro culturing. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (d / differ-02 :polarity "-" :ARG1 (l / level :degree-of (e / express-03 :ARG2 (m / member :mod (d2 / downstream) :ARG2-of (e2 / except-01 :ARG1 (e3 / enzyme :name (n / name :op1 "MEK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))))) :location (a / and :op1 (c6 / cell-line :name (n4 / name :op1 "92.1") :ARG1-of (d3 / derive-01 :ARG2 (t / tumor :ARG1-of (s / same-01) :mod (p / primary)))) :op2 (c / cell-line :name (n2 / name :op1 "92.2") :ARG1-of d3)) :ARG0-of (i / indicate-01 :ARG1 (d4 / diverge-01 :ARG0 (p3 / population :mod (c3 / cell)) :degree (l2 / little) :location (t2 / there) :mod (c2 / clone-01) :time (c4 / culture-01 :manner (i2 / in-vitro))))) # ::id pmid_1592_8660.91 # ::date 2015-06-30T14:23:57 # ::file pmid_1592_8660_91.txt # ::snt Interestingly, compared to the phosphorylation status of these members in Ocm 1, most cell lines show activation of MEK, ERK and ELK; however, these cell lines show this activation in the absence of mutations in the upstream RAS and BRAF genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / show-01 :ARG0 (c / cell-line :quant (m / most)) :ARG1 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n3 / name :op1 "ELK") :xref (x1 / xref :value "UNIPROT:EPHB1_HUMAN" :prob "1.003"))) :compared-to (s2 / status :mod (p / phosphorylate-01) :poss (m2 / member :mod (t / this)) :location (c2 / cell-line :name (n4 / name :op1 "Ocm" :op2 "1")))) :mod (i / interesting) :concession-of (s3 / show-01 :ARG0 c :ARG1 a :condition (a3 / absent-01 :ARG1 (m3 / mutate-01 :ARG1 (a4 / and :op1 (g / gene :name (n5 / name :op1 "RAS") :location (u / upstream) :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op2 (g2 / gene :name (n6 / name :op1 "BRAF") :location u :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) # ::id pmid_1592_8660.92 # ::date 2015-06-30T21:20:26 # ::file pmid_1592_8660_92.txt # ::snt The levels of total ERK were remarkably similar across all cell lines, with the exception of two cell lines Mel 285 and Mel 290, which had significantly higher levels of total ERK than the others. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r2 / resemble-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK") :mod (t / total) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (r / remarkable-02) :location (a / across :op1 (c / cell-line :mod (a2 / all) :ARG2-of (e2 / except-01 :ARG1 (a3 / and :op1 (c3 / cell-line :name (n3 / name :op1 "Mel" :op2 "285") :ARG0-of (h / have-03 :ARG1 (l2 / level :ARG1-of (h2 / high-02 :degree (m / more) :ARG1-of (s / significant-02) :compared-to (c2 / cell-line :mod (o / other))) :quant-of e))) :op2 (c4 / cell-line :name (n5 / name :op1 "Mel" :op2 "290") :ARG0-of h)))))) # ::id pmid_1592_8660.93 # ::date 2015-07-01T03:03:20 # ::file pmid_1592_8660_93.txt # ::snt In keeping with this observation, these two cell lines also have the highest levels of phosphorylated-ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-03 :ARG0 (c / cell-line :quant "2" :mod (t / this)) :ARG1 (l / level :ARG1-of (h2 / high-02 :degree (m / most)) :quant-of (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :mod (a / also) :ARG1-of (k / keep-06 :ARG2 (o / observe-01 :ARG1 (t2 / this)))) # ::id pmid_1592_8660.94 # ::date 2015-07-01T09:03:14 # ::file pmid_1592_8660_94.txt # ::snt Figure 2 shows that there is no significant influence of serum on the activity of ERK1/2 in these cell lines, as reported recently by Calipel et al (2003). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 21, 2015 (s / show-01 :ARG0 (f / figure :mod "2") :ARG1 (i / influence-01 :ARG0 (s3 / serum) :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ERK1/2"))) :ARG1-of (s2 / significant-02 :polarity "-") :location (c / cell-line :mod (t / this))) :ARG1-of (r / report-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and :op1 (p / person :name (n2 / name :op1 "Calipel")) :op2 (p2 / person :mod (o / other))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :time (d2 / date-entity :year "2003")))) # ::id pmid_1592_8660.95 # ::date 2015-07-01T09:36:22 # ::file pmid_1592_8660_95.txt # ::snt Immunohistochemistry # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (i / immunohistochemistry) # ::id pmid_1592_8660.96 # ::date 2015-07-01T09:41:34 # ::file pmid_1592_8660_96.txt # ::snt Immunofluorescence results of total and phospho-ERK1/2 on a panel of 19 fresh frozen uveal melanoma sections are listed in Table 2 (B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (l / list-01 :ARG1 (r / result-01 :ARG2 (a / and :op1 (e / enzyme :name (n / name :op1 "ERK1/2") :mod (t / total)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :location (p2 / panel :consist-of (s / section-01 :mod (m / medical-condition :name (n2 / name :op1 "melanoma")) :mod (u / uveal :quant "19" :ARG1-of (f / fresh-04) :ARG1-of (f2 / freeze-01)))) :instrument (i / immunofluoresce-01)) :ARG2 (t2 / table :mod "2" :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "B")))) # ::id pmid_1592_8660.97 # ::date 2015-07-01T10:35:38 # ::file pmid_1592_8660_97.txt # ::snt In seven of the 19 primary tumours, less than 5% of the tumour cells stained positively for ERK1/2 and nine tumours for phosphorylated ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (s / stain-01 :ARG1 (c / cell :ARG1-of (i / include-91 :ARG2 (c2 / cell :mod (t / tumor)) :ARG3 (l / less-than :op1 (p / percentage-entity :value "5"))) :mod t) :manner (p2 / positive) :location (t3 / tumor :quant "7" :ARG1-of (i3 / include-91 :ARG2 (t4 / tumor :quant "19" :mod (p4 / primary)))) :beneficiary (e / enzyme :name (n2 / name :op1 "ERK1/2"))) :op2 (s2 / stain-01 :ARG1 (t2 / tumor :quant "9" :ARG1-of (i2 / include-91 :ARG2 t4)) :beneficiary (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p3 / phosphorylate-01)))) # ::id pmid_1592_8660.98 # ::date 2015-07-01T11:14:08 # ::file pmid_1592_8660_98.txt # ::snt Despite the lack of mutations in the RAS and BRAF genes in this set of uveal melanomas, it is noteworthy that we observed phosphorylated (active) ERK1/2 expression in 10 of 19 tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (n / note-01 :ARG1 (o / observe-01 :ARG0 (w / we) :ARG1 (e / express-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01 :ARG1-of (m / mean-01 :ARG2 (a / activity-06))))) :location (t / tumor :quant "10" :ARG1-of (i / include-91 :ARG2 (t2 / tumor :quant "19"))) :concession (l / lack-01 :ARG1 (m2 / mutate-01 :ARG1 (a2 / and :op1 (g / gene :name (n3 / name :op1 "RAS") :location (s / set :mod (t3 / this) :consist-of (m3 / medical-condition :name (n5 / name :op1 "melanoma") :mod (u / uveal))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op2 (g2 / gene :name (n4 / name :op1 "BRAF") :location s :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) :ARG1-of (r / recommend-01)) # ::id pmid_1592_8660.99 # ::date 2015-07-01T12:06:57 # ::file pmid_1592_8660_99.txt # ::snt There was no significant association between ERK1/2 activation and tumour location or cell type. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / associate-01 :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))) :ARG2 (o / or :op1 (l / location :location-of (t / tumor)) :op2 (t2 / type-03 :ARG1 (c / cell))) :ARG1-of (s / significant-02 :polarity "-")) # ::id pmid_1592_8660.100 # ::date 2015-07-01T12:18:55 # ::file pmid_1592_8660_100.txt # ::snt The scoring system for each antibody cannot be compared between antibodies since the antibodies recognise different epitopes and with different affinities; therefore, the staining intensity on Western or by immunohistochemistry is relative only to the other samples for the particular antibody used. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p2 / possible-01 :polarity "-" :ARG1 (c / compare-01 :ARG1 (s / system :instrument-of (s2 / score-01 :ARG1 (a / antibody :mod (e / each)))) :ARG2 (s3 / system :instrument-of (s4 / score-01 :ARG1 (a2 / antibody))) :ARG1-of (c2 / cause-01 :ARG0 (r / recognize-02 :ARG0 a :ARG1 (e2 / epitope :ARG1-of (d / differ-02) :ARG0-of (h / have-03 :ARG1 (a3 / affinity :ARG1-of d))))) :ARG0-of (c3 / cause-01 :ARG1 (r2 / relative-05 :ARG1 (i / intensity :mod (s5 / stain-01) :instrument (o / or :op1 (i3 / immunoblot-01) :op2 (i2 / immunohistochemistry))) :ARG3 (t / thing :mod (o3 / other) :beneficiary (a4 / antibody :mod (p / particular) :ARG1-of (u / use-01)) :ARG1-of (s6 / sample-01)) :mod (o2 / only))))) # ::id pmid_1684_6534.1 # ::date 2015-08-13T06:22:08 # ::file pmid_1684_6534_1.txt # ::snt MUC1 alters oncogenic events and transcription in human breast cancer cells (PMID:16846534) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / alter-01 :ARG0 (p / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG1 (a2 / and :op1 (e / event :ARG0-of (c / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :op2 (t / transcribe-01)) :location (c3 / cell :source (d2 / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer")) :mod (h / human)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID16846534"))) # ::id pmid_1684_6534.8 # ::date 2015-08-13T06:25:56 # ::file pmid_1684_6534_8.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1684_6534.9 # ::date 2015-08-13T06:27:54 # ::file pmid_1684_6534_9.txt # ::snt Transcription of several genes was altered after transfection of MUC1 siRNA, including decreased MAP2K1 (MEK1), JUN, PDGFA, CDC25A, VEGF and ITGAV (integrin αv), and increased TNF, RAF1, and MMP2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (a / alter-01 :ARG1 (t / transcribe-01 :ARG1 (g / gene :quant (s / several)) :ARG2-of (i / include-01 :ARG1 (a3 / and :op1 (a4 / and :op1 (t3 / transcribe-01 :ARG1 (g2 / gene :name (n3 / name :op1 "MAP2K1") :ARG1-of (m / mean-01 :ARG2 (g8 / gene :ARG0-of (e / encode-01 :ARG1 (e2 / enzyme :name (n13 / name :op1 "MEK1") :xref (x9 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))))) :xref (x6 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (t4 / transcribe-01 :ARG1 (g3 / gene :name (n4 / name :op1 "JUN") :xref (x5 / xref :value "UNIPROT:JUN_HUMAN" :prob "1.003"))) :op3 (t5 / transcribe-01 :ARG1 (g4 / gene :name (n5 / name :op1 "PDGFA") :xref (x4 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "1.004"))) :op4 (t6 / transcribe-01 :ARG1 (g5 / gene :name (n6 / name :op1 "CDC25A") :xref (x3 / xref :value "UNIPROT:MPIP1_HUMAN" :prob "1.002"))) :op5 (t7 / transcribe-01 :ARG1 (g6 / gene :name (n7 / name :op1 "VEGF") :xref (x2 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003"))) :op6 (t8 / transcribe-01 :ARG1 (g7 / gene :name (n8 / name :op1 "ITGAV") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n9 / name :op1 "integrin" :op2 "αv") :xref (x10 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.301"))) :xref (x1 / xref :value "UNIPROT:ITAV_HUMAN" :prob "1.003"))) :ARG1-of (d / decrease-01)) :op2 (a5 / and :op1 (t9 / transcribe-01 :ARG1 (g9 / gene :name (n10 / name :op1 "TNF") :xref (x7 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))) :op2 (t10 / transcribe-01 :ARG1 (g10 / gene :name (n11 / name :op1 "RAF1") :xref (x11 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.004"))) :op3 (t11 / transcribe-01 :ARG1 (g11 / gene :name (n12 / name :op1 "MMP2") :xref (x8 / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.003"))) :ARG1-of (i2 / increase-01))))) :time (a2 / after :op1 (t2 / transfect-01 :ARG2 (n14 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))))) # ::id pmid_1684_6534.10 # ::date 2015-08-13T06:36:42 # ::file pmid_1684_6534_10.txt # ::snt Additional changes were seen at the protein level, such as increased expression of c-Myc, heightened phosphorylation of AKT, and decreased activation of MEK1/2 and ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (s / see-01 :ARG1 (c / change-01 :ARG1 (l / level :quant-of (p / protein)) :mod (a / additional) :example (a2 / and :op1 (e / express-03 :ARG2 (p3 / protein :name (n / name :op1 "c-Myc") :xref (x5 / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.661")) :ARG1-of (i / increase-01)) :op2 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT") :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (h / heighten-01)) :op3 (a3 / activate-01 :ARG1 (a4 / and :op1 (e3 / enzyme :name (n3 / name :op1 "MEK1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n4 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :op3 (e5 / enzyme :name (n5 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op4 (e6 / enzyme :name (n6 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1-of (d / decrease-01))))) # ::id pmid_1684_6534.11 # ::date 2015-08-13T06:42:53 # ::file pmid_1684_6534_11.txt # ::snt These were correlated with cellular events, as MUC1 siRNA in the MDA-MB-468 line decreased proliferation and invasion, and increased stress-induced apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (c / correlate-01 :ARG1 (t / this) :ARG2 (e / event :mod (c2 / cell)) :ARG1-of (c4 / cause-01 :ARG0 (a / and :op1 (d / decrease-01 :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))) :ARG1 (a3 / and :op1 (p2 / proliferate-01) :op2 (i / invade-01))) :op2 (i2 / increase-01 :ARG0 n4 :ARG1 (a2 / apoptosis :ARG2-of (i3 / induce-01 :ARG0 (s / stress)))) :location (c3 / cell-line :name (n3 / name :op1 "MDA-MB-468"))))) # ::id pmid_1684_6534.12 # ::date 2015-08-13T06:48:18 # ::file pmid_1684_6534_12.txt # ::snt Intriguingly, BT-20 cells displayed similar levels of apoptosis regardless of siRNA, and actually increased proliferation after MUC1 siRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (a5 / and :op1 (d / display-01 :ARG0 (c / cell-line :name (n / name :op1 "BT-20")) :ARG1 (l / level :degree-of (a2 / apoptosis) :ARG1-of (r / resemble-01)) :ARG1-of (r2 / regardless-91 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA")))) :op2 (i / increase-01 :ARG0 c :ARG1 (p / proliferate-01 :ARG0 c) :ARG1-of (a / actual-02) :time (a4 / after :op1 (n6 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))))) :ARG0-of (i2 / intrigue-01)) # ::id pmid_1684_6534.100 # ::date 2015-08-13T06:55:36 # ::file pmid_1684_6534_100.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1684_6534.101 # ::date 2015-08-13T07:00:22 # ::file pmid_1684_6534_101.txt # ::snt siRNA transfection decreases MUC1 expression in breast cancer cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (d / decrease-01 :ARG0 (t / transfect-01 :ARG2 (n3 / nucleic-acid :name (n / name :op1 "siRNA"))) :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG3 (c / cell-line :source (d2 / disease :wiki "Breast_cancer" :name (n4 / name :op1 "breast" :op2 "cancer"))))) # ::id pmid_1684_6534.102 # ::date 2015-08-13T07:03:23 # ::file pmid_1684_6534_102.txt # ::snt Two human breast cancer cell lines, MDA-MB-468 and BT-20, were transiently transfected with a pool of four siRNA oligonucleotides directed against the MUC1 mRNA (468.siMUC1 and BT.siMUC1), or a control oligonucleotide directed against luciferase (468.siLuc and BT.siLuc). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (t / transfect-01 :ARG1 (c / cell-line :quant "2" :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n / name :op1 "MDA-MB-468")) :op2 (c4 / cell-line :name (n2 / name :op1 "BT-20")))) :source (d3 / disease :wiki "Breast_cancer" :name (n8 / name :op1 "breast" :op2 "cancer") :mod (h / human))) :ARG2 (o / or :op1 (p / pool :consist-of (o2 / oligonucleotide :quant "4" :mod (n11 / nucleic-acid :name (n3 / name :op1 "siRNA"))) :ARG1-of (d / direct-01 :ARG2 (n12 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (c6 / cell-line :name (n6 / name :op1 "468.siMUC1")) :op2 (c7 / cell-line :name (n7 / name :op1 "BT.siMUC1"))))) :op2 (o5 / oligonucleotide :mod (c5 / control) :ARG1-of (d2 / direct-01 :ARG2 (l / luciferase)) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and :op1 (c8 / cell-line :name (n9 / name :op1 "468.siLuc")) :op2 (c9 / cell-line :name (n10 / name :op1 "BT.siLuc")))))) :manner (t2 / transient-02)) # ::id pmid_1684_6534.103 # ::date 2015-08-13T07:14:15 # ::file pmid_1684_6534_103.txt # ::snt Both cell lines express high levels of MUC1, making them promising targets for this analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (e / express-03 :ARG2 (l / level :ARG1-of (h / high-02) :quant-of (p / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :ARG3 "c2" :ARG0-of (m / make-02 :ARG1 (c2 / cell-line :mod (b / both) :ARG1-of (t / target-01 :ARG0 (a / analyze-01 :mod (t2 / this))) :ARG0-of (p2 / promise-01)))) # ::id pmid_1684_6534.104 # ::date 2015-08-13T07:21:19 # ::file pmid_1684_6534_104.txt # ::snt Western blots (Figure 1a) show successful knockdown of both the extracellular domain and cytoplasmic tail fragments of MUC1; luciferase siRNA does not substantially change the level of MUC1 compared to parental cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG0 (i / immunoblot-01 :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1a"))) :ARG1 (k / knock-down-02 :ARG1 (a / and :op1 (p / protein-segment :mod (e / extracellular) :part-of (p2 / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :op2 (f2 / fragment :part-of (t2 / tail :mod (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :part-of p2))) :ARG0-of (s3 / succeed-01))) :snt2 (c2 / change-01 :polarity "-" :ARG0 (n4 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 (l2 / luciferase))) :ARG1 (l / level :quant-of (p3 / protein :name (n5 / name :op1 "MUC1") :xref (x1 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :degree (s2 / substantial) :compared-to (c3 / cell :mod (p4 / parental)))) # ::id pmid_1684_6534.105 # ::date 2015-08-13T07:29:42 # ::file pmid_1684_6534_105.txt # ::snt 468.siMUC1 show a substantial decrease in the amount of MUC1-CT, while BT.siMUC1 show slightly less knockdown of MUC1-CT. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "468.siMUC1")) :ARG1 (d / decrease-01 :ARG1 (a / amount :quant-of (p / protein-segment :name (n / name :op1 "MUC1-CT"))) :ARG2 (s2 / substantial))) :ARG2 (s3 / show-01 :ARG0 (c3 / cell-line :name (n3 / name :op1 "BT.siMUC1")) :ARG1 (k / knock-down-02 :ARG1 p :ARG2 (l / less :degree (s4 / slight))))) # ::id pmid_1684_6534.106 # ::date 2015-08-13T07:34:33 # ::file pmid_1684_6534_106.txt # ::snt Both MDA-MB-468 and BT-20 display a less dramatic decrease of MUC1 extracellular domain compared to MUC1-CT (Figure 1a); this likely represents protein synthesized prior to transfection, and may reflect differences in the turnover rates of the two subunits. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (d / display-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "MDA-MB-468")) :op2 (c2 / cell-line :name (n2 / name :op1 "BT-20"))) :ARG1 (d2 / decrease-01 :ARG1 (p2 / protein-segment :mod (e / extracellular) :part-of (p / protein :name (n3 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :ARG2 (d3 / dramatic :degree (l / less)) :compared-to (p3 / protein-segment :name (n4 / name :op1 "MUC1-CT"))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "1a")) :ARG0-of (r / represent-01 :ARG1 (p4 / protein :ARG1-of (s / synthesize-01 :time (p6 / prior :op1 (t / transfect-01)))) :ARG1-of (l2 / likely-01)) :ARG1-of (r2 / reflect-01 :ARG2 (d5 / differ-02 :ARG1 (r3 / rate :degree-of (t2 / turnover) :poss (a2 / and :op1 p2 :op2 p3))) :ARG1-of (p5 / possible-01))) # ::id pmid_1684_6534.107 # ::date 2015-08-13T07:42:39 # ::file pmid_1684_6534_107.txt # ::snt Analysis of the MUC1 extracellular domain by flow cytometry confirms that both cell lines substantially decrease MUC1 expression after siRNA (Figure 1b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / confirm-01 :ARG0 (a / analyze-01 :ARG1 (p / protein-segment :mod (e / extracellular) :part-of (p2 / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :instrument (c2 / cytometry :mod (f / flow))) :ARG1 (d / decrease-01 :ARG0 (c3 / cell-line :mod (b / both)) :ARG1 (e2 / express-03 :ARG2 p2) :ARG2 (s / substantial) :time (a2 / after :op1 (n3 / nucleic-acid :name (n2 / name :op1 "siRNA")))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1b"))) # ::id pmid_1684_6534.108 # ::date 2015-08-13T07:48:54 # ::file pmid_1684_6534_108.txt # ::snt By flow cytometry, 468.siMUC1 averaged 75% knockdown of MUC1 compared to 468.siLuc; and BT.siMUC1 averaged 50% knockdown relative to BT.siLuc. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (a / and :op1 (a2 / average-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "468.siMUC1") :compared-to (c3 / cell-line :name (n3 / name :op1 "468.siLuc"))) :ARG1 (k / knock-down-02 :ARG1 (p2 / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :ARG2 (p / percentage-entity :value "75")) :op2 (a3 / average-01 :ARG0 (c5 / cell-line :name (n5 / name :op1 "BT.siMUC1") :ARG1-of (r / relative-05 :ARG3 (c4 / cell-line :name (n4 / name :op1 "BT.siLuc")))) :ARG1 (k2 / knock-down-02) :ARG2 (p3 / percentage-entity :value "50")) :time (c / cytometry :mod (f / flow))) # ::id pmid_1684_6534.109 # ::date 2015-08-13T07:52:32 # ::file pmid_1684_6534_109.txt # ::snt These effects could be titrated with the concentration of siRNA, were seen as early as 24 hours post-transfection (data not shown) and lasted to at least 96 h post-transfection (Figure 1b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (a / and :op1 (p / possible-01 :ARG1 (t / titrate-01 :ARG0 (c / concentrate-02 :ARG1 (n2 / nucleic-acid :name (n / name :op1 "siRNA"))) :ARG1 (a2 / affect-01 :mod (t2 / this)))) :op2 (s / see-01 :ARG1 a2 :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity "-"))) :time (a3 / after :op1 (t3 / transfect-01) :quant (t4 / temporal-quantity :quant "24" :unit (h / hour) :mod (e2 / early)))) :op3 (l / last-01 :ARG1 a2 :ARG2 (u / until :op1 (a4 / after :op1 t3 :quant (t5 / temporal-quantity :quant "96" :unit h))) :mod (a5 / at-least) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1b")))) # ::id pmid_1684_6534.110 # ::date 2015-08-13T08:03:02 # ::file pmid_1684_6534_110.txt # ::snt All experiments were conducted within 48 to 96 hours after siRNA transfection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / conduct-01 :ARG1 (e / experiment-01 :mod (a / all)) :time (a2 / after :op1 (t / transfect-01 :ARG2 (n2 / nucleic-acid :name (n / name :op1 "siRNA"))) :quant (u / up-to :op1 (v / value-interval :op1 (t2 / temporal-quantity :quant "48" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "96" :unit h))))) # ::id pmid_1684_6534.111 # ::date 2015-08-13T08:07:04 # ::file pmid_1684_6534_111.txt # ::snt Similar results were obtained using two independent oligonucleotides designed in our lab (data not shown), designated '882' and '956' for the initial codon recognized by each. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (o / obtain-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :manner (u / use-01 :ARG1 (o2 / oligonucleotide :quant "2" :ARG0-of (d / depend-01 :polarity "-") :ARG1-of (d3 / describe-01 :ARG0 (d4 / data :ARG1-of (s / show-01 :polarity "-"))) :ARG1-of (d5 / designate-01 :ARG2 (a / and :op1 (o3 / oligonucleotide :mod "882") :op2 (o4 / oligonucleotide :mod "956")) :ARG1-of (c / cause-01 :ARG0 (c2 / codon :mod (i / initial) :ARG1-of (r3 / recognize-02 :location o2)))) :ARG1-of (d2 / design-01 :location (l / laboratory :poss (w / we)))))) # ::id pmid_1684_6534.112 # ::date 2015-08-13T08:16:26 # ::file pmid_1684_6534_112.txt # ::snt Transcriptional changes are seen after MUC1 siRNA # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (s / see-01 :ARG1 (c / change-01 :ARG1 (t / transcribe-01)) :time (a / after :op1 (n3 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))))) # ::id pmid_1684_6534.113 # ::date 2015-08-13T08:19:27 # ::file pmid_1684_6534_113.txt # ::snt Recent work indicates that MUC1 may affect transcription both directly via interaction with transcription factors and indirectly (for example, through modulating signaling). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (i / indicate-01 :ARG0 (w / work-01 :time (r / recent)) :ARG1 (p / possible-01 :ARG1 (a / affect-01 :ARG0 (p2 / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG1 (t / transcribe-01) :manner (a2 / and :op1 (d / direct-02 :manner (i2 / interact-01 :ARG0 p2 :ARG1 (f / factor :ARG0-of t))) :op2 (d2 / direct-02 :polarity "-" :example (m / modulate-01 :ARG0 p2 :ARG1 (s / signal-07))))))) # ::id pmid_1684_6534.114 # ::date 2015-08-13T08:24:05 # ::file pmid_1684_6534_114.txt # ::snt To study the effects of MUC1 knockdown in breast cancer cell lines, real-time PCR arrays were used to analyze transcription of 84 genes implicated in cancer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (u / use-01 :ARG1 (a / array-01 :mod (r2 / react-01 :ARG0 (p / polymerase) :mod (r / real-time) :mod (c4 / chain))) :ARG2 (a2 / analyze-01 :ARG1 (t / transcribe-01 :ARG1 (g / gene :quant "84" :ARG1-of (i / implicate-01 :ARG2 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))) :purpose (s / study-01 :ARG1 (a3 / affect-01 :ARG0 (k / knock-down-02 :ARG1 (p2 / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :ARG1 (c2 / cell-line :source (d2 / disease :wiki "Breast_cancer" :name (n3 / name :op1 "breast" :op2 "cancer")))))) # ::id pmid_1684_6534.115 # ::date 2015-08-13T08:32:00 # ::file pmid_1684_6534_115.txt # ::snt Only genes with greater than two-fold change were considered. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / consider-02 :ARG1 (g / gene :ARG1-of (c2 / change-01 :ARG2 (g2 / great :degree (m / more) :compared-to (c3 / change-01 :ARG2 (p / product-of :op1 "2"))))) :mod (o / only)) # ::id pmid_1684_6534.116 # ::date 2015-08-13T08:34:41 # ::file pmid_1684_6534_116.txt # ::snt Three genes (MAP2K1, VEGF, PDGFA) were altered two-fold or more after MUC1 siRNA in both MDA-MB-468 and BT-20 cells (Figure 2); two genes (ITGAV, MMP2) changed only in 468.siMUC1; and five genes (TIMP3, RAF1, JUN, TNF, CDC25A) only in BT.siMUC1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (a6 / and :op1 (a / alter-01 :ARG1 (g / gene :quant "3" :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (g2 / gene :name (n / name :op1 "MAP2K1") :xref (x6 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n2 / name :op1 "VEGF") :xref (x5 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :op3 (g4 / gene :name (n3 / name :op1 "PDGFA") :xref (x4 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "1.004"))))) :degree (o / or :op1 (p / product-of :op1 "2") :op2 (m3 / more-than :op1 p)) :time (a3 / after :op1 (n17 / nucleic-acid :name (n4 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "MUC1") :xref (x3 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))) :location (a4 / and :op1 (c / cell-line :name (n6 / name :op1 "MDA-MB-468")) :op2 (c2 / cell-line :name (n7 / name :op1 "BT-20"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2"))) :op2 (c3 / change-01 :ARG1 (g5 / gene :quant "2" :ARG1-of (m4 / mean-01 :ARG2 (a5 / and :op1 (g6 / gene :name (n8 / name :op1 "ITGAV") :xref (x / xref :value "UNIPROT:ITAV_HUMAN" :prob "1.003")) :op2 (g7 / gene :name (n9 / name :op1 "MMP2") :xref (x2 / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.003"))))) :mod "o2" :location (c5 / cell-line :name (n15 / name :op1 "468.siMUC1"))) :op3 (c4 / change-01 :ARG1 (g8 / gene :quant "5" :ARG1-of (m / mean-01 :ARG2 (a7 / and :op1 (g9 / gene :name (n10 / name :op1 "TIMP3") :xref (x7 / xref :value "UNIPROT:TIMP3_HUMAN" :prob "1.003")) :op2 (g10 / gene :name (n11 / name :op1 "RAF1") :xref (x10 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.004")) :op3 (g11 / gene :name (n12 / name :op1 "JUN") :xref (x9 / xref :value "UNIPROT:JUN_HUMAN" :prob "1.003")) :op4 (g12 / gene :name (n13 / name :op1 "TNF") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op5 (g13 / gene :name (n14 / name :op1 "CDC25A") :xref (x8 / xref :value "UNIPROT:MPIP1_HUMAN" :prob "1.002"))))) :mod (o2 / only) :location (c6 / cell-line :name (n16 / name :op1 "BT.siMUC1")))) # ::id pmid_1684_6534.117 # ::date 2015-08-13T08:45:07 # ::file pmid_1684_6534_117.txt # ::snt This list represents all genes affected greater than two-fold after MUC1 siRNA, rather than a select group. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (r / represent-01 :ARG0 (l / list :mod (t / this)) :ARG1 (g / gene :mod (a / all) :ARG1-of (a2 / affect-01 :degree (g2 / great :degree (m / more) :compared-to (p / product-of :op1 "2")) :time (a3 / after :op1 (n3 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))))) :ARG1-of (i / instead-of-91 :ARG2 (g3 / group :ARG1-of (s / select-01)))) # ::id pmid_1684_6534.118 # ::date 2015-08-13T08:48:48 # ::file pmid_1684_6534_118.txt # ::snt Three genes whose transcription was changed by less than two-fold are shown, two of which (PDGFB and ITGB1) are listed because they relate closely to genes altered by two-fold (PDGFA and ITGAV). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (s / show-01 :ARG1 (g / gene :quant "3" :ARG1-of (t / transcribe-01 :ARG1-of (c / change-01 :ARG2 (l / less-than :op1 (p / product-of :op1 "2")))) :ARG2-of (i / include-91 :ARG1 (g2 / gene :quant "2" :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (g3 / gene :name (n / name :op1 "PDGFB") :xref (x3 / xref :value "UNIPROT:PDGFB_HUMAN" :prob "1.004")) :op2 (g4 / gene :name (n2 / name :op1 "ITGB1") :xref (x2 / xref :value "UNIPROT:ITB1_HUMAN" :prob "1.003")))) :ARG1-of (l2 / list-01 :ARG1-of (c2 / cause-01 :ARG0 (r / relate-01 :ARG1 g2 :ARG2 (g5 / gene :ARG1-of (a2 / alter-01 :degree p) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (g6 / gene :name (n3 / name :op1 "PDGFA") :xref (x1 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "1.004")) :op2 (g7 / gene :name (n4 / name :op1 "ITGAV") :xref (x / xref :value "UNIPROT:ITAV_HUMAN" :prob "1.003"))))) :manner (c3 / close-10)))))))) # ::id pmid_1684_6534.119 # ::date 2015-08-13T08:55:46 # ::file pmid_1684_6534_119.txt # ::snt The third, MYC, is included because western blots confirmed a substantial change at the protein level (Figure 3a) that may reflect both transcriptional and post-transcriptional regulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (i / include-01 :ARG1 (g / gene :ord (o / ordinal-entity :value "3") :ARG1-of (m / mean-01 :ARG2 (g2 / gene :name (n / name :op1 "MYC") :xref (x / xref :value "UNIPROT:MYC_HUMAN" :prob "1.004")))) :ARG1-of (c / cause-01 :ARG0 (c2 / confirm-01 :ARG0 (i2 / immunoblot-01) :ARG1 (c3 / change-01 :ARG1 (l / level :quant-of (p / protein)) :degree (s / substantial) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3a")) :ARG1-of (r / reflect-01 :ARG2 (a / and :op1 (r2 / regulate-01 :time (t2 / transcribe-01)) :op1 (r3 / regulate-01 :time (a2 / after :op1 t2))) :ARG1-of (p2 / possible-01)))))) # ::id pmid_1684_6534.120 # ::date 2015-08-13T09:02:18 # ::file pmid_1684_6534_120.txt # ::snt Interestingly, transcription of MAP2K1 was decreased in both cell lines after MUC1 siRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (d / decrease-01 :ARG1 (t / transcribe-01 :ARG1 (g / gene :name (n / name :op1 "MAP2K1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :location (c / cell-line :mod (b / both)) :time (a / after :op1 (n4 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "MUC1") :xref (x1 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))) :ARG2-of (i / interest-01)) # ::id pmid_1684_6534.121 # ::date 2015-08-13T09:10:40 # ::file pmid_1684_6534_121.txt # ::snt This gene encodes MEK1, one of the primary regulators of the ERK1/2 MAPK pathway [33], a network that has been linked several times to MUC1 [12,34-36]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (e / encode-01 :ARG0 (g / gene :mod (t / this)) :ARG1 (e2 / enzyme :name (n / name :op1 "MEK1") :ARG1-of (i / include-91 :ARG2 (m / molecular-physical-entity :ARG0-of (r / regulate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "ERK1/2" :op2 "MAPK") :mod (n3 / network :ARG1-of (l / link-01 :ARG2 (p4 / protein :name (n4 / name :op1 "MUC1") :xref (x1 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :frequency (s / several) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "12")) :op2 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 "34" :op2 "36"))))))))) :mod (p / primary)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "33")))) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) # ::id pmid_1684_6534.122 # ::date 2015-08-13T09:18:52 # ::file pmid_1684_6534_122.txt # ::snt We examined MEK1 and MEK2 levels by western blot to confirm decreased protein in MUC1 siRNA-treated cells (Figure 3a), and found that not only were total MEK1/2 levels lower in 468.siMUC1 and BT.siMUC1 compared to controls (0.48 and 0.68 relative to siLuc, respectively), but so were the basal amounts of active (phosphorylated) MEK1/2 (pMEK1/2; 0.12 and 0.42 relative to siLuc, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (e / examine-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (l / level :quant-of (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (l2 / level :quant-of (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :manner (i / immunoblot-01) :purpose (c / confirm-01 :ARG0 w :ARG1 (p / protein :ARG1-of (d / decrease-01 :location (c2 / cell :ARG1-of (t2 / treat-04 :ARG2 (n11 / nucleic-acid :name (n4 / name :op1 "siRNA") :ARG0-of (e4 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "MUC1") :xref (x4 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3a"))) :op2 (f2 / find-01 :ARG0 w :ARG1 (a3 / and :op1 (a4 / and :op1 (l3 / level :quant-of e2) :op2 (l4 / level :quant-of e3) :mod (t3 / total) :ARG1-of (l5 / low-04 :degree (m / more) :compared-to (c3 / control)) :ARG1-of (m2 / mean-01 :ARG2 (a14 / and :op1 (l6 / level :quant "0.48") :op2 (l7 / level :quant "0.68") :manner "r2" :ARG1-of (r3 / relative-05 :ARG3 (c6 / cell-line :name (n8 / name :op1 "siLuc"))) :mod t3))) :op2 (a7 / and :op1 (a8 / amount :quant-of (e5 / enzyme :name (n9 / name :op1 "MEK1") :ARG1-of (a10 / activate-01 :ARG1-of (m3 / mean-01 :ARG2 (p3 / phosphorylate-01 :ARG3 e5))) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (a9 / amount :quant-of (e6 / enzyme :name (n10 / name :op1 "MEK2") :ARG1-of (a11 / activate-01 :ARG1-of (m5 / mean-01 :ARG2 (p4 / phosphorylate-01 :ARG3 e6))) :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (b / basal) :ARG1-of l5 :ARG1-of (m4 / mean-01 :ARG2 (a12 / and :op1 (a6 / amount :quant "0.12") :op2 (a13 / amount :quant "0.42") :manner (r2 / respective) :ARG1-of r3 :mod b)))) :location (a5 / and :op1 (c4 / cell-line :name (n6 / name :op1 "468.siMUC1")) :op2 (c5 / cell-line :name (n7 / name :op1 "BT.siMUC1"))))) # ::id pmid_1684_6534.123 # ::date 2015-08-13T09:34:57 # ::file pmid_1684_6534_123.txt # ::snt Both 468.siMUC1 and BT.siMUC1 also showed reduced activation of ERK1/2 (dpERK1/2; 0.21 and 0.27 relative to siLuc, respectively), as would be expected with diminished signaling through MEK1/2; total ERK1/2 levels remain unchanged. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (m2 / multi-sentence :snt1 (s / show-01 :ARG0 (a / and :op1 (c3 / cell-line :name (n7 / name :op1 "468.siMUC1")) :op2 (c4 / cell-line :name (n8 / name :op1 "BT.siMUC1"))) :ARG1 (a3 / activate-01 :ARG1 (s2 / slash :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of (p / phosphorylate-01 :mod (d3 / dual))) :ARG1-of (r / reduce-01) :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (a5 / activate-01 :degree "0.21") :op2 (a6 / activate-01 :degree "0.27") :manner (r2 / respective) :ARG1-of (r4 / relative-05 :ARG3 (c5 / cell-line :name (n9 / name :op1 "siLuc")))))) :mod (a2 / also) :ARG1-of (e3 / expect-01 :ARG1-of (c / cause-01 :ARG0 (s3 / signal-07 :ARG0 (s4 / slash :op1 (e4 / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n4 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG1-of (d / diminish-01))))) :snt2 (r3 / remain-01 :ARG1 (l2 / level :mod (t / total) :quant-of s2) :ARG3 (c2 / change-01 :polarity "-"))) # ::id pmid_1684_6534.124 # ::date 2015-08-13T09:48:48 # ::file pmid_1684_6534_124.txt # ::snt As both lines have high levels of EGFR and thus activate the MEK-ERK cascade intensely when stimulated with EGF [37], siRNA-transfected cells were treated with EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t / treat-04 :ARG1 (c / cell :ARG1-of (t2 / transfect-01 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA")))) :ARG2 (p3 / protein :name (n3 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1-of (c2 / cause-01 :ARG0 (h / have-03 :ARG0 (c3 / cell-line :mod (b / both)) :ARG1 (l / level :ARG1-of (h2 / high-02) :quant-of (e / enzyme :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG2-of (i / infer-01 :ARG1 (a / activate-01 :ARG0 c3 :ARG1 (p / pathway :name (n4 / name :op1 "MEK-ERK")) :manner (i2 / intense-02) :time (s2 / stimulate-01 :ARG1 c3 :ARG2 p3)))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "37"))))) # ::id pmid_1684_6534.125 # ::date 2015-08-13T09:55:17 # ::file pmid_1684_6534_125.txt # ::snt Notably, MUC1 siRNA impairs this important oncogenic pathway in MDA-MB-468 cells, as 468.siMUC1 display less pMEK1/2 in response to EGF than do 468.siLuc (Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / impair-01 :ARG0 (n11 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e3 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "MUC1") :xref (x3 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))) :ARG1 (p2 / pathway :mod (t / this) :mod (i2 / important) :ARG0-of (c / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n10 / name :op1 "cancer")))) :location (c3 / cell-line :name (n3 / name :op1 "MDA-MB-468")) :ARG1-of (n4 / notable-04) :ARG1-of (c4 / cause-01 :ARG0 (d / display-01 :ARG0 (c5 / cell-line :name (n8 / name :op1 "468.siMUC1")) :ARG1 (s / slash :op1 (e / enzyme :name (n5 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n6 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG3-of (p3 / phosphorylate-01) :quant (l / less)) :ARG2-of (r2 / respond-01 :ARG1 (p4 / protein :name (n7 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :compared-to (d2 / display-01 :ARG0 (c6 / cell-line :name (n9 / name :op1 "468.siLuc")) :ARG1 (s3 / slash :op1 e :op2 e2)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id pmid_1684_6534.126 # ::date 2015-08-13T10:03:21 # ::file pmid_1684_6534_126.txt # ::snt Interestingly, EGF treatment of BT-20 cells results in slightly higher pMEK1/2 levels in BT.siMUC1 compared to BT.siLuc. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG1 (c / cell-line :name (n2 / name :op1 "BT-20")) :ARG2 (s / small-molecule :name (n / name :op1 "EGF") :xref (x2 / xref :value "PUBCHEM:56841751" :prob "18.167522"))) :ARG2 (l / level :ARG1-of (h / high-02 :degree (m / more :degree (s2 / slight)) :compared-to (c2 / cell-line :name (n5 / name :op1 "BT.siLuc"))) :quant-of (s3 / slash :op1 (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG3-of (p / phosphorylate-01)) :location (c3 / cell-line :name (n6 / name :op1 "BT.siMUC1"))) :ARG2-of (i / interest-01)) # ::id pmid_1684_6534.127 # ::date 2015-08-14T01:03:53 # ::file pmid_1684_6534_127.txt # ::snt Though this result seems paradoxical in light of decreased MAP2K1 transcription in BT.siMUC1, it likely results from differential functions of Raf isoforms in combination with the increased RAF1 transcription (Figure 2) and protein level (Figure 3a) in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (h / have-concession-91 :ARG1 (l / likely-01 :ARG1 (r3 / result-01 :ARG1 (c / combine-01 :ARG1 (f / function-01 :ARG0 (e / enzyme :name (n / name :op1 "Raf") :mod (i / isoform) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :mod (d2 / differential)) :ARG2 (a / and :op1 (t4 / transcribe-01 :ARG1 (g2 / gene :name (n4 / name :op1 "RAF1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.004")) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "2"))) :op2 (l2 / level :quant-of (p / protein) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "3a"))) :location "c3" :ARG1-of (i2 / increase-01))) :ARG2 "t")) :ARG2 (s / seem-01 :ARG1 (p2 / paradox :domain (t / thing :ARG2-of (r / result-01) :mod (t2 / this))) :ARG1-of (c4 / cause-01 :ARG0 (d / decrease-01 :ARG1 (t3 / transcribe-01 :ARG1 (g / gene :name (n2 / name :op1 "MAP2K1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :location (c3 / cell-line :name (n3 / name :op1 "BT.siMUC1"))))))) # ::id pmid_1684_6534.128 # ::date 2015-08-14T01:13:56 # ::file pmid_1684_6534_128.txt # ::snt Specifically, B-Raf is thought to be the main activator of MEK under normal conditions; Raf-1 activates MEK in response to stimulus [38]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (a2 / and :op1 (t2 / think-01 :ARG1 (a3 / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :mod (m / main) :condition (n4 / normal))) :op2 (a4 / activate-01 :ARG0 (e4 / enzyme :name (n5 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1 e3 :ARG2-of (r / respond-01 :ARG1 (s / stimulus))) :ARG1-of (s2 / specific-02) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "38")))) # ::id pmid_1684_6534.129 # ::date 2015-08-14T01:24:38 # ::file pmid_1684_6534_129.txt # ::snt Thus, it appears that basal pMEK1/2 levels are not greatly affected by Raf-1 overexpression in BT.siMUC1 cells, likely because MEK is regulated primarily by B-Raf under normal growth conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (c2 / cause-01 :ARG0 (r / regulate-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "B-Raf") :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e5 / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (l2 / likely-01) :manner (p / primary) :condition (g2 / grow-01 :ARG1-of (n7 / normal-02))) :ARG1 (a / appear-02 :ARG1 (a2 / affect-01 :polarity "-" :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Raf-1") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :location (c / cell-line :name (n6 / name :op1 "BT.siMUC1"))) :ARG1 (l / level :quant-of (s / slash :op1 (e3 / enzyme :name (n4 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n5 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG3-of (p2 / phosphorylate-01)) :mod (b / basal)) :extent (g / great)))) # ::id pmid_1684_6534.130 # ::date 2015-08-14T01:31:02 # ::file pmid_1684_6534_130.txt # ::snt In contrast, when the cells are stimulated (EGF), increased Raf-1 levels in BT.siMUC1 leads to heightened pMEK1/2 (Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (l / lead-03 :ARG0 (l2 / level :quant-of (e / enzyme :name (n / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :location (c2 / cell-line :name (n2 / name :op1 "BT.siMUC1")) :ARG1-of (i / increase-01)) :ARG2 (s / slash :op1 (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG3-of (p / phosphorylate-01) :ARG1-of (h / heighten-01)) :time (s2 / stimulate-01 :ARG1 (c3 / cell) :ARG2 (p2 / protein :name (n5 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id pmid_1684_6534.131 # ::date 2015-08-14T01:34:58 # ::file pmid_1684_6534_131.txt # ::snt MUC1 siRNA increases apoptosis in MDA-MB-468 but not BT-20 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (c / contrast-01 :ARG1 (i / increase-01 :ARG0 (n5 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))) :ARG1 (a / apoptosis) :location (c2 / cell-line :name (n3 / name :op1 "MDA-MB-468"))) :ARG2 (i2 / increase-01 :polarity "-" :ARG0 n5 :ARG1 a :location (c3 / cell-line :name (n4 / name :op1 "BT-20")))) # ::id pmid_1684_6534.132 # ::date 2015-08-14T02:18:32 # ::file pmid_1684_6534_132.txt # ::snt We next examined whether MUC1 knockdown and its associated transcriptional alterations would affect overall cellular events. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :mode "interrogative" :ARG0 (a2 / and :op1 (k / knock-down-02 :ARG1 (p / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :op2 (a3 / alter-01 :ARG1 (t / transcribe-01 :ARG1 p) :ARG1-of (a4 / associate-01 :ARG2 k))) :ARG1 (e2 / event :mod (c / cell) :mod (o / overall))) :time (n / next)) # ::id pmid_1684_6534.133 # ::date 2015-08-14T02:22:33 # ::file pmid_1684_6534_133.txt # ::snt As several of the genes shown in Figure 2 are important in regulating proliferation and survival, and because of the recently described role of MUC1 in modulating apoptosis in response to cellular stresses [20,21,24], we first analyzed whether MUC1 siRNA would alter apoptosis in these lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (a2 / alter-01 :mode "interrogative" :ARG0 (n3 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))) :ARG1 (a3 / apoptosis) :location (c / cell-line :mod (t / this))) :time (f / first) :ARG1-of (c2 / cause-01 :ARG0 (a4 / and :op1 (i / important :domain (g / gene :quant (s / several) :ARG1-of (i2 / include-91 :ARG2 (g2 / gene :ARG1-of (s2 / show-01 :medium (f2 / figure :mod "2"))))) :purpose (r2 / regulate-01 :ARG1 (a5 / and :op1 (p2 / proliferate-01) :op2 (s3 / survive-01)))) :op2 (p3 / play-02 :ARG0 p :ARG1 (m / modulate-01 :ARG0 p :ARG1 a3 :ARG2-of (r3 / respond-01 :ARG1 (s4 / stress :mod (c3 / cell)))) :ARG1-of (d / describe-01 :time (r4 / recent))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "20")) :op2 (p5 / publication :ARG1-of (c5 / cite-01 :ARG2 "21")) :op3 (p6 / publication :ARG1-of (c6 / cite-01 :ARG2 "24"))))))) # ::id pmid_1684_6534.134 # ::date 2015-08-14T02:29:39 # ::file pmid_1684_6534_134.txt # ::snt Although there was no change in basal apoptosis in either line (Figure 4a), we observed that the cell lines responded differently when trypsinized for re-plating 24 hours after transfection (Figure 4b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (h2 / have-concession-91 :ARG1 (o / observe-01 :ARG0 (w / we) :ARG1 (r / respond-01 :ARG0 "c2" :ARG1-of (d2 / differ-01) :time (t2 / trypsinize-00 :ARG1 "c2" :purpose (r2 / replate-00) :time (a2 / after :op1 (t3 / transfect-01 :ARG1 "c2") :quant (t / temporal-quantity :quant "24" :unit (h / hour))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "4b"))) :ARG2 (c / change-01 :polarity "-" :ARG1 (a / apoptosis :mod (b / basal)) :location (c2 / cell-line :mod (e / either)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4a")))) # ::id pmid_1684_6534.135 # ::date 2015-08-14T02:35:58 # ::file pmid_1684_6534_135.txt # ::snt Interestingly, 468.siMUC1 cells show greater apoptosis after trypsinization than do 468.siLuc (49.8% versus 34.0%, respectively), while BT-20 cells from both siRNA treatments display similar levels of apoptosis (around 22%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (c2 / cell-line :name (n / name :op1 "468.siMUC1")) :ARG1 (a / apoptosis :mod (g / great :degree (m / more) :compared-to (c3 / cell-line :name (n2 / name :op1 "468.siLuc") :ARG1-of (m3 / mean-01 :ARG2 (p2 / percentage-entity :value "34.0"))) :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value "49.8")))) :time (a2 / after :op1 (t / trypsinize-00))) :ARG2 (d / display-01 :ARG0 (c4 / cell-line :name (n3 / name :op1 "BT-20") :source (t2 / treat-04 :ARG2 (n5 / nucleic-acid :name (n4 / name :op1 "siRNA")) :mod (b / both))) :ARG1 (l / level :degree-of a :ARG1-of (r / resemble-01) :ARG1-of (m4 / mean-01 :ARG2 (p3 / percentage-entity :value "22")))) :ARG2-of (i / interest-01)) # ::id pmid_1684_6534.136 # ::date 2015-08-14T02:40:34 # ::file pmid_1684_6534_136.txt # ::snt To examine whether this phenomenon is specific to trypsin treatment or part of a general stress response involving MUC1, we subjected cells to a panel of stresses and measured cell death. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (a / and :op1 (s / subject-01 :ARG0 (w / we) :ARG1 (c / cell) :ARG2 (p / panel :consist-of (s2 / stress))) :op2 (m / measure-01 :ARG0 w :ARG1 (d / die-01 :ARG1 c)) :purpose (e2 / examine-01 :ARG0 w :ARG1 (o / or :mode "interrogative" :op1 (s3 / specific-02 :ARG1 "p2" :ARG2 (t2 / treat-04 :ARG2 (e / enzyme :name (n / name :op1 "trypsin") :xref (x1 / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342")))) :op2 (p2 / phenomenon :mod (t / this) :subevent-of (r / respond-01 :ARG1 (s4 / stress) :ARG1-of (g / general-02) :ARG2-of (i / involve-01 :ARG1 (p3 / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))))))) # ::id pmid_1684_6534.137 # ::date 2015-08-14T02:49:17 # ::file pmid_1684_6534_137.txt # ::snt In agreement with the patterns seen with trypsinization, BT.siLuc and BT.siMUC1 respond similarly to all treatments (data not shown), while 468.siMUC1 die more readily than 468.siLuc in response to trypsin, G418, hydrogen peroxide, or celecoxib, a chemotherapeutic that targets the cyclooxygenase-2 (COX-2) pathway (Figure 4c); these data were confirmed with two independent siRNA constructs (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (r / respond-01 :ARG0 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "BT.siLuc")) :op2 (c3 / cell-line :name (n3 / name :op1 "BT.siMUC1"))) :ARG1 (t / treat-04 :mod (a2 / all)) :ARG1-of (r2 / resemble-01) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s / show-01 :polarity "-")))) :ARG2 (d3 / die-01 :ARG1 (c4 / cell-line :name (n4 / name :op1 "468.siMUC1")) :manner (r3 / ready-02 :degree (m2 / more) :compared-to (c5 / cell-line :name (n5 / name :op1 "468.siLuc"))) :ARG2-of (r4 / respond-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "trypsin") :xref (x / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342")) :op2 (s2 / small-molecule :name (n6 / name :op1 "G418") :xref (x2 / xref :value "PUBCHEM:123865" :prob "18.013371")) :op3 (s3 / small-molecule :name (n7 / name :op1 "hydrogen" :op2 "peroxide") :xref (x1 / xref :value "PUBCHEM:784" :prob "9.462467")) :op4 (s4 / small-molecule :name (n8 / name :op1 "celecoxib") :mod (s5 / small-molecule :mod (c6 / chemotherapy) :ARG0-of (t2 / target-01 :ARG1 (p / pathway :name (n9 / name :op1 "cyclooxygenase-2")))) :xref (x3 / xref :value "PUBCHEM:2662" :prob "16.493546"))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "4c")) :ARG0-of (a3 / agree-01 :ARG2 (p2 / pattern :ARG1-of (s7 / see-01 :time (t4 / trypsinize-00))))) :snt2 (c7 / confirm-01 :ARG0 (c8 / construct :quant "2" :mod (n11 / nucleic-acid :name (n10 / name :op1 "siRNA")) :ARG0-of (d6 / depend-01 :polarity "-")) :ARG1 (d5 / data :mod (t3 / this)) :ARG1-of (d7 / describe-01 :ARG0 (d8 / data :ARG1-of (s6 / show-01 :polarity "-"))))) # ::id pmid_1684_6534.138 # ::date 2015-08-14T03:04:36 # ::file pmid_1684_6534_138.txt # ::snt Like the MAPK pathway, AKT signaling has been linked to MUC1 in cancer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (l / link-01 :ARG1 (s / signal-07 :ARG0 (e / enzyme :name (n3 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG2 (p2 / protein :name (n4 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG1-of (r / resemble-01 :ARG2 (p / pathway :name (n / name :op1 "MAPK"))) :location (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) # ::id pmid_1684_6534.139 # ::date 2015-08-14T03:07:43 # ::file pmid_1684_6534_139.txt # ::snt Although transcription of AKT was not altered in MUC1 siRNA-treated cells, the results of our apoptosis studies prompted us to investigate levels of AKT further. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (h / have-concession-91 :ARG1 (p / prompt-02 :ARG0 (t / thing :ARG2-of (r / result-01 :ARG1 (s / study-01 :ARG0 (w / we) :ARG1 (a / apoptosis)))) :ARG1 w :ARG2 (i / investigate-01 :ARG0 w :ARG1 (l / level :quant-of (e / enzyme :name (n2 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :degree (f / further))) :ARG2 (a2 / alter-01 :polarity "-" :ARG1 (t2 / transcribe-01 :ARG1 (g / gene :name (n / name :op1 "AKT") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :location (c / cell :ARG1-of (t3 / treat-04 :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))))))) # ::id pmid_1684_6534.140 # ::date 2015-08-14T03:12:21 # ::file pmid_1684_6534_140.txt # ::snt As expected, the total AKT protein level is not greatly changed after MUC1 siRNA in either cell line, though the active form (pAKT) is increased in both 468.siMUC1 and BT.siMUC1 compared to controls (Figure 3a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c / change-01 :polarity "-" :ARG1 (l / level :mod (t / total) :quant-of (e4 / enzyme :name (n / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :degree (g / great) :time (a / after :op1 (n7 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n3 / name :op1 "MUC1") :xref (x1 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))) :location (c2 / cell-line :mod (e / either)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3a")) :ARG1-of (e2 / expect-01) :concession (i / increase-01 :ARG1 (f2 / form :mod e4 :ARG1-of (a2 / activate-01) :ARG1-of (m / mean-01 :ARG2 (e5 / enzyme :name (n6 / name :op1 "AKT") :ARG3-of (p5 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :location (a3 / and :op1 (c3 / cell-line :name (n4 / name :op1 "468.siMUC1")) :op2 (c4 / cell-line :name (n5 / name :op1 "BT.siMUC1"))) :compared-to (c5 / control))) # ::id pmid_1684_6534.141 # ::date 2015-08-14T03:16:22 # ::file pmid_1684_6534_141.txt # ::snt This result disagrees with MUC1 activation of the AKT pathway in rat 3Y1 cells [18], and may reflect regulation more appropriate to breast cancer cells; this is supported by activation of AKT in response to MUC1 siRNA in other lines [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / and :op1 (d3 / disagree-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG1 (a2 / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG1 (p2 / pathway :name (n3 / name :op1 "AKT")) :location (c / cell :name (n4 / name :op1 "3Y1") :source (r2 / rat))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "18")))) :op2 (p4 / possible-01 :ARG1 (r3 / reflect-01 :ARG1 t :ARG2 (r4 / regulate-01 :ARG1-of (a3 / appropriate-02 :ARG2 (c3 / cell :source (d2 / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))) :degree (m / more))))) :ARG1-of (s / support-01 :ARG0 (a4 / activate-01 :ARG1 p2 :ARG2-of (r5 / respond-01 :ARG1 (n6 / nucleic-acid :name (n5 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 p))) :location (c5 / cell-line :mod (o / other))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c6 / cite-01 :ARG2 "21"))))) # ::id pmid_1684_6534.142 # ::date 2015-08-14T03:34:15 # ::file pmid_1684_6534_142.txt # ::snt In addition, there is a striking difference in the relative amounts of AKT and pAKT in the two cell lines (Figure 4d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (a4 / and :op2 (d / differ-02 :ARG1 (a2 / and :op1 (a / amount :ARG1-of (r / relative-05) :quant-of (e / enzyme :name (n / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op2 (a3 / amount :ARG1-of r :quant-of (e2 / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :ARG0-of (s / strike-01) :location (c / cell-line :quant "2") :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4d")))) # ::id pmid_1684_6534.143 # ::date 2015-08-14T03:41:50 # ::file pmid_1684_6534_143.txt # ::snt When lysates from both lines are exposed to film for the same length of time (overexposure masks the differences between BT.siLuc and BT.siMUC1 that are apparent in Figure 3a), it is clear that pAKT levels are much higher in BT-20 than in MDA-MB-468, despite lower total AKT expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / clear-06 :ARG1 (h2 / high-02 :ARG1 (l2 / level :quant-of (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :degree (m / more :quant (m3 / much)) :location (c2 / cell-line :name (n2 / name :op1 "BT-20")) :compared-to (c3 / cell-line :name (n3 / name :op1 "MDA-MB-468"))) :time (e3 / expose-01 :ARG1 (l3 / lysate :source (a / and :op1 c2 :op2 c3)) :ARG2 (f / film) :duration (s / same-01) :ARG1-of (m4 / mean-01 :ARG2 (m5 / mask-01 :ARG0 (o / overexpose-00 :ARG1 l3) :ARG1 (d / differ-02 :ARG1 (c4 / cell-line :name (n4 / name :op1 "BT.siLuc")) :ARG2 (c5 / cell-line :name (n5 / name :op1 "BT.siMUC1")) :ARG1-of (a2 / appear-02 :medium (f2 / figure :mod "3a")))))) :concession (e2 / express-03 :ARG2 e :degree (t / total) :ARG1-of (l / low-04 :degree (m2 / more)))) # ::id pmid_1684_6534.144 # ::date 2015-08-14T00:41:43 # ::file pmid_1684_6534_144.txt # ::snt This difference in AKT activation between MDA-MB-468 and BT-20 likely contributes to the disparity in their sensitivity to the increased apoptosis expected with loss of MUC1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (l / likely-01 :ARG1 (c / contribute-01 :ARG0 (d / differ-02 :ARG1 (c3 / cell-line :name (n2 / name :op1 "MDA-MB-468")) :ARG2 (c2 / cell-line :name (n3 / name :op1 "BT-20")) :ARG3 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :mod (t / this)) :ARG2 (d2 / disparity :domain (s / sensitive-03 :ARG0 (a3 / and :op1 c3 :op2 c2) :ARG1 (a2 / apoptosis :ARG1-of (i / increase-01) :ARG1-of (e2 / expect-01 :time (l2 / lose-02 :ARG1 (p / protein :name (n4 / name :op1 "MUC1") :xref (x1 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))))))) # ::id pmid_1684_6534.145 # ::date 2015-08-14T01:34:31 # ::file pmid_1684_6534_145.txt # ::snt MUC1 siRNA alters proliferation and invasion # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (a / alter-01 :ARG0 (n3 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))) :ARG1 (a2 / and :op1 (p / proliferate-01) :op2 (i / invade-01))) # ::id pmid_1684_6534.146 # ::date 2015-08-14T01:40:06 # ::file pmid_1684_6534_146.txt # ::snt As MUC1 is involved in apoptosis, we next analyzed its effects on proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (c / cause-01 :ARG0 (i / involve-01 :ARG1 (p2 / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG2 (a3 / apoptosis)) :ARG1 (a / analyze-01 :ARG0 (w / we) :ARG1 (a2 / affect-01 :ARG0 p2 :ARG1 (p / proliferate-01)) :time (n / next))) # ::id pmid_1684_6534.147 # ::date 2015-08-14T01:43:41 # ::file pmid_1684_6534_147.txt # ::snt BrdU and [3H]thymidine incorporation were used to analyze proliferation after MUC1 siRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (u / use-01 :ARG1 (a / and :op1 (i / incorporate-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU") :xref (x1 / xref :value "PUBCHEM:6035" :prob "18.013371"))) :op2 (i2 / incorporate-02 :ARG1 (s / small-molecule :name (n2 / name :op1 "3H-thymidine") :xref (x2 / xref :value "PUBCHEM:162681" :prob "11.68539")))) :ARG2 (a2 / analyze-01 :ARG1 (p / proliferate-01)) :time (a3 / after :op1 (n5 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p3 / protein :name (n4 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))))) # ::id pmid_1684_6534.148 # ::date 2015-08-15T12:22:08 # ::file pmid_1684_6534_148.txt # ::snt 468.siMUC1 cells show a significant decrease in [3H]thymidine incorporation compared to 468.siLuc, while intriguingly, BT.siMUC1 cells show a significant increase in proliferation (Figure 5a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (c3 / cell-line :name (n / name :op1 "468.siMUC1")) :ARG1 (d2 / decrease-01 :ARG1 (i / incorporate-02 :ARG1 (s5 / small-molecule :name (n3 / name :op1 "3H-thymidine") :xref (x / xref :value "PUBCHEM:162681" :prob "11.68539"))) :ARG1-of (s3 / significant-02)) :compared-to (s2 / show-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "468.siLuc")))) :ARG2 (s4 / show-01 :ARG0 (c4 / cell-line :name (n4 / name :op1 "BT.siMUC1")) :ARG1 (i2 / increase-01 :ARG1 (p / proliferate-01) :ARG1-of s3) :ARG0-of (i3 / intrigue-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5a"))) # ::id pmid_1684_6534.149 # ::date 2015-08-15T11:58:09 # ::file pmid_1684_6534_149.txt # ::snt Growth curves mirror these results, as do experiments with the two independent MUC1 siRNA oligonucleotides (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (m / mirror-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (c / curve-01 :ARG1 (g / grow-01)) :ARG1-of (r3 / resemble-01 :ARG2 (m2 / mirror-01 :ARG2 (e2 / experiment-01 :ARG1 (o / oligonucleotide :quant "2" :mod (n3 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))) :ARG0-of (d / depend-01 :polarity "-"))))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s / show-01 :polarity "-")))) # ::id pmid_1684_6534.150 # ::date 2015-08-15T12:03:35 # ::file pmid_1684_6534_150.txt # ::snt Note that these assays require trypsinizing cells 24 hours post-transfection; therefore, the results in the MDA-MB-468 line could stem from the changes in apoptosis described in the previous section, rather than a true effect on proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (m / multi-sentence :snt1 (n / note-01 :ARG1 (r2 / require-01 :ARG0 (a3 / assay-01 :mod (t4 / this)) :ARG1 (t5 / trypsinize-00 :ARG1 (c4 / cell) :time (a4 / after :op1 (t6 / transfect-01) :quant (t / temporal-quantity :quant "24" :unit (h / hour)))))) :snt2 (c / cause-01 :ARG1 (p2 / possible-01 :ARG1 (i / instead-of-91 :ARG1 (s / stem-01 :ARG1 (t2 / thing :ARG2-of (r / result-01) :location (c3 / cell-line :name (n2 / name :op1 "MDA-MB-468"))) :ARG2 (c2 / change-01 :ARG1 (a2 / apoptosis) :ARG1-of (d / describe-01 :ARG0 (s2 / section :mod (p4 / previous))))) :ARG2 (a / affect-01 :ARG0 t2 :ARG1 (p3 / proliferate-01) :ARG1-of (t3 / true-01)))))) # ::id pmid_1684_6534.151 # ::date 2015-08-15T11:48:01 # ::file pmid_1684_6534_151.txt # ::snt To control for this, we incubated non-trypsinized, siRNA-transfected cells at similar confluence with BrdU to measure incorporation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (i / incubate-01 :ARG0 (w / we) :ARG1 (c / cell :ARG1-of (t / transfect-01 :ARG2 (n3 / nucleic-acid :name (n / name :op1 "siRNA"))) :ARG1-of (t2 / trypsinize-00 :polarity "-")) :ARG3 (c2 / confluence :ARG1-of (r / resemble-01 :ARG2 (c3 / confluence :mod (s / small-molecule :name (n2 / name :op1 "BrdU") :xref (x / xref :value "PUBCHEM:6035" :prob "18.013371"))))) :ARG4 (m / measure-01 :ARG0 w :ARG1 (i2 / incorporate-02)) :purpose (c4 / control-01 :ARG0 w :ARG1 (t3 / this))) # ::id pmid_1684_6534.152 # ::date 2015-08-15T11:57:15 # ::file pmid_1684_6534_152.txt # ::snt The 'clumped' profile of cells (contrast to Figure 4b) is likely a result of the acid denaturation (recommended by the antibody manufacturer), as it occurs uniformly in these experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 16, 2015 (c2 / cause-01 :ARG0 (u / uniform-02 :ARG1 "p" :location (t / thing :ARG1-of (e / experiment-01) :mod (t2 / this))) :ARG1 (l / likely-01 :ARG1 (r / result-01 :ARG1 (n / natural-02 :polarity "-" :ARG1 (a / acid) :ARG1-of (r2 / recommend-01 :ARG0 (t3 / thing :ARG0-of (m / manufacture-01 :ARG1 (a2 / antibody))))) :ARG2 (p / profile-01 :ARG1 (c3 / cell) :ARG1-of (c4 / clump-02))) :ARG1-of (c / contrast-01 :ARG2 (f / figure :mod "4b")))) # ::id pmid_1684_6534.153 # ::date 2015-08-16T10:55:53 # ::file pmid_1684_6534_153.txt # ::snt BrdU incorporation (Figure 5b) confirms that the [3H]thymidine results are not solely due to alterations in apoptosis, as 468.siMUC1 cells incorporate less BrdU than 468.siLuc; once again, BT.siMUC1 cells show increased proliferation over BT.siLuc. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (m / multi-sentence :snt2 (s / show-01 :ARG0 (c / cell-line :name (n / name :op1 "BT.siMUC1")) :ARG1 (i / increase-01 :ARG1 (p / proliferate-01 :compared-to (c2 / cell-line :name (n2 / name :op1 "BT.siLuc")))) :mod (a / again :mod (o / once))) :snt1 (c3 / confirm-01 :ARG0 (i2 / incorporate-02 :ARG1 (s4 / small-molecule :name (n3 / name :op1 "BrdU") :xref (x1 / xref :value "PUBCHEM:6035" :prob "18.013371")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5b"))) :ARG1 (c4 / cause-01 :polarity "-" :ARG0 (a2 / alter-01 :ARG1 (a3 / apoptosis) :mod (s2 / sole)) :ARG1 (r / result-01 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "3H-thymidine") :xref (x / xref :value "PUBCHEM:162681" :prob "11.68539"))) :ARG1-of (c5 / cause-01 :ARG0 (i3 / incorporate-02 :ARG0 (c6 / cell-line :name (n5 / name :op1 "468.siMUC1")) :ARG1 s4 :degree (l / less) :compared-to (i4 / incorporate-02 :ARG0 (c7 / cell-line :name (n6 / name :op1 "468.siLuc")) :ARG1 s4)))))) # ::id pmid_1684_6534.154 # ::date 2015-08-14T01:44:10 # ::file pmid_1684_6534_154.txt # ::snt Given the role of MUC1 in adhesion, we examined whether MUC1 siRNA affects cellular invasion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (c / cause-01 :ARG0 (r / role :poss (p / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :purpose (a / adhere-01)) :ARG1 (e / examine-01 :ARG0 (w / we) :ARG1 (a2 / affect-01 :mode "interrogative" :ARG0 (n3 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 p)) :ARG1 (i / invade-01 :ARG1 (c2 / cell))))) # ::id pmid_1684_6534.155 # ::date 2015-08-14T01:47:01 # ::file pmid_1684_6534_155.txt # ::snt In transwell assays, BT-20 cells invaded poorly, regardless of the siRNA used (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (i / invade-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "BT-20")) :ARG1 (a / assay-01 :mod (t / transwell)) :manner (p / poor) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s / show-01 :polarity "-"))) :ARG1-of (d3 / describe-01 :ARG0 (d4 / data :ARG1-of (s2 / show-01 :polarity "-"))) :ARG1-of (r / regardless-91 :ARG2 (n3 / nucleic-acid :name (n / name :op1 "siRNA") :ARG1-of (u / use-01)))) # ::id pmid_1684_6534.156 # ::date 2015-08-14T01:54:05 # ::file pmid_1684_6534_156.txt # ::snt However, MDA-MB-468 cells invade more readily, and were analyzed on a panel of three different extracellular matrix proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (h / have-concession-91 :ARG1 (a / and :op1 (i / invade-01 :ARG0 (c2 / cell-line :name (n / name :op1 "MDA-MB-468")) :manner (r / ready-02 :degree (m / more))) :op2 (a2 / analyze-01 :ARG1 c2 :location (p / panel :consist-of (p2 / protein :quant "3" :ARG1-of (d / differ-02) :mod (m2 / matrix :mod (e / extracellular))))))) # ::id pmid_1684_6534.157 # ::date 2015-08-14T02:04:35 # ::file pmid_1684_6534_157.txt # ::snt Interestingly, 468.siMUC1 cells display somewhat decreased invasion on collagen IV, laminin, and fibronectin matrices, and on a no-matrix control (Figure 5c), which is in agreement with the trend towards decreased metastasis observed in Muc1-/- × MMTV-PyV MT mice [8]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (d / display-01 :ARG0 (c / cell-line :name (n / name :op1 "468.siMUC1")) :ARG1 (i2 / invade-01 :ARG0 c :ARG1 (a / and :op1 (p4 / protein :name (n5 / name :op1 "collagen" :op2 "IV") :xref (x1 / xref :value "UNIPROT:COLLAGEN_IV_HUMAN" :prob "0.681")) :op2 (l / laminin) :op3 (m / matrix :mod (f / fibronectin)) :op4 (c3 / control-01 :ARG1 (m2 / matrix :polarity "-"))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5c")) :ARG1-of (d5 / decrease-01 :degree (s / somewhat))) :ARG2-of (i / interest-01) :ARG0-of (a2 / agree-01 :ARG2 (t / trend-01 :ARG1 (m3 / metastasis :ARG1-of (d3 / decrease-01) :ARG1-of (o / observe-01 :location (p2 / protein :name (n2 / name :op1 "Muc1") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "0.603")) :location (m5 / mouse :mod (p3 / protein :name (n3 / name :op1 "PyV" :op2 "MT") :mod (o2 / organism :name (n4 / name :op1 "MMTV")))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG0-of (c4 / cite-01 :ARG1 "8")))))))) # ::id pmid_1684_6534.158 # ::date 2015-08-14T15:04:44 # ::file pmid_1684_6534_158.txt # ::snt Transfection of MUC1 rescues the 468.siMUC1 phenotype # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (r / rescue-01 :ARG0 (t / transfect-01 :ARG1 (p2 / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :ARG1 (p / phenotype :mod (c / cell-line :name (n2 / name :op1 "468.siMUC1")))) # ::id pmid_1684_6534.159 # ::date 2015-08-14T15:07:41 # ::file pmid_1684_6534_159.txt # ::snt To determine if the above effects are specific to MUC1, we created stable transfectants of the MDA-MB-468 line using empty vector (468.Neo) or a full-length MUC1 construct (468.MUC1Δ8) that is resistant to one of the independent MUC1-directed oligonucleotides ('882'). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (c / create-01 :ARG0 (w / we) :ARG1 (t / transfect-01 :ARG1 (c2 / cell-line :name (n / name :op1 "MDA-MB-468")) :ARG1-of (s2 / stable-02)) :ARG2 (o / or :op1 (v / vector :name (n3 / name :op1 "468.Neo") :ARG1-of (e / empty-02)) :op2 (c3 / construct-01 :ARG2 "p2" :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :name (n4 / name :op1 "468.MUC1Δ8"))) :ARG0-of (r / resist-01 :ARG1 (o2 / oligonucleotide :mod "882" :ARG1-of (i / include-91 :ARG2 (o3 / oligonucleotide :ARG1-of (d2 / direct-01 :ARG0 "p2") :ARG0-of (d3 / depend-01 :polarity "-"))))) :ARG1-of (l / long-03 :mod (f / full)))) :purpose (d / determine-01 :ARG0 w :ARG1 (s / specific-02 :mode "interrogative" :ARG1 (a / affect-02 :mod (a2 / above)) :ARG2 (p2 / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))) # ::id pmid_1684_6534.160 # ::date 2015-08-14T02:05:50 # ::file pmid_1684_6534_160.txt # ::snt These cells were maintained in G418-containing medium to retain transgene selection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m / maintain-01 :ARG1 (c / cell :mod (t2 / this)) :purpose (r / retain-01 :ARG0 c :ARG1 (s / select-01 :ARG1 (t / transgene))) :location (m2 / medium :ARG0-of (c2 / contain-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "G418") :xref (x / xref :value "PUBCHEM:123865" :prob "18.013371"))))) # ::id pmid_1684_6534.161 # ::date 2015-08-14T02:09:30 # ::file pmid_1684_6534_161.txt # ::snt As expected, 468.MUC1Δ8 cells show higher levels of both the MUC1 extracellular domain and the MUC1-CT than do 468.Neo (Figure 6a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s3 / show-01 :ARG0 (c / cell-line :name (n2 / name :op1 "468.MUC1Δ8")) :ARG1 (a2 / and :op1 (l / level :quant-of (p / protein-segment :name (n4 / name :op1 "MUC1"))) :op2 (l2 / level :quant-of (p2 / protein-segment :name (n3 / name :op1 "MUC1-CT"))) :ARG1-of (h / high-02 :degree (m / more) :compared-to "c2") :mod (d / domain :mod (e2 / extracellular))) :compared-to (c2 / cell-line :name (n / name :op1 "468.Neo")) :ARG1-of (e / expect-01) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6a"))) # ::id pmid_1684_6534.162 # ::date 2015-08-14T12:30:40 # ::file pmid_1684_6534_162.txt # ::snt Note that 468.Neo have MUC1 expression comparable to parental MDA-MB-468; the exposures in Figure 6a are lighter than those in Figure 1a, in order to clearly show the relative levels of MUC1 in the stable transfectants. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (n / note-01 :ARG1 (e3 / express-03 :ARG2 "p2" :ARG3 (c2 / cell-line :name (n4 / name :op1 "468.Neo")) :ARG1-of (c5 / comparable-03 :ARG2 (c3 / cell-line :name (n5 / name :op1 "MDA-MB-468") :mod (p / parent))))) :snt2 (l / light-06 :ARG1 (e / exposure :medium (f / figure :mod "6a")) :degree (m2 / more) :compared-to (e2 / expose-01 :source (f2 / figure :mod "1a")) :purpose (s / show-01 :ARG0 e :ARG1 (l2 / level :quant-of (p2 / protein :name (n2 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG1-of (r / relative-05)) :ARG1-of (c / clear-06) :location (c4 / cell :ARG1-of (s2 / stable-02) :ARG1-of (t / transfect-01))))) # ::id pmid_1684_6534.163 # ::date 2015-08-16T04:01:17 # ::file pmid_1684_6534_163.txt # ::snt After MUC1 siRNA, 468.MUC1Δ8 lose some MUC1 (likely endogenous protein, which is not siRNA-resistant) but retain high-level expression, while 468.Neo show a decrease in MUC1 levels similar to parental 468.siMUC1 cells (Figures 6a,b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (c5 / contrast-01 :ARG1 (l / lose-02 :ARG0 (c2 / cell-line :name (n2 / name :op1 "468.MUC1Δ8")) :ARG1 (p3 / protein :name (n3 / name :op1 "MUC1") :mod (s2 / some) :ARG1-of (m / mean-01 :ARG2 (l3 / likely-01 :ARG1 (p2 / protein :mod (m2 / monocot) :ARG0-of (r / resist-01 :polarity "-" :ARG1 "n6")))) :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG2 (r3 / retain-01 :ARG0 c2 :ARG1 (e / express-03) :ARG1-of (h / high-02)) :time (a / after :op1 (n6 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 p3))))) :ARG2 (s / show-01 :ARG0 (c3 / cell-line :name (n4 / name :op1 "468.Neo")) :ARG1 (d / decrease-01 :ARG1 (l2 / level :quant-of p3) :ARG1-of (r4 / resemble-01 :ARG2 (c4 / cell-line :name (n5 / name :op1 "468.siMUC1") :mod (p / parent))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "6a") :op2 (f2 / figure :mod "6b")))) # ::id pmid_1684_6534.164 # ::date 2015-08-15T13:15:30 # ::file pmid_1684_6534_164.txt # ::snt The difference in the amount of MUC1 knockdown between 468.Neo and 468.MUC1Δ8 is highlighted by the purple shading in Figure 6b. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (h / highlight-01 :ARG0 (s / shade-01 :ARG0 (p / purple)) :ARG1 (d / differ-02 :ARG1 (a / amount-01) :ARG2 (c2 / cell-line :name (n3 / name :op1 "468.MUC1Δ8")) :ARG3 (k / knock-down-02 :ARG1 (p2 / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))) :ARG1 (c / cell-line :name (n2 / name :op1 "468.Neo"))) :medium (f / figure :mod "6b")) # ::id pmid_1684_6534.165 # ::date 2015-08-15T13:21:59 # ::file pmid_1684_6534_165.txt # ::snt BrdU incorporation (Figure 6c) indicates that 468.Neo show decreased nucleotide incorporation after MUC1 siRNA compared to control (3.3% versus 25.0%, respectively); this is not seen in 468.MUC1Δ8 cells, which show similar levels of BrdU incorporation regardless of the siRNA used (21.5% for luciferase, 23.9% for MUC1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (m / multi-sentence :snt1 (i / indicate-01 :ARG0 (i3 / incorporate-02 :ARG1 (s5 / small-molecule :name (n4 / name :op1 "BrdU") :xref (x2 / xref :value "PUBCHEM:6035" :prob "18.013371"))) :ARG1 (s3 / show-01 :ARG0 (c2 / cell-line :name (n5 / name :op1 "468.Neo")) :ARG1 (i4 / incorporate-02 :ARG1 (n6 / nucleotide) :ARG1-of (d / decrease-01 :compared-to (c3 / control :ARG1-of (m2 / mean-01 :ARG2 (v / versus :op1 (p / percentage-entity :value "3.3") :op2 (p2 / percentage-entity :value "25.0")))))) :time (a / after :op1 (n10 / nucleic-acid :name (n7 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p7 / protein :name (n8 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6c"))) :snt2 (s / see-01 :polarity "-" :ARG1 (t / this) :location (c / cell-line :name (n / name :op1 "468.MUC1Δ8") :ARG0-of (s2 / show-01 :ARG1 (l / level :ARG1-of (r2 / resemble-01) :degree-of (i2 / incorporate-02 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "BrdU") :xref (x3 / xref :value "PUBCHEM:6035" :prob "18.013371")))) :ARG1-of (r / regardless-91 :ARG2 (n11 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG1-of (u / use-01) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and :op1 (p3 / percentage-entity :value "21.5" :prep-for (l2 / luciferase)) :op2 (p4 / percentage-entity :value "23.9" :quant-of (p8 / protein :name (n9 / name :op1 "MUC1") :xref (x1 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))))))))) # ::id pmid_1684_6534.166 # ::date 2015-08-16T04:04:39 # ::file pmid_1684_6534_166.txt # ::snt 468.Neo cells display a more dramatic decrease in BrdU incorporation after MUC1 siRNA than what is seen in parental 468.siMUC1 cells, which may reflect the additional stress of being maintained in G418-containing medium. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / display-01 :ARG0 (c / cell-line :name (n5 / name :op1 "468.Neo")) :ARG1 (d2 / decrease-01 :ARG1 (i / incorporate-02 :ARG1 (s3 / small-molecule :name (n / name :op1 "BrdU") :xref (x1 / xref :value "PUBCHEM:6035" :prob "18.013371"))) :ARG2 (d3 / dramatic :degree (m / more)) :compared-to (t / thing :ARG1-of (s / see-01 :location (c2 / cell-line :name (n4 / name :op1 "468.siMUC1") :mod (p2 / parent))) :ARG1-of (r2 / reflect-01 :ARG2 (s2 / stress-01 :ARG0 (m2 / maintain-01 :location (m3 / medium :ARG0-of (c3 / contain-01 :ARG1 (s4 / small-molecule :name (n6 / name :op1 "G418") :xref (x2 / xref :value "PUBCHEM:123865" :prob "18.013371"))))) :mod (a2 / additional)) :ARG1-of (p / possible-01)))) :time (a / after :op1 (n7 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p4 / protein :name (n3 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))))) # ::id pmid_1684_6534.167 # ::date 2015-08-16T04:16:52 # ::file pmid_1684_6534_167.txt # ::snt Similarly, analysis of apoptosis in trypsinized cells indicates that the increased apoptosis seen in parental 468.siMUC1 cells is also present in the 468.Neo line after MUC1 siRNA (Figure 6d; 43.6% in control versus 59.6% in MUC1 siRNA). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (a / analyze-01 :ARG1 (a2 / apoptosis :ARG1-of (p5 / present-02 :ARG2 (c / cell :ARG1-of (t / trypsinize-00))))) :ARG1 (p6 / present-02 :ARG1 (a3 / apoptosis :ARG1-of (s / see-01 :location (c2 / cell-line :name (n / name :op1 "468.siMUC1") :mod (p3 / parent))) :ARG1-of (i2 / increase-01)) :ARG2 (c3 / cell-line :name (n2 / name :op1 "468.Neo")) :mod (a4 / also) :time (a5 / after :op1 "n5") :mod (c4 / control-01 :location (n5 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p4 / protein :name (n4 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))) :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value "43.6" :compared-to (p2 / percentage-entity :value "59.6")))) :ARG1-of (r / resemble-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6d"))) # ::id pmid_1684_6534.168 # ::date 2015-08-16T04:33:41 # ::file pmid_1684_6534_168.txt # ::snt However, in 468.MUC1Δ8 cells, the level of apoptosis after luciferase siRNA (34.1%) is lower than that in 468.Neo cells; MUC1 siRNA increases the amount of apoptosis slightly (42.8%), restoring it to a level similar to that seen in luciferase siRNA-treated 468.Neo cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (m2 / multi-sentence :snt1 (h / have-concession-91 :ARG1 (l2 / low-04 :ARG1 (l3 / level :quant-of (a / apoptosis) :location (c2 / cell-line :name (n2 / name :op1 "468.MUC1Δ8")) :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value "34.1"))) :time (a2 / after :op1 (n8 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (l4 / luciferase)))) :compared-to (l5 / level :quant-of a :location (c4 / cell-line :name (n3 / name :op1 "468.Neo"))) :degree (m / more))) :snt2 (i / increase-01 :ARG0 (n9 / nucleic-acid :name (n5 / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 (p3 / protein :name (n4 / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")))) :ARG1 (a3 / amount :quant-of (a4 / apoptosis) :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value "42.8"))) :ARG2 (s / slight) :ARG0-of (r / restore-02 :ARG1 a3 :ARG2 (l / level :ARG1-of (r4 / resemble-01 :ARG2 (l6 / level :ARG1-of (s2 / see-01 :location (c3 / cell-line :name (n6 / name :op1 "468.Neo") :ARG1-of (t / treat-04 :ARG2 (n10 / nucleic-acid :name (n7 / name :op1 "siRNA") :ARG0-of (e3 / encode-01 :ARG1 (l7 / luciferase)))))))))))) # ::id pmid_1684_6534.169 # ::date 2015-08-15T13:24:41 # ::file pmid_1684_6534_169.txt # ::snt Together, these studies suggest that the above-described results are specific to MUC1, as stable transfection of an siRNA-resistant MUC1 rescues the phenotype seen in 468.siMUC1 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (s7 / study-01 :mod (t3 / together) :mod (t / this)) :ARG1 (c / cause-01 :ARG0 (r / rescue-01 :ARG0 (t4 / transfect-01 :ARG2 (p3 / protein :name (n2 / name :op1 "MUC1") :ARG0-of (r2 / resist-01 :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "siRNA"))) :xref (x1 / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003")) :ARG1-of (s6 / stable-03)) :ARG1 (p / phenotype :ARG1-of (s5 / see-01 :location (c2 / cell-line :name (n4 / name :op1 "468.siMUC1"))))) :ARG1 (s3 / specific-02 :ARG1 (t2 / thing :ARG2-of (r4 / result-01) :ARG1-of (d / describe-01 :location (a / above))) :ARG2 (p2 / protein :name (n / name :op1 "MUC1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "1.003"))))) # ::id pmid_1901_8267.1 # ::date 2015-07-09T12:02:58 # ::file pmid_1901_8267_1.txt # ::snt KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer (PMID:19018267) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (u / useful-05 :ARG1 (o / or :op1 (s / status :mod (m / mutate-01 :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :op2 (s2 / status :mod (m2 / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG2 (p / predict-01 :ARG0 o :ARG1 (s3 / sensitive-03 :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :location (d / disease :wiki "Ovarian_cancer" :name (n2 / name :op1 "ovarian" :op2 "cancer"))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID19018267"))) # ::id pmid_1901_8267.119 # ::date 2015-07-09T12:47:35 # ::file pmid_1901_8267_119.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1901_8267.120 # ::date 2015-07-09T12:48:36 # ::file pmid_1901_8267_120.txt # ::snt Identification of KRAS and BRAF mutations # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (i / identify-01 :ARG1 (a2 / and :op1 (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) # ::id pmid_1901_8267.121 # ::date 2015-07-09T12:49:58 # ::file pmid_1901_8267_121.txt # ::snt The mutational status of KRAS and BRAF in all 45 ovarian carcinomas is summarised in Table 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (s / summarize-01 :ARG1 (s2 / status :mod (m / mutate-01) :poss (a / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :location (c / carcinoma :quant "45" :mod (o / ovary) :mod (a2 / all))) :location (t / table :mod "1")) # ::id pmid_1901_8267.122 # ::date 2015-07-09T13:02:24 # ::file pmid_1901_8267_122.txt # ::snt Somatic mutations of KRAS were identified in 8 (13.7%) out of 58 ovarian carcinomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 11, 2015 (i / identify-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :mod (s / somatic)) :location (c / carcinoma :quant "8" :ARG1-of (i2 / include-91 :ARG2 (c2 / carcinoma :quant "58" :mod (o / ovary)) :ARG3 (p / percentage-entity :value "13.7")))) # ::id pmid_1901_8267.123 # ::date 2015-07-09T13:06:40 # ::file pmid_1901_8267_123.txt # ::snt In contrast, somatic mutations of BRAF were identified in 5 (8.6%) out of 58 ovarian carcinomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 9, 2015 (c / contrast-01 :ARG2 (i / identify-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (s / somatic)) :location (c2 / carcinoma :quant "5" :ARG1-of (i2 / include-91 :ARG2 (c3 / carcinoma :quant "58" :mod (o / ovary)) :ARG3 (p / percentage-entity :value "8.6"))))) # ::id pmid_1901_8267.124 # ::date 2015-07-09T13:09:29 # ::file pmid_1901_8267_124.txt # ::snt Somatic mutations of either KRAS or BRAF were identified in 12 (20.6%) out of 58 ovarian carcinomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 9, 2015 (i / identify-01 :ARG1 (m / mutate-01 :ARG1 (o / or :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :mod (s / somatic)) :location (c / carcinoma :quant "12" :ARG1-of (i2 / include-91 :ARG2 (c2 / carcinoma :quant "58" :mod (o2 / ovary)) :ARG3 (p / percentage-entity :value "20.6")))) # ::id pmid_1901_8267.125 # ::date 2015-07-09T13:13:40 # ::file pmid_1901_8267_125.txt # ::snt Most KRAS mutations were located at codon 12 and all BRAF mutations at codon 600. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 9, 2015 (a / and :op1 (b / be-located-at-91 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :mod (m2 / most)) :ARG2 (c / codon :mod "12")) :op2 (b2 / be-located-at-91 :ARG1 (m3 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (a2 / all)) :ARG2 (c2 / codon :mod "600"))) # ::id pmid_1901_8267.126 # ::date 2015-07-09T13:19:54 # ::file pmid_1901_8267_126.txt # ::snt Both of these codons are mutation hot spots. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / spot :ARG1-of (h / hot-03) :location-of (m / mutate-01) :domain (c / codon :mod (t / this) :mod (b / both))) # ::id pmid_1901_8267.127 # ::date 2015-07-09T13:22:58 # ::file pmid_1901_8267_127.txt # ::snt Interestingly, simultaneous mutations of KRAS and BRAF did not occur in the tested ovarian carcinomas with the exception of one mucinous case. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (b / be-located-at-91 :polarity "-" :ARG1 (a / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :mod (s / simultaneous)) :ARG2 (c / carcinoma :ARG1-of (t / test-01) :mod (o / ovary)) :ARG2-of (e / except-01 :ARG1 (c2 / case-04 :ARG1 (m3 / mucin))) :ARG2-of (i / interest-01)) # ::id pmid_1901_8267.128 # ::date 2015-07-09T13:53:31 # ::file pmid_1901_8267_128.txt # ::snt A panel of ovarian cancer cell lines and primary cultures was first analysed for tumour mutation status in the KRAS and BRAF genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / analyze-01 :ARG1 (p / panel :consist-of (a2 / and :op1 (c / cell-line :mod (d / disease :wiki "Ovarian_cancer" :name (n / name :op1 "ovarian" :op2 "cancer"))) :op2 (t2 / thing :ARG1-of (c3 / culture-01) :mod (p2 / primary)))) :time (f / first) :purpose (s / status :mod (m / mutate-01 :ARG1 (t / tumor)) :location (a3 / and :op1 (g / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) # ::id pmid_1901_8267.129 # ::date 2015-07-09T14:01:29 # ::file pmid_1901_8267_129.txt # ::snt As shown in Figure 1, three ovarian cancer cell lines harboured either KRAS or BRAF mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (h / harbor-01 :ARG0 (c / cell-line :quant "3" :mod (d / disease :wiki "Ovarian_cancer" :name (n / name :op1 "ovarian" :op2 "cancer"))) :ARG1 (o2 / or :op1 (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "1"))) # ::id pmid_1901_8267.130 # ::date 2015-07-09T14:06:45 # ::file pmid_1901_8267_130.txt # ::snt The frequency of either KRAS or BRAF mutations in conventional serous high-grade carcinomas (4.0% : 1/25) was significantly lower than in the other histological type (32.2% : 10/31). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (l2 / low-04 :ARG1 (o3 / or :op1 (h3 / have-frequency-91 :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :op2 (h4 / have-frequency-91 :ARG1 (m3 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :location (c / carcinoma :quant "1" :ARG1-of (i / include-91 :ARG2 (c3 / carcinoma :quant "25" :mod (g3 / grade :ARG1-of (h / high-02)) :mod (s / serum :mod (c2 / conventional))) :ARG3 (p / percentage-entity :value "4"))) :compared-to (t / type :quant "10" :ARG1-of (i2 / include-91 :ARG2 (t2 / type :quant "31" :mod (h2 / histology) :mod (o2 / other)) :ARG3 (p2 / percentage-entity :value "32.2")))) :degree (m / more)) # ::id pmid_1901_8267.131 # ::date 2015-07-09T14:20:08 # ::file pmid_1901_8267_131.txt # ::snt Relationship between KRAS/BRAF mutations and p-ERK1/2 expression or clinicopathological factors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (r / relation-03 :ARG0 (m / mutate-01 :ARG1 (s / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (o / or :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :op2 (f / factor :mod (c / clinicopathologic)))) # ::id pmid_1901_8267.132 # ::date 2015-07-09T14:24:53 # ::file pmid_1901_8267_132.txt # ::snt The immunoreactivity of active p-ERK1/2 was detected in both the nucleus and the cytoplasm of the tumour cells (Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (d / detect-01 :ARG1 (i / immunoreact-00 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01) :ARG1-of (a / activate-01))) :location (a2 / and :op1 (n2 / nucleus :part-of (c / cell :mod (t / tumor)) :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :op2 (c2 / cytoplasm :part-of c :xref (x / xref :value "GO:0005737" :prob "0.8"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2"))) # ::id pmid_1901_8267.133 # ::date 2015-07-09T14:28:12 # ::file pmid_1901_8267_133.txt # ::snt This is consistent with an earlier report (Mizumoto et al, 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 9, 2015 (c / consistent-01 :ARG1 (t / this) :ARG2 (r / report-01 :time (e2 / early :degree (m / more))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Mizumoto")) :op2 (p3 / person :mod (o / other))) :time (d2 / date-entity :year "2007")))) # ::id pmid_1901_8267.134 # ::date 2015-07-10T11:50:58 # ::file pmid_1901_8267_134.txt # ::snt Positive active p-ERK1/2 was identified in 27 (46.6%) out of 58 ovarian carcinomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (i / identify-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01) :ARG1-of (a / activate-01) :mod (p2 / positive)) :location (c / carcinoma :quant "27" :ARG1-of (i2 / include-91 :ARG2 (c2 / carcinoma :quant "58" :mod (o / ovary)) :ARG3 (p3 / percentage-entity :value "46.6")))) # ::id pmid_1901_8267.135 # ::date 2015-07-10T11:53:27 # ::file pmid_1901_8267_135.txt # ::snt The patients were stratified into two groups depending on the mutational status of KRAS/BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / stratify-01 :ARG1 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p / patient))) :manner (g / group :quant "2") :ARG0-of (d / depend-01 :ARG1 (s2 / status :mod (m / mutate-01) :poss (s3 / slash :op1 (g2 / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) # ::id pmid_1901_8267.136 # ::date 2015-07-10T11:56:44 # ::file pmid_1901_8267_136.txt # ::snt The relationships between KRAS/BRAF mutations and clinicopathological factors, including p-ERK1/2 expression are shown in Table 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (s / show-01 :ARG0 (t / table :mod "2") :ARG1 (a2 / and :op1 (r / relation-03 :ARG0 (m / mutate-01 :ARG1 (s2 / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (f / factor :mod (c / clinicopathologic) :ARG2-of (i / include-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)))))))) # ::id pmid_1901_8267.137 # ::date 2015-07-10T12:02:59 # ::file pmid_1901_8267_137.txt # ::snt There was no significant correlation between KRAS/BRAF mutations and the patient's age. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / correlate-01 :polarity "-" :ARG1 (m / mutate-01 :ARG1 (s2 / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (a / age-01 :ARG1 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p / patient)))) :ARG1-of (s / significant-02)) # ::id pmid_1901_8267.138 # ::date 2015-07-10T12:05:31 # ::file pmid_1901_8267_138.txt # ::snt The results in Table 2 show that KRAS/BRAF mutation is correlated significantly with FIGO stage I, II (P<0.001), and p-ERK1/2 (P<0.001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (s / show-01 :ARG0 (t2 / thing :ARG2-of (r / result-01 :location (t / table :mod "2"))) :ARG1 (a / and :op1 (c / correlate-01 :ARG1 (m / mutate-01 :ARG1 (s5 / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (a3 / and :op1 (s3 / stage :mod "I") :op2 (s4 / stage :mod "II") :mod (o / organization :name (n3 / name :op1 "FIGO"))) :ARG1-of (s6 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :op2 (c2 / correlate-01 :ARG1 m :ARG2 (e / enzyme :name (n4 / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)) :ARG1-of (s7 / statistical-test-91 :ARG2 l)) :ARG1-of (s2 / significant-02))) # ::id pmid_1901_8267.139 # ::date 2015-07-10T12:14:33 # ::file pmid_1901_8267_139.txt # ::snt In addition, there were significant correlations between KRAS/BRAF mutations and pathological grade (P=0.004), and histological subtype (P=0.014). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / and :op2 (a2 / and :op1 (c / correlate-01 :ARG1 (m / mutate-01 :ARG1 (s3 / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (g3 / grade :mod (p / pathology)) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.004")) :op2 (c2 / correlate-01 :ARG1 m :ARG2 (s2 / subtype :mod (h / histology)) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.014")) :ARG1-of (s / significant-02))) # ::id pmid_1901_8267.140 # ::date 2015-07-10T12:20:39 # ::file pmid_1901_8267_140.txt # ::snt Effect of KRAS/BRAF mutations or p-ERK1/2 on the prognosis of ovarian carcinomas # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (a / affect-01 :ARG0 (o / or :op1 (m / mutate-01 :ARG1 (s / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (e / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01))) :ARG1 (p / prognosis :mod (c / carcinoma :mod (o2 / ovary)))) # ::id pmid_1901_8267.141 # ::date 2015-07-10T12:28:43 # ::file pmid_1901_8267_141.txt # ::snt Next, we examined the prognostic effect of KRAS/BRAF mutations and p-ERK1/2 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (m / mutate-01 :ARG1 (s / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)))) :mod (p / prognostic)) :time (n4 / next)) # ::id pmid_1901_8267.142 # ::date 2015-07-10T12:37:05 # ::file pmid_1901_8267_142.txt # ::snt Out of the 58 samples that we examined, 45 were available for prognostic analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / available-02 :ARG1 (a2 / analyze-01 :mod (p / prognostic)) :ARG2 (t / thing :quant "45" :ARG1-of (i / include-91 :ARG2 (t2 / thing :quant "58" :ARG2-of (s2 / sample-01) :ARG1-of (e / examine-01 :ARG0 (w / we)))))) # ::id pmid_1901_8267.143 # ::date 2015-07-10T12:40:50 # ::file pmid_1901_8267_143.txt # ::snt Kaplan–Meier estimates of overall survival are plotted in Figure 3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (p / plot-01 :ARG1 (e / estimate-01 :ARG1 (s / survive-01 :mod (o / overall)) :instrument (t / thing :name (n / name :op1 "Kaplan–Meier"))) :medium (f / figure :mod "3")) # ::id pmid_1901_8267.144 # ::date 2015-07-10T12:45:52 # ::file pmid_1901_8267_144.txt # ::snt There was no significant relationship between KRAS/BRAF mutations or p-ERK1/2 expression and overall survival in patients with ovarian carcinoma (P=0.2460, P=0.9339, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (r / relation-03 :polarity "-" :ARG0 (o4 / or :op1 (m / mutate-01 :ARG1 (s3 / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :mod (r2 / respective) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.2460")) :ARG2 (s2 / survive-01 :ARG0 (p5 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h2 / have-03 :ARG1 (c / carcinoma :mod (o3 / ovary)))) :mod (o2 / overall) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.9339")) :ARG1-of (s / significant-02)) # ::id pmid_1901_8267.145 # ::date 2015-07-10T12:52:48 # ::file pmid_1901_8267_145.txt # ::snt Univariate analysis showed that only FIGO stage III, IV affected the overall survival of patients with ovarian carcinoma significantly(P=0.014). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (a / analyze-01 :mod (u / univariate)) :ARG1 (a2 / affect-01 :ARG0 (a3 / and :op1 (s2 / stage :mod "III") :op2 (s3 / stage :mod "IV") :mod (o / organization :name (n / name :op1 "FIGO")) :mod (o4 / only)) :ARG1 (s4 / survive-01 :ARG0 (p3 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p / patient)) :ARG0-of (h / have-03 :ARG1 (c / carcinoma :mod (o3 / ovary)))) :mod (o2 / overall)) :ARG1-of (s5 / significant-02) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.014"))) # ::id pmid_1901_8267.146 # ::date 2015-07-10T12:59:27 # ::file pmid_1901_8267_146.txt # ::snt Effects of ERK1/2 inactivation on ovarian carcinoma in vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 10, 2015 (a / affect-01 :ARG0 (a2 / activate-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))) :ARG1 (c / carcinoma :mod (o / ovary)) :manner (i / in-vitro)) # ::id pmid_1901_8267.147 # ::date 2015-07-10T13:04:45 # ::file pmid_1901_8267_147.txt # ::snt A panel of ovarian cancer cell lines and primary cultures of ovarian cancer were first analysed for KRAS and BRAF gene mutation status. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / analyze-01 :ARG1 (a2 / and :op1 (p / panel :consist-of (c / cell-line :mod (d / disease :wiki "Ovarian_cancer" :name (n / name :op1 "ovarian" :op2 "cancer")))) :op2 (c3 / culture-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")) :mod (p2 / primary))) :time (f / first) :purpose (s / status :mod (m / mutate-01 :ARG1 (a4 / and :op1 (g / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) # ::id pmid_1901_8267.148 # ::date 2015-07-10T13:09:35 # ::file pmid_1901_8267_148.txt # ::snt Mutational status was correlated with growth inhibition and apoptosis induction by the MEK inhibitor CI-1040 that prevented activation of the downstream target, ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / correlate-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "CI-1040") :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))) :ARG0-of (p / prevent-01 :ARG1 (a3 / activate-01 :ARG1 (t2 / target :ARG1-of (m2 / mean-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"))) :location (d / downstream)))) :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG1 (s / status :mod (m / mutate-01)) :ARG2 (a / and :op1 (i2 / inhibit-01 :ARG1 (g / grow-01)) :op2 (i3 / induce-01 :ARG2 (a2 / apoptosis)))) # ::id pmid_1901_8267.149 # ::date 2015-07-11T01:55:31 # ::file pmid_1901_8267_149.txt # ::snt Western blot analysis showed a dose-dependent effect on the expression of active ERK1/2 in ES2 cells, and active ERK1/2 was not detectable 6 h after treating the cells with CI-1040 at a concentration of 5 μM (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op1 (s / show-01 :ARG0 (a2 / analyze-01 :manner (i / immunoblot-01)) :ARG1 (a3 / affect-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG1-of (a4 / activate-01) :location (c / cell-line :name (n4 / name :op1 "ES2")))) :ARG0-of (d / depend-01 :ARG1 (d2 / dose)))) :op2 (p / possible-01 :polarity "-" :ARG1 (d3 / detect-01 :ARG1 e2 :time (a5 / after :op1 (t3 / treat-04 :ARG1 c :ARG2 (s2 / small-molecule :name (n5 / name :op1 "CI-1040") :quant (c3 / concentration-quantity :quant "5" :unit (m / micromolar)) :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357"))) :quant (t2 / temporal-quantity :quant "6" :unit (h / hour))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "4"))) # ::id pmid_1901_8267.150 # ::date 2015-07-11T02:05:12 # ::file pmid_1901_8267_150.txt # ::snt As shown in Figure 5, four of the tumours harbouring either KRAS or BRAF mutations showed a marked reduction (<50% of DMSO control) in the cell number in the CI-1040-treated group as compared with the other 14 tumours containing wild-type KRAS and BRAF (P<0.001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (t / tumor :quant "4" :ARG1-of (i / include-01 :ARG2 (t2 / tumor :ARG0-of (h / harbor-01 :ARG1 (o / or :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))))) :ARG1 (r / reduce-01 :ARG1 (n4 / number :quant-of (c2 / cell)) :ARG2 (l / less-than :op1 (p / percentage-entity :value "50" :quant-of (c / control :mod (s4 / small-molecule :name (n3 / name :op1 "DMSO") :xref (x5 / xref :value "PUBCHEM:679" :prob "16.740406"))))) :ARG1-of (m3 / mark-01) :location (g3 / group :ARG1-of (t3 / treat-04 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "CI-1040") :xref (x4 / xref :value "PUBCHEM:6918454" :prob "17.207357")))) :compared-to (t4 / tumor :quant "14" :mod (o2 / other) :ARG0-of (c3 / contain-01 :ARG1 (a / and :op1 (g4 / gene :name (n6 / name :op1 "KRAS") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g5 / gene :name (n7 / name :op1 "BRAF") :mod w :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) :ARG1-of (s3 / show-01 :ARG0 (f / figure :mod "5")) :ARG1-of (s5 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.001"))) # ::id pmid_1901_8267.151 # ::date 2015-07-11T02:22:17 # ::file pmid_1901_8267_151.txt # ::snt CI-1040 had no significant effect on the growth of normal cells, including the OSE cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / affect-01 :polarity "-" :ARG0 (s2 / small-molecule :name (n / name :op1 "CI-1040") :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG1 (g / grow-01 :ARG1 (c / cell :ARG1-of (n2 / normal-02) :ARG2-of (i / include-01 :ARG1 (c2 / cell :source (e / epithelium :location (s3 / surface) :part-of (o / ovary)))))) :ARG1-of (s / significant-02)) # ::id pmid_1901_8267.152 # ::date 2015-07-11T02:26:44 # ::file pmid_1901_8267_152.txt # ::snt It is likely that KRAS/BRAF mutation is not the only determinant for activating ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (l / likely-01 :ARG1 (d / determine-01 :polarity "-" :ARG0 (m / mutate-01 :ARG1 (s / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2"))) :mod (o / only))) # ::id pmid_1901_8267.153 # ::date 2015-07-11T02:33:19 # ::file pmid_1901_8267_153.txt # ::snt Therefore, we analysed p-ERK1/2 expression in each of the cell lines listed in Figure 5. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (c / cause-01 :ARG1 (a / analyze-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG3 (c2 / cell-line :mod (e3 / each) :ARG1-of (l / list-01 :ARG2 (f / figure :mod "5")))))) # ::id pmid_1901_8267.154 # ::date 2015-07-11T02:40:40 # ::file pmid_1901_8267_154.txt # ::snt Only four of these cell lines, MDAH2774, ES2, MPSC1, and POC1, strongly expressed p-ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (e / express-03 :ARG2 (e2 / enzyme :name (n5 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG3 (c / cell-line :quant "4" :mod (o / only) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :mod (t / this))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n / name :op1 "MDAH2774")) :op2 (c4 / cell-line :name (n2 / name :op1 "ES2")) :op3 (c5 / cell-line :name (n3 / name :op1 "MPSC1")) :op4 (c6 / cell-line :name (n4 / name :op1 "POC1"))))) :ARG1-of (s / strong-02)) # ::id pmid_1901_8267.155 # ::date 2015-07-11T12:38:54 # ::file pmid_1901_8267_155.txt # ::snt SKOV3 and A2780 showed weak expression of ERK1/2.These results suggest that activation of ERK1/2 may depend on KRAS/BRAF mutation in ovarian cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG0 (a / and :op1 (c / cell-line :name (n2 / name :op1 "SKOV3")) :op2 (c2 / cell-line :name (n3 / name :op1 "A2780"))) :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")) :ARG1-of (w / weak-02))) :snt2 (s2 / suggest-01 :ARG0 (t2 / thing :ARG2-of (r / result-01) :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (d2 / depend-01 :ARG0 (a2 / activate-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "ERK1/2"))) :ARG1 (m2 / mutate-01 :ARG1 (s3 / slash :op1 (g / gene :name (n6 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n7 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :location (c3 / cell :mod (d / disease :wiki "Ovarian_cancer" :name (n / name :op1 "ovarian" :op2 "cancer")))))))) # ::id pmid_1901_8267.156 # ::date 2015-07-11T12:46:17 # ::file pmid_1901_8267_156.txt # ::snt To assess the mechanisms underlying growth inhibition by CI-1040, we measured the percentages of BrdUrd-labelled cells and Annexin V-labelled cells to estimate proliferation and apoptosis, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / measure-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p / percentage :ARG3-of (i3 / include-91 :ARG1 (c / cell :ARG1-of (l / label-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "BrdUrd") :xref (x1 / xref :value "PUBCHEM:6035" :prob "19.266134")))))) :op2 (p2 / percentage :ARG3-of (i2 / include-91 :ARG1 (c2 / cell :ARG1-of (l2 / label-01 :ARG0 (p4 / protein :name (n2 / name :op1 "Annexin" :op2 "V") :xref (x / xref :value "UNIPROT:ANXA5_HUMAN" :prob "1.002"))))))) :purpose (e / estimate-01 :ARG0 w :ARG1 (a2 / and :op1 (p3 / proliferate-01) :op2 (a3 / apoptosis) :mod (r / respective))) :purpose (a4 / assess-01 :ARG0 w :ARG1 (m4 / mechanism :ARG0-of (u / underlie-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "CI-1040") :xref (x2 / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG1 (g / grow-01)))))) # ::id pmid_1901_8267.157 # ::date 2015-07-11T12:55:02 # ::file pmid_1901_8267_157.txt # ::snt We found that CI-1040 significantly reduced cellular proliferation and induced apoptosis in cell lines with either KRAS or BRAF mutations in comparison with cell lines with wild-type sequences (Figure 6, Supplementary Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (r / reduce-01 :ARG0 (s / small-molecule :name (n / name :op1 "CI-1040") :xref (x2 / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG1 (p / proliferate-01 :ARG0 (c / cell)) :ARG2 (s2 / significant-02)) :op2 (i / induce-01 :ARG0 s :ARG2 (a / apoptosis)) :location (c2 / cell-line :ARG0-of (h / have-03 :ARG1 (o / or :op1 (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :compared-to (c3 / cell-line :ARG0-of (h2 / have-03 :ARG1 (s3 / sequence :mod (w2 / wild-type)))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "6") :op2 (f3 / figure :mod "1" :ARG1-of (s4 / supplement-01))))) # ::id pmid_1901_8267.158 # ::date 2015-07-11T13:02:40 # ::file pmid_1901_8267_158.txt # ::snt Effects of CI-1040 ERK1/2 inactivation on ovarian carcinomas in vivo # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 22, 2015 (a / affect-01 :ARG0 (a2 / activate-01 :polarity "-" :ARG0 (s / small-molecule :name (n2 / name :op1 "CI-1040") :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))) :ARG1 (c / carcinoma :mod (o / ovary)) :manner (i / in-vivo)) # ::id pmid_1901_8267.159 # ::date 2015-07-11T13:10:17 # ::file pmid_1901_8267_159.txt # ::snt On the basis of the above findings, we investigated whether CI-1040 had a growth-inhibitory effect on tumour formation and development in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :mode "interrogative" :ARG0 (s / small-molecule :name (n / name :op1 "CI-1040") :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG1 (a2 / and :op1 (f / form-01 :ARG1 (t / tumor)) :op2 (d / develop-01 :ARG2 t)) :ARG2 (i3 / inhibit-01 :ARG0 s :ARG1 (g / grow-01)) :manner (i2 / in-vivo)) :ARG1-of (b / base-02 :ARG0 (t2 / thing :ARG1-of (f2 / find-01) :mod (a3 / above)))) # ::id pmid_1901_8267.160 # ::date 2015-07-11T13:17:34 # ::file pmid_1901_8267_160.txt # ::snt Tumour xenografts from both MDAH2774 (KRAS mutant) and SKOV3 (wild type of KRAS and BRAF) cell lines were established in a nu/nu mouse model. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (e / establish-01 :ARG1 (a2 / and :op1 (x / xenograft :mod (t / tumor) :source (c / cell-line :name (n / name :op1 "MDAH2774") :ARG1-of (m4 / mean-01 :ARG2 (g / gene :name (n2 / name :op1 "KRAS") :ARG2-of (m / mutate-01) :xref (x4 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))) :op2 (x2 / xenograft :mod t :source (c2 / cell-line :name (n3 / name :op1 "SKOV3") :ARG1-of (m5 / mean-01 :ARG2 (a / and :op1 (g2 / gene :name (n4 / name :op1 "KRAS") :mod (w / wild-type) :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n5 / name :op1 "BRAF") :mod w :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) :location (m2 / model :mod (m3 / mouse :mod (n6 / nude)))) # ::id pmid_1901_8267.161 # ::date 2015-07-11T13:26:20 # ::file pmid_1901_8267_161.txt # ::snt All mice injected with CI-1040 developed significantly smaller intra-abdominal xenograft tumours than the mice carrying diluent control cells of the KRAS mutant cell line MADH2774 (Figure 7A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (d / develop-01 :ARG1 (m / mouse :mod (a / all) :ARG2-of (i / inject-01 :ARG1 (s / small-molecule :name (n / name :op1 "CI-1040") :xref (x2 / xref :value "PUBCHEM:6918454" :prob "17.207357")))) :ARG2 (t / tumor :mod (x / xenograft) :mod (i2 / intra-abdominal) :mod (s2 / small :degree (m2 / more)) :ARG1-of (s3 / significant-02)) :compared-to (m3 / mouse :ARG0-of (c / carry-01 :ARG1 (c2 / cell :mod (c3 / control) :mod (d2 / diluent) :poss (c4 / cell-line :name (n2 / name :op1 "MADH2774") :mod (g / gene :name (n3 / name :op1 "KRAS") :ARG2-of (m4 / mutate-01) :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "7A"))) # ::id pmid_1901_8267.162 # ::date 2015-07-11T13:33:49 # ::file pmid_1901_8267_162.txt # ::snt There were no differences in intra-abdominal xenograft tumour weights between the CI-1040-treated group and control groups transplanted with the wild-type KRAS/BRAF cell line SKOV3 (Figure 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (d / differ-02 :polarity "-" :ARG1 (g / group :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :wiki "-" :name (n / name :op1 "CI-1040") :xref (x3 / xref :value "PUBCHEM:6918454" :prob "17.207357")))) :ARG2 (g2 / group :mod (c / control) :ARG2-of (t2 / transplant-01 :ARG1 (c2 / cell-line :wiki "-" :name (n2 / name :op1 "SKOV3") :mod (g5 / gene :mod (s2 / slash :op1 (g3 / gene :wiki "-" :name (n3 / name :op1 "KRAS") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g4 / gene :wiki "BRAF_(gene)" :name (n4 / name :op1 "BRAF") :mod w :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) :ARG3 (w2 / weight-01 :ARG1 (t3 / tumor :mod (x / xenograft) :mod (i / intra-abdominal))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7B"))) # ::id pmid_1901_8267.163 # ::date 2015-07-11T13:43:37 # ::file pmid_1901_8267_163.txt # ::snt Histological examination of the tumours after CI-1040 treatment showed inactivation of p-ERK1/2 in tumour cells based on immunohistochemistry (Figure 7C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s / show-01 :ARG0 (e / examine-01 :ARG1 (t / tumor) :mod (h / histologic) :time (a / after :op1 (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "CI-1040") :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357"))))) :ARG1 (a2 / activate-01 :polarity "-" :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :location (c / cell :mod t) :ARG1-of (b / base-02 :ARG2 (i / immunohistochemistry))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "7C") :op2 (f2 / figure :mod "7D")))) # ::id pmid_1956_8237.1 # ::date 2015-08-15T04:21:12 # ::file pmid_1956_8237_1.txt # ::snt Episodic Src activation in uveal melanoma revealed by kinase activity profiling (PMID:19568237) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :location (m / medical-condition :name (n2 / name :op1 "melanoma") :mod (u / uveal)) :ARG1-of (r / reveal-01 :ARG0 (p2 / profile-01 :ARG1 (a2 / activity-06 :ARG0 (k / kinase)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID19568237")) :mod (e / episodic)) # ::id pmid_1956_8237.8 # ::date 2015-08-15T07:27:16 # ::file pmid_1956_8237_8.txt # ::snt Results: # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 15, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1956_8237.9 # ::date 2015-08-15T07:27:39 # ::file pmid_1956_8237_9.txt # ::snt We identified Src as a kinase that is associated with ERK1/2 activation in UM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / identify-01 :ARG0 (w / we) :ARG1 (p / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :ARG2 (k / kinase :ARG1-of (a / associate-01 :ARG2 (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")) :location (m / medical-condition :name (n3 / name :op1 "melanoma") :mod (u / uveal)))))) # ::id pmid_1956_8237.10 # ::date 2015-08-15T07:30:45 # ::file pmid_1956_8237_10.txt # ::snt However, low Src levels and reduced ERK1/2 activation in metastatic cell lines suggest that proliferation in metastases can become independent of Src and RAS/RAF/MEK/ERK signalling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (h / have-concession-91 :ARG1 (s / suggest-01 :ARG0 (a / and :op1 (l / level :ARG1-of (l2 / low-04) :quant-of (p / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) :op2 (a4 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")) :ARG1-of (r / reduce-01)) :location (c / cell-line :ARG1-of (m / metastasize-101))) :ARG1 (p2 / possible-01 :ARG1 (b / become-01 :ARG1 (p3 / proliferate-01 :location m) :ARG2 (d / depend-01 :polarity "-" :ARG0 p3 :ARG1 (a3 / and :op1 p :op2 (s2 / signal-07 :ARG0 (p4 / pathway :name (n3 / name :op1 "RAS/RAF/MEK/ERK"))))))))) # ::id pmid_1956_8237.11 # ::date 2015-08-15T07:42:29 # ::file pmid_1956_8237_11.txt # ::snt Inhibition of Src led to the growth reduction of primary UM cultures and cell lines, whereas metastatic cell line growth was only slightly reduced. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG1 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (p / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) :ARG2 (r / reduce-01 :ARG1 (g / grow-01 :ARG1 (a / and :op1 (c2 / cell-line :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma") :mod (u / uveal)) :mod (p2 / primary)) :op2 (c3 / culture-01 :mod m2 :mod p2))))) :ARG2 (r2 / reduce-01 :ARG1 (g2 / grow-01 :ARG1 (c4 / cell-line :ARG1-of (m / metastasize-101))) :mod (o / only) :degree (s / slight))) # ::id pmid_1956_8237.92 # ::date 2015-08-15T07:47:31 # ::file pmid_1956_8237_92.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 15, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1956_8237.93 # ::date 2015-08-15T07:47:58 # ::file pmid_1956_8237_93.txt # ::snt ERK1/2 activation in UM # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (m / medical-condition :name (n2 / name :op1 "melanoma") :mod (u / uveal))) # ::id pmid_1956_8237.94 # ::date 2015-08-15T07:48:49 # ::file pmid_1956_8237_94.txt # ::snt An antibody array was applied to investigate the MAPK pathway in 10 UM cell lines, in three primary UM and three UM metastasis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / apply-03 :ARG1 (a2 / array-01 :ARG1 (a3 / antibody)) :purpose (i / investigate-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :location (a4 / and :op1 (c / cell-line :quant "10" :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma") :mod (u / uveal))) :op2 (m3 / medical-condition :quant "3" :name (n3 / name :op1 "melanoma") :mod u :mod (p2 / primary)) :op3 (m / metastasize-101 :quant "3" :mod m2)))) # ::id pmid_1956_8237.95 # ::date 2015-08-15T07:56:17 # ::file pmid_1956_8237_95.txt # ::snt We observed a uniform HSP27 phosphorylation, with the exception of in three UM cell lines (OCM1, -3, -8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "HSP27") :xref (x / xref :value "UNIPROT:HSPB1_HUMAN" :prob "1.002")) :ARG1-of (u / uniform-02) :ARG2-of (e / except-01 :ARG1 (p3 / phosphorylate-01 :ARG1 p2 :location (c / cell-line :quant "3" :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma") :mod (u2 / uveal)) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c2 / cell-line :name (n3 / name :op1 "OCM1")) :op2 (c3 / cell-line :name (n4 / name :op1 "OCM3")) :op3 (c4 / cell-line :name (n5 / name :op1 "OCM8"))))))))) # ::id pmid_1956_8237.96 # ::date 2015-08-15T08:02:04 # ::file pmid_1956_8237_96.txt # ::snt UMs displaying activated ERK1/2 as well as phosphorylated HSP27 were most common, whereas signals for phosphorylated ERK1/2 were low in metastasis tissue (MET1-3) and metastatic UM cell lines (OMM1, OMM2.3 and OMM2.5) (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG1 (c2 / common :domain (m4 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal) :ARG0-of (d2 / display-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "ERK1/2") :ARG1-of (a2 / activate-01)) :op2 (p2 / protein :name (n3 / name :op1 "HSP27") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:HSPB1_HUMAN" :prob "1.002"))))) :degree (m / most)) :ARG2 (l / low-04 :ARG1 (s / signal-07 :beneficiary (e2 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG3-of (p3 / phosphorylate-01))) :location (a3 / and :op1 (t / tissue :ARG1-of (m2 / metastasize-101) :ARG1-of (l2 / label-01 :ARG2 (t2 / thing :name (n5 / name :op1 "MET") :value (v / value-interval :op1 "1" :op2 "3")))) :op2 (c3 / cell-line :mod m4 :mod m2 :ARG1-of (m3 / mean-01 :ARG2 (a4 / and :op1 (c4 / cell-line :name (n6 / name :op1 "OMM1")) :op2 (c5 / cell-line :name (n7 / name :op1 "OMM2.3")) :op3 (c6 / cell-line :name (n8 / name :op1 "OMM2.5"))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1"))) # ::id pmid_1956_8237.97 # ::date 2015-08-15T08:21:25 # ::file pmid_1956_8237_97.txt # ::snt Remarkably, two of the metastatic cell lines (OMM2.3, OMM2.5) are derived from the same patient as cell line Mel270 but contained far less activated ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG1 (d / derive-01 :ARG1 (c2 / cell-line :quant "2" :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (c4 / cell-line :name (n / name :op1 "OMM2.3")) :op2 (c5 / cell-line :name (n2 / name :op1 "OMM2.5"))) :ARG1-of (m / metastasize-101)) :ARG1-of (i / include-91 :ARG2 (c3 / cell-line))) :ARG2 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (s / same-01)) :ARG4 (c6 / cell-line :name (n3 / name :op1 "Mel270"))) :ARG2 (c7 / contain-01 :ARG0 c2 :ARG1 (e / enzyme :name (n4 / name :op1 "ERK1/2") :ARG1-of (a2 / activate-01) :quant (l / less :degree (f / far)))) :ARG1-of (r / remarkable-02)) # ::id pmid_1956_8237.98 # ::date 2015-08-15T08:30:04 # ::file pmid_1956_8237_98.txt # ::snt Differential kinase activity in UM # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / activity-06 :ARG0 (k / kinase) :mod (d / differential) :location (m / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal))) # ::id pmid_1956_8237.99 # ::date 2015-08-15T08:32:15 # ::file pmid_1956_8237_99.txt # ::snt Reduction of ERK1/2 activation in metastatic cell lines compared with that in primary UM cell lines provides a model to identify the underlying mechanism of ERK1/2 activation in the absence of BRAF and NRAS mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p / provide-01 :ARG0 (r / reduce-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (c / cell-line :ARG1-of (m / metastasize-101))) :ARG1-of (c2 / compare-01 :ARG2 (r2 / reduce-01 :ARG1 a :location (c3 / cell-line :mod (m6 / medical-condition :name (n2 / name :op1 "melanoma") :mod (u / uveal) :mod (p2 / primary)))))) :ARG1 (m2 / model-01 :purpose (i / identify-01 :ARG1 (m3 / mechanism :ARG1-of (u2 / underlie-01) :mod (a2 / activate-01 :ARG1 e :condition (a3 / absent-01 :ARG1 (a4 / and :op1 (m4 / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (m5 / mutate-01 :ARG1 (g2 / gene :name (n4 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))))))))) # ::id pmid_1956_8237.100 # ::date 2015-08-15T08:41:09 # ::file pmid_1956_8237_100.txt # ::snt To investigate whether a kinase is differentially activated between primary UM cell lines and metastatic UM cell lines, we used peptide-based tyrosine kinase arrays (Lemeer et al, 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (u3 / use-01 :ARG0 (w / we) :ARG1 (a3 / array-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "tyrosine" :op2 "kinase") :xref (x / xref :value "UNIPROT:FER_HUMAN" :prob "0.392")) :ARG1-of (b / base-02 :ARG2 (p2 / peptide)) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and :op1 (p4 / person :name (n4 / name :op1 "Lemeer")) :op2 (p5 / person :mod (o / other))) :time (d5 / date-entity :year "2007")))) :ARG2 (i / investigate-01 :ARG0 w :ARG1 (a / activate-01 :mode "interrogative" :ARG1 (k / kinase) :manner (d / differential) :location (a2 / and :op1 (c / cell-line :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal) :mod (p / primary))) :op2 (c2 / cell-line :mod (m3 / medical-condition :name (n2 / name :op1 "melanoma") :mod u :ARG1-of (m / metastasize-101))))))) # ::id pmid_1956_8237.101 # ::date 2015-08-15T08:52:19 # ::file pmid_1956_8237_101.txt # ::snt The UM cell lines displayed a high kinase activity, whereas the metastatic UM cell lines displayed a low kinase activity, although the same amount of lysate was incubated (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h2 / have-concession-91 :ARG1 (c / contrast-01 :ARG1 (d / display-01 :ARG0 (c2 / cell-line :mod (m3 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal))) :ARG1 (a / activity-06 :ARG0 (k / kinase) :ARG1-of (h / high-02))) :ARG2 (d3 / display-01 :ARG0 (c3 / cell-line :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma") :ARG1-of (m / metastasize-101))) :ARG1 (a2 / activity-06 :ARG0 k :ARG1-of (l / low-04)))) :ARG2 (i / incubate-01 :ARG1 (a3 / amount :quant-of (l2 / lysate) :ARG1-of (s / same-01))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_1956_8237.102 # ::date 2015-08-15T08:59:57 # ::file pmid_1956_8237_102.txt # ::snt After normalisation, we could analyse the kinase data and identify nine substrates that were significantly differentially phosphorylated between primary and metastatic UM cell lines (Figure 2B, Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p / possible-01 :ARG1 (a / and :op1 (a2 / analyze-01 :ARG0 (w / we) :ARG1 (d / data :topic (k / kinase))) :op2 (i / identify-01 :ARG0 w :ARG1 (s / substrate :quant "9" :ARG3-of (p2 / phosphorylate-01 :ARG1-of (s2 / significant-02) :manner (d2 / differential) :location (a3 / and :op1 (c / cell-line :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal) :mod (p3 / primary))) :op2 (c2 / cell-line :mod (m3 / medical-condition :name (n2 / name :op1 "melanoma") :mod (u2 / uveal) :ARG1-of (m / metastasize-101)))))))) :time (a4 / after :op1 (n3 / normalize-01)) :ARG1-of (d5 / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "2B") :op2 (t / table :mod "1")))) # ::id pmid_1956_8237.103 # ::date 2015-08-15T09:08:13 # ::file pmid_1956_8237_103.txt # ::snt Primary UM and metastatic tissue also showed differential phosphorylation of these nine peptides, although not as clearly as observed in the cell lines (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / show-01 :ARG0 (a / and :op1 (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal) :mod (p / primary)) :op2 (t / tissue :ARG1-of (m / metastasize-101))) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / peptide :quant "9" :mod (t2 / this)) :mod (d2 / differential)) :concession (c / clear-06 :polarity "-" :ARG1 "s" :compared-to (p4 / phosphorylate-01 :ARG1-of (o / observe-01 :location (c2 / cell-line)))) :mod (a2 / also) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2C"))) # ::id pmid_1956_8237.104 # ::date 2015-08-15T09:17:31 # ::file pmid_1956_8237_104.txt # ::snt Candidate kinase: Src # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (p / protein :domain (k / kinase :name (n / name :op1 "Src") :mod (c / candidate) :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) # ::id pmid_1956_8237.105 # ::date 2015-08-15T09:18:54 # ::file pmid_1956_8237_105.txt # ::snt We identified nine peptides derived from eight proteins that were differentially phosphorylated between primary and metastatic cell line lysates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (i / identify-01 :ARG0 (w / we) :ARG1 (p / peptide :quant "9" :ARG1-of (d / derive-01 :ARG2 (p2 / protein :quant "8" :ARG3-of (p3 / phosphorylate-01 :manner (d2 / differential) :location (a / and :op1 (l / lysate :mod (c / cell-line) :mod (p4 / primary)) :op2 (l2 / lysate :mod (c2 / cell-line) :ARG1-of (m / metastasize-101)))))))) # ::id pmid_1956_8237.106 # ::date 2015-08-15T09:22:18 # ::file pmid_1956_8237_106.txt # ::snt On the basis of a literature search, we identified candidate tyrosine kinases for eight out of nine peptides (Table 1) (Cooper et al, 1983; Thomas and Brugge, 1997; Koike et al, 2003; Diella et al, 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (i / identify-01 :ARG0 (w / we) :ARG1 (e / enzyme :name (n7 / name :op1 "tyrosine" :op2 "kinase") :mod (c / candidate) :xref (x / xref :value "UNIPROT:FER_HUMAN" :prob "0.392")) :beneficiary (p / peptide :quant "8" :ARG1-of (i2 / include-91 :ARG2 (p2 / peptide :quant "9"))) :ARG1-of (d5 / describe-01 :ARG0 (t / table :mod "1")) :ARG1-of (b / base-02 :ARG2 (s / search-01 :ARG1 (l / literature :ARG2-of (i3 / include-91 :ARG1 (a / and :op1 (p3 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n2 / name :op1 "Cooper")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "1983")) :op2 (p6 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n3 / name :op1 "Thomas")) :op2 (p8 / person :name (n4 / name :op1 "Brugge"))) :time (d2 / date-entity :year "1997")) :op3 (p9 / publication-91 :ARG0 (a4 / and :op1 (p10 / person :name (n5 / name :op1 "Koike")) :op2 (p11 / person :mod (o2 / other))) :time (d3 / date-entity :year "2003")) :op4 (p12 / publication-91 :ARG0 (a5 / and :op1 (p13 / person :name (n6 / name :op1 "Diella")) :op2 (p14 / person :mod (o3 / other))) :time (d4 / date-entity :year "2004")))))))) # ::id pmid_1956_8237.107 # ::date 2015-08-15T09:32:25 # ::file pmid_1956_8237_107.txt # ::snt Among the candidates, Src and Src family members were most prominent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (p / prominent :domain (a / and :op1 (p2 / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :op2 (m / member :ARG1-of (i2 / include-91 :ARG2 (p3 / protein-family :name (n2 / name :op1 "Src")))) :ARG1-of (i / include-91 :ARG2 (c / candidate))) :degree (m2 / most)) # ::id pmid_1956_8237.108 # ::date 2015-08-15T09:36:03 # ::file pmid_1956_8237_108.txt # ::snt To validate the candidacy of Src, we performed in vitro inhibition experiments with the Src-kinase-specific inhibitors PP1 and the PP1 analogue, PP2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG1 (i / inhibit-01) :ARG2 (s / small-molecule :ARG0-of (i3 / inhibit-01) :ARG1-of (s2 / specific-02 :ARG2 (k / kinase :name (n / name :op1 "Src") :xref (x2 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n3 / name :op1 "PP2") :mod (a2 / analogue :mod p2) :xref (x1 / xref :value "UNIPROT:NPY6R_HUMAN" :prob "1.002"))))) :manner (i2 / in-vitro)) :purpose (v / validate-01 :ARG0 w :ARG1 (c / candidacy :mod k))) # ::id pmid_1956_8237.109 # ::date 2015-08-15T09:46:46 # ::file pmid_1956_8237_109.txt # ::snt We added PP1 and PP2 (10 μM) to lysates of primary UM tissue and of a primary UM cell line and measured the inhibitory effect of these Src inhibitors using kinase array (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / add-02 :ARG0 (w / we) :ARG1 (a3 / and :op1 (s / small-molecule) :op2 (s2 / small-molecule) :quant (c2 / concentration-quantity :quant "10" :unit (m / micromolar))) :ARG2 (a7 / and :op1 (l / lysate :source (t / tissue :mod (m3 / medical-condition :name (n3 / name :op1 "melanoma") :mod (u / uveal) :mod (p / primary)))) :op1 (l2 / lysate :source (c / cell-line :mod m3)))) :op2 (m2 / measure-01 :ARG0 w :ARG1 (a5 / affect-01 :ARG0 (s3 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n4 / name :op1 "Src")))) :ARG2 (i / inhibit-01)) :instrument (a6 / array-01 :ARG1 (k / kinase))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_1956_8237.110 # ::date 2015-08-15T09:55:58 # ::file pmid_1956_8237_110.txt # ::snt A total of seven out of nine substrates that identified Src in the first screen displayed a significantly reduced phosphorylation when PP1 or PP2 were added to lysates of UM1 and Mel270 (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / display-01 :ARG0 (s / substrate :quant "7" :ARG1-of (i2 / include-91 :ARG2 (s3 / substrate :quant "9" :ARG0-of (i / identify-01 :ARG1 (p / protein :name (n / name :op1 "Src") :xref (x2 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :location (s2 / screen :ord (o / ordinal-entity :value "1"))))) :ARG1-of (t / total-01)) :ARG1 (p2 / phosphorylate-01 :ARG1-of (r / reduce-01 :ARG2 (s4 / significant-02))) :time (a / add-02 :ARG1 (o2 / or :op1 (p3 / protein :name (n2 / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n3 / name :op1 "PP2") :xref (x1 / xref :value "UNIPROT:NPY6R_HUMAN" :prob "1.002"))) :ARG2 (a3 / and :op1 (l / lysate :source (t2 / thing :name (n4 / name :op1 "UM1"))) :op2 (l2 / lysate :source (c / cell-line :name (n5 / name :op1 "Mel270"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_1956_8237.111 # ::date 2015-08-15T10:06:58 # ::file pmid_1956_8237_111.txt # ::snt The PLCG1 peptide and one of the PAX1 (Y31) substrates did not reach significance but were still phosphorylated at a reduced level after PP1 and PP2 treatments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / reach-01 :polarity "-" :ARG0 (a / and :op1 (p / peptide :name (n / name :op1 "PLCG1")) :op1 (s / substrate :name (n2 / name :op1 "Y31") :ARG1-of (i / include-91 :ARG2 (s2 / substrate :name (n3 / name :op1 "PAX1"))))) :ARG1 (s3 / significance)) :ARG2 (p2 / phosphorylate-01 :ARG1 a :degree (l / level :ARG1-of (r2 / reduce-01)) :time (a2 / after :op1 (t / treat-04 :ARG2 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n5 / name :op1 "PP2") :xref (x1 / xref :value "UNIPROT:NPY6R_HUMAN" :prob "1.002"))))) :mod (s6 / still))) # ::id pmid_1956_8237.112 # ::date 2015-08-15T10:14:03 # ::file pmid_1956_8237_112.txt # ::snt The peptide representing FAK1 Y576/Y577 is a genuine substrate for Src, which was not detected in the UM cell line comparison, but phosphorylation was significantly downregulated by PP1 and PP2 treatments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (s / substrate :mod (g / genuine) :domain (p / peptide :ARG0-of (r / represent-01 :ARG1 (o / or :op1 (a / amino-acid :mod "576" :name (n / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a2 / amino-acid :mod "577" :name (n2 / name :op1 "tyrosine") :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :part-of (e / enzyme :mod "1" :name (n3 / name :op1 "FAK") :xref (x2 / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003"))))) :beneficiary (p2 / protein :name (n4 / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :ARG1-of (d / detect-01 :polarity "-" :time (c2 / compare-01 :ARG1 (c3 / cell-line :mod (m / medical-condition :name (n5 / name :op1 "melanoma") :mod (u / uveal)))))) :ARG2 (d3 / downregulate-01 :ARG1 (p3 / phosphorylate-01) :ARG2 (t / treat-04 :ARG2 (a3 / and :op1 (p4 / protein :name (n6 / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002")) :op2 (p5 / protein :name (n7 / name :op1 "PP2") :xref (x3 / xref :value "UNIPROT:NPY6R_HUMAN" :prob "1.002")))) :ARG1-of (s4 / significant-02))) # ::id pmid_1956_8237.113 # ::date 2015-08-15T12:22:11 # ::file pmid_1956_8237_113.txt # ::snt In the control experiment, in which we added the inactive analogue of PP1 (PP3) to cell lysates, we did not observe a loss of kinase activity (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / observe-01 :polarity "-" :ARG0 (w / we) :ARG1 (l / lose-02 :ARG1 (a / activity-06 :ARG0 (k / kinase)) :ARG1-of (s2 / show-01 :polarity "-")) :location (e / experiment-01 :mod (c / control) :location-of (a2 / add-02 :ARG0 w :ARG1 (a3 / analogue :name (n2 / name :op1 "PP3") :ARG0-of (a4 / activity-06 :polarity "-") :poss (p / protein :name (n / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002"))) :ARG2 (l2 / lysate :mod (c2 / cell))))) # ::id pmid_1956_8237.114 # ::date 2015-08-15T12:29:33 # ::file pmid_1956_8237_114.txt # ::snt The kinase activity of metastasis tissue and UM tissue differed marginally (Figure 2C), and incubation with PP1 (10 μM) resulted in a decimation of kinase activity similar to the inhibition that we observed in UM tissue (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (d / differ-02 :ARG1 (t2 / tissue :mod (m4 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal))) :ARG2 (t / tissue :ARG1-of (m / metastasize-101)) :ARG3 (a2 / activity-06 :mod (k / kinase)) :ARG1-of (m2 / marginal-02) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2C"))) :op2 (r / result-01 :ARG1 (i / incubate-01 :ARG2 (s / small-molecule :quant (c / concentration-quantity :quant "10" :unit (m3 / micromolar)))) :ARG2 (d4 / decimate-01 :ARG1 (a4 / activity-06 :mod (k2 / kinase) :ARG1-of (r2 / resemble-01 :ARG2 (i2 / inhibit-01 :ARG1-of (o / observe-01 :ARG0 (w / we) :location t2))))) :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure :mod "3B")))) # ::id pmid_1956_8237.115 # ::date 2015-08-15T12:36:16 # ::file pmid_1956_8237_115.txt # ::snt To validate Src activity, Mel270 was transfected with two siRNA constructs that target Src and reduced kinase activity (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 15, 2015 (a / and :op1 (t / transfect-01 :ARG1 (c / cell-line :name (n / name :op1 "Mel270")) :ARG2 (c2 / construct :quant "2" :mod (n4 / nucleic-acid :name (n2 / name :op1 "siRNA")) :ARG0-of (t2 / target-01 :ARG1 (p / protein :name (n3 / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))))) :op2 (r2 / reduce-01 :ARG1 (a2 / activity-06 :mod (k / kinase))) :purpose (v / validate-01 :ARG1 (a3 / activity-06 :ARG0 p)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_1956_8237.116 # ::date 2015-08-15T12:48:53 # ::file pmid_1956_8237_116.txt # ::snt Regulation of ERK1/2 and growth # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 15, 2015 (a / and :op1 (r / regulate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))) :op2 (g / grow-01)) # ::id pmid_1956_8237.117 # ::date 2015-08-15T12:49:54 # ::file pmid_1956_8237_117.txt # ::snt To investigate whether Src contributes to ERK1/2 activation in Mel270, we analysed the two Src siRNA-transfected cell cultures with the MAPK antibody array. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (c / culture :quant "2" :mod (c2 / cell) :ARG1-of (t / transfect-01 :ARG2 (n6 / nucleic-acid :name (n / name :op1 "siRNA"))) :mod (p2 / protein :name (n3 / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) :instrument (a2 / array-01 :ARG1 (a3 / antibody :ARG0-of (c5 / counter-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))))) :purpose (i / investigate-01 :ARG0 w :ARG1 (c3 / contribute-01 :mode "interrogative" :ARG0 p2 :ARG1 (a4 / activate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "ERK1/2")) :location (c4 / cell-line :name (n5 / name :op1 "Mel270")))))) # ::id pmid_1956_8237.118 # ::date 2015-08-15T12:54:56 # ::file pmid_1956_8237_118.txt # ::snt At 24 and 48 h after transfection with Src siRNA, we observed a reduced ERK1 phosphorylation, whereas ERK2 phosphorylation was minimally affected (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 15, 2015 (c / contrast-01 :ARG1 (o / observe-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :ARG1-of (r / reduce-01))) :ARG2 (a / affect-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1-of (m / minimal-02)) :time (a2 / after :op1 (t / transfect-01 :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "siRNA") :mod (p3 / protein :name (n4 / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")))) :quant (a3 / and :op1 (t2 / temporal-quantity :quant "24" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "48" :unit (h2 / hour)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4"))) # ::id pmid_1956_8237.119 # ::date 2015-08-15T13:02:49 # ::file pmid_1956_8237_119.txt # ::snt Whether Src inhibition and consequently a lowered ERK activation in UM cell lines is associated with a reduced growth was investigated with the WST-1 viability assay (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / investigate-01 :ARG1 (a / associate-01 :mode "interrogative" :ARG1 (a2 / and :op1 (i2 / inhibit-01 :ARG1 (p / protein :name (n / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) :op2 (a3 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (l / lower-05) :location (c / cell-line :mod (m / medical-condition :name (n3 / name :op1 "melanoma") :mod (u / uveal))) :manner (c2 / consequent))) :ARG2 (g / grow-01 :ARG1-of (r / reduce-01))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5")) :instrument (a4 / assay-01 :mod (v / viable) :mod (t / thing :name (n4 / name :op1 "WST-1")))) # ::id pmid_1956_8237.120 # ::date 2015-08-15T13:10:11 # ::file pmid_1956_8237_120.txt # ::snt All UM cell lines showed a PP1-dose and time (1–6 days)-dependent reduction in cell viability but the magnitude of the response differed widely. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (c2 / cell-line :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal)) :mod (a / all)) :ARG1 (r / reduce-01 :ARG1 (v / viable :mod (c3 / cell)) :ARG0-of (d3 / depend-01 :ARG1 (a2 / and :op1 (d4 / dose-01 :ARG2 (p / protein :name (n2 / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002"))) :op2 (t / time :quant (b / between :op1 (t2 / temporal-quantity :quant "1" :unit (d5 / day)) :op2 (t3 / temporal-quantity :quant "6" :unit d5))))))) :ARG2 (d2 / differ-02 :ARG1 (m / magnitude :mod (r2 / respond-01)) :ARG2-of (w / wide-02))) # ::id pmid_1956_8237.121 # ::date 2015-08-15T13:19:50 # ::file pmid_1956_8237_121.txt # ::snt In general, the metastatic UM cell lines were less affected by PP1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (p / protein :name (n2 / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002")) :ARG1 (c / cell-line :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uveal) :ARG1-of (m / metastasize-101))) :degree (l / less) :ARG1-of (g / general-02)) # ::id pmid_1956_8237.122 # ::date 2015-08-15T13:22:34 # ::file pmid_1956_8237_122.txt # ::snt We also determined the growth inhibition rate of PP1 in cultures of five primary UM cell cultures and observed an increased sensitivity to PP1 treatment compared with the cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (d / determine-01 :ARG0 (w / we) :ARG1 (r / rate :degree-of (i / inhibit-01 :ARG0 (p2 / protein :name (n / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002")) :ARG1 (g / grow-01)) :location (c / culture :ARG1-of (i2 / include-91 :ARG2 (c2 / culture :quant "5" :mod (c3 / cell) :mod (m / medical-condition :name (n2 / name :op1 "melanoma") :mod (u / uveal) :mod (p / primary)))))) :mod (a2 / also)) :op2 (o / observe-01 :ARG0 w :ARG1 (s2 / sensitive-03 :ARG1 (t / treat-04 :ARG2 p2) :ARG1-of (i3 / increase-01) :compared-to (c4 / cell-line)))) # ::id pmid_1956_8237.123 # ::date 2015-08-15T13:29:10 # ::file pmid_1956_8237_123.txt # ::snt We had to take samples at day 3 of PP1 treatment because, thereafter, massive cell death occurred (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / obligate-01 :ARG1 (w / we) :ARG2 (t / take-01 :ARG0 w :ARG1 (t4 / thing :ARG1-of (s / sample-01)) :time (a / after :op1 (t2 / treat-04 :ARG2 (p / protein :name (n / name :op1 "PP1") :xref (x / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002"))) :quant (t3 / temporal-quantity :quant "3" :unit (d / day)))) :ARG1-of (c / cause-01 :ARG0 (d2 / die-01 :ARG1 (c2 / cell) :mod (m / massive) :time (a2 / after :op1 a))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id pmid_1956_8237.124 # ::date 2015-08-15T13:35:53 # ::file pmid_1956_8237_124.txt # ::snt Src protein is reduced in metastasis cell line # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (r / reduce-01 :ARG1 (p / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :location (c / cell-line :ARG1-of (m / metastasize-101))) # ::id pmid_1956_8237.125 # ::date 2015-08-15T13:36:45 # ::file pmid_1956_8237_125.txt # ::snt Src is regulated by the phosphorylation of tyrosine residues at position 416 (Y416) and 527 (Y527). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (r / regulate-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (a3 / and :op1 (r2 / residue :mod (a / amino-acid :mod "416" :name (n2 / name :op1 "tyrosine") :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (r3 / residue :mod (a4 / amino-acid :mod "527" :name (n3 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :ARG1 (p / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) # ::id pmid_1956_8237.126 # ::date 2015-08-15T13:43:45 # ::file pmid_1956_8237_126.txt # ::snt The expression of phosphorylated Src Y416, which is associated with an active conformation, was low in the metastatic UM cell lines (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (l / low-04 :ARG1 (e / express-03 :ARG2 (a3 / amino-acid :mod "416" :name (n3 / name :op1 "tyrosine") :part-of (p2 / protein :name (n / name :op1 "Src") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (a / associate-01 :ARG2 (c / conformation :ARG0-of (a2 / activity-06)))) :location (c2 / cell-line :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma") :mod (u / uveal) :ARG1-of (m / metastasize-101))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_1956_8237.127 # ::date 2015-08-15T13:49:40 # ::file pmid_1956_8237_127.txt # ::snt Surprisingly, the phosphorylation of Y527, which is associated with an inactive conformation, was also low, and a subsequent analysis indicated that Src expression is low in metastatic UM cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (l / low-04 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "527" :name (n / name :op1 "tyrosine") :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (a3 / associate-01 :ARG2 (c / conformation :ARG0-of (a4 / activity-06 :polarity "-")))) :mod (a5 / also) :manner (s2 / surprise-01)) :op2 (i / indicate-01 :ARG0 (a6 / analyze-01 :time (s / subsequent)) :ARG1 (l2 / low-04 :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :ARG3 (c2 / cell-line :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma") :mod (u / uveal) :ARG1-of (m / metastasize-101))))))) # ::id pmid_1956_8237.128 # ::date 2015-08-15T13:55:18 # ::file pmid_1956_8237_128.txt # ::snt Therefore, the difference between kinase activity in metastatic cell lines (OMM1, OMM2.3 and OMM2.5) and UM cell lines (OCM1, OCM3, OCM8, Mel202, Mel270, Mel285, Mel290 and 92.1) seems to be the result of a difference in Src expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c14 / cause-01 :ARG1 (s / seem-01 :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (d / differ-02 :ARG3 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))))) :domain (d2 / differ-02 :ARG1 (c / cell-line :ARG1-of (m / metastasize-101) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (c2 / cell-line :name (n2 / name :op1 "OMM1")) :op2 (c3 / cell-line :name (n3 / name :op1 "OMM2.3")) :op3 (c4 / cell-line :name (n4 / name :op1 "OMM2.5"))))) :ARG2 (c5 / cell-line :mod (m3 / medical-condition :name (n5 / name :op1 "melanoma") :mod (u / uveal)) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (c6 / cell-line :name (n6 / name :op1 "OCM1")) :op2 (c7 / cell-line :name (n7 / name :op1 "OCM3")) :op3 (c8 / cell-line :name (n8 / name :op1 "OCM8")) :op4 (c9 / cell-line :name (n9 / name :op1 "Mel202")) :op5 (c10 / cell-line :name (n10 / name :op1 "Mel270")) :op6 (c11 / cell-line :name (n11 / name :op1 "Mel285")) :op7 (c12 / cell-line :name (n12 / name :op1 "Mel290")) :op8 (c13 / cell-line :name (n13 / name :op1 "Mel292.1"))))) :ARG3 (a / activity-06 :ARG0 (k / kinase)))))) # ::id pmid_1956_8237.129 # ::date 2015-08-15T14:08:25 # ::file pmid_1956_8237_129.txt # ::snt To investigate the origin of a lowered Src expression, we performed a gene expression analysis (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (p / perform-02 :ARG0 (w / we) :ARG1 (a / analyze-01 :ARG0 w :ARG1 (e / express-03 :ARG2 (g / gene))) :purpose (i / investigate-01 :ARG0 w :ARG1 (o / originate-01 :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :ARG1-of (l / lower-05)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id pmid_1956_8237.130 # ::date 2015-08-15T14:11:06 # ::file pmid_1956_8237_130.txt # ::snt Src gene expression varied widely in the cell lines and in the metastatic cell lines, but a correlation between protein and gene expression was not observed in UM cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG1 (v / vary-01 :ARG0 (e / express-03 :ARG2 (g / gene :wiki "-" :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :ARG3 (a / and :op1 (c2 / cell-line) :op2 (c3 / cell-line :ARG1-of (m / metastasize-101)))) :ARG1-of (w / wide-02)) :ARG2 (o / observe-01 :polarity "-" :ARG1 (c4 / correlate-01 :ARG1 (e2 / express-03 :ARG2 (p / protein) :ARG3 (c5 / cell-line :mod (m2 / medical-condition :wiki "Melanoma" :name (n2 / name :op1 "melanoma") :mod (u / uveal)))) :ARG2 (e3 / express-03 :ARG2 (g2 / gene) :ARG3 c5)))) # ::id pmid_1956_8237.131 # ::date 2015-08-15T14:19:02 # ::file pmid_1956_8237_131.txt # ::snt A western analysis of Src expression in UM and metastasis tissue revealed a very high Src expression in only one out of three primary UM, whereas all three metastasis tissues displayed medium expression of Src protein (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / contrast-01 :ARG1 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :ARG3 (a2 / and :op1 (m6 / medical-condition :name (n3 / name :op1 "melanoma") :mod (u / uveal)) :op2 (t / tissue :mod (m / metastasis)))) :mod (w / western)) :ARG1 (e2 / express-03 :ARG2 p :ARG3 (m4 / medical-condition :quant "1" :name (n4 / name :op1 "melanoma") :ARG1-of (i / include-91 :ARG2 (m5 / medical-condition :quant "3" :name (n5 / name :op1 "melanoma") :mod (p2 / primary) :mod u)) :mod u) :ARG1-of (h / high-02 :degree (v / very)) :mod (o / only))) :ARG2 (d4 / display-01 :ARG0 (t2 / tissue :quant "3" :ARG1-of (m2 / metastasize-101) :mod (a3 / all)) :ARG1 (e3 / express-03 :ARG2 p :degree (m3 / medium))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id pmid_1991_9690.1 # ::date 2015-08-13T06:32:51 # ::file pmid_1991_9690_1.txt # ::snt Expression and function of hypoxia inducible factor-1 alpha in human melanoma under non-hypoxic conditions (PMID:19919690) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "hypoxia" :op2 "inducible" :op3 "factor-1" :op4 "alpha") :xref (x / xref :value "UNIPROT:HIF1A_HUMAN" :prob "0.692"))) :op2 (f / function-01 :ARG0 p) :location (m / medical-condition :name (n2 / name :op1 "melanoma") :mod (h / human)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID19919690")) :ARG1-of (c / condition-01 :ARG2 (h2 / hypoxia :polarity "-"))) # ::id pmid_1991_9690.6 # ::date 2015-08-13T09:35:46 # ::file pmid_1991_9690_6.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1991_9690.7 # ::date 2015-08-13T09:51:45 # ::file pmid_1991_9690_7.txt # ::snt HIF-1α mRNA and protein was increased in RGP vs melanocytes, VGP vs RGP and MET vs VGP melanoma cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / increase-01 :ARG1 (a / and :op1 (n3 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))) :op2 p) :location (a2 / and :op1 (c / contrast-01 :ARG1 (c2 / cell-line :mod (m / medical-condition :name (n6 / name :op1 "melanoma")) :mod (p2 / phase :mod (g / grow-01 :manner (r2 / radius)))) :ARG2 (m3 / melanocyte :mod m)) :op2 (c4 / contrast-01 :ARG1 (c5 / cell-line :mod m :mod (p3 / phase :mod (g2 / grow-01 :manner (v / vertical)))) :ARG2 c2) :op3 (c7 / contrast-01 :ARG1 (c6 / cell-line :mod m :ARG1-of (m2 / metastasize-101)) :ARG2 c5))) # ::id pmid_1991_9690.8 # ::date 2015-08-13T10:05:00 # ::file pmid_1991_9690_8.txt # ::snt We also detected expression of a HIF-1α mRNA splice variant that lacks part of the oxygen-dependent regulation domain in WM1366 and WM9 melanoma cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / detect-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (v / variant :ARG1-of (s / splice-01) :mod (n6 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))) :ARG0-of (l / lack-01 :ARG1 (t / thing :part-of (d2 / domain :ARG0-of (r2 / regulate-01) :ARG0-of (d3 / depend-01 :ARG1 (o / oxygen)))) :location (a2 / and :op1 (c / cell-line :name (n3 / name :op1 "WM1366") :mod (m / medical-condition :name (n4 / name :op1 "melanoma"))) :op2 (c2 / cell-line :name (n5 / name :op1 "WM9") :mod m))))) :mod (a / also)) # ::id pmid_1991_9690.9 # ::date 2015-08-13T14:08:13 # ::file pmid_1991_9690_9.txt # ::snt Over-expression of HIF-1α and its splice variant in the RGP cell line SbCl2 resulted in a small increase in soft agar colony formation and a large increase in matrigel invasion relative to control transfected cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 16, 2015 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "HIF-1α") :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :op2 (v / variant :ARG1-of (s / splice-01) :poss p)) :location (c / cell-line :name (n2 / name :op1 "SbCl2") :mod (p3 / phase :mod (g / grow-01 :manner (r3 / radius))))) :ARG2 (a / and :op1 (i / increase-01 :ARG1 (f / form-01 :ARG1 (c2 / colony :mod (a3 / agar :ARG1-of (s3 / soft-02)))) :mod (s2 / small)) :op2 (i2 / increase-01 :ARG1 (i3 / invade-01 :ARG0 (p2 / protein :name (n4 / name :op1 "matrigel") :xref (x / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.253"))) :mod (l / large)) :ARG1-of (r2 / relative-05 :ARG3 (c3 / cell :mod (c4 / control) :ARG1-of (t2 / transfect-01))))) # ::id pmid_1991_9690.10 # ::date 2015-08-13T14:19:28 # ::file pmid_1991_9690_10.txt # ::snt Knockdown of HIF-1α expression by siRNA in the MET WM9 melanoma cell line resulted in a large decrease in both soft agar colony formation and matrigel invasion relative to cells treated with non-specific siRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / result-01 :ARG1 (k / knock-down-02 :ARG0 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA")) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "HIF-1α") :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG3 (c / cell-line :name (n3 / name :op1 "WM9") :mod (m / medical-condition :name (n4 / name :op1 "melanoma")) :ARG1-of (m2 / metastasize-101)))) :ARG2 (d2 / decrease-01 :ARG1 (a / and :op1 (f / form-01 :ARG1 (c2 / colony :mod (a2 / agar :ARG1-of (s / soft-02)))) :op2 (i / invade-01 :ARG0 (p2 / protein :name (n6 / name :op1 "matrigel") :xref (x / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.253")))) :ARG1-of (r3 / relative-05 :ARG3 (c3 / cell :ARG1-of (t2 / treat-04 :ARG2 (n8 / nucleic-acid :name (n7 / name :op1 "siRNA") :ARG1-of (s2 / specific-02 :polarity "-"))))) :mod (l / large))) # ::id pmid_1991_9690.11 # ::date 2015-08-14T06:57:56 # ::file pmid_1991_9690_11.txt # ::snt There is a high level of ERK1/2 phosphorylation in WM9 cells, indicating an activated Ras-Raf-MEK-ERK1/2 MAPK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (l2 / level :ARG1-of (h / high-02) :quant-of (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")) :location (c / cell-line :name (n3 / name :op1 "WM9"))) :ARG0-of (i / indicate-01 :ARG1 (p3 / pathway :name (n4 / name :op1 "Ras-Raf-MEK-ERK1/2" :op2 "MAPK") :ARG1-of (a / activate-01)))) # ::id pmid_1991_9690.12 # ::date 2015-08-14T07:11:55 # ::file pmid_1991_9690_12.txt # ::snt Treatment of WM9 cells with 30 μM U0126 MEK inhibitor, decreased ERK1/2 phosphorylation and resulted in a decrease in HIF-1α expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (d / decrease-01 :ARG0 (t2 / treat-04 :ARG1 (c / cell-line :name (n3 / name :op1 "WM9")) :ARG2 (s2 / small-molecule :name (n4 / name :op1 "U0126") :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n5 / name :op1 "MEK"))) :quant (c2 / concentration-quantity :quant "30" :unit (m / micromolar)) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "ERK1/2")))) :op2 (r / result-01 :ARG1 t2 :ARG2 (d2 / decrease-01 :ARG1 (e3 / express-03 :ARG2 (p3 / protein :name (n7 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))))) # ::id pmid_1991_9690.13 # ::date 2015-08-14T07:17:27 # ::file pmid_1991_9690_13.txt # ::snt However, a 24 h treatment with 10 μM U0126 totally eliminated Erk1/2 phosphorylation, but did not change HIF-1alpha levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (c / contrast-01 :ARG2 (c2 / contrast-01 :ARG1 (e / eliminate-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :quant (c3 / concentration-quantity :quant "10" :unit (m / micromolar)) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour))) :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))) :degree (t3 / total)) :ARG2 (c4 / change-01 :polarity "-" :ARG0 t :ARG1 (l / level :quant-of (p2 / protein :name (n3 / name :op1 "HIF-1alpha") :xref (x / xref :value "UNIPROT:HIF1A_HUMAN" :prob "0.692")))))) # ::id pmid_1991_9690.14 # ::date 2015-08-14T07:25:55 # ::file pmid_1991_9690_14.txt # ::snt Furthermore, siRNA knockdown of MEK siRNA did not change HIF-1alpha levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (a / and :op2 (c / change-01 :polarity "-" :ARG0 (k / knock-down-02 :ARG0 (n / nucleic-acid :name (n2 / name :op1 "siRNA")) :ARG1 (n6 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :ARG1 (l / level :quant-of (p2 / protein :name (n5 / name :op1 "HIF-1alpha") :xref (x / xref :value "UNIPROT:HIF1A_HUMAN" :prob "0.692"))))) # ::id pmid_1991_9690.47 # ::date 2015-08-14T07:58:59 # ::file pmid_1991_9690_47.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1991_9690.48 # ::date 2015-08-14T08:04:21 # ::file pmid_1991_9690_48.txt # ::snt Expression of HIF-1α in human melanoma cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG3 (c / cell :mod (m / medical-condition :name (n2 / name :op1 "melanoma")) :mod (h / human))) # ::id pmid_1991_9690.49 # ::date 2015-08-14T08:12:39 # ::file pmid_1991_9690_49.txt # ::snt In addition to the well known pathway of HIF-1alpha protein stabilization under hpoxic conditions, it has been established that many oncoproteins and growth factor signaling pathways up-regulate HIF-1α expression under normoxic conditions [18,19]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (e / establish-01 :ARG1 (a / and :op1 (o / oncoprotein :quant (m / many)) :op2 (p / pathway :ARG0-of (s2 / signal-07) :ARG0-of (u / upregulate-01 :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682"))) :ARG1-of (c / condition-01 :ARG2 (n3 / normoxia))) :mod (g / growth-factor))) :ARG1-of (a2 / add-02 :ARG2 (k / know-01 :ARG1 (p3 / pathway :ARG0-of (s3 / stabilize-01 :ARG1 p2 :ARG1-of (c2 / condition-01 :ARG2 (h / hypoxia)))) :ARG1-of (w / well-09))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 "18" :op2 "19"))))) # ::id pmid_1991_9690.50 # ::date 2015-08-14T08:51:55 # ::file pmid_1991_9690_50.txt # ::snt However, there are few investigations into the normoxic expression of HIF-1α in human melanoma and its role in the malignant progression of this disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG2 (i / investigate-01 :ARG1 (a / and :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG3 (m2 / medical-condition :name (n2 / name :op1 "melanoma") :mod (h / human)) :mod (n3 / normoxia)) :op2 (r / role :poss e :topic (p2 / progress-01 :ARG1 m2 :ARG1-of (m / malignant-02)))) :quant (f / few))) # ::id pmid_1991_9690.51 # ::date 2015-08-14T08:57:27 # ::file pmid_1991_9690_51.txt # ::snt Here, we show that in human melanoma cells, the oxygen-labile HIF-1α protein as well as its mRNA is expressed endogenously under normoxic conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n2 / name :op1 "HIF-1α") :mod (l2 / labile :topic (o / oxygen)) :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :op2 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 p))) :ARG3 (c / cell :mod (m / medical-condition :name (n / name :op1 "melanoma")) :mod (h / human)) :manner (e3 / endogenous) :ARG1-of (c2 / condition-01 :ARG2 (n4 / normoxic))) :medium (h2 / here)) # ::id pmid_1991_9690.52 # ::date 2015-08-14T09:07:06 # ::file pmid_1991_9690_52.txt # ::snt Figure 1A shows that HIF-1α protein is highly expressed in WM9 cells relative to normal human melanocyte (HEMn-LP), but radial growth phase (SbCl2), and vertical growth phase (WM1366) also express a higher amount of HIF-1α protein relative to human melanocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (s / show-01 :ARG0 (f / figure :mod "1A") :ARG1 (c / contrast-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG3 (c2 / cell-line :name (n2 / name :op1 "WM9")) :ARG1-of (h2 / high-02) :ARG1-of (r / relative-05 :ARG3 (m3 / melanocyte :ARG1-of (n9 / normal-02) :mod (h3 / human) :ARG1-of (m2 / mean-01 :ARG2 (c7 / cell-line :name (n8 / name :op1 "HEMn-LP")))))) :ARG2 (e2 / express-03 :ARG2 (a3 / amount-01 :ARG1 p :ARG1-of (h / high-02 :degree (m / more))) :ARG3 (a / and :op1 (p2 / phase :mod (g / grow-01 :manner (r2 / radius)) :example (c4 / cell-line :name (n5 / name :op1 "SbCI2"))) :op2 (p3 / phase :mod (g2 / grow-01 :manner (v / vertical)) :example (c5 / cell-line :name (n6 / name :op1 "WM1366")))) :mod (a2 / also) :ARG1-of (r3 / relative-05 :mod (m4 / melanocyte :mod h3))))) # ::id pmid_1991_9690.53 # ::date 2015-08-14T10:16:13 # ::file pmid_1991_9690_53.txt # ::snt Similar results are seen in second set of RGP, VGP and MET melanoma cell lines (Fig. 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / see-01 :ARG1 (t / thing :ARG2-of (r2 / result-01) :ARG1-of (r / resemble-01)) :location (s2 / set :ord (o / ordinal-entity :value "2") :consist-of (a / and :op1 (c / cell-line :mod (p / phase :mod (g / grow-01 :manner (r3 / radius)))) :op2 (c2 / cell-line :mod (p2 / phase :mod (g2 / grow-01 :manner (v / vertical)))) :op3 (c3 / cell-line :ARG1-of (m2 / metastasize-101)) :mod (m / medical-condition :name (n / name :op1 "melanoma")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id pmid_1991_9690.54 # ::date 2015-08-14T10:37:38 # ::file pmid_1991_9690_54.txt # ::snt HIF-1α was detected as 120 kD protein in nuclear extracts while no protein was detected in cytoplasmic extracts (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (c / contrast-01 :ARG1 (d / detect-01 :ARG1 (p / protein :name (n / name :op1 "HIF-1α") :quant (m / mass-quantity :quant "120" :unit (k / kilodalton)) :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :location (t / thing :ARG1-of (e / extract-01) :mod (n2 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")))) :ARG2 (d2 / detect-01 :polarity "-" :ARG1 (p2 / protein) :location (t2 / thing :ARG1-of (e2 / extract-01) :mod (c2 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")))) :ARG1-of (d3 / describe-01 :ARG0 (d4 / data :ARG1-of (s / show-01 :polarity "-")))) # ::id pmid_1991_9690.55 # ::date 2015-08-14T11:12:27 # ::file pmid_1991_9690_55.txt # ::snt Hypoxic stabilization of HIF-1α occurs at the protein level [3]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (s / stabilize-01 :ARG1 (p / protein :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG2 (l / level :quant-of (p2 / protein)) :mod (h / hypoxia) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "3")))) # ::id pmid_1991_9690.56 # ::date 2015-08-14T11:15:07 # ::file pmid_1991_9690_56.txt # ::snt Since HIF-1α protein was increased in human melanoma cells under normoxic conditions, we determined whether this increase might be due to increased HIF-1α mRNA levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / determine-01 :ARG0 (w / we) :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (c / cause-01 :ARG0 (l / level :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p3 / protein :name (n2 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))) :ARG1-of (i3 / increase-01)) :ARG1 (i / increase-01 :mod (t / this)))) :ARG1-of (c4 / cause-01 :ARG0 (i2 / increase-01 :ARG1 p3 :location (c2 / cell :mod (m / medical-condition :name (n3 / name :op1 "melanoma")) :mod (h / human) :ARG1-of (c3 / condition-01 :ARG2 (n4 / normoxia)))))) # ::id pmid_1991_9690.57 # ::date 2015-08-14T12:05:32 # ::file pmid_1991_9690_57.txt # ::snt Initially we used semi-quantitative RT-PCR to assess expression of HIF-1α full length (FL) and a splice variant HIF-1α785 that is missing the acetylation site lys532 due to lack of exon 11 (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (t / thing :name (n / name :op1 "RT-PCR") :mod (q / quantitative :degree (s / semi))) :ARG2 (a / assess-01 :ARG0 w :ARG1 (a2 / and :op1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "HIF-1α") :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG1-of (l / long-03 :degree (f / full))) :op2 (v / variant :ARG1-of (s2 / splice-01) :ARG1-of (m2 / mean-01 :ARG2 (p2 / protein :name (n4 / name :op1 "HIF-1α785") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272"))) :ARG0-of (m / miss-01 :ARG1 (s3 / site-01 :ARG0-of (a4 / acetylate-01) :mod (a3 / amino-acid :mod "532" :name (n3 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295"))) :ARG1-of (c / cause-01 :ARG0 (l2 / lack-01 :ARG1 (e2 / exon :mod "11"))))))) :time (i / initial) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2A"))) # ::id pmid_1991_9690.58 # ::date 2015-08-15T02:35:20 # ::file pmid_1991_9690_58.txt # ::snt This splice variant encodes HIF-1α protein that has been reported to be stable under normoxic conditions [17,20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (e / encode-01 :ARG0 (v / variant :ARG1-of (s / splice-01) :mod (t / this)) :ARG1 (p / protein :name (n / name :op1 "HIF-1α") :ARG1-of (s2 / stable-03 :ARG1-of (c / condition-01 :ARG2 (n2 / normoxia)) :ARG1-of (r / report-01)) :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "17" :op2 "20"))))) # ::id pmid_1991_9690.59 # ::date 2015-08-15T02:46:07 # ::file pmid_1991_9690_59.txt # ::snt Primers were designed so that full length HIF-1α would exclude HIF-1α785 by targeting exon 11, which is absent in HIF-1α785. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (d / design-01 :ARG1 (p3 / primer) :ARG3 (e / exclude-01 :ARG0 (p / protein :name (n2 / name :op1 "HIF-1α") :ARG1-of (l2 / long-03 :degree (f / full)) :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG1 (p2 / protein :name (n3 / name :op1 "HIF-1α785") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272")) :manner (t / target-01 :ARG0 p :ARG1 (e2 / exon :mod "11" :ARG1-of (a / absent-01 :ARG2 p2))))) # ::id pmid_1991_9690.60 # ::date 2015-08-15T03:01:12 # ::file pmid_1991_9690_60.txt # ::snt Primers for HIF-1α785 excluded HIF-1α by targeting the exon 10:12 boundary only present in HIF-1α785. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (e / exclude-01 :ARG0 (p4 / primer :beneficiary (p / protein :name (n2 / name :op1 "HIF-1α758") :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272"))) :ARG1 (p2 / protein :name (n3 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :manner (t / target-01 :ARG0 p4 :ARG1 (b / boundary :ARG1-of (p3 / present-02 :ARG2 p :mod (o / only)) :mod (b2 / between :op1 (e2 / exon :mod "10") :op2 (e3 / exon :mod "12"))))) # ::id pmid_1991_9690.61 # ::date 2015-08-15T03:08:45 # ::file pmid_1991_9690_61.txt # ::snt Fig. 2B shows that human melanoma cell lines express both full-length and the 785 splice variant HIF-1α mRNA at a level that appeared to be higher than normal human melanocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (f / figure :mod "2B") :ARG1 (e / express-03 :ARG2 (a / and :op1 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "HIF-1α") :ARG1-of (l3 / long-03 :degree (f2 / full)) :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))) :op2 (n7 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (v / variant :ARG1-of (s2 / splice-01) :ARG1-of (m2 / mean-01 :ARG2 (p2 / protein :name (n5 / name :op1 "HIF-1α785") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272"))))))) :ARG3 (c / cell-line :mod (m4 / medical-condition :name (n / name :op1 "melanoma")) :mod (h2 / human)) :manner (l2 / level :ARG1-of (a2 / appear-01) :ARG1-of (h / high-02 :degree (m / more) :compared-to (m3 / melanocyte :ARG1-of (n8 / normal-02) :mod (h3 / human)))))) # ::id pmid_1991_9690.62 # ::date 2015-08-15T03:20:33 # ::file pmid_1991_9690_62.txt # ::snt These findings were verified by qRT-PCR measurement of full-length and HIF-1α785 mRNA levels (Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (v / verify-01 :ARG0 (m / measure-01 :ARG1 (a / and :op1 (l / level :quant-of (n3 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG1-of (l4 / long-03 :degree (f2 / full)))) :op2 (l3 / level :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein-segment :name (n5 / name :op1 "HIF-1α785")))))) :mod (t3 / thing :name (n / name :op1 "RT-PCR") :mod (q / quantitative))) :ARG1 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "3"))) # ::id pmid_1991_9690.63 # ::date 2015-08-15T03:57:36 # ::file pmid_1991_9690_63.txt # ::snt All melanoma cell lines had increased expression of HIF-1α mRNA relative to normal human melanocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / increase-01 :ARG1 (e / express-03 :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))) :ARG3 (c / cell-line :mod (m2 / medical-condition :name (n / name :op1 "melanoma")) :mod (a / all)) :ARG1-of (r2 / relative-05 :ARG3 (m / melanocyte :ARG1-of (n6 / normal-02) :mod (h / human))))) # ::id pmid_1991_9690.64 # ::date 2015-08-15T04:02:27 # ::file pmid_1991_9690_64.txt # ::snt In addition VGP and MET cell lines expressed more of the 785 HIF-1α mRNA than full length HIF-1α mRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (e / express-03 :ARG2 (n / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n4 / name :op1 "HIF-1α785") :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272")))) :ARG3 (a2 / and :op1 (c / cell-line :mod (p3 / phase :mod (g / grow-01 :manner (v / vertical)))) :op2 (c2 / cell-line :mod (m2 / metastasis))) :compared-to (e3 / express-03 :ARG2 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (p2 / protein :name (n6 / name :op1 "HIF-1α") :ARG1-of (l2 / long-03 :degree (f / full)) :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))) :ARG3 a2) :degree (m / more))) # ::id pmid_1991_9690.65 # ::date 2015-08-15T04:13:53 # ::file pmid_1991_9690_65.txt # ::snt Overall the WM9 metastatic melanoma expressed the highest amount of 785 HIF-1α mRNA (~79× higher than normal human melanocytes). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / express-03 :ARG2 (a / amount-01 :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein-segment :name (n4 / name :op1 "HIF-1α785")))) :ARG2 (h2 / high-02 :degree (m2 / more) :mod (a2 / approximately :op1 (p2 / product-of :op1 "79")) :compared-to (m3 / melanocyte :ARG1-of (n7 / normal-02) :mod (h3 / human))) :ARG1-of (h / high-02 :degree (m / most))) :ARG3 (c / cell-line :name (n / name :op1 "WM9") :mod (m5 / medical-condition :name (n2 / name :op1 "melanoma") :ARG1-of (m4 / metastasize-101))) :mod (o / overall)) # ::id pmid_1991_9690.66 # ::date 2015-08-15T04:31:21 # ::file pmid_1991_9690_66.txt # ::snt HIFαFL and HIF-1α785 gain-of-function in radial growth phase SbCl2 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (m / mutate-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "HIFα") :ARG1-of (l2 / long-03 :degree (f / full)) :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.252")) :op2 (p2 / protein-segment :name (n2 / name :op1 "HIF-1α785"))) :location (c / cell-line :name (n3 / name :op1 "SbCl2") :mod (p3 / phase :mod (g2 / grow-01 :manner (r / radius)))) :manner (g3 / gain-02 :ARG0 a :ARG1 (f2 / function-01))) # ::id pmid_1991_9690.67 # ::date 2015-08-15T04:58:43 # ::file pmid_1991_9690_67.txt # ::snt The level of HIF-1α protein is low in the radial growth phase SbCl2 cells relative to VGP or MET cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (l / low-04 :ARG1 (l2 / level :quant-of (p / protein :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682"))) :location (c / cell-line :name (n2 / name :op1 "SbCl2") :mod (p2 / phase :mod (g / grow-01 :manner (r / radius)))) :ARG1-of (r2 / relative-05 :ARG3 (a / and :op1 (c2 / cell-line :mod (p3 / phase :mod (g2 / grow-01 :manner (v / vertical)))) :op2 (c3 / cell-line :ARG1-of (m / metastasize-101))))) # ::id pmid_1991_9690.68 # ::date 2015-08-15T05:31:43 # ::file pmid_1991_9690_68.txt # ::snt We determined the effect of HIF-1αFL or HIF-1α785 overexpression on SbCl2 anchorage-independent growth and Matrigel invasion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / determine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (o / overexpress-01 :ARG1 (o2 / or :op1 (p / protein :wiki "HIF1A" :name (n / name :op1 "HIF-1α") :ARG1-of (l2 / long-03 :degree (f / full)) :xref (x2 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :op2 (p2 / protein :wiki "-" :name (n2 / name :op1 "HIF-1α785") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272"))) :location (c / cell-line :wiki "-" :name (n4 / name :op1 "SbCl2"))) :ARG1 (a2 / and :op1 (g / grow-01 :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 (a3 / anchorage))) :op2 (i / invade-01 :ARG0 (p3 / protein :wiki "Matrigel" :name (n3 / name :op1 "Matrigel") :xref (x1 / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.273")))))) # ::id pmid_1991_9690.69 # ::date 2015-08-15T05:40:38 # ::file pmid_1991_9690_69.txt # ::snt HIF-1αFL and HIF-1α785 were cloned into the pLenti-V5-D-TOPO vector and transiently overexpressed in SbCl2 cells (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (c / clone-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "HIF-1α") :ARG1-of (l2 / long-03 :degree (f3 / full)) :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n2 / name :op1 "HIF-1α785") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272"))) :instrument (v / vector :name (n3 / name :op1 "pLenti-V5-D-TOPO"))) :op2 (o / overexpress-01 :ARG1 a2 :ARG1-of (t / transient-02) :location (c2 / cell-line :name (n4 / name :op1 "SbCl2"))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4A"))) # ::id pmid_1991_9690.70 # ::date 2015-08-15T06:25:07 # ::file pmid_1991_9690_70.txt # ::snt HIF-1α785 overexpression resulted in a small, but statistically significant increase in anchorage-independent growth, relative to mock or lacz transfected cells (Fig. 4C and 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "HIF-1α785") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272"))) :ARG2 (i2 / increase-01 :ARG1 (g / grow-01 :ARG0-of (d / depend-01 :ARG1 (a / anchorage))) :mod (s / small :ARG1-of (c / contrast-01 :ARG2 (s2 / significant-02 :mod (s3 / statistics))) :ARG1-of (r2 / relative-05 :ARG3 (o2 / or :op1 (c4 / cell :ARG1-of (t2 / transfect-01 :mod (m / mock))) :op2 (c2 / cell :ARG1-of (t / transfect-01 :ARG2 (p2 / protein :name (n3 / name :op1 "lacz")))))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "4C") :op2 (f2 / figure :mod "4D")))) # ::id pmid_1991_9690.71 # ::date 2015-08-16T03:28:58 # ::file pmid_1991_9690_71.txt # ::snt In contrast overexpression of both HIF-1αFL and HIF-α785 in SbCl2 resulted in a large and significant 3-fold increase in Matrigel invasion relative to mock or Lacz transfected cells (Fig. 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (c / contrast-01 :ARG2 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "HIF-1α") :ARG1-of (l4 / long-03 :degree (f / full)) :xref (x2 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n2 / name :op1 "HIF-1α785") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.272"))) :location (c2 / cell-line :name (n3 / name :op1 "SbCl2"))) :ARG2 (i / increase-01 :ARG1 (i2 / invade-01 :ARG0 (p4 / protein :name (n4 / name :op1 "matrigel") :xref (x1 / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.253"))) :ARG2 (p3 / product-of :op1 "3") :mod (l3 / large) :ARG1-of (s / significant-02) :ARG1-of (r2 / relative-05 :ARG3 (t2 / transfect-01 :ARG1 (c5 / cell) :ARG2 (o3 / or :op1 (v / vector :mod (m / mock)) :op2 (p5 / protein :name (n6 / name :op1 "lacz"))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4B"))) # ::id pmid_1991_9690.72 # ::date 2015-08-16T04:26:12 # ::file pmid_1991_9690_72.txt # ::snt HIF-1α loss-of-function in human metastatic melanoma WM9 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (l2 / lose-02 :ARG0 (p / protein :name (n / name :op1 "HIF-1α") :mod (l / lose-01) :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG1 (f / function-01) :location (c / cell-line :name (n2 / name :op1 "WM9") :mod (h / human) :mod (m / medical-condition :name (n3 / name :op1 "melanoma")) :ARG1-of (m2 / metastasize-101))) # ::id pmid_1991_9690.73 # ::date 2015-08-16T04:31:24 # ::file pmid_1991_9690_73.txt # ::snt HIF-1α protein is highly expressed under normoxic conditions in the WM9 human metastatic melanoma cell line. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG3 (c / cell-line :name (n2 / name :op1 "WM9") :mod (h / human) :mod (m / medical-condition :name (n3 / name :op1 "melanoma")) :ARG1-of (m2 / metastasize-101)) :ARG1-of (c2 / condition-01 :ARG2 (n4 / normoxia)) :ARG1-of (h2 / high-02)) # ::id pmid_1991_9690.74 # ::date 2015-08-16T04:35:16 # ::file pmid_1991_9690_74.txt # ::snt To determine whether HIF-1α could be contributing to the malignant characteristics of these cells, we knocked down its expression and examine how this affected anchorage independent growth and Matrigel invasion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (a / and :op1 (k / knock-down-02 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))) :op2 (e2 / examine-01 :ARG0 w :ARG1 (t2 / thing :manner-of (a2 / affect-01 :ARG0 k :ARG1 (a3 / and :op1 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a4 / anchorage))) :op2 (i / invade-01 :ARG0 (p3 / protein :name (n2 / name :op1 "matrigel") :xref (x1 / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.253"))))))) :purpose (d2 / determine-01 :ARG0 w :ARG1 (p / possible-01 :mode "interrogative" :ARG1 (c / contribute-01 :ARG0 p2 :ARG1 (c2 / characteristic-02 :ARG1 (c3 / cell :mod (t / this)) :ARG2 (m / malignant-02)))))) # ::id pmid_1991_9690.75 # ::date 2015-08-16T04:43:42 # ::file pmid_1991_9690_75.txt # ::snt WM9 cells were treated with 100 nM siRNA targeting HIF-1α (Dharmacon) which consistently decreased its expression by ~75-85% (Fig. 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (t / treat-04 :ARG1 (c / cell-line :name (n / name :op1 "WM9")) :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (t2 / target-01 :ARG1 (p / protein :name (n3 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682"))) :quant (c2 / concentration-quantity :quant "100" :unit (n4 / nanomolar)) :source (c4 / company :name (n6 / name :op1 "Dharmacon"))) :ARG0-of (d / decrease-01 :ARG1 (e / express-03 :ARG2 p) :ARG2 (a / approximately :op1 (v / value-interval :op1 (p2 / percentage-entity :value "75") :op2 (p3 / percentage-entity :value "85"))) :manner (c3 / consistent-02)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id pmid_1991_9690.76 # ::date 2015-08-16T04:54:11 # ::file pmid_1991_9690_76.txt # ::snt Colony formation after 5 days in soft agarose was inhibited by 70% in HIF-1α-siRNA transfected WM9 cells in comparison to cells transfected with control siRNA (Fig. 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i / inhibit-01 :ARG1 (f / form-01 :ARG1 (c / colony) :time (a / after :quant (t2 / temporal-quantity :quant "5" :unit (d2 / day))) :location (a2 / agarose :ARG1-of (s / soft-02))) :quant (p / percentage-entity :value "70") :location (c2 / cell-line :name (n2 / name :op1 "WM9") :ARG1-of (t3 / transfect-01 :ARG2 (n6 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))))) :compared-to (c3 / cell :ARG1-of (t4 / transfect-01 :ARG2 (n7 / nucleic-acid :name (n5 / name :op1 "siRNA") :mod (c4 / control)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "5B"))) # ::id pmid_1991_9690.77 # ::date 2015-08-16T05:04:33 # ::file pmid_1991_9690_77.txt # ::snt A photo (Fig. 5C) of the colonies formed at this time point in control vs. HIF-1α transfected cells verifies this decrease in soft agar colony formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (v / verify-01 :ARG0 (p / photograph-01 :ARG1 (c / colony :ARG1-of (f / form-01 :time (p2 / point) :location (c2 / contrast-01 :ARG1 (c3 / cell :ARG1-of (t / transfect-01 :ARG2 (p3 / protein :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))) :ARG2 (c4 / cell :mod (c5 / control) :ARG1-of (t2 / transfect-01))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "5C"))) :ARG1 (d / decrease-01 :ARG1 (f2 / form-01 :ARG1 (c6 / colony :location (a / agar :ARG1-of (s / soft-02)))) :mod (t3 / this))) # ::id pmid_1991_9690.78 # ::date 2015-08-16T05:16:14 # ::file pmid_1991_9690_78.txt # ::snt Matrigel invasion was also significantly decreased in HIF-1α-siRNA transfected WM9 cells compared to control siRNA transfected WM9 cells (Fig. 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 16, 2015 (d / decrease-01 :ARG1 (i / invade-01 :ARG0 (p / protein :name (n / name :op1 "matrigel") :xref (x1 / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.253"))) :mod (a / also) :ARG1-of (s / significant-02) :location (c / cell-line :name (n2 / name :op1 "WM9") :ARG1-of (t / transfect-01 :ARG2 (n7 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")))))) :compared-to (c2 / cell-line :name (n5 / name :op1 "WM9") :ARG1-of (t2 / transfect-01 :ARG2 (n8 / nucleic-acid :name (n6 / name :op1 "siRNA") :mod (c3 / control)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id pmid_1991_9690.79 # ::date 2015-08-16T05:23:15 # ::file pmid_1991_9690_79.txt # ::snt Measurement of cell viability in the Matrigel chambers shows no difference between control vs. HIF-1α siRNA transfected cells (Fig. 5E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (s / show-01 :ARG0 (m / measure-01 :ARG1 (v / viable :domain (c / cell)) :location (c2 / chamber :mod (p / protein :name (n / name :op1 "matrigel") :xref (x1 / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.253")))) :ARG1 (d / differ-02 :polarity "-" :ARG1 (c4 / cell :ARG1-of (t / transfect-01 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA") :mod (c5 / control)))) :ARG2 (c6 / cell :ARG1-of (t2 / transfect-01 :ARG2 (n6 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682"))))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5E"))) # ::id pmid_1991_9690.80 # ::date 2015-08-16T06:02:49 # ::file pmid_1991_9690_80.txt # ::snt These knock down studies suggest that increased non-hypoxic expression of HIF-1α plays an important role in key malignant properties exhibited by these human melanoma cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (s / suggest-01 :ARG0 (s2 / study-01 :ARG1 (k / knock-down-02) :mod (t / this)) :ARG1 (p / play-02 :ARG0 (e / express-03 :ARG2 (p2 / protein :wiki "HIF1A" :name (n / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :mod (h / hypoxic :polarity "-") :ARG1-of (i / increase-01)) :ARG1 (r / role :mod (i2 / important) :topic (p3 / property :ARG1-of (m / malignant-02) :ARG1-of (k2 / key-02) :ARG1-of (e2 / exhibit-01 :ARG0 (c / cell :mod (m2 / medical-condition :wiki "Melanoma" :name (n2 / name :op1 "melanoma")) :mod (h2 / human) :mod (t2 / this))))))) # ::id pmid_1991_9690.81 # ::date 2015-08-16T06:26:20 # ::file pmid_1991_9690_81.txt # ::snt Regulation of HIF-1α expression in human melanoma by the ERK1/2 MAPK pathway # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / regulate-01 :ARG0 (p2 / pathway :name (n2 / name :op1 "ERK1/2" :op2 "MAPK")) :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG3 (m / medical-condition :name (n4 / name :op1 "melanoma") :mod (h / human)))) # ::id pmid_1991_9690.82 # ::date 2015-08-16T06:28:49 # ::file pmid_1991_9690_82.txt # ::snt Hypoxia independent expression of HIF-1α is thought to be regulated by growth signaling pathways [18,19] and the majority of melanomas have constitutively active ERK1/2 MAPK pathway due to BRAF or N-Ras mutations [14,15]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a2 / and :op1 (t / think-01 :ARG1 (r / regulate-01 :ARG0 (p3 / pathway :ARG0-of (s / signal-07 :ARG1 (g / grow-01))) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "HIF-1α") :xref (x2 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (h / hypoxia)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 "18" :op2 "19"))))) :op2 (h2 / have-03 :ARG0 (m4 / medical-condition :name (n3 / name :op1 "melanoma") :quant (m / majority) :ARG1-of (i / include-91 :ARG2 (m5 / medical-condition :name (n4 / name :op1 "melanoma")))) :ARG1 (p5 / pathway :name (n5 / name :op1 "ERK1/2" :op2 "MAPK") :mod (c2 / constitutive) :ARG1-of (c3 / cause-01 :ARG0 (o / or :op1 (m2 / mutate-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (m3 / mutate-01 :ARG1 (e3 / enzyme :name (n7 / name :op1 "N-Ras") :xref (x / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))))) :ARG0-of (a5 / activity-06)) :ARG1-of (d5 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 (a4 / and :op1 "14" :op2 "15")))))) # ::id pmid_1991_9690.83 # ::date 2015-08-16T06:54:04 # ::file pmid_1991_9690_83.txt # ::snt Therefore, we determined whether HIF-1α expression in human metastatic melanoma WM9 cells was dependent on activation of ERK1/2 MAPK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / cause-01 :ARG1 (d / determine-01 :ARG0 (w / we) :ARG1 (d2 / depend-01 :mode "interrogative" :ARG0 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG3 (c2 / cell-line :name (n3 / name :op1 "WM9") :mod (m / medical-condition :name (n4 / name :op1 "melanoma")) :mod (h / human) :ARG1-of (m2 / metastasize-101))) :ARG1 (a / activate-01 :ARG1 (s / signal-07 :ARG0 (p3 / pathway :name (n5 / name :op1 "ERK1/2" :op2 "MAPK"))))))) # ::id pmid_1991_9690.84 # ::date 2015-08-16T07:07:13 # ::file pmid_1991_9690_84.txt # ::snt These cells have an active ERK1/2 MAPK pathway as evidenced by the high phosphorylation of ERK (Fig. 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-03 :ARG0 (c / cell :mod (t / this)) :ARG1 (p4 / pathway :name (n3 / name :op1 "ERK1/2" :op2 "MAPK") :ARG0-of (a2 / activity-06)) :ARG1-of (e / evidence-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (h2 / high-02))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_1991_9690.85 # ::date 2015-08-16T07:40:03 # ::file pmid_1991_9690_85.txt # ::snt Treatment of WM9 cells with 30 μM U0126, a selective U0126 MEK inhibitor, decreased ERK1/2 phosphorylation and led to a time-dependent decrease in HIF-1α protein expression (Fig. 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / and :op1 (d / decrease-01 :ARG0 (t2 / treat-04 :ARG1 (c / cell-line :name (n3 / name :op1 "WM9")) :ARG2 (s2 / small-molecule :name (n4 / name :op1 "U0126") :quant (c2 / concentration-quantity :quant "30" :unit (m / micromolar)) :ARG1-of (m2 / mean-01 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"))) :ARG0-of (s / select-01) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n6 / name :op1 "ERK1/2")))) :op2 (l / lead-03 :ARG1 t2 :ARG2 (d2 / decrease-01 :ARG1 (e2 / express-03 :ARG2 (p3 / protein :name (n7 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682"))) :ARG0-of (d3 / depend-01 :ARG1 (t3 / time)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_1991_9690.86 # ::date 2015-08-16T08:00:17 # ::file pmid_1991_9690_86.txt # ::snt Although 30 μM U0126 has been used in published studies to selectively inhibit MEK [16,21], the original paper describing this inhibitor [22] used much lower concentrations to achieve high selectivity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (h / have-concession-91 :ARG1 (u2 / use-01 :ARG0 (p4 / paper :mod (o / original) :ARG0-of (d2 / describe-01 :ARG1 "s" :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "22"))))) :ARG1 (c4 / concentrate-02 :ARG1-of (l / low-04 :degree (m / more :degree (m3 / much)))) :ARG2 (a2 / achieve-01 :ARG0 p4 :ARG1 (s4 / select-01 :ARG1-of (h2 / high-02)))) :ARG2 (u / use-01 :ARG1 (s / small-molecule :name (n / name :op1 "U0126") :quant (c / concentration-quantity :quant "30" :unit (m2 / micromolar)) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG2 (i2 / inhibit-01 :ARG0 s :ARG1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG0-of (s5 / select-01)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "16" :op2 "21")))) :location (s2 / study-01 :ARG1-of (p2 / publish-01)))) # ::id pmid_1991_9690.87 # ::date 2015-08-16T08:20:18 # ::file pmid_1991_9690_87.txt # ::snt Therefore we repeated this experiment using 10 μM U0126 (Fig. 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (c / cause-01 :ARG1 (r / repeat-01 :ARG0 (w / we) :ARG1 (e / experiment-01 :mod (t / this)) :manner (u / use-01 :ARG0 w :ARG1 (s / small-molecule :name (n / name :op1 "U0126") :quant (c2 / concentration-quantity :quant "10" :unit (m / micromolar)) :xref (x / xref :value "PUBCHEM:3006531" :prob "17.656696")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id pmid_1991_9690.88 # ::date 2015-08-16T08:26:49 # ::file pmid_1991_9690_88.txt # ::snt At 24 h of treatment, 10 μM U0126 completely suppressed the phosphorylation of ERK1/2, yet there was minimal change in the level of HIF-1α relative to control cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (s2 / suppress-01 :ARG0 (s / small-molecule :name (n / name :op1 "U0126") :quant (c / concentration-quantity :quant "10" :unit (m / micromolar)) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2"))) :ARG1-of (c2 / complete-02) :ARG1-of (c3 / contrast-01 :ARG2 (c4 / charge-03 :ARG1 (l / level :quant-of (p2 / protein :name (n3 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682"))) :ARG1-of (m2 / minimal-02) :ARG1-of (r / relative-05 :ARG3 (c5 / cell :mod (c6 / control))))) :time (a / after :op1 (t / treat-04) :quant (t2 / temporal-quantity :quant "24" :unit (h / hour)))) # ::id pmid_1991_9690.89 # ::date 2015-08-16T08:34:36 # ::file pmid_1991_9690_89.txt # ::snt With further time of inhibitor treatment, phosphorylation of ERK was not totally suppressed, but HIF-1α levels decreased. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / suppress-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (c / contrast-01 :ARG2 (d / decrease-01 :ARG1 (l / level :quant-of (p3 / protein :name (n2 / name :op1 "HIF-1α") :xref (x / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682"))))) :degree (t / total :polarity "-") :condition (t4 / time :mod (f / further) :duration-of (t3 / treat-04 :ARG2 (s2 / small-molecule :ARG0-of (i / inhibit-01))))) # ::id pmid_1991_9690.90 # ::date 2015-08-16T08:42:33 # ::file pmid_1991_9690_90.txt # ::snt We also used siRNA specifically targeting MEK1 and 2 in WM9 cells to inhibit ERK1/2 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (n6 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (t / target-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :location (c / cell-line :name (n4 / name :op1 "WM9")) :manner (s / specific-02))) :ARG2 (i / inhibit-01 :ARG0 n6 :ARG1 (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "ERK1/2")))) :mod (a / also)) # ::id pmid_1991_9690.91 # ::date 2015-08-16T08:53:11 # ::file pmid_1991_9690_91.txt # ::snt Treatment of WM9 cells with siRNA targeting MEK1 and 2 consistently decreased its expression by greater than 90% and also decreased ERK1/2 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (a / and :op1 (d / decrease-01 :ARG0 (t / treat-04 :ARG1 (c / cell-line :name (n / name :op1 "WM9")) :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (t2 / target-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))))) :ARG1 (e3 / express-03 :ARG3 c) :ARG2 (m / more-than :op1 (p / percentage-entity :value "90")) :manner (c2 / consistent-02)) :op2 (d2 / decrease-01 :ARG0 t :ARG1 (p2 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK1/2"))) :mod (a3 / also))) # ::id pmid_1991_9690.92 # ::date 2015-08-16T09:00:08 # ::file pmid_1991_9690_92.txt # ::snt However, knockdown of MEK1 and 2 did not decrease the normoxic expression of HIF-1α protein in human metastatic melanoma WM9 cells (Fig. 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG2 (d / decrease-01 :polarity "-" :ARG0 (k / knock-down-02 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (e3 / express-03 :ARG2 (p / protein :name (n4 / name :op1 "HIF-1α") :xref (x1 / xref :value "UNIPROT:SETD2_HUMAN" :prob "0.682")) :ARG3 (c2 / cell-line :name (n5 / name :op1 "WM9") :mod (m / medical-condition :name (n6 / name :op1 "melanoma")) :mod (h / human) :ARG1-of (m2 / metastasize-101)) :mod (n3 / normoxia))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id pmid_2000_3375.1 # ::date 2015-06-19T16:50:37 # ::file pmid_2000_3375_1.txt # ::snt Aurora-A overexpression enhances cell-aggregation of Ha-ras transformants through the MEK/ERK signaling pathway (PMID:20003375) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / enhance-01 :ARG0 (o / overexpress-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :ARG1 (a / aggregate-01 :ARG1 (c3 / cell :ARG2-of (t / transform-01 :ARG0 (g / gene :name (n2 / name :op1 "Ha-ras") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "0.673"))))) :manner (s / signal-07 :ARG0 (p / pathway :name (n3 / name :op1 "MEK/ERK"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID20003375"))) # ::id pmid_2000_3375.12 # ::date 2015-06-19T17:20:43 # ::file pmid_2000_3375_12.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2000_3375.13 # ::date 2015-06-19T18:45:48 # ::file pmid_2000_3375_13.txt # ::snt Overexpression of wild-type Aurora-A and mutation of RasV12 were detected in human bladder and colon cancer tissues. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / detect-01 :ARG1 (a / and :op1 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Aurora-A") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :op2 (m / mutate-01 :value "V12" :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :location (a3 / and :op1 (t / tissue :mod (h / human) :mod (d4 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer") :mod (b / bladder))) :op2 (t2 / tissue :mod h :mod (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer"))))) # ::id pmid_2000_3375.14 # ::date 2015-06-19T18:52:24 # ::file pmid_2000_3375_14.txt # ::snt Wild-type Aurora-A induces focus formation and aggregation of the RasV12 transformants. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 19, 2015 (i / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "Aurora-A") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG2 (a / and :op1 (f / form-01 :ARG1 (f2 / focus)) :op2 (a2 / aggregate-01 :ARG1 (c / cell :ARG2-of (t / transform-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) # ::id pmid_2000_3375.15 # ::date 2015-06-19T18:57:07 # ::file pmid_2000_3375_15.txt # ::snt Aurora-A activates Ral A and the phosphorylation of AKT as well as enhances the phosphorylation of MEK, ERK of WT cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (a2 / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG1 (a3 / and :op1 (e5 / enzyme :name (n2 / name :op1 "Ral" :op2 "A") :xref (x2 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.593")) :op2 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "AKT") :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))))) :op2 (e3 / enhance-01 :ARG0 e :ARG1 (p3 / phosphorylate-01 :ARG1 (a4 / and :op1 (e4 / enzyme :name (n4 / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e6 / enzyme :name (n5 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :part-of (c / cell :mod (w / wild-type)))))) # ::id pmid_2000_3375.16 # ::date 2015-06-20T16:51:14 # ::file pmid_2000_3375_16.txt # ::snt Finally, the Ras/MEK/ERK signaling pathway is responsible for Aurora-A induced aggregation of the RasV12 transformants. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (r / responsible-01 :li "-1" :ARG0 (p / pathway :name (n / name :op1 "Ras/MEK/ERK") :ARG0-of (s / signal-07)) :ARG1 (a / aggregate-01 :ARG1 (c / cell :ARG1-of (t / transform-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))))) # ::id pmid_2000_3375.109 # ::date 2015-06-20T16:51:44 # ::file pmid_2000_3375_109.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2000_3375.110 # ::date 2015-06-20T17:22:15 # ::file pmid_2000_3375_110.txt # ::snt Detection of Aurora-A overexpression accompanied with Ha-ras mutation in bladder cancers # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jun 20, 2015 (d / detect-01 :ARG1 (a / accompany-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "Ha-ras") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "0.673"))) :ARG1 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")))) :location (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :mod (b / bladder))) # ::id pmid_2000_3375.111 # ::date 2015-06-20T17:28:55 # ::file pmid_2000_3375_111.txt # ::snt Aurora-A overexpression accompanied with Ha-ras codon 12 mutation has been reported in bladder cancers [41]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (r / report-01 :ARG1 (a / accompany-01 :ARG0 (m / mutate-01 :ARG1 (c2 / codon :mod "12" :part-of (g / gene :name (n3 / name :op1 "Ha-ras") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "0.673")))) :ARG1 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :location (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (b / bladder))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG1-of (c / cite-01 :ARG2 "41")))) # ::id pmid_2000_3375.112 # ::date 2015-06-20T17:42:56 # ::file pmid_2000_3375_112.txt # ::snt In this study, Ha-rasV12 mutation was detected in the tumour part of the bladder cancer specimen by SNP-real-time PCR and verified by sequence analysis (Figure 1A, Gly12 -> Val 12). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a2 / and :op1 (d3 / detect-01 :ARG1 (m2 / mutate-01 :value "V12" :ARG2 (e / enzyme :name (n3 / name :op1 "Ha-ras") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "0.673"))) :ARG2 (p / polymorphism :mod (n2 / nucleotide :ARG1-of (s / single-02)) :ARG1-of (a / analyze-01 :manner (r / real-time) :mod (r2 / react-01 :ARG0 (p2 / polymerase) :mod (c / chain) :subevent (t / transcribe-01 :ARG1-of (r3 / reverse-01))))) :location (t2 / tumor :part-of (s2 / specimen :mod (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (b2 / bladder))))) :op2 (v / verify-01 :ARG1 m2 :manner (a3 / analyze-01 :mod (s3 / sequence))) :medium (s4 / study-01 :mod (t3 / this)) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "1A") :ARG2 (m3 / mutate-01 :ARG1 (a4 / amino-acid :mod "12" :name (n5 / name :op1 "glycine") :xref (x2 / xref :value "PUBCHEM:750" :prob "9.915467")) :ARG2 (a5 / amino-acid :mod "12" :name (n6 / name :op1 "valine") :xref (x1 / xref :value "PUBCHEM:6287" :prob "10.890044"))))) # ::id pmid_2000_3375.113 # ::date 2015-06-20T18:08:32 # ::file pmid_2000_3375_113.txt # ::snt The Aurora-A protein overexpression was detected in the same cancer part of the bladder tissue compared to the normal part by IHC staining (Figure 1B, T vs. N). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / detect-01 :ARG1 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :manner (s2 / stain-01 :ARG2 (i / immunohistochemistry)) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "1B")) :location (p2 / part :part-of (t / tissue :mod (b / bladder)) :ARG1-of (c2 / compare-01 :ARG2 (p4 / part :ARG1-of (n4 / normal-02))) :ARG1-of (s / same-01) :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))) # ::id pmid_2000_3375.114 # ::date 2015-06-20T18:24:07 # ::file pmid_2000_3375_114.txt # ::snt Similarly, Ki-ras codon 12 mutation and higher expression level of Aurora-A were only detected in the cancer part of the colon tissue (Figure 1C and 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / resemble-01 :ARG2 (d / detect-01 :ARG1 (a / and :op1 (m / mutate-01 :ARG1 (c3 / codon :mod "12" :part-of (g / gene :name (n2 / name :op1 "Ki-ras") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.673")))) :op2 (l / level :degree-of (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :ARG1-of (h / high-02 :degree (m2 / more)))) :location (p / part :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")) :part-of (t / tissue :mod (c2 / colon))) :manner (o / only) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1C") :op2 (f2 / figure :mod "1D"))))) # ::id pmid_2000_3375.115 # ::date 2015-06-20T18:25:36 # ::file pmid_2000_3375_115.txt # ::snt Taken together, despite of the difference in transformation of NIH3T3 cells by Ki-ras and Ha-ras, overexpression of Aurora-A and RasV12 (Ki- or Ha-) mutations are simultaneously detected in various cancers including bladder and colon. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / detect-01 :ARG1 (a / and :op1 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x2 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :op2 (m / mutate-01 :value "V12" :ARG1 (o2 / or :op1 (e2 / enzyme :name (n2 / name :op1 "Ki-Ras") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "Ha-Ras") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))) :ARG1-of (t3 / take-01 :mod (t2 / together))) :manner (s / simultaneous) :concession (d2 / differ-02 :ARG1 e2 :ARG2 e3 :ARG3 (t / transform-01 :ARG1 (c / cell-line :name (n4 / name :op1 "NIH3T3")))) :location (d6 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer") :mod (v / various) :ARG1-of (i / include-91 :ARG2 (a2 / and :op1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :mod (b / bladder)) :op2 (d4 / disease :wiki "Colorectal_cancer" :name (n7 / name :op1 "colon" :op2 "cancer")))))) # ::id pmid_2000_3375.116 # ::date 2015-06-20T18:55:05 # ::file pmid_2000_3375_116.txt # ::snt Establishment of stable cell lines over-expressing Aurora-A and mutant RasV12 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (e / establish-01 :ARG1 (c / cell-line :ARG1-of (s / stable-03) :ARG0-of (o / overexpress-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :op2 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) # ::id pmid_2000_3375.117 # ::date 2015-06-20T19:01:09 # ::file pmid_2000_3375_117.txt # ::snt It is intriguing to unravel the combined effects of Aurora-A and mutant RasV12 on the morphological change and tumorigenesis of the cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 24, 2015 (i / intrigue-01 :ARG0 (u / unravel-01 :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :op2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (a3 / and :op1 (c2 / change-01 :ARG1 "c3" :mod (m2 / morphology)) :op2 (c4 / create-01 :ARG1 (t / tumor :mod (c3 / cell)))) :ARG1-of (c / combine-01)))) # ::id pmid_2000_3375.118 # ::date 2015-06-21T16:11:15 # ::file pmid_2000_3375_118.txt # ::snt Stable cell lines were established by transfecting Vector DNA, wild-type Aurora-A or kinase-inactivated Aurora-A into 7-4 cells, which was derived from NIH/3T3 cells harboring the inducible Ha-rasV12 oncogene [23], designated Vector, WT and KD cell line, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (e / establish-01 :ARG1 (c / cell-line :ARG1-of (s / stable-03)) :manner (t / transfect-01 :ARG1 (c2 / cell :mod (b / between :op1 "7" :op2 "4") :ARG1-of (d3 / derive-01 :ARG2 (c3 / cell-line :name (n3 / name :op1 "NIH/3T3") :ARG0-of (h / harbor-01 :ARG1 (a / and :op1 (g / gene :name (n5 / name :op1 "Ha-ras") :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "23"))) :ARG2-of (m / mutate-01 :value "V12") :ARG2-of (i / induce-01 :ARG1-of (p2 / possible-01)) :ARG0-of (c7 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:RASH_HUMAN" :prob "0.673")) :op2 (d5 / designate-01 :ARG1 (v2 / vector)) :op3 (a2 / and :op1 (c5 / cell-line :mod (w3 / wild-type)) :op2 (c6 / cell-line :mod (k3 / knock-down-02)))) :manner (r / respective))))) :ARG2 (o / or :op1 (n4 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :mod (v / vector)) :op2 (e2 / enzyme :name (n / name :op1 "Aurora-A") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :op3 (e3 / enzyme :name (n2 / name :op1 "Aurora-A") :ARG1-of (d2 / deactivate-01 :ARG0 (k / kinase)) :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))))) # ::id pmid_2000_3375.119 # ::date 2015-06-21T16:42:04 # ::file pmid_2000_3375_119.txt # ::snt The expression levels of Ha-rasV12 in Vector, WT and KD cells in the presence of IPTG were much higher compared to the cells without IPTG (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / high-02 :ARG1 (l / level :degree-of (e / express-03 :ARG2 (g / gene :name (n / name :op1 "Ha-ras") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "0.673")) :ARG3 (a2 / and :op1 (c / cell :mod (v / vector)) :op2 (c2 / cell :mod (w / wild-type)) :op3 (c3 / cell :mod (k / knock-down-02)))) :condition (s2 / small-molecule :name (n2 / name :op1 "IPTG") :xref (x1 / xref :value "PUBCHEM:552632" :prob "17.879841"))) :degree (m / more :degree (m2 / much)) :compared-to (l2 / level :degree-of (e3 / express-03 :ARG3 (c4 / cell :ARG0-of (l3 / lack-01 :ARG1 s2)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2000_3375.120 # ::date 2015-06-21T17:25:40 # ::file pmid_2000_3375_120.txt # ::snt Aurora-A can physically interact with the tail of Histone H3 (H3) and efficiently phosphorylates H3 at serine10 [45-48]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG1 (t / tail :part-of (p2 / protein :name (n2 / name :op1 "Histone" :op2 "H3") :xref (x / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "1.001"))) :ARG2 (p5 / physical))) :op2 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "10" :name (n3 / name :op1 "serine") :part-of p2 :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 e :ARG2-of (e2 / efficient-01)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 "45" :op2 "48"))))) # ::id pmid_2000_3375.121 # ::date 2015-06-21T17:33:42 # ::file pmid_2000_3375_121.txt # ::snt In addition, activation of ERK pathway in Ha-ras transformed mouse fibroblasts increases the level of p-H3S10. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 18, 2015 (a / and :op2 (i / increase-01 :ARG0 (a2 / activate-01 :ARG1 (p / pathway :name (n / name :op1 "ERK")) :location (f / fibroblast :source (m / mouse) :ARG1-of (t / transform-01 :ARG0 (g / gene :name (n2 / name :op1 "Ha-ras") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "0.673"))))) :ARG1 (l / level :quant-of (a4 / amino-acid :mod "10" :name (n5 / name :op1 "serine") :part-of (p2 / protein :name (n4 / name :op1 "H3")) :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))))) # ::id pmid_2000_3375.122 # ::date 2015-06-21T17:42:59 # ::file pmid_2000_3375_122.txt # ::snt Consistently, our data showed the level of phosphorylated H3S10 (p-H3S10 detected by anti-p-H3S10 antibody) in WT cells (Figure 2A, lane 2, 1.8 fold) was higher than in Vector cells (Figure 2A, lane 1, 1.0 fold) and KD cells (Figure 2A, lane 3, 0.9 fold) in the absent of IPTG where Ras was not overexpressed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (s / show-01 :ARG0 (d / data :poss (w / we)) :ARG1 (h / high-02 :ARG1 (l / level :quant-of (a5 / amino-acid :mod "10" :name (n / name :op1 "serine") :ARG3-of (p2 / phosphorylate-01) :ARG1-of (d2 / detect-01 :ARG0 (a / antibody :ARG0-of (c5 / counter-01 :ARG1 a5))) :part-of (p / protein :name (n5 / name :op1 "H3")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (d3 / describe-01 :part-of (l2 / lane :mod "2" :part-of (f2 / figure :mod "2A")) :quant (p4 / product-of :op1 "1.8")) :location (c / cell :mod (w2 / wild-type))) :degree (m / more) :compared-to (a3 / and :op1 (c2 / cell :mod (v / vector) :ARG1-of (d4 / describe-01 :part-of (l3 / lane :mod "1" :part-of f2) :quant (p5 / product-of :op1 "1.0"))) :op2 (c3 / cell :mod (k / knock-down-02) :ARG1-of (d5 / describe-01 :part-of (l4 / lane :mod "3" :part-of f2) :quant (p6 / product-of :op1 "0.9")))) :condition (a6 / and :op1 (a7 / absent-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "IPTG") :xref (x1 / xref :value "PUBCHEM:552632" :prob "17.879841"))) :op2 (o / overexpress-01 :polarity "-" :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :manner (c4 / consistent-02)) # ::id pmid_2000_3375.123 # ::date 2015-06-21T18:08:24 # ::file pmid_2000_3375_123.txt # ::snt Our data showed that the Aurora-A overexpressed in WT cells is functional. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 19, 2015 (s / show-01 :ARG0 (d / data :poss (w / we)) :ARG1 (f / function-01 :ARG0 (e / enzyme :name (n / name :op1 "Aurora-A") :ARG1-of (o / overexpress-01 :location (c / cell :mod (w2 / wild-type))) :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")))) # ::id pmid_2000_3375.124 # ::date 2015-06-21T18:10:28 # ::file pmid_2000_3375_124.txt # ::snt In the presence of IPTG, where RasV12 protein was overexpressed, the level of phosphorylated H3S10 was increased both in Vector (Figure 2A, lane 4, 2.8 fold), WT (Figure 2A, lane 5, 3.8 fold) and KD (Figure 2A, lane 6, 2.8 fold) cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / increase-01 :ARG1 (l / level :quant-of (a3 / amino-acid :mod "10" :name (n / name :op1 "serine") :ARG3-of (p2 / phosphorylate-01) :part-of (p / protein :name (n4 / name :op1 "H3")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :location (a4 / and :op1 (c / cell :mod (v / vector :ARG1-of (d / describe-01 :ARG0 (l2 / lane :mod "4" :part-of (f2 / figure :mod "2A")) :quant (p4 / product-of :op1 "2.8")))) :op2 (c2 / cell :mod (w / wild-type :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane :mod "5" :part-of f2) :quant (p5 / product-of :op1 "3.8")))) :op3 (c3 / cell :mod (k / knock-down-02 :ARG1-of (d3 / describe-01 :ARG0 (l4 / lane :mod "6" :part-of f2) :quant (p6 / product-of :op1 "2.8"))))) :condition (a5 / and :op1 (s / small-molecule :name (n2 / name :op1 "IPTG") :xref (x1 / xref :value "PUBCHEM:552632" :prob "17.879841")) :op2 (o / overexpress-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) # ::id pmid_2000_3375.125 # ::date 2015-06-21T18:22:43 # ::file pmid_2000_3375_125.txt # ::snt Biological activity analysis showed that WT cells over-expressing wild-type Aurora-A became rounded and formed aggregates in the presence of IPTG compared to the Vector cells and KD cells (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (a2 / activity-06 :mod (b / biology))) :ARG1 (a3 / and :op1 (r / round-04 :ARG1 (c / cell :mod (w / wild-type) :ARG0-of (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Aurora-A") :mod (w2 / wild-type) :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :compared-to (a5 / and :op1 (c2 / cell :mod (v / vector)) :op2 (c3 / cell :mod (k / knock-down-02))))) :op2 (f / form-01 :ARG0 c :ARG1 (a4 / aggregate-01)) :condition (s2 / small-molecule :name (n2 / name :op1 "IPTG") :xref (x1 / xref :value "PUBCHEM:552632" :prob "17.879841"))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2B"))) # ::id pmid_2000_3375.126 # ::date 2015-06-21T18:38:24 # ::file pmid_2000_3375_126.txt # ::snt Transforming analysis showed that WT cells form more foci compared to Vector and KD cells (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 9, 2015 (s / show-01 :ARG0 (a / analyze-01 :mod (t / transform-01)) :ARG1 (f / form-01 :ARG0 (c / cell :mod (w / wild-type)) :ARG1 (f2 / focus :mod (m / more)) :compared-to (a3 / and :op1 (c2 / cell :mod (v / vector)) :op2 (c3 / cell :mod (k / knock-down-02)))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "2C"))) # ::id pmid_2000_3375.127 # ::date 2015-06-23T07:19:26 # ::file pmid_2000_3375_127.txt # ::snt Despite the fact that focus numbers were also increased in the other two cell lines, a further increase of focus number in WT cells was observed after IPTG induction (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (o / observe-01 :ARG1 (i / increase-01 :ARG1 (n / number :quant-of (f / focus)) :degree (f2 / further) :location (c / cell :mod (w / wild-type))) :time (a / after :op1 (i2 / induce-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "IPTG") :xref (x / xref :value "PUBCHEM:552632" :prob "17.879841")))) :ARG1-of (d / describe-01 :ARG0 (f5 / figure :mod "2C")) :concession (i3 / increase-01 :ARG1 n :mod (a2 / also) :location (c2 / cell-line :quant "2" :mod (o2 / other)))) # ::id pmid_2000_3375.128 # ::date 2015-06-23T07:26:47 # ::file pmid_2000_3375_128.txt # ::snt Taken together, both Aurora-A and mutant RasV12 overexpression can induce focus formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (h / have-condition-91 :ARG1 (p / possible-01 :ARG1 (i / induce-01 :ARG0 (a / and :op1 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :op2 (o2 / overexpress-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (f / form-01 :ARG1 (f2 / focus)))) :ARG2 (t / take-01 :ARG1 a :mod (t2 / together))) # ::id pmid_2000_3375.129 # ::date 2015-06-23T07:32:44 # ::file pmid_2000_3375_129.txt # ::snt Further induction of focus formation was detected when these two genes were overexpressed simultaneously. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 4, 2016 (d / detect-01 :ARG1 (i / induce-01 :ARG2 (f2 / form-01 :ARG1 (f3 / focus)) :degree (f / further)) :condition (o / overexpress-01 :ARG1 (g / gene :quant "2" :mod (t / this)) :mod (s / simultaneous))) # ::id pmid_2000_3375.130 # ::date 2015-06-23T07:34:41 # ::file pmid_2000_3375_130.txt # ::snt Cell proliferation analysis showed that WT cells grew slower than Vector and KD cells in the absence of IPTG. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (p / proliferate-01 :ARG0 (c / cell))) :ARG1 (g / grow-01 :ARG1 (c2 / cell :mod (w / wild-type)) :ARG2 (s2 / slow-05 :degree (m / more) :compared-to (a2 / and :op1 (c3 / cell :mod (v / vector)) :op2 (c4 / cell :mod (k / knock-down-02)))) :condition (a3 / absent-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "IPTG") :xref (x / xref :value "PUBCHEM:552632" :prob "17.879841"))))) # ::id pmid_2000_3375.131 # ::date 2015-06-23T07:42:00 # ::file pmid_2000_3375_131.txt # ::snt Growth rate of Vector, WT and KD cells were decreased when mutant Ras was overexpressed (Fig. 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / decrease-01 :ARG1 (a / and :op1 (r / rate :degree-of (g / grow-01 :ARG1 (c / cell :mod (v / vector)))) :op2 (r2 / rate :degree-of (g2 / grow-01 :ARG1 (c2 / cell :mod (w / wild-type)))) :op3 (r3 / rate :degree-of (g3 / grow-01 :ARG1 (c3 / cell :mod (k / knock-down-02))))) :time (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2D"))) # ::id pmid_2000_3375.132 # ::date 2015-06-23T07:45:33 # ::file pmid_2000_3375_132.txt # ::snt The increase of cell aggregation of WT cells in the presence of IPTG was independent of cell growth rate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / depend-01 :polarity "-" :ARG0 (i / increase-01 :ARG1 (a / aggregate-01 :ARG1 (c / cell :mod (w / wild-type)) :mod (c2 / cell)) :condition (p / present-02 :ARG1 (s / small-molecule :name (n / name :op1 "IPTG") :xref (x / xref :value "PUBCHEM:552632" :prob "17.879841")))) :ARG1 (r / rate :degree-of (g / grow-01 :ARG1 c))) # ::id pmid_2000_3375.133 # ::date 2015-06-23T07:52:55 # ::file pmid_2000_3375_133.txt # ::snt Aurora-A overexpression increases phosphorylation status of MEK/ERK and AKT as well as the activity of RalA in the RasV12 transformants # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / increase-01 :ARG0 (o / overexpress-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Aurora-A") :xref (x2 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :ARG1 (a2 / and :op1 (s / status :mod (p / phosphorylate-01) :poss (a / and :op1 (p2 / pathway :name (n2 / name :op1 "MEK/ERK")) :op2 (p4 / pathway :name (n3 / name :op1 "AKT")))) :op2 (a3 / activity-06 :ARG0 (p3 / protein :name (n4 / name :op1 "RalA") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604")) :location (e3 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (t / transform-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) # ::id pmid_2000_3375.134 # ::date 2015-06-23T08:05:53 # ::file pmid_2000_3375_134.txt # ::snt To clarify the effects of Aurora-A on the signaling pathways related to Ras overexpression, three downstream signaling pathways of Ras, Raf/MEK, PI3K/AKT and RalGDS/Ral A were investigated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (i / investigate-01 :ARG1 (p / pathway :quant "3" :location (d / downstream) :ARG0-of (s / signal-07 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (p2 / pathway :name (n2 / name :op1 "Raf/MEK")) :op2 (p3 / pathway :name (n3 / name :op1 "PI3K/AKT")) :op3 (p4 / pathway :name (n4 / name :op1 "RalGDS/RalA"))))) :ARG2 (c / clarify-10 :ARG1 (a2 / affect-01 :ARG0 (e2 / enzyme :name (n5 / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG1 (p6 / pathway :ARG0-of s :ARG1-of (r / relate-01 :ARG2 (o / overexpress-01 :ARG2 e)))))) # ::id pmid_2000_3375.135 # ::date 2015-06-23T08:16:40 # ::file pmid_2000_3375_135.txt # ::snt The phosphorylation of MEK (p-MEK) was higher in WT cells (Figure 3A, lane 2, 1.7 fold) than that in Vector (Figure 3A, lane 1, 1.0 fold) and KD cells (Figure 3A, lane 3, 0.8 fold). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (h / high-02 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :degree (m / more) :location (c / cell :mod (w / wild-type) :ARG1-of (d / describe-01 :ARG0 (l2 / lane :mod "2" :part-of (f / figure :mod "3A")) :ARG2 (p3 / product-of :op1 "1.7"))) :compared-to (p2 / phosphorylate-01 :ARG1 e :location (a / and :op1 (c2 / cell :mod (v / vector) :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane :mod "1" :part-of f) :ARG2 (p4 / product-of :op1 "1.0"))) :op2 (c3 / cell :mod (k / knock-down-02) :ARG1-of (d3 / describe-01 :ARG0 (l4 / lane :mod "3" :part-of f) :ARG2 (p5 / product-of :op1 "0.8")))))) # ::id pmid_2000_3375.136 # ::date 2015-06-23T08:25:44 # ::file pmid_2000_3375_136.txt # ::snt P-MEK levels in each cell line were further increased after IPTG induction (RasV12 is over-expressed) (Figure 3A, lane 4, 5, and 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (i / increase-01 :ARG1 (l / level :location (c / cell-line :mod (e2 / each)) :quant-of (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :degree (f / further) :time (a / after :op1 (i2 / induce-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "IPTG") :xref (x2 / xref :value "PUBCHEM:552632" :prob "17.879841")))) :ARG1-of (m / mean-01 :ARG2 (o / overexpress-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (l2 / lane :mod "4") :op2 (l3 / lane :mod "5") :op3 (l4 / lane :mod "6") :part-of (f2 / figure :mod "3A")))) # ::id pmid_2000_3375.137 # ::date 2015-06-24T05:09:24 # ::file pmid_2000_3375_137.txt # ::snt The same phenomenon was also been observed in p-ERK1/2 (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (o / observe-01 :ARG1 (p / phenomenon :ARG1-of (s / same-01)) :mod (a / also) :condition (s2 / slash :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of (p2 / phosphorylate-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2000_3375.138 # ::date 2015-06-24T05:12:44 # ::file pmid_2000_3375_138.txt # ::snt These results indicated that Aurora-A may further increase Ras induced MEK/ERK phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p3 / possible-01 :ARG1 (i2 / increase-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG1 (p5 / phosphorylate-01 :ARG1 (p / pathway :name (n2 / name :op1 "MEK/ERK")) :ARG2-of (i3 / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :degree (f / further)))) # ::id pmid_2000_3375.139 # ::date 2015-06-24T05:18:34 # ::file pmid_2000_3375_139.txt # ::snt The effect of Aurora-A on the PI3K/AKT pathway was evaluated by detecting phosphorylation of AKT (p-AKT). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (e / evaluate-01 :ARG1 (a / affect-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG1 (p4 / pathway :name (n3 / name :op1 "PI3K/AKT"))) :manner (d / detect-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))))) # ::id pmid_2000_3375.140 # ::date 2015-06-24T05:21:51 # ::file pmid_2000_3375_140.txt # ::snt The p-AKT level was also higher in WT cells (Figure 3A, lane 2, 2.1 fold) compared to Vector and KD cells (Figure 3A, lane 1, 1.0 fold and lane 3, 1.1 fold, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (h / high-02 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :degree (m / more) :mod (a / also) :location (c / cell :mod (w / wild-type) :ARG1-of (d / describe-01 :ARG0 (l2 / lane :mod "2" :part-of (f / figure :mod "3A")) :ARG2 (p2 / product-of :op1 "2.1"))) :compared-to (a2 / and :op1 (c2 / cell :mod (v / vector) :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane :mod "1" :part-of f) :ARG2 (p3 / product-of :op1 "1.0"))) :op2 (c3 / cell :mod (k / knock-down-02) :ARG1-of (d3 / describe-01 :ARG0 (l4 / lane :mod "3" :part-of f) :ARG2 (p4 / product-of :op1 "1.1"))))) # ::id pmid_2000_3375.141 # ::date 2015-06-24T05:27:47 # ::file pmid_2000_3375_141.txt # ::snt Upon IPTG induction, RasV12 overexpression increased the level of p-AKT in Vector and KD cells (Figure 3A, lane 4, 1.8 fold and lane 6, 2.1 fold, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (i / increase-01 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :location (a / and :op1 (c / cell :mod (v / vector) :ARG1-of (d / describe-01 :ARG0 (l2 / lane :mod "4" :part-of (f / figure :mod "3A")) :ARG2 (p2 / product-of :op1 "1.8"))) :op2 (c2 / cell :mod (k / knock-down-02) :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane :mod "6" :part-of f) :ARG2 (p3 / product-of :op1 "2.1"))))) :ARG1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :condition (i2 / induce-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "IPTG") :xref (x2 / xref :value "PUBCHEM:552632" :prob "17.879841")))) # ::id pmid_2000_3375.142 # ::date 2015-06-24T06:10:24 # ::file pmid_2000_3375_142.txt # ::snt Co-expression of RasV12 and wild-type Aurora-A in WT cells increases the level of p-AKT (Figure 3A, lane 5, 3.5 fold) as compared to RasV12overexpression alone (Figure 3A, lane 4, 1.8 fold). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / increase-01 :ARG0 (c / coexpress-01 :ARG2 (a / and :op1 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n2 / name :op1 "Aurora-A") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :ARG3 (c2 / cell :mod w)) :ARG1 (l / level :quant-of (e2 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (d / describe-01 :ARG0 (l2 / lane :mod "5" :part-of (f / figure :mod "3A")) :ARG2 (p3 / product-of :op1 "3.5"))) :compared-to (o / overexpress-01 :ARG1 e :mod (a2 / alone) :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane :mod "4" :part-of f) :ARG2 (p4 / product-of :op1 "1.8")))) # ::id pmid_2000_3375.143 # ::date 2015-06-24T06:16:23 # ::file pmid_2000_3375_143.txt # ::snt The RalGDS/RalA signaling pathway was determined by detecting the activity of RalA using GST-RalBD pull-down assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / determine-01 :ARG1 (p / pathway :name (n / name :op1 "RalGDS/RalA") :ARG0-of (s / signal-07)) :manner (d2 / detect-01 :ARG1 (a / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "RalA") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604"))) :manner (u / use-01 :ARG1 (a2 / assay-01 :manner (p3 / pull-down-08 :ARG3 (p4 / protein :name (n3 / name :op1 "GST-RalBD") :xref (x1 / xref :value "UNIPROT:CHST3_HUMAN" :prob "0.202"))))))) # ::id pmid_2000_3375.144 # ::date 2015-06-24T06:19:50 # ::file pmid_2000_3375_144.txt # ::snt As shown in Figure 3A, Aurora-A overexpression alone activated RalA (Figure 3A, lane 2, 2.0 fold) as compared to the parental Vector cells (Figure 3A, lane 1, 1.0 fold). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (a / activate-01 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :mod (a2 / alone)) :ARG1 (p2 / protein :name (n2 / name :op1 "RalA") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604")) :ARG1-of (d / describe-01 :ARG0 (l / lane :mod "2" :part-of (f / figure :mod "3A")) :ARG2 (p3 / product-of :op1 "2.0")) :compared-to (c / cell :mod (p4 / parental) :mod (v / vector) :ARG1-of (d2 / describe-01 :ARG0 (l2 / lane :mod "1" :part-of f) :ARG2 (p5 / product-of :mod "1.0"))) :ARG1-of (s / show-01 :medium f)) # ::id pmid_2000_3375.145 # ::date 2015-06-24T06:24:16 # ::file pmid_2000_3375_145.txt # ::snt After IPTG induction, The RalA activity was increased by RasV12 overexpression (Figure 3A, lane 4, 2.5 fold). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / increase-01 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (a / activity-06 :ARG0 (p / protein :name (n2 / name :op1 "RalA") :xref (x1 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604"))) :time (a2 / after :op1 (i2 / induce-01 :ARG2 (s / small-molecule :name (n / name :op1 "IPTG") :xref (x2 / xref :value "PUBCHEM:552632" :prob "17.879841")))) :ARG1-of (d / describe-01 :ARG0 (l / lane :mod "4" :part-of (f / figure :mod "3A")) :ARG2 (p2 / product-of :op1 "2.5"))) # ::id pmid_2000_3375.146 # ::date 2015-06-24T06:27:58 # ::file pmid_2000_3375_146.txt # ::snt Co-expression of RasV12 and wild-type Aurora-A in WT cells increase the activity of RalA of RasV12 (Figure 3A, lane 5, 3.7 fold). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / increase-01 :ARG0 (c / coexpress-01 :ARG2 (a / and :op1 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n3 / name :op1 "Aurora-A") :mod "w" :xref (x2 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :ARG3 (c2 / cell :mod (w / wild-type))) :ARG1 (a2 / activity-06 :ARG0 (p2 / protein :name (n / name :op1 "RalA") :location (c3 / cell :mod e) :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604"))) :ARG1-of (d / describe-01 :ARG0 (l / lane :mod "5" :part-of (f / figure :mod "3A")) :ARG2 (p3 / product-of :op1 "3.7"))) # ::id pmid_2000_3375.147 # ::date 2015-06-24T06:34:51 # ::file pmid_2000_3375_147.txt # ::snt Taken together, both Aurora-A and RasV12 increased the levels of p-MEK, pERK1/2, and p-AKT and the activation of RalA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (h / have-condition-91 :ARG1 (i / increase-01 :ARG0 (a / and :op1 (e / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x6 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (a2 / and :op1 (l / level :quant-of (e3 / enzyme :name (n4 / name :op1 "MEK") :ARG3-of (p2 / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op2 (l2 / level :quant-of (s / slash :op1 (e4 / enzyme :name (n5 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n6 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of p2)) :op3 (l3 / level :quant-of (e6 / enzyme :name (n7 / name :op1 "AKT") :ARG3-of p2 :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op4 (a3 / activate-01 :ARG1 (p3 / protein :name (n / name :op1 "RalA") :xref (x5 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604"))))) :ARG2 (t / take-01 :ARG1 a :mod (t2 / together))) # ::id pmid_2000_3375.148 # ::date 2015-06-24T06:54:56 # ::file pmid_2000_3375_148.txt # ::snt This induction was further enhanced when Aurora-A and RasV12 were overexpressed simultaneously. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 4, 2016 (e2 / enhance-01 :ARG1 (i / induce-01 :mod (t / this)) :degree (f / further) :time (o / overexpress-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :op2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :mod (s / simultaneous))) # ::id pmid_2000_3375.149 # ::date 2015-06-24T06:57:48 # ::file pmid_2000_3375_149.txt # ::snt To further confirm our results, Aurora-A specific small interference RNA (siRNA) was used. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (u / use-01 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "small" :op2 "interference" :op3 "RNA") :ARG1-of (s / specific-02 :ARG2 (e / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")))) :ARG2 (c / confirm-01 :ARG1 (t / thing :ARG2-of (r2 / result-01) :poss (w / we)) :degree (f / further))) # ::id pmid_2000_3375.150 # ::date 2015-06-24T07:01:06 # ::file pmid_2000_3375_150.txt # ::snt As shown in Figure 3B, Aurora-A specific siRNA decreased the expression level of Aurora-A in WT cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / decrease-01 :ARG0 (n3 / nucleic-acid :name (n / name :op1 "siRNA") :ARG1-of (s / specific-02 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")))) :ARG1 (l / level :degree-of (e / express-03 :ARG1 e2 :ARG3 (c / cell :mod (w / wild-type)))) :ARG1-of (s2 / show-01 :medium (f / figure :mod "3B"))) # ::id pmid_2000_3375.151 # ::date 2015-06-24T07:03:28 # ::file pmid_2000_3375_151.txt # ::snt Accordingly, levels of p-MEK/p-ERK, p-AKT and activation of RalA were also decreased when Aurora-A siRNA was introduced into WT cells upon IPTG induction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (d / decrease-01 :ARG1 (a / and :op1 (l / level :quant-of (s / slash :op1 (e / enzyme :name (n / name :op1 "MEK") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG3-of (p / phosphorylate-01))) :op2 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of p :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op3 (l3 / level :degree-of (a2 / activate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "RalA") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604"))))) :mod (a3 / also) :time (i / introduce-02 :ARG1 (n8 / nucleic-acid :name (n5 / name :op1 "siRNA") :mod (e4 / enzyme :name (n6 / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))) :ARG2 (c / cell :mod (w / wild-type)) :condition (i2 / induce-01 :ARG2 (s3 / small-molecule :name (n7 / name :op1 "IPTG") :xref (x5 / xref :value "PUBCHEM:552632" :prob "17.879841")))) :manner (a4 / accordingly)) # ::id pmid_2000_3375.152 # ::date 2015-06-24T07:11:06 # ::file pmid_2000_3375_152.txt # ::snt Our results confirmed that wild-type-Aurora-A enhance Ras downstream signaling pathways including MEK/ERK, AKT and RalA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / confirm-01 :ARG0 (t / thing :poss (w / we) :ARG2-of (r / result-01)) :ARG1 (e2 / enhance-01 :ARG0 (e4 / enzyme :name (n3 / name :op1 "Aurora-A") :mod (w2 / wild-type) :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG1 (p3 / pathway :location (d / downstream) :ARG0-of (s / signal-07 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2-of (i / include-91 :ARG1 (a / and :op1 (p / pathway :name (n2 / name :op1 "MEK/ERK")) :op2 (p2 / pathway :name (n4 / name :op1 "AKT")) :op3 (p4 / pathway :name (n5 / name :op1 "RalA"))))))) # ::id pmid_2000_3375.153 # ::date 2015-06-24T07:16:41 # ::file pmid_2000_3375_153.txt # ::snt The MEK/ERK pathway is involved in WT cell aggregation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (i / involve-01 :ARG1 (p / pathway :name (n / name :op1 "MEK/ERK")) :ARG2 (a / aggregate-01 :ARG1 (c / cell :mod (w / wild-type)))) # ::id pmid_2000_3375.154 # ::date 2015-06-24T07:17:46 # ::file pmid_2000_3375_154.txt # ::snt The involvement of MEK/ERK, PI3K/AKT and RalGDS/RalA signaling pathways in Aurora-A-related cell aggregation (Fig. 2B, WT + IPTG) was clarified by treatment of the cells with the following inhibitors: FTI-277, a farnesylation inhibitor of Ras; PD-98059, the inhibitor of MEK kinase and LY-294002, the inhibitor of PI3K kinase and RalASa94A, a mutant of Ral. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / clarify-10 :ARG1 (i2 / involve-01 :ARG1 (a / and :op1 (p / pathway :name (n / name :op1 "MEK/ERK")) :op2 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT")) :op3 (p3 / pathway :name (n5 / name :op1 "RalGDS/RalA")) :ARG0-of (s / signal-07)) :ARG2 (a2 / aggregate-01 :ARG1 (c2 / cell) :ARG1-of (r / relate-01 :ARG2 (e2 / enzyme :name (n6 / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B"))) :manner (t2 / treat-04 :ARG1 c2 :ARG2 (m / molecular-physical-entity :ARG0-of (i3 / inhibit-01) :ARG1-of (f2 / follow-01) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (s2 / small-molecule :name (n7 / name :op1 "FTI-277") :ARG0-of (i4 / inhibit-01 :ARG1 (p4 / protein-family :name (n3 / name :op1 "Ras")) :ARG2-of (f3 / farnesylate-01)) :xref (x6 / xref :value "PUBCHEM:3005532" :prob "16.91732")) :op2 (s3 / small-molecule :name (n8 / name :op1 "PD-98059") :ARG0-of (i5 / inhibit-01 :ARG1 (k / kinase :name (n4 / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :xref (x5 / xref :value "PUBCHEM:4713" :prob "18.818951")) :op3 (s4 / small-molecule :name (n9 / name :op1 "LY-294002") :ARG0-of (i6 / inhibit-01 :ARG1 (a4 / and :op1 (k2 / kinase :name (n10 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op1 (p5 / protein :name (n11 / name :op1 "RalASa94A") :ARG3-of (m6 / mutate-01 :ARG1 (p6 / protein :name (n12 / name :op1 "Ral") :xref (x2 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.603"))) :xref (x4 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.223")))) :xref (x7 / xref :value "PUBCHEM:3973" :prob "19.135918"))))))) # ::id pmid_2000_3375.155 # ::date 2015-06-24T07:28:27 # ::file pmid_2000_3375_155.txt # ::snt FTI-277 restrains Ras protein as a non-farnesylated form and inhibits p-ERK1/2 expression dose-dependently but had no effect on p-AKT (Figure 4A, lanes 2 and 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (a / and :op1 (r / restrain-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "FTI-277") :xref (x3 / xref :value "PUBCHEM:3005532" :prob "16.91732")) :ARG1 (p / protein-family :name (n / name :op1 "Ras")) :manner (f2 / form :ARG1-of (f / farnesylate-01 :polarity "-"))) :op2 (i / inhibit-01 :ARG0 s2 :ARG1 (e / express-03 :ARG2 (s / slash :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of (p2 / phosphorylate-01))) :manner (d / depend-01 :ARG1 (d2 / dose)))) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 s2 :ARG1 (e4 / enzyme :name (n5 / name :op1 "AKT") :ARG3-of p2 :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (l / lane :mod "2") :op2 (l2 / lane :mod "3") :part-of (f3 / figure :mod "4A")))) # ::id pmid_2000_3375.156 # ::date 2015-06-24T07:34:20 # ::file pmid_2000_3375_156.txt # ::snt PD-98059 decreased the phosphorylation of ERK1/2 (p-ERK1/2) but had no effect on other signaling pathways (Figure 4A, lanes 4 and 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (c / contrast-01 :ARG1 (d / decrease-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "PD-98059") :xref (x2 / xref :value "PUBCHEM:4713" :prob "18.818951")) :ARG1 (p2 / phosphorylate-01 :ARG1 (s / slash :op1 (e / enzyme :name (n2 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))))) :ARG2 (a / affect-01 :polarity "-" :ARG0 s3 :ARG1 (p3 / pathway :ARG0-of (s2 / signal-07) :mod (o / other))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (l2 / lane :mod "4") :op2 (l3 / lane :mod "5") :part-of (f / figure :mod "4A")))) # ::id pmid_2000_3375.157 # ::date 2015-06-24T07:41:01 # ::file pmid_2000_3375_157.txt # ::snt LY-294002 reduced the phosphorylation of AKT (p-AKT) but had no effect on another signaling pathway (Figure 4A, lanes 6 and 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "LY-294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "19.135918")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :ARG2 (a / affect-01 :polarity "-" :ARG0 s2 :ARG1 (p2 / pathway :ARG0-of (s / signal-07) :mod (o / other))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (l2 / lane :mod "6") :op2 (l3 / lane :mod "7") :part-of (f / figure :mod "4A")))) # ::id pmid_2000_3375.158 # ::date 2015-06-24T07:43:38 # ::file pmid_2000_3375_158.txt # ::snt In summary, in WT cells Aurora-A increases the expression of p-ERK1/2 in a Ras dependent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (i / increase-01 :ARG0 (e5 / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG1 (e2 / express-03 :ARG2 (s2 / slash :op1 (e3 / enzyme :name (n3 / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n4 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of (p2 / phosphorylate-01)) :ARG3 (c / cell :mod (w / wild-type))) :manner (d / depend-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2-of (s / summarize-01)) # ::id pmid_2000_3375.159 # ::date 2015-06-24T07:46:55 # ::file pmid_2000_3375_159.txt # ::snt However, FTI-277 does not reduce the p-AKT in WT cells co-expressing RasV12 and wild-type Aurora-A. Wild-type Aurora-A activates RalA (Figure 3A and 3B) and phosphorylates RalA at serine194 to promote cellular transformation and migration [38]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / multi-sentence :snt1 (h / have-concession-91 :ARG1 (r / reduce-01 :polarity "-" :ARG0 (s / small-molecule :name (n2 / name :op1 "FTI-277") :xref (x6 / xref :value "PUBCHEM:3005532" :prob "16.91732")) :ARG1 (e2 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :location (c / cell :mod (w / wild-type) :ARG3-of (c2 / coexpress-01 :ARG2 (a / and :op1 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n4 / name :op1 "Aurora-A") :mod w :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))))))) :snt2 (a2 / and :op1 (a3 / activate-01 :ARG0 (e4 / enzyme :name (n5 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :ARG1 (p4 / protein :name (n6 / name :op1 "RalA") :xref (x4 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604")) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B")))) :op2 (p5 / phosphorylate-01 :ARG1 (a5 / amino-acid :mod "194" :name (n7 / name :op1 "serine") :part-of p4 :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 e4 :purpose (p6 / promote-02 :ARG0 e4 :ARG1 (a6 / and :op1 (t / transform-01 :ARG1 (c3 / cell)) :op2 (m4 / migrate-01 :ARG0 c3)))) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 "38"))))) # ::id pmid_2000_3375.160 # ::date 2015-06-24T07:54:16 # ::file pmid_2000_3375_160.txt # ::snt To reveal the role of RalA phosphorylation at ser194 in Aurora-A induced RalA activation in WT cells, the mutants RalAS183A or RalAS194A were transiently transfected into WT cells and the RalA activity was evaluated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (t / transfect-01 :ARG1 (c / cell :mod (w / wild-type)) :ARG2 (o / or :op1 (p2 / protein :name (n / name :op1 "RalAS183A") :xref (x1 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.223")) :op2 (p3 / protein :name (n2 / name :op1 "RalAS194A") :xref (x2 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.223")) :ARG2-of (m / mutate-01)) :ARG1-of (t2 / transient-02)) :op2 (e / evaluate-01 :ARG1 (a2 / activity-06 :ARG0 (p4 / protein :name (n3 / name :op1 "RalA") :xref (x3 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604")))) :purpose (r / reveal-01 :ARG1 (p5 / play-08 :ARG0 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "194" :name (n4 / name :op1 "serine") :part-of p4 :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (a4 / activate-01 :ARG1 p4 :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n5 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")))) :location c))) # ::id pmid_2000_3375.161 # ::date 2015-06-24T08:02:31 # ::file pmid_2000_3375_161.txt # ::snt Consistent with a previous report [38], only RalAS194A could reduce the Ral A activity (Figure 4B, lane 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / consistent-01 :ARG1 (p2 / possible-01 :ARG1 (r / reduce-01 :ARG0 (p3 / protein :name (n / name :op1 "RalAS194A") :mod (o / only) :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.223")) :ARG1 (a / activity-06 :ARG0 (p4 / protein :name (n2 / name :op1 "RalA") :xref (x1 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604")))) :ARG1-of (d2 / describe-01 :ARG0 (l / lane :mod "3" :part-of (f / figure :mod "4B")))) :ARG2 (r2 / report :time (p / previous) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "38"))))) # ::id pmid_2000_3375.162 # ::date 2015-06-24T08:06:08 # ::file pmid_2000_3375_162.txt # ::snt To determine which signaling pathway is involved in the aggregation of WT cells during RasV12 overexpression, we first demonstrated that Aurora-A induced cell aggregation was blocked by Aurora-A specific small interfering RNA (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (b / block-01 :ARG1 (a / aggregate-01 :ARG1 (c / cell) :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")))) :ARG2 (n4 / nucleic-acid :name (n3 / name :op1 "small" :op2 "interfering" :op3 "RNA") :ARG1-of (s / specific-02 :ARG2 e2))) :time (f / first) :purpose (d2 / determine-01 :ARG0 w :ARG1 (i2 / involve-01 :mode "interrogative" :ARG1 (p2 / pathway :ARG0-of (s2 / signal-07)) :ARG2 (a2 / aggregate-01 :ARG1 (c2 / cell :mod (w3 / wild-type))) :time (o2 / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "4C"))) # ::id pmid_2000_3375.163 # ::date 2015-06-24T08:11:16 # ::file pmid_2000_3375_163.txt # ::snt The WT cells were treated with FTI-277, PD-98059 or LY-294002 for 24 h and cell aggregation was observed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 29, 2015 (a / and :op1 (t / treat-04 :ARG1 (c / cell :mod (w / wild-type)) :ARG2 (o / or :op1 (s / small-molecule :name (n / name :op1 "FTI-277") :xref (x2 / xref :value "PUBCHEM:3005532" :prob "16.91732")) :op2 (s2 / small-molecule :name (n2 / name :op1 "PD-98059") :xref (x1 / xref :value "PUBCHEM:4713" :prob "18.818951")) :op3 (s3 / small-molecule :name (n3 / name :op1 "LY-294002") :xref (x / xref :value "PUBCHEM:3973" :prob "19.135918"))) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour))) :op2 (o2 / observe-01 :ARG1 (a2 / aggregate-01 :ARG1 c))) # ::id pmid_2000_3375.164 # ::date 2015-06-24T08:13:39 # ::file pmid_2000_3375_164.txt # ::snt Both FTI-277 and PD98059 reversed the aggregation of WT cells, whereas LY-294002 showed no effect on cell aggregation (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 29, 2015 (c / contrast-01 :ARG1 (r / reverse-01 :ARG0 (a / and :op1 (s3 / small-molecule :name (n / name :op1 "FTI-277") :xref (x / xref :value "PUBCHEM:3005532" :prob "16.91732")) :op2 (s4 / small-molecule :name (n2 / name :op1 "PD98059") :xref (x2 / xref :value "PUBCHEM:4713" :prob "18.349844"))) :ARG1 (a2 / aggregate-01 :ARG1 (c2 / cell :mod (w / wild-type)))) :ARG2 (s / show-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "LY-294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "19.135918")) :ARG1 (a3 / affect-01 :polarity "-" :ARG0 s2 :ARG1 a2)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id pmid_2000_3375.165 # ::date 2015-06-24T08:16:08 # ::file pmid_2000_3375_165.txt # ::snt Because mutant RalAS194A was unable to block cell aggregation, its role in Aurora-A induced cell aggregation was excluded (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (e / exclude-01 :ARG1 (p / play-08 :ARG0 (p2 / protein :name (n / name :op1 "RalAS194A") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.223")) :ARG1 (a / aggregate-01 :ARG1 (c / cell) :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Aurora-A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))))) :ARG1-of (c2 / cause-01 :ARG0 (c3 / capable-01 :polarity "-" :ARG1 p2 :ARG2 (b / block-01 :ARG0 p2 :ARG1 a)))) # ::id pmid_2000_3375.166 # ::date 2015-06-24T08:20:11 # ::file pmid_2000_3375_166.txt # ::snt Taken together, the Ras/MEK/ERK signaling pathway but not the PI3K/AKT or RalGDS/RalA pathway is responsible for Aurora-A induced cell aggregation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (h / have-condition-91 :ARG1 (c / contrast-01 :ARG1 (r / responsible-01 :ARG0 (p2 / pathway :name (n2 / name :op1 "Ras/MEK/ERK") :ARG0-of (s / signal-07)) :ARG1 (a / aggregate-01 :ARG1 (c2 / cell) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n3 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312"))))) :ARG2 (r2 / responsible-01 :polarity "-" :ARG0 (o / or :op1 (p / pathway :name (n / name :op1 "PI3K/AKT")) :op2 (p4 / pathway :name (n4 / name :op1 "RalGDS/RalA"))) :ARG1 a)) :ARG2 (t / take-01 :ARG1 p2 :mod (t2 / together))) # ::id a_pmid_2094_2929.7 # ::date 2015-05-20T09:19:50 # ::file a_pmid_2094_2929_7.txt # ::snt 1- RT-PCR and western blot analyses confirmed the strong up-regulation of serpinE2 expression and secretion by IECs expressing oncogenic MEK, Ras or BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / confirm-01 :li "1" :ARG0 (a / and :op1 (a2 / analyze-01 :instrument (t / thing :name (n4 / name :op1 "RT-PCR"))) :op2 (i / immunoblot-01)) :ARG1 (a4 / and :op1 (u / upregulate-01 :ARG1 (e3 / express-03 :ARG2 (p / protein :name (n6 / name :op1 "serpinE2") :xref (x3 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :ARG1-of (s / strong-02)) :op2 (s2 / secrete-01 :ARG0 (c2 / cell :name (n7 / name :op1 "IEC") :ARG3-of (e4 / express-03 :ARG2 (o2 / or :op1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op3 (e5 / enzyme :name (n8 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))))) :ARG1 p))) # ::id a_pmid_2094_2929.8 # ::date 2015-05-20T10:16:34 # ::file a_pmid_2094_2929_8.txt # ::snt 2- Interestingly, serpinE2 mRNA and protein were also markedly enhanced in human CRC cells exhibiting mutation in KRAS and BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / enhance-01 :li "2" :ARG1 (a3 / and :op1 (n6 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 "p")) :op2 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :manner (m / marked) :mod (a2 / also) :location (c / cell :ARG0-of (e3 / exhibit-01 :ARG1 (m2 / mutate-01 :ARG1 (a4 / and :op1 (g / gene :name (n4 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n5 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :mod (h / human) :mod (d / disease :name (n3 / name :op1 "CRC"))) :manner (i / interesting)) # ::id a_pmid_2094_2929.9 # ::date 2015-05-20T10:25:33 # ::file a_pmid_2094_2929_9.txt # ::snt 3- RNAi directed against serpinE2 in caMEK-transformed rat IECs or in human CRC cell lines HCT116 and LoVo markedly decreased foci formation, anchorage-independent growth in soft agarose, cell migration and tumor formation in nude mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (d / decrease-01 :li "3" :ARG0 (i2 / interfere-01 :ARG1 (n / nucleic-acid :name (n11 / name :op1 "RNA")) :ARG1-of (d2 / direct-01 :ARG2 (o2 / oppose-01 :ARG1 (o / or :op1 (p / protein :name (n2 / name :op1 "serpinE2") :location (c / cell :name (n3 / name :op1 "IEC") :mod (r / rat) :ARG1-of (t / transform-01 :ARG0 (e / enzyme :name (n4 / name :op1 "MEK") :ARG2-of (m5 / mutate-01) :mod (c3 / constitutive) :ARG1-of (a4 / activate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :op2 (p2 / protein :name (n5 / name :op1 "serpinE2") :location (c6 / cell :ARG2-of (i / include-91 :ARG1 (a3 / and :op1 (c2 / cell-line :name (n6 / name :op1 "HCT116")) :op2 (c4 / cell-line :name (n8 / name :op1 "LoVo")))) :mod (h / human) :mod (d4 / disease :name (n10 / name :op1 "CRC"))) :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))))) :ARG1 (a / and :op1 (f / form-01 :ARG1 (f2 / focus)) :op2 (g / grow-01 :ARG1-of (d3 / depend-01 :polarity "-" :ARG0 (a2 / anchorage)) :location (a5 / agarose :ARG1-of (s / soft-02))) :op3 (m3 / migrate-01 :ARG0 (c5 / cell)) :op4 (f3 / form-01 :ARG1 (t2 / tumor) :location (m4 / mouse :mod (n9 / nude)))) :manner (m2 / marked)) # ::id a_pmid_2094_2929.10 # ::date 2015-05-20T10:50:46 # ::file a_pmid_2094_2929_10.txt # ::snt 4- Treatment of CRC cell lines with U0126 markedly reduced serpinE2 mRNA levels, indicating that expression of serpinE2 is likely dependent of ERK activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reduce-01 :li "4" :ARG0 (t / treat-04 :ARG1 (c / cell-line :mod (d2 / disease :name (n3 / name :op1 "CRC"))) :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 (l / level :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n5 / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))))) :manner (m / marked) :ARG0-of (i / indicate-01 :ARG1 (l2 / likely-01 :ARG1 (d / depend-01 :ARG0 (e3 / express-03 :ARG2 p) :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))))) # ::id a_pmid_2094_2929.11 # ::date 2015-05-20T11:37:23 # ::file a_pmid_2094_2929_11.txt # ::snt 5- Finally, Q-PCR analyses demonstrated that mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues and in colorectal tumors, regardless of tumor stage and grade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (d / demonstrate-01 :li "5" :li "-1" :ARG0 (a / analyze-01 :mod (t / thing :name (n / name :op1 "Q-PCR"))) :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (n4 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))))) :location (a2 / and :op1 (a3 / adenomas :mod (h / human)) :op2 (t3 / tumor :mod (c / colon))) :ARG1-of (r / regardless-91 :ARG2 (a5 / and :op1 (t5 / thing :ARG2-of (s / stage-02 :ARG1 (t4 / tumor))) :op2 (g / grade :mod t4))) :manner (m / marked) :compared-to (t2 / tissue :mod (a4 / adjacent) :mod (h2 / healthy)))) # ::id a_pmid_2094_2929.39 # ::date 2015-05-20T11:47:11 # ::file a_pmid_2094_2929_39.txt # ::snt SerpinE2 is overexpressed in intestinal epithelial cells transformed by activated MEK1 and oncogenic RAS and BRAF # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (o / overexpress-01 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :location (c / cell :mod (e2 / epithelium) :part-of (i / intestine) :ARG1-of (t / transform-01 :ARG0 (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "MEK1") :ARG1-of (a2 / activate-01) :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n4 / name :op1 "RAS") :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op3 (e / enzyme :name (n5 / name :op1 "BRAF") :ARG0-of c2 :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) # ::id a_pmid_2094_2929.40 # ::date 2015-05-20T12:22:30 # ::file a_pmid_2094_2929_40.txt # ::snt Among the most harmful of all genetic abnormalities that appear in CRC development are mutations of KRAS and its downstream effector BRAF as they result in abnormal ERK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / include-91 :ARG1 (a4 / and :op1 (m2 / mutate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (e2 / effector :mod (d2 / downstream) :mod (e3 / enzyme :name (n4 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :poss e4) :ARG1-of (r / result-01 :ARG2 (s / signal-07 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (n6 / normal-02 :polarity "-")))) :ARG2 (n5 / normal-02 :polarity "-" :ARG2 (g / genetics) :mod (a2 / all) :ARG0-of (h / harmful-02 :degree (m / most)) :ARG1-of (a3 / appear-01 :time (d / develop-02 :ARG1 (c / cell :mod (d3 / disease :name (n2 / name :op1 "CRC"))))))) # ::id a_pmid_2094_2929.41 # ::date 2015-05-20T12:49:26 # ::file a_pmid_2094_2929_41.txt # ::snt In a previous report, we had shown that expression of a constitutive active mutant of MEK1 (caMEK) in the intestinal epithelial cell line IEC-6 induced morphological transformation and growth in soft agar; in marked contrast, wtMEK overexpression had no effect on IEC-6 phenotype [3]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (s / show-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG0 (e / express-03 :ARG2 (m / mutate-01 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :mod (c / constitutive) :ARG0-of (a2 / activity-06)) :ARG3 (c2 / cell-line :name (n3 / name :op1 "IEC-6") :mod (e4 / epithelium :part-of (i2 / intestine)))) :ARG2 (a3 / and :op1 (t / transform-01 :mod (m3 / morphological)) :op2 (g / grow-01 :location (a4 / agar :ARG1-of (s2 / soft-02))))) :medium (r / report :time (p / previous))) :op2 (a5 / affect-01 :polarity "-" :ARG0 (o / overexpress-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "MEK") :mod (w2 / wild-type) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1 (p2 / phenotype :mod (c3 / cell-line :name (n5 / name :op1 "IEC-6"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "3"))) :ARG2-of (c5 / contrast-01 :ARG1-of (m4 / mark-01)))) # ::id a_pmid_2094_2929.42 # ::date 2015-05-20T13:09:11 # ::file a_pmid_2094_2929_42.txt # ::snt In order to understand the mechanisms by which activated MEK1 induces intestinal cell tumorigenesis, the pattern of gene expression was analyzed by microarray in IEC-6 cells overexpressing activated MEK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a3 / analyze-01 :ARG0 (m2 / microarray) :ARG1 (p / pattern-01 :ARG1 (e2 / express-03 :ARG2 (g / gene))) :location (c2 / cell-line :name (n2 / name :op1 "IEC-6") :ARG0-of (o / overexpress-01 :ARG1 "e")) :purpose (u / understand-01 :ARG1 (m / mechanism :instrument-of (i / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "MEK1") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :ARG2 (c3 / create-01 :ARG1 (t / tumor :mod (c / cell :part-of (i2 / intestine)))))))) # ::id a_pmid_2094_2929.43 # ::date 2015-05-20T13:24:51 # ::file a_pmid_2094_2929_43.txt # ::snt Results from microarrays comparing control (wtMEK) to caMEK-expressing IEC-6 cells identified the Serpin clade E member 2 (serpinE2 or PN-1) gene as a potential target of activated MEK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 30, 2015 (i / identify-01 :ARG0 (t / thing :ARG2-of (r / result-01) :source (m / microarray :ARG0-of (c / compare-01 :ARG1 (c2 / control :ARG1-of (m2 / mean-01 :ARG2 (e / enzyme :name (n / name :op1 "MEK") :mod (w / wild-type) :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG2 (c3 / cell-line :name (n2 / name :op1 "IEC-6") :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "MEK") :ARG2-of (m4 / mutate-01) :mod (c4 / constitutive) :ARG1-of (a4 / activate-01) :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))))) :ARG1 (g / gene :name (n4 / name :op1 "Serpin" :op2 "clade" :op3 "E" :op4 "member" :op5 "2") :ARG1-of (m3 / mean-01 :ARG2 (a / and :op1 (g2 / gene :name (n5 / name :op1 "serpinE2") :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :op2 (g3 / gene :name (n6 / name :op1 "PN-1") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "1.002")))) :xref (x5 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.242")) :ARG2 (t2 / target-01 :ARG0 (e4 / enzyme :name (n7 / name :op1 "MEK1") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :ARG1 g :mod (p / potential))) # ::id a_pmid_2094_2929.44 # ::date 2015-05-20T13:31:22 # ::file a_pmid_2094_2929_44.txt # ::snt Indeed, serpinE2 expression was significantly induced by more that 28-fold (p < 0.05) in cells overexpressing activated MEK1 in comparison to cells expressing wtMEK (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG2 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "serpinE2") :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :mod (i2 / indeed) :ARG1-of (s / significant-02) :location (c / cell :location-of (o / overexpress-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1") :ARG1-of (a / activate-01) :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")))) :compared-to (c2 / cell :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MEK") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity "-"))) :quant (m2 / more-than :op1 (p / product-of :op1 "28")) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) # ::id a_pmid_2094_2929.45 # ::date 2015-05-20T13:46:38 # ::file a_pmid_2094_2929_45.txt # ::snt Overexpression of serpinE2 in caMEK-expressing IECs was furthermore confirmed following RT-PCR analysis as shown in Figure 1A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op2 (c / confirm-01 :ARG1 (o / overexpress-01 :ARG1 (g / gene :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :location (c2 / cell :name (n2 / name :op1 "IEC") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "MEK") :mod (c3 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a4 / activate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :time (f / follow-01 :ARG2 (a2 / analyze-01 :mod (t / thing :name (n4 / name :op1 "RT-PCR"))))) :ARG1-of (s / show-01 :ARG0 (f2 / figure :mod "1A"))) # ::id a_pmid_2094_2929.46 # ::date 2015-05-20T13:59:27 # ::file a_pmid_2094_2929_46.txt # ::snt SerpinE2 expression was also markedly enhanced in IEC-6 cells transformed by oncogenic RAS (26-fold) or BRAF (12-fold after 12 h of 4-hydroxytamoxifen (4-OHT) (Figure 1B and 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (o / or :op1 (e2 / enhance-01 :ARG1 (e3 / express-03 :ARG2 (p / protein :name (n2 / name :op1 "SerpinE2") :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.692"))) :ARG3 (p2 / product-of :op1 "26") :manner (m / marked) :mod (a / also) :location (c / cell-line :name (n3 / name :op1 "IEC-6") :ARG1-of (t / transform-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :op2 (e4 / enhance-01 :ARG1 e3 :ARG3 (p4 / product-of :op1 "12") :time (a2 / after :op1 (s / stimulate-01 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "4-hydroxytamoxifen") :xref (x3 / xref :value "PUBCHEM:449459" :prob "11.717745"))) :quant (t2 / temporal-quantity :quant "12" :unit (h / hour))) :location (c4 / cell-line :name (n7 / name :op1 "IEC-6") :ARG1-of (t3 / transform-01 :ARG0 (e5 / enzyme :name (n4 / name :op1 "BRAF") :ARG0-of c2 :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "1C")))) # ::id a_pmid_2094_2929.47 # ::date 2015-05-20T14:21:28 # ::file a_pmid_2094_2929_47.txt # ::snt Of note, the induction of serpinE2 was induced within 1 h following ERK activation as observed in cells expressing the inducible BRAF:ER fusion protein stimulated with 4-OHT (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (n2 / note-02 :ARG1 (i / induce-01 :ARG2 (i2 / induce-01 :ARG2 (p / protein :name (n3 / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :time (a / after :op1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :quant (u / up-to :op1 (t / temporal-quantity :quant "1" :unit (h / hour)))) :ARG1-of (f / follow-01) :ARG1-of (o / observe-01 :location (c / cell :ARG3-of (e2 / express-03 :ARG2 (p3 / protein :name (n5 / name :op1 "BRAF:ER" :op2 "fusion") :ARG1-of (i3 / induce-01 :ARG1-of (p2 / possible-01)) :ARG1-of (s / stimulate-01 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "4-OHT") :xref (x2 / xref :value "PUBCHEM:449459" :prob "9.856737")))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1C"))) # ::id a_pmid_2094_2929.48 # ::date 2015-05-21T09:43:34 # ::file a_pmid_2094_2929_48.txt # ::snt Treatment with the MEK-inhibitor U0126 completely abrogated serpinE2 gene expression induced by oncogenic MEK1 (Figure 1A) and BRAF (Figure 1C), indicating that induction of serpinE2 is an early and direct event occurring following the activation of ERK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / abrogate-01 :ARG1 (e3 / express-03 :ARG2 (g / gene :name (n5 / name :op1 "serpinE2") :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG2-of (i2 / induce-01 :ARG0 (e4 / enzyme :name (n6 / name :op1 "MEK1") :ARG0-of (c2 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) :ARG2-of (i3 / induce-01 :ARG0 (e7 / enzyme :name (n7 / name :op1 "BRAF") :ARG0-of c2 :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1C")))) :ARG2 (t / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n4 / name :op1 "MEK"))) :xref (x3 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1-of (c / complete-02) :ARG0-of (i4 / indicate-01 :ARG1 (e5 / event :mod (e6 / early) :ARG1-of (d3 / direct-02) :domain (i5 / induce-01 :ARG1 g) :ARG1-of (f3 / follow-01 :ARG2 (a2 / activate-01 :ARG1 (s3 / signal-07 :ARG0 (p / protein-family :name (n2 / name :op1 "ERK")))))))) # ::id a_pmid_2094_2929.49 # ::date 2015-05-21T10:05:41 # ::file a_pmid_2094_2929_49.txt # ::snt Since serpinE2 protein is known to be secreted [22,33], we easily confirmed its presence in conditioned culture medium of caMEK-expressing IECs whereas no serpinE2 protein was detected in the culture medium of wtMEK-expressing or parental IECs (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (c / confirm-01 :ARG0 (w2 / we) :ARG1 (p / present-02 :ARG1 (p2 / protein :name (n / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG2 (m / medium :mod (c3 / culture) :ARG1-of (c4 / condition-01) :poss (c7 / cell :name (n4 / name :op1 "IEC") :ARG3-of (e2 / express-03 :ARG2 (e / enzyme :name (n3 / name :op1 "MEK") :ARG2-of (m2 / mutate-01) :mod (c6 / constitutive) :ARG1-of (a3 / activate-01) :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1D")) :ARG1-of (e5 / easy-05) :ARG0-of (c10 / cause-01 :ARG1 (k / know-01 :ARG1 (s2 / secrete-01 :ARG1 p2)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c9 / cite-01 :ARG2 (a2 / and :op1 "22" :op2 "33"))))) :ARG1-of (c2 / contrast-01 :ARG2 (d / detect-01 :polarity "-" :ARG1 p2 :location (o / or :op1 (m3 / medium :mod (c5 / culture-01) :poss (c12 / cell :name (n2 / name :op1 "IEC") :ARG3-of (e4 / express-03 :ARG2 (e3 / enzyme :name (n5 / name :op1 "MEK") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :op2 (m4 / medium :mod (c11 / culture-01) :poss (c8 / cell :name (n6 / name :op1 "IEC") :mod (p4 / parent))))))) # ::id a_pmid_2094_2929.50 # ::date 2015-05-21T10:23:01 # ::file a_pmid_2094_2929_50.txt # ::snt Again, treatment with the MEK-inhibitor U0126 completely abrogated serpinE2 secretion (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / abrogate-01 :ARG1 (s2 / secrete-01 :ARG1 (p / protein :name (n3 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :ARG2 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"))) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :mod (a2 / again) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1D")) :ARG1-of (c / complete-02)) # ::id a_pmid_2094_2929.51 # ::date 2015-05-21T10:26:14 # ::file a_pmid_2094_2929_51.txt # ::snt Interestingly, serpinE2 protein was difficult to detect in total cell lysates (Figure 1E, lane 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (d / difficult :ARG1-of (d3 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1E" :part (l2 / lane :mod "2")))) :mod (i / interesting) :domain (d2 / detect-01 :ARG1 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :location (l / lysate :mod (c / cell) :mod (t / total)))) # ::id a_pmid_2094_2929.52 # ::date 2015-05-21T10:42:36 # ::file a_pmid_2094_2929_52.txt # ::snt However, serpinE2 was easily observed in lysates prepared from foci of post-confluent caMEK-expressing cells (Figure 1E, lane 4), while it was not detectable in the surrounding monolayer (Figure 1E, lane 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (h / have-concession-91 :ARG1 (c / contrast-01 :ARG1 (o / observe-01 :ARG1 (p / protein :name (n / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG1-of (e / easy-05) :location (l / lysate :ARG1-of (p2 / prepare-01 :ARG2 (f / focus :part-of (c2 / cell :time (a / after :op1 (c4 / confluent :domain c2)) :ARG3-of (e3 / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "MEK") :mod (c3 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a4 / activate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1E" :part (l2 / lane :mod "4"))))) :ARG2 (p4 / possible-01 :ARG1 (d2 / detect-01 :polarity "-" :ARG1 p :location (m2 / monolayer :ARG1-of (s / surround-01)) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f3 / figure :mod "1E" :part (l3 / lane :mod "3")))))))) # ::id a_pmid_2094_2929.53 # ::date 2015-05-21T10:57:06 # ::file a_pmid_2094_2929_53.txt # ::snt This indicates a stronger expression of serpinE2 protein by the transformed IECs forming the foci. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 10, 2015 (i / indicate-01 :ARG0 (t / this) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (c / cell :name (n2 / name :op1 "IEC") :ARG1-of (t2 / transform-01) :ARG0-of (f / form-01 :ARG1 (f2 / focus))) :ARG1-of (s / strong-02 :degree (m / more)))) # ::id a_pmid_2094_2929.54 # ::date 2015-05-21T11:03:14 # ::file a_pmid_2094_2929_54.txt # ::snt Gene silencing of serpinE2 decreases foci formation, growth in soft agarose and migration induced by activated MEK # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (d / decrease-01 :ARG0 (s / silence-01 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :mod (g / gene)) :ARG1 (a / and :op1 (f / form-01 :ARG1 (f2 / focus)) :op2 (g2 / grow-01 :location (a3 / agarose :ARG1-of (s2 / soft-02))) :op3 (m2 / migrate-01 :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEK") :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))))) # ::id a_pmid_2094_2929.55 # ::date 2015-05-21T11:19:25 # ::file a_pmid_2094_2929_55.txt # ::snt In order to determine the contribution of serpinE2 in intestinal transformation induced by activated MEK, foci from post-confluent caMEK-expressing IECs were retrieved by aspiration with a pipette and pooled as one caMEK-expressing cell population. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (a5 / and :op1 (r / retrieve-01 :ARG1 (f / focus) :ARG2 (c2 / cell :name (n3 / name :op1 "IEC") :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n4 / name :op1 "MEK") :mod (c3 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a4 / activate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :time (a2 / after :op1 (c5 / confluent :domain c2))) :manner (a3 / aspirate-101 :ARG1 f :ARG2 c2 :instrument (p3 / pipette))) :op2 (p4 / pool-01 :ARG1 f :ARG2 (p5 / population :mod (c4 / cell :ARG3-of (e4 / express-03 :ARG2 e3)))) :purpose (d / determine-01 :ARG1 (c / contribute-01 :ARG0 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG2 (t / transform-01 :mod (i / intestine) :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "MEK") :ARG1-of (a / activate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))))) # ::id a_pmid_2094_2929.56 # ::date 2015-05-21T11:35:30 # ::file a_pmid_2094_2929_56.txt # ::snt All further experiments were performed with this previously characterized caMEK-expressing IEC population [14] and compared with wtMEK-expressing cell populations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a3 / and :op1 (p / perform-02 :ARG1 (e / experiment-01 :ARG1 (p2 / population :ARG1-of (c / characterize-01 :time (p3 / previous)) :mod (c2 / cell :name (n / name :op1 "IEC") :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK") :mod (c3 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a4 / activate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :mod (t / this)) :degree (f / further) :mod (a / all)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "14")))) :op2 (c5 / compare-01 :ARG1 e :ARG2 (p5 / population :mod (c6 / cell :ARG3-of (e4 / express-03 :ARG2 (e5 / enzyme :name (n3 / name :op1 "MEK") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))))) # ::id a_pmid_2094_2929.57 # ::date 2015-05-21T11:50:42 # ::file a_pmid_2094_2929_57.txt # ::snt Recombinant lentiviruses encoding anti-serpinE2 short hairpin RNA (shRNA) were therefore developed to stably suppress serpinE2 levels in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / cause-01 :ARG1 (d / develop-02 :ARG1 (l / lentivirus :ARG3-of (r / recombine-01) :ARG0-of (e / encode-01 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "short" :op2 "hairpin") :ARG0-of (e2 / encode-01 :ARG1 (a / antibody :ARG0-of (o / oppose-01 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))))) :ARG1-of (m / mean-01 :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "shRNA")))))) :ARG4 (s / suppress-01 :ARG1 (l2 / level :quant-of p) :ARG1-of (s2 / stable-03) :location (c2 / cell :mod (t / this))))) # ::id a_pmid_2094_2929.58 # ::date 2015-05-21T12:13:53 # ::file a_pmid_2094_2929_58.txt # ::snt Several lentiviral constructs were generated and tested for their ability to knock down serpinE2 protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (a / and :op1 (g / generate-01 :ARG1 (c / construct-01 :ARG1 (l / lentiviral) :quant (s / several))) :op2 (t / test-01 :ARG1 c :ARG2 (c2 / capable-01 :ARG1 c :ARG2 (k / knock-down-02 :ARG0 c :ARG1 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))))) # ::id a_pmid_2094_2929.59 # ::date 2015-05-21T12:19:50 # ::file a_pmid_2094_2929_59.txt # ::snt One of these viral shRNAs was selected and designated as shSerpinE2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (s / select-01 :ARG1 (n6 / nucleic-acid :ARG1-of (i / include-91 :ARG2 (n4 / nucleic-acid :name (n / name :op1 "shRNA") :mod (v / virus) :mod (t / this))))) :op2 (d / designate-01 :ARG1 n6 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "shRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))))) # ::id a_pmid_2094_2929.60 # ::date 2015-05-21T12:27:20 # ::file a_pmid_2094_2929_60.txt # ::snt caMEK-expressing cells were henceforth infected with shSerpinE2 lentiviruses or with lentiviruses expressing a control shRNA (shScrambled). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (i / infect-01 :ARG1 (c / cell :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK") :mod (c2 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG2 (o / or :op1 (l / lentivirus :mod (n6 / nucleic-acid :name (n2 / name :op1 "shRNA") :ARG0-of (e3 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))))) :op2 (l2 / lentivirus :ARG1-of (e4 / express-03 :ARG2 (n7 / nucleic-acid :name (n4 / name :op1 "shRNA") :ARG0-of (c3 / control-01) :ARG1-of (m2 / mean-01 :ARG2 (n8 / nucleic-acid :name (n5 / name :op1 "shScrambled"))))))) :time (h / henceforth)) # ::id a_pmid_2094_2929.61 # ::date 2015-05-21T12:35:49 # ::file a_pmid_2094_2929_61.txt # ::snt Secretion of serpinE2 protein was analyzed 14 days after selection with blasticidin S in these populations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / analyze-01 :ARG1 (s / secrete-01 :ARG1 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :time (a2 / after :op1 (s2 / select-01 :ARG2 (p2 / population :mod (t2 / this)) :instrument (s3 / small-molecule :name (n2 / name :op1 "blasticidin" :op2 "S") :xref (x1 / xref :value "PUBCHEM:258" :prob "11.580318"))) :quant (t / temporal-quantity :quant "14" :unit (d2 / day)))) # ::id a_pmid_2094_2929.62 # ::date 2015-05-21T12:49:09 # ::file a_pmid_2094_2929_62.txt # ::snt As shown in Figure 2A, secreted serpinE2 levels were markedly reduced (> 60%) in cells-expressing shSerpinE2; in contrast, shScrambled had no effect on the secretion of serpinE2 (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 21, 2015 (a / and :op1 (r / reduce-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG1-of (s / secrete-01)) :ARG2 (m2 / more-than :op1 (p / percentage-entity :value "60")) :manner (m / marked) :location (c / cell :ARG3-of (e2 / express-03 :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA") :ARG0-of (e / encode-01 :ARG1 p2)))) :ARG1-of (s3 / show-01 :ARG0 (f / figure :mod "2A"))) :op2 (c2 / contrast-01 :ARG2 (a2 / affect-01 :polarity "-" :ARG0 (n5 / nucleic-acid :name (n3 / name :op1 "shScrambled")) :ARG1 (s2 / secrete-01 :ARG1 p2)) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s4 / show-01 :polarity "-"))))) # ::id a_pmid_2094_2929.63 # ::date 2015-05-21T13:19:55 # ::file a_pmid_2094_2929_63.txt # ::snt To determine the functional role of serpinE2 in caMEK-expressing cells, the proliferation rate of these cell populations was assessed when cultured on plastic. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (a3 / assess-01 :ARG1 (r2 / rate :degree-of (p2 / proliferate-01 :ARG0 (p3 / population :mod (c3 / cell) :mod (t / this)))) :time (c4 / culture-01 :ARG1 p3 :manner (p4 / plastic)) :purpose (d / determine-01 :ARG1 (r / role :topic (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG1-of (f / function-01) :location (c / cell :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "MEK") :mod (c2 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))))) # ::id a_pmid_2094_2929.64 # ::date 2015-05-20T05:45:12 # ::file a_pmid_2094_2929_64.txt # ::snt No difference was observed in the proliferation rate of subconfluent caMEK-expressing cells when serpinE2 expression was downregulated (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 20, 2015 (o / observe-01 :ARG1 (d / differ-02 :polarity "-" :ARG1 (r / rate :degree-of (p / proliferate-01 :ARG0 (c / cell :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "caMEK") :xref (x1 / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.233"))) :mod (s / subconfluent))))) :time (d2 / downregulate-01 :ARG1 (e3 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id a_pmid_2094_2929.65 # ::date 2015-05-20T05:53:44 # ::file a_pmid_2094_2929_65.txt # ::snt In a previous study, we had shown that expression of activated MEK in intestinal epithelial cells resulted in loss of cell-cell contact growth inhibition and produced colonies or multilayered domes which grew to increased saturation density and formed tumors when transplanted into nude mice [14]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (r / result-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG3 (c / cell :source (e3 / epithelium :part-of (i / intestine)))) :ARG2 (l / lose-02 :ARG1 (i2 / inhibit-01 :ARG0 (c2 / contact-01 :ARG0 (c4 / cell) :ARG1 (c3 / cell)) :ARG1 (g / grow-01)))) :op2 (p / produce-01 :ARG0 e :ARG1 (o / or :op1 (c5 / colony) :op2 (d / dome :mod (m / multilayered)) :ARG1-of (g2 / grow-01 :ARG4 (d2 / density :mod (s2 / saturate-01) :ARG1-of (i3 / increase-01))) :ARG0-of (f / form-01 :ARG1 (t / tumor) :time (t2 / transplant-01 :ARG1 o :ARG2 (m2 / mouse :mod (n2 / nude))))))) :medium (s3 / study-01 :time (p2 / previous)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 "14")))) # ::id a_pmid_2094_2929.66 # ::date 2015-05-20T06:09:22 # ::file a_pmid_2094_2929_66.txt # ::snt Of note, focus formation assays performed herein revealed that initially, there was little difference in the number of foci obtained between control cells and serpinE2-depleted cells (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / reveal-01 :ARG0 (a / assay-01 :ARG1 (f2 / form-01 :ARG1 (f3 / focus)) :ARG1-of (p / perform-02 :medium (h / herein))) :ARG1 (d / differ-02 :ARG1 (c / cell :mod (c2 / control)) :ARG2 (c3 / cell :ARG1-of (d2 / deplete-01 :ARG2 (p2 / protein :name (n3 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :ARG3 (n2 / number :quant-of (f / focus) :ARG1-of (o / obtain-01)) :degree (l / little) :time (i / initial)) :ARG1-of (n4 / note-02) :ARG1-of (d3 / describe-01 :ARG0 (d4 / data :ARG1-of (s / show-01 :polarity "-")))) # ::id a_pmid_2094_2929.67 # ::date 2015-05-20T06:21:04 # ::file a_pmid_2094_2929_67.txt # ::snt However, serpinE2 silencing markedly reduced the size of foci (Figure 2C) suggesting a reduced capacity of these foci to grow. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 5, 2015 (c2 / contrast-01 :ARG2 (r / reduce-01 :ARG0 (s / silence-01 :ARG1 (g2 / gene :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :ARG1 (s2 / size :poss (f / focus)) :manner (m / marked) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2C")) :ARG0-of (s3 / suggest-01 :ARG1 (c / capable-01 :ARG1 f :ARG2 (g / grow-01 :ARG1 f) :ARG1-of (r2 / reduce-01))))) # ::id a_pmid_2094_2929.68 # ::date 2015-05-20T06:29:21 # ::file a_pmid_2094_2929_68.txt # ::snt Indeed, phase-contrast microscopy revealed that the colonies were smaller when serpinE2 was downregulated (Figure 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 20, 2015 (r / reveal-01 :ARG0 (t / thing :name (n / name :op1 "phase-contrast" :op2 "microscopy")) :ARG1 (s / small :degree (m / more) :domain (c / colony) :time (d / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2D")) :mod (i / indeed)) # ::id a_pmid_2094_2929.69 # ::date 2015-05-20T06:32:08 # ::file a_pmid_2094_2929_69.txt # ::snt Finally, expression of shSerpinE2 led to a significant decrease in the ability of caMEK-expressing cells to grow under anchorage-independent conditions in soft agarose (Figure 2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (l / lead-03 :li "-1" :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "shSerpinE2"))) :ARG1 (d / decrease-01 :ARG1 (c / capable-01 :ARG1 (c2 / cell :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "caMEK") :xref (x / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.233")))) :ARG2 (g / grow-01 :ARG1 c2 :location (a2 / agarose :ARG1-of (s2 / soft-02)) :condition (d2 / depend-01 :polarity "-" :ARG0 g :ARG1 (a / anchorage)))) :ARG2 (s / significant-02)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2E"))) # ::id a_pmid_2094_2929.70 # ::date 2015-05-20T06:46:14 # ::file a_pmid_2094_2929_70.txt # ::snt Cell migration is an important process of tumorigenesis and metastasis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (p / process-02 :ARG1 (m / migrate-01 :ARG0 (c / cell)) :mod (i / important) :subevent-of (a / and :op1 (c2 / create-01 :ARG1 (t / tumor)) :op2 (m2 / metastasis))) # ::id a_pmid_2094_2929.71 # ::date 2015-05-20T06:48:09 # ::file a_pmid_2094_2929_71.txt # ::snt Moreover, we recently reported that intestinal epithelial cells expressing activated MEK1 clearly acquire an increased capacity to migrate as compared to wtMEK-expressing cells [14]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op2 (r / report-01 :ARG0 (w / we) :ARG1 (a2 / acquire-01 :ARG0 (c2 / cell :source (e / epithelium :part-of (i / intestine)) :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n / name :op1 "MEK1") :ARG1-of (a3 / activate-01) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")))) :ARG1 (c3 / capable-01 :ARG1 c2 :ARG2 (m / migrate-01 :ARG0 c2) :ARG1-of (i2 / increase-01) :compared-to (c4 / capable-01 :ARG1 (c5 / cell :ARG3-of (e4 / express-03 :ARG2 (e5 / enzyme :name (n2 / name :op1 "MEK") :mod (w2 / wild-type) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG2 m)) :ARG1-of (c / clear-06)) :time (r2 / recent)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c6 / cite-01 :ARG2 "14")))) # ::id a_pmid_2094_2929.72 # ::date 2015-05-20T06:54:31 # ::file a_pmid_2094_2929_72.txt # ::snt Herein, in an in vitro transwell migration assay, serpinE2 deficiency significantly reduced caMEK-expressing IEC migration to the undersurface of the polycarbonate membrane of Boyden chambers coated with fibronectin or vitronectin (Figure 2F), two extracellular matrix proteins which can interact with serpinE2 [34,35]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / reduce-01 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "serpinE2") :xref (x3 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :ARG1 (m / migrate-01 :ARG0 (c / cell :name (n2 / name :op1 "IEC") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "caMEK") :xref (x / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.233")))) :ARG1 (u / undersurface :part-of (m2 / membrane :consist-of (p2 / polycarbonate) :poss (t / thing :name (n4 / name :op1 "Boyden" :op2 "chamber")) :xref (x4 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (c2 / coat-01 :ARG2 (o / or :op1 (p3 / protein :name (n5 / name :op1 "fibronectin") :xref (x1 / xref :value "UNIPROT:FINC_HUMAN" :prob "0.703")) :op2 (p4 / protein :name (n6 / name :op1 "vitronectin") :xref (x2 / xref :value "UNIPROT:VTNC_HUMAN" :prob "0.703")) :ARG1-of (m3 / mean-01 :ARG2 (p5 / protein :quant "2" :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 (a / and :op1 "34" :op2 "35")))) :ARG0-of (i / interact-01 :ARG1 p :ARG1-of (p6 / possible-01)) :mod (m4 / matrix :mod (e3 / extracellular)))))))) :ARG2 (s / significant-02) :medium (h / herein) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2F")) :condition (a2 / assay-01 :ARG1 (m5 / migrate-01 :mod (t3 / transwell)) :manner (i2 / in-vitro))) # ::id a_pmid_2094_2929.73 # ::date 2015-05-20T07:10:51 # ::file a_pmid_2094_2929_73.txt # ::snt Taken together, these results support a role of serpinE2 in MEK1-induced transformation whereby serpinE2 activates anchorage-independent growth and cell migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-condition-91 :ARG1 (s / support-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG1 (r2 / role :poss (p / protein :name (n / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :purpose (t3 / transform-01 :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :subevent (a / activate-01 :ARG0 p :ARG1 (a2 / and :op1 (g / grow-01 :ARG1 (c2 / cell) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a3 / anchorage))) :op2 (m / migrate-01 :ARG0 c2)))))) :ARG2 (t4 / take-01 :ARG1 t :mod (t5 / together))) # ::id a_pmid_2094_2929.74 # ::date 2015-05-20T07:17:12 # ::file a_pmid_2094_2929_74.txt # ::snt Expression of serpinE2 in colorectal cancer cells is dependent on MEK/ERK activity # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (d / depend-01 :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (c / cell :source (d2 / disease :name (n3 / name :op1 "colorectal" :op2 "cancer")))) :ARG1 (a / activity-06 :ARG0 (p2 / pathway :name (n2 / name :op1 "MEK/ERK")))) # ::id a_pmid_2094_2929.75 # ::date 2015-05-20T07:19:36 # ::file a_pmid_2094_2929_75.txt # ::snt To assess the contribution of serpinE2 in human colorectal cancer, serpinE2 expression was first examined in various CRC cell lines including Caco-2/15 as well as others exhibiting mutation in KRAS (HCT-116, DLD-1, LoVo, SW480, T84) or BRAF (Colo-205, HT-29) [36]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / examine-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "serpinE2") :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :time (f / first) :location (c / cell-line :mod (v / various) :ARG2-of (i / include-01 :ARG1 (a / and :op1 (c2 / cell-line :name (n3 / name :op1 "Caco-2/15")) :op2 (c3 / cell-line :mod (o / other) :ARG0-of (e3 / exhibit-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n4 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and :op1 (c5 / cell-line :name (n6 / name :op1 "HCT-116")) :op2 (c6 / cell-line :name (n7 / name :op1 "DLD-1")) :op3 (c7 / cell-line :name (n8 / name :op1 "LoVo")) :op4 (c8 / cell-line :name (n9 / name :op1 "SW480")) :op5 (c9 / cell-line :name (n10 / name :op1 "T84"))))) :op3 (c4 / cell-line :ARG0-of (e4 / exhibit-01 :ARG1 (m2 / mutate-01 :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :mod o :ARG1-of (m4 / mean-01 :ARG2 (a3 / and :op1 (c10 / cell-line :name (n11 / name :op1 "Colo-205")) :op2 (c11 / cell-line :name (n12 / name :op1 "HT-29"))))))) :mod (d3 / disease :name (n2 / name :op1 "CRC"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c12 / cite-01 :ARG2 "36"))) :purpose (a4 / assess-01 :ARG1 (c13 / contribute-01 :ARG0 p :ARG2 (d2 / disease :name (n13 / name :op1 "colorectal" :op2 "cancer") :mod (h / human))))) # ::id a_pmid_2094_2929.76 # ::date 2015-05-20T07:31:52 # ::file a_pmid_2094_2929_76.txt # ::snt As shown in Figure 3A, serpinE2 mRNA levels were barely detectable in the Caco-2/15 cell line while being markedly expressed in all other CRC cell lines tested. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (d / detect-01 :ARG1 (l / level :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (g / gene :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))))) :degree (b / bare) :location (c2 / cell-line :name (n3 / name :op1 "Caco-2/15")))) :ARG2 (e2 / express-03 :ARG1 n5 :ARG3 (c3 / cell-line :mod (a / all) :mod (o / other) :ARG1-of (t / test-01) :mod (d2 / disease :name (n4 / name :op1 "CRC"))) :manner (m / marked)) :ARG1-of (s / show-01 :medium (f / figure :mod "3A"))) # ::id a_pmid_2094_2929.77 # ::date 2015-05-20T07:45:39 # ::file a_pmid_2094_2929_77.txt # ::snt Two human CRC cell lines, namely HCT116 and LoVo, which have an activating mutation in the KRAS gene resulting in elevated MEK/ERK activities [37], were thereby chosen to further analyze the regulation and role of serpinE2 expression in human colorectal cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c9 / cause-01 :ARG1 (c / choose-01 :ARG1 (c2 / cell-line :quant "2" :mod (h / human) :location-of (m2 / mutate-01 :ARG1 (g / gene :name (n4 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (r / result-01 :ARG2 (a3 / act-02 :ARG0 (p3 / pathway :name (n8 / name :op1 "MEK/ERK")) :ARG1-of (e / elevate-01))) :ARG0-of (a2 / activate-01) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 "37")))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n2 / name :op1 "HCT116")) :op2 (c4 / cell-line :name (n3 / name :op1 "LoVo")))) :mod (d3 / disease :name (n / name :op1 "CRC"))) :purpose (a4 / analyze-01 :ARG1 (a5 / and :op1 (r2 / regulate-01 :ARG1 (e4 / express-03 :ARG2 (p2 / protein :name (n7 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (c6 / cell :source (d2 / disease :name (n5 / name :op1 "colorectal" :op2 "cancer") :mod (h2 / human))))) :op2 (r3 / role :poss e4)) :degree (f / further)))) # ::id a_pmid_2094_2929.78 # ::date 2015-05-20T10:43:47 # ::file a_pmid_2094_2929_78.txt # ::snt In addition, the impact of U0126 treatment was also investigated to evaluate the contribution of endogenous MEK/ERK activities in serpinE2 expression in human cell models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 4, 2015 (a / and :op2 (i2 / investigate-01 :ARG1 (i / impact-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")))) :ARG2 (e / evaluate-01 :ARG1 (c / contribute-01 :ARG0 (a3 / act-02 :ARG0 (p / pathway :name (n2 / name :op1 "MEK/ERK") :mod (e2 / endogenous))) :ARG2 (e3 / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (m / model :mod (c2 / cell :mod (h / human)))))) :mod (a2 / also))) # ::id a_pmid_2094_2929.79 # ::date 2015-05-20T10:49:34 # ::file a_pmid_2094_2929_79.txt # ::snt Forty-eight-hour treatment of HCT116 and LoVo cell lines with U0126 efficiently blocked endogenous MEK activity as confirmed by the marked inhibition of ERK1/2 phosphorylation (data not shown) [14]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (b2 / block-01 :ARG0 (t2 / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n3 / name :op1 "HCT116")) :op2 (c2 / cell-line :name (n4 / name :op1 "LoVo"))) :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x3 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :duration (t / temporal-quantity :quant "48" :unit (h / hour))) :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n2 / name :op1 "MEK") :mod (e3 / endogenous) :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2-of (e2 / efficient-01) :ARG1-of (c3 / confirm-01 :ARG0 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (s2 / slash :op1 (e4 / enzyme :name (n5 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n6 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :mod (m / marked))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (d2 / data :ARG1-of (s3 / show-01 :polarity "-")) :op2 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 "14"))))) # ::id a_pmid_2094_2929.80 # ::date 2015-05-20T10:59:16 # ::file a_pmid_2094_2929_80.txt # ::snt As shown in Figure 3B, treatment of these CRC cell lines with U0126 markedly and significantly reduced serpinE2 mRNA levels, indicating that expression of serpinE2 is likely dependent of ERK activity in these cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reduce-01 :ARG0 (t / treat-04 :ARG1 (c / cell-line :mod (t2 / this) :mod (d2 / disease :name (n3 / name :op1 "CRC"))) :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 (l / level :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n5 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))))) :ARG2 (a / and :op1 (m / marked) :op2 (s2 / significant-02)) :ARG0-of (i / indicate-01 :ARG1 (l2 / likely-01 :ARG1 (d / depend-01 :ARG0 (e3 / express-03 :ARG1 g :ARG3 c) :ARG1 (a2 / activity-06 :ARG0 (p / protein-family :name (n2 / name :op1 "ERK")))))) :ARG1-of (s3 / show-01 :medium (f / figure :mod "3B"))) # ::id a_pmid_2094_2929.81 # ::date 2015-05-20T11:05:19 # ::file a_pmid_2094_2929_81.txt # ::snt Down-regulation of serpinE2 expression in human colorectal cancer cells inhibits soft agarose colony formation, migration and tumor growth in nude mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / inhibit-01 :ARG0 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (c / cell :source (d2 / disease :name (n3 / name :op1 "colorectal" :op2 "cancer") :mod (h / human))))) :ARG1 (a / and :op1 (f / form-01 :ARG1 (c4 / colony) :location (a2 / agarose :ARG1-of (s / soft-02))) :op2 (m / migrate-01) :op3 (g / grow-01 :ARG1 (t / tumor))) :location (m2 / mouse :mod (n2 / nude))) # ::id a_pmid_2094_2929.82 # ::date 2015-05-20T11:08:56 # ::file a_pmid_2094_2929_82.txt # ::snt We next investigated the effect of serpinE2 knockdown on anchorage independent growth and cell migration after downregulation of serpinE2 gene expression by RNA interference in HCT116 and LoVo cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :ARG1 (a2 / and :op1 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a3 / anchorage))) :op2 (m / migrate-01 :ARG0 (c / cell)))) :time (n / next) :time (a4 / after :op1 (d2 / downregulate-01 :ARG1 (e / express-03 :ARG1 (g2 / gene :name (n3 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (a5 / and :op1 (c2 / cell-line :name (n4 / name :op1 "HCT116")) :op2 (c3 / cell-line :name (n5 / name :op1 "LoVo")))) :ARG2 (i2 / interfere-01 :ARG0 (n6 / nucleic-acid :name (n7 / name :op1 "RNA")))))) # ::id a_pmid_2094_2929.83 # ::date 2015-05-20T11:17:25 # ::file a_pmid_2094_2929_83.txt # ::snt As shown in Figure 4A, serpinE2 mRNA were significantly reduced by respectively 37% and 88% in LoVo cells expressing shSerpinE2(#15) or shSerpinE2(#16) and by 77% and 92% in HCT116 expressing shSerpinE2(#15) or shSerpinE2(#16); conversely, expression of the control shRNA (shTGFP) had no effect on endogenous serpinE2 expression (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c5 / contrast-01 :ARG1 (a5 / and :op1 (r / reduce-01 :ARG1 (n12 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (g / gene :name (n2 / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :ARG2 (p / percentage-entity :value "37") :ARG1-of (s / significant-02) :location (c / cell-line :name (n3 / name :op1 "LoVo") :ARG3-of (e2 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "shSerpinE2") :ARG1-of (l / label-01 :ARG2 "15"))))) :op2 (r8 / reduce-01 :ARG1 n12 :ARG2 (p2 / percentage-entity :value "88") :location (c6 / cell-line :name (n10 / name :op1 "LoVo") :ARG3-of (e6 / express-03 :ARG2 (p6 / protein :name (n4 / name :op1 "shSerpinE2") :ARG1-of (l2 / label-01 :ARG2 "16")))) :ARG1-of s) :op3 (r9 / reduce-01 :ARG1 n12 :ARG2 (p3 / percentage-entity :value "77") :location (c2 / cell-line :name (n6 / name :op1 "HCT116") :ARG3-of e2) :ARG1-of s) :op4 (r10 / reduce-01 :ARG1 n12 :ARG2 (p4 / percentage-entity :value "92") :ARG1-of s :location (c7 / cell-line :name (n11 / name :op1 "HCT116") :ARG3-of e6)) :ARG1-of (s3 / show-01 :medium (f / figure :mod "4A"))) :ARG2 (c3 / contrast-01 :ARG1 (a4 / affect-01 :polarity "-" :ARG0 (e3 / express-03 :ARG2 (n15 / nucleic-acid :name (n7 / name :op1 "shRNA") :mod (c4 / control) :ARG1-of (d / describe-01 :ARG2 (p7 / protein :name (n8 / name :op1 "shTGFP"))))) :ARG1 (e4 / express-03 :ARG1 (g2 / gene :name (n9 / name :op1 "serpinE2") :mod (e5 / endogenous) :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s2 / show-01 :polarity "-"))))) # ::id a_pmid_2094_2929.84 # ::date 2015-05-20T11:40:23 # ::file a_pmid_2094_2929_84.txt # ::snt Again, the proliferation rate of these cell populations was assessed when cultured on plastic. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 21, 2015 (a / assess-01 :ARG1 (r / rate :degree-of (p / proliferate-01 :ARG0 (p2 / population :mod (t / this) :mod (c / cell)))) :time (c2 / culture-01 :ARG1 p2 :location (p3 / plastic)) :mod (a2 / again)) # ::id a_pmid_2094_2929.85 # ::date 2015-05-20T11:43:30 # ::file a_pmid_2094_2929_85.txt # ::snt No difference was observed in the proliferation rate of subconfluent cells when serpinE2 expression was downregulated (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 21, 2015 (o / observe-01 :ARG1 (d / differ-02 :polarity "-" :ARG1 (r / rate :degree-of (p / proliferate-01 :ARG0 (c / cell :mod (s / subconfluent))))) :time (d2 / downregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id a_pmid_2094_2929.86 # ::date 2015-05-20T11:46:44 # ::file a_pmid_2094_2929_86.txt # ::snt We then verified whether the reduction in serpinE2 expression alters the ability of colon cancer cells to form colonies in soft agarose. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (v / verify-01 :ARG0 (w / we) :ARG1 (a / alter-01 :mode "interrogative" :ARG0 (r / reduce-01 :ARG1 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :ARG1 (c / capable-01 :ARG1 (c2 / cell :source (d / disease :name (n2 / name :op1 "colon" :op2 "cancer"))) :ARG2 (f / form-01 :ARG0 c2 :ARG1 (c5 / colony) :location (a2 / agarose :ARG1-of (s / soft-02))))) :time (t / then)) # ::id a_pmid_2094_2929.87 # ::date 2015-05-20T11:50:05 # ::file a_pmid_2094_2929_87.txt # ::snt As shown in Figure 4C, expression of both shRNA against SerpinE2 (#15 and #16) decreased the ability of HCT116 and LoVo cells to form colonies in soft agarose. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (d / decrease-01 :ARG0 (e / express-03 :ARG2 (n7 / nucleic-acid :name (n / name :op1 "shRNA") :mod (b / both) :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n2 / name :op1 "SerpinE2") :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (p2 / protein :name (n3 / name :op1 "SerpinE2") :ARG1-of (l / label-01 :ARG2 "15") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.692")) :op2 (p3 / protein :name (n4 / name :op1 "SerpinE2") :ARG1-of (l2 / label-01 :ARG2 "16") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.692")))) :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.692"))))) :ARG1 (c2 / capable-01 :ARG1 (a2 / and :op1 (c3 / cell-line :name (n5 / name :op1 "HCT116")) :op2 (c4 / cell-line :name (n6 / name :op1 "LoVo"))) :ARG2 (f / form-01 :ARG0 a2 :ARG1 (c5 / colony) :location (a3 / agarose :ARG1-of (s / soft-02)))) :ARG1-of (s2 / show-01 :ARG0 (f2 / figure :mod "4C"))) # ::id a_pmid_2094_2929.88 # ::date 2015-05-21T00:44:50 # ::file a_pmid_2094_2929_88.txt # ::snt Of note, shSerpinE2(#15) which was less efficient than the shRNA (#16) to reduce serpinE2 gene expression (Figure 4A) was also less efficient to reduce colony formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (e / efficient-01 :ARG1 (p / protein :name (n / name :op1 "shSerpinE2") :ARG1-of (e2 / efficient-01 :ARG2 (r4 / reduce-01 :ARG0 p :ARG1 (e3 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :degree (l / less) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4A")) :compared-to (n6 / nucleic-acid :name (n2 / name :op1 "shRNA") :ARG1-of (l3 / label-01 :ARG2 "16"))) :ARG1-of (l2 / label-01 :ARG2 "15") :ARG1-of (n4 / note-02)) :ARG2 (r / reduce-01 :ARG0 p :ARG1 (f / form-01 :ARG1 (c / colony))) :mod (a / also) :degree l) # ::id a_pmid_2094_2929.89 # ::date 2015-05-21T00:50:43 # ::file a_pmid_2094_2929_89.txt # ::snt This indicates that serpinE2 controls anchorage-independent growth of human colon carcinoma cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 21, 2015 (i / indicate-01 :ARG0 (t / this) :ARG1 (c / control-01 :ARG0 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG1 (g / grow-01 :ARG1 (c2 / cell :source (c3 / carcinoma :mod (h / human) :mod (c4 / colon))) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a / anchorage))))) # ::id a_pmid_2094_2929.90 # ::date 2015-05-21T00:52:39 # ::file a_pmid_2094_2929_90.txt # ::snt Additionally, as observed in caMEK-expressing IECs, the size of foci formed at post-confluency was significantly decreased in serpinE2-depleted LoVo cells (Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jun 6, 2015 (a / and :op2 (d / decrease-01 :ARG1 (s2 / size :poss (f / focus :ARG1-of (f2 / form-01 :time (a2 / after :op1 (c3 / confluency))))) :ARG2 (s / significant-02) :location (c / cell-line :name (n / name :op1 "LoVo") :ARG1-of (d2 / deplete-01 :ARG2 (p2 / protein :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")))) :ARG1-of (o / observe-01 :location (c2 / cell :name (n3 / name :op1 "IEC") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n4 / name :op1 "caMEK") :xref (x1 / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.233")))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "4D"))) # ::id a_pmid_2094_2929.91 # ::date 2015-05-21T00:57:22 # ::file a_pmid_2094_2929_91.txt # ::snt The tumorigenicity of colorectal cell lines was next assessed after subcutaneous (s.c.) injection into the flank of nude mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 24, 2015 (a / assess-01 :ARG1 (p / possible-01 :ARG1 (c3 / create-01 :ARG0 (c / cell-line :source (c2 / colorectal)) :ARG1 (t / tumor))) :time (n / next) :time (a2 / after :op1 (i / inject-01 :ARG2 (f / flank :poss (m / mouse :mod (n2 / nude))) :mod (s / subcutaneous)))) # ::id a_pmid_2094_2929.92 # ::date 2015-05-21T01:00:22 # ::file a_pmid_2094_2929_92.txt # ::snt As shown in Figure 5A and 5B, HCT116 and LoVo cell lines induced palpable tumors with a short latency period of respectively 15 and 10 days after their injection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / induce-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "HCT116")) :op2 (c2 / cell-line :name (n2 / name :op1 "LoVo"))) :ARG2 (t2 / tumor :mod (p / palpable) :mod (p2 / period :mod (l / latency) :ARG1-of (s / short-07) :time (a3 / after :op1 (i2 / inject-01 :ARG1 a) :quant (a2 / and :op1 (t3 / temporal-quantity :quant "15" :unit (d2 / day)) :op2 (t4 / temporal-quantity :quant "10" :unit (d / day)) :mod (r / respective))))) :ARG1-of (s2 / show-01 :medium (a4 / and :op1 (f / figure :mod "5A") :op2 (f2 / figure :mod "5B")))) # ::id a_pmid_2094_2929.93 # ::date 2015-05-21T01:06:14 # ::file a_pmid_2094_2929_93.txt # ::snt More importantly, downregulation of serpinE2 expression with shSerpinE2(#16) in these cell lines severely impaired their capacity to grow as tumors in nude mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / impair-01 :ARG0 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (c / cell-line :mod (t / this))) :ARG2 (p2 / protein :name (n2 / name :op1 "shSerpinE2") :ARG1-of (l / label-01 :ARG2 "16"))) :ARG1 (c2 / capable-01 :ARG1 c :ARG2 (g / grow-02 :ARG1 c :ARG2 (t2 / tumor) :location (m / mouse :mod (n3 / nude)))) :manner (s / severe) :mod (i2 / important :degree (m2 / more))) # ::id a_pmid_2094_2929.94 # ::date 2015-05-21T01:10:20 # ::file a_pmid_2094_2929_94.txt # ::snt Finally, in vitro transwell migration assays were performed to verify the importance of serpinE2 in colon carcinoma cell migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (p / perform-02 :li "-1" :ARG1 (a / assay-01 :ARG1 (m2 / migrate-01 :mod (t2 / transwell)) :manner (i / in-vitro)) :purpose (v / verify-01 :ARG1 (i2 / important :domain (p2 / protein :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :purpose (m / migrate-01 :ARG0 (c / cell :source (c2 / carcinoma :mod (c3 / colon))))))) # ::id a_pmid_2094_2929.95 # ::date 2015-05-21T01:17:17 # ::file a_pmid_2094_2929_95.txt # ::snt As illustrated in Figure 6A, serpinE2 deficiency significantly reduced HCT116 (not shown) and LoVo cell migration to the undersurface of the membrane coated or not with fibronectin or vitronectin (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 5, 2015 (r / reduce-01 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "serpinE2") :xref (x2 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :ARG1 (m / migrate-01 :ARG0 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "HCT116") :ARG1-of (s2 / show-01 :polarity "-")) :op2 (c4 / cell-line :name (n3 / name :op1 "LoVo"))) :ARG2 (u / undersurface :part-of (m2 / membrane :xref (x3 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (c5 / coat-01 :ARG2 (o / or :op1 (p2 / protein :name (n4 / name :op1 "fibronectin") :xref (x / xref :value "UNIPROT:FINC_HUMAN" :prob "0.703")) :op2 (p3 / protein :name (n5 / name :op1 "vitronectin") :xref (x1 / xref :value "UNIPROT:VTNC_HUMAN" :prob "0.703"))) :op1-of (o2 / or :op2 (c6 / coat-01 :polarity "-" :ARG1 u :ARG2 o))))) :ARG2 (s / significant-02) :ARG1-of (i / illustrate-01 :medium (f / figure :mod "6A")) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of s2))) # ::id a_pmid_2094_2929.96 # ::date 2015-05-21T01:28:49 # ::file a_pmid_2094_2929_96.txt # ::snt The net effect of serpinE2 knockdown was also determined on invasion by using BD Biocoat Matrigel invasion chambers, in presence of hydroxyurea. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 14, 2015 (d / determine-01 :ARG1 (a / affect-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :mod (n / net)) :mod (a2 / also) :time (i / invade-01) :manner (u / use-01 :ARG1 (t / thing :name (n3 / name :op1 "BD" :op2 "Biocoat" :op3 "Matrigel" :op4 "invasion" :op5 "chamber"))) :condition (p2 / present-02 :ARG1 (s / small-molecule :name (n4 / name :op1 "hydroxyurea") :xref (x1 / xref :value "PUBCHEM:3657" :prob "12.395561")))) # ::id a_pmid_2094_2929.97 # ::date 2015-05-21T01:35:43 # ::file a_pmid_2094_2929_97.txt # ::snt As shown in Figure 6B, the capacity of LoVo cells to invade Matrigel was also altered by serpinE2 silencing # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / alter-01 :ARG0 (s / silence-01 :ARG1 (p2 / protein :name (n3 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :ARG1 (c / capable-01 :ARG1 (c2 / cell-line :name (n / name :op1 "LoVo")) :ARG2 (i / invade-01 :ARG0 c2 :ARG1 (p / protein :name (n2 / name :op1 "Matrigel") :xref (x1 / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.273")))) :mod (a2 / also) :ARG1-of (s2 / show-01 :medium (f / figure :mod "6B"))) # ::id a_pmid_2094_2929.98 # ::date 2015-05-21T01:41:10 # ::file a_pmid_2094_2929_98.txt # ::snt To test the hypothesis that this altered migration and invasion capacity could result from a defect in cell adhesion, adhesion strength to the substrate was examined for control and shSerpinE2(#16)-expressing LoVo cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (e / examine-01 :ARG1 (s / strong-02 :degree-of (a / adhere-01 :ARG1 (a2 / and :op1 (c / cell-line :name (n / name :op1 "LoVo") :mod (c2 / control)) :op2 (c3 / cell-line :name (n2 / name :op1 "LoVo") :ARG3-of (e2 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "shSerpinE2") :ARG1-of (l / label-01 :ARG2 "16"))))) :ARG2 (s2 / substrate))) :ARG2 (t2 / test-01 :ARG1 (h / hypothesize-01 :ARG1 (p / possible-01 :ARG1 (r2 / result-01 :ARG1 (d / defect :topic (a5 / adhere-01 :ARG1 (c5 / cell))) :ARG2 (c4 / capable-01 :ARG2 (a3 / and :op1 (m / migrate-01) :op2 (i / invade-01)) :ARG1-of (a4 / alter-01) :mod (t3 / this))))))) # ::id a_pmid_2094_2929.99 # ::date 2015-05-21T01:49:37 # ::file a_pmid_2094_2929_99.txt # ::snt Using a trypsin-mediated de-adhesion assay, downregulation of serpinE2 significantly delayed LoVo cell detachment after trypsinization (Figure 6C), suggesting that serpinE2 expression decreases adhesion of colorectal carcinoma cells to the substrate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (d / delay-01 :ARG0 (d2 / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "serpinE2") :xref (x1 / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))) :ARG1 (d3 / detach-01 :ARG1 (c / cell-line :name (n2 / name :op1 "LoVo"))) :ARG2 (s / significant-02) :time (a / after :op1 (t / trypsinize-00)) :manner (u / use-01 :ARG1 (a2 / assay-01 :ARG1 (a3 / adhere-01 :polarity "-") :ARG1-of (m / mediate-01 :ARG0 (e / enzyme :name (n4 / name :op1 "trypsin") :xref (x / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342"))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "6C")) :ARG0-of (s2 / suggest-01 :ARG1 (d5 / decrease-01 :ARG0 (e2 / express-03 :ARG2 p) :ARG1 (a4 / adhere-01 :ARG1 (c2 / cell :source (c3 / carcinoma :mod (c4 / colorectal))) :ARG2 (s3 / substrate))))) # ::id a_pmid_2094_2929.100 # ::date 2015-05-21T01:59:48 # ::file a_pmid_2094_2929_100.txt # ::snt SerpinE2 gene expression is up-regulated in human colorectal cancers # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (u / upregulate-01 :ARG1 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :mod (h / human) :mod (c2 / colorectal)))) # ::id a_pmid_2094_2929.101 # ::date 2015-05-21T02:00:52 # ::file a_pmid_2094_2929_101.txt # ::snt We next analyzed serpinE2 gene expression in a series of human paired specimens (resection margins and primary tumors) by Q-PCR analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 21, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG1 (g / gene :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (s / series :consist-of (s2 / specimen :mod (h / human) :ARG1-of (p / pair-01) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (m2 / margin :mod (r / resection)) :op2 (t / tumor :mod (p2 / primary))))))) :time (n / next) :manner (t2 / thing :name (n3 / name :op1 "Q-PCR" :op2 "analysis"))) # ::id a_pmid_2094_2929.102 # ::date 2015-05-21T02:08:57 # ::file a_pmid_2094_2929_102.txt # ::snt As shown in Figure 7, mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (i / increase-01 :ARG1 (l / level :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672"))))) :manner (m / marked) :ARG1-of (s / show-01 :medium (f / figure :mod "7")) :compared-to (l2 / level :location (t / tissue :mod (h2 / healthy) :mod (a2 / adjacent)) :quant-of n4) :location (m2 / medical-condition :name (n3 / name :op1 "adenoma") :mod (h / human))) # ::id a_pmid_2094_2929.103 # ::date 2015-05-21T02:14:26 # ::file a_pmid_2094_2929_103.txt # ::snt Furthermore, serpinE2 expression was also significantly enhanced in colorectal tumors, regardless of tumor stage and grade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (a / and :op2 (e / enhance-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "serpinE2") :xref (x / xref :value "UNIPROT:GDN_HUMAN" :prob "0.672")) :ARG3 (t / tumor :mod (c / colorectal))) :ARG3 (s / significant-02) :mod (a2 / also) :ARG1-of (r / regardless-91 :ARG2 (a3 / and :op1 (t2 / thing :ARG2-of (s2 / stage-02 :ARG1 t)) :op2 (g / grade :mod t))))) # ::id a_pmid_2139_2397.12 # ::date 2015-05-26T08:45:19 # ::file a_pmid_2139_2397_12.txt # ::snt The average level of phosphorylation of YB-1 in the breast cancer cell lines SKBr3, MCF-7, HBL100 and MDA-MB-231 was significantly higher than that in normal cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / high-02 :ARG1 (l / level :ARG1-of (a / average-04) :degree-of (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :location (a2 / and :op1 (c3 / cell-line :name (n3 / name :op1 "SKBr3")) :op2 (c4 / cell-line :name (n4 / name :op1 "MCF-7")) :op3 (c5 / cell-line :name (n5 / name :op1 "HBL100")) :op4 (c6 / cell-line :name (n6 / name :op1 "MDA-MB-231")) :mod (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer")))) :degree (m / more) :ARG1-of (s / significant-02) :compared-to (c7 / cell :ARG1-of (n7 / normal-02))) # ::id a_pmid_2139_2397.13 # ::date 2015-05-26T09:06:52 # ::file a_pmid_2139_2397_13.txt # ::snt Exposure to IR and stimulation with erbB1 ligands resulted in phosphorylation of YB-1 in K-RASwt SKBr3, MCF-7 and HBL100 cells, which was shown to be K-Ras-independent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (r / result-01 :ARG1 (a / and :op1 (e / expose-01 :ARG2 (r2 / radiate-01 :ARG0-of (i / ionize-01))) :op2 (s / stimulate-01 :ARG2 (l / ligand :name (n2 / name :op1 "erbB1")))) :ARG2 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :location (a2 / and :op1 (c / cell-line :name (n4 / name :op1 "SKBr3")) :op2 (c2 / cell-line :name (n5 / name :op1 "MCF-7")) :op3 (c3 / cell-line :name (n6 / name :op1 "HBL100")) :mod (g / gene :name (n7 / name :op1 "K-Ras") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG1-of (d / depend-01 :polarity "-" :ARG0 g :ARG1-of (s2 / show-01)))) # ::id a_pmid_2139_2397.14 # ::date 2015-05-26T09:24:42 # ::file a_pmid_2139_2397_14.txt # ::snt In contrast, lack of YB-1 phosphorylation after stimulation with either IR or erbB1 ligands was observed in K-RASmt MDA-MB-231 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (l / lack-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :time (a / after :op1 (s / stimulate-01 :ARG2 (o2 / or :op1 (r / radiate-01 :ARG0-of (i / ionize-01)) :op2 (l3 / ligand :name (n3 / name :op1 "erbB1")))))) :location (c2 / cell-line :name (n4 / name :op1 "MDA-MB-231") :mod (g / gene :name (n5 / name :op1 "K-RAS") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))))) # ::id a_pmid_2139_2397.15 # ::date 2015-05-26T09:29:24 # ::file a_pmid_2139_2397_15.txt # ::snt Similarly to MDA-MB-231 cells, YB-1 became constitutively phosphorylated in K-RASwt cells following the overexpression of mutated K-RAS, and its phosphorylation was not further enhanced by IR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (a / and :op1 (b / become-01 :ARG1 (p / protein :name (n / name :op1 "YB-1") :xref (x2 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2 (p2 / phosphorylate-01 :ARG1 p :mod (c / constitutive) :location (c2 / cell :mod (g2 / gene :name (n2 / name :op1 "K-RAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))) :ARG2-of (f / follow-01 :ARG1 (o / overexpress-01 :ARG1 (g / gene :name (n3 / name :op1 "K-RAS") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))))) :op2 (e3 / enhance-01 :polarity "-" :ARG1 p2 :ARG2 (r2 / radiate-01 :ARG0-of (i / ionize-01)) :degree (f2 / further)) :ARG1-of (r / resemble-01 :ARG2 (c3 / cell-line :name (n5 / name :op1 "MDA-MB-231")))) # ::id a_pmid_2139_2397.16 # ::date 2015-05-26T09:43:38 # ::file a_pmid_2139_2397_16.txt # ::snt Phosphorylation of YB-1 as a result of irradiation or K-RAS mutation was dependent on erbB1 and its downstream pathways, PI3K and MAPK/ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (d / depend-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2-of (r / result-01 :ARG1 (a / and :op1 (i / irradiate-01) :op2 (m / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "K-RAS") :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))))) :ARG1 (a3 / and :op1 (p / protein :name (n6 / name :op1 "erbB1") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.633")) :op2 (p4 / pathway :mod (d2 / downstream) :ARG2-of (i2 / include-91 :ARG1 (a2 / and :op1 (p5 / pathway :name (n4 / name :op1 "PI3K")) :op2 (p6 / pathway :name (n5 / name :op1 "MAPK/ERK")))) :poss p))) # ::id a_pmid_2139_2397.17 # ::date 2015-05-26T09:50:26 # ::file a_pmid_2139_2397_17.txt # ::snt In K-RASmt cells K-RAS siRNA as well as YB-1 siRNA blocked repair of DNA-DSB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (b / block-01 :ARG0 (a / and :op1 (n7 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :op2 (n8 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (e3 / encode-01 :ARG1 (p / protein :name (n4 / name :op1 "YB-1") :xref (x2 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))))) :ARG1 (r3 / repair-01 :ARG1 (t / thing :name (n5 / name :op1 "DNA-DSB"))) :location (c / cell :mod (g2 / gene :name (n6 / name :op1 "K-RAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))) # ::id a_pmid_2139_2397.18 # ::date 2015-05-26T10:05:55 # ::file a_pmid_2139_2397_18.txt # ::snt Likewise, YB-1 siRNA increased radiation sensitivity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (i / increase-01 :ARG0 (n3 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")))) :ARG1 (s / sensitive-03 :ARG1 (r2 / radiate-01)) :manner (l / likewise)) # ::id a_pmid_2139_2397.115 # ::date 2015-05-26T13:17:25 # ::file a_pmid_2139_2397_115.txt # ::snt Stimulation of YB-1 phosphorylation in breast cancer cells by IR and exposure to erbB1 ligands # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (s / stimulate-01 :ARG0 (r / radiate-01 :ARG0-of (i / ionize-01)) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :location (c / cell :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")))) :op2 (e / expose-01 :ARG1 (l / ligand :name (n4 / name :op1 "erbB1")))) # ::id a_pmid_2139_2397.116 # ::date 2015-05-26T13:20:02 # ::file a_pmid_2139_2397_116.txt # ::snt The level of basal YB-1 phosphorylation at S102 in a panel of breast cancer cells (MDA-MB-231, MCF-7, HBL100 and SKBr3) was compared to the level of YB-1 phosphorylation in normal cells, that is, human skin and lung fibroblasts (HSF1, HSF7 and HFL) as well as normal mammary epithelial cells (MCF-10A) (Figures 1A and 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / compare-01 :ARG1 (l / level :degree-of (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "102" :name (n2 / name :op1 "serine") :part-of (p2 / protein :name (n3 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :location (p3 / panel :consist-of (c2 / cell-line :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (c4 / cell-line :name (n4 / name :op1 "MDA-MB-231")) :op2 (c5 / cell-line :name (n5 / name :op1 "MCF-7")) :op3 (c6 / cell-line :name (n6 / name :op1 "HBL100")) :op4 (c7 / cell-line :name (n7 / name :op1 "SKBr3")))) :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")))) :mod (b2 / basal))) :ARG2 (l2 / level :degree-of (p4 / phosphorylate-01 :ARG1 p2 :location (c8 / cell-line :ARG1-of (n8 / normal-02) :ARG2-of (m3 / mean-01 :ARG1 (a4 / and :op1 (s / skin :mod (h / human)) :op2 (f / fibroblast :mod (l3 / lung)) :op3 (c12 / cell :mod (e / epithelium) :mod (m / mammary) :ARG1-of (m2 / mean-01 :ARG2 (c13 / cell-line :name (n14 / name :op1 "MCF-10A"))) :ARG1-of n8) :ARG2-of (i3 / include-91 :ARG1 (a3 / and :op1 (c10 / cell-line :name (n10 / name :op1 "HSF1")) :op2 (c9 / cell-line :name (n11 / name :op1 "HSF7")) :op3 (c11 / cell-line :name (n12 / name :op1 "HFL"))))))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f2 / figure :mod "1A") :op2 (f3 / figure :mod "1B")))) # ::id a_pmid_2139_2397.117 # ::date 2015-05-26T13:40:47 # ::file a_pmid_2139_2397_117.txt # ::snt As shown in Figure 1C, the ratio of P-YB-1/YB-1 is significantly higher in tumor cells than in fibroblasts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (h2 / high :domain (r / ratio-of :op1 (p2 / protein :name (n / name :op1 "YB-1") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n2 / name :op1 "YB-1") :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG1-of (h / high-02 :degree (m / more) :ARG1-of (s2 / significant-02)) :location (c / cell :mod (t / tumor)) :compared-to (f2 / fibroblast)) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2139_2397.118 # ::date 2015-05-26T13:49:13 # ::file a_pmid_2139_2397_118.txt # ::snt The comparisons of the ratio of P-YB-1/YB-1 in tumor cells and normal mammary epithelial cells indicated an even stronger significant difference as tested for MDA-MB-231 and MCF-10A cells (Figures 1B and 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / indicate-01 :ARG0 (c / compare-01 :ARG2 (r / ratio-of :op1 (p2 / protein :name (n / name :op1 "YB-1") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n2 / name :op1 "YB-1") :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :location (a3 / and :op1 (c2 / cell :mod (t / tumor)) :op2 (c3 / cell :mod (e / epithelium) :mod (m / mammary) :ARG1-of (n5 / normal-02)))) :ARG1 (d / differ-02 :mod (s / strong :degree (m2 / more) :mod (e2 / even)) :ARG1-of (s2 / significant-02) :ARG1-of (t2 / test-01 :ARG2 (a / and :op1 (c4 / cell-line :name (n3 / name :op1 "MDA-MB-231")) :op2 (c5 / cell-line :name (n4 / name :op1 "MCF-10A"))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "1C")))) # ::id a_pmid_2139_2397.119 # ::date 2015-05-26T13:56:53 # ::file a_pmid_2139_2397_119.txt # ::snt YB-1 has been identified as a direct substrate of Akt [12,35]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / identify-01 :ARG1 (p / protein :name (n / name :op1 "YB-1") :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2 (s / substrate :mod (e / enzyme :name (n2 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of (d / direct-02)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 "12" :op2 "35"))))) # ::id a_pmid_2139_2397.120 # ::date 2015-05-26T14:01:38 # ::file a_pmid_2139_2397_120.txt # ::snt As previously reported, IR can activate the Akt ligand independently [30,36]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (r2 / radiate-01 :ARG0-of (i / ionize-01)) :ARG1 (l / ligand :mod (e / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :manner (d2 / depend-01 :polarity "-")) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 "30" :op2 "36")))) :ARG1-of (r / report-01 :time (p2 / previous))) # ::id a_pmid_2139_2397.121 # ::date 2015-05-26T14:08:00 # ::file a_pmid_2139_2397_121.txt # ::snt Therefore, we asked whether IR could induce YB-1 phosphorylation as well. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / cause-01 :ARG1 (a / ask-01 :mode "interrogative" :ARG0 (w / we) :ARG1 (p3 / possible-01 :ARG1 (i / induce-01 :ARG0 (r / radiate-01 :ARG0-of (i2 / ionize-01)) :ARG2 (p2 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :mod (a2 / as-well))))) # ::id a_pmid_2139_2397.122 # ::date 2015-05-26T14:12:54 # ::file a_pmid_2139_2397_122.txt # ::snt As shown in Figure 1D, IR induces YB-1 phosphorylation differentially. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / induce-01 :ARG0 (r / radiate-01 :ARG0-of (i2 / ionize-01)) :ARG2 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "1D")) :manner (d / differential)) # ::id a_pmid_2139_2397.123 # ::date 2015-05-26T14:17:15 # ::file a_pmid_2139_2397_123.txt # ::snt A strong phosphorylation signal was observed in SKBr3, whereas HBL100 showed moderate phosphorylation of YB-1 and phosphorylation in MCF-7 was weak. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (o / observe-01 :ARG1 (s / signal-07 :ARG1 (p / phosphorylate-01) :mod (s2 / strong) :location (c2 / cell-line :name (n / name :op1 "SKBr3")))) :ARG2 (a / and :op1 (s3 / show-01 :ARG0 (c3 / cell-line :name (n2 / name :op1 "HBL100")) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG1-of (m / moderate-03))) :op2 (p4 / phosphorylate-01 :location (c4 / cell-line :name (n4 / name :op1 "MCF-7")) :ARG1-of (w / weak-02)))) # ::id a_pmid_2139_2397.124 # ::date 2015-05-26T14:26:27 # ::file a_pmid_2139_2397_124.txt # ::snt However, in MDA-MB-231 cells, a lack of IR-induced YB-1 phosphorylation was observed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (h / have-concession-91 :ARG1 (o / observe-01 :ARG1 (l / lack-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2-of (i / induce-01 :ARG0 (r / radiate-01 :ARG0-of (i2 / ionize-01)))) :location (c / cell-line :name (n3 / name :op1 "MDA-MB-231"))))) # ::id a_pmid_2139_2397.125 # ::date 2015-05-26T14:34:37 # ::file a_pmid_2139_2397_125.txt # ::snt In this cell line, stimulation with the erbB1 ligand EGF, AREG or TGFα did not induce YB-1 phosphorylation, whereas strong phosphorylation at the indicated times after stimulation was observed in the cell lines SKBr3, HBL100 and MCF-7 (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (c / contrast-01 :ARG1 (i / induce-01 :polarity "-" :ARG0 (s / stimulate-01 :ARG2 (l / ligand :name (n / name :op1 "erbB1") :ARG2-of (i2 / include-91 :ARG1 (a / and :op1 (p6 / protein :name (n2 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (p2 / protein :name (n3 / name :op1 "AREG") :xref (x / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n4 / name :op1 "TGFα") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.253")))))) :ARG2 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n5 / name :op1 "YB-1") :xref (x3 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :location (c5 / cell-line :mod (t2 / this))) :ARG2 (o / observe-01 :ARG1 (p5 / phosphorylate-01 :mod (s3 / strong) :time (t / time :ARG1-of (i3 / indicate-01)) :time (a2 / after :op1 s)) :location (a3 / and :op1 (c2 / cell-line :name (n6 / name :op1 "SKBr3")) :op2 (c3 / cell-line :name (n7 / name :op1 "HBL100")) :op3 (c4 / cell-line :name (n8 / name :op1 "MCF-7")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1D"))) # ::id a_pmid_2139_2397.126 # ::date 2015-05-26T14:54:13 # ::file a_pmid_2139_2397_126.txt # ::snt Although the MCF-7 and HBL100 cell lines have K-RASwt status, these cells presented high basal YB-1 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (h / have-concession-91 :ARG1 (p2 / present-01 :ARG0 "a" :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG1-of (h3 / high-02) :mod (b / basal))) :ARG2 (h2 / have-03 :ARG0 (a / and :op1 (c / cell-line :name (n2 / name :op1 "MCF-7")) :op2 (c2 / cell-line :name (n3 / name :op1 "HBL100"))) :ARG1 (s / status :mod (g / gene :name (n / name :op1 "K-RAS") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))))) # ::id a_pmid_2139_2397.127 # ::date 2015-05-27T08:54:46 # ::file a_pmid_2139_2397_127.txt # ::snt To prove whether the high basal phosphorylation status of YB-1 was due to stimulation by growth factors in the culture medium, P-YB-1 was compared under serum supplementation and serum depletion in MCF-7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (c5 / compare-01 :ARG0 (a / and :op1 (s4 / supplement-01 :ARG1 (s5 / serum)) :op2 (d / deplete-01 :ARG1 s5) :location (c4 / cell-line :name (n3 / name :op1 "MCF-7"))) :ARG1 (p4 / protein :name (n4 / name :op1 "YB-1") :ARG3-of (p5 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :purpose (p2 / prove-01 :ARG1 (c / cause-01 :mode "interrogative" :ARG0 (s2 / stimulate-01 :ARG0 (g / growth-factor) :location (m / medium :mod (c2 / culture))) :ARG1 (s / status :mod (p / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :degree (h / high-02) :mod (b / basal)))))) # ::id a_pmid_2139_2397.128 # ::date 2015-05-27T09:07:45 # ::file a_pmid_2139_2397_128.txt # ::snt As shown in Figure 1F, P-YB-1 was markedly reduced when cells were incubated in serum-free medium for 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (r / reduce-01 :ARG1 (p / protein :name (n / name :op1 "YB-1") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :manner (m / marked) :time (i / incubate-01 :ARG1 (c / cell) :ARG2 (m2 / medium :ARG1-of (f / free-04 :ARG2 (s / serum))) :duration (t2 / temporal-quantity :quant "24" :unit (h2 / hour))) :ARG1-of (s2 / show-01 :ARG0 (f2 / figure :mod "1F"))) # ::id a_pmid_2139_2397.129 # ::date 2015-05-27T09:12:09 # ::file a_pmid_2139_2397_129.txt # ::snt In contrast, serum depletion did not reduce basal YB-1 phosphorylation in K-RASmt MDA-MB-231 cells (Figure 1F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / contrast-01 :ARG2 (r / reduce-01 :polarity "-" :ARG0 (d / deplete-01 :ARG1 (s / serum)) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (b / basal)) :location (c2 / cell-line :name (n3 / name :op1 "MDA-MB-231") :mod (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1F"))) # ::id a_pmid_2139_2397.130 # ::date 2015-05-27T09:15:59 # ::file a_pmid_2139_2397_130.txt # ::snt Constitutive phosphorylation of YB-1 in MDA-MB-231 cells is K-Ras-dependent # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 5, 2015 (d / depend-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (c / constitutive) :location (c2 / cell-line :name (n2 / name :op1 "MDA-MB-231"))) :ARG1 (e / enzyme :name (n3 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) # ::id a_pmid_2139_2397.131 # ::date 2015-05-27T09:18:22 # ::file a_pmid_2139_2397_131.txt # ::snt MDA-MB-231 cells are characterized by a point mutation at codon 13 in the K-RAS gene [37]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 27, 2015 (c / characterize-01 :ARG0 (m / mutate-01 :ARG1 (c3 / codon :mod "13" :part-of (g / gene :name (n3 / name :op1 "K-RAS") :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :mod (p / point)) :ARG1 (c2 / cell-line :name (n2 / name :op1 "MDA-MB-231")) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 "37")))) # ::id a_pmid_2139_2397.132 # ::date 2015-05-27T09:24:03 # ::file a_pmid_2139_2397_132.txt # ::snt This mutation is responsible for the constitutive phosphorylation of ERK1/2 [30]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 27, 2015 (r / responsible-01 :ARG0 (m / mutate-01 :mod (t / this)) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :mod (c / constitutive)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "30")))) # ::id a_pmid_2139_2397.133 # ::date 2015-05-27T09:28:03 # ::file a_pmid_2139_2397_133.txt # ::snt In addition to ERK1/2 phosphorylation, these cells also present a constitutive phosphorylation of YB-1, which is not further modified after exposure to IR or stimulation with erbB1 ligands (Figures 1D and 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p5 / present-01 :ARG0 (c / cell :mod (t / this)) :ARG1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (c2 / constitutive) :ARG1-of (m / modify-01 :polarity "-" :ARG0 (o / or :op1 (e2 / expose-01 :ARG1 c :ARG2 (r / radiate-01 :ARG0-of (i / ionize-01))) :op2 (s / stimulate-01 :ARG1 c :ARG2 (l / ligand :name (n4 / name :op1 "erbB1")))) :degree (f3 / further))) :mod (a2 / also) :ARG1-of (a4 / add-02 :ARG2 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1D") :op2 (f2 / figure :mod "1E")))) # ::id a_pmid_2139_2397.134 # ::date 2015-05-27T09:36:55 # ::file a_pmid_2139_2397_134.txt # ::snt Thus, we investigated whether the constitutive phosphorylation of YB-1 in MDA-MB-231 cells is due to the described endogenous expression of mutated K-RAS [37]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / cause-01 :ARG1 (i / investigate-01 :ARG0 (w / we) :ARG1 (c2 / cause-01 :mode "interrogative" :ARG0 (e2 / express-03 :ARG2 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")) :ARG1-of (d / describe-01) :mod (m / monocot)) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :location (c3 / cell-line :name (n3 / name :op1 "MDA-MB-231")) :mod (c4 / constitutive)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "37")))) # ::id a_pmid_2139_2397.135 # ::date 2015-05-27T09:43:01 # ::file a_pmid_2139_2397_135.txt # ::snt Therefore, K-Ras expression was downregulated by siRNA, and the level of P-YB-1 was investigated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (c / cause-01 :ARG1 (a / and :op1 (d / downregulate-01 :ARG1 (e2 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "siRNA"))) :op2 (i / investigate-01 :ARG1 (l / level :quant-of (p / protein :name (n3 / name :op1 "YB-1") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")))))) # ::id a_pmid_2139_2397.136 # ::date 2015-05-27T09:47:42 # ::file a_pmid_2139_2397_136.txt # ::snt Using a similar approach, we analyzed the effect of ERK1 on YB-1 phosphorylation downstream of mutated K-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (a4 / analyze-01 :ARG0 (w / we) :ARG1 (a3 / affect-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :location (r2 / relative-position :op1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :direction (d / downstream)))) :manner (u / use-01 :ARG1 (a / approach-02 :ARG1-of (r / resemble-01)))) # ::id a_pmid_2139_2397.137 # ::date 2015-05-27T09:53:55 # ::file a_pmid_2139_2397_137.txt # ::snt As shown in Figure 2A, K-RAS siRNA led to a strong reduction in P-ERK1/2 and P-YB-1 (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (l / lead-03 :ARG0 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :ARG2 (r2 / reduce-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG1-of (p / phosphorylate-01)) :op2 (p2 / protein :name (n4 / name :op1 "YB-1") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :mod (s / strong)) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2139_2397.138 # ::date 2015-05-27T09:59:01 # ::file a_pmid_2139_2397_138.txt # ::snt Yet, ERK1/2 and YB-1 protein levels were not affected. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (h / have-concession-91 :ARG1 (a / affect-01 :polarity "-" :ARG1 (a2 / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK1/2"))) :op2 (l2 / level :quant-of (p / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")))))) # ::id a_pmid_2139_2397.139 # ::date 2015-05-27T11:48:06 # ::file a_pmid_2139_2397_139.txt # ::snt Likewise, a marked reduction of P-YB-1 was observed when ERK1 was targeted with siRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 5, 2015 (o / observe-01 :ARG1 (r / reduce-01 :ARG1 (p / protein :name (n / name :op1 "YB-1") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :time (t / target-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :ARG2 (n4 / nucleic-acid :name (n3 / name :op1 "siRNA"))) :degree (m / marked)) :manner (l / likewise)) # ::id a_pmid_2139_2397.140 # ::date 2015-05-27T12:44:40 # ::file a_pmid_2139_2397_140.txt # ::snt The role of stimulated ERK1/2 phosphorylation on YB-1 phosphorylation was further supported by the results when a MEK inhibitor was used. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / support-01 :ARG0 (t2 / thing :ARG2-of (r2 / result-01)) :ARG1 (r / role :poss (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")) :ARG1-of (s2 / stimulate-01)) :topic (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")))) :degree (f / further) :time (u / use-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK")))))) # ::id a_pmid_2139_2397.141 # ::date 2015-05-27T13:10:48 # ::file a_pmid_2139_2397_141.txt # ::snt As shown in Figure 2B, pretreatment of MDA-MB-231 cells with the MEK inhibitor PD98059 markedly blocked YB-1 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (b / block-01 :ARG0 (p2 / pretreat-01 :ARG1 (c / cell-line :name (n2 / name :op1 "MDA-MB-231")) :ARG3 (s2 / small-molecule :name (n3 / name :op1 "PD98059") :ARG0-of (i2 / inhibit-01 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"))) :xref (x1 / xref :value "PUBCHEM:4713" :prob "18.349844"))) :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :degree (m2 / marked) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "2B"))) # ::id a_pmid_2139_2397.142 # ::date 2015-05-27T13:16:54 # ::file a_pmid_2139_2397_142.txt # ::snt Similar to the data shown in Figure 1D, exposure to IR did not induce YB-1 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i2 / induce-01 :polarity "-" :ARG0 (e / expose-01 :ARG2 (r2 / radiate-01 :ARG0-of (i / ionize-01))) :ARG2 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :ARG1-of (r / resemble-01 :ARG2 (d / data)) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "1D"))) # ::id a_pmid_2139_2397.143 # ::date 2015-05-27T13:20:06 # ::file a_pmid_2139_2397_143.txt # ::snt These results indicates that the constitutive YB-1 phosphorylation in MDA-MB-231 cells is a consequence of mutated K-Ras-mediated ERK1/2 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (c / consequence :domain (p / phosphorylate-01 :ARG1 (p2 / protein :wiki "Y_box_binding_protein_1" :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (c2 / constitutive) :location (c3 / cell-line :wiki "-" :name (n2 / name :op1 "MDA-MB-231"))) :ARG1-of (c4 / cause-01 :ARG0 (p3 / phosphorylate-01 :ARG1 (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n3 / name :op1 "ERK1/2")) :ARG1-of (m / mediate-01 :ARG0 (e2 / enzyme :wiki "KRAS" :name (n4 / name :op1 "K-Ras") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))))) # ::id a_pmid_2139_2397.144 # ::date 2015-05-27T13:33:31 # ::file a_pmid_2139_2397_144.txt # ::snt Overexpression of mutated K-RASV12 enhances basal YB-1 phosphorylation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (e2 / enhance-01 :ARG0 (o / overexpress-01 :ARG1 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (b / basal))) # ::id a_pmid_2139_2397.145 # ::date 2015-05-27T13:36:13 # ::file a_pmid_2139_2397_145.txt # ::snt To investigate the role of K-Ras in the constitutive phosphorylation of YB-1, we further analyzed the status of K-RAS in SKBr3, MCF-7 and HBL100 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (s / status :location (a2 / and :op1 (c / cell-line :name (n2 / name :op1 "SKBr3")) :op2 (c2 / cell-line :name (n3 / name :op1 "MCF-7")) :op3 (c3 / cell-line :name (n4 / name :op1 "HBL100"))) :poss (g / gene :name (n6 / name :op1 "K-RAS") :xref (x2 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :degree (f / further) :purpose (i / investigate-01 :ARG0 w :ARG1 (r / role :topic (p / phosphorylate-01 :ARG1 (p2 / protein :name (n5 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (c4 / constitutive)) :poss (e / enzyme :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) # ::id a_pmid_2139_2397.146 # ::date 2015-05-27T13:52:03 # ::file a_pmid_2139_2397_146.txt # ::snt Sequencing of the K-RAS gene revealed that none of these cell lines presents a K-RAS point mutation in codon 12, codon 13 or 61. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (r / reveal-01 :ARG0 (s / sequence-01 :ARG1 (g / gene :name (n2 / name :op1 "K-RAS") :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :ARG1 (p / present-01 :ARG0 (c / cell-line :quant (n3 / none) :mod (t / this)) :ARG1 (m / mutate-01 :ARG1 g :mod (p2 / point) :location (o / or :op1 (c2 / codon :mod "12") :op2 (c3 / codon :mod "13") :op3 (c4 / codon :mod "61"))))) # ::id a_pmid_2139_2397.147 # ::date 2015-05-29T03:10:45 # ::file a_pmid_2139_2397_147.txt # ::snt To investigate whether mutated K-RASV12 could upregulate YB-1 phosphorylation, we introduced mutated K-RAS into K-RASwt, SKBr3 and MCF-7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (i / introduce-02 :ARG0 (w / we) :ARG1 "g" :ARG2 (a / and :op1 (c / cell-line :name (n4 / name :op1 "SKBr3")) :op2 (c2 / cell-line :name (n5 / name :op1 "MCF-7")) :mod (g2 / gene :name (n3 / name :op1 "K-RAS") :mod (w2 / wild-type) :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :purpose (i2 / investigate-01 :ARG0 w :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (u / upregulate-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (p / protein :name (n2 / name :op1 "YB-1") :xref (x2 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :ARG2 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))))) # ::id a_pmid_2139_2397.148 # ::date 2015-05-29T03:19:16 # ::file a_pmid_2139_2397_148.txt # ::snt Cells were transiently transfected with either a control pEGFP-C1 vector (indicated as con.-vector) or a vector expressing mutated K-RAS, pEGFP-C1/K-RASV12 (indicated as K-RASV12). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (t / transfect-01 :ARG1 (c / cell) :ARG2 (o / or :op1 (v / vector :name (n2 / name :op1 "pEGFP-C1") :mod (c2 / control) :ARG1-of (i / indicate-01 :ARG0 (v4 / vector :name (n5 / name :op1 "con.-vector")))) :op2 (v2 / vector :name (n4 / name :op1 "pEGFP-C1/K-RASV12") :ARG3-of (e2 / express-03 :ARG1 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :ARG1-of (i2 / indicate-01 :ARG0 (v3 / vector :name (n3 / name :op1 "K-RASV12"))))) :ARG1-of (t2 / transient-02)) # ::id a_pmid_2139_2397.149 # ::date 2015-05-29T03:32:44 # ::file a_pmid_2139_2397_149.txt # ::snt Fluorescence images of living cells transfected with con.-vector and K-RASV12 revealed that GFP in K-RASV12 vector-transfected cells was localized to the plasma membrane, but that in con.-vector-transfected cells it was not (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / reveal-01 :ARG0 (i / image-101 :ARG1 (a / and :op1 (c / cell :ARG0-of (l / live-01) :ARG1-of (t / transfect-01 :ARG2 (v / vector :name (n2 / name :op1 "con.-vector")))) :op2 (c3 / cell :ARG0-of l :ARG1-of (t2 / transfect-01 :ARG2 (v2 / vector :name (n / name :op1 "K-RASV12")))))) :ARG1 (c2 / contrast-01 :ARG1 (l2 / localize-01 :ARG1 (p / protein :name (n3 / name :op1 "GFP") :xref (x / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")) :location (m / membrane :mod (p2 / plasma) :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :location (c4 / cell :ARG2-of t2)) :ARG2 (l3 / localize-01 :polarity "-" :ARG1 p :location (c5 / cell :ARG2-of t) :location m)) :mod (f / fluorescence) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3A"))) # ::id a_pmid_2139_2397.150 # ::date 2015-05-29T03:43:20 # ::file a_pmid_2139_2397_150.txt # ::snt This is due to posttranslational modification and membrane association of K-Ras (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 8, 2015 (c / cause-01 :ARG0 (a / and :op1 (m / modify-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :time (a2 / after :op1 (t2 / translate-02 :ARG1 e))) :op2 (a3 / associate-01 :ARG1 e :ARG2 (m2 / membrane :xref (x1 / xref :value "GO:0016020" :prob "0.8")))) :ARG1 (t / this) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id a_pmid_2139_2397.151 # ::date 2015-05-29T03:46:30 # ::file a_pmid_2139_2397_151.txt # ::snt In con.-vector-transfected cells, GFP expression was not accumulated at the cell membrane, but rather it was equally distributed throughout the cytoplasm. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (i / instead-of-91 :ARG1 (d / distribute-01 :ARG1 "e" :location (c / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :mod (r / rather) :ARG1-of (e2 / equal-01)) :ARG2 (a / accumulate-01 :polarity "-" :ARG0 (m / membrane :part-of "c2" :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "GFP") :xref (x / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")) :ARG3 (c2 / cell :ARG1-of (t / transfect-01 :ARG2 (v / vector :name (n2 / name :op1 "con.-vector"))))))) # ::id a_pmid_2139_2397.152 # ::date 2015-05-29T03:53:52 # ::file a_pmid_2139_2397_152.txt # ::snt The efficiency of transfection was verified by immunoblotting as well (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (v / verify-01 :ARG1 (e / efficient-01 :ARG1 (t / transfect-01)) :mod (a / as-well) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B")) :manner (i / immunoblot-01)) # ::id a_pmid_2139_2397.153 # ::date 2015-05-29T03:58:18 # ::file a_pmid_2139_2397_153.txt # ::snt In cells transfected with K-RASV12 vector, the expression of K-Ras (21 kDa) resulted in a shift of GFP from 27 kDa to 48 kDa (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / result-01 :ARG1 (e2 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "K-Ras") :quant (m2 / mass-quantity :quant "21" :unit (k / kilodalton)) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG3 (c / cell :ARG1-of (t / transfect-01 :ARG2 (v / vector :name (n2 / name :op1 "K-RASV12"))))) :ARG2 (s / shift-01 :ARG1 (p / protein :name (n3 / name :op1 "GFP") :xref (x1 / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")) :ARG2 (m4 / mass-quantity :quant "48" :unit k) :ARG3 (m3 / mass-quantity :quant "27" :unit k)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id a_pmid_2139_2397.154 # ::date 2015-05-29T04:06:56 # ::file a_pmid_2139_2397_154.txt # ::snt The expression of GFP-tagged K-Ras with a molecular weight of 48 kDa was further confirmed by stripping the anti-GFP antibody from the membrane and reincubating the blots with a K-Ras antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (c / confirm-01 :ARG1 (e2 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "K-Ras") :ARG1-of (t / tag-01 :ARG2 (p / protein :name (n2 / name :op1 "GFP") :xref (x1 / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342"))) :mod (w / weight :mod (m / molecule) :quant (m2 / mass-quantity :quant "48" :unit (k / kilodalton))) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :degree (f / further) :manner (a2 / and :op1 (s / strip-01 :ARG1 (a3 / antibody :ARG0-of (c2 / counter-01 :ARG1 p)) :ARG2 (m3 / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :op2 (i / incubate-01 :ARG1 (b / blot) :ARG2 (a4 / antibody :ARG0-of (c3 / counter-01 :ARG1 e)) :mod (a5 / again)))) # ::id a_pmid_2139_2397.155 # ::date 2015-05-29T04:16:28 # ::file a_pmid_2139_2397_155.txt # ::snt In line with our observations of MDA-MB-231 cells, exogenous expression of K-RASV12 in K-RASwt, SKBr3 and MCF-7 cells resulted in markedly enhanced basal phosphorylation of YB-1 at S102 (Figure 3B), which prevents further enhancement of phosphorylation by IR (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / result-01 :ARG1 (e2 / express-03 :ARG1 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")) :ARG3 (a / and :op1 (c / cell-line :name (n3 / name :op1 "SKBr3")) :op2 (c2 / cell-line :name (n4 / name :op1 "MCF-7")) :mod (g2 / gene :name (n2 / name :op1 "K-RAS") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :mod (e3 / exogenous)) :ARG2 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "102" :name (n5 / name :op1 "serine") :part-of (p2 / protein :name (n6 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :mod (b / basal) :ARG1-of (e5 / enhance-01 :manner (m2 / marked)) :ARG0-of (p3 / prevent-01 :ARG1 (e6 / enhance-01 :ARG1 p :ARG2 (r3 / radiate-01 :ARG0-of (i / ionize-01)) :degree (f2 / further)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "3C")))) :ARG1-of (r2 / resemble-01 :ARG2 (o / observe-01 :ARG0 (w2 / we) :ARG1 (c3 / cell-line :name (n7 / name :op1 "MDA-MB-231")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id a_pmid_2139_2397.156 # ::date 2015-05-29T04:36:53 # ::file a_pmid_2139_2397_156.txt # ::snt Thus, these data support the hypothesis that in cells expressing mutated K-RAS, the basal phosphorylation of YB-1 is constitutively enhanced and cannot be further stimulated by IR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / infer-01 :ARG1 (s / support-01 :ARG0 (d / data :mod (t2 / this)) :ARG1 (h2 / hypothesize-01 :ARG1 (a / and :op1 (e2 / enhance-01 :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (b / basal)) :mod (c / constitutive)) :op2 (p2 / possible-01 :polarity "-" :ARG1 (s2 / stimulate-01 :ARG1 p :ARG2 (r / radiate-01 :ARG0-of (i2 / ionize-01)) :degree (f / further))) :location (c2 / cell :ARG3-of (e3 / express-03 :ARG1 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))))))) # ::id a_pmid_2139_2397.157 # ::date 2015-05-29T04:43:20 # ::file a_pmid_2139_2397_157.txt # ::snt IR-induced YB-1 phosphorylation is mediated by erbB1-dependent PI3K/Akt and MAPK/ERK pathways # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / mediate-01 :ARG0 (a / and :op1 (p2 / pathway :name (n / name :op1 "PI3K/AKT")) :op2 (p4 / pathway :name (n4 / name :op1 "MAPK/ERK")) :ARG0-of (d / depend-01 :ARG1 (p5 / protein :name (n5 / name :op1 "erbB1") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.633")))) :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1") :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2-of (i / induce-01 :ARG0 (r / radiate-01 :ARG0-of (i2 / ionize-01))))) # ::id a_pmid_2139_2397.158 # ::date 2015-05-29T04:46:42 # ::file a_pmid_2139_2397_158.txt # ::snt The phosphorylation of YB-1 at S102 in response to stimulation with EGF has been described as being dependent on p90 ribosomal S6 kinase [11]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / describe-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "102" :name (n2 / name :op1 "serine") :part-of (p2 / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2-of (r / respond-01 :ARG1 (s / stimulate-01 :ARG1 p2 :ARG2 (p4 / protein :name (n3 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :ARG2 (d2 / depend-01 :ARG0 p :ARG1 (e / enzyme :name (n5 / name :op1 "p90" :op2 "ribosomal" :op3 "S6" :op4 "kinase"))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "11")))) # ::id a_pmid_2139_2397.159 # ::date 2015-05-29T04:55:41 # ::file a_pmid_2139_2397_159.txt # ::snt In that study [11], Stratford et al. showed that the stimulation of SUM149 breast cancer cells with serum, EGF and phorbol 12-myristate 13-acetate (PMA) leads to phosphorylation of YB-1 at S102, which is dependent on the MAP kinase pathway [11]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (a / and :op1 (p2 / person :name (n2 / name :op1 "Stratford")) :op2 (p3 / person :mod (o / other))) :ARG1 (l / lead-03 :ARG0 (s2 / stimulate-01 :ARG1 (c / cell-line :name (n3 / name :op1 "SUM149") :source (d4 / disease :wiki "Breast_cancer" :name (n9 / name :op1 "breast" :op2 "cancer"))) :ARG2 (a2 / and :op1 (s3 / serum) :op2 (p7 / protein :name (n4 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op3 (s5 / small-molecule :name (n5 / name :op1 "phorbol" :op2 "12-myristate" :op3 "13-acetate") :ARG1-of (d2 / describe-01 :ARG2 (s6 / small-molecule :name (n6 / name :op1 "PMA") :xref (x2 / xref :value "PUBCHEM:4792" :prob "16.591986"))) :xref (x3 / xref :value "PUBCHEM:4792" :prob "12.67005")))) :ARG2 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "102" :name (n7 / name :op1 "serine") :part-of (p4 / protein :name (n / name :op1 "YB-1") :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG0-of (d / depend-01 :ARG1 (p5 / pathway :name (n8 / name :op1 "MAP" :op2 "kinase"))))) :medium (s7 / study-01 :mod (t / that) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "11")))) :ARG1-of d3) # ::id a_pmid_2139_2397.161 # ::date 2015-05-29T05:03:47 # ::file a_pmid_2139_2397_161.txt # ::snt Because we and others have shown that IR induces activation of erbB1 in a ligand-independent manner [24,25], we tested whether the IR-induced YB-1 phosphorylation shown in Figure 1D could be blocked by erbB1 tyrosine kinase inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (t2 / test-01 :ARG0 (w / we) :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (b / block-01 :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2-of (i2 / induce-01 :ARG0 (r / radiate-01 :ARG0-of (i4 / ionize-01))) :ARG1-of (s / show-01 :medium (f / figure :mod "1D"))) :ARG3 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "erB1" :op2 "tyrosine" :op3 "kinase")))))) :ARG1-of (c / cause-01 :ARG0 (s2 / show-01 :ARG0 (a / and :op1 (w2 / we) :op2 (p5 / person :mod (o / other))) :ARG1 (i3 / induce-01 :ARG0 r :ARG2 (a2 / activate-01 :ARG1 e) :manner (d / depend-01 :polarity "-" :ARG0 a2 :ARG1 (l / ligand))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "24")) :op2 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 "25"))))))) # ::id a_pmid_2139_2397.162 # ::date 2015-05-29T05:20:55 # ::file a_pmid_2139_2397_162.txt # ::snt To test this hypothesis, the effect of the erbB1-RTK inhibitor erlotinib on YB-1 phosphorylation was analyzed in whole cell extracts as well as in cytoplasmic and nuclear fractions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (a / analyze-01 :ARG1 (a2 / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "erlotinib") :ARG0-of (i / inhibit-01 :ARG1 (p3 / pathway :name (n4 / name :op1 "erbB1-RTK"))) :xref (x3 / xref :value "PUBCHEM:176870" :prob "16.13064")) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")))) :location (a3 / and :op1 (e / extract-01 :ARG1 (c / cell :mod (w / whole))) :op2 (f / fraction :part-of (c2 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8"))) :op3 (f2 / fraction :part-of (n3 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")))) :purpose (t3 / test-01 :ARG1 (t / thing :ARG1-of (h / hypothesize-01) :mod (t4 / this)))) # ::id a_pmid_2139_2397.163 # ::date 2015-05-29T05:28:37 # ::file a_pmid_2139_2397_163.txt # ::snt Pretreatment of SKBr3 cells with erlotinib resulted in complete inhibition of YB-1 phosphorylation in whole cell extract (Figure 4A) as well as in cytoplasmic and nuclear fractions (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (r / result-01 :ARG1 (p3 / pretreat-01 :ARG1 (c / cell-line :name (n / name :op1 "SKBr3")) :ARG3 (s / small-molecule :name (n2 / name :op1 "erlotinib") :xref (x3 / xref :value "PUBCHEM:176870" :prob "16.13064"))) :ARG2 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :ARG1-of (c2 / complete-02) :location (a / and :op1 (e / extract-01 :ARG1 (c3 / cell :mod (w / whole)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) :op2 (a2 / and :op1 (f2 / fraction :part-of (c4 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8"))) :op2 (f3 / fraction :part-of (n4 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8"))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure :mod "4B")))))) # ::id a_pmid_2139_2397.164 # ::date 2015-05-29T05:33:47 # ::file a_pmid_2139_2397_164.txt # ::snt As expected, erlotinib also blocked basal- and radiation-induced P-Akt and P-ERK1/2 in these cells (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (b / block-01 :ARG0 (s / small-molecule :name (n / name :op1 "erlotinib") :xref (x3 / xref :value "PUBCHEM:176870" :prob "16.13064")) :ARG1 (a / and :op1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "Akt") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op2 (s2 / slash :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :mod (b2 / basal) :ARG1-of (p / phosphorylate-01)) :op2 (a4 / and :op1 e :op2 s2 :ARG1-of p :ARG2-of (i / induce-01 :ARG0 (r / radiate-01)))) :location (c / cell :mod (t / this)) :ARG1-of (e4 / expect-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A")) :mod (a2 / also)) # ::id a_pmid_2139_2397.165 # ::date 2015-05-29T05:39:05 # ::file a_pmid_2139_2397_165.txt # ::snt To rule out off-target effects of erlotinib, the efficacy of the highly specific erbB1-RTK inhibitor BIBX1382BS [38] on radiation-induced YB-1 phosphorylation was tested in cytoplasmic and nuclear fractions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (t2 / test-01 :ARG1 (e / efficient-01 :ARG1 (s3 / small-molecule :wiki "-" :name (n2 / name :op1 "BIBX1382BS") :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :wiki "-" :name (n5 / name :op1 "erbB1-RTK") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.223"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "38"))) :ARG1-of (s / specific-02 :ARG1-of (h / high-02)) :xref (x4 / xref :value "PUBCHEM:16760413" :prob "19.266134")) :ARG2 (p / phosphorylate-01 :ARG1 (p2 / protein :wiki "Y_box_binding_protein_1" :name (n / name :op1 "YB-1") :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2-of (i2 / induce-01 :ARG0 (r / radiate-01)))) :location (a2 / and :op1 (f / fraction :part-of (c2 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8"))) :op2 (f2 / fraction :mod (n3 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")))) :purpose (r2 / rule-out-02 :ARG1 (a3 / affect-01 :ARG0 (s2 / small-molecule :wiki "Erlotinib" :name (n4 / name :op1 "erlotinib") :xref (x5 / xref :value "PUBCHEM:176870" :prob "16.13064")) :mod (o / off-target)))) # ::id a_pmid_2139_2397.166 # ::date 2015-05-29T05:44:26 # ::file a_pmid_2139_2397_166.txt # ::snt EGF was included as positive control. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / include-01 :ARG1 (p2 / protein :name (n / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :condition (c / control :mod (p / positive))) # ::id a_pmid_2139_2397.167 # ::date 2015-05-29T05:45:39 # ::file a_pmid_2139_2397_167.txt # ::snt As shown at the bottom of Figure 4B, in both cytoplasmic and nuclear protein fractions treatment with BIBX1382BS resulted in a marked reduction of YB-1 phosphorylation stimulated by IR as well as EGF treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / result-01 :ARG1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "BIBX1382BS") :xref (x4 / xref :value "PUBCHEM:16760413" :prob "19.266134"))) :ARG2 (r2 / reduce-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :mod (m2 / marked) :ARG1-of (s / stimulate-01 :ARG0 (a / and :op1 (r3 / radiate-01 :ARG0-of (i / ionize-01)) :op2 (t2 / treat-04 :ARG2 (p5 / protein :name (n4 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))))) :ARG1-of (s4 / show-01 :medium (b / bottom :mod (f / figure :mod "4B"))) :location (a2 / and :op1 (f2 / fraction :part-of (p3 / protein :mod (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")))) :op2 (f3 / fraction :part-of (p4 / protein :mod (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")))) :mod (b2 / both))) # ::id a_pmid_2139_2397.168 # ::date 2015-05-29T05:52:02 # ::file a_pmid_2139_2397_168.txt # ::snt These data indicate that erbB1-RTK activity is necessary for radiation-induced YB-1 phosphorylation, and this is most likely due to activation of the PI3K/Akt and MAPK/ERK pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a2 / and :op1 (i / indicate-01 :ARG0 (d / data :mod (t / this)) :ARG1 (n / need-01 :ARG0 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2-of (i2 / induce-01 :ARG0 (r / radiate-01))) :ARG1 (a / activate-01 :ARG1 (p5 / pathway :name (n5 / name :op1 "erbB1-RTK"))))) :op2 (l / likely-01 :ARG1 (c / cause-01 :ARG0 (a3 / activate-01 :ARG1 (a4 / and :op1 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT")) :op2 (p4 / pathway :name (n4 / name :op1 "MAPK/ERK")))) :ARG1 n) :degree (m / most))) # ::id a_pmid_2139_2397.169 # ::date 2015-05-29T05:57:58 # ::file a_pmid_2139_2397_169.txt # ::snt To test the function of PI3K/Akt and MAPK/ERK pathways in YB-1 phosphorylation, we further investigated whether the inhibitors of PI3K, Akt and MAPK affect YB-1 phosphorylation in irradiated cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i2 / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :mode "interrogative" :ARG0 (a4 / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :op3 (m3 / molecular-physical-entity :ARG0-of (i5 / inhibit-01 :ARG1 (p5 / protein-family :name (n5 / name :op1 "MAPK"))))) :ARG1 (p2 / phosphorylate-01 :ARG1 (p4 / protein :name (n6 / name :op1 "YB-1") :xref (x2 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :location (c / cell :ARG1-of (i3 / irradiate-01))) :degree (f / further) :purpose (t / test-01 :ARG0 w :ARG1 (f2 / function-01 :ARG0 (a3 / and :op1 (p / pathway :name (n / name :op1 "PI3K/Akt")) :op2 (p3 / pathway :name (n2 / name :op1 "MAPK/ERK"))) :ARG1 p2))) # ::id a_pmid_2139_2397.170 # ::date 2015-05-29T06:03:30 # ::file a_pmid_2139_2397_170.txt # ::snt The data shown in Figures 4C and 4D indicate that treatment with either of the inhibitors markedly reduced the phosphorylation of YB-1 at S102. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (i2 / indicate-01 :ARG0 (d / data :ARG1-of (s2 / show-01 :medium (a / and :op1 (f / figure :mod "4C") :op2 (f2 / figure :mod "4D")))) :ARG1 (r / reduce-01 :ARG0 (t / treat-04 :ARG2 (m2 / molecular-physical-entity :mod (e / either) :ARG0-of (i / inhibit-01))) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "102" :name (n / name :op1 "serine") :part-of (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :manner (m / marked))) # ::id a_pmid_2139_2397.171 # ::date 2015-05-29T06:09:34 # ::file a_pmid_2139_2397_171.txt # ::snt However, optimal inhibition was observed when cells were treated with a combination of PI3K and MEK inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (o / observe-01 :ARG1 (i / inhibit-01 :mod (o2 / optimal)) :time (t2 / treat-04 :ARG1 (c / cell) :ARG2 (c2 / combine-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "PI3K")))) :ARG2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))))))) # ::id a_pmid_2139_2397.172 # ::date 2015-05-29T06:14:22 # ::file a_pmid_2139_2397_172.txt # ::snt Constitutive YB-1 phosphorylation due to K-RAS mutation depends on erbB1 and downstream PI3K/Akt and MAPK/ERK pathways # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (d / depend-01 :ARG0 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (c / constitutive) :ARG1-of (c2 / cause-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n4 / name :op1 "K-RAS") :xref (x2 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))))) :ARG1 (a / and :op1 (p4 / protein :name (n5 / name :op1 "erbB1") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.633")) :op2 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT") :location (d2 / downstream)) :op3 (p5 / pathway :name (n6 / name :op1 "MAPK/ERK") :location d2))) # ::id a_pmid_2139_2397.173 # ::date 2015-05-29T06:17:55 # ::file a_pmid_2139_2397_173.txt # ::snt As IR-induced YB-1 phosphorylation was shown to be dependent on erbB1, PI3K/Akt and MAPK/ERK, we further investigated whether K-RASmt-dependent constitutive phosphorylation of YB-1 might be sensitive to the inhibition of erbB1, PI3K and MEK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (s / sensitive-03 :ARG0 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "YB-1") :xref (x3 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (c / constitutive) :ARG0-of (d / depend-01 :ARG1 (g / gene :name (n2 / name :op1 "K-RAS") :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))) :ARG1 (i2 / inhibit-01 :ARG1 (a / and :op1 (p5 / protein :name (n5 / name :op1 "erbB1") :xref (x4 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.633")) :op2 (e / enzyme :name (n6 / name :op1 "PI3K") :xref (x2 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op3 (e2 / enzyme :name (n3 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))))) :degree (f / further) :ARG1-of (c2 / cause-01 :ARG0 (s2 / show-01 :ARG1 (d2 / depend-01 :ARG0 (p6 / phosphorylate-01 :ARG1 p4 :ARG2-of (i3 / induce-01 :ARG0 (r / radiate-01 :ARG0-of (i4 / ionize-01)))) :ARG1 (a2 / and :op1 p5 :op2 (p2 / pathway :name (n / name :op1 "PI3K/Akt")) :op3 (p7 / pathway :name (n8 / name :op1 "MAPK/ERK"))))))) # ::id a_pmid_2139_2397.174 # ::date 2015-05-29T07:05:42 # ::file a_pmid_2139_2397_174.txt # ::snt To this end, K-RASwt MCF-7 cells were transiently transfected with con.-vector or K-RASV12 vector, and 48 hours after transfection the cells were treated with the erbB1 inhibitor erlotinib, the PI3K inhibitor LY294002 or the MEK inhibitor PD98059 for 2 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (t4 / transfect-01 :ARG1 (c / cell-line :name (n3 / name :op1 "MCF-7") :mod (g / gene :name (n / name :op1 "K-RAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :ARG2 (o / or :op1 (v2 / vector :name (n2 / name :op1 "con.-vector")) :op2 (v / vector :name (n4 / name :op1 "K-RASV12"))) :ARG1-of (t5 / transient-02)) :op2 (t / treat-04 :ARG1 c :ARG2 (a2 / and :op1 (s / small-molecule :name (n5 / name :op1 "erlotinib") :ARG0-of (i / inhibit-01 :ARG1 (p / protein :name (n6 / name :op1 "erbB1") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.633"))) :xref (x4 / xref :value "PUBCHEM:176870" :prob "16.13064")) :op2 (s3 / small-molecule :name (n7 / name :op1 "LY294002") :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n9 / name :op1 "PI3K"))) :xref (x2 / xref :value "PUBCHEM:3973" :prob "18.86067")) :op3 (s2 / small-molecule :name (n8 / name :op1 "PD98059") :ARG0-of (i3 / inhibit-01 :ARG1 (p3 / protein-family :name (n10 / name :op1 "MEK"))) :xref (x3 / xref :value "PUBCHEM:4713" :prob "18.349844"))) :time (a3 / after :op1 t4 :quant (t2 / temporal-quantity :quant "48" :unit (h / hour))) :duration (t3 / temporal-quantity :quant "2" :unit h)) :purpose (t6 / this)) # ::id a_pmid_2139_2397.175 # ::date 2015-05-29T07:16:08 # ::file a_pmid_2139_2397_175.txt # ::snt Similar to the results shown in Figure 3, overexpression of K-RASV12 resulted in an about 2.5-fold stimulation of YB-1 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r2 / result-01 :ARG1 (o / overexpress-01 :ARG1 (g / gene :name (n2 / name :op1 "K-RAS") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :ARG2 (s / stimulate-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :degree (a / about :op1 (p3 / product-of :op1 "2.5"))) :ARG1-of (r / resemble-01 :ARG2 (t / thing :ARG2-of (r3 / result-01) :ARG1-of (s2 / show-01 :medium (f / figure :mod "3"))))) # ::id a_pmid_2139_2397.176 # ::date 2015-05-29T07:21:11 # ::file a_pmid_2139_2397_176.txt # ::snt Erlotinib reduced mutated K-RAS V12-induced YB-1 phosphorylation by about 50%, while the PI3K inhibitor and the MEK inhibitor reduced K-RASV12-induced YB-1 phosphorylation to the control level. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "erlotinib") :xref (x2 / xref :value "PUBCHEM:176870" :prob "16.13064")) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2-of (i2 / induce-01 :ARG0 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))) :ARG2 (p4 / percentage-entity :value "50")) :ARG2 (r2 / reduce-01 :ARG0 (a / and :op1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K")))) :op2 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p5 / protein-family :name (n2 / name :op1 "MEK"))))) :ARG1 p2 :ARG4 (l / level :mod (c2 / control)))) # ::id a_pmid_2139_2397.177 # ::date 2015-05-29T07:29:08 # ::file a_pmid_2139_2397_177.txt # ::snt However, the combination of PD98059 and LY294002 (PD/LY) blocked basal and K-RAS V12-induced YB-1 phosphorylation completely (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (h / have-concession-91 :ARG1 (b / block-01 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "PD98059") :xref (x3 / xref :value "PUBCHEM:4713" :prob "18.349844")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "LY294002") :xref (x2 / xref :value "PUBCHEM:3973" :prob "18.86067"))) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (b2 / basal)) :op2 (p3 / phosphorylate-01 :ARG1 p2 :ARG2-of (i / induce-01 :ARG0 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))))) :ARG1-of (c2 / complete-02)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id a_pmid_2139_2397.178 # ::date 2015-05-29T07:34:42 # ::file a_pmid_2139_2397_178.txt # ::snt These data indicate that phosphorylation of YB-1 due to mutation of K-RAS in part depends on activation of erbB1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (i / indicate-01 :ARG0 (d / data :mod (t / this)) :ARG1 (d2 / depend-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG1-of (c / cause-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-RAS") :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))))) :ARG1 (a / activate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "erbB1") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.633"))) :degree (p4 / part))) # ::id a_pmid_2139_2397.179 # ::date 2015-05-29T07:37:35 # ::file a_pmid_2139_2397_179.txt # ::snt This is most likely mediated by autocrine production of ligands and is in part independent of erbB1, but it is dependent on activation of the PI3K/Akt and MAPK/ERK pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c / contrast-01 :ARG1 (a / and :op1 (l / likely-01 :ARG1 (m2 / mediate-01 :ARG0 (p2 / produce-01 :ARG1 (l2 / ligand) :mod (a2 / autocrine)) :ARG1 (t / this)) :degree (m / most)) :op2 (d / depend-01 :polarity "-" :ARG0 t :ARG1 (p3 / protein :name (n2 / name :op1 "erbB1") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.633")) :degree (p5 / part))) :ARG2 (d2 / depend-01 :ARG0 t :ARG1 (a3 / activate-01 :ARG1 (a4 / and :op1 (p / pathway :name (n / name :op1 "PI3K/Akt")) :op2 (p4 / pathway :name (n3 / name :op1 "MAPK/ERK")))))) # ::id a_pmid_2139_2397.180 # ::date 2015-05-29T07:41:26 # ::file a_pmid_2139_2397_180.txt # ::snt Because K-Ras strongly induces YB-1 phosphorylation when it is mutated (Figures 3 and 5A), we next analyzed whether phosphorylation of YB-1 in K-RASwt cells after irradiation or stimulation with EGF depends on K-Ras expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (d / depend-01 :mode "interrogative" :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :location (c / cell :mod (g / gene :name (n3 / name :op1 "K-RAS") :mod (w2 / wild-type) :xref (x3 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")))) :ARG1 (e2 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :time (a2 / after :op1 (o / or :op1 (i / irradiate-01 :ARG1 c) :op2 (s / stimulate-01 :ARG1 c :ARG2 (p3 / protein :name (n7 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))))) :time (n5 / next) :ARG1-of (c2 / cause-01 :ARG0 (i2 / induce-01 :ARG0 e :ARG2 p :condition (m / mutate-01 :ARG2 e) :manner (s3 / strong)) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3") :op2 (f2 / figure :mod "5A"))))) # ::id a_pmid_2139_2397.181 # ::date 2015-05-29T07:48:43 # ::file a_pmid_2139_2397_181.txt # ::snt Therefore, following downregulation of K-Ras by siRNA, SKBr3 cells were irradiated or stimulated with EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / infer-01 :ARG1 (o / or :op1 (i2 / irradiate-01 :ARG1 (c / cell-line :name (n2 / name :op1 "SKBr3"))) :op2 (s / stimulate-01 :ARG1 c :ARG2 (p / protein :name (n3 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG1-of (f / follow-01 :ARG2 (d / downregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2 (n5 / nucleic-acid :name (n4 / name :op1 "siRNA")))))) # ::id a_pmid_2139_2397.182 # ::date 2015-05-29T07:52:14 # ::file a_pmid_2139_2397_182.txt # ::snt As shown in Figure 5B, downregulation of K-Ras did not affect either IR- or EGF-induced YB-1 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :polarity "-" :ARG0 (d / downregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG1 (o / or :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2-of (i / induce-01 :ARG0 (r / radiate-01 :ARG0-of (i3 / ionize-01)))) :op2 (p3 / phosphorylate-01 :ARG1 p2 :ARG2-of (i2 / induce-01 :ARG0 (p4 / protein :name (n4 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :ARG1-of (s3 / show-01 :medium (f / figure :mod "5B"))) # ::id a_pmid_2139_2397.183 # ::date 2015-05-29T07:57:28 # ::file a_pmid_2139_2397_183.txt # ::snt A lack of effect of K-RAS-siRNA on P-ERK1/2 was observed as well (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (o / observe-01 :ARG1 (l / lack-01 :ARG1 (a / affect-01 :ARG0 (n / nucleic-acid :name (n2 / name :op1 "siRNA") :mod (g / gene :name (n3 / name :op1 "K-RAS") :xref (x / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :ARG1 (s / slash :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n5 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1-of (p / phosphorylate-01)))) :manner (a2 / as-well) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id a_pmid_2139_2397.184 # ::date 2015-05-29T08:00:19 # ::file a_pmid_2139_2397_184.txt # ::snt YB-1 regulates repair of IR-induced DNA-DSB and postirradiation survival # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / regulate-01 :ARG0 (p / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG1 (a / and :op1 (r2 / repair-01 :ARG1 (e / event :name (n2 / name :op1 "DSB") :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")) :ARG2-of (i / induce-01 :ARG0 (r3 / radiate-01 :ARG0-of (i3 / ionize-01))))) :op2 (s2 / survive-01 :time (a2 / after :op1 (i2 / irradiate-01))))) # ::id a_pmid_2139_2397.185 # ::date 2015-05-29T08:05:03 # ::file a_pmid_2139_2397_185.txt # ::snt In addition to its function as a transcription factor, YB-1 is also involved in DNA repair, that is, base excision repair and mismatch repair [39]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (i / involve-01 :ARG1 (p / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2 (r / repair-01 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (e / event :name (n2 / name :op1 "base" :op2 "excision" :op3 "repair")) :op2 (e2 / event :name (n3 / name :op1 "mismatch" :op2 "repair"))))) :mod (a / also) :ARG1-of (a2 / add-02 :ARG2 (f / function-01 :ARG0 p :ARG1 (f2 / factor :ARG0-of (t / transcribe-01)))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "39")))) # ::id a_pmid_2139_2397.186 # ::date 2015-05-29T08:10:16 # ::file a_pmid_2139_2397_186.txt # ::snt In line with this function, it has been demonstrated that YB-1 binds to double-stranded, single-stranded and DNA-containing abasic sites [40]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (d / demonstrate-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2 (a / and :op1 (n2 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA") :mod (s / strand :mod (d3 / double))) :op2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :mod (s2 / strand :ARG1-of (s3 / single-02))) :op3 (d2 / dna-sequence :name (n3 / name :op1 "abasic" :op2 "site") :ARG0-of (c / contain-01 :ARG1 (n7 / nucleic-acid :wiki "DNA" :name (n8 / name :op1 "DNA")))))) :ARG1-of (d7 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "40"))) :ARG1-of (r / resemble-01 :ARG2 (f / function :mod (t / this)))) # ::id a_pmid_2139_2397.187 # ::date 2015-05-29T08:16:19 # ::file a_pmid_2139_2397_187.txt # ::snt So far, however, no data demonstrating the function of YB-1 in repair of IR-induced DNA-DSB and postirradiation survival exist. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (h / have-concession-91 :ARG1 (e / exist-01 :ARG1 (d / data :polarity "-" :ARG0-of (d2 / demonstrate-01 :ARG1 (f / function-01 :ARG0 (p / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG1 (a / and :op1 (r / repair-01 :ARG1 (e2 / event :name (n2 / name :op1 "DSB") :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))) :ARG2-of (i / induce-01 :ARG0 (r2 / radiate-01 :ARG0-of (i3 / ionize-01)))) :op2 (s3 / survive-01 :time (a2 / after :op1 (i2 / irradiate-01)))))))) :time (s / so-far)) # ::id a_pmid_2139_2397.188 # ::date 2015-05-29T08:20:53 # ::file a_pmid_2139_2397_188.txt # ::snt The function of erbB1 and its downstream pathways and the impact of mutated K-RAS on repair of DNA-DSB have been demonstrated previously [15,34,41,42]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (d / demonstrate-01 :ARG1 (a / and :op1 (f / function-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "erbB1") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.633")) :op2 (p3 / pathway :poss p2 :location (d2 / downstream)))) :op2 (i / impact-01 :ARG0 (g / gene :name (n / name :op1 "K-RAS") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001")) :ARG1 (r / repair-01 :ARG1 (e / event :name (n3 / name :op1 "DSB") :mod (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")))))) :time (p / previous) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and :op1 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "15")) :op2 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "34")) :op3 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "41")) :op4 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 "42"))))) # ::id a_pmid_2139_2397.189 # ::date 2015-05-29T08:27:58 # ::file a_pmid_2139_2397_189.txt # ::snt Therefore, we next asked whether the cells presenting a differential pattern of basal- and radiation-induced YB-1 phosphorylation additionally exert a differential sensitivity to IR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / cause-01 :ARG1 (a / ask-01 :ARG0 (w / we) :ARG1 (e / exert-01 :mode "interrogative" :ARG0 (c / cell :ARG0-of (p2 / present-01 :ARG1 (p3 / pattern :mod (d / differential) :topic (a3 / and :op1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :mod (b / basal)) :op2 (p5 / phosphorylate-01 :ARG1 p4 :ARG2-of (i2 / induce-01 :ARG0 (r / radiate-01))))))) :ARG1 (s / sensitive-03 :ARG0 c :ARG1 (r2 / radiate-01 :ARG0-of (i / ionize-01)) :mod d) :manner (a2 / additional)) :time (n / next))) # ::id a_pmid_2139_2397.190 # ::date 2015-05-29T08:43:16 # ::file a_pmid_2139_2397_190.txt # ::snt The results obtained by clonogenic assay indicate a differential response in terms of postirradiation survival of the cell lines analyzed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :ARG1-of (o / obtain-01 :manner (a3 / assay-01 :mod (c2 / clonogenic)))) :ARG1 (r2 / respond-01 :ARG2 (s / survive-01 :ARG0 (c / cell-line :ARG1-of (a2 / analyze-01)) :time (a / after :op1 (i2 / irradiate-01))) :ARG1-of (d / differ-02))) # ::id a_pmid_2139_2397.191 # ::date 2015-05-29T08:49:16 # ::file a_pmid_2139_2397_191.txt # ::snt The radiation dose, D37, which is required to reduce cell survival to 37%, is 1.95 Gy for SKBr3, 1.65 Gy for MDA-MB-23, 1.35 Gy for MCF-7 and 1.10 Gy for HBL100 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (e / equal-01 :ARG1 (d / dose-01 :ARG1 (r5 / radiate-01) :ARG1-of (r6 / require-01 :ARG0 (r7 / reduce-01 :ARG1 (s / survive-01 :ARG0 "c") :ARG4 (p2 / percentage-entity :value "37"))) :ARG1-of (l / label-01 :ARG2 (s2 / string-entity :value "D37"))) :ARG2 (a / and :op1 (r / radiation-quantity :quant "1.95" :unit (g / gray) :location (c / cell-line :name (n / name :op1 "SKBr3"))) :op2 (r2 / radiation-quantity :quant "1.65" :unit g :location (c2 / cell-line :name (n2 / name :op1 "MDA-MB-23"))) :op3 (r3 / radiation-quantity :quant "1.35" :unit g :location (c3 / cell-line :name (n3 / name :op1 "MCF-7"))) :op4 (r4 / radiation-quantity :quant "1.10" :unit g :location (c4 / cell-line :name (n4 / name :op1 "HBL100"))))) # ::id a_pmid_2139_2397.192 # ::date 2015-05-29T08:57:52 # ::file a_pmid_2139_2397_192.txt # ::snt We further investigated whether YB-1 activity is involved in the process of DNA-DSB repair and postirradiation survival. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / investigate-01 :ARG0 (w / we) :ARG1 (i2 / involve-01 :mode "interrogative" :ARG1 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :ARG2 (a2 / and :op1 (p2 / process-02 :ARG1 (r / repair-01 :ARG1 (e / event :name (n2 / name :op1 "DSB") :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))))) :op2 (s / survive-01 :time (a3 / after :op1 (i3 / irradiate-01))))) :degree (f / further)) # ::id a_pmid_2139_2397.193 # ::date 2015-05-29T09:02:30 # ::file a_pmid_2139_2397_193.txt # ::snt For this purpose, a siRNA approach was used. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (u / use-01 :ARG1 (a / approach-02 :mod (n2 / nucleic-acid :name (n / name :op1 "siRNA"))) :purpose (t / this)) # ::id a_pmid_2139_2397.194 # ::date 2015-05-29T09:04:07 # ::file a_pmid_2139_2397_194.txt # ::snt As shown in Figure 6, downregulation of YB-1 by siRNA, either in K-RASmt MDA-MB-231 or in K-RASwt SKBr3 cells, resulted in impaired repair of DNA-DSB as shown by enhanced residual γ-H2AX foci 24 hours after irradiation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (r / result-01 :ARG1 (d / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "YB-1") :xref (x3 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002")) :ARG2 (n11 / nucleic-acid :name (n3 / name :op1 "siRNA")) :location (o / or :op1 (c / cell-line :name (n4 / name :op1 "MDA-MB-231") :mod (g / gene :name (n6 / name :op1 "K-RAS") :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))) :op2 (c2 / cell-line :name (n5 / name :op1 "SKBr3") :mod (g2 / gene :name (n7 / name :op1 "K-RAS") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:Q7KZ06_HUMAN" :prob "1.001"))))) :ARG2 (r4 / repair-01 :ARG1 (e2 / event :name (n8 / name :op1 "DSB") :mod (n / nucleic-acid :wiki "DNA" :name (n10 / name :op1 "DNA"))) :ARG1-of (i / impair-01)) :ARG1-of (s2 / show-01 :medium (f2 / figure :mod "6")) :ARG1-of (s / show-01 :ARG0 (f / focus :mod (p2 / protein :name (n9 / name :op1 "γ-H2AX") :xref (x / xref :value "UNIPROT:H2AX_HUMAN" :prob "0.682")) :mod (r3 / residual) :ARG1-of (e3 / enhance-01)) :time (a / after :op1 (i2 / irradiate-01) :quant (t / temporal-quantity :quant "24" :unit (h / hour))))) # ::id a_pmid_2139_2397.195 # ::date 2015-05-29T09:13:13 # ::file a_pmid_2139_2397_195.txt # ::snt Interestingly, downregulating K-Ras resulted in enhanced frequency of residual DSB to the level observed with YB-1 siRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (r / result-01 :ARG1 (d / downregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG2 (h / have-frequency-91 :ARG1 (e3 / event :name (n2 / name :op1 "DSB") :mod (r3 / residual)) :ARG1-of (e2 / enhance-01 :ARG3 (l / level :ARG1-of (o / observe-01 :location (n5 / nucleic-acid :name (n3 / name :op1 "siRNA") :mod (p / protein :name (n4 / name :op1 "YB-1") :xref (x1 / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))))))) :ARG2-of (i / interest-01)) # ::id a_pmid_2139_2397.196 # ::date 2015-05-29T09:13:52 # ::file a_pmid_2139_2397_196.txt # ::snt Likewise, siRNA targeting of YB-1 increased radiation sensitivity tested in MDA-MB-231 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / increase-01 :ARG0 (t / target-01 :ARG0 (n4 / nucleic-acid :name (n2 / name :op1 "siRNA")) :ARG1 (p / protein :name (n / name :op1 "YB-1") :xref (x / xref :value "UNIPROT:YBOX1_HUMAN" :prob "1.002"))) :ARG1 (s / sensitive-03 :ARG1 (r / radiate-01) :ARG2-of (t2 / test-01 :ARG1 (c / cell-line :name (n3 / name :op1 "MDA-MB-231")))) :ARG1-of (r3 / resemble-01)) # ::id a_pmid_2169_9731.11 # ::date 2015-05-20T09:32:36 # ::file a_pmid_2169_9731_11.txt # ::snt Primary macrophages from both naïve and lung-tumor bearing mice stimulated epithelial cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (s / stimulate-01 :ARG0 (m / macrophage :mod (p2 / primary) :source (a / and :op1 (m2 / mouse :mod (n / naive)) :op2 (m3 / mouse :ARG0-of (b / bear-01 :ARG1 (t / tumor :mod (l / lung)))))) :ARG1 (p / proliferate-01 :ARG0 (c / cell :mod (e / epithelium)))) # ::id a_pmid_2169_9731.12 # ::date 2015-05-20T09:37:16 # ::file a_pmid_2169_9731_12.txt # ::snt The lungs of tumor-bearing mice contained 3.5-times more IGF-1 than naïve littermates, and media conditioned by freshly isolated tumor-educated macrophages contained more IGF-1 than media conditioned by naïve macrophages; IL-4 stimulated IGF-1 production by both macrophage subsets. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (a / and :op1 (c / contain-01 :ARG0 (l / lung :part-of (m2 / mouse :ARG0-of (b / bear-01 :ARG1 (t / tumor)))) :ARG1 (p2 / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :compared-to (l2 / littermate :mod (n2 / naive)) :quant (m3 / more :degree (p / product-of :op1 "3.5"))) :op2 (c2 / contain-01 :ARG0 (m4 / medium :ARG1-of (c3 / condition-01 :ARG0 (m5 / macrophage :ARG1-of (e / educate-01 :ARG0 (t2 / tumor)) :ARG1-of (i / isolate-01 :ARG1-of (f / fresh-04))))) :ARG1 p2 :compared-to (m6 / medium :ARG1-of (c4 / condition-01 :ARG0 (m7 / macrophage :mod (n3 / naive)))) :quant (m9 / more))) :snt2 (s / stimulate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "IL-4") :xref (x1 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :ARG1 (p5 / produce-01 :ARG0 (s2 / subset :part-of (m8 / macrophage) :mod (b2 / both)) :ARG1 (p4 / protein :name (n5 / name :op1 "IGF-1") :xref (x2 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))))) # ::id a_pmid_2169_9731.13 # ::date 2015-05-20T10:11:54 # ::file a_pmid_2169_9731_13.txt # ::snt The ability of macrophage conditioned media to stimulate neoplastic proliferation correlated with media IGF-1 levels, and recombinant IGF-1 alone was sufficient to induce epithelial proliferation in all cell lines evaluated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / suffice-01 :ARG0 (c4 / capable-01 :ARG1 "m" :ARG2 (s2 / stimulate-01 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :ARG1 (p2 / proliferate-01 :ARG0 (t / tumor) :ARG1-of (c2 / correlate-01 :ARG2 (a / and :op1 (l / level :quant-of (p3 / protein :name (n2 / name :op1 "IGF-1") :mod (m3 / medium) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :op2 (p4 / protein :name (n3 / name :op1 "IGF-1") :mod (a2 / alone) :ARG3-of (r2 / recombine-01) :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))))))) :ARG1 (i / induce-01 :ARG0 c4 :ARG2 (p5 / proliferate-01 :ARG0 (e / epithelium)) :location (c5 / cell-line :ARG1-of (e2 / evaluate-01) :mod (a3 / all)))) # ::id a_pmid_2169_9731.14 # ::date 2015-05-20T10:54:48 # ::file a_pmid_2169_9731_14.txt # ::snt Macrophage-conditioned media and IGF-1 stimulated lung tumor cell growth in an additive manner, while EGF had no effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (c3 / contrast-01 :ARG1 (s / stimulate-01 :ARG0 (a / and :op1 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :op2 (p / protein :name (n / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG1 (g / grow-01 :ARG1 (c2 / cell :mod (t / tumor :mod (l / lung)))) :manner (a2 / additive)) :ARG2 (a3 / affect-01 :polarity "-" :ARG0 (p2 / protein :name (n2 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 g)) # ::id a_pmid_2169_9731.15 # ::date 2015-05-20T11:08:13 # ::file a_pmid_2169_9731_15.txt # ::snt Macrophage-derived factors increased p-Erk1/2, p-Akt and cyclin D1 levels in neoplastic cells, and the combined inhibition of both MEK and PI3K ablated macrophage-mediated increases in epithelial growth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (a / and :op1 (i / increase-01 :ARG0 (f / factor :ARG1-of (d / derive-01 :ARG2 (m3 / macrophage))) :ARG1 (a2 / and :op1 (l / level :quant-of (e4 / enzyme :name (n / name :op1 "Erk1/2") :ARG3-of (p / phosphorylate-01))) :op2 (l2 / level :quant-of (e5 / enzyme :name (n2 / name :op1 "Akt") :ARG3-of p :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :op3 (l3 / level :quant-of (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D1") :xref (x2 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")))) :location (c / cell :mod (t / tumor))) :op2 (a3 / ablate-01 :ARG1 (i3 / increase-01 :ARG1 (g / grow-01 :ARG1 (e3 / epithelium)) :ARG1-of (m / mediate-01 :ARG0 m3)) :ARG3 (i2 / inhibit-01 :ARG1 (a4 / and :op1 (e / enzyme :name (n5 / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n6 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1-of (c2 / combine-01)))) # ::id a_pmid_2169_9731.60 # ::date 2015-05-20T11:51:31 # ::file a_pmid_2169_9731_60.txt # ::snt Macrophage conditioned media profoundly stimulates the anchorage-independent growth of lung tumor cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (s / stimulate-01 :ARG0 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage))) :ARG1 (g / grow-01 :ARG1 (c / cell :mod (t / tumor :mod (l / lung))) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a / anchorage))) :manner (p / profound)) # ::id a_pmid_2169_9731.61 # ::date 2015-05-20T11:56:03 # ::file a_pmid_2169_9731_61.txt # ::snt Despite the correlation between lung macrophage content and lung tumor growth, the direct contribution of alveolar macrophages to lung tumor growth is unclear [6,7,13]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / clear-06 :polarity "-" :ARG1 (c2 / contribute-01 :ARG0 (m / macrophage :mod (a / alveolus)) :ARG2 (g / grow-01 :ARG1 (t / tumor :mod (l / lung))) :ARG1-of (d / direct-02)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 (a2 / and :op1 "6" :op2 "7" :op3 "13")))) :concession (c3 / correlate-01 :ARG1 (c4 / content :mod (m2 / macrophage :mod (l2 / lung))) :ARG2 g)) # ::id a_pmid_2169_9731.62 # ::date 2015-05-20T12:21:01 # ::file a_pmid_2169_9731_62.txt # ::snt Media conditioned by an immortalized lung macrophage cell line, MH-S, has been previously reported to stimulate the migration of lung epithelial cells harboring Kras mutations [18]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (r / report-01 :ARG1 (s / stimulate-01 :ARG0 (m3 / medium :ARG1-of (c2 / condition-01 :ARG0 (c6 / cell-line :ARG1-of (i / immortalize-03) :ARG1-of (m5 / mean-01 :ARG2 (c4 / cell-line :name (n2 / name :op1 "MH-S"))) :mod (m4 / macrophage :mod (l / lung))))) :ARG1 (m / migrate-01 :ARG0 (c / cell :mod (e / epithelium) :ARG0-of (h / harbor-01 :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "Kras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.671")))) :mod l))) :time (p / previous) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "18")))) # ::id a_pmid_2169_9731.63 # ::date 2015-05-20T12:42:26 # ::file a_pmid_2169_9731_63.txt # ::snt To determine if MH-S conditioned media directly stimulates neoplastic growth, we first evaluated neoplastic colony formation and cell number after long-term conditioned media exposure. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (e / evaluate-01 :ARG0 (w / we) :ARG1 (a / and :op1 (f / form-01 :ARG1 (c / colony :mod (t / tumor))) :op2 (n2 / number :quant-of (c2 / cell))) :ord (o / ordinal-entity :value "1") :time (a2 / after :op1 (e2 / expose-01 :ARG2 (m / medium :ARG1-of (c3 / condition-01)) :duration (l / long-03))) :purpose (d / determine-01 :ARG0 w :ARG1 (s / stimulate-01 :ARG0 (m2 / medium :ARG1-of (c4 / condition-01) :mod (c5 / cell-line :name (n4 / name :op1 "MH-S"))) :ARG1 (g / grow-01 :mod t) :ARG1-of (d2 / direct-02)))) # ::id a_pmid_2169_9731.64 # ::date 2015-05-20T13:10:21 # ::file a_pmid_2169_9731_64.txt # ::snt In both the classic model of anchorage-independent neoplastic growth on soft agar (Figure 1A-C), and colonization on new ultra-low adherence, neutrally-charged plastic (Figure 1D-F), macrophage-conditioned media potently stimulated the proliferation of two Kras mutant lung tumor-derived cell lines (LM2 and JF32). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / stimulate-01 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :ARG1 (p2 / proliferate-01 :ARG0 (c2 / cell-line :quant "2" :ARG1-of (m3 / mutate-01) :ARG2-of (m5 / mean-01 :ARG1 (a / and :op1 (c3 / cell-line :name (n2 / name :op1 "LM2")) :op2 (c4 / cell-line :name (n3 / name :op1 "JF32")))) :ARG1-of (d / derive-01 :ARG2 (t / tumor :mod (l / lung))) :mod (e / enzyme :name (n / name :op1 "Kras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.671")))) :manner (p / potent) :location (a2 / and :op1 (m4 / model :mod (c5 / classic) :topic (g / grow-01 :location (a3 / agar :ARG1-of (s2 / soft-02)) :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 (a4 / anchorage)) :mod (t2 / tumor)) :ARG1-of (d3 / describe-01 :ARG0 (a7 / and :op1 (f / figure :mod "1A") :op2 (f5 / figure :mod "1B") :op3 (f6 / figure :mod "1C")))) :op2 (c6 / colonize-01 :ARG0 c2 :location (p3 / plastic :ARG1-of (c7 / charge-03 :ARG0-of (n4 / neutral-02)) :ARG1-of (a5 / adhere-01 :ARG1-of (n5 / new-01) :ARG1-of (l2 / low-04 :degree (u / ultra)))) :ARG1-of (d4 / describe-01 :ARG0 (a6 / and :op1 (f2 / figure :mod "1D") :op2 (f3 / figure :mod "1E") :op3 (f4 / figure :mod "1F")))))) # ::id a_pmid_2169_9731.65 # ::date 2015-05-20T13:12:48 # ::file a_pmid_2169_9731_65.txt # ::snt Thus, macrophages secrete soluble molecules capable of greatly stimulating neoplastic colony formation and proliferation in vitro, which may shed light on the role of macrophage recruitment to lung cancer in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / cause-01 :ARG1 (s / secrete-01 :ARG0 (m / macrophage) :ARG1 (m2 / molecule :ARG1-of (c2 / capable-01 :ARG2 (s2 / stimulate-01 :ARG0 m2 :ARG1 (a / and :op1 (f / form-01 :ARG1 (c3 / colony :mod (t / tumor))) :op2 (p / proliferate-01 :ARG0 c3)) :manner (i / in-vitro) :manner (g / great))) :ARG1-of (d / dissolve-01 :ARG1-of (p3 / possible-01))) :ARG0-of (s3 / shed-03 :ARG1 (l / light) :ARG2 (r / role :topic (r2 / recruit-01 :ARG1 m :ARG2 (d2 / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer")) :manner (i2 / in-vivo))) :ARG1-of p3))) # ::id a_pmid_2169_9731.66 # ::date 2015-05-20T13:43:56 # ::file a_pmid_2169_9731_66.txt # ::snt Naïve and tumor-educated primary macrophage co-culture stimulates the proliferation of neoplastic and non-neoplastic pulmonary epithelial cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (s / stimulate-01 :ARG0 (a / and :op1 (c / co-culture :mod (n / naive) :mod (p / primary) :mod (m / macrophage)) :op2 (c2 / co-culture :mod p :mod (m2 / macrophage :ARG1-of (e / educate-01 :ARG0 (t / tumor))))) :ARG1 (p2 / proliferate-01 :ARG0 (a2 / and :op1 (c3 / cell :mod (e2 / epithelium) :mod (l / lung) :mod t) :op2 (c4 / cell :mod e2 :mod l :mod (t2 / tumor :polarity "-"))))) # ::id a_pmid_2169_9731.67 # ::date 2015-05-20T13:53:34 # ::file a_pmid_2169_9731_67.txt # ::snt The relative ability of naïve vs. tumor-educated alveolar macrophages to directly stimulate lung epithelial cell proliferation not been reported. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (r / report-01 :polarity "-" :ARG1 (c2 / capable-01 :ARG1 (m / macrophage :mod (n / naive) :mod (a / alveolus)) :ARG2 (s / stimulate-01 :ARG0 m :ARG1 (p2 / proliferate-01 :ARG0 (c / cell :mod (e2 / epithelium) :mod (l / lung))) :ARG1-of (d / direct-02)) :ARG2-of (r2 / relative-05) :compared-to (m2 / macrophage :ARG1-of (e / educate-01 :ARG0 (t / tumor)) :mod a))) # ::id a_pmid_2169_9731.68 # ::date 2015-05-20T14:03:02 # ::file a_pmid_2169_9731_68.txt # ::snt To determine if macrophages from the lungs of tumor-bearing mice could directly stimulate neoplastic cell growth in a co-culture system, neoplastic LM2 cells were co-cultured with bronchoalveolar lavage (BAL) macrophages (MØ) isolated from tumor-bearing mice, and monolayer growth was assessed (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a2 / and :op1 (c / culture-01 :ARG1 (a / and :op1 (c2 / cell-line :name (n / name :op1 "LM2") :mod (n2 / neoplastic)) :op2 (m / macrophage :mod (b / bronchoalveolar :mod (l / lavage)) :ARG1-of (i / isolate-01 :ARG2 (m2 / mouse :ARG0-of (b2 / bear-01 :ARG1 (t / tumor))))))) :op2 (a3 / assess-01 :ARG1 (g / grow-01 :ARG1 (l2 / layer :quant "1"))) :purpose (d / determine-01 :ARG1 (p2 / possible-01 :ARG1 (s / stimulate-01 :ARG0 (m3 / macrophage :source (l3 / lung :part-of m2)) :ARG1 (g2 / grow-01 :mod (c3 / cell :mod (n3 / neoplastic)) :location (s2 / system :mod (c4 / co-culture))) :ARG1-of (p / possible-01) :ARG1-of (d3 / direct-02)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2169_9731.69 # ::date 2015-05-21T10:49:28 # ::file a_pmid_2169_9731_69.txt # ::snt Growth in standard tissue culture conditions measures proliferation per se, and not cell motility or the requirement for solid support, and permits the evaluation of non-neoplastic epithelial cells which do not proliferate in anchorage-independent systems. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (a / and :op1 (c2 / contrast-01 :ARG1 (m / measure-01 :ARG0 (g / grow-01 :ARG1 (c / culture-01 :ARG1 (t / tissue :ARG1-of (s / standard-02)))) :ARG1 (p4 / proliferate-01) :manner (p / per-se)) :ARG2 (m2 / measure-01 :polarity "-" :ARG0 g :ARG1 (o / or :op1 (m3 / motility :mod (c3 / cell)) :op2 (r / require-01 :ARG1 (s2 / support-01 :ARG1-of (s3 / solid-02)))))) :op2 (p2 / permit-01 :ARG0 g :ARG1 (e / evaluate-01 :ARG1 (c4 / cell :mod (e2 / epithelium) :mod (t2 / tumor :polarity "-") :ARG0-of (p3 / proliferate-01 :polarity "-" :location (s4 / system :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a2 / anchorage)))))))) # ::id a_pmid_2169_9731.70 # ::date 2015-05-21T11:07:49 # ::file a_pmid_2169_9731_70.txt # ::snt LM2 cell number significantly increased with BAL macrophage co-culture at 48 (2.3 vs. 4.1-fold) and 72 hrs (3.5 vs. 7.5-fold) (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (i / increase-01 :ARG0 (c / co-culture :mod (m / macrophage :mod (l / lavage :mod (a4 / alveolus :mod (b / bronchus))))) :ARG1 (n2 / number :quant-of (c2 / cell-line :name (n3 / name :op1 "LM2"))) :ARG2 (s / significant-02) :ARG3 (p / product-of :op1 "2.3") :ARG4 (p2 / product-of :op1 "4.1") :time (a2 / after :op1 (t2 / temporal-quantity :quant "48" :unit (h / hour)))) :op2 (i2 / increase-01 :ARG0 c :ARG1 n2 :ARG2 s :ARG3 (p3 / product-of :op1 "3.5") :ARG4 (p4 / product-of :op1 "7.5") :time (a3 / after :op1 (t3 / temporal-quantity :quant "72" :unit (h2 / hour)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2169_9731.71 # ::date 2015-05-21T11:52:20 # ::file a_pmid_2169_9731_71.txt # ::snt As 72 hrs of macrophage co-culture resulted in ≥ 2-times more tumor cells, this time point was used in subsequent experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (u / use-01 :ARG0 (p / point :mod (t / time) :mod (t4 / this)) :ARG1 (e / experiment-01 :time (s / subsequent)) :ARG1-of (c / cause-01 :ARG0 (r / result-01 :ARG1 (c2 / co-culture :mod (m / macrophage) :duration (t2 / temporal-quantity :quant "72" :unit (h / hour))) :ARG2 (c3 / cell :mod (t3 / tumor) :quant (m2 / more :degree (v / value-interval :op1 (m3 / more-than :op1 (p2 / product-of :op1 "2")) :op2 (p3 / product-of :op1 "2"))))))) # ::id a_pmid_2169_9731.72 # ::date 2015-05-21T12:12:40 # ::file a_pmid_2169_9731_72.txt # ::snt To determine if tumor-educated macrophages stimulated neoplastic growth more effectively than naïve, BAL macrophages from either naïve or tumor-bearing mice were co-cultured with neoplastic LM2 (Figure 2B) and JF32 (Figure 2C) cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / culture-01 :ARG1 (a / and :op1 (m / macrophage :source (o / or :op1 (m2 / mouse :mod (n / naive)) :op2 (m3 / mouse :ARG0-of (b / bear-01 :ARG1 (t / tumor)))) :mod (l / lavage :mod (a2 / alveolus :mod (b2 / bronchus)))) :op2 (c2 / cell-line :name (n2 / name :op1 "LM2") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B")) :mod t) :op3 (c3 / cell-line :name (n3 / name :op1 "JF32") :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2C")) :mod t)) :purpose (d3 / determine-01 :ARG1 (s / stimulate-01 :mode "interrogative" :ARG0 (m4 / macrophage :ARG1-of (e / educate-01 :ARG0 t)) :ARG1 (g / grow-01 :ARG1 t) :ARG1-of (e2 / effective-04 :degree (m5 / more) :compared-to (m6 / macrophage :mod (n6 / naive)))))) # ::id a_pmid_2169_9731.73 # ::date 2015-05-21T12:25:41 # ::file a_pmid_2169_9731_73.txt # ::snt LM2 growth was equally stimulated by both naïve and tumor-educated BAL macrophages, while the growth of JF32 cells was enhanced slightly upon co-culture with tumor-educated BAL macrophages (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / contrast-01 :ARG1 (s / stimulate-01 :ARG0 (g / grow-01 :ARG1 (c2 / cell-line :name (n2 / name :op1 "LM2"))) :ARG1 (a / and :op1 (m / macrophage :mod (n / naive) :mod (l / lavage :mod (a4 / alveolus :mod (b / bronchus)))) :op2 (m2 / macrophage :ARG1-of (e / educate-01 :ARG0 (t / tumor)))) :ARG1-of (e2 / equal-01)) :ARG2 (e3 / enhance-01 :ARG1 (g2 / grow-01 :ARG1 (c3 / cell-line :name (n3 / name :op1 "JF32"))) :manner (s2 / slight) :time (a3 / after :op1 (c4 / culture-01 :ARG1 (a2 / and :op1 c3 :op2 m2)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2C"))) # ::id a_pmid_2169_9731.74 # ::date 2015-05-21T12:37:27 # ::file a_pmid_2169_9731_74.txt # ::snt To determine if primary alveolar macrophages also stimulated the proliferation of non-tumor cells, the non-neoplastic E10 cell line was co-cultured with naïve and tumor-educated BAL macrophages. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / culture-01 :ARG1 (a / and :op1 (c2 / cell-line :name (n / name :op1 "E10") :mod (t3 / tumor :polarity "-")) :op2 (m / macrophage :mod (n2 / naive)) :op3 (m2 / macrophage :ARG1-of (e / educate-01 :ARG0 (t / tumor)) :mod (l / lavage :mod (a4 / alveolus :mod (b / bronchus))))) :purpose (d / determine-01 :ARG1 (s / stimulate-01 :mode "interrogative" :ARG0 (m3 / macrophage :mod (p2 / primary) :mod (a2 / alveolus)) :ARG1 (p / proliferate-01 :ARG0 (c3 / cell :mod t3)) :mod (a3 / also)))) # ::id a_pmid_2169_9731.75 # ::date 2015-05-21T12:48:37 # ::file a_pmid_2169_9731_75.txt # ::snt Both macrophage types increased E10 cell number 3.5-fold (Figure 2D) when maintained in serum-free conditions; only tumor-educated macrophages stimulated E10 proliferation when cultured in the presence of serum (Figure 2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (i / increase-01 :ARG0 (t / type-03 :ARG1 (m2 / macrophage) :mod (b / both)) :ARG1 (n / number :quant-of (c / cell-line :name (n2 / name :op1 "E10"))) :ARG2 (p / product-of :op1 "3.5") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2D")) :time (m3 / maintain-01 :ARG1 t :ARG2 (c2 / condition :ARG1-of (f2 / free-04 :ARG2 (s / serum))))) :snt2 (s2 / stimulate-01 :ARG0 (m4 / macrophage :ARG1-of (e / educate-01 :ARG0 (t2 / tumor)) :mod (o / only)) :ARG1 (p2 / proliferate-01 :ARG0 (c3 / cell-line :name (n3 / name :op1 "E10"))) :time (c4 / culture-01 :ARG1 c3) :condition (p3 / present-02 :ARG1 (s3 / serum)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "2E")))) # ::id a_pmid_2169_9731.76 # ::date 2015-05-21T13:16:10 # ::file a_pmid_2169_9731_76.txt # ::snt Both types of primary macrophages equally stimulated LM2 proliferation in the presence of serum, though the magnitude was reduced when compared to serum-free co-culture (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / stimulate-01 :ARG0 (t / type-03 :ARG1 (m / macrophage :mod (p3 / primary)) :mod (b / both)) :ARG1 (p / proliferate-01 :ARG0 (c / cell-line :name (n / name :op1 "LM2"))) :ARG1-of (e / equal-01) :condition (p2 / present-02 :ARG1 (s2 / serum)) :ARG1-of (d / describe-01 :ARG0 (d3 / data :ARG1-of (s3 / show-01 :polarity "-"))) :concession (r / reduce-01 :ARG1 (m2 / magnitude) :time (c2 / compare-01 :ARG1 m2 :ARG2 (c3 / co-culture :ARG1-of (f / free-04 :ARG2 s2))))) # ::id a_pmid_2169_9731.77 # ::date 2015-05-21T14:14:27 # ::file a_pmid_2169_9731_77.txt # ::snt To determine if MH-S macrophages could recapitulate the effects of primary alveolar macrophages in this in vitro model, we co-cultured MH-S macrophages with both neoplastic and non-neoplastic lung epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (c / culture-01 :ARG0 (w / we) :ARG1 (a / and :op1 (m / macrophage :mod (c2 / cell-line :name (n / name :op1 "MH-S"))) :op2 (c3 / cell :mod (l / lung) :mod (e / epithelium) :mod (t2 / tumor)) :op3 (c4 / cell :mod l :mod (n3 / neoplastic :polarity "-") :mod t2)) :purpose (d / determine-01 :ARG0 w :ARG1 (p / possible-01 :ARG1 (r / recapitulate-01 :ARG0 m :ARG1 (a2 / affect-01 :ARG0 (m2 / macrophage :mod (a3 / alveolar) :mod (p2 / primary))) :location (m3 / model :mod (i / in-vitro) :mod (t / this)))))) # ::id a_pmid_2169_9731.78 # ::date 2015-05-21T14:24:54 # ::file a_pmid_2169_9731_78.txt # ::snt MH-S co-culture increased the growth rate of all pulmonary epithelial cell lines similar to co-culture with tumor-educated BAL macrophages (Figure 2B-E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / increase-01 :ARG0 (c / co-culture :mod (c2 / cell-line :name (n / name :op1 "MH-S"))) :ARG1 (r / rate :degree-of (g / grow-01 :ARG1 (c3 / cell-line :mod (a / all) :mod (e / epithelium) :mod (l / lung) :ARG1-of (r2 / resemble-01 :ARG2 (c4 / culture-01 :ARG1 (m / macrophage :ARG1-of (e2 / educate-01 :ARG0 (t / tumor)) :mod (l2 / lavage :mod (a3 / alveolus :mod (b / bronchus))))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2B") :op2 (f2 / figure :mod "2C") :op3 (f3 / figure :mod "2D") :op4 (f4 / figure :mod "2E")))) # ::id a_pmid_2169_9731.79 # ::date 2015-05-21T14:34:25 # ::file a_pmid_2169_9731_79.txt # ::snt These results indicate that primary lung macrophages produce diffusible signals which can augment the proliferation of both non-neoplastic and neoplastic cells in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p / produce-01 :ARG0 (m / macrophage :mod (p4 / primary) :mod (l / lung)) :ARG1 (s / signal-07 :ARG1-of (d / diffuse-01 :ARG1-of (p2 / possible-01)) :ARG0-of (a / augment-01 :ARG1 (p3 / proliferate-01 :ARG0 (a2 / and :op1 (c / cell :mod (t3 / tumor :polarity "-")) :op2 (c2 / cell :mod (n2 / neoplastic))) :manner (i2 / in-vitro)) :ARG1-of p2)))) # ::id a_pmid_2169_9731.80 # ::date 2015-05-21T14:40:55 # ::file a_pmid_2169_9731_80.txt # ::snt Further, we observed that in vivo tumor education of primary lung macrophages slightly enhances this ability to stimulate epithelial proliferation, an effect similar to co-culture with MH-S macrophages. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 31, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (e / enhance-01 :ARG0 (e2 / educate-01 :ARG0 (t / tumor) :ARG1 (m / macrophage :mod (l / lung) :mod (p / primary)) :manner (i / in-vivo)) :manner (s / slight) :ARG1-of (c / capable-01 :ARG2 (s2 / stimulate-01 :ARG1 (p2 / proliferate-01 :ARG0 (e3 / epithelium)))) :ARG2-of (a / affect-01 :ARG1 c :ARG1-of (r / resemble-01 :ARG2 (c2 / culture-01 :ARG1 (a2 / and :op1 m :op2 (m2 / macrophage :mod (c3 / cell-line :name (n / name :op1 "MH-S")))))))) :mod (f / further)) # ::id a_pmid_2169_9731.81 # ::date 2015-05-22T11:16:53 # ::file a_pmid_2169_9731_81.txt # ::snt Macrophage co-culture stimulates epithelial proliferation through kinase activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / stimulate-01 :ARG0 (c / coculture-01 :ARG1 (m / macrophage)) :ARG1 (p / proliferate-01 :ARG0 (e / epithelium)) :ARG2 (a / activate-01 :ARG1 (k / kinase))) # ::id a_pmid_2169_9731.82 # ::date 2015-05-22T23:20:29 # ::file a_pmid_2169_9731_82.txt # ::snt Since MH-S macrophages and tumor-educated primary macrophages stimulated epithelial proliferation to a similar degree, MH-S macrophages were used to elucidate the mechanisms of increased epithelial proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / use-01 :ARG1 (m2 / macrophage :mod (c2 / cell-line :name (n / name :op1 "MH-S"))) :ARG2 (e / elucidate-01 :ARG0 m2 :ARG1 (m / mechanism :poss (p / proliferate-01 :ARG0 (e2 / epithelium) :ARG1-of (i / increase-01)))) :ARG1-of (c / cause-01 :ARG0 (s / stimulate-01 :ARG0 (a / and :op1 m2 :op2 (m3 / macrophage :mod (p2 / primary) :ARG1-of (e3 / educate-01 :ARG0 (t / tumor)))) :ARG1 p :degree (r / resemble-01)))) # ::id a_pmid_2169_9731.83 # ::date 2015-05-23T12:28:15 # ::file a_pmid_2169_9731_83.txt # ::snt Because Kras pathways are commonly hyper-activated in lung tumorigenesis [22,23], and the tumorigenic lines examined herein contain Kras mutations, activities of downstream mediators Erk and Akt were examined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / examine-01 :ARG1 (a / act-02 :ARG0 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "Erk") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :name (n2 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG0-of (m / mediate-01 :direction (d / downstream)))) :ARG1-of (c / cause-01 :ARG0 (a3 / and :op1 (a4 / activate-01 :ARG1 (p / pathway :name (n3 / name :op1 "K-Ras")) :degree (h / hyper) :time (c2 / create-01 :ARG1 (t / tumor :mod (l / lung))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a5 / and :op1 "22" :op2 "23")))) :manner (c4 / common)) :op2 (c5 / contain-01 :ARG0 (l2 / line :ARG1-of (e5 / examine-01 :medium (h2 / herein)) :ARG0-of (c6 / create-01 :ARG1 (t2 / tumor) :ARG1-of (p3 / possible-01))) :ARG1 (m2 / mutate-01 :ARG2 (g / gene :name (n4 / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))))) # ::id a_pmid_2169_9731.84 # ::date 2015-05-24T09:44:46 # ::file a_pmid_2169_9731_84.txt # ::snt Cytosolic Raf functionally links the Erk and Akt pathways; activated Akt can phosphorylate cRaf at S259, placing Erk regulation downstream of Akt activation [32,33]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (a / and :op1 (l / link-01 :ARG0 (e / enzyme :name (n / name :op1 "Raf") :location (c / cytosol :xref (x2 / xref :value "GO:0005829" :prob "0.8")) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1 (a2 / and :op1 (p2 / pathway :name (n2 / name :op1 "Erk")) :op2 (p3 / pathway :name (n3 / name :op1 "Akt"))) :ARG0-of (f / function-01)) :op2 (p4 / possible-01 :ARG1 (p / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "259" :name (n6 / name :op1 "serine") :part-of (e2 / enzyme :name (n4 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (p7 / pathway :name (n5 / name :op1 "Akt") :ARG1-of (a3 / activate-01)) :ARG0-of (c2 / cause-01 :ARG1 (p5 / place-01 :ARG1 (r / regulate-01 :ARG1 p2) :ARG2 (r3 / relative-position :op1 p7 :direction (d / downstream))))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 "32" :op2 "33")))))) # ::id a_pmid_2169_9731.85 # ::date 2015-05-25T00:20:41 # ::file a_pmid_2169_9731_85.txt # ::snt MH-S co-culture stimulated cRaf phosphorylation at S259 in all three cell lines, resulting in significantly higher levels of p-cRaf (Figure 3A-C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / stimulate-01 :ARG0 (c / coculture-01 :ARG1 (m / macrophage :mod (c3 / cell-line :name (n / name :op1 "MH-S")))) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "259" :name (n2 / name :op1 "serine") :part-of (e / enzyme :name (n3 / name :op1 "C-Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG3 (l / level :ARG1-of (h / high-02 :degree (m2 / more) :ARG1-of (s2 / significant-02)) :quant-of (e2 / enzyme :name (n4 / name :op1 "C-Raf") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :location (c2 / cell-line :quant "3" :mod (a2 / all)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B") :op3 (f3 / figure :mod "3C")))) # ::id a_pmid_2169_9731.86 # ::date 2015-06-11T03:24:02 # ::file a_pmid_2169_9731_86.txt # ::snt The smaller (~74 kDa) p-cRaf isoform was most highly abundant and its phosphorylation significantly increased with macrophage co-culture in the LM2 and E10 cells, but a larger (~100 kDa) isoform was heavily phosphorylated at the expense of the 74 kDa isoform in neoplastic JF32 cells (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / contrast-01 :ARG1 (a / and :op1 (a2 / abundant :domain (i / isoform :mod (e / enzyme :name (n / name :op1 "C-Raf") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG1-of (e2 / equal-01 :ARG2 (a4 / approximately :op1 (m2 / mass-quantity :quant "74" :unit (k / kilodalton)))) :mod (s / small :degree (m3 / more))) :ARG1-of (h / high-02 :degree (m / most))) :op2 (i2 / increase-01 :ARG1 (p3 / phosphorylate-01 :ARG1 e) :ARG2 (s2 / significant-02) :instrument (c2 / coculture-01 :ARG1 (m4 / macrophage) :location (a3 / and :op1 (c3 / cell-line :name (n2 / name :op1 "LM2")) :op2 (c4 / cell-line :name (n3 / name :op1 "E10")))))) :ARG2 (p / phosphorylate-01 :ARG1 (i3 / isoform :mod (l / large :degree (m5 / more)) :ARG1-of (e3 / equal-01 :ARG2 (a5 / approximately :op1 (m6 / mass-quantity :quant "100" :unit (k2 / kilodalton))))) :manner (h2 / heavy) :ARG0-of (c5 / compromise-02 :ARG1 (i4 / isoform :quant m2)) :location (c6 / cell-line :name (n5 / name :op1 "JF32") :mod (n6 / neoplastic))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id a_pmid_2169_9731.87 # ::date 2015-05-24T09:44:51 # ::file a_pmid_2169_9731_87.txt # ::snt The 74 kDa isoform was the most abundant in total cRaf immunoblots from all three cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / abundant :degree (m / most) :location (i2 / immunoblot-01 :ARG1 (e / enzyme :name (n2 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG2 (c / cell-line :quant "3" :mod (a2 / all)) :mod (t / total)) :domain (i / isoform :quant (m2 / mass-quantity :quant "74" :unit (k / kilodalton)))) # ::id a_pmid_2169_9731.88 # ::date 2015-05-24T22:39:58 # ::file a_pmid_2169_9731_88.txt # ::snt MH-S co-culture significantly increased the levels of active Erk1/2 (p-Erk) in LM2 and JF32 cells, as well as non-neoplastic E10 cells, when normalized either to total Erk (panErk) or β-actin levels (Figure 3A, D and 3E), which correlates with the observed increases in proliferation (Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / increase-01 :ARG0 (c / coculture-01 :ARG1 (m / macrophage :mod (c7 / cell-line :name (n / name :op1 "MH-S")))) :ARG1 (l / level :quant-of (s2 / slash :op1 (e3 / enzyme :name (n10 / name :op1 "Erk1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n11 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")) :ARG0-of (a / activity-06) :ARG1-of (m2 / mean-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Erk") :ARG3-of (p3 / phosphorylate-01) :xref (x4 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))))) :ARG2 (s / significant-02) :location (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "LM2")) :op2 (c3 / cell-line :name (n4 / name :op1 "JF32")) :op3 (c4 / cell-line :name (n5 / name :op1 "E10") :mod (n6 / neoplastic :polarity "-"))) :condition (n7 / normalize-01 :ARG1 s2 :ARG1-of (c6 / conform-01 :ARG2 (o / or :op1 (l3 / level :quant-of (e2 / enzyme :name (n8 / name :op1 "Erk") :mod (t / total) :ARG1-of (m3 / mean-01 :ARG2 (e5 / enzyme :name (n12 / name :op1 "Erk") :mod (p4 / pan) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))) :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))) :op2 (l2 / level :quant-of (p / protein :name (n9 / name :op1 "β-actin") :xref (x5 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.282")))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3D") :op3 (f3 / figure :mod "3E"))) :ARG1-of (c5 / correlate-01 :ARG2 (i2 / increase-01 :ARG1 (p2 / proliferate-01) :ARG1-of (o2 / observe-01)) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure :mod "2")))) # ::id a_pmid_2169_9731.89 # ::date 2015-05-29T00:28:05 # ::file a_pmid_2169_9731_89.txt # ::snt E10 cells expressed lower basal p-Erk/panErk vs. the neoplastic cell lines, consistent with previous observations [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / express-03 :ARG2 (s / slash :op1 (e3 / enzyme :name (n4 / name :op1 "Erk") :ARG3-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n5 / name :op1 "Erk") :mod (p5 / pan) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :mod (b / basal) :ARG1-of (l / low-04 :degree (m / more))) :ARG3 (c / cell-line :name (n / name :op1 "E10")) :ARG1-of (c2 / contrast-01 :ARG2 (e2 / express-03 :ARG2 s :ARG3 (c3 / cell-line :mod (n3 / neoplastic)))) :ARG1-of (c4 / consistent-01 :ARG2 (o / observe-01 :time (p2 / previous))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG1-of (c5 / cite-01 :ARG2 "21")))) # ::id a_pmid_2169_9731.90 # ::date 2015-05-29T01:21:42 # ::file a_pmid_2169_9731_90.txt # ::snt Total Erk remained unchanged in both neoplastic cell lines, while macrophage co-culture caused Erk2 (42 kDa) to nearly disappear in the E10 cells, with little effect on Erk1 (Figure 3A, D and 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / contrast-01 :ARG1 (r / remain-01 :ARG1 (e / enzyme :name (n / name :op1 "Erk") :mod (t / total) :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :ARG3 (c2 / change-01 :polarity "-" :ARG1 e :location (c6 / cell-line :mod (b / both) :mod (n6 / neoplastic)))) :ARG2 (c3 / cause-01 :ARG0 (c4 / coculture-01 :ARG1 (m / macrophage)) :ARG1 (d / disappear-01 :ARG0 c4 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")) :mod (n3 / near) :location (c5 / cell-line :name (n4 / name :op1 "E10"))) :ARG0-of (a / affect-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "Erk1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :degree (l / little))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3D") :op3 (f3 / figure :mod "3E")))) # ::id a_pmid_2169_9731.91 # ::date 2015-05-30T05:16:55 # ::file a_pmid_2169_9731_91.txt # ::snt Activated Akt (p-Akt) levels rose significantly in both neoplastic cell lines when normalized to either total Akt (panAkt) or β-actin, but macrophage co-culture caused both p-Akt and panAkt levels to rise to similar extents in E10 cells (Figure 3A and 3F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / contrast-01 :ARG1 (r / rise-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "Akt") :ARG1-of (a / activate-01) :ARG1-of (m2 / mean-01 :ARG2 (e3 / enzyme :name (n6 / name :op1 "Akt") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG2 (s / significant-02) :location (c3 / cell-line :mod (b / both) :mod (n2 / neoplastic)) :condition (n3 / normalize-01 :ARG1 e :ARG1-of (c5 / conform-01 :ARG2 (o / or :op1 (e2 / enzyme :name (n4 / name :op1 "Akt") :mod (t / total) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op2 (p / protein :name (n5 / name :op1 "β-actin") :xref (x3 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.282")))))) :ARG2 (c2 / cause-01 :ARG0 (c4 / coculture-01 :ARG1 (m / macrophage)) :ARG1 (r3 / rise-01 :ARG0 c4 :ARG1 (l2 / level :quant-of (a2 / and :op1 e :op2 e2)) :ARG2 (e4 / extent :ARG1-of (r4 / resemble-01 :ARG2 l)) :location c3)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3F")))) # ::id a_pmid_2169_9731.92 # ::date 2015-05-27T00:33:11 # ::file a_pmid_2169_9731_92.txt # ::snt When p-Akt was normalized to panAkt expression, there was no change in E10 cells with MH-S co-culture (Figure 3F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / change-01 :polarity "-" :ARG1 (c2 / cell-line :name (n / name :op1 "E10") :ARG0-of (c3 / contain-01 :ARG1 (c4 / coculture-01 :ARG1 (m / macrophage :mod (c6 / cell-line :name (n2 / name :op1 "MH-S")))))) :time (n3 / normalize-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Akt") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of (c5 / conform-01 :ARG2 (e3 / enzyme :name (n6 / name :op1 "Akt") :mod (p3 / pan) :ARG2-of (e / express-03) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3F"))) # ::id a_pmid_2169_9731.93 # ::date 2015-05-25T23:39:20 # ::file a_pmid_2169_9731_93.txt # ::snt Total Akt expression increased slightly in LM2 cells but decreased in JF32 cells (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i2 / increase-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "Akt") :mod (t / total) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG2 (s / slight) :location (c2 / cell-line :name (n2 / name :op1 "LM2"))) :ARG2 (d / decrease-01 :ARG1 e :location (c3 / cell-line :name (n3 / name :op1 "JF32"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id a_pmid_2169_9731.94 # ::date 2015-05-26T23:50:42 # ::file a_pmid_2169_9731_94.txt # ::snt When normalized to β-actin, p-Akt levels significantly increased upon MH-S co-culture in all three cell lines (Figure 3A and 3G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / increase-01 :ARG0 (c / coculture-01 :ARG1 (m / macrophage :mod (c4 / cell-line :name (n4 / name :op1 "MH-S")))) :ARG1 (l / level :quant-of (e / enzyme :name (n3 / name :op1 "Akt") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG2 (s / significant-02) :condition (n / normalize-01 :ARG1 e :ARG1-of (c3 / conform-01 :ARG2 (p / protein :name (n2 / name :op1 "β-actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.282")))) :location (c2 / cell-line :quant "3" :mod (a / all)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3G")))) # ::id a_pmid_2169_9731.95 # ::date 2015-05-28T22:53:38 # ::file a_pmid_2169_9731_95.txt # ::snt Increased p-S473 Akt content suggests increased enzymatic activity, which can be confirmed by enhanced phosphorylation of downstream substrates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (s / suggest-01 :ARG0 (c / contain-01 :ARG1 (e / enzyme :name (n / name :op1 "Akt") :part (a / amino-acid :mod "473" :name (n2 / name :op1 "serine") :ARG1-of (p / phosphorylate-01) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of (i / increase-01)) :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme) :ARG1-of i :ARG1-of (c2 / confirm-01 :ARG0 (p3 / phosphorylate-01 :ARG1 (s2 / substrate :direction (d / downstream)) :ARG1-of (e3 / enhance-01)) :ARG1-of (p2 / possible-01)))) # ::id a_pmid_2169_9731.96 # ::date 2015-05-28T23:24:20 # ::file a_pmid_2169_9731_96.txt # ::snt To determine if macrophage co-culture increases Akt activity, we measured levels of p-GSK-3β, a known target of Akt [32]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / measure-01 :ARG0 (w / we) :ARG1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "GSK-3β") :ARG1-of (t / target-01 :ARG0 "e" :ARG1-of (k / know-01)) :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252"))) :purpose (d / determine-01 :ARG0 w :ARG1 (i / increase-01 :ARG0 (c / coculture-01 :ARG1 (m2 / macrophage)) :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 "32")))) # ::id a_pmid_2169_9731.97 # ::date 2015-06-02T00:51:25 # ::file a_pmid_2169_9731_97.txt # ::snt Consistent with the elevation in p-Akt, MH-S co-culture significantly increased p-GSK-3β in both LM2 and E10 cells and trended towards an increase in JF32 cells (Figure 3A and 3H); panGSK-3β levels were unchanged (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / multi-sentence :snt2 (c / change-01 :polarity "-" :ARG1 (l / level :quant-of (e2 / enzyme :name (n6 / name :op1 "GSK-3β") :mod (p2 / pan) :xref (x1 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252"))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s2 / show-01 :polarity "-")))) :snt1 (a2 / and :op1 (i / increase-01 :ARG0 (c2 / coculture-01 :ARG1 (m2 / macrophage :mod (c7 / cell-line :name (n / name :op1 "MH-S")))) :ARG1 (e / enzyme :name (n2 / name :op1 "GSK-3β") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252")) :ARG2 (s / significant-02) :location (a / and :op1 (c3 / cell-line :name (n3 / name :op1 "LM2")) :op2 (c4 / cell-line :name (n4 / name :op1 "E10")))) :op2 (t / trend-01 :ARG1 c2 :ARG2 i :location (c5 / cell-line :name (n5 / name :op1 "JF32"))) :ARG1-of (c6 / consistent-01 :ARG2 (e3 / elevate-01 :ARG1 (e4 / enzyme :name (n7 / name :op1 "Akt") :ARG3-of p :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3H"))))) # ::id a_pmid_2169_9731.98 # ::date 2015-05-30T12:17:20 # ::file a_pmid_2169_9731_98.txt # ::snt Phospho-S259 cRaf is another measure of Akt activity, and p-cRaf levels increased in all three cell lines with macrophage co-culture (Figure 3A-C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (m / measure-01 :ARG0 (e / enzyme :name (n / name :op1 "C-Raf") :part (a2 / amino-acid :mod "259" :name (n2 / name :op1 "serine") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG1 (a3 / activity-06 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :mod (a4 / another)) :op2 (i / increase-01 :ARG1 (l / level :quant-of e) :location (c / cell-line :quant "3" :mod (a5 / all) :ARG0-of (c2 / contain-01 :ARG1 (c3 / coculture-01 :ARG1 (m2 / macrophage))))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3C")))) # ::id a_pmid_2169_9731.99 # ::date 2015-06-01T23:52:24 # ::file a_pmid_2169_9731_99.txt # ::snt Together, the observed increases in epithelial proliferation and the known roles for Erk and Akt in neoplastic lung cell division suggest that macrophage co-culture stimulates lung cell proliferation through increased Erk and Akt activity [34]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / suggest-01 :ARG0 (a / and :op1 (i / increase-01 :ARG1 (p / proliferate-01 :ARG0 (e / epithelium)) :ARG1-of (o / observe-01)) :op2 (r / role :ARG1-of (k / know-01) :poss (a3 / and :op1 (e2 / enzyme :name (n / name :op1 "Erk") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :name (n2 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :topic (d / divide-02 :ARG1 (c / cell :mod (l / lung) :mod (n3 / neoplasm)))) :mod (t / together)) :ARG1 (s2 / stimulate-01 :ARG0 (c2 / coculture-01 :ARG1 (m / macrophage)) :ARG1 (p2 / proliferate-01 :ARG0 (c4 / cell :mod l)) :manner (a2 / activity-06 :ARG0 a3 :ARG1-of (i2 / increase-01))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 "34")))) # ::id a_pmid_2169_9731.100 # ::date 2015-05-31T04:40:57 # ::file a_pmid_2169_9731_100.txt # ::snt Combined inhibition of MEK and PI3K abrogates macrophage stimulation of neoplastic growth # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (a / abrogate-01 :ARG0 (i / inhibit-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n2 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG3-of (c / combine-01)) :ARG1 (s / stimulate-01 :ARG0 (m / macrophage) :ARG1 (g / grow-01 :ARG1 (n3 / neoplasm)))) # ::id a_pmid_2169_9731.101 # ::date 2015-05-31T08:05:23 # ::file a_pmid_2169_9731_101.txt # ::snt Erk and Akt regulate both proliferation and resistance to apoptotic cell death, are more active in lung tumors than in normal tissue [21,35], and were activated with macrophage co-culture. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (r / regulate-01 :ARG0 (a4 / and :op1 (e / enzyme :name (n / name :op1 "Erk") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n2 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG1 (a5 / and :op1 (p / proliferate-01) :op2 (r2 / resist-01 :ARG1 (d / die-01 :ARG1 (c / cell) :mod (a6 / apoptosis))))) :op2 (a2 / activity-06 :ARG0 a4 :degree (m / more) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a7 / and :op1 "21" :op2 "35")))) :location (t / tumor :mod (l / lung) :compared-to (t2 / tissue :ARG1-of (n3 / normal-02)))) :op3 (a3 / activate-01 :ARG0 (c2 / coculture-01 :ARG1 (m2 / macrophage)) :ARG1 a4)) # ::id a_pmid_2169_9731.102 # ::date 2015-06-01T13:06:36 # ::file a_pmid_2169_9731_102.txt # ::snt Since combined MEK and PI3K inhibition slowed mutant Kras-driven lung tumor growth in vivo [25], we determined whether selective inhibition of MEK and PI3K affected macrophage-stimulated proliferation in these Kras mutant lung tumor cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (d / determine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :mode "interrogative" :ARG0 (i / inhibit-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n2 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :manner (s / selective)) :ARG1 (p / proliferate-01 :ARG1-of (s2 / stimulate-01 :ARG0 (m / macrophage)) :location (c / cell-line :mod (g2 / gene :name (n3 / name :op1 "K-Ras") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :mod (t / tumor) :mod (l / lung)))) :ARG1-of (c2 / cause-01 :ARG0 (s3 / slow-01 :ARG0 (i4 / inhibit-01 :ARG3-of (c4 / combine-01)) :ARG1 (g / grow-01 :ARG1 (t2 / tumor :mod (l2 / lung) :ARG1-of (d2 / drive-02 :ARG0 g2)) :manner (i2 / in-vivo)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 "25")))))) # ::id a_pmid_2169_9731.103 # ::date 2015-06-10T01:46:23 # ::file a_pmid_2169_9731_103.txt # ::snt Selective inhibition of either MEK (by U0126) or PI3K (by LY294002) significantly decreased basal proliferation, and blocked growth stimulated by macrophage co-culture to different extents in LM2 and JF32 cells (Figure 4A and 4B, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (d / decrease-01 :ARG0 (o2 / or :op1 (i2 / inhibit-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "U0126") :xref (x3 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op2 (i3 / inhibit-01 :ARG0 (s3 / small-molecule :name (n4 / name :op1 "LY294002") :xref (x2 / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :manner (s / selective)) :ARG1 (p / proliferate-01 :mod (b2 / basal)) :ARG2 (s4 / significant-02)) :op2 (b / block-01 :ARG0 o2 :ARG1 (g / grow-01 :ARG1-of (s5 / stimulate-01 :ARG0 (c / coculture-01 :ARG1 (m / macrophage)) :degree (e3 / extent :ARG1-of (d2 / differ-02)))) :location (a2 / and :op1 (c2 / cell-line :name (n5 / name :op1 "LM2")) :op2 (c3 / cell-line :name (n6 / name :op1 "JF32")))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B")) :mod (r / respective))) # ::id a_pmid_2169_9731.104 # ::date 2015-06-10T00:59:40 # ::file a_pmid_2169_9731_104.txt # ::snt Only the combined inhibition of both kinases ablated the stimulatory effect of macrophage co-culture on neoplastic proliferation (U0 + LY, Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / ablate-01 :ARG1 (a2 / affect-01 :ARG0 (c / coculture-01 :ARG1 (m / macrophage)) :ARG1 (p / proliferate-01 :ARG0 (n / neoplasm)) :ARG2 (s / stimulate-01)) :ARG3 (i / inhibit-01 :ARG0 "a3" :ARG1 (k / kinase :mod (b / both)) :ARG3-of (c2 / combine-01 :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (s3 / small-molecule :name (n2 / name :op1 "U0")) :op2 (s4 / small-molecule :name (n3 / name :op1 "LY") :xref (x / xref :value "PUBCHEM:16196600" :prob "11.455812"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4")))) :mod (o / only))) # ::id a_pmid_2169_9731.105 # ::date 2015-06-01T13:07:52 # ::file a_pmid_2169_9731_105.txt # ::snt Kinase inhibitors were applied at concentrations reported to be cytostatic and not cytotoxic [34,36,37], and none of these treatments significantly increased LM2 or JF32 cell death (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / apply-02 :ARG1 (c / concentrate-02 :ARG1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (k / kinase))) :ARG1-of (r / report-01) :mod (c2 / cytostatic) :mod (c3 / cytotoxic :polarity "-")) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG1-of (c6 / cite-01 :ARG2 (a3 / and :op1 "34" :op2 "36" :op3 "37"))))) :op2 (i / increase-01 :ARG0 (t / treatment :mod (t2 / this) :quant (n / none)) :ARG1 (d3 / die-01 :ARG1 (o / or :op1 (c4 / cell-line :name (n2 / name :op1 "LM2")) :op2 (c5 / cell-line :name (n3 / name :op1 "JF32")))) :ARG2 (s2 / significant-02)) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s / show-01 :polarity "-")))) # ::id a_pmid_2169_9731.106 # ::date 2015-05-31T05:09:30 # ::file a_pmid_2169_9731_106.txt # ::snt These results suggest that both the MEK and PI3K pathways must be blocked to effectively inhibit macrophage-stimulated neoplastic growth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 3, 2016 (o / obligate-01 :ARG1 (a / and :op1 (p / pathway :name (n / name :op1 "MEK")) :op2 (p2 / pathway :name (n2 / name :op1 "PI3K"))) :ARG2 (b / block-01 :ARG1 a :purpose (i / inhibit-01 :ARG0 a :ARG1 (g / grow-01 :ARG1 (n3 / neoplasm) :ARG1-of (s2 / stimulate-01 :ARG0 (m / macrophage))) :ARG1-of (e / effective-04))) :ARG1-of (s / suggest-01 :ARG0 (t2 / thing :ARG2-of (r / result-01) :mod (t / this)))) # ::id a_pmid_2169_9731.107 # ::date 2015-05-30T13:19:48 # ::file a_pmid_2169_9731_107.txt # ::snt Macrophage conditioned media contains 3-10 kDa factors which stimulate neoplastic proliferation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (c / contain-01 :ARG0 (m / medium :ARG1-of (c2 / condition-01 :ARG2 (m2 / macrophage))) :ARG1 (f / factor :ARG0-of (s / stimulate-01 :ARG1 (p / proliferate-01 :ARG0 (n / neoplasm))) :quant (b / between :op1 (m3 / mass-quantity :quant "3" :unit (k3 / kilodalton)) :op2 (m4 / mass-quantity :quant "10" :unit (k4 / kilodalton))))) # ::id a_pmid_2169_9731.108 # ::date 2015-06-11T02:01:32 # ::file a_pmid_2169_9731_108.txt # ::snt Macrophages produce numerous cytokines, eicosanoids and other soluble factors depending upon tissue location and environmental stimuli [4,18], any number of which could be responsible for the observed neoplastic growth stimulation described above. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (p / produce-01 :ARG0 (m / macrophage) :ARG1 (a / and :op1 (c / cytokine :quant (n / numerous)) :op2 (e / eicosanoid) :op3 (f / factor :mod (s / soluble) :mod (o / other)) :ARG0-of (r / responsible-01 :ARG1 (s3 / stimulate-01 :ARG1 (g / grow-01 :ARG1 (n2 / neoplasm) :ARG1-of (o2 / observe-01)) :ARG1-of (d2 / describe-01 :location (a4 / above))) :ARG1-of (p2 / possible-01)) :quant (n3 / number :mod (a3 / any))) :ARG0-of (d / depend-01 :ARG1 (a2 / and :op1 (l / location :mod (t / tissue)) :op2 (s2 / stimulus :mod (e2 / environment)))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 "4" :op2 "18"))))) # ::id a_pmid_2169_9731.109 # ::date 2015-05-20T06:07:46 # ::file a_pmid_2169_9731_109.txt # ::snt Media conditioned by primary BAL macrophages (MØCM) stimulated the proliferation of LM2 cells, albeit to a lesser extent than primary macrophage co-culture (Figure 5 "Total" vs. Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / stimulate-01 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage :source (a / alveolus :mod (b / bronchus)) :mod (p / primary)))) :ARG1 (p2 / proliferate-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "LM2"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5") :ARG2 (t / total)) :concession (s2 / stimulate-01 :ARG0 m :ARG1 p2 :degree (l / less :degree (m4 / more)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2B")) :compared-to (c3 / coculture-01 :ARG1 (m5 / macrophage :mod (p3 / primary))))) # ::id a_pmid_2169_9731.110 # ::date 2015-05-20T06:36:04 # ::file a_pmid_2169_9731_110.txt # ::snt When size-fractionated MØCM was added to LM2 cells, molecules between 3 and 10 kDa stimulated LM2 growth to the greatest extent (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / stimulate-01 :ARG0 (m2 / molecule :mod (m3 / mass-quantity :quant (b / between :op1 "3" :op2 "10") :unit (k / kilodalton))) :ARG1 (g2 / grow-01 :ARG1 (c / cell-line :name (n / name :op1 "LM2"))) :degree (g / great :degree (m / most)) :condition (a / add-02 :ARG1 (m4 / medium :ARG1-of (f / fractionate-00 :mod (s2 / size)) :ARG1-of (c2 / condition-01 :ARG0 (m5 / macrophage))) :ARG2 c) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5"))) # ::id a_pmid_2169_9731.111 # ::date 2015-05-20T06:44:30 # ::file a_pmid_2169_9731_111.txt # ::snt Thus, factors of this size mediated the majority of MØCM effects on LM2 growth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / infer-01 :ARG1 (m / mediate-01 :ARG0 (f / factor :mod (s / size :mod (t / this))) :ARG1 (a / affect-01 :ARG0 (m3 / medium :ARG1-of (c2 / condition-01 :ARG0 (m4 / macrophage))) :ARG1 (g / grow-01 :ARG0 (c / cell-line :name (n2 / name :op1 "LM2"))) :quant (m2 / majority)))) # ::id a_pmid_2169_9731.112 # ::date 2015-05-20T06:53:29 # ::file a_pmid_2169_9731_112.txt # ::snt Alveolar macrophages produce numerous growth factors in this size range, including IGF-1, GM-CSF and EGF [11,18]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (p / produce-01 :ARG0 (m / macrophage :mod (a / alveolus)) :ARG1 (g / growth-factor :ARG2-of (i / include-01 :ARG1 (a2 / and :op1 (p5 / protein :name (n2 / name :op1 "IGF-1") :xref (x2 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (p4 / protein :name (n3 / name :op1 "GM-CSF") :xref (x1 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n4 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :quant (n5 / numerous)) :prep-in (r / range :mod (s2 / size) :mod (t / this)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "11" :op2 "18"))))) # ::id a_pmid_2169_9731.113 # ::date 2015-05-20T06:59:27 # ::file a_pmid_2169_9731_113.txt # ::snt To further narrow down the list of possible candidates, an in silico analysis was performed for each fraction size as described in Materials and Methods. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (p / perform-02 :ARG1 (a / analyze-01 :ARG1 (s / size :mod (f / fraction) :mod (e / each)) :manner (i / in-silico)) :purpose (n / narrow-down-03 :ARG1 (l / list :consist-of (c / candidate :ARG1-of (p2 / possible-01))) :degree (f2 / further)) :ARG1-of (d / describe-01 :ARG0 (s2 / section :name (n2 / name :op1 "Materials" :op2 "and" :op3 "Methods")))) # ::id a_pmid_2169_9731.114 # ::date 2015-05-20T07:11:31 # ::file a_pmid_2169_9731_114.txt # ::snt The resulting data points were separately fit for each fraction size to the general equation y = y0 + a(1-e-bx) as described, with regression r2 = 0.997, 0.842 and 0.918 for the > 3, > 10 and > 30 kDa fractions, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (f / fit-06 :ARG1 (p / point :mod (d / data) :ARG1-of (r / result-01)) :ARG2 (e2 / equation :ARG1-of (g / general-02) :mod (s6 / string-entity :value "y=y0+a(1-e-bx)")) :manner (s / separate-02) :beneficiary (s2 / size :mod (f2 / fraction) :mod (e / each)) :condition (a / and :op1 (s3 / statistical-test-91 :ARG1 (f3 / fraction :mod (m4 / more-than :op1 (m / mass-quantity :quant "3" :unit (k / kilodalton)))) :ARG3 "0.997") :op2 (s4 / statistical-test-91 :ARG1 (f4 / fraction :mod (m5 / more-than :op1 (m2 / mass-quantity :quant "10" :unit (k2 / kilodalton)))) :ARG3 "0.842") :op3 (s5 / statistical-test-91 :ARG1 (f5 / fraction :mod (m6 / more-than :op1 (m3 / mass-quantity :quant "30" :unit (k3 / kilodalton)))) :ARG3 "0.918")) :ARG1-of (d2 / describe-01)) # ::id a_pmid_2169_9731.115 # ::date 2015-05-20T07:12:18 # ::file a_pmid_2169_9731_115.txt # ::snt From regression analysis, the responsible factor(s) appeared to be 7.23-10.8 kDa in size, suggesting that growth factors such as IGF-1 (7.5 kDa) may be responsible for the MØCM-stimulated neoplastic proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a / appear-02 :ARG1 (h / have-03 :ARG0 (f / factor :ARG0-of (r / responsible-01)) :ARG1 (s / size :mod (m / mass-quantity :unit (k / kilodalton) :quant (b / between :op1 "7.23" :op2 "10.8"))) :ARG0-of (s2 / suggest-01 :ARG1 (p / possible-01 :ARG1 (r3 / responsible-01 :ARG0 (g / growth-factor :example (p3 / protein :name (n2 / name :op1 "IGF-1") :mod (m2 / mass-quantity :quant "7.5" :unit (k2 / kilodalton)) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG1 (p2 / proliferate-01 :ARG0 (t / tumor) :ARG1-of (s4 / stimulate-01 :ARG0 (m3 / medium :ARG1-of (c / condition-01 :ARG0 (m4 / macrophage))))))))) :ARG1-of (d2 / deduce-01 :ARG2 (a2 / analysis :mod (r2 / regress-01)))) # ::id a_pmid_2169_9731.116 # ::date 2015-05-20T07:30:00 # ::file a_pmid_2169_9731_116.txt # ::snt Macrophage-conditioned media IGF-1 levels correlate to effects on neoplastic proliferation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 21, 2015 (c / correlate-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :source (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG2 (a / affect-01 :ARG1 (p / proliferate-01 :ARG0 (t / tumor)))) # ::id a_pmid_2169_9731.117 # ::date 2015-05-20T07:33:14 # ::file a_pmid_2169_9731_117.txt # ::snt IGF-1 has a well-established role in the metastasis of cancer cells in vivo, as well as stimulating growth in vitro [27], and alveolar macrophages produce high levels of IGF-1 in response to quartz dust-induced lung injury [30]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (h / have-03 :ARG0 (p4 / protein :name (n2 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (r / role :ARG1-of (e2 / establish-01 :mod (w / well)) :prep-in (a2 / and :op1 (m / metastasize-101 :ARG1 (c / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :manner (i / in-vivo)) :op2 (s / stimulate-01 :ARG0 p4 :ARG1 (g / grow-01) :manner (i2 / in-vitro))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 "27"))))) :op2 (p2 / produce-01 :ARG0 (m2 / macrophage :mod (a3 / alveolus)) :ARG1 (l / level :ARG1-of (h2 / high-02) :quant-of p4) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "30"))) :ARG2-of (r2 / respond-01 :ARG1 (i3 / injure-01 :ARG1 (l2 / lung) :ARG2-of (i4 / induce-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "quartz" :op2 "dust") :xref (x1 / xref :value "PUBCHEM:24261" :prob "14.492002"))))))) # ::id a_pmid_2169_9731.118 # ::date 2015-05-20T07:54:18 # ::file a_pmid_2169_9731_118.txt # ::snt While alveolar macrophages are an important component of the chronic inflammatory milieu responsible for promoting lung tumorigenesis, IGF-1 has not been examined as a possible connection between macrophage recruitment and lung cancer progression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (e / examine-01 :polarity "-" :ARG1 (p / protein :name (n2 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG2 (c2 / connect-01 :ARG0 p :ARG1 (r / recruit-01 :ARG1 (m / macrophage)) :ARG1 (p3 / progress-01 :ARG1 (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer"))) :ARG1-of (p2 / possible-01))) :ARG2 (c4 / component :mod (i3 / important) :ARG1-of (i / include-91 :ARG2 (m3 / milieu :mod (c3 / chronic) :mod (i2 / inflame-01) :ARG0-of (r2 / responsible-01 :ARG1 (p4 / promote-01 :ARG1 (c5 / create-01 :ARG1 (t2 / tumor :mod (l / lung))))))) :domain (m2 / macrophage :mod (a / alveolus)))) # ::id a_pmid_2169_9731.119 # ::date 2015-05-20T08:11:42 # ::file a_pmid_2169_9731_119.txt # ::snt BALF from tumor-bearing lungs contained 3.5-times more IGF-1 than BALF from naïve mice, while EGF levels were unchanged (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / contrast-01 :ARG1 (c3 / contain-01 :ARG0 (f3 / fluid :source (l2 / lung :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :mod "l3") :ARG1 (p2 / protein :name (n3 / name :op1 "IGF-1") :quant (m2 / more :degree (p3 / product-of :op1 "3.5")) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :compared-to (f2 / fluid :part-of (m4 / mouse :mod (n5 / naive)) :mod (l3 / lavage :mod (a / alveolus :mod (b2 / bronchus))))) :ARG2 (c2 / change-01 :polarity "-" :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id a_pmid_2169_9731.120 # ::date 2015-05-20T08:30:27 # ::file a_pmid_2169_9731_120.txt # ::snt Even after normalizing to total BALF protein levels, BALF IGF-1 was significantly higher in tumor-bearing animals than naïve controls (1.81 ± 0.33 vs. 0.95 ± 0.36 pg IGF-1/ug BALF protein, respectively, P < 0.01, mean ± SD), suggesting that more IGF-1 is produced in the lungs of tumor-bearing mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 4, 2016 (h / high-02 :ARG1 (l3 / level :quant-of (p / protein :name (n / name :op1 "IGF-1") :source (f / fluid :mod (l5 / lavage :mod (a3 / alveolus :mod (b2 / bronchus)))) :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1-of (e2 / equal-01 :ARG2 (m4 / mass-quantity :unit (r / ratio-of :op1 (p5 / picogram :mod p) :op2 (m6 / microgram :mod f)) :quant (v / value-interval :op1 (s4 / subtract-01 :ARG1 "0.33" :ARG2 "1.81") :op2 (a4 / add-02 :ARG1 "0.33" :ARG2 "1.81"))) :condition (a2 / and :op1 (s6 / statistical-test-91 :ARG2 (l6 / less-than :op1 "0.01")) :op2 (d / deviate-01 :mod (m8 / mean) :ARG1-of (s3 / standard-02))))) :compared-to (l4 / level :quant-of (p4 / protein :name (n5 / name :op1 "IGF-1") :source (c / control :mod (n3 / naive)) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1-of (e3 / equal-01 :ARG2 (m7 / mass-quantity :unit r :quant (v2 / value-interval :op1 (s5 / subtract-01 :ARG1 "0.36" :ARG2 "0.95") :op2 (a5 / add-02 :ARG1 "0.36" :ARG2 "0.95"))) :condition a2)) :location (a / animal :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG0-of (s2 / suggest-01 :ARG1 (p3 / produce-01 :ARG1 p :quant (m2 / more) :location (l2 / lung :part-of (m3 / mouse :ARG0-of b)))) :degree (m5 / more) :ARG1-of (s / significant-02) :concession (n4 / normalize-01 :ARG1 p :prep-to (l / level :quant-of (p2 / protein :mod f) :mod (t2 / total)))) # ::id a_pmid_2169_9731.121 # ::date 2015-05-20T08:58:27 # ::file a_pmid_2169_9731_121.txt # ::snt Measurement of IGF-1 levels in MØCM from primary naïve and tumor-educated BAL macrophages showed that tumor-educated macrophages produced significantly more IGF-1 than naïve macrophages (Figure 6B, grey bars). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / show-01 :ARG0 (m / measure-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :location (m2 / medium :source (a / and :op1 (m3 / macrophage :mod (n4 / naive)) :op2 (m5 / macrophage :ARG1-of (e / educate-01 :ARG0 (t / tumor))) :mod (f2 / fluid :mod (a2 / alveolus :mod (b2 / bronchus))) :mod (p2 / primary)) :ARG1-of (c / condition-01 :ARG0 (m7 / macrophage)))) :ARG1 (p3 / produce-01 :ARG0 m5 :ARG1 (l2 / level :quant-of p :quant (m6 / more :ARG1-of (s2 / significant-02))) :compared-to m3) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B") :ARG2 (b / bar :ARG1-of (g / gray-02)))) # ::id a_pmid_2169_9731.122 # ::date 2015-05-20T09:13:12 # ::file a_pmid_2169_9731_122.txt # ::snt IL-4 potently stimulates alternative macrophage activation, and is more abundant in tumor-bearing lungs than naïve [38]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (a / and :op1 (s / stimulate-01 :ARG0 (p2 / protein :name (n / name :op1 "IL-4") :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :ARG1 (a2 / activate-01 :ARG1 (m / macrophage) :mod (a3 / alternative)) :manner (p / potent)) :op2 (a4 / abundant :domain p2 :degree (m2 / more) :location (l / lung :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :compared-to (n2 / naive)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "38")))) # ::id a_pmid_2169_9731.123 # ::date 2015-05-20T09:15:59 # ::file a_pmid_2169_9731_123.txt # ::snt Alternative macrophage polarization is associated with tumorigenesis [6] and increased macrophage IGF-1 production [39]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (a / associate-01 :ARG1 (p / polarize-01 :ARG1 (m / macrophage) :mod (a2 / alternative)) :ARG2 (a3 / and :op1 (c3 / create-01 :ARG1 (t / tumor) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "6")))) :op2 (p3 / produce-01 :ARG0 m :ARG1 (p4 / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1-of (i / increase-01) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "39")))))) # ::id a_pmid_2169_9731.124 # ::date 2015-05-20T09:21:15 # ::file a_pmid_2169_9731_124.txt # ::snt Therefore, IL-4 was added to wells containing primary naïve and tumor-educated BAL macrophages to determine if alternative activation could increase IGF-1 production in either macrophage group. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / cause-01 :ARG1 (a / add-02 :ARG1 (p2 / protein :name (n / name :op1 "IL-4") :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :ARG2 (w / well :ARG0-of (c2 / contain-01 :ARG1 (a2 / and :op1 (m2 / macrophage :mod (n3 / naive)) :op2 (m3 / macrophage :ARG1-of (e / educate-01 :ARG0 (t / tumor))) :mod (p3 / primary) :mod (m / medium :ARG1-of (c3 / condition-01 :ARG0 (m4 / macrophage)))))) :purpose (d / determine-01 :ARG1 (p4 / possible-01 :ARG1 (i / increase-01 :ARG0 (a3 / activate-01 :mod (a4 / alternative)) :ARG1 (p5 / produce-01 :ARG1 p2) :location a2))))) # ::id a_pmid_2169_9731.125 # ::date 2015-05-20T09:29:17 # ::file a_pmid_2169_9731_125.txt # ::snt Both naïve and tumor-educated macrophages produced significantly more IGF-1 after IL-4 treatment; tumor-educated macrophages more than doubled IGF-1 output compared to naïve samples (Figure 6B, green bars). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (p / produce-01 :ARG0 (a / and :op1 (m2 / macrophage :mod (n / naive)) :op2 (m3 / macrophage :ARG1-of (e / educate-01 :ARG0 (t / tumor)))) :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1") :quant (m4 / more :degree (s / significant)) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :condition (t2 / treat-04 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-4") :xref (x1 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")))) :snt2 (d / double-01 :ARG0 (m6 / macrophage :ARG1-of (e2 / educate-01 :ARG0 (t3 / tumor))) :ARG1 (o / output :mod (p4 / protein :name (n4 / name :op1 "IGF-1") :xref (x2 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :degree (m5 / more-than) :compared-to (t4 / thing :mod (n5 / naive) :ARG1-of (s2 / sample-01))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6B") :ARG2 (b / bar :ARG1-of (g / green-02)))) # ::id a_pmid_2169_9731.126 # ::date 2015-05-20T09:35:19 # ::file a_pmid_2169_9731_126.txt # ::snt MH-S macrophages produced 20-times more IGF-1 than either non-neoplastic or neoplastic lung cell lines, and all three cell lines produced only trace amounts (< 2 pg/mL) of EGF (Figure 6E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (p / produce-01 :ARG0 (m / macrophage :source (c / cell-line :name (n / name :op1 "MH-S"))) :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1") :quant (m2 / more :degree (p3 / product-of :op1 "20")) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :compared-to (o / or :op1 (c5 / cell-line :mod (t / tumor :polarity "-")) :op2 (c6 / cell-line :mod (t2 / tumor)) :source (l2 / lung))) :op2 (p4 / produce-01 :ARG0 (a2 / and :op1 m :op2 c5 :op3 c6) :ARG1 (a3 / amount :mod (t3 / trace) :mod (p5 / protein :name (n3 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1-of (e / equal-01 :ARG2 (l5 / less-than :op1 (c4 / concentration-quantity :quant "2" :unit (p6 / picogram-per-milliliter)))) :mod (o2 / only))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6E"))) # ::id a_pmid_2169_9731.127 # ::date 2015-05-21T00:09:30 # ::file a_pmid_2169_9731_127.txt # ::snt In order to determine whether the growth effects of MØCM from samples generated in Figure 6B correlated with their IGF-1 content, MØCM was added to neoplastic LM2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / add-02 :ARG1 (m / medium :ARG1-of (c4 / condition-01 :ARG0 (m2 / macrophage))) :ARG2 (c / cell-line :name (n2 / name :op1 "LM2") :mod (t / tumor)) :purpose (d / determine-01 :ARG1 (c2 / correlate-01 :mode "interrogative" :ARG1 (a2 / affect-01 :ARG0 m :ARG1 (g / grow-01) :location (t2 / thing :ARG1-of (s / sample-01)) :ARG1-of (g2 / generate-01 :location (f / figure :mod "6B"))) :ARG2 (c3 / contain-01 :ARG0 t2 :ARG1 (p / protein :name (n3 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))))) # ::id a_pmid_2169_9731.128 # ::date 2015-05-21T00:29:44 # ::file a_pmid_2169_9731_128.txt # ::snt IL-4 stimulated naïve and tumor-educated MØCM significantly augmented LM2 proliferation (Figure 6C, green bars), with IL-4 treated tumor-educated MØCM being the most potent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (a2 / augment-01 :ARG0 (a3 / and :op1 (m / medium :mod (n3 / naive) :ARG1-of (c2 / condition-01 :ARG0 (m4 / macrophage))) :op2 (m2 / medium :ARG1-of (e / educate-01 :ARG0 (t / tumor)) :ARG1-of c2) :ARG1-of (s / stimulate-01 :ARG0 (p / protein :name (n4 / name :op1 "IL-4") :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")))) :ARG1 (p2 / proliferate-01 :ARG0 (c / cell-line :name (n5 / name :op1 "LM2"))) :ARG1-of (s2 / significant-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C") :ARG2 (b / bar :ARG1-of (g / green-02)))) :op2 (p3 / potent :degree (m3 / most) :domain m2)) # ::id a_pmid_2169_9731.129 # ::date 2015-05-21T00:38:19 # ::file a_pmid_2169_9731_129.txt # ::snt MØCM from untreated tumor-educated macrophages did not stimulate LM2 growth significantly more than untreated naïve MØCM (Figure 6C, grey bars), corresponding to previous co-culture results (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / stimulate-01 :polarity "-" :ARG0 (m / medium :source (m2 / macrophage :ARG1-of (t / treat-04 :polarity "-") :ARG1-of (e / educate-01 :ARG0 (t2 / tumor))) :ARG1-of "c4") :ARG1 (g / grow-01 :ARG1 (c / cell-line :name (n2 / name :op1 "LM2"))) :degree (m3 / more :degree (s2 / significant)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C") :ARG2 (b / bar :ARG1-of (g2 / gray-02))) :ARG1-of (c2 / correspond-02 :ARG2 (t3 / thing :ARG2-of (r / result-01 :ARG1 (c3 / co-culture) :time (p / previous) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2B"))))) :compared-to (m4 / medium :ARG1-of t :mod (n4 / naive) :ARG1-of (c4 / condition-01 :ARG0 (m5 / macrophage)))) # ::id a_pmid_2169_9731.130 # ::date 2015-05-21T00:46:56 # ::file a_pmid_2169_9731_130.txt # ::snt As the growth-stimulating ability of MØCM appeared to correlate to media IGF-1 levels, the levels of IGF-1 present were plotted against the fold-change in LM2 cell number after MØCM addition (Figure 6D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (p / plot-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "IGF-1") :location "m" :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1-of (p4 / present-02)) :ARG2 (c / change-01 :ARG1 (n2 / number :quant-of (c2 / cell-line :name (n3 / name :op1 "LM2"))) :condition (a / add-02 :ARG1 (m / medium :ARG1-of (c6 / condition-01 :ARG0 (m3 / macrophage)))) :mod (p3 / product-of)) :ARG1-of (c3 / cause-01 :ARG0 (a2 / appear-02 :ARG1 (c4 / correlate-01 :ARG1 (c5 / capable-01 :ARG1 m :ARG2 (s / stimulate-01 :ARG0 m :ARG1 (g / grow-01))) :ARG2 l))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6D"))) # ::id a_pmid_2169_9731.131 # ::date 2015-05-21T00:56:37 # ::file a_pmid_2169_9731_131.txt # ::snt The correlation between IGF-1 levels and neoplastic growth stimulation was highly significant (p < 0.001), indicating that MØCM IGF-1 levels were directly related to the ability of MØCM to stimulate neoplastic proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / significant-02 :ARG1 (c / correlate-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG2 (s2 / stimulate-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)))) :ARG1-of (h / high-02) :ARG0-of (i / indicate-01 :ARG1 (r / relate-01 :ARG1 (l2 / level :quant-of p :location (m / medium :ARG1-of (c3 / condition-01 :ARG0 (m3 / macrophage)))) :ARG2 (c2 / capable-01 :ARG1 m :ARG2 (s3 / stimulate-01 :ARG0 m :ARG1 (p2 / proliferate-01 :ARG0 t))) :ARG1-of (d / direct-02))) :ARG1-of (m2 / mean-01 :ARG2 (l4 / less-than :op1 "0.001"))) # ::id a_pmid_2169_9731.132 # ::date 2015-05-21T01:02:29 # ::file a_pmid_2169_9731_132.txt # ::snt IGF-1 stimulates lung epithelial cell proliferation and is additive with MØCM # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / stimulate-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG1 (p2 / proliferate-01 :ARG0 (c / cell :source (l / lung) :mod (e / epithelium)))) # ::id a_pmid_2169_9731.133 # ::date 2015-05-21T01:07:18 # ::file a_pmid_2169_9731_133.txt # ::snt While IGF-1 levels correlated strongly with the ability of MØCM to stimulate neoplastic growth, IGF-1 induced proliferation of these non-neoplastic and neoplastic mouse lung cell lines has not been demonstrated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c3 / contrast-01 :ARG1 (d / demonstrate-01 :polarity "-" :ARG1 (p / proliferate-01 :ARG0 (a / and :op1 (c / cell-line :mod (t / tumor :polarity "-")) :op2 (c2 / cell-line :mod (t2 / tumor)) :source (l / lung :part-of (m / mouse)) :mod (t3 / this)) :ARG2-of (i / induce-01 :ARG0 (p2 / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))))) :ARG2 (c4 / correlate-01 :ARG1 (l2 / level :quant-of p2) :ARG2 (c5 / capable-01 :ARG1 (m2 / medium :ARG1-of (c6 / condition-01 :ARG0 (m3 / macrophage))) :ARG2 (s2 / stimulate-01 :ARG0 m2 :ARG1 (g / grow-01 :ARG1 t2))) :ARG1-of (s / strong-02))) # ::id a_pmid_2169_9731.134 # ::date 2015-05-21T01:11:01 # ::file a_pmid_2169_9731_134.txt # ::snt Recombinant mouse IGF-1 or MH-S macrophage-conditioned media was sufficient to stimulate the proliferation of neoplastic LM2, JF32 and E9 cells and non-neoplastic E10 cells (Figure 7A-D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / suffice-01 :ARG0 (o / or :op1 (m3 / medium :ARG1-of (c3 / condition-01 :ARG0 (p / protein :name (n2 / name :op1 "IGF-1") :source (m4 / mouse) :ARG3-of (r / recombine-01) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))) :op2 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage :source (c2 / cell-line :name (n / name :op1 "MH-S")))))) :ARG1 (s2 / stimulate-01 :ARG0 o :ARG1 (p2 / proliferate-01 :ARG0 (a / and :op1 (a2 / and :op1 (c4 / cell-line :name (n3 / name :op1 "LM2")) :op2 (c5 / cell-line :name (n4 / name :op1 "JF32")) :op3 (c6 / cell-line :name (n5 / name :op1 "E9")) :mod (t / tumor)) :op2 (c7 / cell-line :name (n6 / name :op1 "E10") :mod (t2 / tumor :polarity "-"))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7B") :op3 (f3 / figure :mod "7C") :op4 (f4 / figure :mod "7D")))) # ::id a_pmid_2169_9731.135 # ::date 2015-05-21T01:39:39 # ::file a_pmid_2169_9731_135.txt # ::snt The degree of growth stimulated by 50 ng/mL IGF-1 was similar to that of MØCM in each line (Figure 7A-D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / resemble-01 :ARG1 (g / grow-01 :ARG1-of (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "IGF-1") :quant (c / concentration-quantity :quant "50" :unit (n2 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))) :ARG2 (g2 / grow-01 :ARG1 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :location (l / line :mod (e / each)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7B") :op3 (f3 / figure :mod "7C") :op4 (f4 / figure :mod "7D")))) # ::id a_pmid_2169_9731.136 # ::date 2015-05-21T01:44:37 # ::file a_pmid_2169_9731_136.txt # ::snt These results confirm that IGF-1 alone can stimulate the growth of long-established neoplastic and non-neoplastic cell lines, as well as cells isolated more recently from primary mouse lung tumors (JF32), consistent with previous reports on human cancer cell lines [27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / confirm-01 :ARG0 (t / thing :ARG1-of (r / result-01 :ARG1-of (c6 / consistent-01 :ARG2 (t6 / thing :ARG1-of (r3 / report-01) :time (p4 / previous) :topic (c7 / cell-line :source (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod (h / human))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c9 / cite-01 :ARG2 "27")))))) :mod (t2 / this)) :ARG1 (p / possible-01 :ARG1 (s / stimulate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "IGF-1") :mod (a / alone) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (g / grow-01 :ARG1 (a2 / and :op1 (a3 / and :op1 (c2 / cell-line :mod (t3 / tumor)) :op2 (c3 / cell-line :mod (t4 / tumor :polarity "-")) :ARG1-of (e / establish-01 :ARG1-of (l / long-03))) :op2 (c4 / cell :ARG1-of (i / isolate-01 :ARG2 (t5 / tumor :mod (l2 / lung :part-of (m2 / mouse)) :mod (p3 / primary) :ARG1-of (m3 / mean-01 :ARG2 (c5 / cell-line :name (n3 / name :op1 "JF32")))) :time (r2 / recent :degree (m / more))))))))) # ::id a_pmid_2169_9731.137 # ::date 2015-05-21T01:51:28 # ::file a_pmid_2169_9731_137.txt # ::snt In order to determine any relevant role of EGFR in mediating macrophage-stimulated tumor cell proliferation in these cell lines, recombinant mouse EGF was added at 2 ng/mL. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 30, 2015 (a / add-02 :ARG1 (p / protein :name (n2 / name :op1 "EGF") :quant (c / concentration-quantity :quant "2" :unit (n3 / nanogram-per-milliliter)) :source (m / mouse) :ARG3-of (r / recombine-01) :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :purpose (d / determine-01 :ARG1 (r3 / relevant-01 :ARG1 (r4 / role :poss (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG2 (m2 / mediate-01 :ARG0 p :ARG1 (p2 / proliferate-01 :ARG0 (c2 / cell :mod (t / tumor)) :ARG1-of (s / stimulate-01 :ARG0 (m3 / macrophage)) :location (c3 / cell-line :mod (t2 / this))))))) # ::id a_pmid_2169_9731.138 # ::date 2015-05-21T01:59:46 # ::file a_pmid_2169_9731_138.txt # ::snt This is roughly 500-times the reported EC50 for growth stimulation and 20-times higher than levels found in the BALF from tumor-bearing animals (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (e / equal-01 :ARG1 (t / this) :ARG2 (r2 / roughly :op1 (p / product-of :op1 "500" :op2 (c / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-effective-concentration-01 :ARG2 "50" :ARG3 (s / stimulate-01 :ARG1 (g / grow-01))) :ARG1-of (r / report-01))))) :op2 (e2 / equal-01 :ARG1 t :ARG2 (r3 / roughly :op1 (h / high-02 :ARG1 t :degree (m / more) :degree (p2 / product-of :op1 "20") :compared-to (l / level :ARG1-of (f / find-01 :location (f3 / fluid :mod (l2 / lavage :mod (a3 / alveolus :mod (b2 / bronchus))) :source (a2 / animal :ARG0-of (b / bear-01 :ARG1 (t3 / tumor))))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6A"))) # ::id a_pmid_2169_9731.139 # ::date 2015-05-26T00:07:32 # ::file a_pmid_2169_9731_139.txt # ::snt EGF had no significant effect on tumor cell proliferation when added alone, and did not significantly affect the ability of either IGF-1 or MØCM to stimulate neoplastic growth (Figure 7E, F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a4 / and :op1 (a / affect-01 :polarity "-" :ARG0 (p / protein :name (n / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p2 / proliferate-01 :ARG0 (c / cell :mod (t / tumor))) :ARG1-of (s / significant-02) :condition (a2 / add-02 :ARG1 p :manner (a3 / alone))) :op2 (a5 / affect-01 :polarity "-" :ARG0 p :ARG1 (c3 / capable-01 :ARG1 "o" :ARG2 (s3 / stimulate-01 :ARG0 (o / or :op1 (p4 / protein :name (n3 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG1 (g / grow-01 :ARG1 (n2 / neoplasm)))) :ARG1-of s) :ARG1-of (d / describe-01 :ARG0 (a6 / and :op1 (f / figure :mod "7E") :op2 (f2 / figure :mod "7F")))) # ::id a_pmid_2169_9731.140 # ::date 2015-05-26T00:37:37 # ::file a_pmid_2169_9731_140.txt # ::snt This is not surprising in view of recent studies showing that EGFR inhibitors do not inhibit growth of lung cells with KRAS mutations [40]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (s / surprise-01 :polarity "-" :ARG0 (t2 / this) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "40"))) :ARG2-of (v / view-02 :ARG1 (s2 / show-01 :ARG0 (s3 / study-01 :time (r / recent)) :ARG1 (i2 / inhibit-01 :polarity "-" :ARG0 (m / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG1 (g / grow-01 :ARG1 (c2 / cell :mod (l / lung) :mod (g2 / gene :name (n2 / name :op1 "KRAS") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))))))) # ::id a_pmid_2169_9731.141 # ::date 2015-05-26T00:59:38 # ::file a_pmid_2169_9731_141.txt # ::snt As IGF-1 was sufficient to induce neoplastic proliferation, we determined whether the IGF-1 and MØCM growth effects were additive. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (d / determine-01 :ARG0 (w / we) :ARG1 (a / add-02 :mode "interrogative" :ARG1 (a5 / and :op1 (a2 / affect-01 :ARG0 (p / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG2 (g / grow-01)) :op2 (a3 / affect-01 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :ARG2 g))) :ARG1-of (c2 / cause-01 :ARG0 (s / suffice-01 :ARG0 p :ARG1 (i / induce-01 :ARG0 p :ARG2 (p2 / proliferate-01 :ARG0 (n3 / neoplasm)))))) # ::id a_pmid_2169_9731.142 # ::date 2015-05-26T05:53:58 # ::file a_pmid_2169_9731_142.txt # ::snt A dose of 50 ng/ml IGF-1 stimulated neoplastic growth to a similar extent as MØCM (Figure 7A-D); 2 ng/mL IGF is the reported EC50 for IGF-1 stimulated proliferation in vitro as well as the concentration detected in the BALF of tumor-bearing mice in vivo (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a2 / and :op1 (s / stimulate-01 :ARG0 (d / dose-01 :ARG2 (p / protein :name (n / name :op1 "IGF-1") :quant (c / concentration-quantity :quant "50" :unit (n5 / nanogram-per-milliliter)) :xref (x2 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG1 (g / grow-01 :ARG1 (n2 / neoplasm)) :ARG3 (e / extent :ARG1-of (r2 / resemble-01 :ARG2 (s2 / stimulate-01 :ARG0 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m4 / macrophage))) :ARG1 g))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "7A") :op2 (f3 / figure :mod "7B") :op3 (f4 / figure :mod "7C") :op4 (f5 / figure :mod "7D")))) :op2 (p2 / protein :name (n4 / name :op1 "IGF") :quant (c3 / concentration-quantity :quant "2" :unit n5) :ARG1-of (e2 / equal-01 :ARG2 (a / and :op1 (h / have-percentage-maximal-effective-concentration-01 :ARG2 "50" :ARG1-of (r3 / report-01)) :op2 (c4 / concentrate-02 :ARG1 (f6 / fluid :mod (l / lavage :mod (a4 / alveolus :mod (b2 / bronchus))) :source (m2 / mouse :ARG0-of (b / bear-01 :ARG1 (t / tumor)))) :ARG1-of (d3 / detect-01) :manner (i2 / in-vivo)))) :condition (p3 / proliferate-01 :ARG1-of (s3 / stimulate-01 :ARG0 (p5 / protein :name (n6 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :manner (i / in-vitro)) :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.263")) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "6A"))) # ::id a_pmid_2169_9731.143 # ::date 2015-05-26T08:10:38 # ::file a_pmid_2169_9731_143.txt # ::snt IGF-1 dose-dependently stimulated the proliferation of both LM2 and JF32 cells, and augmented the growth-stimulating effects of MØCM when added in combination. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (p2 / proliferate-01 :ARG0 (a3 / and :op1 (c / cell-line :name (n2 / name :op1 "LM2")) :op2 (c2 / cell-line :name (n3 / name :op1 "JF32")))) :ARG0-of (d2 / depend-01 :ARG1 (d3 / dose))) :op2 (a2 / augment-01 :ARG0 p :ARG1 (a5 / affect-01 :ARG0 (m / medium :ARG1-of (c3 / condition-01 :ARG0 (m2 / macrophage))) :ARG2 (s2 / stimulate-01 :ARG1 (g / grow-01))) :condition (a4 / add-02 :ARG1 p :ARG2 (c4 / combine-01)))) # ::id a_pmid_2169_9731.144 # ::date 2015-05-26T08:47:40 # ::file a_pmid_2169_9731_144.txt # ::snt To determine if IGF-1R signaling mediates both IGF-1 and MØCM stimulation, lung cancer cells were pre-treated with vehicle or 5 μM NVP-AEW541 (- or +, respectively), and cell numbers determined as indicated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (p3 / pretreat-01 :ARG1 (c / cell :source (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer"))) :ARG3 (o / or :op1 (v / vehicle) :op2 (s3 / small-molecule :name (n2 / name :op1 "NVP-AEW541") :quant (c3 / concentration-quantity :quant "5" :unit (m / micromolar)) :xref (x2 / xref :value "PUBCHEM:11476171" :prob "20.615713")))) :op2 (d2 / determine-01 :ARG1 (n3 / number :quant-of (c4 / cell)) :ARG1-of (i / indicate-01)) :purpose (d3 / determine-01 :ARG1 (m2 / mediate-01 :mode "interrogative" :ARG0 (s / signal-07 :ARG0 (p / protein :name (n4 / name :op1 "IGF-1R") :xref (x1 / xref :value "UNIPROT:IGF1R_HUMAN" :prob "0.683"))) :ARG1 (s2 / stimulate-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n5 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (m3 / medium :ARG1-of (c2 / condition-01 :ARG0 (m4 / macrophage)))))))) # ::id a_pmid_2169_9731.145 # ::date 2015-05-26T08:59:13 # ::file a_pmid_2169_9731_145.txt # ::snt IGF-1 and MØCM each significantly increased cell numbers after 48 and 72 hrs, while pharmacological inhibition of IGF-1R signaling blocked IGF-1 and MØCM growth effects in both neoplastic lines (Figure 7G, H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / contrast-01 :ARG1 (i / increase-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG1 (n3 / number :quant-of (c3 / cell)) :ARG1-of (s / significant-02) :time (a2 / after :quant (a3 / and :op1 (t / temporal-quantity :quant "48" :unit (h / hour)) :op2 (t2 / temporal-quantity :quant "72" :unit h)))) :ARG2 (b / block-01 :ARG0 (i2 / inhibit-01 :ARG1 (s2 / signal-07 :ARG0 (p3 / protein :name (n4 / name :op1 "IGF-1R") :xref (x / xref :value "UNIPROT:IGF1R_HUMAN" :prob "0.683"))) :mod (p2 / pharmacology)) :ARG1 (a6 / affect-01 :ARG2 (g / grow-01 :ARG0 (a4 / and :op1 p :op2 m))) :location (l / line :mod (n5 / neoplasm) :mod (b2 / both))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "7G") :op2 (f2 / figure :mod "7H")))) # ::id a_pmid_2169_9731.146 # ::date 2015-05-26T23:32:51 # ::file a_pmid_2169_9731_146.txt # ::snt Parallel comparison of MTS values indicated a highly significant correlation between live cell numbers and relative MTS scores (r2 = 0.7912 and 0.8201 for LM2 and JF32, respectively, p < 0.0001, data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (c / compare-01 :ARG1 (v / value :mod (t / thing :name (n / name :op1 "MTS"))) :ARG2 v :manner (p / parallel)) :ARG1 (c2 / correlate-01 :ARG1 (n3 / number :quant-of (c3 / cell :ARG0-of (l / live-01))) :ARG2 (s / score-01 :ARG1 t :ARG1-of (r / relative-05) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (s4 / statistical-test-91 :ARG1 (c4 / cell-line :name (n5 / name :op1 "LM2")) :ARG3 "0.7912") :op2 (s5 / statistical-test-91 :ARG1 (c5 / cell-line :name (n6 / name :op1 "JF32")) :ARG3 "0.8201") :op3 (s6 / statistical-test-91 :ARG2 (l2 / less-than :quant "0.0001"))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s3 / show-01 :polarity "-"))))) :ARG1-of (s2 / significant-02 :ARG1-of (h / high-02)))) # ::id a_pmid_2169_9731.147 # ::date 2015-05-27T00:55:54 # ::file a_pmid_2169_9731_147.txt # ::snt Furthermore, both IGF-1 and MØCM increased the fraction of BrdU+ LM2 cells 12-24 hrs after treatment, corresponding with significantly increased cell numbers (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op2 (i / increase-01 :ARG0 (a2 / and :op1 (p / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG1 (f / fraction :quant-of (c / cell-line :name (n4 / name :op1 "LM2") :mod (s3 / small-molecule :name (n3 / name :op1 "BrdU") :mod (w / wild-type) :xref (x1 / xref :value "PUBCHEM:6035" :prob "18.013371")))) :time (a3 / after :op1 (t / treat-04) :quant (t2 / temporal-quantity :quant (v / value-interval :op1 "12" :op2 "24") :unit (h / hour))) :ARG1-of (c3 / correspond-02 :ARG2 (n5 / number :quant-of (c4 / cell) :ARG1-of (i2 / increase-01 :ARG2 (s / significant-02))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity "-")))) # ::id a_pmid_2169_9731.148 # ::date 2015-05-27T01:07:33 # ::file a_pmid_2169_9731_148.txt # ::snt These observations suggest that IGF-1, but not EGF, plays a major role in macrophage stimulated neoplastic growth in vitro, consistent with the elevated IGF-1 levels observed in lung-tumor bearing animals in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (s / suggest-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (c / contrast-01 :ARG1 (p / play-08 :ARG0 (p2 / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (g / grow-01 :ARG1 (n2 / neoplasm :ARG1-of (s2 / stimulate-01 :ARG0 (m2 / macrophage)))) :manner (i / in-vitro) :ARG1-of (m / major-02)) :ARG2 (p3 / play-08 :polarity "-" :ARG0 (p4 / protein :name (n3 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG1-of (c2 / consistent-01 :ARG2 (l / level :ARG1-of (o2 / observe-01 :manner (i2 / in-vivo) :location (a / animal :ARG0-of (b / bear-01 :ARG1 (t2 / tumor :mod (l2 / lung))))) :ARG1-of (e / elevate-01) :quant-of p2))) # ::id a_pmid_2169_9731.149 # ::date 2015-05-27T01:27:32 # ::file a_pmid_2169_9731_149.txt # ::snt MØCM stimulation of neoplastic growth is diminished when IGF-1 content is decreased # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (d / diminish-01 :ARG1 (s / stimulate-01 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :ARG1 (g / grow-01 :ARG1 (n2 / neoplasm))) :time (d2 / decrease-01 :ARG1 (c2 / content :quant-of (p / protein :name (n3 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))))) # ::id a_pmid_2169_9731.150 # ::date 2015-05-27T01:33:27 # ::file a_pmid_2169_9731_150.txt # ::snt In order to determine if IGF-1 was a molecular mediator directly responsible for growth stimulated by MØCM, we decreased MØCM IGF-1 content through two independent avenues: immuno-depletion and siRNA interference. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (d / decrease-01 :ARG0 (w / we) :ARG1 (c / contain-01 :ARG0 "m4" :ARG1 "p3") :instrument (a2 / avenue :quant "2" :ARG0-of (d2 / depend-01 :polarity "-") :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (i / immunodeplete-00) :op2 (i2 / interfere-01 :ARG1 (n / nucleic-acid :name (n3 / name :op1 "siRNA")))))) :purpose (d3 / determine-01 :ARG0 (w2 / we) :ARG1 (r2 / responsible-01 :mode "interrogative" :ARG0 (p3 / protein :name (n4 / name :op1 "IGF-1") :ARG0-of (m / mediate-01) :mod (m3 / molecule) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (g / grow-01 :ARG1-of (s / stimulate-01 :ARG0 (m4 / medium :ARG1-of (c2 / condition-01 :ARG0 (m5 / macrophage))))) :ARG1-of (d4 / direct-02)))) # ::id a_pmid_2169_9731.151 # ::date 2015-05-27T01:45:03 # ::file a_pmid_2169_9731_151.txt # ::snt MØCM was concentrated to contain ~3.5 ng/mL IGF-1, and then incubated with control IgG (Con IgG) or α-IGF-1 IgG coated resin, as described [39]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / and :op1 (c / concentrate-02 :ARG1 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage))) :purpose (c3 / contain-01 :ARG0 m :ARG1 (p4 / protein :name (n5 / name :op1 "IGF-1") :quant (a3 / approximately :op1 (c4 / concentration-quantity :quant "3.5" :unit (n6 / nanogram-per-milliliter))) :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))) :op2 (i / incubate-01 :ARG1 m :ARG2 (o / or :op1 (p / protein :name (n2 / name :op1 "IgG") :ARG0-of (c5 / control-01) :xref (x2 / xref :value "UNIPROT:Q9Y298_HUMAN" :prob "0.211")) :op2 (r2 / resin :ARG1-of (c6 / coat-01 :ARG2 (a2 / and :op1 (p2 / protein :name (n4 / name :op1 "α-IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.553")) :op2 p)))) :time (t / then)) :ARG1-of (r / resemble-01 :ARG2 (t2 / thing :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 "39")))))) # ::id a_pmid_2169_9731.152 # ::date 2015-05-27T08:56:32 # ::file a_pmid_2169_9731_152.txt # ::snt This procedure successfully decreased MØCM IGF-1 levels to 40-50% of control (Figure 8A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (d / decrease-01 :ARG0 (p2 / procedure :mod (t / this)) :ARG1 (l / level :quant-of (p3 / protein :name (n2 / name :op1 "IGF-1") :mod (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG4 (c3 / control :quant (p4 / percentage-entity :value (v / value-interval :op1 "40" :op2 "50"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "8A")) :ARG1-of (s / succeed-01)) # ::id a_pmid_2169_9731.153 # ::date 2015-05-27T09:03:09 # ::file a_pmid_2169_9731_153.txt # ::snt When this IGF-1 depleted media was added to LM2 and JF32 cells, growth stimulation was significantly decreased compared to untreated MØCM or IgG controls, which were identical (Figure 8B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (d4 / decrease-01 :ARG1 (s / stimulate-01 :ARG1 (g / grow-01)) :ARG2 (s2 / significant-02) :time (a / add-02 :ARG1 (m / media :ARG1-of (d2 / deplete-01 :ARG2 (p2 / protein :name (n3 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :mod (t2 / this)) :ARG2 (a2 / and :op1 (c / cell-line :name (n4 / name :op1 "LM2")) :op2 (c4 / cell-line :name (n5 / name :op1 "JF32")))) :compared-to (c3 / control-01 :ARG0 (o / or :op1 (m2 / medium :ARG1-of (t / treat-04 :polarity "-") :ARG1-of (c2 / condition-01 :ARG0 (m3 / macrophage))) :op2 (p / protein :name (n2 / name :op1 "IgG") :ARG1-of (i / identical-01 :ARG2 m2) :ARG1-of t :xref (x1 / xref :value "UNIPROT:Q9Y298_HUMAN" :prob "0.211")))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "8B"))) # ::id a_pmid_2169_9731.154 # ::date 2015-05-27T09:24:03 # ::file a_pmid_2169_9731_154.txt # ::snt In addition, MH-S macrophage IGF-1 secretion was interrupted by transfection with scrambled control (scr siRNA) or siRNA constructs designed against mouse IGF-1 (α-IGF siRNA). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (i / interrupt-01 :ARG0 (t / transfect-01 :ARG2 (o / or :op1 (c / control :ARG1-of (s2 / scramble-02) :ARG1-of (m4 / mean-01 :ARG2 (n8 / nucleic-acid :name (n7 / name :op1 "siRNA") :ARG1-of s2))) :op2 (c2 / construct :mod (n9 / nucleic-acid :name (n3 / name :op1 "siRNA")) :ARG1-of (d / design-01 :purpose (o2 / oppose-01 :ARG1 (p2 / protein :name (n4 / name :op1 "IGF-1") :source (m2 / mouse) :ARG1-of (m3 / mean-01 :ARG2 (n10 / nucleic-acid :name (n5 / name :op1 "siRNA") :mod (p3 / protein :name (n6 / name :op1 "α-IGF") :xref (x2 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.253")))) :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))))))) :ARG1 (s / secrete-01 :ARG0 (m / macrophage :mod (c3 / cell-line :name (n / name :op1 "MH-S"))) :ARG1 (p / protein :name (n2 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))))) # ::id a_pmid_2169_9731.155 # ::date 2015-05-27T09:30:54 # ::file a_pmid_2169_9731_155.txt # ::snt One α-IGF siRNA construct was more effective than the scr siRNA, and significantly decreased MØCM IGF-1 levels to 25% of control (Figure 8C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (e / effective-04 :ARG0 (c / construct-01 :quant "1" :ARG2 (n6 / nucleic-acid :name (n / name :op1 "siRNA") :mod (p2 / protein :name (n2 / name :op1 "α-IGF") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.253")))) :degree (m / more) :compared-to (n7 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG1-of (s / scramble-02))) :op2 (d / decrease-01 :ARG1 (l / level :quant-of (p3 / protein :name (n4 / name :op1 "IGF-1") :mod (m2 / medium :ARG1-of (c2 / condition-01 :ARG0 (m3 / macrophage))) :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG2 (s2 / significant-02) :ARG4 (c3 / control :quant (p / percentage-entity :value "25"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "8C"))) # ::id a_pmid_2169_9731.156 # ::date 2015-05-27T10:14:06 # ::file a_pmid_2169_9731_156.txt # ::snt The scr siRNA construct decreased macrophage IGF-1 secretion to a lesser extent (Figure 8C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 27, 2015 (d / decrease-01 :ARG0 (c / construct :topic (n3 / nucleic-acid :name (n / name :op1 "siRNA") :ARG1-of (s / scramble-02))) :ARG1 (s2 / secrete-01 :ARG0 (m / macrophage) :ARG1 (p / protein :name (n2 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG4 (e / extent :degree (l / less)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "8C"))) # ::id a_pmid_2169_9731.157 # ::date 2015-05-27T10:18:23 # ::file a_pmid_2169_9731_157.txt # ::snt Transfection reagents and conditions were chosen to minimize cellular toxicity, and media IGF-1 content significantly decreased when normalized to MH-S viability (media IGF-1/MTS relative viability, data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (c / choose-01 :ARG1 (a2 / and :op1 (r / reagent :ARG2-of (t / transfect-01)) :op2 (c2 / condition :mod t)) :purpose (m / minimize-01 :ARG0 a2 :ARG1 (t2 / toxicity :mod (c3 / cell)))) :op2 (d / decrease-01 :ARG1 (c4 / content :quant-of (p / protein :name (n / name :op1 "IGF-1") :mod (m2 / media) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG2 (s / significant-02) :time (n2 / normalize-01 :ARG1 c4 :topic (v / viable :domain (m3 / macrophage :mod (c5 / cell-line :name (n3 / name :op1 "MH-S"))) :ARG1-of (m4 / mean-01 :ARG2 (s2 / slash :op1 p :op2 (v2 / viable :ARG2-of (r2 / relative-05)) :ARG1-of (s3 / show-01 :polarity "-" :ARG0 (d2 / data)))))))) # ::id a_pmid_2169_9731.158 # ::date 2015-05-27T10:24:34 # ::file a_pmid_2169_9731_158.txt # ::snt Neoplastic growth reflected the level of IGF-1 in the media conditioned by siRNA-treated macrophages, with all three groups differing significantly in JF32 cells (Figure 8D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (a / and :op1 (r / reflect-01 :ARG1 (g / grow-01 :ARG1 (n / neoplasm)) :ARG2 (l / level :quant-of (p / protein :name (n2 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :location (m / media :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage :ARG1-of (t / treat-04 :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "siRNA")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "8D"))) :op2 (d / differ-02 :ARG1 (g2 / group :quant "3" :mod (a2 / all)) :ARG1-of (s / significant-02) :location (c2 / cell :name (n4 / name :op1 "JF32")))) # ::id a_pmid_2169_9731.159 # ::date 2015-05-27T22:39:13 # ::file a_pmid_2169_9731_159.txt # ::snt While scr siRNA-treated media did not significantly lower LM2 cell growth, the correlation of media IGF-1 levels vs. LM2 proliferation was highly significant, as in JF32 cells (Figure 8D-F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (l2 / lower-05 :polarity "-" :ARG0 (m2 / medium :ARG1-of (t / treat-04 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "siRNA") :ARG1-of (s2 / scramble-02)))) :ARG1 (g / grow-01 :ARG1 (c2 / cell-line :name (n2 / name :op1 "LM2"))) :ARG1-of (s / significant-02)) :ARG2 (c3 / correlate-01 :ARG1 (l3 / level :quant-of (p / protein :name (n3 / name :op1 "IGF-1") :mod (m / medium) :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :ARG2 (p2 / proliferate-01 :ARG0 c2) :ARG1-of (s3 / significant-02 :ARG1-of (h / high-02)) :ARG1-of (r2 / resemble-01 :ARG2 (p3 / proliferate-01 :ARG0 (c4 / cell-line :name (n4 / name :op1 "JF32"))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "8D") :op2 (f2 / figure :mod "8E") :op3 (f3 / figure :mod "8F")))) # ::id a_pmid_2169_9731.160 # ::date 2015-05-27T22:58:47 # ::file a_pmid_2169_9731_160.txt # ::snt Taken together, these experiments demonstrate that IGF-1 is responsible for the majority of neoplastic growth stimulated by MØCM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (t / take-01 :ARG1 (e / experiment-01 :ARG0-of (d / demonstrate-01 :ARG1 (r / responsible-01 :ARG0 (p / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (g / grow-01 :ARG1 (n2 / neoplasm) :mod (m / majority) :ARG1-of (s / stimulate-01 :ARG0 (m2 / medium :ARG1-of (c / condition-01 :ARG0 (m3 / macrophage))))))) :mod (t3 / this)) :mod (t2 / together)) # ::id a_pmid_2169_9731.161 # ::date 2015-05-27T23:12:21 # ::file a_pmid_2169_9731_161.txt # ::snt Combined MEK and PI3K inhibition blocks IGF-1 and MØCM induced neoplastic proliferation by decreasing cyclin D1 expression # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (b / block-01 :ARG0 (c / combine-01 :ARG1 (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2 (i3 / inhibit-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "PI3K") :xref (x2 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :ARG1 (p / protein :name (n4 / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))) :op2 (i / induce-01 :ARG0 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage))) :ARG2 (p2 / proliferate-01 :ARG0 (n6 / neoplasm)) :instrument (d / decrease-01 :ARG1 (e4 / express-03 :ARG2 (p3 / protein :name (n7 / name :op1 "cyclin-D1") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.691")))))) # ::id a_pmid_2169_9731.162 # ::date 2015-05-27T23:19:17 # ::file a_pmid_2169_9731_162.txt # ::snt IGF-1 stimulated neoplastic proliferation and mediated a significant portion of macrophage-induced tumor cell growth in culture. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (p2 / proliferate-01 :ARG0 (n2 / neoplasm))) :op2 (m / mediate-01 :ARG0 p :ARG1 (p3 / portion :ARG1-of (i / include-01 :ARG2 (g2 / grow-01 :ARG1 (c2 / cell :mod (t2 / tumor)) :ARG2-of (i3 / induce-01 :ARG0 (m3 / macrophage)))) :ARG1-of (s2 / significant-02)) :location (c3 / culture))) # ::id a_pmid_2169_9731.163 # ::date 2015-05-27T23:26:16 # ::file a_pmid_2169_9731_163.txt # ::snt To determine if MØCM and/or IGF-1 were similarly blocked by MEK and PI3K inhibition, LM2 and JF32 cells were treated with combinations of MEK and/or PI3K inhibitors, in the presence of IGF-1 or MØCM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n2 / name :op1 "LM2")) :op2 (c2 / cell-line :name (n3 / name :op1 "JF32"))) :ARG2 (c3 / combine-01 :ARG1 (a4 / and-or :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n7 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :op2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n8 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))))) :condition (p / present-02 :ARG1 (o / or :op1 (p2 / protein :name (n5 / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (m2 / medium :ARG1-of (c4 / condition-01 :ARG0 (m4 / macrophage))))) :purpose (d / determine-01 :ARG1 (b / block-01 :ARG0 (i3 / inhibit-01 :ARG1 (a3 / and :op1 e :op2 e2)) :ARG1 (a2 / and-or :op1 m2 :op2 p2) :ARG1-of (r / resemble-01)))) # ::id a_pmid_2169_9731.164 # ::date 2015-05-27T23:37:43 # ::file a_pmid_2169_9731_164.txt # ::snt Analogous to previous results with macrophage co-culture, growth stimulated by either IGF-1 or MØCM was blocked by combined inhibition of MEK and PI3K, to a greater extent than either pathway by itself (Figure 9A, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (b3 / block-01 :ARG0 (i / inhibit-01 :ARG3-of (c2 / combine-01 :ARG1 (p2 / pathway :name (n / name :op1 "MEK")) :ARG2 (p3 / pathway :name (n4 / name :op1 "PI3K")))) :ARG1 (g2 / grow-01 :ARG1-of (s / stimulate-01 :ARG0 (o / or :op1 (p / protein :name (n2 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (m3 / medium :ARG1-of (c / condition-01 :ARG0 (m4 / macrophage)))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "9A") :op2 (f2 / figure :mod "9B"))) :degree (g / great :degree (m / more) :compared-to (b2 / block-01 :ARG1 (g3 / grow-01 :ARG1-of (s2 / stimulate-01 :ARG0 (o2 / or :op1 p :op2 m3))))) :mod (a2 / analogous :topic (t / thing :ARG2-of (r2 / result-01 :ARG1 (c3 / co-culture :mod (m2 / macrophage)) :mod (p4 / previous))))) # ::id a_pmid_2169_9731.165 # ::date 2015-05-27T23:53:49 # ::file a_pmid_2169_9731_165.txt # ::snt Consistent with the proliferation results, cyclin D1 content (a biochemical correlate of lung cell proliferation [41]) was reduced by these inhibitors (Figure 9C-E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / consistent-01 :ARG1 (r2 / reduce-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (t / this)) :ARG1 (c2 / content :quant-of (p2 / protein :name (n / name :op1 "cyclin-D1") :ARG1-of (m2 / mean-01 :ARG2 (t3 / thing :ARG1-of (c3 / correlate-01 :ARG2 (p3 / proliferate-01 :ARG0 (c4 / cell :mod (l / lung))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "41")))) :mod (b / biochemistry))) :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.691")))) :ARG2 (t2 / thing :ARG2-of (r / result-01 :mod (p / proliferate-01))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "9C") :op2 (f2 / figure :mod "9D") :op3 (f3 / figure :mod "9E")))) # ::id a_pmid_2169_9731.166 # ::date 2015-05-28T00:13:14 # ::file a_pmid_2169_9731_166.txt # ::snt MØCM induced early increases in cRaf, Akt and GSK-3β phosphorylation, and Erk1/2 phosphorylation peaked at 24 hrs (Figure 9C, D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (i / induce-01 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :ARG2 (i2 / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "cRaf") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "Akt") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op3 (e4 / enzyme :name (n4 / name :op1 "GSK-3β") :xref (x1 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252")))) :time (e / early))) :op2 (p2 / peak-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (s / slash :op1 (e5 / enzyme :name (n5 / name :op1 "Erk1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e6 / enzyme :name (n6 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :time (a3 / after :quant (t / temporal-quantity :quant "24" :unit (h / hour)))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "9C") :op2 (f2 / figure :mod "9D")))) # ::id a_pmid_2169_9731.167 # ::date 2015-05-28T00:23:14 # ::file a_pmid_2169_9731_167.txt # ::snt In both LM2 and JF32 cells, increased Akt phosphorylation corresponded to more phosphorylation of the Akt substrate, pGSK-3β (Figure 9H and 9I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / correspond-02 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of (i / increase-01)) :ARG2 (p2 / phosphorylate-01 :ARG1 (s / substrate :poss e :ARG1-of (m2 / mean-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "GSK-3β") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252")))) :degree (m / more)) :location (a / and :op1 (c2 / cell-line :name (n3 / name :op1 "LM2")) :op2 (c3 / cell-line :name (n4 / name :op1 "JF32"))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "9H") :op2 (f2 / figure :mod "9I")))) # ::id a_pmid_2169_9731.168 # ::date 2015-05-28T00:34:51 # ::file a_pmid_2169_9731_168.txt # ::snt Phospho-cRaf levels, another marker of Akt activity, also increased in concert with heightened increased Akt activity from 4-24 hrs; although p-cRaf abruptly dropped at 48 hrs, pAkt and pGSK-3β levels remained highly elevated (Figure 9F, H and 9I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (a9 / and :op1 (i / increase-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "cRaf") :ARG3-of (p / phosphorylate-01) :ARG1-of (m2 / mean-01 :ARG2 (m3 / marker :mod (a / activity-06 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Akt") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :mod (a2 / another))) :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :mod (a3 / also) :manner (i2 / in-concert :op1 i :op2 (a5 / activity-06 :ARG0 e2 :ARG1-of (h / heighten-01) :ARG1-of (i3 / increase-01))) :time (b / between :op1 (t / temporal-quantity :quant "4" :unit (h6 / hour)) :op2 (t4 / temporal-quantity :quant "24" :unit h6))) :op2 (h2 / have-concession-91 :ARG1 (r / remain-01 :ARG1 (a8 / and :op1 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "Akt") :ARG3-of p :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :op2 (l3 / level :quant-of (e4 / enzyme :name (n4 / name :op1 "GSK-3β") :ARG3-of p :xref (x / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252")))) :ARG3 (e5 / elevate-01 :ARG1-of (h4 / high-02))) :ARG2 (d / drop-01 :ARG1 e :manner (a6 / abrupt) :time (a7 / after :quant (t2 / temporal-quantity :quant "48" :unit (h3 / hour))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "9F") :op2 (f2 / figure :mod "9H") :op3 (f3 / figure :mod "9I")))) # ::id a_pmid_2169_9731.169 # ::date 2015-05-28T00:52:13 # ::file a_pmid_2169_9731_169.txt # ::snt We observed reciprocal changes in the Erk and Akt pathways in response to their respective enzyme inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (c / change-01 :ARG1 (a / and :op1 (p / pathway :name (n2 / name :op1 "Erk")) :op2 (p2 / pathway :name (n3 / name :op1 "Akt"))) :mod (r / reciprocal) :ARG2-of (r2 / respond-01 :ARG1 (t / thing :ARG0-of (i / inhibit-01 :ARG1 (a2 / and :op1 (p3 / protein-family :name (n4 / name :op1 "Erk")) :op2 (p4 / protein-family :name (n5 / name :op1 "Akt")))) :mod (r3 / respective))))) # ::id a_pmid_2169_9731.170 # ::date 2015-05-28T00:56:49 # ::file a_pmid_2169_9731_170.txt # ::snt In LM2 cells, MEK inhibition (by U0126) suppressed early Erk1/2 phosphorylation while p-Akt levels increased. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (s2 / suppress-01 :ARG0 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "U0126") :xref (x4 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (s3 / slash :op1 (e3 / enzyme :name (n3 / name :op1 "Erk1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n4 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :time (e2 / early))) :ARG2 (i2 / increase-01 :ARG1 (l / level :quant-of (e5 / enzyme :name (n5 / name :op1 "Akt") :ARG1-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :location (c2 / cell-line :name (n6 / name :op1 "LM2"))) # ::id a_pmid_2169_9731.171 # ::date 2015-05-28T01:03:47 # ::file a_pmid_2169_9731_171.txt # ::snt Conversely, PI3K inhibition (by LY294002) increased basal p-Erk1/2 levels at the expense of p-Akt (4 hrs time point; Figure 9C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (c / contrast-01 :ARG2 (i / increase-01 :ARG0 (i2 / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "LY294002") :xref (x4 / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (e2 / enzyme :name (n / name :op1 "PI3K") :xref (x3 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1 (l / level :quant-of (s2 / slash :op1 (e3 / enzyme :name (n3 / name :op1 "Erk1") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n4 / name :op1 "Erk2") :ARG3-of p :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :mod (b / basal)) :ARG0-of (c2 / compromise-02 :ARG1 (e5 / enzyme :name (n5 / name :op1 "Akt") :ARG3-of p :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :time (a / after :quant (t2 / temporal-quantity :quant "4" :unit "4")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "9C"))) # ::id a_pmid_2169_9731.172 # ::date 2015-05-28T01:11:05 # ::file a_pmid_2169_9731_172.txt # ::snt MEK inhibition raised p-Erk1/2 and total Erk1/2 levels at 24 and 48 hrs, while PI3K inhibition caused a compensatory increase in cellular p-Akt levels from 24-48 hrs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 26, 2015 (c / contrast-01 :ARG1 (r / raise-01 :ARG0 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :xref (x6 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1 (a2 / and :op1 (a / and :op1 (l / level :quant-of (e3 / enzyme :name (n3 / name :op1 "Erk1") :ARG3-of (p / phosphorylate-01) :xref (x5 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603"))) :op2 (l2 / level :quant-of (e4 / enzyme :name (n4 / name :op1 "Erk2") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :op2 (s / slash :op1 (l3 / level :quant-of (e5 / enzyme :name (n5 / name :op1 "Erk1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603"))) :op2 (l4 / level :quant-of (e6 / enzyme :name (n6 / name :op1 "Erk2") :xref (x4 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :mod (t / total))) :time (a4 / and :op1 (a5 / after :quant (t2 / temporal-quantity :quant "24" :unit (h / hour))) :op2 (a6 / after :quant (t3 / temporal-quantity :quant "48" :unit (h2 / hour))))) :ARG2 (c2 / cause-01 :ARG0 (i2 / inhibit-01 :ARG1 (e7 / enzyme :name (n7 / name :op1 "PI3K") :xref (x3 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1 (i3 / increase-01 :ARG1 (l5 / level :quant-of (e8 / enzyme :name (n8 / name :op1 "Akt") :mod (c4 / cell) :ARG3-of p :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG0-of (c3 / compensate-01) :time (b / between :op1 (t5 / temporal-quantity :quant "24" :unit (h4 / hour)) :op2 (t6 / temporal-quantity :quant "28" :unit h4))))) # ::id a_pmid_2169_9731.173 # ::date 2015-05-28T01:20:31 # ::file a_pmid_2169_9731_173.txt # ::snt JF32 cell growth was also suppressed by each drug; although MEK inhibition did not affect p-Erk1/2 levels at 4 hrs, p-Erk1/2 levels decreased at 48 hrs (Figure 9D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a5 / and :op1 (s / suppress-01 :ARG0 (d / drug :mod (e2 / each)) :ARG1 (g / grow-01 :ARG1 (c / cell-line :name (n2 / name :op1 "JF32"))) :mod (a / also)) :op2 (h / have-concession-91 :ARG1 (d2 / decrease-01 :ARG1 "s2" :time (a4 / after :quant (t2 / temporal-quantity :quant "48" :unit (h3 / hour)))) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 (i / inhibit-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1 (s2 / slash :op1 (l / level :quant-of (e4 / enzyme :name (n4 / name :op1 "Erk1") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603"))) :op2 (l2 / level :quant-of (e5 / enzyme :name (n5 / name :op1 "Erk2") :ARG3-of p :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :time (a3 / after :quant (t / temporal-quantity :quant "4" :unit (h2 / hour))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "9D"))) # ::id a_pmid_2169_9731.174 # ::date 2015-05-28T01:29:59 # ::file a_pmid_2169_9731_174.txt # ::snt PI3K inhibition stimulated Erk1/2 phosphorylation from 4-24 hrs, and increased Akt phosphorylation throughout the treatment time-course (Figure 9G, H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 11, 2015 (a / and :op1 (s / stimulate-01 :ARG0 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "PI3K") :xref (x3 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (s2 / slash :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :name (n3 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :time (b / between :op1 (t3 / temporal-quantity :quant "4" :unit (h2 / hour)) :op2 (t4 / temporal-quantity :quant "24" :unit h2))) :op2 (i / increase-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :time (t2 / treat-04)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "9G") :op2 (f2 / figure :mod "9H")))) # ::id a_pmid_2169_9731.175 # ::date 2015-05-28T01:34:55 # ::file a_pmid_2169_9731_175.txt # ::snt While each inhibitor decreased basal proliferation rates (Figure 9A, B), combinations of kinase inhibitors and MØCM increased cRaf, Erk1/2, Akt and GSK-3β phosphorylation in an additive manner, with the highest levels observed in cells treated with both kinase inhibitors and MØCM ("U+L +", Figure 9C-I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / contrast-01 :ARG1 (d / decrease-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01) :mod (e / each)) :ARG1 (r / rate :mod (p2 / proliferate-01) :mod (b / basal)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "9A") :op2 (f2 / figure :mod "9B")))) :ARG2 (i3 / increase-01 :ARG0 (c2 / combine-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 (k / kinase))) :ARG2 (m / medium :ARG1-of (c3 / condition-01 :ARG0 (m4 / macrophage)))) :ARG1 (p3 / phosphorylate-01 :ARG1 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "cRaf") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (s / slash :op1 (e4 / enzyme :name (n4 / name :op1 "Erk1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e5 / enzyme :name (n5 / name :op1 "Erk2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :op3 (e6 / enzyme :name (n6 / name :op1 "Akt") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op4 (e7 / enzyme :name (n7 / name :op1 "GSK-3β") :xref (x2 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252")))) :manner (a3 / add-02) :manner (o / observe-01 :ARG1 (l / level :ARG1-of (h / high-02 :degree (m5 / most))) :location (c4 / cell :ARG1-of (t / treat-04 :ARG2 (a4 / and :op1 m3 :op2 m))))) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and :op1 (f3 / figure :mod "9C") :op2 (f4 / figure :mod "9D") :op3 (f5 / figure :mod "9E") :op4 (f6 / figure :mod "9F") :op5 (f7 / figure :mod "9G") :op6 (f8 / figure :mod "9H") :op7 (f9 / figure :mod "9I")))) # ::id a_pmid_2169_9731.176 # ::date 2015-05-28T02:51:56 # ::file a_pmid_2169_9731_176.txt # ::snt Total and p-cRaf, p-Akt and p-GSK-3β were each significantly higher after 4-24 hrs of treatment in all groups receiving any combination of drug and MØCM, and p-Erk1/2 levels spiked after 24 hrs of treatment (Figure 9F-I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a6 / and :op1 (h / high-02 :ARG1 (a / and :op1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "cRaf") :mod (t / total) :xref (x6 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "Akt") :mod t :xref (x5 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op3 (e3 / enzyme :name (n3 / name :op1 "GSK-3β") :mod t :xref (x4 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252"))) :op2 (a3 / and :op1 (e4 / enzyme :name (n4 / name :op1 "cRaf") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n5 / name :op1 "Akt") :ARG3-of p :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op3 (e6 / enzyme :name (n6 / name :op1 "GSK-3β") :ARG3-of p :xref (x3 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.252")))) :degree (m2 / more) :ARG1-of (s / significant-02) :time (a4 / after :op1 (t3 / treat-04) :quant (t2 / temporal-quantity :quant (v / value-interval :op1 "4" :op2 "24") :unit (h3 / hour))) :location (g / group :mod (a5 / all) :ARG0-of (r / receive-01 :ARG1 (c / combine-01 :ARG1 (d / drug) :ARG2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m3 / macrophage))) :mod (a8 / any))))) :op2 (s2 / spike-04 :ARG1 (l / level :quant-of (s3 / slash :op1 (e7 / enzyme :name (n8 / name :op1 "Erk1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e8 / enzyme :name (n9 / name :op1 "Erk2") :xref (x7 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :time (a7 / after :op1 (t4 / treat-04) :quant (t5 / temporal-quantity :quant "24" :unit (h4 / hour)))) :ARG1-of (d2 / describe-01 :ARG0 (a9 / and :op1 (f / figure :mod "9F") :op2 (f2 / figure :mod "9G") :op3 (f3 / figure :mod "9H") :op4 (f4 / figure :mod "9I")))) # ::id a_pmid_2169_9731.177 # ::date 2015-05-28T03:03:52 # ::file a_pmid_2169_9731_177.txt # ::snt Either inhibitor alone partially prevented the increase in cyclin D1 in cells treated with MØCM; cells receiving both inhibitors had the lowest cyclin D1 levels and were unresponsive to MØCM-induced growth (Figure 9E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (p / prevent-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01) :mod (e / either) :mod (a3 / alone)) :ARG1 (i3 / increase-01 :ARG1 (p3 / protein :name (n / name :op1 "cyclin-D1") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.691")) :location (c / cell :ARG1-of (t / treat-04 :ARG2 (m4 / medium :ARG1-of (c2 / condition-01 :ARG0 (m5 / macrophage)))))) :degree (p2 / part)) :op2 (a2 / and :op1 (h / have-03 :ARG0 (c3 / cell :ARG0-of (r / receive-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of i2 :mod (b / both)))) :ARG1 (l / level :quant-of p3 :ARG1-of (l2 / low-04 :degree (m2 / most)))) :op2 (r2 / respond-01 :polarity "-" :ARG0 c3 :ARG1 (g / grow-01 :ARG2-of (i4 / induce-01 :ARG0 m4)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "9E"))) # ::id a_pmid_2169_9731.178 # ::date 2015-05-28T03:20:16 # ::file a_pmid_2169_9731_178.txt # ::snt Taken together, MØCM-induced neoplastic Akt and Erk1/2 phosphorylation was magnified several-fold by inhibitor treatment, dissociating kinase activity from proliferation in drug-treated cells; however, cyclin D1 levels were suppressed by either drug alone, which corresponded to decreased cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m2 / magnify-01 :ARG0 (t / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i4 / inhibit-01))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Akt") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op2 (s / slash :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :name (n3 / name :op1 "Erk2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :ARG1-of (t2 / take-01 :mod (t3 / together))) :mod (n4 / neoplasm) :ARG2-of (i2 / induce-01 :ARG0 (m3 / medium :ARG1-of (c / condition-01 :ARG0 (m4 / macrophage)))) :ARG0-of (d / dissociate-01 :ARG1 (a2 / activity-06 :ARG0 (k / kinase)) :ARG2 (p5 / proliferate-01 :ARG0 (p4 / protein) :location (c2 / cell :ARG1-of (t5 / treat-03 :ARG3 (d2 / drug)))))) :ARG1-of (c5 / contrast-01 :ARG2 (s3 / suppress-01 :ARG0 (d4 / drug :mod (e4 / either) :mod (a3 / alone)) :ARG1 (l / level :quant-of (p6 / protein :name (n7 / name :op1 "cyclin-D1") :xref (x3 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.691"))) :ARG1-of (c3 / correspond-02 :ARG2 (p7 / proliferate-01 :ARG0 (c4 / cell) :ARG1-of (d3 / decrease-01))))) :quant (p3 / product-of :op1 (s2 / several))) # ::id a_pmid_2169_9731.179 # ::date 2015-05-29T00:57:52 # ::file a_pmid_2169_9731_179.txt # ::snt As with MØCM, IGF-1 stimulated both Akt and Erk1/2 activities. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / resemble-01 :ARG1 (s / stimulate-01 :ARG0 (p / protein :name (n2 / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (a / act-02 :ARG0 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op2 (s2 / slash :op1 (e2 / enzyme :name (n4 / name :op1 "Erk1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :name (n5 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))))) :ARG2 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage)))) # ::id a_pmid_2169_9731.180 # ::date 2015-05-29T01:02:25 # ::file a_pmid_2169_9731_180.txt # ::snt Kinase activation was greatest within 4 hrs of treatment, and remained elevated 48 hrs later, corresponding with increased cyclin D1 expression (Figure 10A-E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (a / and :op1 (g2 / great :domain (a2 / activate-01 :ARG1 (k / kinase)) :degree (m / most) :time (a3 / after :op1 (t / treat-03) :quant (u / up-to :op1 (t2 / temporal-quantity :quant "4" :unit (h / hour))))) :op2 (r / remain-01 :ARG1 a2 :ARG3 (e2 / elevate-01 :ARG1 a2) :time (a4 / after :quant (t3 / temporal-quantity :quant "48" :unit (h2 / hour))) :ARG1-of (c / correspond-02 :ARG2 (e3 / express-03 :ARG2 (p / protein :name (n2 / name :op1 "cyclin-D1") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.691")) :ARG1-of (i / increase-01)))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "10A") :op2 (f2 / figure :mod "10B") :op3 (f3 / figure :mod "10C") :op4 (f4 / figure :mod "10D") :op5 (f5 / figure :mod "10E")))) # ::id a_pmid_2169_9731.181 # ::date 2015-05-29T05:33:55 # ::file a_pmid_2169_9731_181.txt # ::snt When treated with 2 ng/mL EGF, a concentration 1,000-times higher than the amount of EGF in cell-conditioned media and 40-times higher than what is detected in BAL fluid, Erk1/2 activity was not significantly elevated and Akt levels were unaffected (Figure 10C, D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a2 / and :op1 (e / elevate-01 :polarity "-" :ARG1 (a / activity-06 :ARG0 (s / slash :op1 (e2 / enzyme :name (n / name :op1 "Erk1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :name (n2 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :ARG1-of (s2 / significant-02)) :op2 (a3 / affect-01 :polarity "-" :ARG1 (l / level :quant-of (e4 / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :condition (t / treat-04 :ARG2 (p / protein :name (n4 / name :op1 "EGF") :quant (c / concentration-quantity :quant "2" :unit (n6 / nanogram-per-milliliter)) :ARG1-of (e5 / equal-01 :ARG2 (c2 / concentrate-02 :ARG1 p :ARG1-of (h / high-02 :degree (m2 / more :quant (p2 / product-of :op1 "1000")) :compared-to (a4 / and :op1 (a5 / amount :quant-of p :location (m3 / media :ARG1-of (c3 / condition-01 :ARG2 (c4 / cell)))))) :ARG1-of (h2 / high-02 :degree (m4 / more :quant (p3 / product-of :op1 "40")) :compared-to (t2 / thing :ARG1-of (d2 / detect-01 :location (f / fluid :mod (l2 / lavage :mod (a7 / alveolus :mod (b / bronchus))))))))) :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG1-of (d / describe-01 :ARG0 (a6 / and :op1 (f2 / figure :mod "10C") :op2 (f3 / figure :mod "10D")))) # ::id a_pmid_2169_9731.182 # ::date 2015-05-29T06:13:15 # ::file a_pmid_2169_9731_182.txt # ::snt EGF may partially stimulate Erk1/2 activity at supra-physiological levels, but this was not sufficient to stimulate cellular growth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (s / stimulate-01 :ARG0 (p2 / protein :name (n / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (a / activity-06 :ARG0 (s2 / slash :op1 (e / enzyme :name (n2 / name :op1 "Erk1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :degree (p3 / part) :location (l / level :mod (p4 / physiological :degree (s3 / supra))))) :ARG2 (s4 / suffice-01 :polarity "-" :ARG0 (t / this) :ARG1 (s5 / stimulate-01 :ARG0 t :ARG1 (g / grow-01 :ARG1 (c2 / cell))))) # ::id a_pmid_2169_9731.183 # ::date 2015-05-29T06:19:58 # ::file a_pmid_2169_9731_183.txt # ::snt When administered at cell-and tissue-relevant levels, IGF-1 stimulated both Erk1/2 and Akt activation, elevated cellular cyclin D1 content, and induced neoplastic proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a4 / and :op1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "IGF-1") :xref (x4 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (s2 / slash :op1 (e / enzyme :name (n2 / name :op1 "Erk1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :op2 (a3 / activate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))))) :op2 (e4 / elevate-01 :ARG0 p :ARG1 (c / content :quant-of (p2 / protein :name (n5 / name :op1 "cyclin-D1") :source (c2 / cell) :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.691")))) :op3 (i / induce-01 :ARG0 p :ARG2 (p3 / proliferate-01 :ARG0 (n6 / neoplasm))) :condition (a5 / administer-01 :ARG1 p :location (a6 / and :op1 (l / level :mod c2 :ARG1-of (r / relevant-01)) :op2 (l2 / level :mod (t / tissue) :ARG1-of r)))) # ::id a_pmid_2194_3101.13 # ::date 2015-05-21T10:17:54 # ::file a_pmid_2194_3101_13.txt # ::snt Evidence presented here indicate that BRAFV600E significantly induces cell migration and invasion properties in vitro in colon cancer cells, at least in part through activation of RhoA GTPase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (e / evidence :ARG1-of (p / present-01 :medium (h / here))) :ARG1 (i2 / induce-01 :ARG0 (e3 / enzyme :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG2 (a / and :op1 (p2 / property :mod (m2 / migrate-01 :ARG0 (c / cell))) :op2 (p3 / property :mod (i3 / invade-01 :ARG0 c)) :manner (i4 / in-vitro) :location (c2 / cell :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :mod (c3 / colon)))) :ARG1-of (s / significant-02) :manner (a2 / activate-01 :ARG0 e3 :ARG1 (p5 / pathway :name (n3 / name :op1 "RhoA" :op2 "GTPase")) :degree (a3 / at-least :op1 (p4 / part))))) # ::id a_pmid_2194_3101.14 # ::date 2015-05-22T03:41:49 # ::file a_pmid_2194_3101_14.txt # ::snt The relationship established between BRAFV600E and RhoA activation is mediated by the MEK-ERK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / mediate-01 :ARG0 (p / pathway :name (n / name :op1 "MEK-ERK")) :ARG1 (r / relation-03 :ARG0 (a / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (a2 / activate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :ARG1-of (e / establish-01))) # ::id a_pmid_2194_3101.15 # ::date 2015-05-22T03:49:36 # ::file a_pmid_2194_3101_15.txt # ::snt In parallel, KRASG12V enhances the ability of colon adenocarcinoma cells Caco-2 to migrate and invade through filopodia formation and PI3K-dependent Cdc42 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / enhance-01 :ARG0 (e2 / enzyme :name (n / name :op1 "KRAS") :ARG1-of (m / mutate-01 :value "G12V") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1 (c / capable-01 :ARG1 (c2 / cell-line :name (n2 / name :op1 "Caco-2") :source (a / adenocarcinoma :part-of (c3 / colon))) :ARG2 (a2 / and :op1 (m2 / migrate-01 :ARG0 c2) :op2 (i / invade-01 :ARG0 c2) :manner (a3 / and :op1 (f / form-01 :ARG0 c2 :ARG1 (f2 / filopodia)) :op2 (a4 / activate-01 :ARG0 c2 :ARG1 (p2 / protein :name (n3 / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG0-of (d / depend-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))))))) :mod (p / parallel)) # ::id a_pmid_2194_3101.16 # ::date 2015-05-22T04:28:21 # ::file a_pmid_2194_3101_16.txt # ::snt Ultimately increased cell migration and invasion, mediated by Rac1, along with the mesenchymal morphology obtained through the Epithelial-Mesenchymal Transition (EMT) were the main characteristics rendered by HRASG12V in Caco-2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / characteristic-02 :ARG2 (a / and :op1 (m4 / migrate-01 :ARG0 (c3 / cell)) :op2 (i2 / invade-01 :ARG0 c3) :op3 (m5 / morphology :mod (m6 / mesenchyme) :ARG1-of (o / obtain-01 :ARG2 (t / transition-01 :ARG2 (m7 / mesenchyme) :ARG3 (e / epithelium)))) :ARG1-of (m3 / mediate-01 :ARG0 (p / protein :name (n3 / name :op1 "Rac1") :xref (x1 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG1-of (i / increase-01 :manner (u / ultimate))) :mod (m2 / main) :ARG1-of (r / render-01 :ARG0 (g / gene :name (n / name :op1 "HRAS") :ARG1-of (m / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :location (c2 / cell-line :name (n2 / name :op1 "Caco-2")))) # ::id a_pmid_2194_3101.17 # ::date 2015-05-22T04:34:22 # ::file a_pmid_2194_3101_17.txt # ::snt Moreover, BRAF and KRAS oncogenes are shown to cooperate with the TGFβ-1 pathway to provide cells with additional transforming properties. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op2 (s / show-01 :ARG1 (c / cooperate-01 :ARG0 (a2 / and :op1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :ARG1 (p2 / pathway :name (n3 / name :op1 "TGFβ-1")) :ARG2 (p / provide-01 :ARG0 (a4 / and :op1 a2 :op2 p2) :ARG1 (p3 / property :mod (t / transform-01) :mod (a3 / additional)) :ARG2 (c2 / cell))))) # ::id a_pmid_2194_3101.131 # ::date 2015-05-22T04:41:41 # ::file a_pmid_2194_3101_131.txt # ::snt BRAFV600E induces distinct morphological changes in colon adenocarcinoma cells as compared to KRASG12V and loss of their epithelial architecture in 3D culture # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / induce-01 :ARG0 (e2 / enzyme :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG2 (a4 / and :op1 (c / change-01 :ARG0 e2 :ARG1 (c2 / cell :source (a / adenocarcinoma :mod (c3 / colon))) :mod (m2 / morphology) :mod (d / distinct) :compared-to (e3 / enzyme :name (n2 / name :op1 "KRAS") :ARG1-of (m3 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (l / lose-02 :ARG0 c2 :ARG1 (a3 / architecture :mod (e / epithelium) :location (c4 / culture :mod (d2 / dimension :quant "3")))))) # ::id a_pmid_2194_3101.132 # ::date 2015-05-22T04:48:56 # ::file a_pmid_2194_3101_132.txt # ::snt Previously established Caco-BR cells have adopted a substantially different morphology when compared to the parental Caco-2 cells [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 2, 2015 (a / adopt-01 :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-BR") :ARG1-of (e / establish-01 :time (p2 / previous))) :ARG1 (m / morphology :ARG1-of (d2 / differ-02 :degree (s / substantial))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "21"))) :time (c3 / compare-01 :ARG1 c2 :ARG2 (c4 / cell-line :name (n2 / name :op1 "Caco-2") :mod (p3 / parent)))) # ::id a_pmid_2194_3101.133 # ::date 2015-05-22T04:54:27 # ::file a_pmid_2194_3101_133.txt # ::snt The elongated morphology acquired by Caco-BR cells was characterized by long membrane protrusions (Figure 1A, Additional Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / characterize-01 :ARG1 (m / morphology :ARG1-of (a3 / acquire-01 :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-BR"))) :ARG1-of (e / elongate-01)) :ARG2 (p / protrude-01 :ARG1 (m2 / membrane :xref (x / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (l / long-03)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1A") :op2 (f2 / figure :mod "1" :mod (a2 / additional))))) # ::id a_pmid_2194_3101.134 # ::date 2015-05-22T03:33:13 # ::file a_pmid_2194_3101_134.txt # ::snt We present evidence that the morphology of Caco-BR13 cells show properties of both Caco-2 epithelial nature and of the mesenchymal phenotype of Caco-H2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / present-01 :ARG0 (w / we) :ARG1 (e / evidence-01 :ARG1 (s / show-01 :ARG0 (m / morphology :poss (c / cell-line :name (n / name :op1 "Caco-BR13"))) :ARG1 (a / and :op1 (p2 / property :poss (n2 / nature :mod (e2 / epithelium) :poss (c2 / cell-line :name (n3 / name :op1 "Caco-2")))) :op2 (p3 / property :poss (p4 / phenotype :mod (m2 / mesenchyme) :poss (c3 / cell-line :name (n4 / name :op1 "Caco-H2")))))))) # ::id a_pmid_2194_3101.135 # ::date 2015-05-22T05:15:48 # ::file a_pmid_2194_3101_135.txt # ::snt On the other hand, Caco-K15 cells, which overexpress KRASG12V, have retained the overall parental morphology of Caco-2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c3 / contrast-01 :ARG2 (r2 / retain-01 :ARG0 (c / cell-line :name (n / name :op1 "Caco-K15") :location-of (o / overexpress-01 :ARG1 (g / gene :name (n2 / name :op1 "KRAS") :ARG1-of (m / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG1 (m2 / morphology :mod (o2 / overall) :mod (p / parent) :poss (c2 / cell-line :name (n3 / name :op1 "Caco-2"))))) # ::id a_pmid_2194_3101.136 # ::date 2015-05-22T05:19:05 # ::file a_pmid_2194_3101_136.txt # ::snt For comparison, established adenocarcinoma cell lines HT29 and DLD-1, bearing mutant BRAFV600E and KRASG13D respectively, have also been analyzed in the present study. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / analyze-01 :ARG1 (a3 / and :op1 (c2 / cell-line :name (n / name :op1 "HT29") :ARG0-of (b / bear-01 :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (c3 / cell-line :name (n2 / name :op1 "DLD-1") :ARG0-of (b2 / bear-01 :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS") :ARG1-of (m2 / mutate-01 :value "G13D") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :mod (a4 / adenocarcinoma) :ARG1-of (e / establish-01) :mod (r / respective)) :purpose (c / compare-01) :medium (s / study-01 :time (p / present)) :mod (a2 / also)) # ::id a_pmid_2194_3101.137 # ::date 2015-05-22T05:24:04 # ::file a_pmid_2194_3101_137.txt # ::snt It is of interest that the phenotype of Caco-BR cells resembles that of DLD-1 cells (KRASG13D), especially since both of these cell types share high levels of p-BRAF (later analyzed). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / interest-01 :ARG0 (r / resemble-01 :ARG1 (p / phenotype :poss (c2 / cell-line :name (n / name :op1 "Caco-BR"))) :ARG2 (p2 / phenotype :poss (c3 / cell-line :name (n2 / name :op1 "DLD-1") :mod (e3 / enzyme :name (n3 / name :op1 "KRAS") :ARG1-of (m2 / mutate-01 :value "G13D") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))) :ARG1-of (c / cause-01 :ARG0 (s / share-01 :ARG0 (a / and :op1 c2 :op2 c3) :ARG1 (l / level :ARG1-of (h / high-02) :quant-of (e2 / enzyme :name (n4 / name :op1 "BRAF") :ARG3-of (p4 / phosphorylate-01) :ARG1-of (a2 / analyze-01 :time (l2 / late :degree (m3 / more))) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :mod (e / especially))) # ::id a_pmid_2194_3101.138 # ::date 2015-05-22T05:32:19 # ::file a_pmid_2194_3101_138.txt # ::snt Our previous study shows important similarities between Caco-BR and DLD-1 cells regarding their tumourigenic properties and signaling pathways, suggesting that their transformation process occurs mainly through the constitutive activation of the MAPK (Mitogen-Activated Protein Kinase) pathway [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (s2 / study-01 :ARG0 (w / we) :time (p / previous)) :ARG1 (r / resemble-01 :ARG1 (c / cell-line :name (n / name :op1 "Caco-BR")) :ARG2 (c2 / cell-line :name (n2 / name :op1 "DLD-1")) :topic (a / and :op1 (p2 / possible-01 :ARG1 (c5 / create-01 :ARG1 (t / tumor))) :op2 (p3 / pathway :ARG0-of (s3 / signal-07))) :mod (i / important)) :ARG0-of (s4 / suggest-01 :ARG1 (p4 / process-02 :ARG1 (t2 / transform-01 :ARG1 (a3 / and :op1 c :op2 c2))) :manner (a4 / activate-01 :ARG1 (p5 / pathway :name (n3 / name :op1 "MAPK") :ARG1-of (m / mean-01 :ARG2 (p6 / pathway :name (n4 / name :op1 "Mitogen-Activated" :op2 "Protein" :op3 "Kinase")))) :mod (c3 / constitutive))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 "21")))) # ::id a_pmid_2194_3101.139 # ::date 2015-05-22T09:40:51 # ::file a_pmid_2194_3101_139.txt # ::snt Staining with phalloidin resolved the morphological differences within the cell line panel indicating major actin cytoskeleton changes (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / resolve-01 :ARG0 (s / stain-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "phalloidin") :xref (x2 / xref :value "PUBCHEM:4752" :prob "16.525295"))) :ARG1 (d2 / differ-02 :ARG1 (p / panel :mod (c / cell-line) :ARG0-of (i / indicate-01 :ARG1 (c2 / change-01 :ARG1 (c3 / cytoskeleton :mod (p2 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :xref (x1 / xref :value "GO:0005856" :prob "0.8")) :ARG1-of (m3 / major-02)))) :mod (m2 / morphology)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id a_pmid_2194_3101.140 # ::date 2015-05-22T09:54:35 # ::file a_pmid_2194_3101_140.txt # ::snt More specifically, in Caco-BR13 cells the formation of stress fibers was enhanced, whereas formation of filopodia-membrane protrusions enriched with actin- is evident in Caco-K15 cells (Figure 1A-ii, arrow). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (e / enhance-01 :ARG1 (f4 / form-01 :ARG1 (f5 / fiber :mod (s2 / stress))) :location (c3 / cell-line :name (n3 / name :op1 "Caco-BR13"))) :ARG2 (e2 / evident :domain (f / form-01 :ARG1 (p / protrusion :mod (m2 / membrane :mod (f2 / filopodia) :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (e3 / enrich-01 :ARG2 (p2 / protein :name (n / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))))) :location (c2 / cell-line :name (n2 / name :op1 "Caco-K15"))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f3 / figure :mod "1A.ii") :op2 (a2 / arrow))) :ARG1-of (s / specific-02 :degree (m / more))) # ::id a_pmid_2194_3101.141 # ::date 2015-05-22T13:33:03 # ::file a_pmid_2194_3101_141.txt # ::snt In order to study in depth the morphology and architecture of the different cell lines under conditions that resemble the real tissue microenvironment, the three-dimensional (3D) culture system was adopted. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / adopt-01 :ARG1 (s / system :mod (c / culture :mod (d3 / dimension :quant "3")) :condition (c4 / condition :ARG1-of (r2 / resemble-01 :ARG2 (m3 / microenvironment :mod (t2 / tissue :ARG1-of (r / real-04)))))) :purpose (s2 / study-01 :ARG1 (a2 / and :op1 (m2 / morphology :poss (c2 / cell-line :ARG1-of (d2 / differ-02))) :op2 (a3 / architecture :poss c2)) :ARG1-of (d / deep-03))) # ::id a_pmid_2194_3101.142 # ::date 2015-05-22T12:03:37 # ::file a_pmid_2194_3101_142.txt # ::snt As also previously shown [22], Caco-2 cells were organized into cyst-like structures that resemble normal colon cell architecture following their growth in Matrigel for about 12 days (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG1 (o / organize-01 :ARG1 (c2 / cell-line :name (n2 / name :op1 "Caco-2")) :ARG4 (s2 / structure :ARG1-of (r / resemble-01 :ARG2 (c3 / cyst)) :ARG1-of (r2 / resemble-01 :ARG2 (a3 / architecture :mod (c4 / cell :source (c5 / colon :ARG1-of (n3 / normal-02)))))) :ARG1-of (f / follow-01 :ARG2 (g / grow-03 :ARG1 c2 :medium (p3 / protein :name (n / name :op1 "Matrigel") :xref (x / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.273")) :duration (a / about :op1 (t / temporal-quantity :quant "12" :unit (d / day))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "1B"))) :time (p / previous) :mod (a2 / also) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "22")))) # ::id a_pmid_2194_3101.143 # ::date 2015-05-22T13:20:04 # ::file a_pmid_2194_3101_143.txt # ::snt In contrast, Caco-H cells (EMT model) formed invasive masses with elongated protrusions, an architecture not shared by Caco-BR13 and Caco-K15 cells (Figure 1B, upper panel, black arrow). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (f / form-01 :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-H") :mod (t / transition-01 :ARG2 (m2 / mesenchyme) :ARG3 (e2 / epithelium))) :ARG1 (m / mass :ARG0-of (i / invade-01) :ARG1-of (p / protrude-01 :ARG1-of (e / elongate-01) :mod (a / architecture :ARG1-of (s / share-01 :polarity "-" :ARG0 (a2 / and :op1 (c3 / cell-line :name (n2 / name :op1 "Caco-BR13")) :op2 (c4 / cell-line :name (n3 / name :op1 "Caco-K15")))))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "1B") :op2 (p2 / panel :mod (u / upper)) :op3 (a4 / arrow :ARG1-of (b / black-04))))) # ::id a_pmid_2194_3101.144 # ::date 2015-05-22T13:24:30 # ::file a_pmid_2194_3101_144.txt # ::snt During 3D culture conditions, normal epithelial cells are organized into spheroids presenting a characteristic centrally-localized hollow lumen and distinct polarization of cells surrounding this lumen. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (o2 / organize-01 :ARG1 (c3 / cell :ARG1-of (n / normal-02) :source (e / epithelium)) :ARG4 (s / spheroid :ARG0-of (p / present-01 :ARG1 (a / and :op1 (l / lumen :ARG1-of (h / hollow-02) :location (c / center) :ARG1-of (c6 / characteristic-02)) :op2 (p2 / polarize-01 :ARG1 (c4 / cell :ARG1-of (s2 / surround-01 :ARG2 l)) :mod (d / distinct))))) :condition (c2 / culture :mod (d2 / dimension :quant "3"))) # ::id a_pmid_2194_3101.145 # ::date 2015-05-22T06:05:15 # ::file a_pmid_2194_3101_145.txt # ::snt Epithelial cancer cells do not form such structures; instead they develop non-polarized clusters with limited differentiation [23,24]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (d / develop-02 :ARG0 "c" :ARG1 (c2 / cluster :ARG1-of (p / polarize-01 :polarity "-") :mod (d3 / differentiate-01 :ARG1-of (l / limit-01))) :ARG1-of (i / instead-of-91 :ARG2 (f / form-01 :ARG0 (c / cell :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")) :mod (e / epithelium)) :ARG1 (s / structure :degree (s2 / such)))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "23")) :op2 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "24"))))) # ::id a_pmid_2194_3101.146 # ::date 2015-05-22T06:09:32 # ::file a_pmid_2194_3101_146.txt # ::snt Following staining with Hoechst and phalloidin the ability of Caco-2 cells to form spheroids with lumen was observed, a property also retained by Caco-K15 cells but completely absent in Caco-BR13 and Caco-H2 cells (Figure 1B, lower panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (o / observe-01 :ARG1 (c / capable-01 :ARG1 (c2 / cell-line :name (n3 / name :op1 "Caco-2")) :ARG2 (f3 / form-01 :ARG0 c2 :ARG1 (s2 / spheroid :mod (l / lumen))) :ARG1-of (m4 / mean-01 :ARG2 (p2 / property :ARG1-of (r / retain-01 :ARG0 (c3 / cell-line :name (n4 / name :op1 "Caco-K15")) :mod (a2 / also)) :ARG1-of (a3 / absent-01 :ARG2 (a4 / and :op1 (c4 / cell-line :name (n5 / name :op1 "Caco-BR13")) :op2 (c6 / cell-line :name (n6 / name :op1 "Caco-H2"))) :ARG1-of (c5 / complete-02))))) :ARG2-of (f / follow-01 :ARG1 (s / stain-01 :ARG2 (a / and :op1 (s4 / small-molecule :name (n / name :op1 "Hoechst") :xref (x1 / xref :value "PUBCHEM:1464" :prob "9.793014")) :op2 (s3 / small-molecule :name (n2 / name :op1 "phalloidin") :xref (x / xref :value "PUBCHEM:4752" :prob "16.525295"))))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f2 / figure :mod "1B") :op2 (p / panel :ARG1-of (l2 / low-04 :degree (m3 / more)))))) # ::id a_pmid_2194_3101.147 # ::date 2015-05-22T05:32:52 # ::file a_pmid_2194_3101_147.txt # ::snt Significantly enlarged and more compact spheroids without lumen were formed by Caco-BR13 cells as compared to Caco-2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (f / form-01 :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-BR13")) :ARG1 (s / spheroid :ARG1-of (e / enlarge-01 :ARG2 (s2 / significant-02)) :ARG1-of (c / compact-01 :degree (m / more)) :ARG0-of (h / have-03 :polarity "-" :ARG1 (l2 / lumen))) :compared-to (c3 / cell-line :name (n2 / name :op1 "Caco-2"))) # ::id a_pmid_2194_3101.148 # ::date 2015-05-22T05:57:00 # ::file a_pmid_2194_3101_148.txt # ::snt In the case of Caco-H2 cells, no typical spheroids were formed, instead large masses with non-canonical shape were observed, typical of cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (o / observe-01 :ARG1 (m / mass :mod (l / large) :ARG1-of (s2 / shape-01 :polarity "-" :ARG2 (c3 / canonical)) :ARG0-of (t2 / typify-01 :ARG1 (c4 / cell :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))) :ARG1-of (i / instead-of-91 :ARG2 (f / form-01 :ARG1 (s / spheroid :ARG1-of (t / typical-02)))) :topic (c2 / cell-line :name (n / name :op1 "Caco-H2"))) # ::id a_pmid_2194_3101.149 # ::date 2015-05-22T06:01:40 # ::file a_pmid_2194_3101_149.txt # ::snt Therefore, under 2D as well as 3D culture conditions BRAFV600E overexpression managed to alter the morphology of colon adenocarcinoma cells, rendering them a more mesenchymal-like phenotype, while KRASG12V conserved the epithelial architecture of Caco-2 cells in general. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (c10 / contrast-01 :ARG1 (m / manage-02 :ARG0 (o / overexpress-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "BRAF") :ARG1-of (m3 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (a2 / alter-01 :ARG1 (m4 / morphology :poss (c5 / cell :source (a3 / adenocarcinoma :part-of (c6 / colon)))))) :ARG0-of (r / render-02 :ARG1 (p / phenotype :ARG1-of (r2 / resemble-01 :ARG2 (p2 / phenotype :mod (m5 / mesenchyme :degree (m6 / more))))) :ARG2 c5)) :ARG2 (c2 / conserve-01 :ARG0 (e2 / enzyme :name (n / name :op1 "KRAS") :ARG1-of (m2 / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1 (a / architecture :mod (e / epithelium) :source (c3 / cell-line :name (n2 / name :op1 "Caco-2"))) :ARG1-of (g2 / general-02)) :condition (a4 / and :op1 (c8 / culture :mod (d / dimension :quant "2")) :op2 (c9 / culture :mod (d2 / dimension :quant "3"))))) # ::id a_pmid_2194_3101.150 # ::date 2015-05-22T06:14:22 # ::file a_pmid_2194_3101_150.txt # ::snt BRAFV600E downregulates E-cadherin at the mRNA level and impairs its distribution in human colon adenocarcinoma cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 1, 2015 (a / and :op1 (d / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG2 (e / enzyme :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location (l / level :quant-of (n4 / nucleic-acid :name (n3 / name :op1 "mRNA")))) :op2 (i / impair-01 :ARG0 e :ARG1 (d2 / distribute-01 :ARG1 p :location (c / cell :source (a2 / adenocarcinoma :mod (c2 / colon :mod (h / human))))))) # ::id a_pmid_2194_3101.151 # ::date 2015-05-22T06:20:35 # ::file a_pmid_2194_3101_151.txt # ::snt It has been previously shown that HRASG12V converts Caco-2 epithelial into mesenchymal cells by inducing loss of E-cadherin and overexpression of vimentin [25]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG1 (c2 / convert-01 :ARG0 (g / gene :name (n3 / name :op1 "HRAS") :ARG1-of (m / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG1 (c3 / cell-line :name (n4 / name :op1 "Caco-2") :mod (e / epithelium)) :ARG2 (c4 / cell :location (m2 / mesenchyme)) :manner (i / induce-01 :ARG0 g :ARG2 (a / and :op1 (l / lose-02 :ARG1 (p4 / protein :name (n2 / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :op2 (o / overexpress-01 :ARG1 (p3 / protein :name (n / name :op1 "vimentin") :xref (x / xref :value "UNIPROT:VIME_HUMAN" :prob "0.702")))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "25"))) :time (p2 / previous)) # ::id a_pmid_2194_3101.152 # ::date 2015-05-22T08:10:51 # ::file a_pmid_2194_3101_152.txt # ::snt In order to examine whether BRAFV600E had a similar effect on Caco-2 cells, the expression and localization of E-cadherin was analyzed (Figure 2A, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / analyze-01 :ARG1 (a3 / and :op1 (e / express-03 :ARG2 "p") :op2 (b / be-located-at-91 :ARG2 (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B"))) :purpose (e2 / examine-01 :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (a4 / affect-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (c / cell-line :name (n3 / name :op1 "Caco-2")) :ARG1-of (r / resemble-01))))) # ::id a_pmid_2194_3101.153 # ::date 2015-05-22T08:30:44 # ::file a_pmid_2194_3101_153.txt # ::snt Transformation of Caco-2 cells with BRAFV600E led to a significant decrease in the mRNA levels of E-cadherin but had no significant effect on the actual protein expression (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (l / lead-03 :ARG0 (t / transform-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (c2 / cell-line :name (n / name :op1 "Caco-2"))) :ARG1 (d / decrease-01 :ARG1 (l2 / level :quant-of (n5 / nucleic-acid :name (n3 / name :op1 "mRNA") :mod (p / protein :name (n4 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG2 (s / significant-02))) :ARG2 (a / affect-01 :polarity "-" :ARG0 t :ARG1 (e / express-03 :ARG2 p :ARG1-of (a2 / actual-02)) :ARG1-of s) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2194_3101.154 # ::date 2015-05-22T09:19:19 # ::file a_pmid_2194_3101_154.txt # ::snt Notably, in Caco-BR cells reduced intensity for E-cadherin was observed mostly in lower molecular weight protein bands representing the mature protein at 120 kDa (Figure 2A-lower panel, high exposure), whereas the decrease in the actual precursors at 135 kDa (Figure 2A-lower panel, low exposure), is considerably less. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (o / observe-01 :ARG1 (i / intensity :ARG1-of (r2 / reduce-01) :poss (p5 / protein :name (n4 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :location (b / band :mod (p3 / protein :ARG1-of (l4 / low-04 :ARG2 (w / weight-01 :ARG1 (m4 / molecule)) :degree (m5 / more))) :ARG0-of (r / represent-01 :ARG1 (p4 / protein :name (n2 / name :op1 "E-cadherin") :ARG1-of (m / mature-02) :quant (m7 / mass-quantity :quant "120" :unit "k") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :degree (m3 / most) :location (c3 / cell-line :name (n3 / name :op1 "Caco-BR")) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "2A") :op2 (p6 / panel :ARG1-of (l5 / low-04 :degree (m8 / more))) :op3 (e2 / expose-01 :ARG1-of (h / high-02))))) :ARG2 (d / decrease-01 :ARG1 (p / precursor :ARG1-of (a / actual-02) :quant (m9 / mass-quantity :quant "135" :unit (k / kilodalton))) :ARG2 (l6 / less :degree (c2 / considerable)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2A") :op2 (p2 / panel :ARG1-of (l / low-04 :degree (m2 / more))) :op3 (e / exposure :ARG1-of (l2 / low-04))))) :ARG1-of (n / notable-04)) # ::id a_pmid_2194_3101.155 # ::date 2015-05-22T07:18:01 # ::file a_pmid_2194_3101_155.txt # ::snt It appears that mutant BRAFV600E but not upstream KRASG12V activation is able to suppress the mature E-cadherin, while the precursor remained mostly unaffected. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / appear-01 :ARG1 (c3 / contrast-01 :ARG1 (c2 / capable-01 :ARG1 (a3 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (c / contrast-01 :ARG2 (a4 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "KRAS") :ARG1-of (m2 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (c4 / capable-01 :polarity "-" :ARG2 "s") :location (u / upstream)))) :ARG2 (s / suppress-01 :ARG1 (p / protein :name (n3 / name :op1 "E-cadherin") :ARG1-of (m3 / mature-02) :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG2 (r / remain-01 :ARG1 (p2 / precursor) :ARG3 (a2 / affect-01 :polarity "-" :degree (m4 / most))))) # ::id a_pmid_2194_3101.156 # ::date 2015-05-22T08:10:15 # ::file a_pmid_2194_3101_156.txt # ::snt Nevertheless, immunostaining with E-cadherin revealed a significant impairment of its distribution at the cell-cell boundaries since staining appeared discontinuous at the adherent junctions (Figure 2B, upper panel magnification). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (h / have-concession-91 :ARG1 (c2 / cause-01 :ARG0 (a / appear-01 :ARG1 (c / continue-01 :polarity "-" :ARG1 (s / stain-01)) :location (m3 / macro-molecular-complex :name (n2 / name :op1 "adherent" :op2 "junction"))) :ARG1 (r / reveal-01 :ARG0 (i / immunostain-01 :ARG2 (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG1 (i2 / impair-01 :ARG1 (d2 / distribute-01 :ARG1 p :ARG2 (b / boundary :mod (b2 / between :op1 "c3" :op2 (c3 / cell)))) :ARG1-of (s2 / significant-02)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "2B") :op2 (m / magnify-01 :ARG1 (p2 / panel :mod (u / upper)))))) # ::id a_pmid_2194_3101.157 # ::date 2015-05-22T09:26:49 # ::file a_pmid_2194_3101_157.txt # ::snt Expression of E-cadherin in the Caco-BR grown in 3D spheroids was found significantly downregulated with diffused distribution (Figure 2B, lower panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 7, 2015 (f / find-01 :ARG1 (d2 / downregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG3 (c / cell-line :name (n2 / name :op1 "Caco-BR") :ARG1-of (g / grow-03 :location (s / spheroid :mod (d5 / dimension :quant "3"))))) :manner (d3 / distribute-01 :ARG1-of (d4 / diffuse-01)) :ARG1-of (s2 / significant-02)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "2B") :op2 (p / panel :ARG1-of (l / low-04 :degree (m / more)))))) # ::id a_pmid_2194_3101.158 # ::date 2015-05-22T06:42:18 # ::file a_pmid_2194_3101_158.txt # ::snt In contrast, the epithelial marker E-cadherin was normally localized at the cell-cell junctions of Caco-2 and Caco-K15 cells (Figure 2B, lower panel magnification). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (b / be-located-at-91 :ARG1 (m3 / marker :name (n2 / name :op1 "E-cadherin") :mod (e / epithelium)) :ARG2 (j3 / junction :mod (b2 / between :op1 (c2 / cell-line :name (n3 / name :op1 "Caco-2")) :op2 (c3 / cell-line :name (n4 / name :op1 "Caco-K15")))) :ARG1-of (n / normal-02)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2B") :op2 (m / magnify-01 :ARG1 (p / panel :ARG1-of (l2 / low-04)))))) # ::id a_pmid_2194_3101.159 # ::date 2015-05-21T11:57:36 # ::file a_pmid_2194_3101_159.txt # ::snt In order to determine whether Caco-BR cells have acquired more mesenchymal characteristics, RNA and protein levels of the mesenchymal marker Vimentin were examined (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / examine-01 :ARG1 (a / and :op1 (l / level :quant-of (n3 / nucleic-acid :name (n4 / name :op1 "RNA"))) :op2 (l2 / level :quant-of (p / protein)) :poss (m4 / marker :name (n / name :op1 "Vimentin") :mod (m / mesenchyme))) :purpose (d / determine-01 :ARG1 (a2 / acquire-01 :mode "interrogative" :ARG0 (c / cell-line :name (n2 / name :op1 "Caco-BR")) :ARG1 (t / thing :quant (m3 / more) :ARG2-of (c2 / characteristic-02 :ARG1 m)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2C"))) # ::id a_pmid_2194_3101.160 # ::date 2015-05-22T10:03:33 # ::file a_pmid_2194_3101_160.txt # ::snt An increase of about 3-fold was observed at the protein level, while confocal images did not show significant difference, as compared to Caco-2 (Figure 2D), since it is known that some cancer epithelial cells abnormally express N-cadherin which has been shown to promote motility and invasion [26,27], N-cadherin expression was examined (Figure 2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a5 / and :op1 (c2 / contrast-01 :ARG1 (o / observe-01 :ARG1 (i2 / increase-01 :ARG1 (l / level :quant-of (p5 / protein)) :ARG3 (a6 / about :quant (a4 / about :op1 (p6 / product-of :op1 "3"))))) :ARG2 (s / show-01 :polarity "-" :ARG0 (i3 / image :mod (c8 / confocal)) :ARG1 (d4 / differ-02 :ARG1-of (s4 / significant-02)) :compared-to (c / cell-line :name (n3 / name :op1 "Caco-2")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2D")))) :op2 (c9 / cause-01 :ARG0 (k / know-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n2 / name :op1 "N-cadherin") :ARG0-of (p2 / promote-01 :ARG1 (a2 / and :op1 (m / motility) :op2 (i / invade-01)) :ARG1-of (s3 / show-01 :ARG0 (a3 / and :op1 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 "26")) :op2 (p4 / publication :ARG1-of (c7 / cite-01 :ARG2 "27"))))) :xref (x / xref :value "UNIPROT:CADH2_HUMAN" :prob "1.003")) :ARG3 (c5 / cell :quant (s2 / some) :source (e3 / epithelium) :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :manner (a / abnormal))) :ARG1 (e / examine-01 :ARG1 e2 :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2E"))))) # ::id a_pmid_2194_3101.161 # ::date 2015-05-22T06:22:40 # ::file a_pmid_2194_3101_161.txt # ::snt In Caco-BR cells N-cadherin expression is increased about 2-fold both at mRNA and protein levels, as compared to Caco-2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / increase-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "N-cadherin") :xref (x / xref :value "UNIPROT:CADH2_HUMAN" :prob "1.003")) :ARG3 (c2 / cell-line :name (n3 / name :op1 "Caco-BR"))) :ARG2 (a2 / about :op1 (p2 / product-of :op1 "12")) :prep-at (a / and :op1 (l2 / level :mod (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"))) :op2 (l / level :mod (p3 / protein))) :compared-to (c / cell-line :name (n / name :op1 "Caco-2"))) # ::id a_pmid_2194_3101.162 # ::date 2015-05-22T05:24:45 # ::file a_pmid_2194_3101_162.txt # ::snt Confocal images confirmed this increase, as shown in Figure 2F. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 22, 2015 (c / confirm-01 :ARG0 (i / images :mod (c2 / confocal)) :ARG1 (i2 / increase-01 :mod (t / this)) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "2F"))) # ::id a_pmid_2194_3101.163 # ::date 2015-05-22T05:26:05 # ::file a_pmid_2194_3101_163.txt # ::snt Taken together these data suggest that BRAFV600E overexpression failed to induce an integrated EMT phenotype, which is the case with HRASG12V overexpression [25], but managed to transform Caco-2 cells through the loss of some important epithelial characteristics. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (d / data :mod (t2 / this) :ARG1-of (t / take-01 :mod (t3 / together))) :ARG1 (c4 / contrast-01 :ARG1 (f / fail-01 :ARG1 (o / overexpress-01 :ARG1 (e3 / enzyme :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (i / induce-01 :ARG0 o :ARG2 (p / phenotype :mod (t5 / transition-01 :ARG2 (m4 / mesenchyme) :ARG3 (e4 / epithelium)) :ARG1-of (i2 / integrate-01))) :ARG2-of (c5 / contrast-01 :ARG1 (o2 / overexpress-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "HRAS") :ARG1-of (m2 / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "25")))))) :ARG2 (m3 / manage-02 :ARG0 o :ARG1 (t4 / transform-01 :ARG0 o :ARG1 (c2 / cell-line :name (n4 / name :op1 "Caco-2"))) :manner (l / lose-02 :ARG0 c2 :ARG1 (t6 / thing :mod (i3 / important) :ARG2-of (c3 / characteristic-02 :ARG1 (e / epithelium) :quant (s2 / some))))))) # ::id a_pmid_2194_3101.164 # ::date 2015-05-22T10:04:13 # ::file a_pmid_2194_3101_164.txt # ::snt Differential BRAFV600E, KRASG12V and HRASG12V effect on the migration and invasion ability of Caco-2 cells in vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n2 / name :op1 "KRAS") :ARG1-of (m2 / mutate-01 :value "G12V") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n3 / name :op1 "HRAS") :ARG1-of (m3 / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG1-of (d / differ-02)) :ARG1 (a3 / and :op1 (c / capable-01 :ARG1 (c3 / cell-line :name (n4 / name :op1 "Caco-2")) :ARG2 (m4 / migrate-01 :ARG0 c3)) :op2 (c2 / capable-01 :ARG1 c3 :ARG2 (i / invade-01 :ARG0 c3)) :manner (i2 / in-vitro))) # ::id a_pmid_2194_3101.165 # ::date 2015-05-22T10:10:29 # ::file a_pmid_2194_3101_165.txt # ::snt To further explore oncogenic effects on the cell cytoskeleton with regard to oncogenic transformation, the invasive and migratory properties of the previously established oncogenic cell models and in colon cancer cell lines HT29 and DLD-1 were analyzed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / analyze-01 :ARG1 (a3 / and :op1 (p / property :mod (i / invade-01) :poss (a4 / and :op1 (m2 / model :ARG1-of (e2 / establish-01 :time (p3 / previous)) :mod "o" :mod (c7 / cell)) :op2 (c4 / cell-line :name (n / name :op1 "HT29") :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :mod (c6 / colon))) :op3 (c5 / cell-line :name (n2 / name :op1 "DLD-1") :mod d))) :op2 (p2 / property :mod (m / migrate-01) :poss a4)) :purpose (e / explore-01 :ARG1 (a2 / affect-01 :ARG0 (o / oncogene) :ARG1 (c / cytoskeleton :part-of (c2 / cell) :xref (x / xref :value "GO:0005856" :prob "0.8"))) :ARG2 (t / transform-01 :mod o) :degree (f / further))) # ::id a_pmid_2194_3101.166 # ::date 2015-05-22T10:11:10 # ::file a_pmid_2194_3101_166.txt # ::snt Transformation induced by each of the three oncogenes KRASG12V (Caco-K cells), BRAFV600E (Caco-BR cells) and HRASG12V (Caco-H cells) managed to increase the ability of Caco-2 cells to migrate and invade in vitro, independently of their proliferating ability, which has been previously analyzed in [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / manage-01 :ARG0 (t / transform-01 :ARG2-of (i / induce-01 :ARG0 (a / and :op1 (g / gene :name (n4 / name :op1 "KRAS") :location-of (c2 / cell :name (n / name :op1 "Caco-K")) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n5 / name :op1 "BRAF") :location-of (c3 / cell-line :name (n2 / name :op1 "Caco-BR") :time (p3 / previous)) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op3 (g3 / gene :name (n6 / name :op1 "HRAS") :location-of (c4 / cell-line :name (n3 / name :op1 "Caco-H")) :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG0-of (c8 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))))) :ARG1 (i2 / increase-01 :ARG0 t :ARG1 (c5 / capable-01 :ARG1 (c6 / cell-line :name (n7 / name :op1 "Caco-2")) :ARG2 (a2 / and :op1 (m2 / migrate-01 :ARG0 c6) :op2 (i3 / invade-01 :ARG0 c6) :manner (i4 / in-vitro) :manner (i5 / independent :topic (c7 / capable-01 :ARG1 c6 :ARG2 (p2 / proliferate-01 :ARG0 c6) :ARG1-of (a3 / analyze-01 :medium (p / publication :ARG1-of (c / cite-01 :ARG2 "21"))))))))) # ::id a_pmid_2194_3101.167 # ::date 2015-05-23T07:23:36 # ::file a_pmid_2194_3101_167.txt # ::snt More specifically, BRAFV600E and HRASG12V provided Caco-2 cells with highly migrating and invasive properties, some similar to those in DLD-1 cells (Figure 3A, B), which is compatible with their more elongated morphology described earlier (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / provide-01 :ARG0 (a / and :op1 (g / gene :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "HRAS") :ARG2-of (m2 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003"))) :ARG1 (p2 / property :mod (i / invade-01 :ARG1-of (h / high-02)) :mod (m3 / migrate-01 :degree h) :ARG1-of (r / resemble-01 :ARG2 (p3 / property :location (c / cell-line :name (n3 / name :op1 "DLD-1")) :quant (s / some)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B"))))) :ARG2 (c2 / cell-line :name (n4 / name :op1 "Caco-2")) :mod (c3 / compatible :prep-with (m4 / morphology :poss c2 :ARG1-of (e3 / elongate-01 :degree (m5 / more)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "1") :time (e4 / early :degree m5)))) :ARG1-of (s2 / specific-02 :degree m5)) # ::id a_pmid_2194_3101.168 # ::date 2015-05-23T09:00:41 # ::file a_pmid_2194_3101_168.txt # ::snt Moreover, Caco-K cells, that retained typical epithelial morphology of Caco-2 parental cells also presented enhanced migrating and invasive properties, but to a lesser extent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (p / present-01 :ARG0 (c / cell :name (n / name :op1 "Caco-K") :ARG0-of (r / retain-01 :ARG1 (m / morphology :mod (e / epithelium) :ARG1-of (t / typical-02) :poss (c2 / cell-line :name (n2 / name :op1 "Caco-2") :mod (p2 / parent))))) :ARG1 (p3 / property :mod (i / invade-01) :mod (m2 / migrate-01) :ARG1-of (e2 / enhance-01)) :mod (a2 / also) :ARG1-of (c3 / contrast-01 :ARG2 (p4 / present-01 :ARG0 c :ARG1 p3 :degree (l / less))))) # ::id a_pmid_2194_3101.169 # ::date 2015-05-23T09:24:57 # ::file a_pmid_2194_3101_169.txt # ::snt Taken together, morphological properties induced by either BRAFV600E or KRASG12V oncogene affected the ability of Caco-2 cells to migrate and invade in vitro, but were not sufficient to fully reverse their epithelial phenotype. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (a / affect-01 :ARG0 (p / property :mod (m / morphological) :ARG2-of (i / induce-01 :ARG0 (o / or :op1 (g / gene :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "KRAS") :ARG2-of (m3 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))) :ARG1 (p2 / possible-01 :ARG1 (a2 / and :op1 (m4 / migrate-01 :ARG0 (c2 / cell-line :name (n3 / name :op1 "Caco-2"))) :op2 (i2 / invade-01 :ARG0 c2) :manner (i3 / in-vitro)))) :ARG2 (s / suffice-01 :polarity "-" :ARG0 p :ARG1 (r / reverse-01 :ARG0 p :ARG1 (p3 / phenotype :mod (e / epithelium) :poss c2) :degree (f / full))) :ARG1-of (t / take-01 :mod (t2 / together))) # ::id a_pmid_2194_3101.170 # ::date 2015-05-23T09:49:32 # ::file a_pmid_2194_3101_170.txt # ::snt The role of BRAF and KRAS oncogenes in altering cytoskeletal properties was further emphasized following depletion of BRAFV600E by shRNA in HT29 cells, where migration ability of HT-ShBR3 cells, with downregulated expression of mtBRAF gene, was significantly impaired as compared to the empty vector control HT-ps cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / emphasize-01 :ARG1 (r / role :poss (a / and :op1 (g2 / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g3 / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG0-of (c7 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n10 / name :op1 "cancer")))) :topic (a2 / alter-01 :ARG0 a :ARG1 (p / property :mod (c / cytoskeleton :xref (x4 / xref :value "GO:0005856" :prob "0.8"))))) :degree (f / further) :ARG1-of (f2 / follow-01 :ARG2 (d / deplete-01 :ARG0 (n9 / nucleic-acid :name (n3 / name :op1 "shRNA")) :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location (c2 / cell-line :name (n5 / name :op1 "HT29") :location-of (i / impair-01 :ARG1 (p2 / possible-01 :ARG1 (m2 / migrate-01 :ARG0 (c3 / cell-line :name (n6 / name :op1 "HT-ShBR3"))) :accompanier (e3 / express-03 :ARG1 (g / gene :name (n7 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (d2 / downregulate-01))) :ARG1-of (s / significant-02) :ARG1-of (c4 / compare-01 :ARG2 (c5 / cell-line :name (n8 / name :op1 "HT-ps") :ARG2-of (c6 / control-01 :ARG0 (v / vector :ARG1-of (e4 / empty-02)))))))))) # ::id a_pmid_2194_3101.171 # ::date 2015-05-23T10:29:36 # ::file a_pmid_2194_3101_171.txt # ::snt Likewise, knock out of KRASG13D in DLD-1 cells (DKO-4) [28] significantly reverted the migration ability of DLD-1 cells (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / revert-01 :ARG0 (k / knock-out-03 :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS") :ARG2-of (m2 / mutate-01 :value "G13D") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :location "c" :ARG1-of (d / describe-01 :ARG0 (c2 / cell-line :name (n3 / name :op1 "DKO-4"))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "28")))) :ARG1 (p / possible-01 :ARG1 (m / migrate-01 :ARG0 (c / cell-line :name (n / name :op1 "DLD-1")))) :ARG1-of (s / significant-02) :mod (l / likewise) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3C"))) # ::id a_pmid_2194_3101.172 # ::date 2015-05-23T10:55:33 # ::file a_pmid_2194_3101_172.txt # ::snt BRAFV600E enhances the ability of Caco-2 cells to migrate and invade in vitro through RhoA activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / enhance-01 :ARG0 (e2 / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (p / possible-01 :ARG1 (a / and :op1 (m2 / migrate-01 :ARG0 (c / cell-line :name (n2 / name :op1 "Caco-2"))) :op2 (i / invade-01 :ARG0 c) :manner (i2 / in-vitro))) :manner (a2 / activate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")))) # ::id a_pmid_2194_3101.173 # ::date 2015-05-23T11:05:09 # ::file a_pmid_2194_3101_173.txt # ::snt Overexpression of BRAFV600E in Caco-2 cells had a profound effect on the RAS effector protein RhoA (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location (c / cell-line :name (n2 / name :op1 "Caco-2"))) :ARG1 (p / protein :name (n3 / name :op1 "RhoA") :mod (e2 / effector :mod (p3 / protein-family :name (n4 / name :op1 "RAS"))) :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :degree (p2 / profound) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4"))) # ::id a_pmid_2194_3101.174 # ::date 2015-05-23T11:24:36 # ::file a_pmid_2194_3101_174.txt # ::snt In Caco-BR cells activation of RhoA is increased (Figure 4A) as well as phosphorylation of its downstream target Cofilin, a protein that is related to stress fibre formation (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / increase-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (p / protein :name (n / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) :op2 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Cofilin") :ARG1-of (t / target-01 :ARG0 (c / cell-line :name (n3 / name :op1 "Caco-BR")) :location (d2 / downstream)) :ARG1-of (r / relate-01 :ARG2 (f2 / form-01 :ARG1 (f3 / fiber :mod (s / stress)))) :xref (x / xref :value "UNIPROT:COF1_HUMAN" :prob "0.362")) :ARG1-of (d3 / describe-01 :ARG0 (f4 / figure :mod "4B")))) :location c) # ::id a_pmid_2194_3101.175 # ::date 2015-05-23T11:34:33 # ::file a_pmid_2194_3101_175.txt # ::snt These findings are closely related to the observation regarding increased stress fibre formation indicated by phalloidin staining in Caco-BR13 cells (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / relate-01 :ARG1 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG2 (o / observe-01 :ARG0-of (r2 / regard-01 :ARG1 (f2 / form-01 :ARG1 (f3 / fiber :mod (s / stress)) :ARG1-of (i / increase-01) :ARG1-of (i2 / indicate-01 :ARG0 (s2 / stain-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "phalloidin") :xref (x / xref :value "PUBCHEM:4752" :prob "16.525295")) :location (c / cell-line :name (n2 / name :op1 "Caco-BR13"))))))) :ARG1-of (c2 / close-10) :ARG1-of (d / describe-01 :ARG0 (f4 / figure :mod "1"))) # ::id a_pmid_2194_3101.176 # ::date 2015-05-23T12:33:16 # ::file a_pmid_2194_3101_176.txt # ::snt Notably, an extra band of lower molecular weight is detected for RhoA in Caco-BR and DLD-1 cells, which potentially represents the main active GTPase form (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / detect-01 :ARG1 (b / band :mod (e / extra) :ARG1-of (w / weight-01 :mod (m / molecule) :ARG1-of (l / low-04 :degree (m2 / more))) :mod (p / protein :name (n / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG0-of (r / represent-01 :ARG1 (f / form :mod (e2 / enzyme :name (n4 / name :op1 "GTPase") :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :ARG1-of (a / activate-01) :mod (m3 / main)) :mod (p2 / potential))) :location (a2 / and :op1 (c / cell-line :name (n2 / name :op1 "Caco-BR")) :op2 (c2 / cell-line :name (n3 / name :op1 "DLD-1"))) :ARG1-of (n5 / notable-04) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4A"))) # ::id a_pmid_2194_3101.177 # ::date 2015-05-23T13:14:05 # ::file a_pmid_2194_3101_177.txt # ::snt A variant of lower molecular weight for RhoA protein has previously been reported both in colon and breast tissues [7]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 1, 2015 (r / report-01 :ARG1 (v / variant :ARG1-of (w / weight-01 :mod (m / molecule) :ARG1-of (l / low-04 :degree (m2 / more))) :poss (p / protein :name (n / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :time (p2 / previous) :location (a / and :op1 (t / tissue :part-of (c / colon)) :op2 (t2 / tissue :part-of (b / breast))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "7")))) # ::id a_pmid_2194_3101.178 # ::date 2015-05-23T13:25:12 # ::file a_pmid_2194_3101_178.txt # ::snt However, RT-PCR analysis and treatment with the proteasome inhibitor MG-132, both in Caco-BR and DLD-1 cells, suggested no association of this faster migrating RhoA band with alternative splicing or proteasomal degradation (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (h / have-concession-91 :ARG1 (s / suggest-01 :ARG0 (a / and :op1 (a2 / analyze-01 :instrument (t3 / thing :name (n / name :op1 "RT-PCR"))) :op2 (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "MG-132") :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "proteasome") :xref (x1 / xref :value "UNIPROT:VP113_HUMAN" :prob "0.352"))) :xref (x2 / xref :value "PUBCHEM:462382" :prob "15.017817"))) :location (a3 / and :op1 (c / cell-line :name (n4 / name :op1 "Caco-BR")) :op2 (c2 / cell-line :name (n5 / name :op1 "DLD-1")))) :ARG1 (a4 / associate-01 :polarity "-" :ARG1 (b / band :mod (p2 / protein :name (n6 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG0-of (m / migrate-01 :ARG1-of (f / fast-02 :degree (m2 / more))) :mod (t2 / this)) :ARG2 (o / or :op1 (s3 / splice-01 :ARG1-of (a5 / alternate-01)) :op2 (d / degrade-01 :ARG1 e)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s4 / show-01 :polarity "-")))) # ::id a_pmid_2194_3101.179 # ::date 2015-05-24T03:06:33 # ::file a_pmid_2194_3101_179.txt # ::snt These data suggested that the additional band potentially represents a post-translational modification of RhoA protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (r / represent-01 :ARG0 (b / band :ARG1-of (a / add-02)) :ARG1 (m / modify-01 :ARG1 (p / protein :name (n / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :time (a2 / after :op1 (t2 / translate-02))) :mod (p3 / potential))) # ::id a_pmid_2194_3101.180 # ::date 2015-05-24T03:32:22 # ::file a_pmid_2194_3101_180.txt # ::snt To further explore the role of BRAFV600E in the activation of the RhoA pathway, transient transfection of the oncogene in Caco-2 cells was performed (Additional Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG1 (t / transfect-01 :ARG1 (c / cell-line :name (n / name :op1 "Caco-2")) :ARG2 (o / oncogene) :ARG1-of (t2 / transient-02)) :purpose (e / explore-01 :ARG1 (r / role :poss (e2 / enzyme :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :topic (a / activate-01 :ARG1 (p2 / pathway :name (n3 / name :op1 "RhoA")))) :degree (f / further)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2" :ARG1-of (a2 / add-02)))) # ::id a_pmid_2194_3101.181 # ::date 2015-05-24T03:51:34 # ::file a_pmid_2194_3101_181.txt # ::snt Subsequent analysis of the migration and invasion properties showed that moderate RhoA activation induced a partial cell migration and cell invasion response (Addition Figure 2A, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (p / property :mod (i / invade-01) :mod (m / migrate-01)) :time (s2 / subsequent)) :ARG1 (i2 / induce-01 :ARG0 (a2 / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG1-of (m2 / moderate-03)) :ARG2 (a3 / and :op1 (r / respond-01 :ARG2 (m3 / migrate-01 :ARG0 (c / cell))) :op2 (r2 / respond-01 :ARG2 (i3 / invade-01 :ARG0 c)) :degree (p3 / part))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B") :ARG1-of (a5 / add-02)))) # ::id a_pmid_2194_3101.182 # ::date 2015-05-24T04:05:42 # ::file a_pmid_2194_3101_182.txt # ::snt Notably in the invasion assay cell phenotype became slightly altered and resembled that of the stable Caco-BR clones (Additional Figure 2C), suggesting that a stable expression of BRAFV600E is required to achieve complete cell transformation and extensive RhoA activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (b / become-01 :ARG1 (p / phenotype :mod (c / cell)) :ARG2 (a2 / alter-01 :ARG1 p :degree (s / slight))) :op2 (r / resemble-01 :ARG1 p :ARG2 (p2 / phenotype :poss (c2 / clone-01 :ARG1 (c3 / cell-line :name (n / name :op1 "Caco-BR")) :ARG1-of (s2 / stable-03)))) :ARG1-of (n2 / notable-04) :time (a3 / assay-01 :ARG1 (i / invade-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2C" :ARG1-of (a4 / add-02))) :ARG0-of (s3 / suggest-01 :ARG1 (r2 / require-01 :ARG0 (a5 / achieve-01 :ARG1 (a6 / and :op1 (t / transform-01 :ARG1 c :ARG1-of (c4 / complete-02)) :op2 (a7 / activate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG1-of (e / extensive-03)))) :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n4 / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of s2)))) # ::id a_pmid_2194_3101.183 # ::date 2015-05-24T04:55:35 # ::file a_pmid_2194_3101_183.txt # ::snt Regarding the importance of RhoA activation in the induced cell migration and invasion observed in Caco-BR cells, siRNA against RhoA was performed leading to significant protein depletion in both Caco-2 and Caco-BR13 cells (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG1 (n6 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (o / oppose-01 :ARG1 (p2 / protein :name (n2 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")))) :topic (i / important :domain (a / activate-01 :ARG1 p2 :location (a2 / and :op1 (m / migrate-01 :ARG0 (c / cell)) :op2 (i2 / invade-01 :ARG0 c) :ARG2-of (i3 / induce-01) :ARG1-of (o2 / observe-01 :location (c2 / cell-line :name (n3 / name :op1 "Caco-BR")))))) :ARG0-of (l / lead-03 :ARG2 (d / deplete-01 :ARG1 (p3 / protein) :ARG1-of (s / significant-02) :location (a3 / and :op1 (c3 / cell-line :name (n4 / name :op1 "Caco-2")) :op2 (c4 / cell-line :name (n5 / name :op1 "Caco-BR13"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id a_pmid_2194_3101.184 # ::date 2015-05-24T05:41:26 # ::file a_pmid_2194_3101_184.txt # ::snt Depletion of RhoA substantially impaired both acquired properties with more profound effect in Caco-BR13 cells, further illustrating its central role in the BRAFV600E oncogene-induced transformation of colon adenocarcinoma cells (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / impair-01 :ARG0 (d / deplete-01 :ARG1 (p / protein :name (n / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :ARG1 (p2 / property :ARG1-of (a / acquire-01) :mod (b / both)) :degree (s / substantial) :ARG0-of (a2 / affect-01 :degree (p3 / profound :degree (m / more)) :location (c / cell-line :name (n2 / name :op1 "Caco-BR13"))) :ARG0-of (i2 / illustrate-01 :ARG1 (r / role :poss d :topic (t / transform-01 :ARG1 (c2 / cell :mod (a3 / adenocarcinoma :mod (c3 / colon))) :ARG2-of (i3 / induce-01 :ARG0 (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :ARG0-of (c5 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :mod (c4 / central)) :mod (f / further)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5B"))) # ::id a_pmid_2194_3101.185 # ::date 2015-05-24T06:09:28 # ::file a_pmid_2194_3101_185.txt # ::snt Moreover, following RhoA depletion in Caco-2 cells, the number and size of stress fibres were notably reduced as compared to Caco-BR cells, where no such alteration was observed (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (r / reduce-01 :ARG1 (a2 / and :op1 (n / number) :op2 (s / size) :quant-of (f / fiber :mod (s2 / stress))) :ARG2 (n3 / notable-04) :compared-to (c / cell-line :name (n2 / name :op1 "Caco-BR") :location-of (o / observe-01 :ARG1 (a3 / alter-01 :polarity "-" :mod (s3 / such)))) :ARG1-of (f2 / follow-01 :ARG2 (d / deplete-01 :ARG1 (p / protein :name (n4 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :location (c2 / cell-line :name (n5 / name :op1 "Caco-2"))))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s4 / show-01 :polarity "-")))) # ::id a_pmid_2194_3101.186 # ::date 2015-05-24T06:23:54 # ::file a_pmid_2194_3101_186.txt # ::snt In order to study further the impact of RhoA GTPase on cell migration, silencing of RhoA was performed in DLD-1 and HT29 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG1 (s / silence-01 :ARG1 (p2 / protein :name (n / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :location (a / and :op1 (c / cell-line :name (n2 / name :op1 "DLD-1")) :op2 (c2 / cell-line :name (n3 / name :op1 "HT29"))) :purpose (s2 / study-01 :ARG1 (i / impact-01 :ARG0 (p3 / pathway :name (n4 / name :op1 "RhoA" :op2 "GTPase")) :ARG1 (m / migrate-01 :ARG0 (c3 / cell))) :degree (f / further))) # ::id a_pmid_2194_3101.187 # ::date 2015-05-24T06:37:30 # ::file a_pmid_2194_3101_187.txt # ::snt Considering that these cell lines bear mutation in KRASG13D and BRAFV600E respectively, RhoA depletion was also performed in selected clones where KRASG13D (DKO4) or BRAFV600E (HTshBR3) was knocked out or down regulated via shRNA respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (p / perform-02 :ARG1 (d / deplete-01 :ARG1 (p2 / protein :name (n / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :mod (a / also) :location (o / or :op1 (c / clone-01 :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS") :ARG2-of (m / mutate-01 :value "G13D") :ARG1-of (d2 / describe-01 :ARG0 (c2 / cell :name (n3 / name :op1 "DKO4"))) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (s / select-01)) :op2 (c3 / clone-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :ARG1-of (d3 / describe-01 :ARG0 (c4 / cell :name (n5 / name :op1 "HTshBR3"))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of s) :ARG1-of (k / knock-out-03 :ARG2 (n7 / nucleic-acid :name (n6 / name :op1 "shRNA")) :mod (r2 / respective)) :ARG1-of (d4 / downregulate-01 :mod r2 :instrument n7)) :ARG2-of (c5 / consider-02 :ARG1 (b / bear-01 :ARG0 (c6 / cell-line :mod (t / this)) :ARG1 (m3 / mutate-01) :location (a2 / and :op1 e :op2 e2 :mod r2)))) # ::id a_pmid_2194_3101.188 # ::date 2015-05-24T07:39:01 # ::file a_pmid_2194_3101_188.txt # ::snt This approach can implement the connection between each oncogene and the small GTPase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p / possible-01 :ARG1 (i / implement-01 :ARG0 (a / approach-02 :mod (t / this)) :ARG1 (c / connect-01 :ARG1 (o / oncogene :mod (e / each)) :ARG1 (p2 / protein-family :name (n / name :op1 "GTPase") :mod (s / small))))) # ::id a_pmid_2194_3101.189 # ::date 2015-05-24T07:52:41 # ::file a_pmid_2194_3101_189.txt # ::snt After silencing of RhoA, cell migration was significantly reduced in DLD-1, while no reduction was observed in DKO4 cells, where mutant KRASG13D is knocked out, (Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / reduce-01 :ARG1 (m / migrate-01 :ARG0 (c2 / cell)) :ARG2 (s / significant-02) :location (c3 / cell-line :name (n / name :op1 "DLD-1"))) :ARG2 (o / observe-01 :ARG1 (r2 / reduce-01 :polarity "-") :location (c4 / cell-line :name (n2 / name :op1 "DKO4") :location-of (k / knock-out-03 :ARG1 (e / enzyme :name (n3 / name :op1 "KRAS") :ARG2-of (m2 / mutate-01 :value "G13D") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))) :time (a / after :op1 (s2 / silence-01 :ARG1 (p / protein :name (n4 / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id a_pmid_2194_3101.190 # ::date 2015-05-24T08:02:21 # ::file a_pmid_2194_3101_190.txt # ::snt Depletion of RhoA in HTshBR3 (transfected with shRNA pSUPER BRAFV600E) cells with suppressed BRAFV600E activity did not reverse the ability of HT29 cell to migrate, while in HTps (HT29 cells transfected with empty vector pSUPER) a moderate reduction in cell migration was observed (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / reverse-01 :polarity "-" :ARG0 (d / deplete-01 :ARG1 (p / protein :name (n / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :location (c2 / cell :name (n2 / name :op1 "HTshBR3") :ARG1-of (t / transfect-01 :ARG2 (e / enzyme :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :mod (v / vector :name (n4 / name :op1 "pSUPER")) :ARG1-of (e2 / encode-01 :ARG0 (n10 / nucleic-acid :name (n5 / name :op1 "shRNA"))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG0-of (h / have-03 :ARG1 (a / activity-06 :ARG0 e :ARG1-of (s / suppress-01))))) :ARG1 (p2 / possible-01 :ARG1 (m2 / migrate-01 :ARG0 (c3 / cell-line :name (n6 / name :op1 "HT29"))))) :ARG2 (o / observe-01 :ARG1 (r3 / reduce-01 :ARG1 (m3 / migrate-01 :ARG0 (c4 / cell)) :ARG1-of (m4 / moderate-03) :location (c5 / cell-line :name (n7 / name :op1 "HTps") :ARG1-of (d2 / describe-01 :ARG0 (c6 / cell-line :name (n8 / name :op1 "HT29") :ARG1-of (t2 / transfect-01 :ARG2 (v2 / vector :name (n9 / name :op1 "pSUPER") :ARG1-of (e3 / empty-02)))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id a_pmid_2194_3101.191 # ::date 2015-05-24T08:25:41 # ::file a_pmid_2194_3101_191.txt # ::snt Taken together, these results indicate that both BRAF and KRAS oncogenes utilize RhoA activation to promote cell migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (u / utilize-01 :ARG0 (a / and :op1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :ARG1 (a2 / activate-01 :ARG1 (p / protein :name (n3 / name :op1 "RhoA") :xref (x2 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :purpose (p2 / promote-01 :ARG0 a :ARG1 (m / migrate-01 :ARG0 (c / cell)))) :ARG1-of (t3 / take-01 :mod (t4 / together))) # ::id a_pmid_2194_3101.192 # ::date 2015-05-24T08:31:00 # ::file a_pmid_2194_3101_192.txt # ::snt In a different approach, inhibition of RhoA downstream signalling was achieved via treatment of cells with UO126, a MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase) inhibitor targeting the MAPK pathway, which is active in Caco-BR cells [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / achieve-01 :ARG1 (i / inhibit-01 :ARG1 (s / signal-07 :ARG0 (p / protein :name (n / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :location (d / downstream))) :manner (t / treat-04 :ARG1 (c / cell) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "UO126") :ARG0-of (i2 / inhibit-01 :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK") :ARG1-of (m / mean-01 :ARG2 (o / or :op1 (p5 / protein-family :name (n4 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase")) :op2 (p6 / protein-family :name (n5 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase")))))) :ARG0-of (t2 / target-01 :ARG1 (p2 / pathway :name (n6 / name :op1 "MAPK") :ARG1-of (a2 / activate-01 :location (c2 / cell-line :name (n7 / name :op1 "Caco-BR"))))))) :ARG1-of (a3 / approach-02 :ARG1-of (d2 / differ-02)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "21")))) # ::id a_pmid_2194_3101.193 # ::date 2015-05-24T08:55:39 # ::file a_pmid_2194_3101_193.txt # ::snt Treatment with UO126, at the most optimal treatment condition (Additional Figure 3), resulted in the decreased activation of RhoA illustrating that mutant BRAFV600E utilises the MAPK pathway to activate RhoA (Figure 5E, upper panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (r / result-01 :ARG1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "UO126")) :condition (o / optimal :degree (m / most)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3" :ARG1-of (a / add-02)))) :ARG2 (a2 / activate-01 :ARG0 t :ARG1 (p / protein :name (n2 / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG1-of (d2 / decrease-01)) :ARG0-of (i / illustrate-01 :ARG1 (u / utilize-01 :ARG0 (e / enzyme :name (n3 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (p2 / pathway :name (n4 / name :op1 "MAPK")) :purpose (a3 / activate-01 :ARG0 e :ARG1 p))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "5E" :part (p3 / panel :mod (u2 / upper)))))) # ::id a_pmid_2194_3101.194 # ::date 2015-05-24T09:18:12 # ::file a_pmid_2194_3101_194.txt # ::snt Alternative regulation of RhoA through the PI3K pathway was analysed in Caco-BR cells, and a mild effect on RhoA downstream components like p-Cofilin and p-Myl was observed (Figure 5E, lower panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / analyze-01 :ARG1 (r / regulate-01 :ARG0 (p / pathway :name (n / name :op1 "PI3K")) :ARG1 (p2 / protein :name (n2 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG1-of (a3 / alternate-01)) :location (c / cell-line :name (n3 / name :op1 "Caco-BR"))) :op2 (o / observe-01 :ARG1 (a4 / affect-01 :ARG1 (c2 / component :location (d / downstream) :part-of p2 :example (a5 / and :op1 (p3 / protein :name (n4 / name :op1 "Cofilin") :ARG1-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:COF1_HUMAN" :prob "0.362")) :op2 (p5 / protein :name (n5 / name :op1 "Myl") :ARG1-of p4 :xref (x2 / xref :value "UNIPROT:PML_HUMAN" :prob "0.602")))) :degree (m / mild))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (f / figure :mod "5E" :part (p6 / panel :ARG1-of (l / low-04 :degree (m2 / more))))))) # ::id a_pmid_2194_3101.195 # ::date 2015-05-24T09:33:19 # ::file a_pmid_2194_3101_195.txt # ::snt Analysis of RhoA-ROCK axis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 24, 2015 (a / analyze-01 :ARG1 (a2 / axis :name (n / name :op1 "RhoA-ROCK"))) # ::id a_pmid_2194_3101.196 # ::date 2015-05-24T09:36:27 # ::file a_pmid_2194_3101_196.txt # ::snt Since RhoA appears to be essential for the attained migration in Caco-BR13 cells, RhoA-Rho kinase signalling was inhibited using the selective ROCK (Rho-associated coiled coil forming protein serine/threonine kinase) inhibitor Y-27632 aiming to inhibit cell migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (a / appear-02 :ARG1 (e / essential :domain (p / protein :name (n / name :op1 "RhoA") :xref (x2 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :purpose (m / migrate-01 :ARG1-of (a2 / attain-01) :location (c2 / cell-line :name (n2 / name :op1 "Caco-BR13"))))) :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "Y-27632") :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "ROCK") :xref (x / xref :value "UNIPROT:ROCK1_HUMAN" :prob "0.313"))) :ARG0-of (s2 / select-01) :xref (x3 / xref :value "PUBCHEM:448042" :prob "16.518612")) :ARG1 (s3 / signal-07 :ARG0 (k / kinase :name (n6 / name :op1 "RhoA-Rho") :xref (x1 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.232"))) :purpose (a3 / aim-01 :ARG1 (i3 / inhibit-01 :ARG1 (m2 / migrate-01 :ARG0 (c3 / cell)))))) # ::id a_pmid_2194_3101.197 # ::date 2015-05-24T10:20:10 # ::file a_pmid_2194_3101_197.txt # ::snt Treatment of Caco-2 and Caco-BR13 cells with the ROCK inhibitor had a moderate effect on downstream target p-Cofilin, while cell motility was found significantly increased in both cell lines (Figure 6A-B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (c / contrast-01 :ARG1 (a / affect-01 :ARG0 (t / treat-04 :ARG1 (a2 / and :op1 (c2 / cell-line :wiki "Caco-2" :name (n / name :op1 "Caco-2")) :op2 (c3 / cell-line :wiki "-" :name (n2 / name :op1 "Caco-BR13"))) :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :wiki "ROCK1" :name (n3 / name :op1 "ROCK") :xref (x / xref :value "UNIPROT:ROCK1_HUMAN" :prob "0.313"))))) :ARG1 (p / protein :wiki "Cofilin" :name (n4 / name :op1 "Cofilin") :ARG1-of (p2 / phosphorylate-01) :ARG1-of (t3 / target-01 :location (d / downstream)) :xref (x1 / xref :value "UNIPROT:COF1_HUMAN" :prob "0.362")) :ARG1-of (m2 / moderate-03)) :ARG2 (f / find-01 :ARG1 (i2 / increase-01 :ARG1 (m3 / motility :mod (c4 / cell)) :ARG2 (s / significant-02)) :location a2) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "6A") :op2 (f3 / figure :mod "6B")))) # ::id a_pmid_2194_3101.198 # ::date 2015-05-24T10:38:29 # ::file a_pmid_2194_3101_198.txt # ::snt To exclude the possibility of this observation being the non-specific effect of the inhibitor targeting several other kinases, siRNA against both ROCK isoforms (ROCK1 and ROCK2) was applied to both Caco-BR clones and parental Caco-2 cells (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / apply-02 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (o / oppose-01 :ARG1 (a2 / and :op1 (i / isoform :name (n2 / name :op1 "ROCK1")) :op2 (i2 / isoform :name (n3 / name :op1 "ROCK2"))))) :ARG2 (a3 / and :op1 (c / clone-01 :ARG1 (c2 / cell-line :name (n5 / name :op1 "Caco-BR"))) :op2 (c3 / cell-line :name (n6 / name :op1 "Caco-2") :mod (p / parent))) :purpose (e2 / exclude-01 :ARG1 (p2 / possible-01 :ARG1 (o2 / observe-01 :ARG1 (a4 / affect-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01) :ARG0-of (t2 / target-01 :ARG1 (k / kinase :mod (o3 / other) :quant (s / several)))) :ARG1-of (s2 / specific-02 :polarity "-")) :mod (t / this)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id a_pmid_2194_3101.199 # ::date 2015-05-24T11:14:19 # ::file a_pmid_2194_3101_199.txt # ::snt Besides, the use of siRNA to deplete a protein and especially a small GTPase can prove more promising since the specific protein sequence is targeted. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / and :op2 (p / possible-01 :ARG1 (p2 / prove-01 :ARG0 (u / use-01 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "siRNA")) :ARG2 (d / deplete-01 :ARG0 n3 :ARG1 (a2 / and :op1 (p3 / protein) :op2 (e / enzyme :name (n2 / name :op1 "GTPase") :mod (s / small) :mod (e2 / especially) :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312"))))) :ARG1 (p4 / promise-01 :degree (m / more))) :ARG1-of (c / cause-01 :ARG0 (t / target-01 :ARG1 (s3 / sequence :ARG1-of (s2 / specific-02) :part-of (p5 / protein)))))) # ::id a_pmid_2194_3101.200 # ::date 2015-05-24T11:25:59 # ::file a_pmid_2194_3101_200.txt # ::snt In several reported studies, treatment with a selective inhibitor may produce more adverse effect through interaction with other (associated) components. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p / possible-01 :ARG1 (p2 / produce-01 :ARG0 (t / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01) :ARG0-of (s / select-01))) :ARG1 (a / affect-01 :mod (a2 / adverse :degree (m2 / more))) :manner (i2 / interact-01 :ARG0 m :ARG1 (c / component :mod (o / other) :ARG1-of (a3 / associate-01)))) :medium (s2 / study-01 :ARG1-of (r / report-01) :quant (s3 / several))) # ::id a_pmid_2194_3101.201 # ::date 2015-05-24T11:36:25 # ::file a_pmid_2194_3101_201.txt # ::snt Regardless efficient ROCK depletion, no inhibition in cell migration or invasion was observed in BRAFV600E transformed cells (Figure 6D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 2, 2015 (o / observe-01 :ARG1 (i / inhibit-01 :polarity "-" :ARG1 (o2 / or :op1 (m / migrate-01 :ARG0 (c / cell)) :op2 (i2 / invade-01 :ARG0 c))) :location (c2 / cell :ARG1-of (t / transform-01 :ARG0 (e / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :concession (d / deplete-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ROCK") :xref (x1 / xref :value "UNIPROT:ROCK1_HUMAN" :prob "0.313")) :ARG1-of (e3 / efficient-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6D"))) # ::id a_pmid_2194_3101.202 # ::date 2015-05-25T03:08:17 # ::file a_pmid_2194_3101_202.txt # ::snt Nevertheless increase motility was recorded in Caco-2 cells suggesting that Rac1 activation may be taking a lead role in the absence of the RhoA-Rho kinase signalling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (h / have-concession-91 :ARG1 (r / record-01 :ARG1 (i / increase-01 :ARG1 (m / motility)) :location (c / cell-line :name (n / name :op1 "Caco-2")) :ARG0-of (s / suggest-01 :ARG1 (p / possible-01 :ARG1 (t / take-01 :ARG0 (a / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Rac1") :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG1 (r2 / role :purpose (l / lead-02)) :condition (a2 / absent-01 :ARG1 (s2 / signal-07 :ARG0 (k / kinase :name (n4 / name :op1 "RhoA-Rho") :xref (x1 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.232"))))))))) # ::id a_pmid_2194_3101.203 # ::date 2015-05-25T04:16:04 # ::file a_pmid_2194_3101_203.txt # ::snt KRASG12V induces Cdc42-dependent migration ability and filopodia formation in Caco-2 cells, partially dependent on PI3K pathway # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (m2 / mutate-01 :value "G12V" :ARG1 (g / gene :name (n4 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG0-of (d3 / depend-01 :ARG1 (p4 / pathway :name (n7 / name :op1 "PI3K")) :degree (p2 / part))) :ARG2 (a / and :op1 (p3 / possible-01 :ARG1 (m / migrate-01 :ARG0 "n2" :condition (d / depend-01 :ARG1 (p / protein :name (n / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634"))))) :op2 (f / form-01 :ARG1 (f2 / filopodium) :location (c / cell-line :name (n2 / name :op1 "Caco-2"))))) # ::id a_pmid_2194_3101.204 # ::date 2015-05-25T07:14:11 # ::file a_pmid_2194_3101_204.txt # ::snt Previous studies have indicated that RhoA, Rac1 and Cdc42 signalling is essential for oncogenic Ras transforming capacity [29,30]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / indicate-01 :ARG0 (s / study-01 :time (p / previous)) :ARG1 (e / essential :domain (s2 / signal-07 :ARG0 (a / and :op1 (p2 / protein :name (n / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "Rac1") :xref (x2 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604")) :op3 (p4 / protein :name (n3 / name :op1 "Cdc42") :xref (x3 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")))) :purpose (c3 / capable-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Disease" :name (n5 / name :op1 "Cancer"))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (t / transform-01 :ARG1 e2))) :ARG1-of (d / describe-01 :ARG0 (c2 / cite-01 :ARG1 (a2 / and :op1 "29" :op2 "30")))) # ::id a_pmid_2194_3101.205 # ::date 2015-05-25T07:48:37 # ::file a_pmid_2194_3101_205.txt # ::snt In the present study, Caco-2 cells overexpressing mutant KRASG12V (Caco-K), selective activation for Cdc42 was detected (Figure 7A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / detect-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :manner (s / selective)) :location (s2 / study-01 :ARG1 (o2 / overexpress-01 :ARG1 (m / mutate-01 :value "G12V" :ARG1 (g / gene :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :location (c / cell-line :name (n2 / name :op1 "Caco-2")) :ARG1-of (m2 / mean-01 :ARG2 (c2 / cell-line :name (n4 / name :op1 "Caco-K")))) :time (p2 / present)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7A"))) # ::id a_pmid_2194_3101.206 # ::date 2015-05-25T08:03:41 # ::file a_pmid_2194_3101_206.txt # ::snt The formation of filopodia in these cells, earlier described, was in agreement with the high Cdc42 activity and is illustrated here by staining with antibody against Fascin, a filopodia marker (Figure 7B, upper panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (a2 / agree-01 :ARG1 (f / form-01 :ARG1 (f2 / filopodium) :location (c / cell :mod (t / this))) :ARG2 (a3 / activity-06 :ARG0 (p / protein :name (n / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG1-of (h / high-02))) :op2 (i / illustrate-01 :ARG1 f :ARG0-of (s / stain-01 :ARG2 (a4 / antibody :ARG0-of (c2 / counter-01 :ARG1 (m / marker :name (n2 / name :op1 "Fascin") :mod (f3 / filopodium))))) :medium (h2 / here)) :ARG1-of (d / describe-01 :ARG0 (p2 / panel :location (u / upper) :part-of (f4 / figure :mod "7B")) :mod (e / early :degree (m3 / more)))) # ::id a_pmid_2194_3101.207 # ::date 2015-05-25T08:49:06 # ::file a_pmid_2194_3101_207.txt # ::snt A large number of relatively short filopodia distributed almost exclusively at the cell periphery was evident in Caco-K cells, while Caco-BR and Caco-H cells formed less but longer structures with a rather polarized shape potentially pointing towards the direction of cell migration (Figure 7B, upper panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (e3 / evident :domain (f / filopodium :ARG1-of (s / short-07 :ARG2-of (r / relative-05)) :quant (n2 / number :mod (l2 / large)) :ARG1-of (d / distribute-01 :location (p6 / periphery :domain (c7 / cell)) :ARG0-of (e / exclusive-02 :degree (a3 / almost)))) :location (c2 / cell :name (n / name :op1 "Caco-K"))) :ARG2 (f2 / form-01 :ARG0 (a2 / and :op1 (c4 / cell-line :name (n3 / name :op1 "Caco-BR")) :op2 (c5 / cell-line :name (n4 / name :op1 "Caco-H"))) :ARG1 (s2 / structure :ARG0-of (h / have-03 :ARG1 (s4 / shape :ARG1-of (p / polarize-01 :degree (r3 / rather)) :ARG0-of (p7 / point-01 :ARG2 (d4 / direction :direction-of (m2 / migrate-01 :ARG0 (c3 / cell))) :mod (p8 / potential)))) :quant (l4 / less :ARG1-of (c6 / contrast-01 :ARG2 (l / long-03 :ARG1 s :degree (m / more)) :compared-to f)))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / panel :location (u / upper) :part-of (f3 / figure :mod "7B")))) # ::id a_pmid_2194_3101.208 # ::date 2015-05-25T09:49:02 # ::file a_pmid_2194_3101_208.txt # ::snt Nevertheless, no changes in Fascin protein expression were recorded in the different cell lines, (Figure 7B, lower panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 12, 2015 (h / have-concession-91 :ARG2 (r / record-01 :ARG1 (c / change-01 :polarity "-" :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Fascin") :xref (x / xref :value "UNIPROT:FSCN1_HUMAN" :prob "1.002")))) :location (c2 / cell-line :ARG1-of (d / differ-02))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / panel :ARG1-of (l / low-04 :degree (m2 / more)) :part-of (f / figure :mod "7B")))) # ::id a_pmid_2194_3101.209 # ::date 2015-05-25T09:58:39 # ::file a_pmid_2194_3101_209.txt # ::snt Increased migration ability in Caco-BR and Caco-H cells may be indicative for the length and the location of filopodia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (i / indicate-01 :ARG0 (i2 / increase-01 :ARG1 (p2 / possible-01 :ARG1 (m / migrate-01 :location (a2 / and :op1 (c / cell-line :name (n / name :op1 "Caco-BR")) :op2 (c2 / cell-line :name (n2 / name :op1 "Caco-H")))))) :ARG1 (a3 / and :op1 (l / length :mod (f / filopodium)) :op2 (l2 / location :location-of f)))) # ::id a_pmid_2194_3101.210 # ::date 2015-05-25T10:10:43 # ::file a_pmid_2194_3101_210.txt # ::snt It has been previously shown that in CHO-K1 cells (Chinese hamster ovary fibroblast- like cells) RhoA expression down-regulates Cdc42 and Rac1 activity in order to regulate membrane protrusions and cell polarity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG1 (d / downregulate-01 :ARG0 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :location (c2 / cell-line :name (n6 / name :op1 "CHO-K1") :ARG1-of (m2 / mean-01 :ARG2 (f2 / fibroblast :location (o2 / ovary :part-of (a5 / animal :mod (h2 / hamster :mod (c5 / country :wiki "China" :name (n / name :op1 "China"))))) :ARG1-of (r3 / resemble-01 :ARG2 (c6 / cell)))))) :ARG1 (a / activity-06 :ARG0 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :op2 (p4 / protein :name (n5 / name :op1 "Rac1") :xref (x2 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604")))) :purpose (r2 / regulate-01 :ARG0 e :ARG1 (a4 / and :op1 (p5 / protrude-01 :ARG1 (m / membrane :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :op2 (p6 / polarity :mod (c4 / cell))))) :time (p / previous)) # ::id a_pmid_2194_3101.211 # ::date 2015-05-25T10:11:53 # ::file a_pmid_2194_3101_211.txt # ::snt In addition, Rac1 activity may down-regulate Cdc42 activity and promote the formation of stabilized rather than transient protrusions [31]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op2 (p / possible-01 :ARG1 (a2 / and :op1 (d2 / downregulate-01 :ARG0 (a3 / activity-06 :ARG0 (p2 / protein :name (n / name :op1 "Rac1") :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG1 (a4 / activity-06 :ARG0 (p3 / protein :name (n2 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")))) :op2 (p4 / promote-02 :ARG1 (f / form-01 :ARG1 (p5 / protrude-01 :ARG1-of (s / stabilize-01)) :ARG1-of (i / instead-of-91 :ARG2 (p6 / protrude-01 :ARG1-of (t / transient-02))))))) :ARG1-of (c / cite-01 :ARG2 "31")) # ::id a_pmid_2194_3101.212 # ::date 2015-05-25T10:49:11 # ::file a_pmid_2194_3101_212.txt # ::snt Indeed, low Cdc42 activity was recorded in Caco-BR and Caco-H cells where RhoA signaling is activated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / record-01 :ARG1 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG1-of (l / low-04)) :location (a2 / and :op1 (c / cell-line :name (n2 / name :op1 "Caco-BR")) :op2 (c2 / cell-line :name (n3 / name :op1 "Caco-H")) :location-of (a4 / activate-01 :ARG1 (s2 / signal-07 :ARG0 (p3 / protein :name (n5 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))))) :mod (i / indeed)) # ::id a_pmid_2194_3101.213 # ::date 2015-05-25T11:26:03 # ::file a_pmid_2194_3101_213.txt # ::snt To explore the role of Cdc42 in mutant KRASG12V induced cell transformation, Caco-2 and Caco-K15 cells were treated with siRNA against this small GTPase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-purpose-91 :ARG1 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n2 / name :op1 "Caco-2")) :op2 (c2 / cell-line :name (n3 / name :op1 "Caco-K15"))) :ARG2 (n7 / nucleic-acid :name (n4 / name :op1 "small" :op2 "interfering" :op3 "RNA")) :purpose (d / defend-01 :ARG2 n7 :ARG3 (e2 / enzyme :name (n5 / name :op1 "GTPase") :mod (s / small) :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")))) :ARG2 (e / explore-01 :ARG1 (t2 / transform-01 :ARG0 (p / protein :name (n / name :op1 "Cdc42") :domain (r / role) :xref (x2 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG1 (c3 / cell) :ARG2-of (i / induce-01 :ARG0 (m / mutate-01 :value "G12V" :ARG1 (g / gene :name (n6 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))))) # ::id a_pmid_2194_3101.214 # ::date 2015-05-25T11:55:26 # ::file a_pmid_2194_3101_214.txt # ::snt Significant downregulation of Cdc42 at the protein level was observed in both cell lines (Figure 7C-upper panel), that caused a significant decrease of cell migration and invasion ability of Caco-K15 and of Caco-2 cells but to a lesser extent (Figure 7C-lower panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (d / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG1-of (s / significant-02) :prep-at (l2 / level :mod (p2 / protein)) :ARG1-of (o / observe-01 :location (c2 / cell-line :mod (b / both))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7C" :part-of (p3 / panel :mod (u / upper))))) :ARG1 (d3 / decrease-01 :ARG0 d :ARG1 (a / and :op1 (a2 / and :op1 (m3 / migrate-01 :ARG0 (c3 / cell-line :name (n2 / name :op1 "Caco-K15"))) :op2 (p5 / possible-01 :ARG1 (i3 / invade-01 :ARG0 c3)) :ARG1-of (c6 / contrast-01 :ARG2 "a4" :mod (e / extent :degree (l / less)))) :op2 (a4 / and :op1 (m4 / migrate-01 :ARG0 (c4 / cell-line :name (n3 / name :op1 "Caco-2"))) :op2 (i2 / invade-01 :ARG0 c4))) :ARG2 (s2 / significant-02) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "7C" :part-of (p4 / panel :ARG1-of (l3 / low-04 :degree (m5 / more))))))) # ::id a_pmid_2194_3101.215 # ::date 2015-05-25T11:55:49 # ::file a_pmid_2194_3101_215.txt # ::snt Depletion of Cdc42 also affected the filopodia formation, when Caco-K cells were treated with siRNA against Cdc42 acquired rounded cell membrane lacking filapodia protrusion suggesting that filopodia formation in Caco-K cells is Cdc42-dependent (Figure 7D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / suggest-01 :ARG0 (a / affect-01 :ARG0 (d / deplete-01 :ARG1 (p / protein :name (n / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634"))) :ARG1 (f / form-01 :ARG1 (f2 / filopodium)) :mod (a2 / also) :condition (a3 / acquire-01 :ARG0 (c2 / cell :name (n4 / name :op1 "Caco-K")) :ARG1-of (c3 / condition-01 :ARG0 (t / treat-04 :ARG1 c2 :ARG2 (n2 / nucleic-acid :name (n5 / name :op1 "small" :op2 "interfere" :op3 "RNA")) :ARG0-of (c4 / counter-01 :ARG1 p)) :ARG1-of (r2 / result-01 :ARG2 (a4 / acquire-01 :ARG0 c2 :ARG1 (m / membrane :ARG1-of (r / round-04) :mod (c5 / cell) :ARG0-of (l / lack-01 :ARG1 (p2 / protrude-01 :ARG1 (f5 / filopodium))) :xref (x1 / xref :value "GO:0016020" :prob "0.8"))))))) :ARG2 (d2 / depend-01 :ARG0 (f3 / form-01 :ARG1 (f4 / filopodium) :location c2) :ARG1 p) :ARG1-of (d3 / describe-01 :ARG0 (f6 / figure :mod "7D"))) # ::id a_pmid_2194_3101.216 # ::date 2015-05-26T00:13:52 # ::file a_pmid_2194_3101_216.txt # ::snt These findings suggest that KRASG12V regulates motility and invasiveness of colon cancer cells through the Cdc42 GTPase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / suggest-01 :ARG0 (t2 / thing :mod (t / this) :ARG1-of (f / find-01)) :ARG1 (r / regulate-01 :ARG0 (m / mutate-01 :value "G12V" :ARG1 (g / gene :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1 (a3 / and :op1 (m2 / motility :mod (c2 / cell :mod (d / disease :name (n / name :op1 "Cancer") :location (c / colon)))) :op2 (i / invade-01 :ARG0 c2)) :manner (p / protein :name (n4 / name :op1 "Cdc42" :op2 "GTPase") :xref (x1 / xref :value "UNIPROT:RHG31_HUMAN" :prob "0.262")))) # ::id a_pmid_2194_3101.217 # ::date 2015-05-25T11:56:55 # ::file a_pmid_2194_3101_217.txt # ::snt Considering that the PI3K pathway is also a KRAS effector pathway, the possibility of a cross-talk between the PI3K signalling pathway and Cdc42 was explored [16,21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (e / explore-01 :ARG1 (p / possible-01 :ARG1 (i / interfere-01 :ARG0 (p2 / pathway :ARG1-of (s / signal-07 :ARG0 (p3 / pathway :name (n / name :op1 "PI3K")))) :ARG1 (p4 / protein :name (n2 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")))) :condition (c / consider-01 :ARG1 (p5 / pathway :mod (e2 / effector :mod (g / gene :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :domain p3) :mod (a / also)) :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "16" :op2 "21"))) # ::id a_pmid_2194_3101.218 # ::date 2015-05-25T12:30:28 # ::file a_pmid_2194_3101_218.txt # ::snt Following treatment with wortmanin at the most optimal treatment condition, as retrieved from inhibition of the active PI3K pathway in Caco-H2 cells that show high p-AKT levels (Additional Figure 4), resulted in reduced Cdc42 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (f3 / follow-01 :ARG2 (t / treat-04 :ARG2 (w2 / wortmanin)) :example (i / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3K") :ARG1-of (a2 / activate-01)) :ARG1-of (r3 / retrieve-01) :location (c / cell-line :name (n3 / name :op1 "Caco-H2") :ARG0-of (s / show-01 :ARG1 (l / level :ARG1-of (h / high-02) :quant-of (e / enzyme :name (n4 / name :op1 "AKT") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4" :mod (a4 / additional))) :condition (t3 / treat-04 :mod (o2 / optimal :degree (m3 / most)))) :ARG2 (r2 / reduce-01 :ARG0 f3 :ARG1 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634"))))) # ::id a_pmid_2194_3101.219 # ::date 2015-05-26T04:30:03 # ::file a_pmid_2194_3101_219.txt # ::snt This illustrates how Cdc42 activation in response to the KRASG12V-PI3K signalling pathway can be potentially essential for Cdc42-dependent cell migration and invasion properties (Figure 7E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (i / illustrate-01 :ARG0 (t / this) :ARG1 (t2 / thing :manner-of (p4 / possible-01 :ARG1 (e2 / essential :domain (a2 / activate-01 :ARG1 (p6 / protein :name (n3 / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG2-of (r2 / respond-01 :ARG1 (p7 / pathway :name (n4 / name :op1 "KRASG12V-PI3K") :ARG1-of (s2 / signal-07)))) :purpose (a3 / and :op1 (m / migrate-01 :ARG0 (c / cell :ARG0-of (d3 / depend-01 :ARG1 p6))) :op2 (p8 / property :mod (i2 / invade-01 :ARG0 c)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7E"))) # ::id a_pmid_2194_3101.220 # ::date 2015-05-25T13:27:22 # ::file a_pmid_2194_3101_220.txt # ::snt HRASG12V induces high cell migration and invasion properties mediated by Rac1 associated with acquired EMT # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 10, 2016 (i / induce-01 :ARG0 (m / mutate-01 :value "G12V" :ARG1 (g / gene :name (n / name :op1 "HRAS") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003"))) :ARG2 (a3 / and :op1 (m2 / migrate-01 :ARG0 (c2 / cell) :ARG1-of (h / high-02)) :op2 (p3 / property :mod (i2 / invade-01 :ARG1-of (m3 / mediate-01 :ARG0 (a4 / associate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "Rac1") :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604")) :ARG2 (e / event :wiki "Epithelial–mesenchymal_transition" :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition") :ARG1-of (a6 / acquire-01)))))))) # ::id a_pmid_2194_3101.221 # ::date 2015-05-26T00:33:47 # ::file a_pmid_2194_3101_221.txt # ::snt Activation of Rac1, another RAS effector protein, was found slightly increased in Caco-H2 cells with EMT characteristics [15,25] (Figure 8A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (i3 / increase-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "Rac1") :mod (a6 / another) :domain (e2 / effector :mod (p2 / protein-family :name (n3 / name :op1 "Ras"))) :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG2 (s2 / slight) :location (c / cell-line :name (n5 / name :op1 "Caco-H2") :ARG1-of (c6 / characteristic-02 :ARG2 (e / event :name (n / name :op1 "epithelial−mesenchymal" :op2 "transition"))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 (a5 / and :op1 "15" :op2 "25"))) :op2 (f2 / figure :mod "8A")))) # ::id a_pmid_2194_3101.222 # ::date 2015-05-26T11:23:06 # ::file a_pmid_2194_3101_222.txt # ::snt Activation of Rac1 in Caco-H2 cells is in agreement with previous studies that correlate Rac1 with EMT and the inhibition of E-cadherin in mammary epithelial and pancreatic carcinoma cells respectively [32]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / agree-01 :ARG0 (a2 / activate-01 :ARG1 (p / protein :name (n / name :op1 "Rac1") :location (c / cell-line :name (n2 / name :op1 "Caco-H2")) :xref (x1 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG2 (s / study-01 :ARG0-of (c2 / correlate-01 :ARG1 p :ARG2 (a3 / and :op1 (e3 / event :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition")) :op2 (i / inhibit-01 :ARG1 (p2 / protein :name (n4 / name :op1 "E-cadherin") :location (a4 / and :op1 (c3 / cell :mod (e / epithelium) :mod (m / mammary)) :op2 (c4 / cell :mod (p3 / pancreas) :mod (c5 / carcinoma)) :mod (r / respective)) :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :time (p5 / previous)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 "32")))) # ::id a_pmid_2194_3101.223 # ::date 2015-05-26T11:48:03 # ::file a_pmid_2194_3101_223.txt # ::snt In contrast, a weak effect on Rac1 GTPase was recorded in Caco-BR cells (Figure 8A) and could be explained by the known antagonistic effect that exists between RhoA and Rac1 [33]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (a / and :op1 (r / record-01 :ARG1 (a2 / affect-01 :ARG1 (p2 / protein :name (n / name :op1 "Rac1" :op2 "GTPase")) :ARG1-of (w / weak-02)) :location (c2 / cell-line :name (n2 / name :op1 "Caco-BR")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8A"))) :op2 (p / possible-01 :ARG1 (e / explain-01 :ARG0 (a3 / affect-01 :ARG2 (a4 / antagonize-02 :ARG1 (p3 / protein :name (n3 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG2 (p4 / protein :name (n4 / name :op1 "Rac1") :xref (x1 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG1-of (k / know-01)) :ARG1 a2))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "33")))) # ::id a_pmid_2194_3101.224 # ::date 2015-05-26T12:34:23 # ::file a_pmid_2194_3101_224.txt # ::snt As described earlier, HRASG12V-transfected Caco-2 cells (Caco-H2) have undergone EMT, followed by the dramatic reduction of E-cadherin expression [16]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / undergo-28 :ARG1 (c / cell-line :name (n / name :op1 "Caco-2") :ARG1-of (t / transfect-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "HRAS") :ARG2-of (m / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))) :ARG2 (e4 / event :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition")) :ARG2-of (f / follow-01 :ARG1 (r / reduce-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :manner (d / dramatic))) :ARG1-of (d2 / describe-01 :time (e2 / early :degree (m2 / more))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "16")))) # ::id a_pmid_2194_3101.225 # ::date 2015-05-26T12:58:03 # ::file a_pmid_2194_3101_225.txt # ::snt Following PI3K pathway depletion using the specific inhibitor wortmanin at the most optimal treatment condition (Additional Figure 4), Rac1 activity was successfully inhibited only in Caco-2 cells, leaving Caco-H2 cells unaffected (Figure 8B, upper panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG1 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "Rac1") :ARG0-of (l / leave-13 :ARG1 (a2 / affect-01 :polarity "-" :ARG1 (c2 / cell-line :name (n3 / name :op1 "Caco-H2")))) :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG1-of (s / succeed-01) :location (c / cell-line :name (n2 / name :op1 "Caco-2") :mod (o / only)) :ARG2-of (f / follow-01 :ARG1 (d / deplete-01 :ARG1 (p2 / pathway :name (n4 / name :op1 "PI3K")) :ARG0-of (u / use-01 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "wortmanin") :ARG0-of (i2 / inhibit-01) :ARG1-of (s3 / specific-02) :xref (x1 / xref :value "PUBCHEM:312145" :prob "19.266134")) :condition (t2 / treat-04 :mod (o2 / optimum :degree (m2 / most)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4" :ARG1-of (a3 / add-02))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "8B" :location (p3 / panel :mod (u2 / upper))))) # ::id a_pmid_2194_3101.226 # ::date 2015-05-26T13:36:04 # ::file a_pmid_2194_3101_226.txt # ::snt Notably, under the same treatment conditions RhoA activity was found to be slightly increased, suggesting an involvement of the PI3K pathway in RhoA regulation (Figure 8B, lower panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (f / find-02 :ARG1 (i / increase-01 :ARG1 (a / activity-06 :ARG0 (p / protein :wiki "RHOA" :name (n / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :ARG2 (s / slight) :ARG0-of (s3 / suggest-01 :ARG1 (i2 / involve-01 :ARG1 (p2 / pathway :wiki "-" :name (n2 / name :op1 "PI3K")) :ARG2 (r / regulate-01 :ARG1 p)))) :condition (t / treat-04 :ARG1-of (s2 / same-01)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "8B" :location (p3 / panel :ARG1-of (l / low-04 :degree (m / more))))) :ARG1-of (n3 / notable-04)) # ::id a_pmid_2194_3101.227 # ::date 2015-05-26T13:50:25 # ::file a_pmid_2194_3101_227.txt # ::snt It is therefore concluded that in Caco-H2 cells, HRASG12V deregulates PI3K-dependent activation of Rac1 as well as mediates RhoA inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / cause-01 :ARG1 (c / conclude-01 :ARG1 (a2 / and :op1 (d / deregulate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "HRAS") :ARG2-of (m / mutate-01 :value "G12V") :xref (x3 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG1 (a / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Rac1") :ARG0-of (d2 / depend-01 :ARG1 (e / enzyme :name (n3 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :location (c3 / cell-line :name (n5 / name :op1 "Caco-H2"))) :op2 (m2 / mediate-01 :ARG0 e2 :ARG1 (i / inhibit-01 :ARG1 (p3 / protein :name (n4 / name :op1 "RhoA") :xref (x2 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))))))) # ::id a_pmid_2194_3101.228 # ::date 2015-05-26T14:11:12 # ::file a_pmid_2194_3101_228.txt # ::snt To further explore the involvement of Rac1 activation in the transforming ability of HRASG12V in Caco-2 cells, pharmacological inhibition of Rac1 was established using the selective inhibitor NSC23766 (Figure 8C) [34]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / establish-01 :ARG1 (i / inhibit-01 :ARG1 (p / protein :name (n / name :op1 "Rac1") :xref (x1 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604")) :mod (p2 / pharmacologic)) :ARG2-of (u / use-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "NSC23766") :ARG0-of (i2 / inhibit-01) :mod (s / selective) :xref (x2 / xref :value "PUBCHEM:409805" :prob "18.349844"))) :purpose (e2 / explore-01 :ARG1 (i3 / involve-01 :ARG1 (a / activate-01 :ARG1 p) :ARG2 (c / capable-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "HRAS") :ARG2-of (m2 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG2 (t / transform-01 :ARG0 e3 :location (c2 / cell-line :name (n4 / name :op1 "Caco-2"))))) :degree (f / further)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "8C") :op2 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "34"))))) # ::id a_pmid_2194_3101.229 # ::date 2015-05-26T14:52:17 # ::file a_pmid_2194_3101_229.txt # ::snt Inhibition of Rac1 not only managed to suppress Rac1 activation but also to abolish cell migration and invasion properties in a dose dependent manner (Figure 8D), indicating the critical role of Rac1 in EMT cell properties of Caco-H cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / manage-01 :ARG0 (i / inhibit-01 :ARG1 (p / protein :name (n / name :op1 "Rac1") :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG1 (a / and :op1 (s / suppress-01 :ARG0 i :ARG1 (a2 / activate-01 :ARG1 p)) :op2 (a3 / abolish-01 :ARG0 i :ARG1 (a4 / and :op1 (p2 / property :mod (c / cell :ARG0-of (m2 / migrate-01))) :op2 (p3 / property :mod (c5 / cell :ARG0-of (i2 / invade-01)))) :mod (a5 / also) :manner (d / depend-01 :ARG1 (d2 / dose)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "8D")) :ARG0-of (i3 / indicate-01 :ARG1 (r / role :ARG1-of (c2 / critical-02 :ARG2 (p4 / property :poss (c3 / cell-line :name (n3 / name :op1 "Caco-H")) :mod (e / event :name (n2 / name :op1 "epithelial−mesenchymal" :op2 "transition")))) :poss p))) # ::id a_pmid_2194_3101.230 # ::date 2015-05-26T15:02:00 # ::file a_pmid_2194_3101_230.txt # ::snt TGFβ-1 co-operates with BRAFV600E and KRASG12V oncogenes to provide Caco-2 cells with enhanced transformation properties # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cooperate-01 :ARG0 (p / protein :name (n / name :op1 "TGFβ-1") :xref (x2 / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303")) :ARG1 (a / and :op1 (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n3 / name :op1 "KRAS") :ARG2-of (m2 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG2 (p2 / provide-01 :ARG0 p :ARG1 (p3 / property :ARG0-of (t / transform-01) :ARG1-of (e / enhance-01)) :ARG2 (c3 / cell-line :name (n4 / name :op1 "Caco-2")))) # ::id a_pmid_2194_3101.231 # ::date 2015-05-26T15:37:43 # ::file a_pmid_2194_3101_231.txt # ::snt Since BRAFV600E and KRASG12V oncogenes did not manage to fully transform Caco-2 cells nor induced an EMT phenotype, as HRASG12V did, it was further investigated whether co-operation of oncogene-growth factor can produce synergistic effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (i / investigate-01 :ARG1 (p2 / possible-01 :ARG1 (p / produce-01 :mode "interrogative" :ARG0 (c / cooperate-01 :ARG0 (g4 / growth-factor :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))))) :ARG1 (a / affect-01 :ARG2 (s / synergize-01)))) :degree (f / further) :ARG1-of (c4 / cause-01 :ARG0 (a2 / and :op1 (m / manage-01 :polarity "-" :ARG0 (a3 / and :op1 (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n3 / name :op1 "KRAS") :ARG2-of (m3 / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG0-of c2) :ARG1 (t / transform-01 :ARG0 a3 :ARG1 (c3 / cell-line :name (n4 / name :op1 "Caco-2")) :degree (f2 / full))) :op2 (i2 / induce-01 :polarity "-" :ARG0 a3 :ARG2 (p4 / phenotype :mod (e / event :name (n5 / name :op1 "epithelial−mesenchymal" :op2 "transition")))) :ARG1-of (c8 / contrast-01 :ARG2 (g3 / gene :name (n6 / name :op1 "HRAS") :ARG2-of (m4 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))))) # ::id a_pmid_2194_3101.232 # ::date 2015-05-26T15:59:38 # ::file a_pmid_2194_3101_232.txt # ::snt The previously established oncogenic models of BRAFV600E and KRASG12V along with the parental Caco-2 cells were treated with Transforming Growth Factor beta-1 (TGFβ-1) for 14 days. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t / treat-04 :ARG1 (a / and :op1 (m / model :poss (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :ARG1-of (e / establish-01 :time (p3 / previous))) :op2 (m3 / model :poss (g2 / gene :name (n3 / name :op1 "KRAS") :ARG2-of (m4 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of e :ARG0-of c) :op3 (c2 / cell-line :name (n4 / name :op1 "Caco-2") :mod (p2 / parent))) :ARG2 (p / protein :name (n / name :op1 "Transforming" :op2 "Growth" :op3 "Factor" :op4 "beta-1") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.703")) :duration (t2 / temporal-quantity :quant "14" :unit (d / day))) # ::id a_pmid_2194_3101.233 # ::date 2015-05-26T16:10:44 # ::file a_pmid_2194_3101_233.txt # ::snt Staining with phalloidin revealed significant morphological changes in TGFβ-1 treated Caco-K15 cells that were not observed in Caco-2 cells following treatment with TGFβ-1, while no morphological changes were recorded in TGFβ-1 treated Caco-BR13 cells (Figure 9A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c4 / contrast-01 :ARG1 (r / reveal-01 :ARG0 (s / stain-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "phalloidin") :xref (x1 / xref :value "PUBCHEM:4752" :prob "16.525295"))) :ARG1 (c / change-01 :ARG1 (c2 / cell-line :name (n2 / name :op1 "Caco-K15") :ARG1-of (t / treat-04 :ARG2 (p / protein :name (n3 / name :op1 "TGFβ-1") :xref (x / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303")))) :mod (m2 / morphological) :ARG1-of (o / observe-01 :polarity "-" :location (c3 / cell-line :name (n4 / name :op1 "Caco-2")) :ARG1-of (f / follow-01 :ARG2 t)) :ARG1-of (s2 / significant-02))) :ARG2 (r2 / record-01 :ARG1 (c5 / change-01 :polarity "-" :ARG1 (c6 / cell-line :name (n5 / name :op1 "Caco-BR13") :ARG1-of t) :mod m2)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "9A"))) # ::id a_pmid_2194_3101.234 # ::date 2015-05-27T09:31:42 # ::file a_pmid_2194_3101_234.txt # ::snt Protein analysis for E-cadherin, in fractionized soluble (intracellular) and insoluble (bound-membrane E-cadherin) extracts indicated a reduction of E-cadherin in the insoluble fraction in Caco-2 and Caco-K15 cells to a greater extend (Figure 9B, upper panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (a / analyze-01 :ARG1 (a2 / and :op1 (e / extract :mod (s / soluble) :location (c / cell)) :op2 (e2 / extract :mod (s2 / soluble :polarity "-") :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n / name :op1 "E-cadherin") :mod (m2 / membrane :ARG1-of (b / bind-01) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG1-of (f / fraction-01)) :mod (p / protein) :purpose (p3 / protein :name (n2 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG1 (r / reduce-01 :ARG1 p3 :ARG2 (g / great :degree (m3 / more)) :location (a3 / and :op1 (f2 / fraction :part-of (c2 / cell-line :name (n3 / name :op1 "Caco-2")) :mod s2) :op2 (f3 / fraction :part-of (c3 / cell-line :name (n4 / name :op1 "Caco-K15")) :mod s2))) :ARG1-of (d / describe-01 :ARG0 (f4 / figure :mod "9B" :location (p4 / panel :mod (u / upper))))) # ::id a_pmid_2194_3101.235 # ::date 2015-05-27T11:07:03 # ::file a_pmid_2194_3101_235.txt # ::snt Interestingly, even though levels of E-cadherin were not altered in Caco-BR13 cells, confocal images clearly presented disrupted cell-cell contacts and discontinuous staining which weakens cell junctions allowing cell migration (Figure 9B, lower panel-arrows). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / present-102 :ARG0 (i / image :mod (c / confocal)) :ARG1 (a / and :op1 (c2 / contact-01 :ARG0 (c3 / cell) :ARG1 c3 :ARG1-of (d / disrupt-01)) :op2 (s / stain-01 :ARG1-of (c4 / continue-01 :polarity "-"))) :ARG0-of (w / weaken-01 :ARG1 (j / junction :mod c3)) :ARG0-of (a2 / allow-01 :ARG1 (m / migrate-01 :ARG0 c3)) :manner (i2 / interesting) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "9B" :location (p3 / panel-arrow :ARG1-of (l2 / low-04 :degree (m2 / more))))) :ARG1-of (c5 / clear-06) :concession (a3 / alter-01 :polarity "-" :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :location (c6 / cell-line :name (n2 / name :op1 "Caco-BR13")))) # ::id a_pmid_2194_3101.236 # ::date 2015-05-27T11:29:02 # ::file a_pmid_2194_3101_236.txt # ::snt Altered localization of E-cadherin is an important mechanism contributing to cell metastasis [35]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 1, 2015 (m / mechanism :mod (i / important) :ARG0-of (c / contribute-01 :ARG2 (m2 / metastasize-101 :ARG1 (c2 / cell))) :domain (l / localize-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG1-of (a / alter-01)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "35")))) # ::id a_pmid_2194_3101.237 # ::date 2015-05-27T11:42:15 # ::file a_pmid_2194_3101_237.txt # ::snt TGFβ-1 was also investigated for its potential effect on cell migration and invasion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 27, 2015 (i / investigate-01 :ARG1 (p / protein :name (n / name :op1 "TGFβ-1") :xref (x / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303")) :ARG2 (a / affect-01 :ARG0 p :ARG1 (a2 / and :op1 (m / migrate-01 :ARG0 (c / cell)) :op2 (i2 / invade-01 :ARG0 c)) :mod (p2 / potential)) :mod (a3 / also)) # ::id a_pmid_2194_3101.238 # ::date 2015-05-27T11:48:23 # ::file a_pmid_2194_3101_238.txt # ::snt Treatment with TGFβ-1 increased the capacity of Caco-BR13 cells to invade in vitro, while no effect in the migrating ability of these cells was recorded (Figure 9C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i / increase-01 :ARG0 (t / treat-04 :ARG1 "c3" :ARG2 (p / protein :name (n / name :op1 "TGFβ-1") :xref (x / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303"))) :ARG1 (c2 / capable-01 :ARG1 (c3 / cell-line :name (n2 / name :op1 "Caco-BR13")) :ARG2 (i2 / invade-01 :ARG0 c3 :manner (i3 / in-vitro)))) :ARG2 (r / record-01 :ARG1 (a / affect-01 :polarity "-" :ARG1 (c4 / capable-01 :ARG1 c3 :ARG2 (m / migrate-01 :ARG0 c3)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "9C"))) # ::id a_pmid_2194_3101.239 # ::date 2015-05-27T12:01:33 # ::file a_pmid_2194_3101_239.txt # ::snt This enhanced invasive capacity of Caco-BR13 cells is independent of their cell proliferation (Additional Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / depend-01 :polarity "-" :ARG0 (c / capable-01 :ARG1 (c2 / cell-line :name (n / name :op1 "Caco-BR13")) :ARG2 (i / invade-01 :ARG0 c2) :ARG1-of (e / enhance-01) :mod (t / this)) :ARG1 (p / proliferate-01 :ARG0 c2) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5" :ARG1-of (a / add-02)))) # ::id a_pmid_2194_3101.240 # ::date 2015-05-27T12:06:53 # ::file a_pmid_2194_3101_240.txt # ::snt In contrast, cell migration and invasion of Caco-2 and Caco-K15 cells were not affected by TGFβ-1 treatment, although KRASG12V-transfected cells acquired a more elongated morphology and slightly downregulated E-cadherin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (a / affect-01 :polarity "-" :ARG0 (t3 / treat-04 :ARG2 (p3 / protein :name (n6 / name :op1 "TGFβ-1") :xref (x2 / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303"))) :ARG1 (a2 / and :op1 (m / migrate-01 :ARG0 (a3 / and :op1 (c2 / cell-line :name (n / name :op1 "Caco-2")) :op2 (c3 / cell-line :name (n2 / name :op1 "Caco-K15")))) :op2 (i / invade-01 :ARG0 a3)) :concession (a5 / and :op1 (a6 / acquire-01 :ARG0 (c4 / cell :ARG1-of (t / transfect-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS") :ARG2-of (m2 / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG1 (m3 / morphology :ARG1-of (e / elongate-01 :degree (m4 / more)))) :op2 (d / downregulate-01 :ARG1 (p2 / protein :name (n5 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG2 c4 :degree (s / slight))))) # ::id a_pmid_2194_3101.241 # ::date 2015-05-27T12:24:36 # ::file a_pmid_2194_3101_241.txt # ::snt Taken together, these results suggest that TGFβ-1 can synergise with KRASG12V and BRAFV600E oncogenes to provide Caco-2 cells with a more transforming phenotype. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this) :ARG1-of (t4 / take-01 :mod (t5 / together))) :ARG1 (p3 / possible-01 :ARG1 (s2 / synergize-01 :ARG0 (g / gene :name (n / name :op1 "TGFβ-1") :xref (x2 / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303")) :ARG1 (a / and :op1 (g2 / gene :name (n2 / name :op1 "KRAS") :ARG2-of (m / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG2 (p / provide-01 :ARG0 g :ARG1 (p2 / phenotype :ARG1-of (t3 / transform-01 :degree (m3 / more))) :ARG2 (c2 / cell-line :name (n4 / name :op1 "Caco-2")))))) # ::id a_pmid_2194_3101.242 # ::date 2015-05-27T12:37:09 # ::file a_pmid_2194_3101_242.txt # ::snt According to previous studies, the mutation in the C-terminal domain of Smad4, D351H, that is present in Caco-2 cells, results in complete Smad4 inactivation [36]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (m / mutate-01 :value "D351H" :ARG1 (p / protein-segment :name (n / name :op1 "C-terminus") :part-of (p2 / protein :name (n2 / name :op1 "Smad4") :xref (x / xref :value "UNIPROT:SMAD4_HUMAN" :prob "1.003"))) :location (c2 / cell-line :name (n4 / name :op1 "Caco-2"))) :ARG2 (a / activate-01 :polarity "-" :ARG1-of (c / complete-02)) :ARG1-of (s / say-01 :ARG0 (t / thing :time (p3 / previous) :ARG1-of (s2 / study-01))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "36")))) # ::id a_pmid_2194_3101.243 # ::date 2015-05-27T13:24:28 # ::file a_pmid_2194_3101_243.txt # ::snt However, TGFβ-1 has been shown to act through alternative non-Smad pathways, such as Rho GTPases and MAPK [37-39]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 1, 2015 (h / have-concession-91 :ARG1 (s / show-01 :ARG1 (a / act-01 :ARG0 (p / protein :name (n / name :op1 "TGFβ-1") :xref (x / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303")) :manner (p7 / pathway :polarity "-" :name (n5 / name :op1 "Smad") :mod (a3 / alternative) :example (a2 / and :op1 (p4 / pathway :name (n3 / name :op1 "Rho" :op2 "GTPase")) :op2 (p5 / pathway :name (n4 / name :op1 "MAPK"))))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 "37" :op2 "39")))))) # ::id a_pmid_2194_3101.244 # ::date 2015-05-27T13:35:14 # ::file a_pmid_2194_3101_244.txt # ::snt Indeed, following TGFβ-1 treatment, enhanced activity for RhoA GTPase as well as pERK1/2 was recorded in Caco-2, Caco-K15 and Caco-BR13 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / record-01 :ARG1 (a / activity-06 :ARG0 (a2 / and :op1 (p / pathway :name (n / name :op1 "RhoA" :op2 "GTPase")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p3 / phosphorylate-01))) :ARG1-of (e / enhance-01)) :location (a3 / and :op1 (c / cell-line :name (n3 / name :op1 "Caco-2")) :op2 (c2 / cell-line :name (n4 / name :op1 "Caco-K15")) :op3 (c3 / cell-line :name (n5 / name :op1 "Caco-BR13"))) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG2 (p2 / protein :name (n6 / name :op1 "TGFβ-1") :xref (x / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303")))) :mod (i / indeed)) # ::id a_pmid_2194_3101.245 # ::date 2015-05-27T13:46:10 # ::file a_pmid_2194_3101_245.txt # ::snt Based on these observations other than non-Smad signaling like RhoA GTPase and pERK1/2 pathways can be regulated by TGF-beta, to induce the morphological changes observed in the Caco-2 transformed and parental cells (Figure 9D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / possible-01 :ARG1 (r / regulate-01 :ARG0 (p2 / protein :name (n / name :op1 "TGF-beta") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.373")) :ARG1 (p7 / pathway :ARG2-of (e / except-01 :ARG1 (p4 / pathway :polarity "-" :name (n4 / name :op1 "Smad") :ARG0-of (s / signal-07) :example (a2 / and :op1 (p5 / pathway :name (n5 / name :op1 "RhoA" :op2 "GTPase")) :op2 (p6 / pathway :name (n6 / name :op1 "pERK1/2")))))) :purpose (i / induce-01 :ARG0 r :ARG2 (c / change-01 :ARG1-of (o / observe-01 :location (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "Caco-2") :ARG1-of (t / transform-01)) :op2 (c3 / cell-line :name (n3 / name :op1 "Caco-2") :mod (p3 / parent)))) :mod (m / morphological)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "9D")) :ARG1-of (b / base-02 :ARG2 (o2 / observe-01 :mod (t2 / this)))) # ::id a_pmid_2256_9000.96 # ::date 2015-06-06T02:10:03 # ::file a_pmid_2256_9000_96.txt # ::snt In-vitro inhibition of cell proliferation by selumetinib treatment in NSCLC and CRC cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1 (p / proliferate-01 :ARG0 (c / cell)) :location (a / and :op1 (c2 / cell-line :mod (d / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c3 / cell-line :mod (d2 / disease :name (n3 / name :op1 "CRC")))) :manner (i2 / in-vitro)) # ::id a_pmid_2256_9000.97 # ::date 2015-06-06T02:57:48 # ::file a_pmid_2256_9000_97.txt # ::snt We first evaluated the sensitivity to the selective MEK1/2 inhibitor, selumetinib, in a panel of five NSCLC (GLC82, H460, A549, H1299, Calu3) and six CRC (GEO, HCT15, HCT116, SW480, SW620, LS174T) cell lines by using the MTT assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (e / evaluate-01 :ARG0 (w / we) :ARG1 (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib") :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1/2"))) :ARG0-of (s3 / select-01) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :mod (f / first) :location (p / panel :consist-of (a / and :op1 (c / cell-line :quant "5" :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (c2 / cell-line :name (n4 / name :op1 "GLC82")) :op2 (c3 / cell-line :name (n5 / name :op1 "H460")) :op3 (c4 / cell-line :name (n6 / name :op1 "A549")) :op4 (c5 / cell-line :name (n7 / name :op1 "H1299")) :op5 (c6 / cell-line :name (n8 / name :op1 "Calu3")))) :mod (d / disease :name (n3 / name :op1 "NSCLC"))) :op2 (c7 / cell-line :quant "6" :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (c8 / cell-line :name (n10 / name :op1 "GEO")) :op2 (c9 / cell-line :name (n11 / name :op1 "HCT15")) :op3 (c10 / cell-line :name (n12 / name :op1 "HCT116")) :op4 (c11 / cell-line :name (n13 / name :op1 "SW480")) :op5 (c12 / cell-line :name (n14 / name :op1 "SW620")) :op6 (c13 / cell-line :name (n15 / name :op1 "LS174T")))) :mod (d2 / disease :name (n9 / name :op1 "CRC"))))) :manner (u / use-01 :ARG0 w :ARG1 (a4 / assay-01 :instrument (s4 / small-molecule :name (n16 / name :op1 "MTT") :xref (x1 / xref :value "PUBCHEM:64965" :prob "17.320225"))))) # ::id a_pmid_2256_9000.98 # ::date 2015-06-06T04:02:40 # ::file a_pmid_2256_9000_98.txt # ::snt Cancer cells were treated with selumetinib at concentrations ranging from 0.01 to 10 μℳ for 48, 72, and 96 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (t / treat-04 :ARG1 (c / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib") :quant (c2 / concentration :ARG1-of (r / range-01 :ARG3 (c3 / concentration-quantity :quant "0.01" :unit (m2 / micromolar)) :ARG4 (c4 / concentration-quantity :quant "10" :unit m2))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :duration (t2 / temporal-quantity :quant (a / and :op1 "48" :op2 "72" :op3 "96") :unit (h / hour))) # ::id a_pmid_2256_9000.99 # ::date 2015-06-06T04:15:40 # ::file a_pmid_2256_9000_99.txt # ::snt As shown in Figure 1, there was a wide range of sensitivity, with IC50 values varying between 0.01 and >10 μℳ. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (s / sensitive-03 :ARG1-of (r / range-01 :ARG1-of (w / wide-02) :ARG1-of (m / mean-01 :ARG2 (v / vary-01 :ARG1 (v2 / value :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50")) :ARG3 (c / concentration-quantity :quant "0.01" :unit (m2 / micromolar)) :ARG4 (m3 / more-than :op1 (c2 / concentration-quantity :quant "10" :unit (m4 / micromolar)))))) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "1"))) # ::id a_pmid_2256_9000.100 # ::date 2015-06-06T07:27:02 # ::file a_pmid_2256_9000_100.txt # ::snt We classified as sensitive (S) or resistant (R) the cancer cell lines according to selumetinib IC50 at 96 h ⩽1 or >1 μℳ, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / and :op1 (c / classify-01 :ARG0 (w / we) :ARG1 (c2 / cell-line :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :ARG2 (s / sensitive-03 :ARG0 c2) :condition (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 "50" :ARG4 (o / or :op1 (c3 / concentration-quantity :quant "1" :unit (m3 / micromolar)) :op2 (l / less-than :op1 (c4 / concentration-quantity :quant "1" :unit (m / micromolar)))) :time (a2 / after :op1 (t2 / temporal-quantity :quant "96" :unit (h / hour))))) :op2 (c5 / classify-01 :ARG0 w :ARG1 c2 :ARG2 (r / resist-01 :ARG0 c2) :condition (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s2 :ARG2 "50" :ARG4 (m2 / more-than :op1 (c7 / concentration-quantity :quant "1" :unit (m4 / micromolar))) :time a2))) # ::id a_pmid_2256_9000.101 # ::date 2015-06-06T08:00:48 # ::file a_pmid_2256_9000_101.txt # ::snt This concentration was chosen based on the data from phase I studies, which indicated that 1 μℳ was within the average plasma concentrations of selumetinib achieved in patients at the maximum tolerated dose for this agent (Adjei et al, 2008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / choose-01 :ARG1 (c2 / concentrate-02 :mod (t / this)) :ARG1-of (b / base-02 :ARG2 (d / data :source (s / study-01 :mod (p / phase :ord (o / ordinal-entity :value "1"))) :ARG0-of (i / indicate-01 :ARG1 (i2 / include-01 :ARG1 (c3 / concentration-quantity :quant "1" :unit (m / micromolar)) :ARG2 (c4 / concentrate-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :location (p2 / plasma) :ARG1-of (a / average-04) :ARG1-of (a2 / achieve-01 :location (p3 / patient)) :quant (d2 / dose :quant (m2 / maximum) :ARG1-of (t2 / tolerate-01 :topic (a3 / agent :mod (t3 / this))))))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and :op1 (p5 / person :name (n2 / name :op1 "Adjei")) :op2 (p6 / person :mod (o2 / other))) :time (d4 / date-entity :year "2008")))) # ::id a_pmid_2256_9000.102 # ::date 2015-06-06T10:23:23 # ::file a_pmid_2256_9000_102.txt # ::snt Overall, 67% (four of six) CRC and 40% (two of five) NSCLC cell lines had a selumetinib IC50 of ⩽1 μℳ. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :ARG0 (a / and :op1 (c / cell-line :quant "4" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "6" :mod (d2 / disease :name (n / name :op1 "CRC"))) :ARG3 (p / percentage-entity :value "67"))) :op2 (c3 / cell-line :quant "2" :ARG1-of (i2 / include-91 :ARG2 (c4 / cell-line :quant "5" :mod (d / disease :name (n3 / name :op1 "NSCLC"))) :ARG3 (p2 / percentage-entity :value "40")))) :ARG1 (s / small-molecule :name (n6 / name :op1 "selumetinib") :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c5 / concentration-quantity :quant (o / or :op1 (l / less-than :op1 "1") :op2 "1") :unit (m / micromolar))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :mod (o2 / overall)) # ::id a_pmid_2256_9000.103 # ::date 2015-06-06T10:49:58 # ::file a_pmid_2256_9000_103.txt # ::snt In particular, among the sensitive cancer cell lines there were four, two NSCLC (Calu3 and H1299) and two CRC (HCT116 and SW620), extremely sensitive to selumetinib with an IC50 of ⩽0.01 μℳ (Figure 1A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 1, 2016 (i / include-91 :ARG1 (c / cell-line :quant "4" :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")) :ARG0-of (s / sensitive-03) :ARG2-of (i2 / include-91 :ARG1 (a / and :op1 (c2 / cell-line :quant "2" :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (c3 / cell-line :name (n3 / name :op1 "Calu3")) :op2 (c4 / cell-line :name (n4 / name :op1 "H1299")))) :mod (d3 / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c5 / cell-line :quant "2" :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (c6 / cell-line :name (n6 / name :op1 "HCT116")) :op2 (c7 / cell-line :name (n7 / name :op1 "SW620")))) :mod (d4 / disease :name (n5 / name :op1 "CRC"))) :ARG0-of (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n8 / name :op1 "selumetinib") :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c8 / concentration-quantity :quant (o / or :op1 (l / less-than :op1 "0.01") :op2 "0.01") :unit (m3 / micromolar))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :degree (e2 / extreme))))) :ARG2 (c9 / cell-line :mod d :ARG0-of s) :mod (p / particular) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "1A") :op2 (f2 / figure :mod "1B")))) # ::id a_pmid_2256_9000.104 # ::date 2015-06-06T11:20:38 # ::file a_pmid_2256_9000_104.txt # ::snt To investigate the mechanisms underlying the different sensitivities to the drug, we conducted experiments on a group of four cancer cell lines representing both selumetinib-sensitive (HCT116 and Calu3) and selumetinib-resistant (HCT15 and H460) models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (c / conduct-01 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG0 w :ARG1 (g / group :consist-of (c2 / cell-line :quant "4" :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")) :ARG0-of (r / represent-01 :ARG1 (a / and :op1 (m / model-01 :ARG0-of (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (c3 / cell-line :name (n3 / name :op1 "HCT116")) :op2 (c4 / cell-line :name (n4 / name :op1 "Calu3"))))) :op2 (m3 / model-01 :ARG0-of (r2 / resist-01 :ARG1 s2) :ARG1-of (m4 / mean-01 :ARG2 (a3 / and :op1 (c5 / cell-line :name (n5 / name :op1 "HCT15")) :op2 (c6 / cell-line :name (n6 / name :op1 "H460")))))))))) :purpose (i / investigate-01 :ARG0 w :ARG1 (m5 / mechanism :ARG0-of (u / underlie-01 :ARG1 (s3 / sensitive-03 :ARG1 (d2 / drug) :ARG1-of (d3 / differ-02)))))) # ::id a_pmid_2256_9000.105 # ::date 2015-06-06T11:32:55 # ::file a_pmid_2256_9000_105.txt # ::snt Effects of selumetinib treatment on cell-cycle distribution in NSCLC and CRC cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1 (d / distribute-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell))) :location (a2 / and :op1 (c3 / cell-line :mod (d2 / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c4 / cell-line :mod (d3 / disease :name (n3 / name :op1 "CRC"))))) # ::id a_pmid_2256_9000.106 # ::date 2015-06-06T12:29:55 # ::file a_pmid_2256_9000_106.txt # ::snt We conducted flow cytometric analysis to compare the cell-cycle distribution following treatment of the selumetinib-sensitive HCT116 and Calu3 cancer cell lines and of the selumetinib-resistant HCT15 and H460 cancer cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / conduct-01 :ARG0 (w / we) :ARG1 (a / analyze-01 :manner (c9 / cytometry :mod (f2 / flow))) :purpose (c2 / compare-01 :ARG0 w :ARG1 (d / distribute-01 :ARG1 (c3 / cycle-02 :ARG1 (c4 / cell)) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG1 (a2 / and :op1 (a3 / and :op1 (c5 / cell-line :name (n2 / name :op1 "HCT116")) :op2 (c6 / cell-line :name (n3 / name :op1 "Calu3")) :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")) :ARG0-of (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :op2 (a4 / and :op1 (c7 / cell-line :name (n6 / name :op1 "HCT15")) :op2 (c8 / cell-line :name (n7 / name :op1 "H460")) :mod d2 :ARG0-of (r / resist-01 :ARG1 s2)))))))) # ::id a_pmid_2256_9000.107 # ::date 2015-06-06T12:47:55 # ::file a_pmid_2256_9000_107.txt # ::snt Cancer cells were treated with selumetinib at the IC50 values for inhibition of cell proliferation for 24, 48, and 72 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (t / treat-04 :ARG1 (c / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib") :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG3 (i / inhibit-01 :ARG1 (p / proliferate-01 :ARG0 (c2 / cell)))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :duration (t3 / temporal-quantity :quant (a / and :op1 "24" :op2 "48" :op3 "72") :unit (h / hour))) # ::id a_pmid_2256_9000.108 # ::date 2015-06-06T12:54:12 # ::file a_pmid_2256_9000_108.txt # ::snt Twenty-four hours selumetinib treatment caused cell accumulation in the G1 phase and concomitant reduction in the S phase as compared with controls in selumetinib-sensitive cancer cell lines (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (c / cause-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour))) :ARG1 (a / and :op1 (a2 / accumulate-01 :ARG1 (c2 / cell) :time (p / phase :name (n2 / name :op1 "G1"))) :op2 (r / reduce-01 :ARG1 c2 :mod (c3 / concomitant) :time (p2 / phase :name (n3 / name :op1 "S"))) :compared-to (m / molecular-physical-entity :ARG2-of (c4 / control-01) :location (c5 / cell-line :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")) :ARG0-of (s2 / sensitive-03 :ARG1 s)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2256_9000.109 # ::date 2015-06-06T13:04:44 # ::file a_pmid_2256_9000_109.txt # ::snt The arrest in the G1 phase was significantly increased with longer (48 and 72 h) treatment with selumetinib in both HCT116 and Calu3 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (i / increase-01 :ARG1 (a / arrest-02 :time (p / phase :name (n / name :op1 "G1"))) :ARG2 (s / significant-02) :instrument (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1-of (l / long-03 :degree (m / more) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 (t2 / temporal-quantity :quant "48" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "72" :unit (h2 / hour)))))) :location (a3 / and :op1 (c / cell-line :name (n3 / name :op1 "HCT116")) :op2 (c2 / cell-line :name (n4 / name :op1 "Calu3")))) # ::id a_pmid_2256_9000.110 # ::date 2015-06-06T13:11:29 # ::file a_pmid_2256_9000_110.txt # ::snt This effect was also paralleled by a time-dependent reduction in the S phase in both selumetinib-sensitive cancer cell lines (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (p / parallel-01 :ARG0 (a / affect-01 :mod (t / this)) :ARG1 (r / reduce-01 :ARG0-of (d / depend-01 :ARG1 (t2 / time)) :time (p2 / phase :name (n / name :op1 "S")) :location (c / cell-line :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")) :ARG0-of (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :mod (b / both))) :mod (a2 / also) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2256_9000.111 # ::date 2015-06-06T13:17:31 # ::file a_pmid_2256_9000_111.txt # ::snt In contrast, no effect was observed on cell-cycle distribution in the two selumetinib-resistant HCT15 and H460 cells (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (a / affect-01 :polarity "-" :ARG1 (d / distribute-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell)))) :location (a2 / and :quant "2" :op1 (c4 / cell-line :name (n / name :op1 "HCT15")) :op2 (c5 / cell-line :name (n2 / name :op1 "H460")) :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2256_9000.112 # ::date 2015-06-06T13:34:03 # ::file a_pmid_2256_9000_112.txt # ::snt These results were supported also by Garon et al (2010), in which the block in G1 phase inducted by selumetinib is evident only in sensitive cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (s / support-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Garon")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2010") :location-of (e / evident :domain (b / block-01 :time (p4 / phase :name (n2 / name :op1 "G1")) :ARG2-of (i / induce-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :location (c / cell-line :ARG0-of (s3 / sensitive-03) :mod (o2 / only)))) :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :mod (a2 / also)) # ::id a_pmid_2256_9000.113 # ::date 2015-06-06T13:44:19 # ::file a_pmid_2256_9000_113.txt # ::snt Effects of selumetinib treatment on the induction of apoptosis in NSCLC and CRC cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1 (i / induce-01 :ARG2 (a2 / apoptosis)) :location (a3 / and :op1 (c / cell-line :mod (d / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d2 / disease :name (n3 / name :op1 "CRC"))))) # ::id a_pmid_2256_9000.114 # ::date 2015-06-06T13:49:46 # ::file a_pmid_2256_9000_114.txt # ::snt Several preclinical models have demonstrated that selumetinib act as a cytotoxic drug rather than cytostatic by inducing proapoptotic activity (Huynh et al, 2007a; Huynh et al, 2007b; Meng et al, 2009; Meng et al, 2010). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / demonstrate-01 :ARG0 (m / model-01 :mod (p / preclinical) :quant (s / several)) :ARG1 (a / act-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1 (d2 / drug :mod (c / cytotoxic) :ARG1-of (i / instead-of-91 :ARG2 (d3 / drug :mod (c2 / cytostatic)))) :manner (i2 / induce-01 :ARG2 (a2 / activity-06 :ARG0-of (f / favor-01 :ARG1 (a3 / apoptosis))))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and :op1 (p2 / publication-91 :ARG0 (a5 / and :op1 (p3 / person :name (n2 / name :op1 "Huynh")) :op2 (p4 / person :mod (o / other))) :time (d5 / date-entity :year "2007")) :op2 (p5 / publication-91 :ARG0 a5 :time d5) :op3 (p6 / publication-91 :ARG0 (a6 / and :op1 (p7 / person :name (n3 / name :op1 "Meng")) :op2 p4) :time (d6 / date-entity :year "2009")) :op4 (p8 / publication-91 :ARG0 a6 :time (d7 / date-entity :year "2010"))))) # ::id a_pmid_2256_9000.115 # ::date 2015-06-06T14:15:55 # ::file a_pmid_2256_9000_115.txt # ::snt To confirm this effect, the induction of apoptosis was evaluated using an FACS-based assay for Annexin V and PI staining. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (e / evaluate-01 :ARG1 (i / induce-01 :ARG2 (a / apoptosis)) :manner (u / use-01 :ARG1 (a2 / assay-01 :ARG1-of (b / base-02 :ARG2 (t / thing :name (n / name :op1 "FACS")))) :purpose (s / stain-01 :ARG1 (a3 / and :op1 (p / protein :name (n2 / name :op1 "Annexin" :op2 "V") :xref (x / xref :value "UNIPROT:ANXA5_HUMAN" :prob "1.002")) :op2 (s2 / small-molecule :name (n3 / name :op1 "PI") :xref (x1 / xref :value "PUBCHEM:448108" :prob "8.655408"))))) :purpose (c / confirm-01 :ARG1 (a4 / affect-01 :mod (t2 / this)))) # ::id a_pmid_2256_9000.116 # ::date 2015-06-06T14:37:57 # ::file a_pmid_2256_9000_116.txt # ::snt After 24 h of selumetinib treatment, a significant induction of apoptosis was detected in the sensitive HCT116 and Calu3 cancer cell lines, which was maximal following 72 h of treatment (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / detect-01 :ARG1 (i / induce-01 :ARG2 (a / apoptosis) :ARG1-of (s / significant-02) :mod (m / maximal) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :duration (t2 / temporal-quantity :quant "72" :unit (h / hour))))) :location (a2 / and :op1 (c / cell-line :name (n2 / name :op1 "HCT116")) :op2 (c2 / cell-line :name (n3 / name :op1 "Calu3")) :ARG0-of (s3 / sensitive-03) :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :time (a3 / after :op1 (t3 / treat-04 :ARG2 s2 :duration (t4 / temporal-quantity :quant "24" :unit h))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2B"))) # ::id a_pmid_2256_9000.117 # ::date 2015-06-06T14:49:33 # ::file a_pmid_2256_9000_117.txt # ::snt Moreover, apoptosis was not detectable following treatment with selumetinib in the two resistant HCT15 and H460 cancer cell lines (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (a / and :op2 (p / possible-01 :polarity "-" :ARG1 (d / detect-01 :ARG1 (a2 / apoptosis) :location (a3 / and :quant "2" :op1 (c / cell-line :name (n / name :op1 "HCT15")) :op2 (c2 / cell-line :name (n2 / name :op1 "H460")) :ARG0-of (r / resist-01) :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG2 (s / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2B"))) # ::id a_pmid_2256_9000.118 # ::date 2015-06-06T14:55:43 # ::file a_pmid_2256_9000_118.txt # ::snt Effects of selumetinib treatment on intracellular signalling in NSCLC and CRC cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1 (s2 / signal-07 :mod (i / intracellular)) :location (a2 / and :op1 (c / cell-line :mod (d / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d2 / disease :name (n3 / name :op1 "CRC"))))) # ::id a_pmid_2256_9000.119 # ::date 2015-06-06T14:59:49 # ::file a_pmid_2256_9000_119.txt # ::snt To assess the effects of selumetinib treatment on key intracellular downstream signalling pathways, western blots were performed to assess total and phosphorylated EGFR and downstream effectors (total MEK1/2, phospho-MEK1/2, total MAPK, phospho-MAPK, total AKT, phospho-AKT, total 4EBP1, and phosho-4EBP1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-01 :ARG1 (i2 / immunoblot-01) :purpose (a / assess-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "EGFR") :mod (t2 / total-01) :xref (x6 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n3 / name :op1 "EGFR") :ARG3-of (p2 / phosphorylate-01) :xref (x4 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op3 (e3 / effector :location (d / downstream) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (e4 / enzyme :name (n4 / name :op1 "MEK1/2") :mod t2) :op2 (e5 / enzyme :name (n5 / name :op1 "MEK1/2") :ARG3-of p2) :op3 (e6 / enzyme :name (n6 / name :op1 "MAPK") :mod t2 :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op4 (e7 / enzyme :name (n7 / name :op1 "MAPK") :ARG3-of p2 :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op5 (e8 / enzyme :name (n8 / name :op1 "AKT") :mod t2 :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op6 (e9 / enzyme :name (n9 / name :op1 "AKT") :ARG3-of p2 :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op7 (p3 / protein :name (n10 / name :op1 "4EBP1") :mod t2 :xref (x5 / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.003")) :op8 (p4 / protein :name (n11 / name :op1 "4EBP1") :ARG3-of p2 :xref (x7 / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.003"))))))) :purpose (a4 / assess-01 :ARG1 (a5 / affect-01 :ARG0 (t3 / treat-04 :ARG2 (s / small-molecule :name (n12 / name :op1 "selumetinib") :xref (x8 / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1 (p5 / pathway :ARG0-of (s2 / signal-07 :direction (d2 / downstream)) :mod (i / intracellular) :ARG1-of (k / key-02))))) # ::id a_pmid_2256_9000.120 # ::date 2015-06-07T05:13:52 # ::file a_pmid_2256_9000_120.txt # ::snt Cancer cells were evaluated at baseline and at different time points after treatment with selumetinib at 0.05 μℳ. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (e / evaluate-01 :ARG1 (c / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :manner (a / and :op1 (b / baseline) :op2 (p / point :mod (t / time) :ARG1-of (d2 / differ-02))) :time (a2 / after :op1 (t2 / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib") :quant (c2 / concentration-quantity :quant "0.05" :unit (m / micromolar)) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) # ::id a_pmid_2256_9000.121 # ::date 2015-06-07T05:28:29 # ::file a_pmid_2256_9000_121.txt # ::snt No change in total and phosphorylated EGFR expression was observed in both selumetinib-sensitive and selumetinib-resistant cancer cell lines (Figure 3A–D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 11, 2015 (o / observe-01 :ARG1 (c / change-01 :polarity "-" :ARG1 (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "EGFR") :mod (t / total-01) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n2 / name :op1 "EGFR") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) :location (a2 / and :op1 (c2 / cell-line :ARG0-of (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :op2 (c3 / cell-line :ARG0-of (r / resist-01 :ARG1 s2)) :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B") :op3 (f3 / figure :mod "3C") :op4 (f4 / figure :mod "3D")))) # ::id a_pmid_2256_9000.122 # ::date 2015-06-07T05:38:40 # ::file a_pmid_2256_9000_122.txt # ::snt Treatment with selumetinib caused a time-dependent inhibition in phospho-MEK1/2 with a complete signal suppression within 60 or 15 min of treatment in HCT116 and Calu3 cells, respectively (Figure 3A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1 (a4 / and :op1 (i / inhibit-01 :ARG0-of (d / depend-01 :ARG1 (t2 / time))) :op2 (s2 / suppress-01 :ARG1 (s3 / signal-07) :degree (c2 / complete-01) :time (a / after :op1 (t3 / treat-04 :ARG2 s :quant (u / up-to :op1 (t4 / temporal-quantity :quant "60" :unit (m / minute))))) :location (c3 / cell-line :name (n2 / name :op1 "HCT116"))) :op3 (s4 / suppress-01 :ARG1 s3 :degree c2 :time (a2 / after :op1 (t5 / treat-04 :ARG2 s) :quant (u2 / up-to :op1 (t6 / temporal-quantity :quant "15" :unit m))) :location (c4 / cell-line :name (n3 / name :op1 "Calu3")))) :location (e / enzyme :name (n4 / name :op1 "MEK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B")))) # ::id a_pmid_2256_9000.123 # ::date 2015-06-07T05:58:59 # ::file a_pmid_2256_9000_123.txt # ::snt This inhibition was sustained for 24 h of selumetinib treatment in both cancer cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (s / sustain-01 :ARG1 (i / inhibit-01 :mod (t / this)) :duration (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :duration (t3 / temporal-quantity :quant "24" :unit (h / hour))) :location (c / cell-line :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")) :mod (b / both))) # ::id a_pmid_2256_9000.124 # ::date 2015-06-07T06:03:58 # ::file a_pmid_2256_9000_124.txt # ::snt In contrast, MEK1/2 inhibition of protein phosphorylation was less effective with only a slight reduction in pospho-MEK1/2 in the two selumetinib-resistant HCT15 and H460 cancer cell lines (Figure 3C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 11, 2015 (c / contrast-01 :ARG2 (e / effective-04 :ARG0 (i / inhibit-01 :ARG0 (e3 / enzyme :name (n6 / name :op1 "MEK1/2")) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein))) :ARG1 (r / reduce-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MEK1/2") :ARG3-of (p / phosphorylate-01)) :ARG2 (s / slight) :mod (o / only) :location (a / and :quant "2" :op1 (c2 / cell-line :name (n2 / name :op1 "HCT15")) :op2 (c3 / cell-line :name (n3 / name :op1 "H460")) :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")) :ARG0-of (r2 / resist-01 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :degree (l / less)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3C") :op2 (f2 / figure :mod "3D")))) # ::id a_pmid_2256_9000.125 # ::date 2015-06-07T06:11:15 # ::file a_pmid_2256_9000_125.txt # ::snt Moreover, MAPK phosphorylation was completely blocked following selumetinib treatment in HCT116 and Calu3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (b / block-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :degree (c / complete-01) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :location (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "HCT116")) :op2 (c3 / cell-line :name (n4 / name :op1 "Calu3"))))) # ::id a_pmid_2256_9000.126 # ::date 2015-06-07T06:20:52 # ::file a_pmid_2256_9000_126.txt # ::snt In contrast, in the two selumetinib-resistant HCT15 and H460 cells MAPK phosphorylation was only reduced but never completely abrogated (Figure 3C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (c2 / contrast-01 :ARG1 (r / reduce-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :mod (o / only)) :ARG2 (a2 / abrogate-01 :ARG1 p :degree (c3 / complete-01) :time (e2 / ever :polarity "-")) :location (a / and :quant "2" :op1 (c4 / cell-line :name (n2 / name :op1 "HCT15")) :op2 (c5 / cell-line :name (n3 / name :op1 "H460")) :ARG0-of (r2 / resist-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3C") :op2 (f2 / figure :mod "3D")))) # ::id a_pmid_2256_9000.127 # ::date 2015-06-03T05:45:27 # ::file a_pmid_2256_9000_127.txt # ::snt We next assessed the levels of AKT, phosphor-AKT, 4EBP1 and poshospho-4EBP1, which are downstream effectors of the PI3 kinase (PI3K) pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 11, 2015 (a / assess-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (l / level :quant-of (e / enzyme :name (n2 / name :op1 "AKT") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op2 (l2 / level :quant-of (e2 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op3 (l3 / level :quant-of (p2 / protein :name (n4 / name :op1 "4EBP1") :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.003"))) :op4 (l4 / level :quant-of (p3 / protein :name (n5 / name :op1 "4EBP1") :ARG3-of p :xref (x1 / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.003")))) :time (n / next) :ARG0-of (a3 / affect-01 :ARG1 (p5 / pathway :name (n6 / name :op1 "PI3" :op2 "kinase")) :mod (d / downstream))) # ::id a_pmid_2256_9000.128 # ::date 2015-06-03T12:50:47 # ::file a_pmid_2256_9000_128.txt # ::snt Previous reports have suggested that resistance to selumetinib treatment in CRC and NSCLC cell lines was associated with baseline increased PI3K signalling (Balmanno et al, 2009). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t / thing :ARG1-of (r / report-01) :time (p / previous)) :ARG1 (a2 / associate-01 :ARG1 (r2 / resist-01 :ARG1 (t2 / treat-04 :ARG2 (s4 / small-molecule :name (n5 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :location (a / and :op1 (c / cell-line :mod (d4 / disease :name (n / name :op1 "CRC"))) :op2 (c2 / cell-line :mod (d3 / disease :name (n2 / name :op1 "NSCLC"))))) :ARG2 (s3 / signal-07 :ARG0 (p2 / pathway :name (n3 / name :op1 "PI3K") :ARG1-of (i / increase-01) :mod (b / baseline)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n4 / name :op1 "Balmanno")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2009")))) # ::id a_pmid_2256_9000.129 # ::date 2015-06-03T13:06:28 # ::file a_pmid_2256_9000_129.txt # ::snt However, as depicted in Figure 3E–H, we failed to segregate the panel of 11 NSCLC and CRC cell lines into selumetinib-sensitive and selumetinib-resistant groups, by using the PI3K pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (f / fail-01 :ARG1 (w / we) :ARG2 (s / segregate-01 :ARG0 w :ARG1 (p / panel :consist-of (a3 / and :quant "11" :op1 (c / cell-line :mod (d2 / disease :name (n / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d3 / disease :name (n2 / name :op1 "CRC"))))) :ARG2 (a2 / and :op1 (g / group :ARG0-of (s2 / sensitive-03 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :op2 (g2 / group :ARG0-of (r / resist-01 :ARG1 s4))) :manner (u / use-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "PI3K"))))) :ARG1-of (d / depict-01 :ARG0 (v / value-interval :op1 (f2 / figure :mod "3E") :op2 (f3 / figure :mod "3H")))) # ::id a_pmid_2256_9000.130 # ::date 2015-06-03T13:18:03 # ::file a_pmid_2256_9000_130.txt # ::snt Effects of selumetinib treatment on NSCLC and CRC tumour xenografts in nude mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1 (a2 / and :op1 (x3 / xenograft :source (t2 / tumor :mod (d / disease :name (n2 / name :op1 "NSCLC")))) :op2 (x / xenograft :source (t3 / tumor :mod (d2 / disease :name (n / name :op1 "CRC"))))) :location (m / mouse :mod (n3 / nude))) # ::id a_pmid_2256_9000.131 # ::date 2015-06-03T13:21:01 # ::file a_pmid_2256_9000_131.txt # ::snt As shown in Figure 4A and B, HCT116 and Calu3 xenograft growth was significantly inhibited by selumetinib treatment in a dose-dependent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (i / inhibit-01 :ARG0 (t / treat-04 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1 (g / grow-01 :ARG1 (a / and :op1 (x3 / xenograft :source (c / cell-line :name (n / name :op1 "HCT116"))) :op2 (x2 / xenograft :source (c2 / cell-line :name (n4 / name :op1 "Calu3"))))) :ARG1-of (s / signify-01) :manner (d / depend-01 :ARG0 g :ARG1 (d2 / dose)) :ARG1-of (s3 / show-01 :ARG0 (a2 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B")))) # ::id a_pmid_2256_9000.132 # ::date 2015-06-03T13:25:49 # ::file a_pmid_2256_9000_132.txt # ::snt As an example, at day 50 from the injection of cancer cells, the mean tumour volume in mice bearing HCT116 tumour xenografts and treated with selumetinib, 25 or 50 mg kg−1 were 40% and 15%, respectively, as compared with control untreated mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a4 / and :op1 (a / average-01 :ARG1 (v / volume :mod (t / tumor)) :ARG2 (p / percentage-entity :value "40") :location (m2 / mouse :ARG0-of (b / bear-01 :ARG1 (x2 / xenograft :source (t3 / tumor :mod (c / cell-line :name (n / name :op1 "HCT116"))))))) :op2 (a5 / average-01 :ARG1 v :ARG2 (p2 / percentage-entity :value "15") :location (m4 / mouse :ARG1-of (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :quant (o / or :op1 (c3 / concentration-quantity :quant "25" :unit (m / milligram-per-kilogram)) :op2 (c2 / concentration-quantity :quant "50" :unit (m3 / milligram-per-kilogram))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :time (a2 / after :op1 (i / inject-01 :ARG2 (c4 / cell :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))) :quant (t5 / temporal-quantity :quant "50" :unit (d2 / day))) :mod (r / respective) :compared-to (m5 / mouse :ARG1-of (t6 / treat-04 :polarity "-") :mod (c6 / control)) :ARG0-of (e / exemplify-01)) # ::id a_pmid_2256_9000.133 # ::date 2015-06-03T14:20:02 # ::file a_pmid_2256_9000_133.txt # ::snt Similarly, at day 50 from the injection of cancer cells, the mean tumour volume in mice bearing Calu3 tumour xenografts and treated with selumetinib, 25 or 50 mg kg−1 were 22% and 8%, respectively, as compared with control untreated mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / average-01 :ARG1 (v / volume :mod (t / tumor)) :ARG2 (p / percentage-entity :value "22") :location (m / mouse :ARG0-of (b / bear-01 :ARG1 (x2 / xenograft :source (t6 / tumor :mod (d3 / disease :name (n / name :op1 "cell-line" :op2 "Calu3"))))))) :op2 (a3 / average-01 :ARG1 v :ARG2 (p2 / percentage-entity :value "8") :location (m2 / mouse :ARG1-of (t3 / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib") :quant (o / or :op1 (c2 / concentration-quantity :quant "25" :unit (m3 / milligram-per-kilogram)) :op2 (c3 / concentration-quantity :quant "50" :unit (m4 / milligram-per-kilogram))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :mod (r / respective) :compared-to (m5 / mouse :ARG1-of (t2 / treat-04 :polarity "-") :mod (c4 / control)) :ARG1-of (r2 / resemble-01) :time (a4 / after :op1 (i / inject-01 :ARG2 (c5 / cell :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))) :quant (t5 / temporal-quantity :quant "50" :unit (d / day)))) # ::id a_pmid_2256_9000.134 # ::date 2015-06-03T14:59:23 # ::file a_pmid_2256_9000_134.txt # ::snt In contrast, selumetinib treatment was unable to affect tumour growth in both HCT15 and H460 tumour xenografts (Figure 4C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (c2 / capable-01 :polarity "-" :ARG1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG2 (a / affect-01 :ARG0 t :ARG1 (g / grow-01 :ARG1 (t2 / tumor) :location (a2 / and :op1 (x3 / xenograft :source (t3 / tumor :mod (c4 / cell-line :name (n3 / name :op1 "HCT15")))) :op2 (x / xenograft :source (t4 / tumor :mod (c3 / cell-line :name (n2 / name :op1 "H460")))))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4C") :op2 (f2 / figure :mod "4D")))) # ::id a_pmid_2256_9000.135 # ::date 2015-06-04T08:25:28 # ::file a_pmid_2256_9000_135.txt # ::snt EGFR, RAS, MEK, and AKT protein expression and selumetinib sensitivity in NSCLC and CRC cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (e4 / express-03 :ARG2 (a2 / and :op1 (e8 / enzyme :name (n4 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e5 / enzyme :name (n5 / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op3 (e6 / enzyme :name (n6 / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op4 (e7 / enzyme :name (n7 / name :op1 "AKT") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG3 "a3") :op2 (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n8 / name :op1 "selumetinib") :xref (x4 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :location (a3 / and :op1 (c / cell-line :mod (d / disease :name (n / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d2 / disease :name (n2 / name :op1 "CRC")))))) # ::id a_pmid_2256_9000.136 # ::date 2015-06-04T08:29:54 # ::file a_pmid_2256_9000_136.txt # ::snt Identification of predictive biomarkers is becoming a fundamental aspect in the development of targeted agents. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 4, 2015 (b / become-01 :ARG1 (i / identify-01 :ARG1 (b2 / biomarker :ARG0-of (p / predict-01))) :ARG2 (a / aspect :topic (d / develop-02 :ARG1 (a2 / agent :ARG1-of (t / target-01))) :mod (f / fundamental))) # ::id a_pmid_2256_9000.137 # ::date 2015-06-04T08:34:01 # ::file a_pmid_2256_9000_137.txt # ::snt So far, several preclinical studies have been published trying to address this aspect for the sensitivity to MEK inhibitors, but, since different results have been reported, no univocal interpretation could be made (Balmanno et al, 2009; Dry et al, 2010; Garon et al, 2010; Tendler et al, 2010). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (p2 / publish-01 :ARG1 (s2 / study-01 :mod (p3 / preclinical) :quant (s3 / several) :ARG0-of (t2 / try-01 :ARG1 (a / address-02 :ARG0 s2 :ARG1 (a2 / aspect :mod (t3 / this) :topic (s4 / sensitive-03 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))))))) :time (s / so-far)) :ARG2 (p4 / possible-01 :ARG1 (i2 / interpret-01 :polarity "-" :mod (u / univocal)) :ARG1-of (c2 / cause-01 :ARG0 (r / report-01 :ARG1 (t4 / thing :ARG2-of (r2 / result-01) :ARG1-of (d4 / differ-02))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n2 / name :op1 "Balmanno")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "2009")) :op2 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n3 / name :op1 "Dry")) :op2 p7) :time (d2 / date-entity :year "2010")) :op3 (p11 / publication-91 :ARG0 (a6 / and :op1 (p12 / person :name (n4 / name :op1 "Garon")) :op2 p7) :time d2) :op4 (p14 / publication-91 :ARG0 (a7 / and :op1 (p15 / person :name (n5 / name :op1 "Tendler")) :op2 p7) :time d2)))) # ::id a_pmid_2256_9000.138 # ::date 2015-06-04T08:51:42 # ::file a_pmid_2256_9000_138.txt # ::snt To identify specific profiles, which could allow identifying different molecular patterns of sensitivity or resistance to MEK inhibition, we first screened the intracellular signalling status of each cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (s / screen-01 :ARG0 (w / we) :ARG1 (s2 / status :mod (s3 / signal-07 :ARG1 (c / cell-line :mod (e2 / each)) :mod (i4 / intracellular))) :purpose (i / identify-01 :ARG0 w :ARG1 (p2 / profile :ARG1-of (s4 / specific-02) :ARG0-of (a / allow-01 :ARG1 (i2 / identify-01 :ARG1 (p3 / pattern-01 :ARG1 (o3 / or :op1 (s5 / sensitive-03 :ARG1 (p / pattern :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (m2 / molecule))) :op2 (r2 / resist-01 :ARG1 p)) :mod (m / molecule) :ARG1-of (d / differ-02))) :ARG1-of (p4 / possible-01)))) :time (f / first)) # ::id a_pmid_2256_9000.139 # ::date 2015-06-04T09:02:19 # ::file a_pmid_2256_9000_139.txt # ::snt As depicted in Supplementary Figure 1A, the NCSLC and CRC cell lines displayed highly variable basal levels of total and phosphorylated EGFR, RAS, MEK, and AKT. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / display-01 :ARG0 (a / and :op1 (c / cell-line :mod (d4 / disease :name (n4 / name :op1 "NCSLC"))) :op2 (c2 / cell-line :mod (d3 / disease :name (n5 / name :op1 "CRC")))) :ARG1 (a2 / and :op1 (l5 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "EGFR") :mod (t2 / total) :xref (x6 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op2 (l / level :quant-of (e / enzyme :name (n / name :op1 "EGFR") :ARG3-of (p / phosphorylate-01) :xref (x7 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op3 (l6 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "RAS") :mod t2 :xref (x5 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263"))) :op4 (l2 / level :quant-of (e4 / enzyme :name (n6 / name :op1 "RAS") :ARG3-of p :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263"))) :op5 (l3 / level :quant-of (e5 / enzyme :name (n7 / name :op1 "MEK") :mod t2 :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op6 (l7 / level :quant-of (e7 / enzyme :name (n9 / name :op1 "MEK") :ARG2-of p :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op7 (l4 / level :quant-of (e6 / enzyme :name (n8 / name :op1 "AKT") :mod t2 :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op8 (l8 / level :quant-of (e8 / enzyme :name (n10 / name :op1 "AKT") :ARG3-of p :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG1-of (v / vary-01 :ARG2 (h / high-02)) :mod (b / basal)) :ARG1-of (d2 / depict-01 :ARG0 (f / figure :mod "1A" :ARG2-of (s / supplement-01)))) # ::id a_pmid_2256_9000.140 # ::date 2015-06-04T09:19:17 # ::file a_pmid_2256_9000_140.txt # ::snt As illustrated in Supplementary Figure 1B, there was no apparent correlation between basal levels of total and phosphorylated proteins listed above in both tumour types. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c2 / correlate-01 :polarity "-" :ARG1 (l / level :quant-of (p / protein :mod (t / total)) :mod (b / basal) :ARG1-of (l3 / list-01 :location (a2 / above)) :location (t2 / type-03 :ARG1 (t3 / tumor) :mod (b2 / both))) :ARG2 (l2 / level :ARG3-of (p3 / phosphorylate-01) :ARG1-of l3 :mod b :location t2) :mod (a / apparent) :ARG1-of (i / illustrate-01 :ARG0 (f / figure :mod "1B" :ARG2-of (s / supplement-01)))) # ::id a_pmid_2256_9000.141 # ::date 2015-06-04T10:12:56 # ::file a_pmid_2256_9000_141.txt # ::snt Gene mutations and selumetinib sensitivity in NSCLC and CRC cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (m / mutate-01 :ARG2 (g / gene)) :op2 (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :location (a2 / and :op1 (c / cell-line :mod (d / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d2 / disease :name (n3 / name :op1 "CRC"))))) # ::id a_pmid_2256_9000.142 # ::date 2015-06-04T10:14:54 # ::file a_pmid_2256_9000_142.txt # ::snt Activation of the classic MAPK cascade (RAS-RAF-MEK-ERK) is a common event in colorectal and lung cancer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (e / event :mod (c / common) :location (a / and :op1 (d / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon" :op2 "cancer")) :op2 (d2 / disease :wiki "Lung_cancer" :name (n7 / name :op1 "cancer"))) :domain (a2 / activate-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK") :mod (c6 / classic) :ARG1-of (m / mean-01 :ARG2 (m2 / macro-molecular-complex :part (e5 / enzyme :name (n3 / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :part (e2 / enzyme :name (n4 / name :op1 "RAF") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :part (e4 / enzyme :name (n5 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :part (e3 / enzyme :name (n6 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))))) # ::id a_pmid_2256_9000.143 # ::date 2015-06-04T10:22:20 # ::file a_pmid_2256_9000_143.txt # ::snt Some genes within this pathway are mutated or aberrantly expressed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 11, 2015 (o / or :op1 (m / mutate-01 :ARG1 (g / gene :quant (s / some) :ARG1-of (i / include-91 :ARG2 (p / pathway :mod (t / this))))) :op2 (e / express-03 :ARG2 g :manner (a / aberrant))) # ::id a_pmid_2256_9000.144 # ::date 2015-06-04T10:25:42 # ::file a_pmid_2256_9000_144.txt # ::snt Moreover, the MAPK pathway can be indirectly activated by mutations of genes encoding for PI3K/PTEN/AKT and p53. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op2 (p2 / possible-01 :ARG1 (a2 / activate-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :ARG0-of (e / encode-01 :ARG1 (a3 / and :op1 (p3 / pathway :name (n2 / name :op1 "PI3K/PTEN/AKT")) :op2 (p4 / protein :name (n3 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))))) :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :ARG1-of (d / direct-02 :polarity "-")))) # ::id a_pmid_2256_9000.145 # ::date 2015-06-04T10:31:29 # ::file a_pmid_2256_9000_145.txt # ::snt We have screened the panel of 11 NSCLC and CRC cell lines for mutations in KRAS, NRAS, BRAF, PIK3CA, p53, PTEN, MEK1/2, AKT, EGFR (Table 1; Supplementary Table 1A–F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / screen-01 :ARG0 (w2 / we) :ARG1 (p / panel :consist-of (a4 / and :quant "11" :op1 (c / cell-line :mod (d2 / disease :name (n / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d3 / disease :name (n2 / name :op1 "CRC"))))) :ARG2 (m / mutate-01 :ARG1 (a2 / and :op1 (g2 / gene :name (n5 / name :op1 "KRAS") :xref (x5 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n6 / name :op1 "NRAS") :xref (x4 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op3 (g4 / gene :name (n7 / name :op1 "BRAF") :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op4 (g5 / gene :name (n8 / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op5 (g6 / gene :name (n9 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :op6 (g7 / gene :name (n10 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :op7 (g8 / gene :name (n11 / name :op1 "MEK1/2")) :op8 (g9 / gene :name (n12 / name :op1 "AKT") :xref (x6 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op9 (g10 / gene :name (n13 / name :op1 "EGFR") :xref (x7 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (t / table :mod "1") :op2 (v / value-interval :op1 (t2 / table :mod "1A") :op2 (t3 / table :mod "1F") :ARG2-of (s2 / supplement-01))))) # ::id a_pmid_2256_9000.146 # ::date 2015-06-04T10:39:47 # ::file a_pmid_2256_9000_146.txt # ::snt In NSCLC cell lines, two out of five (40%) harboured a KRAS mutation, which was located in codon 12 or 13. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / harbor-01 :ARG0 (c4 / cell-line :quant "2" :ARG1-of (i / include-91 :ARG2 (c5 / cell-line :quant "5") :ARG3 (p / percentage-entity :value "40"))) :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (l / locate-01 :location (o / or :op1 (c / codon :mod "12") :op2 (c2 / codon :mod "13")))) :location (c3 / cell-line :mod (d / disease :name (n2 / name :op1 "NSCLC")))) # ::id a_pmid_2256_9000.147 # ::date 2015-06-04T10:48:48 # ::file a_pmid_2256_9000_147.txt # ::snt Moreover, three out of five (60%) of NSCLC cells harboured a PI3KCA mutation, which were located in exon 9 or 20. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (h / harbor-01 :ARG0 (c / cell-line :quant "3" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "5" :mod (d / disease :name (n / name :op1 "NSCLC"))) :ARG3 (p / percentage-entity :value "60"))) :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "PI3KCA") :xref (x / xref :value "UNIPROT:E5FF36_HUMAN" :prob "0.331")) :ARG1-of (l / locate-01 :location (o / or :op1 (e / exon :mod "9") :op2 (e2 / exon :mod "20")))))) # ::id a_pmid_2256_9000.148 # ::date 2015-06-04T10:54:23 # ::file a_pmid_2256_9000_148.txt # ::snt A concomitant mutation in KRAS and PI3KCA gene was found in two out of five (40%) NSCLC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (m / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PI3KCA") :xref (x / xref :value "UNIPROT:E5FF36_HUMAN" :prob "0.331"))) :mod (c / concomitant)) :location (c2 / cell-line :quant "2" :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "5" :mod (d / disease :name (n3 / name :op1 "NSCLC"))) :ARG3 (p / percentage-entity :value "40")))) # ::id a_pmid_2256_9000.149 # ::date 2015-06-04T10:57:16 # ::file a_pmid_2256_9000_149.txt # ::snt One NSCLC cell line had an NRAS mutation (Table 1; Supplementary Table 1A–F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :ARG0 (c / cell-line :quant "1" :mod (d2 / disease :name (n / name :op1 "NSCLC"))) :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (t / table :mod "1") :op2 (v / value-interval :op1 (t2 / table :mod "1A") :op2 (t3 / table :mod "1F") :ARG2-of (s / supplement-01))))) # ::id a_pmid_2256_9000.150 # ::date 2015-06-04T11:00:44 # ::file a_pmid_2256_9000_150.txt # ::snt In the panel of six CRC cell lines, all of them harboured a KRAS gene mutation that was located in codon 12 or 13. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / harbor-01 :ARG0 "c3" :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (l / locate-01 :location (o / or :op1 (c / codon :mod "12") :op2 (c2 / codon :mod "13")))) :location (p / panel :consist-of (c3 / cell-line :quant "6" :mod (d / disease :name (n2 / name :op1 "CRC"))))) # ::id a_pmid_2256_9000.151 # ::date 2015-06-04T11:04:59 # ::file a_pmid_2256_9000_151.txt # ::snt Moreover, half of CRC cell lines had both a PI3KCA mutation in exon 9 or 20 and a KRAS mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (h / have-03 :ARG0 (c / cell-line :quant "1/2" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :mod (d / disease :name (n / name :op1 "CRC"))))) :ARG1 (a2 / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "PI3KCA") :xref (x / xref :value "UNIPROT:E5FF36_HUMAN" :prob "0.331")) :location (a3 / and :op1 (e / exon :mod "9") :op2 (e2 / exon :mod "20"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))))) # ::id a_pmid_2256_9000.152 # ::date 2015-06-04T11:22:42 # ::file a_pmid_2256_9000_152.txt # ::snt None of the CRC cells had an NRAS mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :ARG0 (c / cell-line :quant (n2 / none) :mod (d / disease :name (n / name :op1 "CRC"))) :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))) # ::id a_pmid_2256_9000.153 # ::date 2015-06-04T11:38:35 # ::file a_pmid_2256_9000_153.txt # ::snt No BRAF mutations were observed in the whole panel of NSCLC and CRC cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / observe-01 :ARG1 (m / mutate-01 :polarity "-" :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :location (p / panel :mod (w / whole) :consist-of (a2 / and :op1 (c / cell-line :mod (d / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d2 / disease :name (n3 / name :op1 "CRC")))))) # ::id a_pmid_2256_9000.154 # ::date 2015-06-04T11:43:00 # ::file a_pmid_2256_9000_154.txt # ::snt As reported in Supplementary Table 1E and F, no other gene mutations were found in both NSCLC and CRC cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (m / mutate-01 :polarity "-" :ARG1 (g / gene :mod (o / other))) :location (a / and :op1 (c / cell-line :mod (d2 / disease :name (n / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d / disease :name (n2 / name :op1 "CRC")))) :ARG1-of (r / report-01 :ARG0 (a2 / and :op1 (t / table :mod "1E") :op2 (t2 / table :mod "1F") :ARG2-of (s / supplement-01)))) # ::id a_pmid_2256_9000.155 # ::date 2015-06-04T12:09:14 # ::file a_pmid_2256_9000_155.txt # ::snt After this screening, we tried to correlate the mutational status with selumetinib sensitivity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 11, 2015 (t / try-01 :ARG0 (w / we) :ARG1 (c / correlate-01 :ARG0 w :ARG1 (s / status :mod (m / mutate-01)) :ARG2 (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :time (a / after :op1 (s4 / screen-01 :mod (t2 / this)))) # ::id a_pmid_2256_9000.156 # ::date 2015-06-04T12:16:57 # ::file a_pmid_2256_9000_156.txt # ::snt The analysis was made either considering separately the two sets of cell lines (data not shown) or all together (Supplementary Figure 2A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a4 / analyze-01 :manner (c / consider-01 :ARG1 (o / or :op1 (s / set :quant "2" :consist-of (c2 / cell-line) :ARG1-of (s2 / separate-02) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s3 / show-01 :polarity "-")))) :op2 (s5 / set :quant "2" :consist-of c2 :mod (t2 / together) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B") :ARG2-of (s4 / supplement-01))))))) # ::id a_pmid_2256_9000.157 # ::date 2015-06-04T12:40:13 # ::file a_pmid_2256_9000_157.txt # ::snt Sensitivity to selumetinib did not seem to correlate with any specific gene mutations in this panel of NSCLC and CRC cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / seem-01 :polarity "-" :ARG1 (c / correlate-01 :ARG1 (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG2 (m / mutate-01 :ARG1 (g / gene) :ARG1-of (s4 / specific-02) :mod (a / any)) :location (p / panel :consist-of (a3 / and :op1 (c2 / cell-line :mod (d / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c3 / cell-line :mod (d2 / disease :name (n3 / name :op1 "CRC")))) :mod (t / this)))) # ::id a_pmid_2256_9000.158 # ::date 2015-06-04T12:45:24 # ::file a_pmid_2256_9000_158.txt # ::snt Identification of gene expression profiles that could be predictive of response to selumetinib in NSCLC and CRC cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i2 / identify-01 :ARG1 (p / profile :topic (e / express-03 :ARG2 (g / gene))) :ARG0-of (p5 / predict-01 :ARG1 (r / respond-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :ARG1-of (p2 / possible-01)) :location (a / and :op1 (c / cell-line :mod (d / disease :name (n2 / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d2 / disease :name (n3 / name :op1 "CRC"))))) # ::id a_pmid_2256_9000.159 # ::date 2015-06-04T12:53:38 # ::file a_pmid_2256_9000_159.txt # ::snt RNAs from the 11 cancer cell lines were extracted and used for microarray gene expression analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (a / and :op1 (e / extract-01 :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "RNA") :source (c / cell-line :quant "11" :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))) :op2 (u / use-01 :ARG1 n3 :ARG2 (a2 / analyze-01 :ARG0 (m / microarray) :ARG1 (e2 / express-03 :ARG2 (g / gene))))) # ::id a_pmid_2256_9000.160 # ::date 2015-06-04T13:11:13 # ::file a_pmid_2256_9000_160.txt # ::snt Using Student's t-test with Benjamini–Hochberg multiple test correction, 21 and 18 genes were identified as upregulated or downregulated, respectively, in selumetinib-resistant cancer cell lines (t-test, P<0.05) (Supplementary Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a2 / and :op1 (i / identify-01 :ARG1 (g / gene :quant "21") :ARG2 (u / upregulate-01)) :op2 (i2 / identify-01 :ARG1 (g2 / gene :quant "18") :ARG2 (d2 / downregulate-01)) :location (c / cell-line :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")) :ARG0-of (r2 / resist-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :ARG1-of (s / statistical-test-91 :ARG2 (l / less-than :op1 "0.05") :ARG4 (t / thing :wiki "Student's_t-test" :name (n3 / name :op1 "Student's" :op2 "t-test") :mod (c2 / correct-01 :mod (t2 / test-01 :quant (m / multiple)) :ARG1-of (a3 / accord-02 :ARG2 (a4 / and :op1 (p / person :name (n5 / name :op1 "Benjamini")) :op2 (p2 / person :name (n6 / name :op1 "Hochberg"))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3" :ARG2-of (s3 / supplement-01)))) # ::id a_pmid_2256_9000.161 # ::date 2015-06-04T13:35:27 # ::file a_pmid_2256_9000_161.txt # ::snt Table 2 lists the differentially expressed genes in selumetinib-resistant cancer cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (l / list-01 :ARG0 (t / table :mod "2") :ARG1 (g / gene :ARG2-of (e / express-03 :ARG3 (c / cell-line :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :manner (d2 / differential)))) # ::id a_pmid_2256_9000.162 # ::date 2015-06-02T05:36:06 # ::file a_pmid_2256_9000_162.txt # ::snt Among the 21 genes that were upregulated in selumetinib-resistant cancer cell lines, we identified two genes, ADCY7 and AKAP13, which are involved in the cAMP-dependent protein kinase (PKA) pathway (Table 2A; Supplementary Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / identify-01 :ARG0 (w / we) :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "ADCY7") :xref (x1 / xref :value "UNIPROT:ADCY7_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "AKAP13") :xref (x / xref :value "UNIPROT:AKP13_HUMAN" :prob "1.003")) :ARG1-of (i2 / involve-01 :ARG2 (p / pathway :name (n3 / name :op1 "cAMP-dependent" :op2 "protein" :op3 "kinase"))) :ARG1-of (i3 / include-91 :ARG2 (g3 / gene :quant "21" :ARG1-of (u / upregulate-01 :location (c / cell-line :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :mod (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (t / table :mod "2A") :op2 (f / figure :mod "3" :ARG2-of (s2 / supplement-01))))) # ::id a_pmid_2256_9000.163 # ::date 2015-06-02T05:47:27 # ::file a_pmid_2256_9000_163.txt # ::snt The ADCY7 gene encodes a membrane-bound adenylatecyclase that convert ATP into 3', 5'-adenosine monophosphate (cAMP) and pyrophosphate (Supplementary Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 7, 2015 (e / encode-01 :ARG0 (g / gene :name (n / name :op1 "ADCY7") :xref (x / xref :value "UNIPROT:ADCY7_HUMAN" :prob "1.003")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "adenylatecyclase") :ARG1-of (b / bind-01 :ARG2 (m2 / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :ARG0-of (c / convert-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP") :xref (x5 / xref :value "PUBCHEM:5957" :prob "14.368295")) :ARG2 (a / and :op1 (s2 / small-molecule :name (n4 / name :op1 "3'" :op2 "5'" :op3 "adenosine" :op4 "monophosphate") :xref (x4 / xref :value "PUBCHEM:6076" :prob "8.625096")) :op2 (s3 / small-molecule :name (n5 / name :op1 "pyrophosphate") :xref (x3 / xref :value "PUBCHEM:647" :prob "8.347933")))) :xref (x1 / xref :value "UNIPROT:ADCYA_HUMAN" :prob "0.342")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4" :ARG2-of (s4 / supplement-01)))) # ::id a_pmid_2256_9000.164 # ::date 2015-06-02T05:53:53 # ::file a_pmid_2256_9000_164.txt # ::snt The cAMP is a second messenger that has a key role in intracellular signalling transduction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (h / have-03 :ARG0 (m / messenger :domain (s3 / small-molecule :name (n / name :op1 "cAMP") :xref (x / xref :value "PUBCHEM:6076" :prob "15.374314")) :ord (o / ordinal-entity :value "2")) :ARG1 (r / role :ARG1-of (k / key-02) :prep-in (t / transduce-01 :ARG1 (s2 / signal-07 :mod (i / intracellular))))) # ::id a_pmid_2256_9000.165 # ::date 2015-06-02T06:03:30 # ::file a_pmid_2256_9000_165.txt # ::snt A major function in mammalian cells is the activation of the PKA (Tasken et al, 1997). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (f / function-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "PKA") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG1-of (m / major-02) :location (c / cell :part-of (a2 / animal :name (n2 / name :op1 "Mammalia"))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n3 / name :op1 "Tasken")) :op2 (p2 / person :mod (o / other))) :time (d2 / date-entity :year "1997")))) # ::id a_pmid_2256_9000.166 # ::date 2015-06-02T06:09:59 # ::file a_pmid_2256_9000_166.txt # ::snt The AKAP13 gene encodes the A-kinase anchor protein 13 that has the function of binding to the regulatory subunits of PKA (Supplementary Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 2, 2015 (e / encode-01 :ARG0 (g / gene :name (n / name :op1 "AKAP13") :xref (x / xref :value "UNIPROT:AKP13_HUMAN" :prob "1.003")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "A-kinase" :op2 "anchor" :op3 "protein" :op4 "13") :ARG0-of (f / function-01 :ARG1 (b / bind-01 :ARG1 e2 :ARG2 (s / subunit :ARG0-of (r / regulate-01) :part-of (e3 / enzyme :name (n3 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))))) :xref (x2 / xref :value "UNIPROT:AKP13_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4" :ARG2-of (s2 / supplement-01)))) # ::id a_pmid_2256_9000.167 # ::date 2015-06-02T06:12:35 # ::file a_pmid_2256_9000_167.txt # ::snt Moreover, four genes (NCOA3, TAF3, NR1H2, and RXRA), which are upregulated in selumetinib-resistant cancer cell lines, belong to the retinoic acid pathway, which is also activated by PKA (Altucci et al, 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / and :op2 (b / belong-01 :ARG0 (g5 / gene :quant "4" :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (g / gene :name (n / name :op1 "NCOA3") :xref (x4 / xref :value "UNIPROT:NCOA3_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "TAF3") :xref (x2 / xref :value "UNIPROT:TAF3_HUMAN" :prob "1.003")) :op3 (g3 / gene :name (n3 / name :op1 "NR1H2") :xref (x1 / xref :value "UNIPROT:NR1H2_HUMAN" :prob "1.003")) :op4 (g4 / gene :name (n4 / name :op1 "RXRA") :xref (x / xref :value "UNIPROT:RXRA_HUMAN" :prob "1.003")))) :ARG1-of (u / upregulate-01 :location (c / cell-line :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n5 / name :op1 "selumetinib") :xref (x5 / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :mod (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer"))))) :ARG1 (p / pathway :name (n6 / name :op1 "retinoic" :op2 "acid") :ARG1-of (a3 / activate-01 :ARG0 (e / enzyme :name (n7 / name :op1 "PKA") :xref (x3 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :mod (a4 / also))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a5 / and :op1 (p3 / person :name (n8 / name :op1 "Altucci")) :op2 (p4 / person :mod (o / other))) :time (d2 / date-entity :year "2007"))))) # ::id a_pmid_2256_9000.168 # ::date 2015-06-02T06:18:04 # ::file a_pmid_2256_9000_168.txt # ::snt Treatment with selective PKA inhibitors sensitises selumetinib-resistant cancer cell lines to selumetinib # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / sensitize-01 :ARG0 (t / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "PKA"))) :mod (s2 / selective))) :ARG1 (c / cell-line :ARG0-of (r / resist-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :ARG2 s3) # ::id a_pmid_2256_9000.169 # ::date 2015-06-02T06:27:56 # ::file a_pmid_2256_9000_169.txt # ::snt To functionally evaluate if the cAMP-dependent PKA could mediate resistance to MEK inhibitor treatment, we have treated the panel of NSCLC and CRC with 8-Cl-cAMP, a site-selective cAMP analogue, which specifically inhibits PKAI, the PKA isoform that is directly involved in mitogenic signalling and the transformed phenotype (Tortora and Ciardiello, 2000; Naviglio et al, 2009). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t / treat-04 :ARG0 (w / we) :ARG1 (p / panel :part (c / cell-line :mod (d6 / disease :name (n / name :op1 "NSCLC"))) :part (c2 / cell-line :mod (d7 / disease :name (n2 / name :op1 "CRC")))) :ARG2 (s / small-molecule :name (n3 / name :op1 "8-Cl-cAMP") :mod (a2 / analogue :poss (s2 / small-molecule :name (n4 / name :op1 "cAMP") :xref (x3 / xref :value "PUBCHEM:6076" :prob "15.374314")) :mod (s3 / selective :mod (s4 / site))) :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n5 / name :op1 "PKAI") :mod (i2 / isoform :poss (e2 / enzyme :name (n6 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1-of (i3 / involve-01 :ARG2 (a3 / and :op1 (s6 / signal-07 :mod (m / mitogenic)) :op2 (p2 / phenotype :ARG1-of (t2 / transform-01))) :ARG1-of (d / direct-02))) :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.202")) :ARG1-of (s5 / specific-02)) :xref (x4 / xref :value "PUBCHEM:100299" :prob "15.774576")) :purpose (e3 / evaluate-01 :ARG0 w :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (m2 / mediate-01 :ARG0 (e4 / enzyme :name (n7 / name :op1 "PKA") :ARG0-of (d2 / depend-01 :ARG1 s2) :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1 (r / resist-01 :ARG1 (t3 / treat-04 :ARG2 (m3 / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 (p10 / protein-family :name (n8 / name :op1 "MEK")))))))) :manner (f / functional)) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p4 / publication-91 :ARG0 (a5 / and :op1 (p5 / person :name (n9 / name :op1 "Tortora")) :op2 (p6 / person :name (n10 / name :op1 "Ciardiello"))) :time (d4 / date-entity :year "2000")) :op2 (p7 / publication-91 :ARG0 (a6 / and :op1 (p8 / person :name (n11 / name :op1 "Naviglio")) :op2 (p9 / person :mod (o / other))) :time (d5 / date-entity :year "2009"))))) # ::id a_pmid_2256_9000.170 # ::date 2015-06-02T06:40:26 # ::file a_pmid_2256_9000_170.txt # ::snt A dose-dependent inhibition of growth was observed in all cancer cell lines with a different degree of sensitivity, as illustrated in Figure 5A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (o / observe-01 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01) :ARG0-of (d / depend-01 :ARG1 (d2 / dose))) :location (c / cell-line :ARG0-of (h / have-03 :ARG1 (t / thing :degree-of (s / sensitive-03) :ARG1-of (d4 / differ-02))) :mod (a / all) :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :ARG1-of (i2 / illustrate-01 :ARG0 (f / figure :mod "5A"))) # ::id a_pmid_2256_9000.171 # ::date 2015-06-02T08:00:58 # ::file a_pmid_2256_9000_171.txt # ::snt To evaluate the interaction between selumetinib and 8-Cl-cAMP, combination analyses were done. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 2, 2015 (a / analyze-01 :mod (c / combine-01) :purpose (e / evaluate-01 :ARG1 (i / interact-01 :ARG0 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1 (s2 / small-molecule :name (n2 / name :op1 "8-Cl-cAMP") :xref (x / xref :value "PUBCHEM:100299" :prob "15.774576"))))) # ::id a_pmid_2256_9000.172 # ::date 2015-06-02T08:14:50 # ::file a_pmid_2256_9000_172.txt # ::snt The CRC and NSCLC cancer cells were treated with different concentrations of selumetinib (range, 0.01–10 μℳ) and 8-Cl-cAMP (range, 0.01–5 μℳ) each day, for a total of 3 days at a fixed drug ratio selumetinib to 8-Cl-cAMP of 1 : 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :mod (d6 / disease :name (n / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d7 / disease :name (n2 / name :op1 "CRC"))) :mod (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :ARG2 (a2 / and :op1 (s / small-molecule :name (n3 / name :op1 "selumetinib") :mod (c4 / concentration-quantity :quant (v / value-interval :op1 "0.01" :op2 "10") :unit (m / micromolar) :ARG1-of (d3 / differ-02)) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op2 (s2 / small-molecule :name (n4 / name :op1 "8-Cl-cAMP") :mod (c5 / concentration-quantity :ARG1-of (d4 / differ-02) :quant (v2 / value-interval :op1 "0.01" :op2 "5") :unit m) :xref (x / xref :value "PUBCHEM:100299" :prob "15.774576"))) :frequency (r2 / rate-entity-91 :ARG3 (t2 / temporal-quantity :quant "1" :unit (d / day))) :condition (e / equal-01 :ARG1 (r3 / ratio-of :op1 s :op2 s2 :ARG1-of (f / fix-03)) :ARG2 (r4 / ratio-of :op1 "1" :op2 "1")) :duration (t3 / temporal-quantity :quant "3" :unit (d2 / day) :mod (t4 / total))) # ::id a_pmid_2256_9000.173 # ::date 2015-06-02T08:31:37 # ::file a_pmid_2256_9000_173.txt # ::snt In all selumetinib-resistant cancer cell lines, the combination treatment caused synergistic growth inhibitory effects. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / cause-01 :ARG0 (t / treat-04 :mod (c2 / combine-01)) :ARG1 (a / affect-01 :ARG2 (i / inhibit-01 :ARG1 (g / grow-01)) :ARG0-of (s2 / synergize-01)) :location (c3 / cell-line :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :mod (a2 / all) :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))) # ::id a_pmid_2256_9000.174 # ::date 2015-06-02T08:37:07 # ::file a_pmid_2256_9000_174.txt # ::snt In fact, the CI values for the combinations treatments ranged between 0.013 and 0.350. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / range-01 :ARG1 (v / value :mod (i / interval :mod (c / confidence)) :poss (t / treat-04 :mod (c2 / combine-01))) :ARG3 "0.013" :ARG4 "0.350" :mod (i2 / in-fact)) # ::id a_pmid_2256_9000.175 # ::date 2015-06-02T08:40:44 # ::file a_pmid_2256_9000_175.txt # ::snt This was significantly different in the selumetinib-sensitive cancer cells in which the combination treatment was clearly antagonistic with CI between 1.3 and 3.6 (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (d2 / differ-02 :ARG1 (t / this) :location (c / cell-line :ARG0-of (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :location-of (a / antagonize-02 :ARG1 (t2 / treat-04 :mod (c3 / combine-01)) :ARG1-of (c2 / clear-06)) :ARG0-of (h / have-03 :ARG1 (i / interval :mod (c4 / confidence) :mod (v / value-interval :op1 "1.3" :op2 "3.6"))) :mod (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B")) :ARG1-of (s4 / significant-02)) # ::id a_pmid_2256_9000.176 # ::date 2015-06-02T08:49:49 # ::file a_pmid_2256_9000_176.txt # ::snt We next assessed the phosphorylation state of MEK and MAPK following treatment with selumetinib, 8-Cl-cAMP as single agents or in combination with HCT15 and H460 cancer cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / assess-01 :ARG0 (w / we) :ARG1 (s / state :mod (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n3 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG2 (o / or :op1 (o2 / or :op1 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op2 (s3 / small-molecule :name (n5 / name :op1 "8-Cl-cAMP") :xref (x2 / xref :value "PUBCHEM:100299" :prob "15.774576")) :ARG0-of (a3 / act-01 :ARG1 (a4 / agent :ARG1-of (s4 / single-02)))) :op2 (c / combine-01 :ARG1 (a5 / and :op1 s2 :op2 s3) :ARG2 (a6 / and :op1 (c2 / cell-line :name (n6 / name :op1 "HCT15")) :op2 (c3 / cell-line :name (n7 / name :op1 "H460")) :mod (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))))))) :mod (n / next)) # ::id a_pmid_2256_9000.177 # ::date 2015-06-02T08:56:49 # ::file a_pmid_2256_9000_177.txt # ::snt As shown in Figure 3C, single agent selumetinib or 8-Cl-cAMP slightly inhibited p-MEK and p-MAPK, whereas the combination induced a significant inhibition of both phosphorylated proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (o / or :op1 (s2 / small-molecule :name (n / name :op1 "selumetinib") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op2 (s3 / small-molecule :name (n2 / name :op1 "8-Cl-cAMP") :xref (x2 / xref :value "PUBCHEM:100299" :prob "15.774576")) :ARG0-of (a / act-01 :ARG1 (a2 / agent :ARG1-of (s4 / single-02)))) :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "MEK") :ARG3-of (p5 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n4 / name :op1 "MAPK") :ARG3-of p5 :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :degree (s / slight)) :ARG2 (i2 / induce-01 :ARG0 (c2 / combine-01 :ARG1 s2 :ARG2 s3) :ARG1 (i3 / inhibit-01 :ARG1 a3 :ARG1-of (s7 / significant-02))) :ARG1-of (s6 / show-01 :ARG0 (f / figure :mod "3C"))) # ::id a_pmid_2256_9000.178 # ::date 2015-06-02T09:02:19 # ::file a_pmid_2256_9000_178.txt # ::snt A genetic approach to inhibiting PKAI expression was developed by the use of phosphorothioate antisense oligonucleotides targeting the synthesis of the PKAI regulatory subunit RIα. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (d / develop-02 :ARG1 (a / approach-02 :ARG1 (i / inhibit-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "PKAI") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.202")))) :mod (g / genetics)) :manner (u / use-01 :ARG1 (o / oligonucleotide :ARG0-of (t / target-01 :ARG1 (s / synthesize-01 :ARG1 (p / protein-segment :name (n3 / name :op1 "RIα") :part-of e2 :ARG0-of (r / regulate-01)))) :ARG0-of (c / counter-01 :ARG1 (s2 / sense-01)) :mod (p2 / phosphorothioate)))) # ::id a_pmid_2256_9000.179 # ::date 2015-06-02T09:20:05 # ::file a_pmid_2256_9000_179.txt # ::snt These oligonucleotides inhibit growth of several human cancer cell lines in vitro and in vivo (Yokozaki et al, 1993; Nesterova and Cho-Chung, 1995; Tortora et al, 1997a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / inhibit-01 :ARG0 (o / oligonucleotide :mod (t / this)) :ARG1 (g / grow-01 :ARG1 (c / cell-line :mod (h / human) :quant (s / several) :mod (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :manner (a / and :op1 (i2 / in-vitro) :op2 (i3 / in-vivo)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n / name :op1 "Yokozaki")) :op2 (p5 / person :mod (o2 / other))) :time (d2 / date-entity :year "1993")) :op2 (p2 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n2 / name :op1 "Nesterova")) :op2 (p7 / person :name (n3 / name :op1 "Cho-Chung"))) :time (d3 / date-entity :year "1995")) :op3 (p3 / publication-91 :li "a" :ARG0 (a5 / and :op1 (p8 / person :name (n4 / name :op1 "Tortora")) :op2 p5) :time (d4 / date-entity :year "1997"))))) # ::id a_pmid_2256_9000.180 # ::date 2015-06-02T09:26:05 # ::file a_pmid_2256_9000_180.txt # ::snt Therefore, HYB 190, an 18-mer MBO antisense to the N-terminal 8–13 codons of the RIα subunit of PKAI, and the control HYB 239, containing four mismatched bases, were tested to study the effect on the growth of NSCLC and CRC cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (c3 / cause-01 :ARG1 (t / test-01 :ARG1 (a3 / and :op1 (o / oligonucleotide :name (n3 / name :op1 "HYB" :op2 "190") :mod (b2 / backbone :ARG3-of (m / mix-01)) :mod (a4 / antisense :prep-to (c4 / codon :mod (v / value-interval :op1 "8" :op2 "13") :part-of (p / protein-segment :name (n4 / name :op1 "N-terminus")) :part-of (p2 / protein-segment :name (n5 / name :op1 "RIα") :part-of (e2 / enzyme :name (n6 / name :op1 "PKAI") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.202"))))) :mod (p3 / polymer :ARG1-of (l / long-03 :ARG2 "18"))) :op2 (s2 / small-molecule :name (n7 / name :op1 "HYB" :op2 "239") :ARG0-of (c6 / contain-01 :ARG1 (b / base :quant "4" :mod (m4 / mismatch))) :ARG0-of (c5 / control-01) :xref (x1 / xref :value "PUBCHEM:445659" :prob "8.463266"))) :purpose (s / study-01 :ARG1 (a / affect-01 :ARG1 (g / grow-01 :ARG1 (a2 / and :op1 (c / cell-line :mod (d / disease :name (n / name :op1 "NSCLC"))) :op2 (c2 / cell-line :mod (d2 / disease :name (n2 / name :op1 "CRC"))))))))) # ::id a_pmid_2256_9000.181 # ::date 2015-06-02T09:47:26 # ::file a_pmid_2256_9000_181.txt # ::snt All cancer cell lines treated with HBY 190 displayed a dose-dependent inhibition of growth by MTT assay (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (d2 / display-01 :ARG0 (c / cell-line :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "HYB" :op2 "190") :xref (x1 / xref :value "PUBCHEM:445659" :prob "8.444617"))) :mod (a / all) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :ARG1 (i / inhibit-01 :ARG1 (g / grow-01) :ARG0-of (d3 / depend-01 :ARG1 (d4 / dose))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "6A")) :manner (a2 / assay-01 :instrument (s2 / small-molecule :name (n3 / name :op1 "MTT") :xref (x / xref :value "PUBCHEM:64965" :prob "17.320225")))) # ::id a_pmid_2256_9000.182 # ::date 2015-06-02T09:50:50 # ::file a_pmid_2256_9000_182.txt # ::snt Growth inhibition was more pronounced in selumetinib-resistant cancer cell lines (IC50 between 0.25 and 1 μℳ), while the IC50 values were >5 μℳ in the selumetinib-sensitive cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (p / pronounced-02 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01)) :degree (m / more) :location (c2 / cell-line :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "selumetinib") :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c4 / concentration-quantity :unit (m3 / micromolar) :quant (v / value-interval :op1 "0.25" :op2 "1"))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386"))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (m5 / more-than :op1 (c7 / concentration-quantity :quant "5" :unit m3)) :location (c5 / cell-line :ARG0-of (s2 / sensitive-03 :ARG1 s) :mod d))) # ::id a_pmid_2256_9000.183 # ::date 2015-06-02T09:58:52 # ::file a_pmid_2256_9000_183.txt # ::snt In contrast, the control oligonucleotide, HYB 239, at doses up to 5 μℳ, showed only 5–15% growth inhibition among all of the cell lines tested (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / contrast-01 :ARG2 (s / show-01 :ARG0 (o / oligonucleotide :wiki "-" :name (n / name :op1 "HYB" :op2 "239") :ARG0-of (c2 / control-01)) :ARG1 (i / inhibit-01 :ARG1 (g / grow-01) :mod (p / percentage-entity :value (v / value-interval :op1 "5" :op2 "15") :mod (o2 / only))) :condition (d / dose :quant (u / up-to :op1 (c4 / concentration-quantity :quant "5" :unit (m / micromolar)))) :location (c3 / cell-line :mod (a / all) :ARG1-of (t / test-01))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id a_pmid_2256_9000.184 # ::date 2015-06-02T12:42:11 # ::file a_pmid_2256_9000_184.txt # ::snt To determine whether a combination of selumetinib and oligonucleotide HYB 190 could enhance the antiproliferative effect compared with either agent alone, selumetinib-resistant cells were treated with different combinations of the two agents at a fixed drug ratio of 1 : 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 8, 2015 (t / treat-04 :ARG1 (c4 / cell :ARG0-of (r3 / resist-01 :ARG1 "s")) :ARG2 (c / combine-01 :ARG1 "s" :ARG2 "o" :ARG1-of (d3 / differ-02)) :purpose (d / determine-01 :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (e / enhance-01 :ARG0 (c2 / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG2 (o / oligonucleotide :name (n2 / name :op1 "HYB" :op2 "190"))) :ARG1 (a / affect-01 :ARG2 (c3 / counter-01 :ARG1 (p3 / proliferate-01))) :compared-to (o2 / or :op1 (e2 / enhance-01 :ARG0 s :ARG1 a) :op2 (e3 / enhance-01 :ARG0 o :ARG1 a))))) :condition (e4 / equal-01 :ARG1 (r2 / ratio :mod (d2 / drug) :ARG1-of (f / fix-03)) :ARG2 (r4 / ratio-of :op1 "1" :op2 "1"))) # ::id a_pmid_2256_9000.185 # ::date 2015-06-02T12:58:05 # ::file a_pmid_2256_9000_185.txt # ::snt As shown in Figure 6B, the combination treatment caused synergistic growth inhibitory effects. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 8, 2015 (c / cause-01 :ARG0 (t / treat-04 :mod (c2 / combine-01)) :ARG1 (a / affect-01 :ARG2 (i / inhibit-01 :ARG1 (g / grow-01))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "6B"))) # ::id a_pmid_2256_9000.186 # ::date 2015-06-02T13:00:24 # ::file a_pmid_2256_9000_186.txt # ::snt To determine whether the growth inhibitory effect of oligonucleotide HYB 190 correlated with a reduction in RIα protein levels, we performed protein blots on total cell extracts prepared from H460 cells treated with oligonucleotide HYB 190, oligonucleotide HYB 239, selumetinib, and combinations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (p / perform-01 :ARG0 (w / we) :ARG1 (i2 / immunoblot-01 :ARG1 (p2 / protein) :ARG2 (m / molecular-physical-entity :ARG1-of (e / extract-01 :ARG2 (c2 / cell)) :mod (t / total) :ARG1-of (p4 / prepare-01 :ARG2 (c3 / cell-line :name (n3 / name :op1 "H460") :ARG1-of (t2 / treat-04 :ARG2 (o2 / or :op1 "o" :op2 (o3 / oligonucleotide :name (n4 / name :op1 "HYB" :op2 "239")) :op3 (s / small-molecule :name (n5 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :op4 (c4 / combine-01))))))) :purpose (d / determine-01 :ARG0 w :ARG1 (c / correlate-01 :mode "interrogative" :ARG1 (a / affect-01 :ARG0 (o / oligonucleotide :name (n / name :op1 "HYB" :op2 "190")) :ARG2 (i / inhibit-01 :ARG0 o3 :ARG1 (g / grow-01))) :ARG2 (r / reduce-01 :ARG1 (l / level :quant-of (p3 / protein-segment :name (n2 / name :op1 "RIα"))))))) # ::id a_pmid_2256_9000.187 # ::date 2015-06-02T13:11:21 # ::file a_pmid_2256_9000_187.txt # ::snt Compared with untreated H460 cells, RIα levels were substantially unchanged, even in cells treated with a higher dose of the control oligonucleotide HYB 239 (1 μℳ) and selumetinib (5 μℳ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / change-01 :polarity "-" :ARG1 (l / level :quant-of (p / protein-segment :name (n / name :op1 "RIα")) :compared-to (c2 / cell-line :name (n2 / name :op1 "H460") :ARG1-of (t / treat-04 :polarity "-"))) :degree (s / substantial) :concession (t2 / treat-04 :ARG1 (c3 / cell) :ARG2 (a / and :op1 (d / dose :ARG1-of (h / high-02 :degree (m / more)) :quant-of (o / oligonucleotide :name (n3 / name :op1 "HYB" :op2 "239") :ARG0-of (c4 / control-01)) :ARG1-of (m2 / mean-01 :ARG2 (c5 / concentration-quantity :quant "1" :unit (m3 / micromolar)))) :op1 (d2 / dose :ARG1-of h :quant-of (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")) :ARG1-of (m5 / mean-01 :ARG2 (m6 / mass-quantity :quant "5" :unit m3)))))) # ::id a_pmid_2256_9000.188 # ::date 2015-06-02T13:30:31 # ::file a_pmid_2256_9000_188.txt # ::snt However, reduction of RIα expression was seen when H460 cells were treated with oligonucleotide HYB 190 (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 8, 2015 (c2 / contrast-01 :ARG2 (s / see-01 :ARG1 (r / reduce-01 :ARG1 (e / express-03 :ARG2 (p / protein-segment :name (n / name :op1 "RIα")))) :condition (t / treat-04 :ARG1 (c / cell-line :name (n2 / name :op1 "H460")) :ARG2 (o / oligonucleotide :name (n3 / name :op1 "HYB" :op2 "190"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C")))) # ::id a_pmid_2256_9000.189 # ::date 2015-06-02T13:34:48 # ::file a_pmid_2256_9000_189.txt # ::snt Moreover, a complete inhibition of RIα expression was seen in the combination treatment (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / and :op2 (s / see-01 :ARG1 (i / inhibit-01 :ARG1 (e / express-03 :ARG2 (p / protein-segment :name (n / name :op1 "RIα"))) :degree (c / complete-02)) :condition (t / treat-04 :mod (c2 / combine-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C")))) # ::id a_pmid_2256_9000.190 # ::date 2015-06-02T13:36:16 # ::file a_pmid_2256_9000_190.txt # ::snt We finally evaluated whether the combined inhibition of both PKA and MEK pathways would have antitumour activity in vivo in selumetinib-resistant HCT15 and H460 xenografts (Figure 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e2 / evaluate-01 :li "-1" :ARG0 (w2 / we) :ARG1 (a / activity-06 :mode "interrogative" :ARG0 (i / inhibit-01 :ARG1 (a2 / and :op1 (p / pathway :name (n2 / name :op1 "PKA")) :op2 (p2 / pathway :name (n3 / name :op1 "MEK"))) :ARG1-of (c / combine-01)) :ARG1 (c2 / counter-01 :ARG1 (t / tumor)) :manner (i2 / in-vivo) :location (a3 / and :op1 (x / xenograft :source (c3 / cell-line :name (n / name :op1 "HCT15"))) :op2 (x2 / xenograft :source (c4 / cell-line :name (n4 / name :op1 "H460"))) :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n6 / name :op1 "selumetinib") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "7"))) # ::id a_pmid_2256_9000.191 # ::date 2015-06-02T13:42:54 # ::file a_pmid_2256_9000_191.txt # ::snt At day 50 from cancer cell injection, the mean tumour volume in mice bearing HCT15 and H460 tumour xenografts and treated with selumetinib, 25 mg kg−1, and 8-Cl-cAMP, 0.5 mg kg−1, were 20% and 16%, respectively, as compared with control untreated mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (e / equal-01 :ARG1 (v / volume :mod (t / tumor) :mod (m / mean)) :ARG2 (p / percentage-entity :value "20") :location (m2 / mouse :ARG0-of (b / bear-01 :ARG1 (a2 / and :op1 (x / xenograft :source (t2 / tumor :mod (c6 / cell-line :name (n / name :op1 "HCT15")))) :op2 (x2 / xenograft :source (t3 / tumor :mod (c4 / cell-line :name (n2 / name :op1 "H460")))))) :ARG1-of (t4 / treat-04 :ARG2 (s / small-molecule :name (n4 / name :op1 "selumetinib") :mod (c / concentration-quantity :quant "25" :unit (m3 / milligram-per-kilogram)) :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.561386"))))) :op2 (e2 / equal-01 :ARG1 v :ARG2 (p2 / percentage-entity :value "16") :location (m4 / mouse :ARG0-of b :ARG1-of (t5 / treat-04 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "8-Cl-cAMP") :mod (c2 / concentration-quantity :quant "0.5" :unit (m5 / milligram-per-kilogram)) :xref (x1 / xref :value "PUBCHEM:100299" :prob "15.774576"))))) :time (a3 / after :op1 (i / inject-01 :ARG1 (c3 / cell :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :quant (t6 / temporal-quantity :quant "50" :unit (d2 / day))) :compared-to (m6 / mouse :ARG0-of (c5 / control-01) :ARG1-of (t7 / treat-04 :polarity "-"))) # ::id a_pmid_2458_8908.10 # ::date 2015-06-04T08:56:43 # ::file a_pmid_2458_8908_10.txt # ::snt In a cohort of 144 metastatic melanoma patients we found that patients with N-RAS mutant melanoma had a worse prognosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-03 :ARG1 (m5 / medical-condition :name (n / name :op1 "melanoma") :mod (e / enzyme :name (n2 / name :op1 "N-RAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673")))) :ARG0-of (h4 / have-rel-role-91 :ARG2 (p4 / patient)) :ARG1-of (i / include-91 :ARG2 (c / cohort :consist-of (p3 / person :quant "144" :ARG0-of (h3 / have-03 :ARG1 (m4 / medical-condition :name (n3 / name :op1 "melanoma") :ARG1-of (m3 / metastasize-101))) :ARG0-of (h5 / have-rel-role-91 :ARG2 (p5 / patient)))))) :ARG1 (p2 / prognosis :ARG1-of (b / bad-07 :degree (m2 / more))))) # ::id a_pmid_2458_8908.11 # ::date 2015-06-04T09:02:21 # ::file a_pmid_2458_8908_11.txt # ::snt These patients were more likely to have brain metastases at the time of presentation with metastatic disease than their N-RAS-wild-type counterparts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 14, 2015 (l / likely-01 :ARG1 (h / have-03 :ARG0 (p / person :mod (t / this) :compared-to (c / counterpart :mod (e / enzyme :name (n / name :op1 "N-RAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient))) :ARG1 (m / metastasize-101 :ARG2 (b / brain)) :time (p2 / present-102 :ARG0 p :ARG1 (d / disease :ARG1-of (m2 / metastasize-101)))) :degree (m3 / more)) # ::id a_pmid_2458_8908.12 # ::date 2015-06-04T11:08:51 # ::file a_pmid_2458_8908_12.txt # ::snt All N-RAS mutant melanoma cultures tested in our study (n = 7) were sensitive to MEK inhibition162. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 15, 2016 (s / sensitive-03 :ARG0 (c / culture-01 :quant "7" :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma") :mod (e / enzyme :name (n4 / name :op1 "N-RAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))) :ARG1-of (t / test-01 :medium (s2 / study-01 :ARG0 (w / we))) :mod (a / all)) :ARG1 (i / inhibit-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "MEK" :op2 "162") :xref (x1 / xref :value "PUBCHEM:10288191" :prob "12.541676")))) # ::id a_pmid_2458_8908.13 # ::date 2015-06-04T09:06:40 # ::file a_pmid_2458_8908_13.txt # ::snt Exposure to MEK162 reduced ERK1/2 phosphorylation, and induced apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (r2 / reduce-01 :ARG0 (e2 / expose-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "MEK162") :xref (x / xref :value "PUBCHEM:10288191" :prob "18.572987"))) :ARG1 (p / phosphorylate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "ERK1/2")))) :op2 (i2 / induce-01 :ARG0 e2 :ARG2 (a3 / apoptosis))) # ::id a_pmid_2458_8908.14 # ::date 2015-06-04T09:17:01 # ::file a_pmid_2458_8908_14.txt # ::snt Clonogenic survival was significantly reduced in sensitive melanoma cell cultures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / reduce-01 :ARG1 (s2 / survive-01 :mod (c / clonogen)) :ARG2 (s / significant-02) :location (c2 / culture-01 :ARG1 (c3 / cell :ARG0-of (s3 / sensitive-03) :mod (m / medical-condition :name (n / name :op1 "melanoma"))))) # ::id a_pmid_2458_8908.58 # ::date 2015-06-04T09:55:03 # ::file a_pmid_2458_8908_58.txt # ::snt Clinical profiles of patients whose tumors harbor N-RAS and B-RAF mutations # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 14, 2015 (p / profile-01 :ARG1 (p2 / person :ARG0-of (h2 / have-03 :ARG1 (t / tumor :ARG0-of (h / harbor-01 :ARG1 (m / mutate-01 :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "N-RAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673")) :op2 (e2 / enzyme :name (n4 / name :op1 "B-RAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))))))) :ARG0-of (h3 / have-rel-role-91 :ARG2 (p3 / patient))) :mod (c / clinical)) # ::id a_pmid_2458_8908.59 # ::date 2015-06-04T10:05:57 # ::file a_pmid_2458_8908_59.txt # ::snt Characteristics of our cohort of 144 patients with stage IV melanoma are shown in Table 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (s / show-01 :ARG0 (t / table :mod "1") :ARG1 (c / characteristic-02 :ARG1 (p / person :quant "144" :ARG0-of (h / have-03 :ARG1 (m / medical-condition :name (n / name :op1 "melanoma") :ARG1-of (s2 / stage-02 :ARG2 "IV"))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (i / include-91 :ARG2 (c2 / cohort :poss (w / we)))))) # ::id a_pmid_2458_8908.60 # ::date 2015-06-04T10:24:42 # ::file a_pmid_2458_8908_60.txt # ::snt Mutations were found in B-RAF in 43.7%, N-RAS in 27.7%, and 28.4% were wild type (WT) for both. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 26, 2015 (f / find-01 :ARG1 (m / mutate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "B-RAF") :quant (p4 / percentage-entity :value "43.7") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")) :op2 (e2 / enzyme :name (n4 / name :op1 "N-RAS") :quant (p5 / percentage-entity :value "27.7") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673")) :ARG2-of (i / include-91 :ARG1 (e3 / enzyme :mod (w2 / wild-type)) :ARG3 (p6 / percentage-entity :value "28.4"))))) # ::id a_pmid_2458_8908.61 # ::date 2015-06-04T10:42:40 # ::file a_pmid_2458_8908_61.txt # ::snt The majority of B-RAF mutations were represented by substitution of valine at position 600 to glutamic acid (74.6% were B-RAFV600E) or to lysine (19% were B-RAFV600K). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 26, 2015 (o2 / or :op1 (r / represent-01 :ARG0 (s / substitute-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "glutamic" :op2 "acid") :xref (x3 / xref :value "PUBCHEM:611" :prob "7.558843")) :ARG2 (a2 / amino-acid :mod "600" :name (n5 / name :op1 "valine") :xref (x1 / xref :value "PUBCHEM:6287" :prob "10.890044"))) :ARG1 (m / mutate-01 :ARG1-of (i / include-91 :ARG2 (m5 / mutate-01 :ARG2 (e2 / enzyme :name (n / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))) :ARG3 (m2 / majority)) :ARG2-of (i2 / include-91 :ARG1 (m3 / mutate-01 :value "V600E" :ARG2 e2) :ARG3 (p / percentage-entity :value "74.6")))) :op2 (r2 / represent-01 :ARG0 (s2 / substitute-01 :ARG1 (a4 / amino-acid :name (n7 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG2 a2) :ARG1 (m6 / mutate-01 :ARG1-of i :ARG2-of (i3 / include-91 :ARG1 (m4 / mutate-01 :value "V600K" :ARG2 e2) :ARG3 (p2 / percentage-entity :value "19"))))) # ::id a_pmid_2458_8908.62 # ::date 2015-06-14T01:04:39 # ::file a_pmid_2458_8908_62.txt # ::snt Substitutions of glutamine 61 accounted for 95% of N-RAS mutations (most frequently Q61R/K/L/H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / account-01 :ARG0 (s / substitute-01 :ARG2 (a2 / amino-acid :mod "61" :name (n / name :op1 "glutamine") :xref (x1 / xref :value "PUBCHEM:738" :prob "11.972775"))) :ARG2 (m / mutate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "N-RAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673")) :ARG2-of (i / include-91 :ARG1 (a3 / and :op1 (m2 / mutate-01 :value "Q61R") :op2 (m5 / mutate-01 :value "Q61K") :op3 (m6 / mutate-01 :value "Q61L") :op4 (m7 / mutate-01 :value "Q61H")) :ARG1-of (f / frequent-02 :degree (m3 / most))) :ARG1-of (i2 / include-91 :ARG2 (m4 / mutate-01 :ARG1 e) :ARG3 (p2 / percentage-entity :value "95")))) # ::id a_pmid_2458_8908.63 # ::date 2015-06-04T11:25:19 # ::file a_pmid_2458_8908_63.txt # ::snt The slightly higher percentage of N-RAS mutant melanomas in our population than what is commonly reported may be a result of the relatively small sample size or a reflection of local demographics. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (o2 / or :op1 (r / result-01 :ARG1 (s2 / size-01 :ARG1 (t2 / thing :ARG1-of (s3 / sample-01)) :ARG2 (s4 / small :ARG2-of (r4 / relative-05))) :ARG2 (p2 / percentage :ARG1-of (h / high-02 :degree (m2 / more :degree (s / slight))) :quant-of (m / medical-condition :name (n / name :op1 "melanoma") :mod (e / enzyme :name (n2 / name :op1 "N-RAS") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))) :location (p3 / population :poss (w / we)) :compared-to (t / thing :ARG1-of (r2 / report-01 :mod (c / common))))) :op2 (r3 / reflect-01 :ARG1 p2 :ARG2 (d / demographics :ARG1-of (l / local-02))))) # ::id a_pmid_2458_8908.64 # ::date 2015-06-04T09:03:45 # ::file a_pmid_2458_8908_64.txt # ::snt Clinical and pathological characteristics # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (c / characteristic-02 :mod (c2 / clinical) :mod (p / pathology)) # ::id a_pmid_2458_8908.65 # ::date 2015-06-04T09:05:27 # ::file a_pmid_2458_8908_65.txt # ::snt Patients with B-RAF mutations tended to be younger; median age at initial diagnosis of melanoma was 57.6 in patients with B-RAF mutations, 68.2 in patients with N-RAS mutations and 66.3 years in patients wild-type for both (P <0.0001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a3 / and :op1 (t / tend-02 :ARG1 (p / person :ARG0-of (h4 / have-rel-role-91 :ARG2 (p3 / patient :mod (e3 / enzyme :name (n / name :op1 "B-RAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))))) :ARG2 (p2 / person :mod (y / young :degree (m3 / more)))) :op2 (a / and :op1 (a4 / age-01 :ARG1 p :ARG2 (t2 / temporal-quantity :quant "57.6" :unit (y2 / year))) :op2 (a5 / age-01 :ARG1 (p4 / person :ARG0-of (h6 / have-rel-role-91 :ARG2 (p7 / patient :mod (e / enzyme :name (n4 / name :op1 "N-RAS") :ARG2-of (m6 / mutate-01) :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))))) :ARG2 (t3 / temporal-quantity :quant "68.2" :unit (y3 / year))) :op3 (a6 / age-01 :ARG1 (p5 / person :ARG0-of (h7 / have-rel-role-91 :ARG2 (p8 / patient :mod e :mod e3 :mod (w / wild-type)))) :ARG2 (t4 / temporal-quantity :quant "66.3" :unit (y4 / year))) :mod (m4 / median) :time (d / diagnose-01 :ARG2 (m2 / medical-condition :name (n2 / name :op1 "melanoma")) :mod (i / initial)) :ARG1-of (p6 / possible-01 :quant (l / less-than :value "0.0001")))) # ::id a_pmid_2458_8908.66 # ::date 2015-06-14T02:18:32 # ::file a_pmid_2458_8908_66.txt # ::snt Our cohort included 22 patients who received either dabrafenib (N = 1), vemurafenib (N = 19), a pan-RAF inhibitor (N = 1) or a pan-RAF inhibitor and vemurafenib (N = 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 14, 2015 (i2 / include-01 :ARG1 (p / person :quant "22" :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient :ARG2-of (i7 / include-91 :ARG1 (a2 / and :op1 (p2 / person :quant "1" :ARG0-of (h2 / have-rel-role-91 :ARG2 (p7 / patient)) :ARG0-of (r2 / receive-01 :ARG1 (s / small-molecule :name (n / name :op1 "dabrafenib") :xref (x1 / xref :value "PUBCHEM:44462760" :prob "17.251232")))) :op2 (p3 / person :quant "19" :ARG0-of h2 :ARG0-of (r3 / receive-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")))) :op3 (p4 / person :quant "1" :ARG0-of h2 :ARG0-of (r4 / receive-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "pan-RAF")))))) :op4 (p5 / person :quant "1" :ARG0-of h2 :ARG0-of (r5 / receive-01 :ARG2 (a3 / and :op1 m :op2 s2)))))))) :ARG2 (c / cohort :poss (w / we))) # ::id a_pmid_2458_8908.67 # ::date 2015-06-14T02:45:57 # ::file a_pmid_2458_8908_67.txt # ::snt Patients with N-RAS mutated melanomas appear to have an increased rate of skin and soft tissue involvement (70%) compared to B-RAF mutated counterparts and WT patients (37% and 41% respectively, P = 0.0025). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / appear-01 :ARG1 (i / increase-01 :ARG1 (r / rate :degree-of (i2 / involve-01 :ARG1 (a2 / and :op1 (s / skin) :op2 (t / tissue :ARG1-of (s2 / soft-02)))) :mod (p6 / percentage-entity :value "70")) :ARG1-of (h / have-03 :ARG0 (p2 / person :ARG0-of (h2 / have-03 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma") :mod (e / enzyme :name (n4 / name :op1 "N-RAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673")))) :ARG0-of (h3 / have-rel-role-91 :ARG2 (p3 / patient)))) :ARG1-of (c / compare-01 :ARG2 (a3 / and :op1 (r3 / rate :degree-of i2 :mod (c3 / counterpart :mod (e2 / enzyme :name (n5 / name :op1 "B-RAF") :ARG2-of (m3 / mutate-01) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))) :mod (p7 / percentage-entity :value "37")) :op2 (r4 / rate :degree-of i2 :mod (p4 / person :ARG0-of (h4 / have-rel-role-91 :ARG2 (p5 / patient :mod (e3 / enzyme :name (n / name :op1 "B-RAF") :mod (w2 / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))))) :mod (p8 / percentage-entity :value "41")) :mod (r2 / respective)))) :ARG1-of (p / possible-01 :value "0.0025")) # ::id a_pmid_2458_8908.68 # ::date 2015-06-14T02:55:18 # ::file a_pmid_2458_8908_68.txt # ::snt The rate of lymph node metastasis was also noted to be higher in patients with N-RAS mutations (75%) compared to B-RAF mutant and WT patients (46% and 61%, respectively) (P = 0.01). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (n3 / note-02 :ARG1 (r / rate :mod (p4 / percentage-entity :value "75") :ARG1-of (h2 / high-02 :degree (m3 / more)) :mod (m / metastasize-101 :ARG2 (n4 / node :mod (l / lymph))) :condition (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient :mod (e / enzyme :name (n5 / name :op1 "N-RAS") :ARG2-of (m4 / mutate-01) :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))))) :ARG1-of (c / compare-01 :ARG2 (a / and :op1 (r3 / rate :mod (p3 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 (p5 / patient)) :mod (e2 / enzyme :name (n6 / name :op1 "B-RAF") :ARG2-of (m5 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))) :mod (p7 / percentage-entity :value "46")) :op2 (r2 / rate :mod (p6 / person :ARG0-of h3 :mod (w / wild-type)) :mod (p8 / percentage-entity :value "61"))))) :ARG1-of (p9 / possible-01 :value "0.01") :mod (a2 / also)) # ::id a_pmid_2458_8908.69 # ::date 2015-06-15T08:03:17 # ::file a_pmid_2458_8908_69.txt # ::snt No statistically significant difference was seen between the genotypes and other clinical characteristics, such as M stage and LDH levels.Seeing that B-RAF inhibitors can affect survival in patients with B-RAF mutant melanomas, this group of patients was removed from the survival analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (s / see-01 :polarity "-" :ARG1 (d / differ-02 :ARG1 (g / genotype) :ARG2 (c / characteristic-02 :ARG2 (a / and :op1 (e5 / event :name (n4 / name :op1 "M" :op2 "stage")) :op2 (l / level :quant-of (e3 / enzyme :name (n3 / name :op1 "LDH") :xref (x1 / xref :value "UNIPROT:LDHB_HUMAN" :prob "0.342"))) :ARG1-of (e / exemplify-01)) :mod (c2 / clinic) :mod (o / other)) :ARG1-of (s2 / significant-02 :mod (s3 / statistic)))) :snt2 (s7 / see-01 :ARG1 (p / possible-01 :ARG1 (a2 / affect-01 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e4 / enzyme :name (n / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")))) :ARG1 (s5 / survive-01 :ARG0 (p2 / person :ARG0-of (h / have-03 :ARG1 (m2 / medical-condition :name (n5 / name :op1 "melanoma") :mod (e2 / enzyme :name (n2 / name :op1 "B-RAF") :ARG2-of (m4 / mutate-01) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient)))))) :ARG0-of (c4 / cause-01 :ARG1 (r / remove-01 :ARG1 (g2 / group :mod (t / this) :ARG2-of (i / include-91 :ARG1 p2)) :ARG2 (a3 / analyze-01 :ARG1 (s6 / survive-01)))))) # ::id a_pmid_2458_8908.70 # ::date 2015-06-15T08:21:07 # ::file a_pmid_2458_8908_70.txt # ::snt By Cox univariate analysis we found a trend towards shorter survival in the N-RAS mutant population, compared to the B-RAF and WT groups combined (p = 0.12). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (t / trend-01 :ARG2 (s / survive-01 :ARG1 (p / population :ARG0-of (h / have-03 :ARG1 (e3 / enzyme :name (n3 / name :op1 "N-RAS") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673")))) :ARG1-of (s2 / short-07 :degree (m2 / more)) :ARG1-of (c / compare-01 :ARG2 (a / and :op1 (g / group :mod (e4 / enzyme :name (n4 / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))) :op2 (g2 / group :mod (w2 / wild-type)) :ARG1-of (c3 / combine-01))))) :ARG1-of (p2 / possible-01 :value "0.12") :manner (a3 / analyze-01 :name (n / name :op1 "Cox") :mod (u / univariate))) # ::id a_pmid_2458_8908.71 # ::date 2015-06-14T07:59:42 # ::file a_pmid_2458_8908_71.txt # ::snt The median survival was 13 and 19.6 months, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 23, 2015 (s / survive-01 :mod (m2 / median) :duration (a / and :op1 (t / temporal-quantity :quant "13" :unit (m / month)) :op2 (t4 / temporal-quantity :quant "19.6" :unit m) :mod (r / respective))) # ::id a_pmid_2458_8908.72 # ::date 2015-06-14T08:03:21 # ::file a_pmid_2458_8908_72.txt # ::snt Kaplan-Meier survival curves are shown in Figure 1a for the three groups of patients (BRAF or NRAS mutant or WT for both) and Figure 1b for the two groups (NRAS compared to BRAF mutant and WT combined) to visually demonstrate the differences between the groups. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 14, 2015 (s / show-01 :ARG0 (a / and :op1 (f / figure :mod "1a" :beneficiary (g / group-01 :quant "3" :ARG1 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :mod (o2 / or :op1 (e / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m4 / mutate-01) :xref (x4 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n4 / name :op1 "BRAF") :mod (w2 / wild-type) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op3 (e2 / enzyme :name (n2 / name :op1 "NRAS") :ARG2-of (m5 / mutate-01) :xref (x3 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op4 (e4 / enzyme :name (n5 / name :op1 "NRAS") :mod (w3 / wild-type) :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))))) :op2 (f2 / figure :mod "1b" :beneficiary (g2 / group-01 :quant "2" :mod (c / compare-01 :ARG1 (e5 / enzyme :name (n3 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :ARG2 (c2 / combine-01 :ARG1 e :ARG2 e3))))) :ARG1 (c4 / curve :name (n6 / name :op1 "Kaplan-Meier") :mod (s2 / survive-01)) :purpose (d / demonstrate-01 :ARG1 (d2 / differ-02 :ARG1 g :ARG2 g2) :mod (v / visual))) # ::id a_pmid_2458_8908.73 # ::date 2015-06-14T13:58:23 # ::file a_pmid_2458_8908_73.txt # ::snt Interestingly, analysis of anatomic sites at the time of initial diagnosis of stage IV disease revealed a higher rate of brain involvement among B-RAF (16%) and N-RAS (15%) mutant melanoma patients, compared with patients with WT disease (2.5%) (P =0.04). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (s / site :mod (a2 / anatomy)) :time (d / diagnose-01 :ARG2 (d2 / disease :ARG1-of (s2 / stage-02 :ARG2 "IV")) :mod (i / initial))) :ARG1 (a4 / and :op1 (r3 / rate :mod (i4 / involve-01 :ARG1 (b / brain) :prep-among (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p8 / patient :mod (m3 / medical-condition :name (n5 / name :op1 "melanoma") :mod (e / enzyme :name (n / name :op1 "B-RAF") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))))))) :mod (p4 / percentage-entity :value "16")) :op2 (r4 / rate :mod (i5 / involve-01 :ARG1 b :prep-among (p9 / person :ARG0-of (h5 / have-rel-role-91 :ARG2 (p10 / patient :mod (m5 / medical-condition :name (n2 / name :op1 "melanoma") :mod (e2 / enzyme :name (n6 / name :op1 "N-RAS") :ARG2-of (m4 / mutate-01) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))))))) :mod (p5 / percentage-entity :value "15")) :ARG1-of (h2 / high-02 :degree (m2 / more)) :ARG1-of (c / compare-01 :ARG2 (r2 / rate :mod (i3 / involve-01 :ARG1 b) :condition (p6 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 (p7 / patient :mod (d6 / disease :mod (w2 / wild-type))))) :mod (p / percentage-entity :value "2.5")))) :ARG2-of (i2 / interest-01) :ARG1-of (p2 / possible-01 :value "0.04")) # ::id a_pmid_2458_8908.74 # ::date 2015-06-14T14:27:14 # ::file a_pmid_2458_8908_74.txt # ::snt With longitudinal follow-up, however, the rate of development of brain metastases did not differ among the three groups, possibly because the WT groups lived longer and thus developed brain metastases over time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 26, 2015 (c3 / contrast-01 :ARG2 (d / differ-02 :polarity "-" :ARG1 (g / group :quant "3") :ARG3 (r / rate :mod (d2 / develop-01 :ARG2 (m / metastasize-101 :ARG2 (b / brain)))) :ARG1-of (c2 / cause-01 :ARG0 (a2 / and :op1 (l2 / live-01 :ARG0 (g2 / group :mod (w / wild-type)) :ARG1-of (l3 / long-03 :degree (m2 / more))) :op2 (d3 / develop-01 :ARG2 m :duration (o / over :mod (t / time)) :ARG1-of (c4 / cause-01 :ARG0 l2))) :ARG1-of (p / possible-01))) :ARG1-of (c / condition-01 :ARG2 (f / follow-up-03 :mod (l / longitude)))) # ::id a_pmid_2458_8908.75 # ::date 2015-06-14T02:56:32 # ::file a_pmid_2458_8908_75.txt # ::snt In vitro activity of B-RAF and MEK inhibitors in a large panel of melanoma cultures # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / activity-06 :ARG0 (a2 / and :op1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")))) :op2 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"))))) :manner (i2 / in-vitro) :location (p / panel :mod (l / large) :consist-of (c / culture :mod (m / medical-condition :name (n3 / name :op1 "melanoma"))))) # ::id a_pmid_2458_8908.76 # ::date 2015-06-14T03:05:52 # ::file a_pmid_2458_8908_76.txt # ::snt To investigate the effect of B-RAF and MEK inhibition in melanoma cultures, we used RAF265 (a pan-RAF inhibitor), MEK162 (a MEK1/2 inhibitor) and the MEK inhibitor trametinib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (a / and :op1 (s2 / small-molecule :wiki "-" :name (n4 / name :op1 "RAF265") :ARG0-of (i2 / inhibit-01 :ARG1 (e / enzyme :wiki "-" :name (n5 / name :op1 "pan-RAF"))) :xref (x2 / xref :value "PUBCHEM:11656518" :prob "17.879841")) :op2 (s3 / small-molecule :wiki "Binimetinib" :name (n6 / name :op1 "MEK162") :ARG0-of (i3 / inhibit-01 :ARG1 (e7 / enzyme :wiki "Mitogen-activated_protein_kinase_kinase" :name (n7 / name :op1 "MEK1/2"))) :xref (x1 / xref :value "PUBCHEM:10288191" :prob "18.572987")) :op3 (s / small-molecule :wiki "Trametinib" :name (n8 / name :op1 "trametinib") :ARG0-of (i4 / inhibit-01 :ARG1 (p / protein-family :wiki "Mitogen-activated_protein_kinase_kinase" :name (n9 / name :op1 "MEK"))) :xref (x3 / xref :value "PUBCHEM:11707110" :prob "17.561386"))) :ARG2 (i5 / investigate-01 :ARG0 w :ARG1 (a2 / affect-01 :ARG0 (i6 / inhibit-01 :ARG0 (a3 / and :op1 (e9 / enzyme :wiki "-" :name (n10 / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")) :op2 p)) :ARG1 (c / culture :mod (m / medical-condition :wiki "Melanoma" :name (n12 / name :op1 "melanoma")))))) # ::id a_pmid_2458_8908.77 # ::date 2015-06-14T03:27:04 # ::file a_pmid_2458_8908_77.txt # ::snt A panel of 22 patient-derived melanoma cultures was used; the IC50 for RAF265 and MEK162 are shown in Table 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (m / multi-sentence :snt1 (u / use-01 :ARG1 (p / panel :consist-of (c / culture-01 :quant "22" :ARG1 (m2 / medical-condition :name (n / name :op1 "melanoma")) :ARG1-of (d / derive-01 :ARG2 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient))))))) :snt2 (s / show-01 :ARG0 (t2 / table :mod "1") :ARG1 (c2 / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (a / and :op1 (s2 / small-molecule :name (n3 / name :op1 "RAF265") :xref (x / xref :value "PUBCHEM:11656518" :prob "17.879841")) :op2 (s3 / small-molecule :name (n4 / name :op1 "MEK162") :xref (x1 / xref :value "PUBCHEM:10288191" :prob "18.572987"))) :ARG2 "50")))) # ::id a_pmid_2458_8908.78 # ::date 2015-06-14T03:51:15 # ::file a_pmid_2458_8908_78.txt # ::snt This was compared to the IC50 for trametinib (Additional file 1: Table S1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / compare-01 :ARG1 (t / this) :ARG2 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "trametinib") :xref (x / xref :value "PUBCHEM:11707110" :prob "17.561386")) :ARG2 "50") :ARG1-of (d / describe-01 :ARG0 (t3 / table :mod "S1" :location (f / file :mod "1" :mod (a / additional))))) # ::id a_pmid_2458_8908.79 # ::date 2015-06-14T03:57:10 # ::file a_pmid_2458_8908_79.txt # ::snt Patient-derived melanoma cultures with their B-RAF/N-RAS mutational status and sensitivity to RAF265 and MEK162 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / derive-01 :ARG1 (c / culture-01 :ARG1 (m2 / medical-condition :name (n / name :op1 "melanoma"))) :ARG2 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient))) :accompanier (a / and :op1 (s / status :mod (m / mutate-01 :ARG1 (s5 / slash :op1 (e / enzyme :name (n5 / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")) :op2 (e2 / enzyme :name (n6 / name :op1 "N-RAS") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673")))) :poss c) :op2 (s2 / sensitive-03 :ARG0 c :ARG1 (a2 / and :op1 (s3 / small-molecule :name (n3 / name :op1 "RAF265") :xref (x2 / xref :value "PUBCHEM:11656518" :prob "17.879841")) :op2 (s4 / small-molecule :name (n4 / name :op1 "MEK162") :xref (x3 / xref :value "PUBCHEM:10288191" :prob "18.572987")))))) # ::id a_pmid_2458_8908.80 # ::date 2015-06-14T04:31:40 # ::file a_pmid_2458_8908_80.txt # ::snt Cells were treated with each drug individually at concentrations ranging from 1 nM to 1000 nM and analyzed three days later. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / and :op1 (t / treat-04 :ARG1 (c / cell) :ARG2 (d / drug :mod (c2 / concentration :ARG1-of (r / range-01 :ARG3 (c3 / concentration-quantity :quant "1" :unit (n / nanomolar)) :ARG4 (c4 / concentration-quantity :quant "1000" :unit n))) :mod (e / each)) :manner (i / individual)) :op2 (a2 / analyze-01 :ARG1 c :time (l3 / late :op1 (t3 / temporal-quantity :quant "3" :unit (d3 / day)) :degree (m4 / more)))) # ::id a_pmid_2458_8908.81 # ::date 2015-06-14T04:50:12 # ::file a_pmid_2458_8908_81.txt # ::snt As shown in Table 2, the IC50 for RAF265 ranged from 24 to >10000 nM, 4 to 2004 nM, and 62 to 2082 nM for WT, B-RAF mutant and N-RAS mutant cultures, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (s / show-01 :ARG0 (t / table :mod "2") :ARG1 (a / and :op1 (r / range-01 :ARG1 (c10 / concentration-quantity :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "RAF265") :xref (x2 / xref :value "PUBCHEM:11656518" :prob "17.879841")) :ARG2 "50")) :ARG3 (c4 / concentration-quantity :quant "24" :unit (n5 / nanomolar)) :ARG4 (m / more-than :op1 (c5 / concentration-quantity :quant "10000" :unit n5)) :location (c / culture-01 :mod (w / wild-type))) :op2 (r2 / range-01 :ARG1 (c11 / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s2 :ARG2 "50")) :ARG3 (c6 / concentration-quantity :quant "4" :unit n5) :ARG4 (c7 / concentration-quantity :quant "2004" :unit n5) :location (c2 / culture-01 :mod (m2 / mutate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))))) :op3 (r3 / range-01 :ARG1 (c12 / concentration-quantity :ARG4-of (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s2 :ARG2 "50")) :ARG3 (c8 / concentration-quantity :quant "62" :unit n5) :ARG4 (c9 / concentration-quantity :quant "2082" :unit n5) :location (c3 / culture-01 :mod (m3 / mutate-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "N-RAS") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))))) :mod (r4 / respective))) # ::id a_pmid_2458_8908.82 # ::date 2015-06-15T10:43:18 # ::file a_pmid_2458_8908_82.txt # ::snt The IC50 for MEK162 ranged from 10 to >10000 nM, < 1 to 150 nM, and 4 to 13 nM for WT, B-RAF mutant and N-RAS mutant melanoma cultures, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / and :op1 (r / range-01 :ARG1 (c10 / concentration-quantity :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "MEK162") :xref (x2 / xref :value "PUBCHEM:10288191" :prob "18.572987")) :ARG2 "50") :location (c / culture-01 :mod (w / wild-type))) :ARG3 (c4 / concentration-quantity :quant "10" :unit (n2 / nanomolar)) :ARG4 (m / more-than :op1 (c5 / concentration-quantity :quant "10000" :unit n2))) :op2 (r2 / range-01 :ARG1 (c11 / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s :ARG2 "50") :location (c2 / culture-01 :mod (m2 / medical-condition :name (n5 / name :op1 "melanoma") :mod (e2 / enzyme :name (n6 / name :op1 "B-RAF") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))))) :ARG3 (l / less-than :op1 (c6 / concentration-quantity :quant "1" :unit n2)) :ARG4 (c7 / concentration-quantity :quant "150" :unit n2)) :op3 (r3 / range-01 :ARG1 (c12 / concentration-quantity :ARG4-of (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s :ARG2 "50") :location (c3 / culture-01 :mod (m5 / medical-condition :name n5 :mod (e / enzyme :name (n9 / name :op1 "N-RAS") :ARG2-of (m4 / mutate-01) :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))))) :ARG3 (c8 / concentration-quantity :quant "4" :unit n2) :ARG4 (c9 / concentration-quantity :quant "13" :unit n2)) :mod (r4 / respective)) # ::id a_pmid_2458_8908.83 # ::date 2015-06-14T04:51:15 # ::file a_pmid_2458_8908_83.txt # ::snt The sensitivity to RAF265 in wild type (2 out of 5) and N-RAS (2 out of 7) melanoma cultures was low. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / sensitive-03 :ARG0 (a2 / and :op1 (c2 / culture-01 :quant "2" :ARG1 (m / medical-condition :name (n4 / name :op1 "melanoma") :mod (w2 / wild-type)) :ARG1-of (i3 / include-91 :ARG2 (c / culture-01 :quant "5"))) :op2 (c3 / culture-01 :quant "2" :ARG1 (m2 / medical-condition :name (n5 / name :op1 "melanoma") :mod (e / enzyme :name (n6 / name :op1 "N-RAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))) :ARG1-of (i4 / include-91 :ARG2 (c4 / culture-01 :quant "7")))) :ARG1 (s2 / small-molecule :name (n / name :op1 "RAF265") :xref (x1 / xref :value "PUBCHEM:11656518" :prob "17.879841")) :ARG1-of (l / low-04)) # ::id a_pmid_2458_8908.84 # ::date 2015-06-14T05:44:21 # ::file a_pmid_2458_8908_84.txt # ::snt Two wild type cultures (YUROB and YUSOC) are sensitive to both RAF265 and MEK162. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (s / sensitive-03 :ARG0 (c / culture-01 :quant "2" :mod (w / wild-type) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c2 / cell-line :name (n / name :op1 "YUROB")) :op2 (c3 / cell-line :name (n2 / name :op1 "YUSOC"))))) :ARG1 (a2 / and :op1 (s2 / small-molecule :name (n3 / name :op1 "RAF265") :xref (x1 / xref :value "PUBCHEM:11656518" :prob "17.879841")) :op2 (s3 / small-molecule :name (n4 / name :op1 "MEK162") :xref (x / xref :value "PUBCHEM:10288191" :prob "18.572987")) :mod (b / both))) # ::id a_pmid_2458_8908.85 # ::date 2015-06-14T05:48:43 # ::file a_pmid_2458_8908_85.txt # ::snt Six of ten B-RAF mutant cultures were sensitive to RAF265, and seven out of ten were sensitive to MEK162. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 26, 2015 (a / and :op1 (s / sensitive-03 :ARG0 (c / culture-01 :quant "6" :mod (m / mutate-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))) :ARG1-of (i3 / include-91 :ARG2 (c2 / culture-01 :quant "10"))) :ARG1 (s3 / small-molecule :name (n4 / name :op1 "RAF265") :xref (x1 / xref :value "PUBCHEM:11656518" :prob "17.879841"))) :op2 (s2 / sensitive-03 :ARG0 (c3 / culture-01 :quant "7" :ARG1-of (i / include-91 :ARG2 c2) :mod m) :ARG1 (s4 / small-molecule :name (n5 / name :op1 "MEK162") :xref (x2 / xref :value "PUBCHEM:10288191" :prob "18.572987")))) # ::id a_pmid_2458_8908.86 # ::date 2015-06-14T05:57:55 # ::file a_pmid_2458_8908_86.txt # ::snt In N-RAS mutant melanoma cultures, 2 out of 7 were sensitive to RAF265 and, strikingly, all were sensitive to MEK162. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (s / sensitive-03 :ARG0 (c / culture-01 :quant "2" :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma")) :mod (m / mutate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "N-RAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))) :ARG1-of (i2 / include-91 :ARG2 (c2 / culture-01 :quant "7"))) :ARG1 (s4 / small-molecule :name (n / name :op1 "RAF265") :xref (x2 / xref :value "PUBCHEM:11656518" :prob "17.879841"))) :op2 (s2 / sensitive-03 :ARG0 (a2 / all) :ARG1 (s5 / small-molecule :name (n2 / name :op1 "MEK162") :xref (x1 / xref :value "PUBCHEM:10288191" :prob "18.572987")) :ARG1-of (s3 / strike-04))) # ::id a_pmid_2458_8908.87 # ::date 2015-06-14T06:03:39 # ::file a_pmid_2458_8908_87.txt # ::snt Of the 7 N-RAS mutant cultures, 5 were sensitive to trametinib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (s / sensitive-03 :ARG0 (c / culture-01 :quant "5" :mod (m / mutate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "N-RAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))) :ARG1-of (i / include-91 :ARG2 (c2 / culture-01 :quant "7"))) :ARG1 (s2 / small-molecule :name (n / name :op1 "trametinib") :xref (x1 / xref :value "PUBCHEM:11707110" :prob "17.561386"))) # ::id a_pmid_2458_8908.88 # ::date 2015-06-14T06:11:25 # ::file a_pmid_2458_8908_88.txt # ::snt YUFIC and YUTICA were more resistant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (r / resist-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "YUFIC")) :op2 (c2 / cell-line :name (n2 / name :op1 "YUTICA"))) :degree (m / more)) # ::id a_pmid_2458_8908.89 # ::date 2015-06-14T06:13:12 # ::file a_pmid_2458_8908_89.txt # ::snt Molecular effects of MEK162 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "MEK162") :xref (x / xref :value "PUBCHEM:10288191" :prob "18.572987")) :ARG1 (m / molecule)) # ::id a_pmid_2458_8908.90 # ::date 2015-06-14T06:18:36 # ::file a_pmid_2458_8908_90.txt # ::snt Due to the striking sensitivity patterns of MEK162, we conducted additional studies to verify target down-regulation in the sensitive and resistant cultures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / cause-01 :ARG0 (p / pattern-01 :ARG1 (s / sensitive-03 :ARG1 (s5 / small-molecule :name (n / name :op1 "MEK162") :xref (x / xref :value "PUBCHEM:10288191" :prob "18.572987"))) :ARG1-of (s2 / strike-04)) :ARG1 (c2 / conduct-01 :ARG0 (w / we) :ARG1 (s3 / study-01 :ARG0 w :mod (a / additional)) :purpose (v / verify-01 :ARG0 w :ARG1 (d / downregulate-01 :ARG1 (t / target-01) :location (a2 / and :op1 (c3 / culture-01 :ARG0-of (s6 / sensitive-03)) :op2 (c4 / culture-01 :ARG0-of (r2 / resist-01))))))) # ::id a_pmid_2458_8908.91 # ::date 2015-06-14T06:28:34 # ::file a_pmid_2458_8908_91.txt # ::snt ERK1/2 isoforms are the immediate downstream substrates and best studied effectors of dual specificity kinases MEK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a2 / and :op1 (s / substrate :location (d / downstream) :mod (i2 / immediacy)) :op2 (e3 / effector :ARG1-of (s4 / study-01 :ARG1-of (g / good-02 :degree (m / most))) :poss (k / kinase :name (n2 / name :op1 "MEK1/2") :mod (s3 / specificity :mod (d2 / dual)))) :domain (i / isoform :mod (e2 / enzyme :name (n / name :op1 "ERK1/2")))) # ::id a_pmid_2458_8908.92 # ::date 2015-06-14T06:30:15 # ::file a_pmid_2458_8908_92.txt # ::snt To assess the effect of MEK1/2 inhibition on ERK1/2 activation state (phosphorylation at T202/Y204 sites), melanoma cultures were treated with MEK162 and compared with untreated controls. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (t / treat-04 :ARG1 (c2 / culture-01 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma"))) :ARG2 (s3 / small-molecule :name (n4 / name :op1 "MEK162") :xref (x / xref :value "PUBCHEM:10288191" :prob "18.572987"))) :op2 (c / compare-01 :ARG1 c2 :ARG2 (c3 / control :ARG1-of (t2 / treat-04 :polarity "-"))) :purpose (a2 / assess-01 :ARG1 (a3 / affect-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2"))) :ARG1 (s / state :mod (a4 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")))) :ARG2-of (m / mean-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (s4 / slash :op1 (a5 / amino-acid :mod "202" :name (n6 / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a6 / amino-acid :mod "204" :name (n7 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")))))))) # ::id a_pmid_2458_8908.93 # ::date 2015-06-14T06:43:14 # ::file a_pmid_2458_8908_93.txt # ::snt We selected one sensitive and one resistant culture in the WT and B-RAF mutant categories. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (s / select-01 :ARG0 (w / we) :ARG1 (a3 / and :op1 (c3 / culture-01 :quant "1" :ARG0-of (s3 / sensitive-03)) :op2 (c4 / culture-01 :quant "1" :ARG0-of (r2 / resist-01))) :ARG2 (a / and :op1 (c / category :mod (w4 / wild-type)) :op2 (c5 / category :mod (m / mutate-01 :ARG2 (e3 / enzyme :wiki "-" :name (n3 / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673")))))) # ::id a_pmid_2458_8908.94 # ::date 2015-06-14T07:01:32 # ::file a_pmid_2458_8908_94.txt # ::snt Seeing that all N-RAS mutant cultures were sensitive to MEK162, we selected two sensitive cultures for these studies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (c / cause-01 :ARG0 (s / see-01 :ARG1 (s3 / sensitive-03 :ARG0 (c2 / culture-01 :mod (m / mutate-01 :ARG2 (e / enzyme :name (n / name :op1 "N-RAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673"))) :mod (a / all)) :ARG1 (s6 / small-molecule :name (n2 / name :op1 "MEK162") :xref (x1 / xref :value "PUBCHEM:10288191" :prob "18.572987")))) :ARG1 (s2 / select-01 :ARG0 (w / we) :ARG1 (c3 / culture-01 :quant "2" :ARG0-of (s4 / sensitive-03)) :ARG3 (s5 / study-01 :mod (t / this)))) # ::id a_pmid_2458_8908.95 # ::date 2015-06-14T07:07:30 # ::file a_pmid_2458_8908_95.txt # ::snt WT (YUVON and YUROB), B-RAF mutant (YUKSI and YUMAC) and N-RAS mutant (YUDOSO and YUKIM) cells were treated with increasing doses (10-1000 nM) of MEK162 or left untreated for 4 and 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (o / or :op1 (t2 / treat-04 :ARG1 (a6 / and :op1 (a7 / and :op1 (c2 / cell-line :name (n / name :op1 "YUVON")) :op2 (c3 / cell-line :name (n2 / name :op1 "YUROB")) :mod (w2 / wild-type)) :op2 (a2 / and :op1 (c4 / cell-line :name (n6 / name :op1 "YUKSI")) :op2 (c5 / cell-line :name (n7 / name :op1 "YUMAC")) :mod (e / enzyme :name (n8 / name :op1 "B-RAF") :ARG2-of (m3 / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))) :op3 (a3 / and :op1 (c6 / cell-line :name (n3 / name :op1 "YUDOSO")) :op3 (c7 / cell-line :name (n9 / name :op1 "YUKIM")) :mod (e2 / enzyme :name (n10 / name :op1 "N-RAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "0.673")))) :ARG2 (s / small-molecule :name (n5 / name :op1 "MEK162") :quant (d / dose :quant (b / between :op1 (c8 / concentration-quantity :quant "10" :unit (n4 / nanomolar)) :op2 (c9 / concentration-quantity :quant "1000" :unit n4)) :ARG1-of (i / increase-01)) :xref (x2 / xref :value "PUBCHEM:10288191" :prob "18.572987"))) :op2 (l / leave-14 :ARG1 (t3 / treat-04 :polarity "-" :ARG1 a6)) :duration (a5 / and :op1 (t / temporal-quantity :quant "4" :unit (h / hour)) :op2 (t4 / temporal-quantity :quant "24" :unit h))) # ::id a_pmid_2458_8908.96 # ::date 2015-06-14T07:20:15 # ::file a_pmid_2458_8908_96.txt # ::snt Western blot analysis was performed using phospho-ERK1/2, total ERK1/2 and β-actin antibodies, and results are shown in Figure 2A.In the MEK162 resistant melanoma cultures (YUVON and YUKSI), the baseline level of phospho-ERK1/2 and the ratio of phospho-ERK1/2 to total ERK1/2 was lower compared to sensitive cultures (YUROB, YUMAC, YUDOSO, YUKIM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m2 / multi-sentence :snt1 (a / and :op1 (p / perform-01 :ARG1 (i / immunoblot-01) :ARG2 (a3 / and :op1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)) :op2 (e4 / enzyme :name (n3 / name :op1 "ERK1/2") :mod (t / total)) :op3 (a4 / antibody :ARG0-of (c4 / counter-01 :ARG2 (p7 / protein :name (n4 / name :op1 "β-actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.282")))))) :op2 (s / show-01 :ARG0 (f / figure :mod "2A") :ARG1 (t2 / thing :ARG2-of (r / result-01)))) :snt2 (l2 / low-04 :ARG1 (a5 / and :op1 (l3 / level :domain (b2 / baseline) :quant-of (e / enzyme :name (n8 / name :op1 "ERK1/2") :ARG3-of (p8 / phosphorylate-01))) :op2 (r2 / ratio-of :op1 e :op2 (e2 / enzyme :name (n9 / name :op1 "ERK1/2") :mod (t3 / total))) :ARG1-of (c2 / compare-01 :ARG2 (c3 / culture-01 :ARG0-of (s3 / sensitive-03) :ARG1-of (m4 / mean-01 :ARG2 (a6 / and :op1 (c7 / cell-line :name (n11 / name :op1 "YUROB")) :op2 (c8 / cell-line :name (n12 / name :op1 "YUMAC")) :op3 (c9 / cell-line :name (n13 / name :op1 "YUDOSO")) :op4 (c10 / cell-line :name (n14 / name :op1 "YUKIM"))))))) :degree (m3 / more) :location (c / culture-01 :ARG1 (m5 / medical-condition :name (n6 / name :op1 "melanoma")) :ARG0-of (r3 / resist-01 :ARG1 (s2 / small-molecule :name (n7 / name :op1 "MEK162") :xref (x1 / xref :value "PUBCHEM:10288191" :prob "18.572987"))) :ARG1-of (m / mean-01 :ARG2 (a8 / and :op1 (c5 / cell-line :name (n5 / name :op1 "YUVON")) :op2 (c6 / cell-line :name (n10 / name :op1 "YUKSI"))))))) # ::id a_pmid_2458_8908.97 # ::date 2015-06-14T07:22:57 # ::file a_pmid_2458_8908_97.txt # ::snt In MEK162-sensitive melanomas exposure to MEK162 resulted in a significant decrease in the level of ERK1/2 phosphorylation (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (r / result-01 :ARG1 (e / expose-01 :ARG1 (m / medical-condition :name (n / name :op1 "melanoma") :ARG0-of (s / sensitive-03 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "MEK162") :xref (x / xref :value "PUBCHEM:10288191" :prob "18.572987")))) :ARG2 s4) :ARG2 (d2 / decrease-01 :ARG0 e :ARG1 (l / level :degree-of (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")))) :ARG2 (s2 / significant-02)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2514_2146.9 # ::date 2015-06-08T10:07:47 # ::file a_pmid_2514_2146_9.txt # ::snt Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (m6 / multi-sentence :snt1 (f / fall-04 :ARG1 (s / sensitive-03) :ARG2 (g / group :quant "3" :ARG1-of (m9 / mean-01 :ARG2 (a / and :op1 (s2 / sensitive-03 :ARG1-of (m / mean-01 :ARG2 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (l / less-than :op1 (c / concentration-quantity :quant "1" :unit (m2 / micromolar)))))) :op2 (s3 / sensitive-03 :mod (i / intermediate) :ARG1-of (m3 / mean-01 :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c3 / concentration-quantity :quant (b / between :op1 "1" :op2 "2") :unit m2)))) :op3 (r / resist-01 :ARG1-of (m4 / mean-01 :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (m5 / more-than :op1 (c2 / concentration-quantity :quant "2" :unit m2))))))))) :snt2 (s4 / sensitive-03 :ARG0 (g2 / gene :quant "15" :name (n4 / name :op1 "BRAF") :ARG2-of (m7 / mutate-01) :ARG1-of (i2 / include-91 :ARG2 (g3 / gene :quant "21" :name (n5 / name :op1 "BRAF") :ARG2-of m7 :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG3 (p / percentage-entity :value "71")) :ARG2-of (i3 / include-01 :ARG1 (g4 / gene :quant "4" :name (n6 / name :op1 "BRAF") :ARG0-of (r2 / resist-01 :ARG1 (s5 / small-molecule :name (n7 / name :op1 "vemurafenib") :xref (x4 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :mod (i4 / innate)) :ARG2-of m7 :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (s6 / small-molecule :name (n8 / name :op1 "SCH772984") :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) # ::id a_pmid_2514_2146.10 # ::date 2015-06-08T10:19:11 # ::file a_pmid_2514_2146_10.txt # ::snt All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / sensitive-03 :ARG0 (a / and :op1 (s2 / slash :op1 (g / gene :quant "3" :name (n / name :op1 "BRAF") :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g4 / gene :name (n6 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :ARG2-of (m / mutate-01 :mod (d / double)) :ARG1-of (i3 / include-91 :ARG3 (p / percentage-entity :value "100")) :mod (a2 / all)) :op2 (g2 / gene :quant "11" :name (n2 / name :op1 "NRAS") :ARG2-of (m2 / mutate-01) :ARG1-of (i / include-91 :ARG2 (g3 / gene :quant "14" :name (n3 / name :op1 "NRAS") :ARG2-of m2 :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :ARG3 (p2 / percentage-entity :value "78")) :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op2 (m4 / medical-condition :quant "5" :name (n4 / name :op1 "melanoma") :mod (w / wild-type) :ARG1-of (i2 / include-91 :ARG2 (m3 / medical-condition :quant "7" :name (n5 / name :op1 "melanoma")) :ARG3 (p3 / percentage-entity :value "71"))))) # ::id a_pmid_2514_2146.11 # ::date 2015-06-08T10:57:20 # ::file a_pmid_2514_2146_11.txt # ::snt Among BRAFV600 mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (s / sensitive-03 :ARG0 (g2 / gene :wiki "BRAF_(gene)" :name (n3 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600") :ARG0-of (r2 / reactivate-01 :ARG1 (p / pathway :wiki "MAPK/ERK_pathway" :name (n4 / name :op1 "MAPK")) :ARG1-of (m3 / mean-01 :ARG2 (m4 / mechanism :mod (r3 / resist-01)))) :ARG1-of (i2 / include-91 :ARG2 (g / gene :wiki "BRAF_(gene)" :name (n / name :op1 "BRAF") :ARG2-of m2 :ARG0-of (r / resist-01 :ARG1 (s2 / small-molecule :wiki "Vemurafenib" :name (n2 / name :op1 "vemurafenib") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG1-of (a / acquire-01 :ARG0 g :manner (i / in-vitro))) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (s3 / small-molecule :wiki "-" :name (n5 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) # ::id a_pmid_2514_2146.12 # ::date 2015-06-08T11:29:35 # ::file a_pmid_2514_2146_12.txt # ::snt SCH772984 caused G1 arrest and induced apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (c / cause-01 :ARG0 (s / small-molecule :name (n / name :op1 "SCH772984") :xref (x / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1 (a2 / arrest-02 :ARG1 (t / thing :name (n2 / name :op1 "G1")))) :op2 (i / induce-01 :ARG0 s :ARG2 (a3 / apoptosis))) # ::id a_pmid_2514_2146.54 # ::date 2015-06-08T11:38:34 # ::file a_pmid_2514_2146_54.txt # ::snt BRAF-mutant melanoma cell lines are sensitive to ERK inhibition # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / sensitive-03 :ARG0 (c / cell-line :mod (m / medical-condition :name (n3 / name :op1 "melanoma")) :mod (e / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG1 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) # ::id a_pmid_2514_2146.55 # ::date 2015-06-08T11:54:22 # ::file a_pmid_2514_2146_55.txt # ::snt Twenty-one melanoma cell lines containing mutations in the BRAF gene were evaluated to determine sensitivity to SCH772984 (ERKi). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (e / evaluate-01 :ARG1 (c / cell-line :quant "21" :ARG0-of (c2 / contain-01 :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :mod (m / medical-condition :name (n4 / name :op1 "melanoma"))) :purpose (d / determine-01 :ARG1 (s / sensitive-03 :ARG0 c :ARG1 (s2 / small-molecule :name (n2 / name :op1 "SCH772984") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "ERK"))) :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134"))))) # ::id a_pmid_2514_2146.56 # ::date 2015-06-08T10:19:39 # ::file a_pmid_2514_2146_56.txt # ::snt As a comparison, sensitivity to vemurafenib was also determined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (d / determine-01 :ARG1 (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :mod (a / also) :ARG1-of (c / compare-01)) # ::id a_pmid_2514_2146.57 # ::date 2015-06-08T12:47:23 # ::file a_pmid_2514_2146_57.txt # ::snt BRAFV600E was the most frequently observed BRAF mutation, present in 17 of 21 cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m4 / mutate-01 :ARG2 (g3 / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (o / observe-01 :ARG1-of (f / frequent-02 :degree (m2 / most))) :ARG1-of (p / present-02 :ARG2 (c / cell-line :quant "17" :ARG1-of (i2 / include-91 :ARG2 (c2 / cell-line :quant "21")))) :domain (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id a_pmid_2514_2146.58 # ::date 2015-06-08T13:04:17 # ::file a_pmid_2514_2146_58.txt # ::snt M381 contains BRAFV600R substitution, M414 contains BRAFV600K, M417 contains BRAFG466E and M420 contains BRAFL597S mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (a / and :op1 (c / contain-01 :ARG0 (c2 / cell-line :name (n / name :op1 "M381")) :ARG1 (s / substitute-01 :ARG2 (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600R") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (c3 / contain-01 :ARG0 (c4 / cell-line :name (n3 / name :op1 "M414")) :ARG1 (m3 / mutate-01 :value "V600K" :ARG1 g)) :op3 (c5 / contain-01 :ARG0 (c6 / cell-line :name (n4 / name :op1 "M417")) :ARG1 (m4 / mutate-01 :value "G466E" :ARG1 g)) :op4 (c7 / contain-01 :ARG0 (c8 / cell-line :name (n5 / name :op1 "M420")) :ARG1 (m5 / mutate-01 :value "L597S" :ARG1 g))) # ::id a_pmid_2514_2146.59 # ::date 2015-06-08T13:31:30 # ::file a_pmid_2514_2146_59.txt # ::snt Among the 21 cell lines, sensitivity to vemurafenib or SCH-772984 fell into 3 groups: highly sensitive (50% inhibitory concentration, IC50 < 1 μM), intermediate sensitivity (IC50 1–2 μM) and resistant (IC50 > 2 μM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (f / fall-04 :ARG1 (s / sensitive-03 :ARG0 (c2 / cell-line :quant "21") :ARG1 (o / or :op1 (s2 / small-molecule :name (n / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s3 / small-molecule :name (n2 / name :op1 "SCH-772984") :xref (x / xref :value "PUBCHEM:24866313" :prob "20.371708")))) :ARG2 (g / group :quant "3" :ARG1-of (m6 / mean-01 :ARG2 (a / and :op1 (s4 / sensitive-03 :ARG1-of (h / high-02) :ARG1-of (m / mean-01 :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (l / less-than :op1 (c / concentration-quantity :quant "1" :unit (m2 / micromolar)))))) :op2 (s5 / sensitive-03 :mod (i2 / intermediate) :ARG1-of (m3 / mean-01 :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c3 / concentration-quantity :quant (b / between :op1 "1" :op2 "2") :unit m2)))) :op3 (r / resist-01 :ARG1-of (m4 / mean-01 :ARG2 (h4 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (m5 / more-than :op1 (c4 / concentration-quantity :quant "2" :unit m2))))))))) # ::id a_pmid_2514_2146.60 # ::date 2015-06-08T13:55:17 # ::file a_pmid_2514_2146_60.txt # ::snt 15 cell lines were highly sensitive to SCH-772984 with IC50 less than or equal to 1 μM. Of the 12 cell lines highly sensitive to vemurafenib, all contain BRAFV600E and were also sensitive to SCH-772984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (s / sensitive-03 :ARG0 (c / cell-line :quant "15") :ARG1 (s2 / small-molecule :name (n / name :op1 "SCH-772984") :ARG1-of (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c4 / concentration-quantity :quant "1" :unit (m2 / micromolar))) :xref (x1 / xref :value "PUBCHEM:24866313" :prob "20.371708")) :ARG1-of (h / high-02)) :snt2 (a / and :op1 (c2 / contain-01 :ARG0 (c3 / cell-line :quant "12" :mod (a2 / all) :ARG0-of (s3 / sensitive-03 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "vemurafenib") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG1-of h)) :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m5 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (s5 / sensitive-03 :ARG0 c3 :ARG1 (s6 / small-molecule :name (n4 / name :op1 "SCH-772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "20.371708")) :mod (a3 / also)))) # ::id a_pmid_2514_2146.61 # ::date 2015-06-08T13:58:46 # ::file a_pmid_2514_2146_61.txt # ::snt Interestingly, M399, M414, M308, and M409 were sensitive to SCH-772984 but only intermediately sensitive (M399, M409 and M414) or resistant (M308) to vemurafenib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (s / sensitive-03 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "M399")) :op2 (c2 / cell-line :name (n2 / name :op1 "M414")) :op3 (c3 / cell-line :name (n3 / name :op1 "M308")) :op4 (c5 / cell-line :name (n6 / name :op1 "M409"))) :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH-772984") :xref (x / xref :value "PUBCHEM:24866313" :prob "20.371708")) :ARG1-of (c4 / contrast-01 :ARG2 (o / or :op1 (s3 / sensitive-03 :ARG0 (a3 / and :op1 c :op2 c5 :op3 c2) :ARG1 (s4 / small-molecule :name (n5 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :mod (i2 / intermediate :mod (o2 / only))) :op2 (r / resist-01 :ARG0 c3 :ARG1 s4))) :mod (i / interesting)) # ::id a_pmid_2514_2146.62 # ::date 2015-06-08T14:47:51 # ::file a_pmid_2514_2146_62.txt # ::snt With the exception of M414, all non-V600E mutants were resistant to both vemurafenib and SCH772984 (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (r / resist-01 :ARG0 (m / mutate-01 :value "V600E" :polarity "-" :mod (a2 / all) :ARG2-of (e / except-01 :ARG1 (c / cell-line :name (n3 / name :op1 "M414")))) :ARG1 (a / and :op1 (s / small-molecule :name (n / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id a_pmid_2514_2146.63 # ::date 2015-06-08T15:01:08 # ::file a_pmid_2514_2146_63.txt # ::snt As a comparison, sensitivity to the MEKi trametinib segregated all cell lines into three different groups: highly sensitive (IC50 < 2nM), intermediately sensitive (IC50 2-30nM) and resistant (IC50 > 30 nM) (Additional file 1: Figure S1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / segregate-01 :ARG0 (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n / name :op1 "trametinib") :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :xref (x1 / xref :value "PUBCHEM:11707110" :prob "17.561386"))) :ARG1 (c2 / cell-line :mod (a / all)) :ARG2 (g / group :quant "3" :ARG1-of (d / differ-02) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and :op1 (s4 / sensitive-03 :ARG1-of (h / high-02) :ARG1-of (m / mean-01 :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (l / less-than :op1 (c3 / concentration-quantity :quant "2" :unit (n3 / nanomolar)))))) :op2 (s5 / sensitive-03 :manner (i2 / intermediate) :ARG1-of (m2 / mean-01 :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c4 / concentration-quantity :quant (b / between :op1 "2" :op2 "30") :unit n3)))) :op3 (r / resist-01 :ARG1-of (m3 / mean-01 :ARG2 (h4 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (m4 / more-than :op1 (c5 / concentration-quantity :quant "30" :unit n3)))))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / file :mod "1" :ARG1-of (a4 / add-02) :ARG1-of (m6 / mean-01 :ARG2 (f2 / figure :mod "S1")))) :ARG1-of (c / compare-01)) # ::id a_pmid_2514_2146.64 # ::date 2015-06-08T15:23:12 # ::file a_pmid_2514_2146_64.txt # ::snt In general, cell lines sensitive to SCH772984 were also sensitive to trametinib.

Effect of SCH-722984 on BRAF-mutant melanoma cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / multi-sentence :snt1 (s / sensitive-03 :ARG0 (c / cell-line :ARG0-of (s3 / sensitive-03 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) :ARG1 (s2 / small-molecule :name (n / name :op1 "trametinib") :xref (x1 / xref :value "PUBCHEM:11707110" :prob "17.561386")) :ARG1-of (g / general-02) :mod (a / also)) :snt2 (f2 / figure :mod "1" :ARG1-of (d2 / describe-01 :ARG2 (a2 / affect-01 :ARG0 (s5 / small-molecule :name (n3 / name :op1 "SCH-722984")) :ARG1 (c2 / cell-line :mod (m2 / medical-condition :name (n5 / name :op1 "melanoma")) :mod (e / enzyme :name (n4 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) # ::id a_pmid_2514_2146.65 # ::date 2015-06-08T15:35:44 # ::file a_pmid_2514_2146_65.txt # ::snt A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "A") # ::id a_pmid_2514_2146.66 # ::date 2015-06-08T15:37:31 # ::file a_pmid_2514_2146_66.txt # ::snt IC50 (nM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c / concentration-quantity :unit (n / nanomolar))) # ::id a_pmid_2514_2146.67 # ::date 2015-06-08T15:41:35 # ::file a_pmid_2514_2146_67.txt # ::snt 21 BRAF-mutant melanoma cell lines were exposed to 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars) and cell viability determined by ATP-based bioluminescence assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (e / expose-01 :ARG1 (c / cell-line :quant "21" :mod (m3 / medical-condition :name (n5 / name :op1 "melanoma")) :mod (e2 / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (o / or :op1 (s / small-molecule :name (n2 / name :op1 "SCH-722984") :quant (c2 / concentration-quantity :quant (b / between :op1 "0" :op2 "10") :unit (m / micromolar)) :ARG1-of (d / describe-01 :ARG0 (b2 / bar :ARG1-of (b3 / black-04)))) :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib") :quant c2 :ARG1-of (d4 / describe-01 :ARG0 (b4 / bar :ARG1-of (g2 / gray-02))) :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056")))) :op2 (d2 / determine-01 :ARG1 (v / viability :mod c) :instrument (a2 / assay-01 :ARG1 (b5 / bioluminescence) :ARG1-of (b6 / base-02 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "ATP") :xref (x1 / xref :value "PUBCHEM:5957" :prob "14.368295")))))) # ::id a_pmid_2514_2146.68 # ::date 2015-06-08T16:02:35 # ::file a_pmid_2514_2146_68.txt # ::snt Results are the mean of three experiments, performed in duplicates (n = 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (r / result-01 :ARG2 (m / mean :poss (e / experiment-01 :quant "3" :ARG1-of (p / perform-01 :manner (d / duplicate :quant "6"))))) # ::id a_pmid_2514_2146.69 # ::date 2015-06-08T16:07:12 # ::file a_pmid_2514_2146_69.txt # ::snt Error bars are standard deviation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / deviate-01 :ARG1-of (s / standard-02) :domain (b / bar :mod (e / error))) # ::id a_pmid_2514_2146.70 # ::date 2015-06-08T16:10:24 # ::file a_pmid_2514_2146_70.txt # ::snt Non-V600E substitutions are denoted in the bar graph for each corresponding cell line (M420, BRAFL597S; M381, BRAFV600R , M417, BRAFG466E, M414, BRAFV600K). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / denote-01 :ARG1 (s / substitute-01 :ARG2 (m / mutate-01 :value "V600E" :polarity "-") :ARG1-of (c / correspond-02 :ARG2 (c2 / cell-line))) :location (g / graph :mod (b / bar)) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (c3 / correspond-02 :ARG1 (c4 / cell-line :name (n / name :op1 "M420")) :ARG2 (e / enzyme :name (n5 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "L597S") :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (c5 / correspond-02 :ARG1 (c8 / cell-line :name (n2 / name :op1 "M381")) :ARG2 (e2 / enzyme :name (n6 / name :op1 "BRAF") :ARG2-of (m4 / mutate-01 :value "V600R") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op3 (c6 / correspond-02 :ARG1 (c9 / cell-line :name (n3 / name :op1 "M417")) :ARG2 (e3 / enzyme :name (n7 / name :op1 "BRAF") :ARG2-of (m5 / mutate-01 :value "G466E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op4 (c7 / correspond-02 :ARG1 (c10 / cell-line :name (n4 / name :op1 "M414")) :ARG2 (e4 / enzyme :name (n8 / name :op1 "BRAF") :ARG2-of (m6 / mutate-01 :value "V600K") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) # ::id a_pmid_2514_2146.71 # ::date 2015-06-09T09:52:56 # ::file a_pmid_2514_2146_71.txt # ::snt Bar at 1 μM denotes threshold between sensitive and intermediate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / denote-01 :ARG0 (b / bar :quant (c / concentration-quantity :quant "1" :unit (m / micromolar))) :ARG1 (t / threshold :topic (b2 / between :op1 (s / sensitive-03) :op2 (i / intermediate)))) # ::id a_pmid_2514_2146.72 # ::date 2015-06-09T10:12:32 # ::file a_pmid_2514_2146_72.txt # ::snt Resistant cell lines have IC50 higher than 2 μM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (c / cell-line :ARG0-of (r / resist-01)) :ARG2 "50" :ARG4 (m / more-than :op1 (c2 / concentration-quantity :quant "2" :unit (m2 / micromolar)))) # ::id a_pmid_2514_2146.73 # ::date 2015-06-09T10:32:40 # ::file a_pmid_2514_2146_73.txt # ::snt B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "B") # ::id a_pmid_2514_2146.74 # ::date 2015-06-09T10:37:43 # ::file a_pmid_2514_2146_74.txt # ::snt Timecourse effects of SCH722984 on the MAPK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "SCH722984")) :ARG1 (s2 / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "MAPK"))) :mod (t / timecourse)) # ::id a_pmid_2514_2146.75 # ::date 2015-06-09T10:43:47 # ::file a_pmid_2514_2146_75.txt # ::snt SCH722984-sensitive M238, SCH722984-resistant M233, were treated in a timecourse manner with 500nM SCH722984 at 1, 2, 6, 12, 24 and 48 hours compared to DMSO as solvent control (C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "M238") :ARG0-of (s2 / sensitive-03 :ARG1 (s / small-molecule :name (n2 / name :op1 "SCH722984")))) :op2 (c2 / cell-line :name (n3 / name :op1 "M233") :ARG0-of (r / resist-01 :ARG1 s))) :ARG2 (s3 / small-molecule :name (n4 / name :op1 "SCH722984") :quant (c5 / concentration-quantity :quant "500" :unit (n5 / nanomolar)) :ARG1-of (c3 / compare-01 :ARG2 (s5 / small-molecule :name (n6 / name :op1 "DMSO") :ARG0-of (c4 / control-01 :ARG1 (d / dissolve-01)) :xref (x / xref :value "PUBCHEM:679" :prob "16.740406")))) :time (a2 / after :op1 (a3 / and :op1 (t2 / temporal-quantity :quant "1" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "2" :unit h) :op3 (t4 / temporal-quantity :quant "6" :unit h) :op4 (t5 / temporal-quantity :quant "12" :unit h) :op5 (t6 / temporal-quantity :quant "24" :unit h) :op6 (t7 / temporal-quantity :quant "48" :unit h))) :manner (t8 / timecourse)) # ::id a_pmid_2514_2146.76 # ::date 2015-06-09T11:43:33 # ::file a_pmid_2514_2146_76.txt # ::snt Phosphorylated or total MEK, ERK1/2, RSK, AKT, or beta-actin as loading control were determined by western blot analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / determine-01 :ARG1 (o / or :op1 (a / and :op1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x6 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of p) :op3 (e3 / enzyme :name (n3 / name :op1 "RSK") :ARG3-of p :xref (x5 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e4 / enzyme :name (n4 / name :op1 "AKT") :ARG3-of p :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op2 (a2 / and :op1 (e8 / enzyme :name (n8 / name :op1 "MEK") :mod (t / total) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e7 / enzyme :name (n7 / name :op1 "ERK1/2") :mod t) :op3 (e6 / enzyme :name (n6 / name :op1 "RSK") :mod t :xref (x4 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e5 / enzyme :name (n5 / name :op1 "AKT") :mod t :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op3 (p2 / protein :name (n9 / name :op1 "beta-actin") :ARG0-of (c / control-01 :ARG1 (l / load-01)) :xref (x / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702"))) :manner (a3 / analyze-01 :manner (i / immunoblot-01))) # ::id a_pmid_2514_2146.77 # ::date 2015-06-09T12:17:16 # ::file a_pmid_2514_2146_77.txt # ::snt C. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "C") # ::id a_pmid_2514_2146.78 # ::date 2015-06-09T12:17:50 # ::file a_pmid_2514_2146_78.txt # ::snt Effects of SCH722984 on the MAPK signaling at 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (a2 / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "SCH722984")) :ARG1 (s2 / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "MAPK"))) :time (a / after :quant (t / temporal-quantity :quant "24" :unit (h / hour)))) # ::id a_pmid_2514_2146.79 # ::date 2015-06-09T12:20:29 # ::file a_pmid_2514_2146_79.txt # ::snt SCH722984-sensitive M262, SCH722984-resistant M381, SCH722984-intermediately sensitive M409 cells were treated for 24 h with DMSO as solvent control (-) or 500 nM SCH722984 (+).

# ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "M262") :ARG0-of (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "SCH722984")))) :op2 (c2 / cell-line :name (n3 / name :op1 "M381") :ARG0-of (r / resist-01 :ARG1 s2)) :op3 (c3 / cell-line :name (n4 / name :op1 "M409") :ARG0-of (s3 / sensitive-03 :ARG1 s2 :mod (i / intermediate)))) :ARG2 (o / or :op1 (s4 / small-molecule :name (n5 / name :op1 "DMSO") :ARG0-of (c4 / control-01 :ARG1 (d / dissolve-01)) :xref (x / xref :value "PUBCHEM:679" :prob "16.740406")) :op2 (s5 / small-molecule :name (n6 / name :op1 "SCH722984") :quant (c5 / concentration-quantity :quant "500" :unit (n7 / nanomolar)))) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour))) # ::id a_pmid_2514_2146.80 # ::date 2015-06-09T12:37:21 # ::file a_pmid_2514_2146_80.txt # ::snt We next determined a time-course of SCH772984 on MAPK and PI3K/AKT pathway signaling for M238, a SCH772984-sensitive BRAFV600E-mutant melanoma cell line and M233, a SCH772984-resistant BRAFV600E-mutant melanoma cell line (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (d / determine-01 :ARG0 (w / we) :ARG1 (t / timecourse :poss (s / small-molecule :name (n2 / name :op1 "SCH772984") :ARG2-of (t2 / treat-04 :ARG1 (a / and :op1 (p / pathway :name (n4 / name :op1 "MAPK") :ARG0-of (s2 / signal-07)) :op2 (p2 / pathway :name (n5 / name :op1 "PI3K/AKT") :ARG0-of s2))) :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :beneficiary (a2 / and :op1 (c2 / cell-line :name (n6 / name :op1 "M238") :ARG2-of (m / mean-01 :ARG1 (c3 / cell-line :ARG0-of (s3 / sensitive-03 :ARG1 s) :mod (g / gene :name (n7 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma"))))) :op2 (c5 / cell-line :name (n8 / name :op1 "M233") :ARG1-of (m4 / mean-01 :ARG2 (c4 / cell-line :ARG0-of (r / resist-01 :ARG1 s) :mod m2 :mod g))))) :time (n / next) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id a_pmid_2514_2146.81 # ::date 2015-06-09T13:23:01 # ::file a_pmid_2514_2146_81.txt # ::snt For both M233 and M238, treatment with 500nM SCH772984 inhibited pRSK, a known ERK1/2 downstream target, as well as pERK1/2 itself. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (i / inhibit-01 :ARG0 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n2 / name :op1 "M233")) :op2 (c2 / cell-line :name (n3 / name :op1 "M238"))) :ARG2 (s / small-molecule :name (n / name :op1 "SCH772984") :quant (c3 / concentration-quantity :quant "500" :unit (n4 / nanomolar)) :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG1 (a2 / and :op1 (e / enzyme :name (n5 / name :op1 "RSK") :ARG3-of (p / phosphorylate-01) :ARG1-of (t2 / target-01 :ARG0 (e3 / enzyme :name (n7 / name :op1 "ERK1/2")) :ARG1-of (k / know-01) :location (d / downstream)) :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n6 / name :op1 "ERK1/2") :ARG3-of p))) # ::id a_pmid_2514_2146.82 # ::date 2015-06-09T14:07:27 # ::file a_pmid_2514_2146_82.txt # ::snt For the resistant M233, the MAPK inhibition was strong as early as 1 hour post treatment, with decreased pERK and near-complete disappearance of pRSK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (s / strong :domain (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MAPK") :part-of (c / cell-line :name (n2 / name :op1 "M233") :ARG0-of (r / resist-01)))) :time (a / after :op1 (t / treat-04) :quant (t2 / temporal-quantity :quant "1" :unit (h / hour)))) :op2 (d / decrease-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :part-of c :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op3 (d2 / disappear-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "RSK") :ARG3-of p2 :part-of c :xref (x1 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :ARG1-of (c2 / complete-01 :degree (n4 / near)))) # ::id a_pmid_2514_2146.83 # ::date 2015-06-09T14:18:38 # ::file a_pmid_2514_2146_83.txt # ::snt However, between 12 and 24 hours we observe a rebound in the pathway with a return to baseline pERK1/2 levels and an induction in pMEK above baseline levels by 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (h3 / have-concession-91 :ARG2 (o / observe-01 :ARG0 (w / we) :ARG1 (r / rebound-01 :ARG1 (p / pathway) :ARG0-of (c2 / cause-01 :ARG1 (a / and :op1 (r2 / return-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)) :mod (b2 / baseline))) :op2 (i / induce-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of p2 :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG2 (a2 / above :op1 (l2 / level :quant-of e2 :mod b2))) :time (a3 / after :quant (t3 / temporal-quantity :quant "24" :unit (h2 / hour)))))) :time (b / between :op1 (t / temporal-quantity :quant "12" :unit (h / hour)) :op2 (t2 / temporal-quantity :quant "24" :unit h)))) # ::id a_pmid_2514_2146.84 # ::date 2015-06-09T14:35:03 # ::file a_pmid_2514_2146_84.txt # ::snt Little change in pAKT was seen at any timepoint up to 24 hours, though a mild induction was seen at 48 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / see-01 :ARG1 (c / change-01 :ARG1 (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :mod (l / little)) :time (t / timepoint :mod (a / any) :quant (u / up-to :op1 (t2 / temporal-quantity :quant "24" :unit (h / hour)))) :concession (s2 / see-01 :ARG1 (i / induce-01 :ARG2 e :degree (m / mild)) :time (a2 / after :op1 (t3 / temporal-quantity :quant "48" :unit h)))) # ::id a_pmid_2514_2146.85 # ::date 2015-06-09T14:42:33 # ::file a_pmid_2514_2146_85.txt # ::snt For the sensitive M238, pRSK levels also decreased as early as 1 hour and levels continued to decrease thereafter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (a / and :op1 (d / decrease-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "RSK") :ARG3-of (p / phosphorylate-01) :part-of (c / cell-line :name (n2 / name :op1 "M238") :ARG0-of (s / sensitive-03)) :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262"))) :mod (a2 / also) :time (a3 / after :op1 (t / temporal-quantity :quant "1" :unit (h / hour)))) :op2 (c2 / continue-01 :ARG1 (d2 / decrease-01 :ARG1 l) :time (t2 / thereafter))) # ::id a_pmid_2514_2146.86 # ::date 2015-06-09T14:51:34 # ::file a_pmid_2514_2146_86.txt # ::snt Meanwhile, pERK1/2 remained suppressed through 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (r / remain-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG3 (s / suppress-01 :ARG1 e) :duration (t / temporal-quantity :quant "24" :unit (h / hour)) :time (m / meanwhile)) # ::id a_pmid_2514_2146.87 # ::date 2015-06-09T14:54:51 # ::file a_pmid_2514_2146_87.txt # ::snt By 48 hours, pERK1/2 levels increased, though at reduced levels compared to baseline. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (i / increase-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :time (a / after :op1 (t / temporal-quantity :quant "48" :unit (h / hour))) :concession (l2 / level :ARG1-of (r / reduce-01 :ARG1-of (c / compare-01 :ARG2 (b / baseline))))) # ::id a_pmid_2514_2146.88 # ::date 2015-06-09T15:01:39 # ::file a_pmid_2514_2146_88.txt # ::snt Concomitant with this, pMEK levels remained unchanged until 24 hours and increased further by 48 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (a / and :op1 (r / remain-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG3 (c / change-01 :polarity "-" :ARG1 l) :time (u / until :op1 (t / temporal-quantity :quant "24" :unit (h / hour)))) :op2 (i / increase-01 :ARG1 l :time (a2 / after :op1 (t2 / temporal-quantity :quant "48" :unit h)) :degree (f / further)) :manner (c2 / concomitant :prep-with (t3 / this))) # ::id a_pmid_2514_2146.89 # ::date 2015-06-09T15:11:28 # ::file a_pmid_2514_2146_89.txt # ::snt Regarding pAKT, an early induction at 1 hour occurred, followed by decreases thereafter though never becoming completely suppressed even at 48 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG2 (e2 / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :time (e / early) :time (a / after :op1 (t / temporal-quantity :quant "1" :unit (h / hour))) :ARG2-of (f / follow-01 :ARG1 (d / decrease-01 :ARG1 e :time (t2 / thereafter) :concession (b / become-01 :polarity "-" :ARG1 e2 :ARG2 (s / suppress-01 :ARG1 e2 :time (a2 / after :op1 (t3 / temporal-quantity :quant "48" :unit h)) :mod (e4 / even) :degree (c / complete)) :time (e3 / ever))))) # ::id a_pmid_2514_2146.90 # ::date 2015-06-08T13:42:46 # ::file a_pmid_2514_2146_90.txt # ::snt In both cell lines, pRSK remained blocked at all timepoints, demonstrating ongoing, potent inhibition of ERK1/2 activity by SCH772984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / remain-01 :ARG1 (p / protein :name (n / name :op1 "pRSK")) :ARG3 (b / block-01 :ARG1 p :ARG0-of (d / demonstrate-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "SCH772984") :xref (x / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n2 / name :op1 "ERK1/2"))) :ARG1-of (g / go-on-15) :mod (p2 / potent)) :time (t / timepoint :mod (a / all)))) :location (c2 / cell-line :mod (b2 / both))) # ::id a_pmid_2514_2146.91 # ::date 2015-06-08T14:20:49 # ::file a_pmid_2514_2146_91.txt # ::snt These data supports that the distinction between sensitive and resistant cell lines could be best made based on pERK recovery at 24 hours, as recovery of the feedback loop that restores MAPK activity occurred by 24 hours in the resistant cell line whereas the sensitive cell line required longer than 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / support-01 :ARG0 (d2 / data :mod (t2 / this)) :ARG1 (p / possible-01 :ARG1 (b / base-02 :ARG1 (d / distinguish-01 :ARG1 (a / and :op1 (c / cell-line :ARG0-of (s2 / sensitive-03)) :op2 (c2 / cell-line :ARG0-of (r / resist-01)))) :ARG2 (r2 / recover-02 :ARG0 (e / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :time (a3 / after :op1 (t / temporal-quantity :quant "24" :unit (h / hour))) :ARG1-of (m3 / mean-01 :ARG2 (r5 / recover-02 :ARG0 (l / loop :mod (f / feedback) :ARG0-of (r3 / restore-01 :ARG1 (a2 / activity-06 :ARG0 (p2 / pathway :name (n / name :op1 "MAPK"))) :location c2 :ARG1-of (c3 / contrast-01 :ARG2 (r4 / require-01 :ARG0 c :ARG1 (l2 / long-03 :ARG2 t :degree (m2 / more)))) :time a3))))) :ARG1-of (g / good-02 :degree (m / most))))) # ::id a_pmid_2514_2146.92 # ::date 2015-06-09T10:34:09 # ::file a_pmid_2514_2146_92.txt # ::snt Therefore, for subsequent analyses, we selected 24 hours as the optimal timepoint to compare signaling in our cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / cause-01 :ARG1 (s / select-01 :ARG0 (w / we) :ARG1 (t / temporal-quantity :quant "24" :unit (h / hour)) :ARG3 (t2 / timepoint :mod (o / optimal)) :purpose (c2 / compare-01 :ARG0 w :ARG1 (s2 / signal-07 :location (c3 / cell-line :poss w))) :purpose (a / analyze-01 :ARG0 w :time (s3 / subsequent)))) # ::id a_pmid_2514_2146.93 # ::date 2015-06-09T10:47:48 # ::file a_pmid_2514_2146_93.txt # ::snt As shown in Figure 1C, three BRAF mutant cell lines representative of the different sensitivity groups to SCH772984 were profiled in terms of downstream signaling inhibition at 24 hours: a highly sensitive cell line (M262, BRAFV600E), an intermediately sensitive cell line (M409, BRAFV600E), and a resistant cell line (M381, BRAFV600R). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p2 / profile-01 :ARG1 (c / cell-line :quant "3" :ARG0-of (r2 / represent-01 :ARG1 (g / group :ARG1-of (d2 / differ-02) :ARG0-of (s / sensitive-03 :ARG1 (s6 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134"))))) :ARG1-of (m7 / mean-01 :ARG2 (a / and :op1 (c3 / cell-line :ARG0-of (s3 / sensitive-03 :ARG1-of (h2 / high-02)) :ARG1-of (m2 / mean-01 :ARG2 (c4 / cell-line :name (n3 / name :op1 "M262") :mod (g2 / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "V600E") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :op2 (c5 / cell-line :ARG0-of (s4 / sensitive-03 :mod (i2 / intermediate)) :ARG1-of (m4 / mean-01 :ARG2 (c6 / cell-line :name (n5 / name :op1 "M409") :mod g2))) :op3 (c7 / cell-line :ARG0-of (r4 / resist-01) :ARG1-of (m5 / mean-01 :ARG2 (c8 / cell-line :name (n6 / name :op1 "M381") :mod (g4 / gene :name (n7 / name :op1 "BRAF") :ARG2-of (m6 / mutate-01 :value "V600R") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) :mod (g3 / gene :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :topic (i / inhibit-01 :ARG1 (s2 / signal-07 :location (d / downstream)) :time (a2 / after :op1 (t / temporal-quantity :quant "24" :unit (h / hour)))) :ARG1-of (s5 / show-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2514_2146.94 # ::date 2015-06-09T11:23:26 # ::file a_pmid_2514_2146_94.txt # ::snt For M262, treatment with SCH772984 resulted in disappearance of pRSK, disappearance of pERK1/2, decrease in pAKT, and slight induction of pMEK at 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (t2 / treat-04 :ARG1 (c / cell-line :name (n / name :op1 "M262")) :ARG2 (s / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG2 (a / and :op1 (d / disappear-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "RSK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262"))) :op2 (d2 / disappear-01 :ARG1 (e / enzyme :name (n4 / name :op1 "ERK1/2") :ARG3-of p2)) :op3 (d3 / decrease-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "AKT") :ARG3-of p2 :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op4 (i / induce-01 :ARG2 (e3 / enzyme :name (n6 / name :op1 "MEK") :ARG3-of p2 :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :degree (s2 / slight)) :time (a2 / after :op1 (t / temporal-quantity :quant "24" :unit (h / hour))))) # ::id a_pmid_2514_2146.95 # ::date 2015-06-09T11:33:05 # ::file a_pmid_2514_2146_95.txt # ::snt M409 had a similar cell signaling profile as M262, consistent with its modest sensitivity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (h / have-03 :ARG0 (c / cell-line :name (n / name :op1 "M409")) :ARG1 (p / profile-01 :ARG0-of (s / signal-07 :ARG1 (c2 / cell)) :ARG1-of (r / resemble-01 :ARG2 (c3 / cell-line :name (n2 / name :op1 "M262"))) :ARG1-of (c4 / consistent-01 :ARG2 (s2 / sensitive-03 :ARG0 p :mod (m / modest))))) # ::id a_pmid_2514_2146.96 # ::date 2015-06-09T11:39:15 # ::file a_pmid_2514_2146_96.txt # ::snt For M381induction of pMEK and pERK1/2 were seen with no change in pRSK at 24 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / see-01 :ARG1 (i / induce-01 :ARG2 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of p)) :location (c2 / cell-line :name (n4 / name :op1 "M381"))) :ARG2 (c / change-01 :polarity "-" :ARG1 (e3 / enzyme :name (n3 / name :op1 "RSK") :ARG3-of p :xref (x1 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262"))) :time (a / after :op1 (t / temporal-quantity :quant "24" :unit (h / hour)))) # ::id a_pmid_2514_2146.97 # ::date 2015-06-09T11:47:25 # ::file a_pmid_2514_2146_97.txt # ::snt To determine the effect of SCH772984 on the PI3K/AKT pathway, we first evaluated the baseline pAKT levels for a group of cell lines (Additional file 2: Figure S2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (e / evaluate-01 :ARG0 (w / we) :ARG1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :part-of (g / group :consist-of (c / cell-line)) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :mod (b / baseline)) :purpose (d / determine-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1 (p / pathway :name (n / name :op1 "PI3K/AKT")))) :ARG1-of (d2 / describe-01 :ARG0 (f / file :mod "2" :ARG1-of (m / mean-01 :ARG2 (f2 / figure :mod "S2")) :ARG1-of (a3 / add-02))) :time (f3 / first)) # ::id a_pmid_2514_2146.98 # ::date 2015-06-09T12:08:35 # ::file a_pmid_2514_2146_98.txt # ::snt We found a weak correlation with the activity of the PI3K/AKT pathway and sensitivity to SCH772984 for BRAF mutants. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (c / correlate-01 :ARG1 "e" :ARG2 (a / activity-06 :ARG0 (p / pathway :name (n / name :op1 "PI3K/AKT"))) :ARG1-of (w2 / weak-02)) :op2 (s / sensitive-03 :ARG0 (e / enzyme :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134"))))) # ::id a_pmid_2514_2146.99 # ::date 2015-06-09T12:12:03 # ::file a_pmid_2514_2146_99.txt # ::snt For example, M238 and M409 are two clear examples of cell lines with low levels of pAKT related to sensitivity to SCH772984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (a2 / and :op1 (c / cell-line :name (n / name :op1 "M238")) :op2 (c2 / cell-line :name (n2 / name :op1 "M409")) :ARG0-of (e2 / exemplify-01 :quant "2" :ARG1 (c3 / cell-line :ARG0-of (h / have-03 :ARG1 (l / level :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (l2 / low-04)))) :ARG1-of (c4 / clear-06)) :ARG1-of (r / relate-01 :ARG2 (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) :ARG0-of (e / exemplify-01)) # ::id a_pmid_2514_2146.100 # ::date 2015-06-09T12:17:57 # ::file a_pmid_2514_2146_100.txt # ::snt For both of them, ERK inhibition with SCH772984 was accompanied by an upregulation of pAKT levels even at 24 hours treatment (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / accompany-01 :ARG0 (u / upregulate-01 :ARG1 (l / level :quant-of (e3 / enzyme :name (n4 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :time (a2 / after :op1 (t2 / treat-04) :mod (e / even) :quant (t / temporal-quantity :quant "24" :unit (h / hour))) :beneficiary (t3 / they :mod (b / both)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id a_pmid_2514_2146.101 # ::date 2015-06-09T12:37:14 # ::file a_pmid_2514_2146_101.txt # ::snt M233 was among the resistant BRAFV600E melanoma cell lines, which appeared to have increased pAKT at baseline compared to other BRAF mutant cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c4 / cell-line :name (n5 / name :op1 "M233") :ARG0-of (h / have-03 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :ARG1-of (i2 / increase-01 :location (b / baseline) :compared-to (c3 / cell-line :mod (g2 / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (o / other))) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (a / appear-01)) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :mod (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (m4 / medical-condition :name (n / name :op1 "melanoma")))) :ARG0-of (r / resist-01)) # ::id a_pmid_2514_2146.102 # ::date 2015-06-09T12:44:42 # ::file a_pmid_2514_2146_102.txt # ::snt Consistent with this, M233 is a PTEN null cell line and has a concomitant AKT1 amplification [31]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (c2 / cell-line :mod (n2 / null) :mod (p / protein :name (n3 / name :op1 "PTEN") :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :domain (c / cell-line :name (n / name :op1 "M233"))) :op2 (h / have-03 :ARG0 c :ARG1 (a2 / amplify-01 :ARG1 (g / gene :name (n4 / name :op1 "AKT1") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.004")) :mod (c3 / concomitant))) :ARG1-of (c4 / consistent-01 :ARG2 (t / this)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "31")))) # ::id a_pmid_2514_2146.103 # ::date 2015-06-09T12:56:40 # ::file a_pmid_2514_2146_103.txt # ::snt After treatment with SCH772984 (Figure 1B), these levels stay constant, indicating that dual inhibition with SCH772984 and AKT/mTOR inhibitors may be a useful strategy. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / stay-01 :ARG1 (l / level :mod (t2 / this)) :ARG3 (c / constant) :ARG0-of (i2 / indicate-01 :ARG1 (s2 / strategy :domain (a / and :op1 (i3 / inhibit-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "SCH772984") :xref (x / xref :value "PUBCHEM:24866313" :prob "19.266134")) :mod (d2 / dual)) :op2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "AKT/mTOR"))))) :ARG1-of (u / useful-05) :ARG1-of (p / possible-01))) :time (a2 / after :op1 (t3 / treat-04 :ARG2 s3) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1B")))) # ::id a_pmid_2514_2146.104 # ::date 2015-06-09T13:11:03 # ::file a_pmid_2514_2146_104.txt # ::snt In contrast, M262 is an AKT1 amplified cell line [31] with high sensitivity to SCH772984 and vemurafenib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (c2 / cell-line :ARG1-of (a / amplify-01 :ARG0 (g / gene :name (n / name :op1 "AKT1") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.004"))) :domain (c3 / cell-line :name (n2 / name :op1 "M262") :ARG0-of (s / sensitive-03 :ARG1 (a2 / and :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :op2 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :ARG1-of (h / high-02))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c4 / cite-01 :ARG2 "31"))))) # ::id a_pmid_2514_2146.105 # ::date 2015-06-09T13:15:15 # ::file a_pmid_2514_2146_105.txt # ::snt Treatment of M262 with SCH772984 reduced both pERK1/2 and pAKT levels, indicating blockade of the MAPK pathway and PI3K/AKT pathway at the same time (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (r / reduce-01 :ARG0 (t2 / treat-04 :ARG1 (c / cell-line :name (n3 / name :op1 "M262")) :ARG2 (s2 / small-molecule :name (n4 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG1 (a / and :op1 (l / level :quant-of (e / enzyme :name (n5 / name :op1 "ERK1/2") :ARG3-of (p3 / phosphorylate-01))) :op2 (l2 / level :quant-of (e2 / enzyme :name (n6 / name :op1 "AKT") :ARG3-of p3 :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :ARG0-of (i / indicate-01 :ARG1 (b / blockade-01 :ARG1 (a2 / and :op1 (p / pathway :name (n / name :op1 "MAPK")) :op2 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT"))) :time (t3 / time :ARG1-of (s3 / same-01)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2514_2146.106 # ::date 2015-06-09T13:20:27 # ::file a_pmid_2514_2146_106.txt # ::snt In general, the presence of AKT1 or AKT2 amplification did not preclude sensitivity to SCH772984, as three of five such cell lines were highly sensitive to SCH772984 (M229, M249, and M262), one was intermediately sensitive (M255), and M233 and M308 were resistant (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / preclude-01 :polarity "-" :ARG0 (a / amplify-01 :ARG1 (a2 / and :op1 (g2 / gene :name (n / name :op1 "AKT1") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.004")) :op2 (g3 / gene :name (n2 / name :op1 "AKT2") :xref (x / xref :value "UNIPROT:AKT2_HUMAN" :prob "1.004")))) :ARG1 (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG1-of (c / cause-01 :ARG0 (a3 / and :op1 (s3 / sensitive-03 :ARG0 (c2 / cell-line :quant "3" :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "5")) :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (c4 / cell-line :name (n5 / name :op1 "M229")) :op2 (c5 / cell-line :name (n6 / name :op1 "M249")) :op3 (c6 / cell-line :name (n7 / name :op1 "M262"))))) :ARG1 s2 :ARG1-of (h / high-02)) :op2 (c7 / cell-line :quant "1" :ARG0-of (s5 / sensitive-03 :ARG1 s2 :mod (i2 / intermediate)) :ARG1-of (m2 / mean-01 :ARG2 (c8 / cell-line :name (n8 / name :op1 "M255")))) :op3 (a5 / and :op1 (c9 / cell-line :name (n9 / name :op1 "M233")) :op2 (c10 / cell-line :name (n10 / name :op1 "M308")) :ARG0-of (r / resist-01 :ARG1 s2)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A")) :ARG1-of (g / general-02)) # ::id a_pmid_2514_2146.107 # ::date 2015-06-09T13:37:14 # ::file a_pmid_2514_2146_107.txt # ::snt Given high baseline pAKT levels were seen in some cells resistant to ERK inhibition (Additional file 2: Figure S2) and the persistence of pAKT activity with SCH722984 treatment, we evaluated the effect of SCH772984 in combination with the AKT inhibitor MK-2206 or the mTOR inhibitor MK-8669. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / cause-01 :ARG0 (a / and :op1 (s / see-01 :ARG1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :mod (b / baseline) :ARG1-of (h / high-02)) :location (c2 / cell :quant (s2 / some) :ARG0-of (r / resist-01 :ARG1 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "2" :ARG1-of (m / mean-01 :ARG2 (f2 / figure :mod "S2")) :ARG1-of (a5 / add-02)))) :op2 (p2 / persist-01 :ARG1 (a2 / activity-06 :ARG0 (e4 / enzyme :name (n4 / name :op1 "AKT") :ARG3-of (p3 / phosphorylate-01) :ARG1-of (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "SCH722984"))) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))))) :ARG1 (e5 / evaluate-01 :ARG0 (w / we) :ARG1 (a4 / affect-01 :ARG0 (s4 / small-molecule :name (n6 / name :op1 "SCH772984") :ARG1-of (c3 / combine-01 :ARG2 (o / or :op1 (s6 / small-molecule :name (n7 / name :op1 "MK-2206") :ARG0-of (i3 / inhibit-01 :ARG1 (e6 / enzyme :name (n8 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :xref (x5 / xref :value "PUBCHEM:24964624" :prob "17.692984")) :op2 (s5 / small-molecule :name (n9 / name :op1 "MK-8669") :ARG0-of (i4 / inhibit-01 :ARG1 (p4 / protein :name (n10 / name :op1 "mTOR") :xref (x4 / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004"))) :xref (x6 / xref :value "PUBCHEM:11520894" :prob "18.333639")))) :xref (x7 / xref :value "PUBCHEM:24866313" :prob "19.266134"))))) # ::id a_pmid_2514_2146.108 # ::date 2015-06-09T13:50:54 # ::file a_pmid_2514_2146_108.txt # ::snt The addition of either the AKTi or mTORi always resulted in more potent cell growth inhibition compared to ERKi alone (Additional file 3: Figures S3A and 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (a / add-02 :ARG1 (o / or :op1 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "AKT")))) :op2 (m4 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein :name (n2 / name :op1 "mTOR") :xref (x1 / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")))))) :ARG2 (i3 / inhibit-01 :ARG1 (g / grow-01 :ARG1 (c / cell)) :mod (p2 / potent :mod (m / more)) :compared-to (m5 / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK") :mod (a3 / alone) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :time (a2 / always) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "3" :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (f2 / figure :mod "S3A") :op2 (f3 / figure :mod "S3B"))) :ARG1-of (a6 / add-02)))) # ::id a_pmid_2514_2146.109 # ::date 2015-06-09T14:04:24 # ::file a_pmid_2514_2146_109.txt # ::snt Combining SCH772984 with the mTOR inhibitor MK-8669 was particularly synergistic. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s2 / synergize-01 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "MK-8669") :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein :name (n3 / name :op1 "mTOR") :xref (x / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004"))) :xref (x1 / xref :value "PUBCHEM:11520894" :prob "18.333639"))) :mod (p2 / particular)) # ::id a_pmid_2514_2146.110 # ::date 2015-06-09T14:07:27 # ::file a_pmid_2514_2146_110.txt # ::snt For BRAF-mutant cell line M233, both combinations resulted in more complete decrease in pERK compared to treatment with SCH772984 alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / result-01 :ARG1 (c / combine-01 :mod (b / both)) :ARG2 (d / decrease-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :degree (c2 / complete :mod (m / more)) :compared-to (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "SCH772984") :mod (a / alone) :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) :beneficiary (c3 / cell-line :name (n3 / name :op1 "M233") :mod (e2 / enzyme :name (n4 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) # ::id a_pmid_2514_2146.111 # ::date 2015-06-09T14:14:59 # ::file a_pmid_2514_2146_111.txt # ::snt Despite the improved inhibition of the MAPK pathway, the levels of pAKT were largely unaffected by the addition of MK-2206 or MK-8669 (Additional file 3: Figure S3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (h / have-concession-91 :ARG1 (a / affect-01 :polarity "-" :ARG0 (a2 / add-02 :ARG1 (o / or :op1 (s / small-molecule :name (n3 / name :op1 "MK-2206") :xref (x2 / xref :value "PUBCHEM:24964624" :prob "17.692984")) :op2 (s2 / small-molecule :name (n4 / name :op1 "MK-8669") :xref (x1 / xref :value "PUBCHEM:11520894" :prob "18.333639")))) :ARG1 (l / level :quant-of (e / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :degree (l2 / large)) :ARG2 (i / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :ARG1-of (i2 / improve-01)) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "3" :ARG1-of (m3 / mean-01 :ARG2 (f2 / figure :mod "S3C")) :ARG1-of (a4 / add-02)))) # ::id a_pmid_2514_2146.112 # ::date 2015-06-09T14:34:19 # ::file a_pmid_2514_2146_112.txt # ::snt Potent SCH772984-mediated ERK inhibition in BRAF-wild type melanoma cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (m / mediate-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :location (c / cell-line :mod (m2 / melanoma :mod (g / gene :name (n3 / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :mod (p / potent)) # ::id a_pmid_2514_2146.113 # ::date 2015-06-09T14:37:53 # ::file a_pmid_2514_2146_113.txt # ::snt Currently, there is no effective targeted therapy for BRAF wild-type melanoma, which comprises 50% of all melanomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (t3 / therapy :polarity "-" :ARG0-of (a / affect-01) :ARG1-of (t2 / target-01) :ARG1-of (c2 / comprise-01 :ARG2 (m / medical-condition :name (n3 / name :op1 "melanoma") :ARG1-of (i / include-91 :ARG2 (m2 / medical-condition :name (n4 / name :op1 "melanoma") :mod (a2 / all)) :ARG3 (p / percentage-entity :value "50")))) :time (c / current) :beneficiary (m4 / medical-condition :name (n2 / name :op1 "melanoma") :mod (g / gene :name (n / name :op1 "BRAF") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) # ::id a_pmid_2514_2146.114 # ::date 2015-06-09T14:48:52 # ::file a_pmid_2514_2146_114.txt # ::snt Fourteen NRAS mutant melanoma and seven cells lines with wild-type BRAF and NRAS were evaluated for SCH772984 sensitivity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (e / evaluate-01 :ARG1 (a / and :op1 (m3 / medical-condition :quant "14" :name (n5 / name :op1 "melanoma") :mod (e2 / enzyme :name (n / name :op1 "NRAS") :ARG2-of (m2 / mutate-01) :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :op2 (c / cell-line :quant "7" :ARG0-of (h / have-03 :ARG1 (a2 / and :op1 (g / gene :name (n2 / name :op1 "BRAF") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n3 / name :op1 "NRAS") :mod w :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))))) :purpose (s / sensitive-03 :ARG0 a :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH772984") :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) # ::id a_pmid_2514_2146.115 # ::date 2015-06-09T14:52:25 # ::file a_pmid_2514_2146_115.txt # ::snt As shown in Figure 2A, while all NRAS-mutant cell lines were resistant to vemurafenib, 11 of 14 were highly sensitive to SCH772984 (IC50 < 1 μM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / contrast-01 :ARG1 (r / resist-01 :ARG0 (c2 / cell-line :mod (a / all) :mod (g / gene :name (n / name :op1 "NRAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :ARG1 (s / small-molecule :name (n2 / name :op1 "vemurafenib") :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :ARG2 (s2 / sensitive-03 :ARG0 (c3 / cell-line :quant "11" :ARG1-of (i / include-91 :ARG2 (c4 / cell-line :quant "14" :mod m))) :ARG1 (s3 / small-molecule :name (n3 / name :op1 "SCH772984") :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (l / less-than :op1 (c5 / concentration-quantity :quant "1" :unit (m3 / micromolar)))) :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1-of (h / high-02)) :ARG1-of (s4 / show-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2514_2146.116 # ::date 2015-06-09T15:17:27 # ::file a_pmid_2514_2146_116.txt # ::snt Across the 11 NRAS sensitive cell lines, two of them were Q61L (M296 and M311), four were Q61K (M408, Sbcl2, WM1366, M245 and M244), one was Q61H (M243) and three were Q61R (SKMEL173, M296 and M412a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 15, 2015 (a2 / and :op1 (c3 / cell-line :quant "2" :ARG1-of (m / mutate-01 :value "Q61L") :ARG1-of (m5 / mean-01 :ARG2 (a3 / and :op1 (c5 / cell-line :name (n3 / name :op1 "M296")) :op2 (c6 / cell-line :name (n4 / name :op1 "M311"))))) :op2 (c7 / cell-line :quant "5" :ARG1-of (m2 / mutate-01 :value "Q61K") :ARG1-of (m6 / mean-01 :ARG2 (a4 / and :op1 (c8 / cell-line :name (n5 / name :op1 "M408")) :op2 (c9 / cell-line :name (n6 / name :op1 "Sbcl2")) :op3 (c10 / cell-line :name (n7 / name :op1 "WM1366")) :op4 (c11 / cell-line :name (n8 / name :op1 "M245")) :op5 (c12 / cell-line :name (n9 / name :op1 "M244"))))) :op3 (c13 / cell-line :quant "1" :ARG1-of (m3 / mutate-01 :value "Q61H") :ARG1-of (m7 / mean-01 :ARG2 (c14 / cell-line :name (n10 / name :op1 "M243")))) :op4 (c15 / cell-line :quant "3" :ARG1-of (m4 / mutate-01 :value "Q61R") :ARG1-of (m8 / mean-01 :ARG2 (a5 / and :op1 (c16 / cell-line :name (n11 / name :op1 "SKMEL173")) :op2 c5 :op3 (c18 / cell-line :name (n13 / name :op1 "M412a"))))) :ARG1-of (i2 / include-91 :ARG2 (c4 / cell-line :quant "11" :ARG0-of (s2 / sensitive-03) :mod (e2 / enzyme :name (n2 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))))) # ::id a_pmid_2514_2146.117 # ::date 2015-06-09T15:37:01 # ::file a_pmid_2514_2146_117.txt # ::snt Interestingly, the three cell lines with IC50 > 1uM (M202, M207 and M318) were exclusively NRAS Q61L mutated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / mutate-01 :value "Q61L" :ARG2 (e2 / enzyme :name (n / name :op1 "NRAS") :part-of (c / cell-line :quant "3" :ARG0-of (h / have-03 :ARG1 (c6 / concentrate-02 :quant (m2 / more-than :op1 (c2 / concentration-quantity :quant "1" :unit (m3 / micromolar))) :mod (i2 / inhibit-01 :degree (p / percentage-entity :value "50")))) :ARG1-of (m4 / mean-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n3 / name :op1 "M202")) :op2 (c4 / cell-line :name (n4 / name :op1 "M207")) :op3 (c5 / cell-line :name (n5 / name :op1 "M318"))))) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :ARG0-of (e / exclusive-02) :ARG2-of (i / interest-01)) # ::id a_pmid_2514_2146.118 # ::date 2015-06-09T15:42:35 # ::file a_pmid_2514_2146_118.txt # ::snt Sensitivity to trametinib are shown in Additional file 4: Figures S4A and 4B for NRAS-mutant and wild-type melanoma cell lines, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (f / file :mod "4" :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (f2 / figure :mod "S4A") :op2 (f3 / figure :mod "S4B"))) :ARG1-of (a4 / add-02)) :ARG1 (s2 / sensitive-03 :ARG0 (a3 / and :op1 (c2 / cell-line :mod (e / enzyme :name (n2 / name :op1 "NRAS") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :op2 (c / cell-line :mod (m4 / medical-condition :name (n3 / name :op1 "melanoma") :mod (w / wild-type))) :mod (r / respective)) :ARG1 (s3 / small-molecule :name (n / name :op1 "trametinib") :xref (x1 / xref :value "PUBCHEM:11707110" :prob "17.561386")))) # ::id a_pmid_2514_2146.119 # ::date 2015-06-09T15:47:37 # ::file a_pmid_2514_2146_119.txt # ::snt Consistent with the profile for sensitive cell lines, treatment with SCH772984 for the sensitive M408 resulted in decreased pRSK, disappearance of pERK1/2, and slight induction of pMEK, with no change in total RSK, MEK, ERK 1/2, or AKT. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG1 (c / cell-line :name (n3 / name :op1 "M408") :ARG0-of (s / sensitive-03)) :ARG2 (s2 / small-molecule :name (n4 / name :op1 "SCH772984") :xref (x5 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG2 (a / and :op1 (d / decrease-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "RSK") :ARG3-of (p / phosphorylate-01) :xref (x4 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262"))) :op2 (d2 / disappear-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p4 / phosphorylate-01))) :op3 (i / induce-01 :ARG2 (e4 / enzyme :name (n6 / name :op1 "MEK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :degree (s3 / slight)) :ARG0-of (c2 / change-01 :polarity "-" :ARG1 (a2 / and :op1 (e5 / enzyme :name (n7 / name :op1 "RSK") :mod (t2 / total) :xref (x2 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op2 (e6 / enzyme :name (n8 / name :op1 "MEK") :mod t2 :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op3 (e7 / enzyme :name (n9 / name :op1 "ERK1/2") :mod t2) :op4 (e8 / enzyme :name (n10 / name :op1 "AKT") :mod t2 :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))))) :ARG1-of (c3 / consistent-01 :ARG2 (p3 / profile-01 :beneficiary (c4 / cell-line :ARG0-of (s4 / sensitive-03))))) # ::id a_pmid_2514_2146.120 # ::date 2015-06-11T01:41:00 # ::file a_pmid_2514_2146_120.txt # ::snt For the resistant M202, a modest induction of pMEK with some decrease in pERK and pRSK was observed at 24 hours (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (o / observe-01 :ARG1 (a / and :op1 (i / induce-01 :ARG2 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :mod (m / modest)) :op2 (d / decrease-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "RSK") :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :ARG3-of p) :ARG2 (s / some))) :time (a3 / after :quant (t / temporal-quantity :quant "24" :unit (h / hour))) :location (c / cell-line :name (n4 / name :op1 "M202") :ARG0-of (r / resist-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id a_pmid_2514_2146.121 # ::date 2015-06-11T01:49:13 # ::file a_pmid_2514_2146_121.txt # ::snt Treatment with SCH772984 resulted in upregulation of pAKT levels for M408 and WM1366 (Additional file 3: Figure S3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n3 / name :op1 "M408")) :op2 (c2 / cell-line :name (n4 / name :op1 "WM1366"))) :ARG2 (s / small-molecule :name (n / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG2 (u / upregulate-01 :ARG1 (l / level :quant-of (e / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "3" :mod (f2 / figure :mod "S3C") :mod (a2 / additional)))) # ::id a_pmid_2514_2146.122 # ::date 2015-06-11T01:58:54 # ::file a_pmid_2514_2146_122.txt # ::snt Consistent with the synergistic growth inhibition seen with combining SCH772984 and either MK-2206 or MK-8669, pAKT levels were abrogated with the addition of MK-2206 (AKT inhibitor) and MK-8669 (mTOR inhibitor) (Additional file 3: Figure S3A-C).

Susceptibility of NRAS-mutant melanoma cell lines to SCH-722984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / multi-sentence :snt1 (c / consistent-01 :ARG1 (a / abrogate-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG2 (a2 / add-02 :ARG1 (a3 / and :op1 (s6 / small-molecule :name (n2 / name :op1 "MK-2206") :ARG0-of (i2 / inhibit-01 :ARG1 e) :xref (x5 / xref :value "PUBCHEM:24964624" :prob "17.692984")) :op2 (s7 / small-molecule :name (n3 / name :op1 "MK-8669") :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein :name (n4 / name :op1 "mTOR") :xref (x / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004"))) :xref (x4 / xref :value "PUBCHEM:11520894" :prob "18.333639"))))) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01) :ARG0-of (s / synergize-01) :ARG1-of (s2 / see-01 :manner (c2 / combine-01 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "SCH772984") :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG2 (o / or :op1 s6 :op2 s7)))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "3" :mod (a4 / additional) :part (f2 / figure :mod "S3A") :part (f4 / figure :mod "S3B") :part (f5 / figure :mod "S3C")))) :snt2 (s4 / susceptibility :mod (c3 / cell-line :mod (e3 / enzyme :name (n8 / name :op1 "NRAS") :ARG2-of (m7 / mutate-01) :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :source (m2 / medical-condition :name (n6 / name :op1 "melanoma"))) :ARG2-of (r / respond-01 :ARG1 (s5 / small-molecule :name (n9 / name :op1 "SCH722984"))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "2")))) # ::id a_pmid_2514_2146.123 # ::date 2015-09-01T08:21:22 # ::file a_pmid_2514_2146_123.txt # ::snt A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / string-entity :value "A") # ::id a_pmid_2514_2146.124 # ::date 2015-06-11T02:33:05 # ::file a_pmid_2514_2146_124.txt # ::snt IC50 (nM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c / concentration-quantity :unit (n / nanomolar))) # ::id a_pmid_2514_2146.125 # ::date 2015-06-11T02:39:31 # ::file a_pmid_2514_2146_125.txt # ::snt Melanoma cell lines containing mutations in NRAS were exposed to 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars), and the cell viability determined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (e / expose-01 :ARG1 (c / cell-line :ARG0-of (c2 / contain-01 :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))) :source (m3 / medical-condition :name (n4 / name :op1 "melanoma"))) :ARG2 (o / or :op1 (s / small-molecule :name (n2 / name :op1 "SCH722984") :ARG1-of (d / describe-01 :ARG2 (b / bar :ARG1-of (b2 / black-04)))) :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib") :ARG1-of (d2 / describe-01 :ARG2 (b3 / bar :ARG1-of (g2 / gray-02))) :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :mod (c3 / concentration-quantity :quant (v / value-interval :op1 "0" :op2 "10") :unit (m / micromolar)))) :op2 (d3 / determine-01 :ARG1 (v2 / viability :poss c))) # ::id a_pmid_2514_2146.126 # ::date 2015-06-11T02:53:46 # ::file a_pmid_2514_2146_126.txt # ::snt Results are the mean of three experiments, performed in duplicate (n = 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (m / mean :domain (t / thing :ARG2-of (r / result-01)) :mod (e / experiment-01 :quant "3" :ARG1-of (p / perform-01 :frequency (p2 / product-of :op1 "2")) :ARG1-of (m2 / mean-01 :ARG2 (e2 / equal-01 :ARG1 e :ARG2 "6")))) # ::id a_pmid_2514_2146.127 # ::date 2015-06-11T02:57:31 # ::file a_pmid_2514_2146_127.txt # ::snt Error bars are standard deviation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / deviate-01 :ARG1-of (s / standard-02) :ARG1-of (d2 / describe-01 :ARG0 (b / bar :mod (e / error)))) # ::id a_pmid_2514_2146.128 # ::date 2015-06-11T03:01:20 # ::file a_pmid_2514_2146_128.txt # ::snt Bar at 1 μM denotes threshold between sensitive and intermediate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / denote-01 :ARG0 (b / bar :location (c / concentration-quantity :quant "1" :unit (m / micromolar))) :ARG1 (t / threshold :location (b2 / between :op1 (s / sensitive-03) :op2 (i / intermediate)))) # ::id a_pmid_2514_2146.129 # ::date 2015-06-11T03:04:53 # ::file a_pmid_2514_2146_129.txt # ::snt Resistant cell lines have IC50 higher than 2 μM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (c / cell-line :ARG0-of (r / resist-01)) :ARG2 "50" :ARG4 (m2 / more-than :op1 (c2 / concentration-quantity :quant "2" :unit (m / micromolar)))) # ::id a_pmid_2514_2146.130 # ::date 2015-09-01T08:22:36 # ::file a_pmid_2514_2146_130.txt # ::snt B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (f / figure :mod "B") # ::id a_pmid_2514_2146.131 # ::date 2015-06-11T03:27:11 # ::file a_pmid_2514_2146_131.txt # ::snt Effects of SCH722984 on MAPK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / affect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SCH722984")) :ARG1 (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "MAPK")))) # ::id a_pmid_2514_2146.132 # ::date 2015-06-11T03:30:16 # ::file a_pmid_2514_2146_132.txt # ::snt SCH722984-resistant M202 and SCH722984-sensitive M408 were treated for 24 h with DMSO as solvent control (-) or 500 nM SCH722984 (+). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "M202") :ARG0-of (r / resist-01 :ARG1 "s5")) :op2 (c2 / cell-line :name (n2 / name :op1 "M408") :ARG0-of (s / sensitive-03 :ARG1 "s5"))) :ARG2 (o / or :op1 (s2 / small-molecule :name (n4 / name :op1 "DMSO") :mod (c3 / control :mod (s3 / solvent)) :ARG1-of (l / label-01 :ARG2 (s4 / string-entity :value "-")) :xref (x / xref :value "PUBCHEM:679" :prob "16.740406")) :op2 (s5 / small-molecule :name (n5 / name :op1 "SCH722984") :quant (c4 / concentration-quantity :quant "500" :unit (n3 / nanomolar)) :ARG1-of (l2 / label-01 :ARG2 (s6 / string-entity :value "+")))) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour))) # ::id a_pmid_2514_2146.133 # ::date 2015-06-11T03:42:33 # ::file a_pmid_2514_2146_133.txt # ::snt Phosphorylated or total MEK, ERK 1/2, RSK, AKT or beta-actin as loading control were determined by western blot analysis.

# ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / determine-01 :ARG1 (o / or :op1 (o2 / or :op1 (e / enzyme :name (n / name :op1 "MEK") :xref (x7 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (s / slash :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x5 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2") :xref (x4 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :op3 (e4 / enzyme :name (n5 / name :op1 "RSK") :xref (x2 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e5 / enzyme :name (n6 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op5 (p / protein :name (n7 / name :op1 "beta-actin") :xref (x8 / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702")) :ARG1-of (p2 / phosphorylate-01)) :op2 (o3 / or :op1 (e6 / enzyme :name (n8 / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (s2 / slash :op1 e2 :op2 e3) :op3 (e9 / enzyme :name (n11 / name :op1 "RSK") :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e10 / enzyme :name (n12 / name :op1 "AKT") :xref (x9 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op5 (p3 / protein :name (n13 / name :op1 "beta-actin") :xref (x6 / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702")) :mod (t / total)) :mod (c / control-01 :ARG1 (l / load-01))) :ARG2 (a / analyze-01 :manner (i / immunoblot-01))) # ::id a_pmid_2514_2146.134 # ::date 2015-06-11T03:53:57 # ::file a_pmid_2514_2146_134.txt # ::snt For BRAF and NRAS wild-type melanoma cell lines, all seven were sensitive to ERK inhibition, with six of seven highly sensitive to SCH772984 (Figure 3A), including M418, which is a KRASG12A mutant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / sensitive-03 :ARG0 (c2 / cell-line :quant "7" :mod (a / all) :mod (g / gene :name (n2 / name :op1 "BRAF") :mod (w / wild-type) :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (g2 / gene :name (n3 / name :op1 "NRAS") :mod w :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :source (m / medical-condition :name (n8 / name :op1 "melanoma"))) :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2-of (i2 / include-91 :ARG1 (s2 / sensitive-03 :ARG0 (c / cell-line :quant "6") :ARG1 (s3 / small-molecule :name (n4 / name :op1 "SCH772984") :xref (x4 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1-of (h / high-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A")) :ARG2-of (i3 / include-01 :ARG1 (c3 / cell-line :name (n6 / name :op1 "M418") :mod (g3 / gene :name (n7 / name :op1 "KRAS") :ARG2-of (m3 / mutate-01 :value "G12A") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))))) # ::id a_pmid_2514_2146.135 # ::date 2015-06-11T04:03:55 # ::file a_pmid_2514_2146_135.txt # ::snt Consistent with this, treatment with SCH772984 in the highly sensitive M285 line resulted in complete disappearance of pRSK, decreased pERK1/2 and induction of pMEK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / consistent-01 :ARG1 (r / result-01 :ARG1 (t2 / treat-04 :ARG1 (c2 / cell-line :name (n2 / name :op1 "M285") :ARG0-of (s / sensitive-03 :ARG1-of (h / high-02))) :ARG2 (s3 / small-molecule :name (n / name :op1 "SCH772984") :xref (x4 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG2 (a / and :op1 (d / disappear-01 :ARG1 (e / enzyme :name (n3 / name :op1 "RSK") :ARG3-of (p / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :degree (c3 / complete)) :op2 (d2 / decrease-01 :ARG1 (s2 / slash :op1 (e2 / enzyme :name (n4 / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of p)) :op3 (i / induce-01 :ARG2 (e4 / enzyme :name (n6 / name :op1 "MEK") :ARG3-of p :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :ARG2 (t / this)) # ::id a_pmid_2514_2146.136 # ::date 2015-06-11T04:09:18 # ::file a_pmid_2514_2146_136.txt # ::snt M257, which is intermediately sensitive to SCH722984, had near-complete disappearance of pRSK, though pERK1/2 was slightly induced at 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / disappear-01 :ARG1 (e / enzyme :name (n / name :op1 "RSK") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :degree (c / complete :degree (n2 / near)) :location (c2 / cell-line :name (n3 / name :op1 "M257") :ARG0-of (s / sensitive-03 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "SCH722984")) :degree (i / intermediate))) :concession (i2 / induce-01 :ARG2 (s3 / slash :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n6 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of p) :degree (s2 / slight) :time (a / after :op1 (t / temporal-quantity :quant "24" :unit (h / hour))))) # ::id a_pmid_2514_2146.137 # ::date 2015-06-11T04:14:38 # ::file a_pmid_2514_2146_137.txt # ::snt Phospho-MEK was also induced in treated cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG2 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :mod (a / also) :location (c / cell :ARG1-of (t / treat-04))) # ::id a_pmid_2514_2146.138 # ::date 2015-06-11T04:15:33 # ::file a_pmid_2514_2146_138.txt # ::snt No changes in pAKT with SCH772984 were seen in either M285 or M257 (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (s / see-01 :ARG1 (c / change-01 :polarity "-" :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1 (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :location (o / or :op1 (c2 / cell-line :name (n3 / name :op1 "M285")) :op2 (c3 / cell-line :name (n4 / name :op1 "M257")) :mod (e2 / either)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id a_pmid_2514_2146.139 # ::date 2015-06-11T04:18:45 # ::file a_pmid_2514_2146_139.txt # ::snt These data indicate that SCH772984 may be effective against a majority of BRAF wild-type cell lines including NRAS mutants and BRAF/NRAS wild-type melanoma cell lines which remain dependent on the MAPK pathway for continued growth.

Susceptibility of BRAF/NRAS wild-type melanoma to SCH-722984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m / multi-sentence :snt1 (i / indicate-01 :ARG0 (d2 / data :mod (t / this)) :ARG1 (p2 / possible-01 :ARG1 (e / effective-04 :ARG0 (s4 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x5 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1 (c / counter-01 :ARG0 s4 :ARG1 (c2 / cell-line :mod (g / gene :name (n3 / name :op1 "BRAF") :mod (w / wild-type) :xref (x4 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG2-of (i2 / include-01 :ARG1 (a / and :op1 (c3 / cell-line :mod (g2 / gene :name (n4 / name :op1 "NRAS") :ARG2-of (m4 / mutate-01) :xref (x3 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :op2 (c4 / cell-line :mod (s / slash :op1 g :op2 (g6 / gene :name (n10 / name :op1 "NRAS") :mod w :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))) :ARG1-of (r / remain-01 :ARG3 (d3 / depend-01 :ARG0 a :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :purpose (g3 / grow-01 :ARG1 a :ARG1-of (c5 / continue-01)))) :source (m3 / medical-condition :name (n8 / name :op1 "melanoma")))) :quant (m2 / majority)))))) :snt2 (s2 / susceptibility :ARG2-of (r2 / respond-01 :ARG1 (s5 / small-molecule :name (n7 / name :op1 "SCH722984"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3")) :mod (m5 / medical-condition :name (n9 / name :op1 "melanoma") :mod (s3 / slash :op1 (g4 / gene :name (n5 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g5 / gene :name (n6 / name :op1 "NRAS") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :mod (w2 / wild-type))))) # ::id a_pmid_2514_2146.141 # ::date 2015-06-11T04:33:09 # ::file a_pmid_2514_2146_141.txt # ::snt IC50 (nM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c2 / concentration-quantity :unit (n / nanomolar))) # ::id a_pmid_2514_2146.142 # ::date 2015-06-11T04:34:20 # ::file a_pmid_2514_2146_142.txt # ::snt Cells were treated with 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars) and cell viability determined by ATP-based bioluminescence assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (t / treat-04 :ARG1 (c / cell) :ARG2 (o / or :op1 (s2 / small-molecule :name (n / name :op1 "SCH722984") :ARG1-of (d / describe-01 :ARG0 (b / bar :ARG1-of (b2 / black-04)))) :op2 (s3 / small-molecule :name (n2 / name :op1 "vemurafenib") :ARG1-of (d2 / describe-01 :ARG0 (b3 / bar :ARG1-of (g / gray-02))) :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :mod (c2 / concentration-quantity :quant (v / value-interval :op1 "0" :op2 "10") :unit (m / micromolar)))) :op2 (d3 / determine-01 :ARG1 (v2 / viability :poss c) :manner (a2 / assay-01 :ARG1 (b4 / bioluminescence) :ARG1-of (b5 / base-02 :ARG2 (s / small-molecule :name (n3 / name :op1 "ATP") :xref (x1 / xref :value "PUBCHEM:5957" :prob "14.368295")))))) # ::id a_pmid_2514_2146.143 # ::date 2015-06-11T04:42:01 # ::file a_pmid_2514_2146_143.txt # ::snt Results are the mean of duplicate experiments, performed in triplicate (n = 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (m / mean :domain (t / thing :ARG2-of (r / result-01)) :mod (e / experiment-01 :ARG1-of (p / perform-01 :frequency (p3 / product-of :op1 "3")) :frequency (p2 / product-of :op1 "2") :ARG1-of (m2 / mean-01 :ARG2 (e2 / equal-01 :ARG1 e :ARG2 "6")))) # ::id a_pmid_2514_2146.144 # ::date 2015-06-11T04:44:48 # ::file a_pmid_2514_2146_144.txt # ::snt Error bars are standard deviation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / deviate-01 :ARG1-of (s / standard-02) :ARG1-of (d2 / describe-01 :ARG0 (b / bar :mod (e / error)))) # ::id a_pmid_2514_2146.145 # ::date 2015-06-11T04:45:48 # ::file a_pmid_2514_2146_145.txt # ::snt Bar at 1 μM denotes threshold between sensitive and intermediate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / denote-01 :ARG0 (b / bar :location (c / concentration-quantity :quant "1" :unit (m / micromolar))) :ARG1 (t / threshold :location (b2 / between :op1 (s / sensitive-03) :op2 (i / intermediate)))) # ::id a_pmid_2514_2146.146 # ::date 2015-06-11T04:48:17 # ::file a_pmid_2514_2146_146.txt # ::snt Resistant cell lines have IC50 higher than 2 μM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (c / cell-line :ARG0-of (r / resist-01)) :ARG2 "50" :ARG4 (m2 / more-than :op1 (c2 / concentration-quantity :quant "2" :unit (m / micromolar)))) # ::id a_pmid_2514_2146.148 # ::date 2015-06-11T04:50:33 # ::file a_pmid_2514_2146_148.txt # ::snt Effects of SCH722984 on MAPK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (a / affect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SCH722984")) :ARG1 (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "MAPK")))) # ::id a_pmid_2514_2146.149 # ::date 2015-06-11T04:51:53 # ::file a_pmid_2514_2146_149.txt # ::snt SCH-722984-resistant M257 and SCH-722984-sensitive M285, were treated for 24 h with DMSO (-) or 500 nM SCH722984 (+). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "M257") :ARG0-of (r / resist-01 :ARG1 "s4")) :op2 (c2 / cell-line :name (n2 / name :op1 "M285") :ARG0-of (s / sensitive-03 :ARG1 "s4"))) :ARG2 (o / or :op1 (s2 / small-molecule :name (n4 / name :op1 "DMSO") :ARG1-of (l / label-01 :ARG2 (s3 / string-entity :value "-")) :xref (x / xref :value "PUBCHEM:679" :prob "16.740406")) :op2 (s4 / small-molecule :name (n5 / name :op1 "SCH722984") :quant (c3 / concentration-quantity :quant "500" :unit (n3 / nanomolar)) :ARG1-of (l2 / label-01 :ARG2 (s5 / string-entity :value "+")))) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour))) # ::id a_pmid_2514_2146.150 # ::date 2015-06-11T04:56:55 # ::file a_pmid_2514_2146_150.txt # ::snt Phosphorylated or total MEK, ERK 1/2, RSK, AKT or beta-actin as loading control were determined by western blot analysis.

# ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / determine-01 :ARG1 (o / or :op1 (o2 / or :op1 (e / enzyme :name (n / name :op1 "MEK") :xref (x7 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (s / slash :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x5 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2") :xref (x4 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :op3 (e4 / enzyme :name (n5 / name :op1 "RSK") :xref (x2 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e5 / enzyme :name (n6 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op5 (p / protein :name (n7 / name :op1 "beta-actin") :xref (x8 / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702")) :ARG1-of (p2 / phosphorylate-01)) :op2 (o3 / or :op1 (e6 / enzyme :name (n8 / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (s2 / slash :op1 e2 :op2 e3) :op3 (e9 / enzyme :name (n11 / name :op1 "RSK") :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e10 / enzyme :name (n12 / name :op1 "AKT") :xref (x9 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op5 (p3 / protein :name (n13 / name :op1 "beta-actin") :xref (x6 / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702")) :mod (t / total)) :mod (c / control-01 :ARG1 (l / load-01))) :manner (a / analyze-01 :manner (i / immunoblot-01))) # ::id a_pmid_2514_2146.151 # ::date 2015-06-11T05:02:14 # ::file a_pmid_2514_2146_151.txt # ::snt SCH722984 is effective in BRAF-mutant melanoma with acquired vemurafenib-resistance # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / effective-04 :ARG0 (s / small-molecule :name (n / name :op1 "SCH722984")) :location (m / medical-condition :name (n4 / name :op1 "melanoma") :mod (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (a / acquire-01 :ARG1 (r / resist-01 :ARG0 m :ARG1 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")))))) # ::id a_pmid_2514_2146.152 # ::date 2015-06-11T05:05:37 # ::file a_pmid_2514_2146_152.txt # ::snt The IC50 of SCH722984 or vemurafenib was next determined in eight BRAF-mutant vemurafenib-resistant melanoma cell lines (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / determine-01 :ARG1 (c3 / concentration-quantity :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (o / or :op1 (s / small-molecule :name (n2 / name :op1 "SCH722984")) :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :ARG2 "50")) :time (n4 / next) :location (c / cell-line :quant "8" :mod (g / gene :name (n5 / name :op1 "BRAF") :ARG2-of (m5 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (r / resist-01 :ARG1 s2) :source (m / medical-condition :name (n / name :op1 "melanoma"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id a_pmid_2514_2146.153 # ::date 2015-06-11T05:09:34 # ::file a_pmid_2514_2146_153.txt # ::snt M376 and M398, two BRAF/NRAS double mutant cell lines derived from the same patient tumors, were highly sensitive to SCH722984, despite high resistance to vemurafenib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / sensitive-03 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "M376")) :op2 (c2 / cell-line :name (n2 / name :op1 "M398")) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :quant "2" :mod (s2 / slash :op1 (g / gene :name (n4 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n5 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :ARG2-of (m2 / mutate-01 :mod (d / double))) :ARG1-of (d2 / derive-01 :ARG2 (t / tumor :poss (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient))) :ARG1-of (s3 / same-01 :ARG3 p)))))) :ARG1 (s4 / small-molecule :name (n3 / name :op1 "SCH722984")) :ARG1-of (h / high-02) :concession (r / resist-01 :ARG0 a :ARG1 (s5 / small-molecule :name (n6 / name :op1 "vemurafenib") :ARG1-of h :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056")))) # ::id a_pmid_2514_2146.154 # ::date 2015-06-11T05:16:04 # ::file a_pmid_2514_2146_154.txt # ::snt M376 is a spontaneously arising double mutant, whereas M398 was established from tumor from the same patient upon progression on vemurafenib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (c / contrast-01 :ARG1 (m / mutate-01 :ARG2 (c2 / cell-line :name (n / name :op1 "M376") :ARG1-of (a / arise-02 :manner (s / spontaneous))) :mod (d / double)) :ARG2 (e / establish-01 :ARG0 (p3 / progress-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :ARG1 (c3 / cell-line :name (n2 / name :op1 "M398")) :source (t / tumor :source (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (s2 / same-01))))) # ::id a_pmid_2514_2146.155 # ::date 2015-06-11T05:21:26 # ::file a_pmid_2514_2146_155.txt # ::snt Similar to their isogenic parental cell lines, potent growth inhibition with SCH772984 was also seen for three BRAFV600E mutant melanoma cell lines with in vitro-derived vemurafenib resistance (polyclonal population): M395AR, M397AR, and M249AR4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / see-01 :ARG1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1 (g / grow-01) :mod (p / potent)) :mod (a / also) :location (c / cell-line :quant "3" :mod (g2 / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (r2 / resist-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG1-of (d / derive-01 :ARG2 (i2 / in-vitro))) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and :op1 (c3 / cell-line :name (n4 / name :op1 "M395AR")) :op2 (c4 / cell-line :name (n5 / name :op1 "M397AR")) :op3 (c5 / cell-line :name (n6 / name :op1 "M249AR4")))) :source (m / medical-condition :name (n7 / name :op1 "melanoma")) :ARG1-of (d3 / describe-01 :ARG2 (p3 / population :mod (p4 / polyclone)))) :ARG1-of (r / resemble-01 :ARG2 (c2 / cell-line :poss (t / they) :mod (i3 / isogenic) :mod (p2 / parental)))) # ::id a_pmid_2514_2146.156 # ::date 2015-06-11T05:28:28 # ::file a_pmid_2514_2146_156.txt # ::snt Previously data demonstrated that these cell lines reactivate the MAPK pathway via generation of BRAF splice variants (M395AR and M397AR) [7, 24], or via secondary NRAS mutation (M249AR4) [6]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 12, 2015 (d / demonstrate-01 :ARG0 (d2 / data :mod (p2 / previous)) :ARG1 (r / reactivate-01 :ARG0 (c / cell-line :mod (t / this)) :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :manner (o / or :op1 (g / generate-01 :ARG1 (v / variant :ARG2-of (r2 / result-01 :ARG1 (s / splice-01 :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "7")) :op2 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "24")))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c5 / cell-line :name (n3 / name :op1 "M395AR")) :op2 (c6 / cell-line :name (n4 / name :op1 "M397AR"))))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n5 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :mod (s2 / secondary) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 "6"))) :ARG1-of (m3 / mean-01 :ARG2 (c7 / cell-line :name (n6 / name :op1 "M249AR4"))))))) # ::id a_pmid_2514_2146.157 # ::date 2015-06-11T05:37:42 # ::file a_pmid_2514_2146_157.txt # ::snt In contrast, M229AR9, M238AR2 and M409AR1 remained highly resistant to SCH722984 with IC50s >2uM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / contrast-01 :ARG2 (r / remain-01 :ARG1 (a / and :op1 (c2 / cell-line :name (n / name :op1 "M229AR9")) :op2 (c3 / cell-line :name (n2 / name :op1 "M238AR2")) :op3 (c4 / cell-line :name (n3 / name :op1 "M409AR1"))) :ARG3 (r2 / resist-01 :ARG0 a :ARG1 (s / small-molecule :name (n4 / name :op1 "SCH722984") :ARG1-of (c6 / concentrate-02 :mod (i / inhibit-01 :degree (p / percentage-entity :value "50")) :quant (m2 / more-than :op1 (c5 / concentration-quantity :quant "2" :unit (m / micromolar))))) :ARG1-of (h / high-02)))) # ::id a_pmid_2514_2146.158 # ::date 2015-06-11T05:43:23 # ::file a_pmid_2514_2146_158.txt # ::snt For M229AR9 and M238AR2 upregulation of RTK is the mechanism of vemurafenib resistance [6]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 12, 2015 (m / mechanism :domain (u / upregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "RTK") :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262"))) :mod (r / resist-01 :ARG0 (a / and :op1 (c / cell-line :name (n2 / name :op1 "M229AR9")) :op2 (c2 / cell-line :name (n3 / name :op1 "M238AR2"))) :ARG1 (s / small-molecule :name (n4 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 "6")))) # ::id a_pmid_2514_2146.159 # ::date 2015-06-11T05:51:31 # ::file a_pmid_2514_2146_159.txt # ::snt The mechanism of resistance for M409AR is unknown at this time, and studies are ongoing to delineate the mechanism underlying BRAFi-resistance.

SCH722984 in BRAF-mutant melanoma cell lines with vemurafenib-acquired resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / multi-sentence :snt1 (a / and :op1 (k / know-01 :polarity "-" :ARG1 (m2 / mechanism :mod (r / resist-01 :ARG0 (c / cell-line :name (n / name :op1 "M409AR")))) :time (t / this)) :op2 (g / go-on-15 :ARG1 (s / study-01) :purpose (d / delineate-01 :ARG0 s :ARG1 (m3 / mechanism :ARG0-of (u / underlie-01 :ARG1 (r2 / resist-01 :ARG1 (m4 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))))))) :snt2 (s2 / small-molecule :name (n3 / name :op1 "SCH722984") :location (c2 / cell-line :mod (g2 / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m5 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :source (m6 / medical-condition :name (n5 / name :op1 "melanoma")) :ARG0-of (r3 / resist-01 :ARG1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib") :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG1-of (a2 / acquire-01))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4")))) # ::id a_pmid_2514_2146.161 # ::date 2015-06-11T05:56:49 # ::file a_pmid_2514_2146_161.txt # ::snt IC50 (nM) to SCH-722984 or vemurafenib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (o / or :op1 (s / small-molecule :name (n / name :op1 "SCH722984")) :op2 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :ARG2 "50" :ARG4 (c2 / concentration-quantity :unit (n3 / nanomolar))) # ::id a_pmid_2514_2146.162 # ::date 2015-06-11T07:06:20 # ::file a_pmid_2514_2146_162.txt # ::snt M398 and M376, two melanoma cell lines established from tumors progressing on vemurafenib, as well as six parental BRAF mutant melanoma cell lines and their paired in vitro derived vemurafenib-acquired resistance sublines (AR) were grown in the presence of 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (g / grow-03 :ARG1 (a / and :op1 (a2 / and :op1 (c / cell-line :name (n / name :op1 "M398")) :op2 (c2 / cell-line :name (n2 / name :op1 "M376")) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :quant "2" :ARG1-of (e / establish-01 :source (t / tumor :ARG1-of (p / progress-01 :ARG1-of (c4 / cause-01 :ARG0 "s2")))) :source (m4 / medical-condition :name (n6 / name :op1 "melanoma"))))) :op2 (c5 / cell-line :quant "6" :mod (p2 / parental) :mod (g2 / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :source m4) :op3 (s / subline :poss c5 :ARG1-of (p3 / pair-01) :ARG0-of (a3 / acquire-01 :ARG1 (r / resist-01 :ARG0 s :ARG1 "s2" :ARG1-of (d / derive-01 :ARG2 (i / in-vitro)))))) :condition (o / or :op1 (p4 / present-02 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "SCH722984") :mod (c6 / concentration-quantity :quant (v / value-interval :op1 "0" :op2 "10") :unit (m2 / micromolar))) :ARG1-of (d2 / describe-01 :ARG0 (b / bar :ARG1-of (b2 / black-04)))) :op2 (p5 / present-02 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib") :quant v :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG1-of (d3 / describe-01 :ARG0 (b3 / bar :ARG1-of (g3 / gray-02)))))) # ::id a_pmid_2514_2146.163 # ::date 2015-06-11T07:21:32 # ::file a_pmid_2514_2146_163.txt # ::snt Values are mean of three experiments, performed in duplicate (n = 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (m / mean :domain (v / value) :mod (e / experiment-01 :quant "3" :ARG1-of (p / perform-01 :frequency (p2 / product-of :op1 "2")) :ARG1-of (m2 / mean-01 :ARG2 (e2 / equal-01 :ARG1 e :ARG2 "6")))) # ::id a_pmid_2514_2146.164 # ::date 2015-06-11T07:23:03 # ::file a_pmid_2514_2146_164.txt # ::snt Error bars are standard deviation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / deviate-01 :ARG1-of (s / standard-02) :ARG1-of (d2 / describe-01 :ARG0 (b / bar :mod (e / error)))) # ::id a_pmid_2514_2146.165 # ::date 2015-06-11T07:24:17 # ::file a_pmid_2514_2146_165.txt # ::snt Bar at 1 μM denotes threshold between sensitive and intermediate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / denote-01 :ARG0 (b / bar :location (c / concentration-quantity :quant "1" :unit (m / micromolar))) :ARG1 (t / threshold :location (b2 / between :op1 (s / sensitive-03) :op2 (i / intermediate)))) # ::id a_pmid_2514_2146.166 # ::date 2015-06-11T07:26:03 # ::file a_pmid_2514_2146_166.txt # ::snt Resistant cell lines have IC50 higher than 2 μM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (c3 / cell-line :ARG0-of (r / resist-01)) :ARG2 "50" :ARG4 (m / more-than :op1 (c2 / concentration-quantity :quant "2" :unit (m2 / micromolar)))) # ::id a_pmid_2514_2146.167 # ::date 2015-06-11T07:31:08 # ::file a_pmid_2514_2146_167.txt # ::snt *: BRAF/NRAS double mutant, **: BRAF-splice variant, §: Receptor tyrosine kinase upreguation, +: resistance mechanism unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / multi-sentence :snt1 (s / slash :op1 (e2 / enzyme :name (n / name :op1 "BRAF") :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n2 / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :ARG2-of (m2 / mutate-01 :mod (d / double))) :snt2 (v / variant :ARG2-of (r / result-01 :ARG1 (s2 / splice-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :snt3 (u / upregulate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :xref (x / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392"))) :snt4 (m3 / mechanism :ARG1-of (k2 / know-01 :polarity "-") :mod (r2 / resist-01))) # ::id a_pmid_2514_2146.169 # ::date 2015-06-11T07:38:22 # ::file a_pmid_2514_2146_169.txt # ::snt Effect of SCH722984 on MAPK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (a / affect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SCH722984")) :ARG1 (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "MAPK")))) # ::id a_pmid_2514_2146.170 # ::date 2015-06-11T07:39:24 # ::file a_pmid_2514_2146_170.txt # ::snt Western blot analysis was performed to evaluate the effect of 24 hour exposure to 500 nM SCH&22984 (+) or DMSO (-) on phospho- or total MEK, ERK 1/2, RSK, AKT or beta-actin as loading control.

# ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / perform-01 :ARG1 (a2 / analyze-01 :manner (i / immunoblot-01)) :purpose (e3 / evaluate-01 :ARG1 (a / affect-01 :ARG0 (e4 / expose-01 :ARG1 (o2 / or :op1 (o3 / or :op1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x7 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (s2 / slash :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1") :xref (x6 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n7 / name :op1 "ERK2") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :op3 (e6 / enzyme :name (n8 / name :op1 "RSK") :xref (x5 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e7 / enzyme :name (n9 / name :op1 "AKT") :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op5 (p2 / protein :name (n10 / name :op1 "beta-actin") :xref (x / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702")) :ARG3-of (p3 / phosphorylate-01)) :op2 (o4 / or :op1 (e10 / enzyme :name (n14 / name :op1 "MEK") :xref (x9 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (s3 / slash :op1 e2 :op2 e5) :op3 (e9 / enzyme :name (n13 / name :op1 "RSK") :xref (x1 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e8 / enzyme :name (n12 / name :op1 "AKT") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op5 (p4 / protein :name (n11 / name :op1 "beta-actin") :xref (x8 / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702")) :mod (t / total)) :manner (c2 / control-01 :ARG1 (l / load-01))) :ARG2 (o / or :op1 (s4 / small-molecule :name (n / name :op1 "SCH722984") :quant (c / concentration-quantity :quant "500" :unit (n4 / nanomolar)) :ARG1-of (l2 / label-01 :ARG2 (s5 / string-entity :value "+"))) :op2 (s / small-molecule :name (n6 / name :op1 "DMSO") :ARG1-of (l3 / label-01 :ARG2 (s6 / string-entity :value "-")) :xref (x10 / xref :value "PUBCHEM:679" :prob "16.740406"))) :duration (t3 / temporal-quantity :quant "24" :unit (h2 / hour)))))) # ::id a_pmid_2514_2146.171 # ::date 2015-06-11T07:47:08 # ::file a_pmid_2514_2146_171.txt # ::snt Consistent with the signaling for other sensitive cell lines, all three BRAF/NRAS double mutants (M376, M398, M249AR4) displayed decreased pRSK and pERK1/2 at 24 hours with no detectable change in pMEK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (c / consistent-01 :ARG1 (d / display-01 :ARG0 (c3 / cell-line :quant "3" :mod (s3 / slash :op1 (g / gene :name (n / name :op1 "BRAF") :xref (x5 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :ARG2-of (m / mutate-01 :mod (d2 / double))) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (c4 / cell-line :name (n3 / name :op1 "M376")) :op2 (c5 / cell-line :name (n4 / name :op1 "M398")) :op3 (c6 / cell-line :name (n5 / name :op1 "M249AR4")))) :mod (a2 / all)) :ARG1 (a5 / and :op1 (a3 / and :op1 (e / enzyme :name (n6 / name :op1 "RSK") :xref (x4 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op2 (s4 / slash :op1 (e2 / enzyme :name (n7 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n8 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG3-of (p / phosphorylate-01) :ARG1-of (d3 / decrease-01) :time (a4 / after :op1 (t / temporal-quantity :quant "24" :unit (h / hour)))) :op2 (p2 / possible-01 :polarity "-" :ARG1 (d4 / detect-01 :ARG1 (c7 / change-01 :ARG1 (e4 / enzyme :name (n9 / name :op1 "MEK") :ARG3-of p :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))))) :ARG2 (s / signal-07 :ARG1 (c2 / cell-line :mod (o / other) :ARG0-of (s2 / sensitive-03)))) # ::id a_pmid_2514_2146.172 # ::date 2015-06-11T08:02:55 # ::file a_pmid_2514_2146_172.txt # ::snt In the paired parental and acquired-resistance cell lines, treatment of the parental cell lines (M397, M249, M229, M238 and M409) with SCH722984 resulted in disappearance of pRSK, decrease in pERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "M397")) :op2 (c2 / cell-line :name (n2 / name :op1 "M249")) :op3 (c3 / cell-line :name (n3 / name :op1 "M229")) :op4 (c4 / cell-line :name (n4 / name :op1 "M238")) :op5 (c5 / cell-line :name (n5 / name :op1 "M409")) :mod (p / parental)) :ARG2 (s2 / small-molecule :name (n9 / name :op1 "SCH722984"))) :ARG2 (a2 / and :op1 (d / disappear-01 :ARG1 (e / enzyme :name (n6 / name :op1 "RSK") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262"))) :op2 (d2 / decrease-01 :ARG1 (s / slash :op1 (e2 / enzyme :name (n7 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n8 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of p2))) :location (a3 / and :op1 (c6 / cell-line :mod p) :op2 (c7 / cell-line :ARG0-of (a4 / acquire-01 :ARG1 (r2 / resist-01))) :ARG1-of (p3 / pair-01))) # ::id a_pmid_2514_2146.173 # ::date 2015-06-11T08:07:26 # ::file a_pmid_2514_2146_173.txt # ::snt Interestingly, we observed again upregulation of pAKT levels after treatment with SCH772984 in M398, M376, M397AR, M249AR4, and M409AR1, suggesting a rapid upregulation of the PI3K/AKT/mTOR pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (u / upregulate-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :mod (a / again) :time (a2 / after :op1 (t / treat-04 :ARG1 (a3 / and :op1 (c / cell-line :name (n3 / name :op1 "M398")) :op2 (c2 / cell-line :name (n4 / name :op1 "M376")) :op3 (c3 / cell-line :name (n5 / name :op1 "M397AR")) :op4 (c4 / cell-line :name (n6 / name :op1 "M249AR4")) :op5 (c5 / cell-line :name (n7 / name :op1 "M409AR1"))) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) :ARG0-of (s / suggest-01 :ARG1 (u2 / upregulate-01 :ARG1 (p2 / pathway :name (n8 / name :op1 "PI3K/AKT/mTOR")) :mod (r / rapid))) :ARG2-of (i / interest-01)) # ::id a_pmid_2514_2146.174 # ::date 2015-06-12T03:09:17 # ::file a_pmid_2514_2146_174.txt # ::snt This suggests that dual inhibition with SCH772984 and an AKT or mTOR inhibitor may result in more potent growth inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t / this) :ARG1 (p / possible-01 :ARG1 (r / result-01 :ARG1 (i / inhibit-01 :ARG0 (a / and :op1 (s2 / small-molecule :name (n / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (o / or :op1 (p2 / protein-family :name (n2 / name :op1 "AKT")) :op2 (p4 / protein :name (n3 / name :op1 "mTOR") :xref (x / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")))))) :mod (d / dual)) :ARG2 (i2 / inhibit-01 :ARG1 (g / grow-01) :mod (p3 / potent :degree (m / more)))))) # ::id a_pmid_2514_2146.175 # ::date 2015-06-13T15:15:09 # ::file a_pmid_2514_2146_175.txt # ::snt For M397AR and M249AR4, the disappearance of pERK was robust. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / robust :domain (d / disappear-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :location (a / and :op1 (c / cell-line :name (n / name :op1 "M397AR")) :op2 (c2 / cell-line :name (n2 / name :op1 "M249AR4")))) # ::id a_pmid_2514_2146.176 # ::date 2015-06-13T15:25:21 # ::file a_pmid_2514_2146_176.txt # ::snt In contrast, for the resistant M229AR9, M238AR2 and M409AR1, though treatment with SCH772984 resulted in disappearance of pRSK, pMEK appeared to be induced and pERK1/2 remained almost unchanged (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG2 (c2 / contrast-01 :ARG1 (r2 / result-01 :ARG1 (t / treat-04 :ARG1 (a4 / and :op1 (c5 / cell-line :name (n4 / name :op1 "M229AR9")) :op2 (c6 / cell-line :name (n5 / name :op1 "M238AR2")) :op3 (c7 / cell-line :name (n6 / name :op1 "M409AR1"))) :ARG2 (s / small-molecule :name (n3 / name :op1 "SCH772984") :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG2 (d2 / disappear-01 :ARG1 (a5 / and :op1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e3 / enzyme :name (n7 / name :op1 "RSK") :ARG3-of p :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262"))))) :ARG2 (a / appear-02 :ARG1 (a2 / and :op1 (i / induce-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG3-of p :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op2 (r / remain-01 :ARG3 (c3 / change-01 :polarity "-" :ARG1 (e4 / enzyme :name (n8 / name :op1 "ERK1/2") :ARG3-of p) :degree (a3 / almost)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id a_pmid_2514_2146.177 # ::date 2015-06-13T15:30:36 # ::file a_pmid_2514_2146_177.txt # ::snt Synergistic inhibition with combination BRAF and ERK inhibition # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i3 / inhibit-01 :ARG0-of (s / synergize-01) :manner (c / combine-01 :ARG1 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) # ::id a_pmid_2514_2146.178 # ::date 2015-06-13T15:52:17 # ::file a_pmid_2514_2146_178.txt # ::snt We next determined whether combining BRAF and ERK inhibition could result in synergistic inhibition by dual MAPK pathway inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (d / determine-01 :ARG0 (w / we) :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (r / result-01 :ARG1 (c / combine-01 :ARG1 (a / and :op1 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :ARG2 (i3 / inhibit-01 :ARG0-of (s / synergize-01)) :manner (i4 / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK")) :mod (d2 / dual)))) :mod (n3 / next)) # ::id a_pmid_2514_2146.179 # ::date 2015-06-13T16:03:56 # ::file a_pmid_2514_2146_179.txt # ::snt Treatment of M238 and M792, two BRAFV600E-mutant melanoma cell lines highly sensitive to singular treatment with vemurafenib and SCH772984, with equimolar concentrations of combined vemurafenib and SCH772984 treatment resulted in potent synergistic growth inhibition with IC50 of 10nM (Figure 5A, 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (r / result-01 :ARG1 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "M238")) :op2 (c2 / cell-line :name (n2 / name :op1 "M792")) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :quant "2" :mod (g / gene :name (n3 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (s / sensitive-03 :ARG1 (t2 / treat-04 :ARG1 a :ARG2 (a2 / and :op1 (s4 / small-molecule :name (n6 / name :op1 "vemurafenib") :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s3 / small-molecule :name (n4 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) :ARG1-of (h / high-02)) :prep-with (c5 / concentrate-02 :ARG1 (t3 / treat-04 :ARG2 (a3 / and :op1 s4 :op2 s3) :ARG1-of (c6 / combine-01)) :mod (e / equimolar)) :part-of (m3 / medical-condition :name (n7 / name :op1 "melanoma")))))) :ARG2 (i / inhibit-01 :ARG1 (g2 / grow-03) :mod (p / potent) :ARG0-of (s2 / synergize-01) :ARG3-of (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c7 / concentration-quantity :quant "10" :unit (n5 / nanomolar)))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "5A") :op2 (f2 / figure :mod "5B")))) # ::id a_pmid_2514_2146.180 # ::date 2015-06-15T05:37:28 # ::file a_pmid_2514_2146_180.txt # ::snt Combining vemurafenib with SCH772984 resulted in a more profound decrease in pRSK and pERK for the highly sensitive M262 and M792 lines compared to untreated controls or treatment with either agent alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / result-01 :ARG1 (c / combine-01 :ARG1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib") :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 (s2 / small-molecule :name (n / name :op1 "SCH772984") :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :ARG2 (d / decrease-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "RSK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK") :ARG3-of p2 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :location (a2 / and :op1 (c3 / cell-line :name (n4 / name :op1 "M262")) :op2 (c4 / cell-line :name (n5 / name :op1 "M792")) :ARG0-of (s / sensitive-03 :ARG1-of (h / high-02))) :mod (p / profound :degree (m / more)) :compared-to (o / or :op1 (c5 / control :ARG1-of (t2 / treat-04 :polarity "-")) :op2 (t / treat-04 :ARG2 (a3 / agent :mod (a4 / alone) :mod (e3 / either)))))) # ::id a_pmid_2514_2146.181 # ::date 2015-06-14T02:59:30 # ::file a_pmid_2514_2146_181.txt # ::snt M262 resulted in decreased pAKT levels after all three treatments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (r / result-01 :ARG1 (c / cell-line :name (n / name :op1 "M262")) :ARG2 (l / level :ARG1-of (d / decrease-01) :quant-of (e / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :time (a / after :op1 (t / treat-04 :quant "3" :mod (a2 / all)))) # ::id a_pmid_2514_2146.182 # ::date 2015-06-14T03:06:09 # ::file a_pmid_2514_2146_182.txt # ::snt For M308, which is resistant to vemurafenib and sensitive to SCH772984, as pRSK was already completely absent with treatment with SCH772984 alone, no additional effect of the combination was apparent (Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (c / cause-01 :ARG0 (a / absent-01 :ARG1 (e / enzyme :name (n / name :op1 "RSK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :manner (c2 / complete) :ARG1-of (c3 / cause-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) :time (a3 / already)) :ARG1 (a4 / appear-01 :polarity "-" :ARG1 (a5 / affect-01 :ARG0 (c5 / combine-01) :ARG1 (c6 / cell-line :name (n3 / name :op1 "M308") :ARG0-of (r / resist-01 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :ARG0-of (s / sensitive-03 :ARG1 (s4 / small-molecule :name (n5 / name :op1 "SCH772984") :mod (a2 / alone) :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) :mod (a6 / additional))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id a_pmid_2514_2146.183 # ::date 2015-06-15T14:05:35 # ::file a_pmid_2514_2146_183.txt # ::snt Interestingly, at 24 hours post treatment, induction of pMEK and pERK was already seen, indicating rapid feedback recovery for M308, despite its sensitivity to SCH772984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / see-01 :ARG1 (i2 / induce-01 :ARG2 (a / and :op1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG3-of p2 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :manner (i / interesting) :time (a3 / after :op1 (t3 / treat-04) :quant (t2 / temporal-quantity :quant "24" :unit (h2 / hour))) :time (a2 / already) :ARG0-of (i3 / indicate-01 :ARG1 (r / recover-02 :ARG0 (c2 / cell-line :name (n3 / name :op1 "M308")) :ARG1 (f / feedback) :mod (r2 / rapid) :concession (s2 / sensitive-03 :ARG0 c2 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")))))) # ::id a_pmid_2514_2146.184 # ::date 2015-06-14T02:43:23 # ::file a_pmid_2514_2146_184.txt # ::snt A slight decrease in pERK1/2 was seen with SCH772984 treatment, with a compensatory increase in pMEK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (s / see-01 :ARG1 (a / and :op1 (d / decrease-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of "p") :ARG2 (s2 / slight) :ARG1-of (c / cause-01 :ARG0 (t / treat-04 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134"))))) :op2 (i / increase-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG0-of (c2 / compensate-01)))) # ::id a_pmid_2514_2146.185 # ::date 2015-06-14T02:58:48 # ::file a_pmid_2514_2146_185.txt # ::snt The generally more resistant M308 and M370 lines, in contrast to the generally more sensitive M262 and M792 lines, did not show a decrease in pMEK when combining the two drugs, which seems to be due to the lack of activity of vemurafenib in these resistant cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :polarity "-" :ARG0 (a2 / and :op1 (c5 / cell-line :name (n2 / name :op1 "M308")) :op2 (c6 / cell-line :name (n3 / name :op1 "M370")) :ARG0-of (r2 / resist-01 :degree (m / more) :ARG1-of (g / general-02)) :ARG1-of (c3 / cause-01 :ARG0 (l / lack-01 :ARG0 a2 :ARG1 (a / activity-06 :ARG0 (s4 / small-molecule :name (n6 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")))) :ARG1-of (s2 / seem-01)) :ARG1-of (c / contrast-01 :ARG2 (a3 / and :op1 (c7 / cell-line :name (n4 / name :op1 "M262")) :op2 (c8 / cell-line :name (n5 / name :op1 "M792")) :ARG0-of (s3 / sensitive-03 :degree m :ARG1-of g)))) :ARG1 (d / decrease-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :time (c2 / combine-01 :ARG1 (d2 / drug :quant "2"))) # ::id a_pmid_2514_2146.186 # ::date 2015-06-14T03:53:14 # ::file a_pmid_2514_2146_186.txt # ::snt No additive effect from the dual upstream blockade could be noticed in the immediate downstream targets, indicating that the pathway remained active (Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (p2 / possible-01 :ARG1 (n / notice-01 :polarity "-" :ARG1 (a2 / affect-01 :ARG0 (b / blockade-01 :location (u / upstream) :mod (d2 / dual)) :ARG1-of (a3 / add-02)) :location (t / target :location (d3 / downstream :mod (i2 / immediacy))) :ARG0-of (i / indicate-01 :ARG1 (r / remain-01 :ARG1 (p / pathway) :ARG3 (a / active)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id a_pmid_2514_2146.187 # ::date 2015-06-13T16:08:12 # ::file a_pmid_2514_2146_187.txt # ::snt All cell lines sensitive to BRAFi were also sensitive to the combination. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (s / sensitive-03 :ARG0 (c / cell-line :mod (a / all) :ARG0-of (s2 / sensitive-03 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) :ARG1 (c2 / combine-01) :mod (a2 / also)) # ::id a_pmid_2514_2146.188 # ::date 2015-06-13T16:11:12 # ::file a_pmid_2514_2146_188.txt # ::snt Four intermediately sensitive cell lines to BRAFi became highly sensitive to the combination, with improved pathway inhibition compared to ERK inhibition alone in all cases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (b / become-01 :ARG1 (c / cell-line :quant "4" :ARG0-of (s / sensitive-03 :ARG1 (m / molecular-physical-entity :ARG0-of (i5 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :degree (i / intermediate))) :ARG2 (s2 / sensitive-03 :ARG0 c :ARG1 (c2 / combine-01) :ARG1-of (h / high-02)) :prep-with (i2 / inhibit-01 :ARG1 (p / pathway) :ARG1-of (i3 / improve-01) :compared-to (i4 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :mod (a / alone) :prep-in (c3 / case-04 :mod (a2 / all))))) # ::id a_pmid_2514_2146.189 # ::date 2015-06-15T15:23:14 # ::file a_pmid_2514_2146_189.txt # ::snt More importantly, highly resistant cell lines to BRAFi became sensitive (M420, M308, M410) or intermediately sensitive (M417, M370, M229AR, M409AR1) to the combination. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (b / become-01 :ARG1 (c / cell-line :ARG0-of (r / resist-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1-of (h / high-02))) :ARG2 (o / or :op1 (s / sensitive-03 :ARG0 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "M420")) :op2 (c3 / cell-line :name (n3 / name :op1 "M308")) :op3 (c4 / cell-line :name (n4 / name :op1 "M410"))) :ARG1 (c5 / combine-01)) :op2 (s2 / sensitive-03 :ARG0 (a2 / and :op1 (c6 / cell-line :name (n5 / name :op1 "M417")) :op2 (c7 / cell-line :name (n6 / name :op1 "M370")) :op3 (c8 / cell-line :name (n7 / name :op1 "M229AR")) :op4 (c9 / cell-line :name (n8 / name :op1 "M409AR1"))) :ARG1 c5 :degree (i / intermediate))) :manner (i2 / important :degree (m / more))) # ::id a_pmid_2514_2146.190 # ::date 2015-06-15T15:49:26 # ::file a_pmid_2514_2146_190.txt # ::snt Three remained resistant but with a slightly improved IC50. C.I.s demonstrated synergy with combined BRAF and ERK inhibition for all cell lines except M308, in which dual treatment with vemurafenib and SCH772984 is only additive (Figure 5D).

Susceptibility ofBRAFmutant melanoma cell lines to MAPK inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / multi-sentence :snt2 (d / demonstrate-01 :ARG0 (i3 / index :mod (c3 / combine-01)) :ARG1 (s / synergize-01 :ARG0 i3 :ARG1 (i4 / inhibit-01 :ARG1 (a3 / and :op1 (e4 / enzyme :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (e / enzyme :name (n / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :location (c7 / cell-line :mod (a / all) :ARG2-of (e2 / except-01 :ARG1 (c8 / cell-line :name (n4 / name :op1 "M308") :location-of (a2 / add-02 :ARG1 (t2 / treat-04 :ARG2 (a4 / and :op1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s4 / small-molecule :name (n9 / name :op1 "SCH772984") :xref (x4 / xref :value "PUBCHEM:24866313" :prob "19.266134"))) :mod (d2 / dual)) :mod (o / only))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5D"))) :snt3 (s2 / susceptible :domain (c9 / cell-line :part-of (m6 / medical-condition :name (n8 / name :op1 "melanoma") :mod (e3 / enzyme :name (n5 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :prep-to (m4 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MAPK")))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "5"))) :snt1 (r3 / remain-01 :ARG1 (c2 / cell-line :quant "3") :ARG3 (r / resist-01 :ARG0 c2 :ARG1-of (c / contrast-01 :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 c2 :ARG2 "50" :ARG1-of (i2 / improve-01)))))) # ::id a_pmid_2514_2146.191 # ::date 2015-06-15T15:53:38 # ::file a_pmid_2514_2146_191.txt # ::snt Percent growth inhibition of (A) M238 and (B) M792. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "M238") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) :op2 (c2 / cell-line :name (n2 / name :op1 "M792") :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5B")))) :quant (p / percent))) # ::id a_pmid_2514_2146.192 # ::date 2015-06-15T16:00:09 # ::file a_pmid_2514_2146_192.txt # ::snt After 120 hours treatment with 0–10 μM vemurafenib (V, squares), SCH722984 (E, circles), or the combination (V + E, triangles), cell viability was determined by bioluminescence assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / determine-01 :ARG1 (v / viability :poss (c / cell)) :ARG2 (a / assay-01 :ARG1 (b / bioluminescence)) :time (a2 / after :op1 (t2 / treat-04 :ARG2 (o / or :op1 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib") :ARG1-of (l / label-01 :ARG0 (a4 / and :op2 (s / string-entity :value "V") :op2 (s4 / square))) :quant (v2 / value-interval :op1 (c4 / concentration-quantity :quant "0" :unit (m / micromolar)) :op2 (c5 / concentration-quantity :quant "10" :unit m)) :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s2 / small-molecule :name (n / name :op1 "SCH722984") :ARG1-of (d3 / describe-01 :ARG0 (a5 / and :op1 (s5 / string-entity :value "E") :op2 (c2 / circle)))) :op3 (c3 / combine-01 :ARG1 s3 :ARG2 s2 :ARG1-of (d4 / describe-01 :ARG0 (a6 / and :op1 (s6 / string-entity :value "V+E") :op2 (t4 / triangle))))) :duration (t / temporal-quantity :quant "120" :unit (h / hour))))) # ::id a_pmid_2514_2146.193 # ::date 2015-06-15T11:31:23 # ::file a_pmid_2514_2146_193.txt # ::snt Results are representative data in duplicate from three independent experiments (n = 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (d / data :ARG0-of (r / represent-01) :ARG0-of (d2 / duplicate-01 :ARG1 (e / experiment-01 :quant "3" :ARG0-of (d3 / depend-01 :polarity "-")) :ARG1-of (m / mean-01 :ARG2 (e2 / experiment-01 :quant "6"))) :domain (t / thing :ARG2-of (r2 / result-01))) # ::id a_pmid_2514_2146.194 # ::date 2015-06-15T05:34:20 # ::file a_pmid_2514_2146_194.txt # ::snt C. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (f / figure :mod "5C") # ::id a_pmid_2514_2146.195 # ::date 2015-06-14T04:32:18 # ::file a_pmid_2514_2146_195.txt # ::snt Effect of BRAF-, ERK- inhibition or the combination on MAPK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / affect-01 :ARG0 (o2 / or :op1 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op3 (c / combine-01 :ARG1 i :ARG2 i2)) :ARG1 (s / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "MAPK")))) # ::id a_pmid_2514_2146.196 # ::date 2015-06-14T05:03:53 # ::file a_pmid_2514_2146_196.txt # ::snt Cell lines were treated with DMSO (control, C), 500 nM Vemurafenib (BRAFi, B), 500 nM SCH722984 (ERKi, E) or the combination of vemurafenib and SCH722984 (B + E) for 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t2 / treat-04 :ARG1 (c / cell-line) :ARG2 (o / or :op1 (s4 / small-molecule :name (n5 / name :op1 "DMSO") :ARG1-of (l / label-01 :ARG2 (c2 / control)) :xref (x2 / xref :value "PUBCHEM:679" :prob "16.740406")) :op2 (s2 / small-molecule :name (n4 / name :op1 "vemurafenib") :quant (c4 / concentration-quantity :quant "500" :unit (n2 / nanomolar)) :ARG1-of (l2 / label-01 :ARG2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op3 (s / small-molecule :name (n / name :op1 "SCH722984") :quant (c5 / concentration-quantity :quant "500" :unit (n3 / nanomolar)) :ARG1-of (l3 / label-01 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n6 / name :op1 "ERK")))))) :op4 (c3 / combine-01 :ARG1 s2 :ARG2 s :ARG1-of (l4 / label-01 :ARG2 (s3 / string-entity :value "B+E")))) :duration (t3 / temporal-quantity :quant "24" :unit (h2 / hour))) # ::id a_pmid_2514_2146.197 # ::date 2015-06-14T05:34:14 # ::file a_pmid_2514_2146_197.txt # ::snt Western blots analyzed for phospho- and total MEK, ERK1/2, RSK, AKT and actin as loading control. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a7 / analyze-01 :purpose (a3 / and :op1 (a4 / and :op1 (e2 / enzyme :name (n / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e / enzyme :name (n2 / name :op1 "ERK1/2")) :op3 (e3 / enzyme :name (n4 / name :op1 "RSK") :xref (x2 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")) :op4 (e4 / enzyme :name (n5 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op5 "p2" :ARG3-of (p / phosphorylate-01)) :op2 (a5 / and :op1 e2 :op2 e :op3 e3 :op4 e4 :op5 (p2 / protein :name (n6 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :mod (t / total)) :ARG0-of (c / control-01 :ARG1 (l / load-01))) :manner (i / immunoblot-01)) # ::id a_pmid_2514_2146.198 # ::date 2015-06-14T06:02:13 # ::file a_pmid_2514_2146_198.txt # ::snt D. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / string-entity :value "D") # ::id a_pmid_2514_2146.199 # ::date 2015-06-14T06:02:45 # ::file a_pmid_2514_2146_199.txt # ::snt IC50 (nM) to MAPK inhibitors and synergistic effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :wiki "Mitogen-activated_protein_kinase" :name (n / name :op1 "MAPK")))) :ARG4 (c / concentration-quantity :unit (n2 / nanomolar))) :op2 (a2 / affect-01 :ARG2 (s / synergize-01))) # ::id a_pmid_2514_2146.200 # ::date 2015-06-15T09:33:41 # ::file a_pmid_2514_2146_200.txt # ::snt BRAF-mutant melanoma cell lines were treated with 0–10 μM vemurafenib (BRAFi) or SCH722984 (ERKi), the combination (B + E) or 0–1 μM trametinib (MEKi). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (t / treat-04 :ARG1 (c / cell-line :part-of (m5 / medical-condition :name (n4 / name :op1 "melanoma") :mod (e3 / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (o / or :op1 (s2 / small-molecule :name (n7 / name :op1 "vemurafenib") :quant (c2 / concentration-quantity :unit (m3 / micromolar) :quant (v / value-interval :op1 "1" :op2 "10")) :ARG0-of (i2 / inhibit-01 :ARG1 (e4 / enzyme :name (n9 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :xref (x4 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s / small-molecule :name (n2 / name :op1 "SCH722984") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "ERK")))) :op3 (c3 / combine-01 :ARG1 s2 :ARG2 s :ARG1-of (l / label-01 :ARG2 (s4 / string-entity :value "B+E"))) :op4 (s3 / small-molecule :name (n8 / name :op1 "trametinib") :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :quant (c4 / concentration-quantity :unit (m4 / micromolar) :quant (b2 / between :op1 "0" :op2 "1")) :xref (x3 / xref :value "PUBCHEM:11707110" :prob "17.561386")))) # ::id a_pmid_2514_2146.201 # ::date 2015-06-14T03:07:21 # ::file a_pmid_2514_2146_201.txt # ::snt Green indicates sensitivity, yellow intermediately sensitive, and red for resistant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (i / indicate-01 :ARG0 (g / green-02) :ARG1 (s / sensitive-03)) :op2 (i2 / indicate-01 :ARG0 (y / yellow-02) :ARG1 (s2 / sensitive-03 :degree (i4 / intermediate))) :op3 (i3 / indicate-01 :ARG0 (r / red-02) :ARG1 (r2 / resist-01))) # ::id a_pmid_2514_2146.202 # ::date 2015-06-14T03:10:24 # ::file a_pmid_2514_2146_202.txt # ::snt The CI column indicates the combination index of vemurafenib and SCH722984.

# ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / indicate-01 :ARG0 (c / column :mod (s3 / string-entity :value "CI")) :ARG1 (i2 / index :mod (c2 / combine-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"))))) # ::id a_pmid_2514_2146.203 # ::date 2015-06-14T03:18:42 # ::file a_pmid_2514_2146_203.txt # ::snt We next examined whether cells inherently resistant to BRAFi could be sensitive to a MEK inhibitor (MEKi) or ERKi. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e2 / examine-01 :ARG0 (w / we) :ARG1 (p / possible-01 :mode "interrogative" :ARG1 (s / sensitive-03 :ARG0 (c / cell :ARG0-of (r / resist-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :mod (i4 / inherent))) :ARG1 (o / or :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n4 / name :op1 "ERK"))))))) :mod (n2 / next)) # ::id a_pmid_2514_2146.204 # ::date 2015-06-14T03:19:57 # ::file a_pmid_2514_2146_204.txt # ::snt Sensitivity of BRAF mutant melanoma cell lines to BRAFi predicted sensitivity to MEK and ERK inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (p / predict-01 :ARG0 (s2 / sensitive-03 :ARG0 (c / cell-line :mod (g / gene :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :part-of (m / medical-condition :name (n5 / name :op1 "melanoma"))) :ARG1 (m5 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG1 (s / sensitive-03 :ARG1 (a / and :op1 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / protein-family :name (n3 / name :op1 "MEK")))) :op2 (m4 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n4 / name :op1 "ERK"))))))) # ::id a_pmid_2514_2146.205 # ::date 2015-06-14T03:36:53 # ::file a_pmid_2514_2146_205.txt # ::snt Furthermore, 10 cell lines inherently resistant to BRAFi were often sensitive to MEK and ERK inhibition, and cell lines resistant to BRAFi or MEKi were relatively more sensitive to SCH722984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op2 (a2 / and :op1 (s / sensitive-03 :ARG0 (c / cell-line :quant "10" :ARG0-of (r / resist-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :manner (i / inherent))) :ARG1 (i2 / inhibit-01 :ARG1 (a3 / and :op1 (e3 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n5 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :frequency (o / often))) :op2 (s2 / sensitive-03 :ARG0 (c2 / cell-line :ARG0-of (r3 / resist-01 :ARG1 (o2 / or :op1 m2 :op2 (m3 / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 e3))))) :ARG1 (s3 / small-molecule :name (n / name :op1 "SCH722984")) :degree (m / more) :ARG2-of (r2 / relative-05))) # ::id a_pmid_2514_2146.206 # ::date 2015-06-15T09:52:29 # ::file a_pmid_2514_2146_206.txt # ::snt Indeed, combining BRAF with ERK inhibition potently decreased the equimolar IC50 of all cell lines and resulted in synergy in all but one case (M308), including M255, M399 and M420, which are completely resistant to individual inhibitors (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (d / decrease-01 :ARG0 (c2 / combine-01 :ARG1 (i5 / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (c3 / cell-line :mod (a3 / all)) :ARG2 "50" :mod (e4 / equimolar)) :manner (p / potent)) :op2 (r / result-01 :ARG1 c2 :ARG2 (s / synergize-01) :prep-in (c / case-04 :ARG1-of (i2 / include-91 :ARG2 (a4 / and :op1 (c6 / cell-line :name (n5 / name :op1 "M255")) :op2 (c7 / cell-line :name (n6 / name :op1 "M399")) :op3 (c8 / cell-line :name (n7 / name :op1 "M420")) :ARG0-of (r2 / resist-01 :ARG1 (m2 / molecular-physical-entity :mod (i3 / individual) :ARG0-of (i4 / inhibit-01))))) :mod a3 :ARG2-of (e3 / except-01 :ARG1 (c5 / cell-line :name (n4 / name :op1 "M308"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5D")) :mod (i6 / indeed)) # ::id a_pmid_2514_2146.207 # ::date 2015-06-14T04:09:18 # ::file a_pmid_2514_2146_207.txt # ::snt Because the combination on BRAF combined with MEK inhibition is currently FDA approved for BRAFV600 mutant melanoma, we also determined the IC50 for the combination of vemurafenib and trametinib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / cause-01 :ARG0 (a2 / approve-01 :ARG0 (o / organization :name (n4 / name :op1 "FDA")) :ARG1 (c3 / combine-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF") :ARG1-of (c4 / combine-01 :ARG2 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :time (c5 / current) :purpose (m3 / medical-condition :name (n2 / name :op1 "melanoma") :mod (g / gene :name (n5 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1 (d / determine-01 :ARG0 (w / we) :ARG1 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (c2 / combine-01 :ARG1 (s / small-molecule :name (n6 / name :op1 "vemurafenib") :xref (x4 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 (s2 / small-molecule :name (n7 / name :op1 "trametinib") :xref (x3 / xref :value "PUBCHEM:11707110" :prob "17.561386"))) :ARG2 "50") :mod (a / also))) # ::id a_pmid_2514_2146.208 # ::date 2015-06-13T14:55:05 # ::file a_pmid_2514_2146_208.txt # ::snt The results showed potent growth inhibition and synergy in all cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01)) :ARG1 (a / and :op1 (i / inhibit-01 :ARG1 (g / grow-01) :mod (p / potent)) :op2 (s2 / synergize-01) :location (c / cell-line :mod (a2 / all)))) # ::id a_pmid_2514_2146.209 # ::date 2015-06-13T14:58:19 # ::file a_pmid_2514_2146_209.txt # ::snt Sensitivity to the vemurafenib + trametinib combination generally overlapped with sensitivity to the vemurafenib + SCH722984 combination (Figure 5D), consistent with the idea that both combinations cause dual MAPK blockade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (o / overlap-01 :ARG0 (s / sensitive-03 :ARG1 (t / thing :ARG3-of (c / combine-01 :ARG1 (s4 / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 (s5 / small-molecule :name (n4 / name :op1 "trametinib") :xref (x / xref :value "PUBCHEM:11707110" :prob "17.561386"))))) :ARG1 (s2 / sensitive-03 :ARG1 (t2 / thing :ARG3-of (c2 / combine-01 :ARG1 s4 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "SCH722984"))))) :ARG1-of (g / general-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5D")) :ARG1-of (c4 / consistent-01 :ARG2 (i / idea :topic (c5 / cause-01 :ARG0 (a / and :op1 t :op2 t2) :ARG1 (b / blockade-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :mod (d2 / dual)))))) # ::id a_pmid_2514_2146.210 # ::date 2015-06-15T14:14:50 # ::file a_pmid_2514_2146_210.txt # ::snt The growth curves for the vemurafenib + trametinib combinations are shown in Additional file 5: Figure S5. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (s / show-01 :ARG0 (f / file :mod "5" :mod (a / additional) :ARG1-of (m / mean-01 :ARG2 (f2 / figure :mod "S5"))) :ARG1 (c / curve :topic (g / grow-01 :ARG1 (c2 / combine-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "trametinib") :xref (x / xref :value "PUBCHEM:11707110" :prob "17.561386")))))) # ::id a_pmid_2514_2146.211 # ::date 2015-06-14T04:03:50 # ::file a_pmid_2514_2146_211.txt # ::snt Effects of MAPK pathway inhibition on cell cycle progression and apoptosis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / affect-01 :ARG0 (i / inhibit-01 :ARG0 (p / pathway :name (n / name :op1 "MAPK"))) :ARG1 (a2 / and :op1 (p2 / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell))) :op2 (a3 / apoptosis))) # ::id a_pmid_2514_2146.212 # ::date 2015-06-14T04:08:21 # ::file a_pmid_2514_2146_212.txt # ::snt To determine the effect of BRAF or ERK inhibition on cell cycle progression and apoptosis, cells were treated with SCH772984, alone or in combination with vemurafenib for 48 hours then stained with DAPI and intracellularly for cleaved PARP and analyzed by flow cytometry. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (t2 / treat-04 :ARG1 (c6 / cell-line) :ARG2 (o2 / or :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984") :mod (a5 / alone) :xref (x4 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :op2 (c4 / combine-01 :ARG1 s2 :ARG2 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib") :xref (x3 / xref :value "PUBCHEM:42611257" :prob "17.762056")))) :duration (t / temporal-quantity :quant "48" :unit (h / hour))) :op2 (s / stain-01 :ARG1 c6 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "DAPI") :xref (x5 / xref :value "PUBCHEM:2954" :prob "18.167522")) :manner (i3 / intracellular) :purpose (p2 / protein :name (n5 / name :op1 "PARP") :ARG1-of (c3 / cleave-01) :xref (x1 / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :time (t3 / then)) :op3 (a6 / analyze-01 :ARG1 c6 :manner (c5 / cytometry :mod (f / flow))) :purpose (d / determine-01 :ARG1 (a2 / affect-01 :ARG0 (i / inhibit-01 :ARG1 (o3 / or :op1 (e2 / enzyme :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (a3 / and :op1 (p / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell))) :op2 (a4 / apoptosis))))) # ::id a_pmid_2514_2146.213 # ::date 2015-06-15T15:22:10 # ::file a_pmid_2514_2146_213.txt # ::snt Treatment with either of these two inhibitors resulted in an increase in the sub-G0 population, the G1 population, as well as an increase in cleaved PARP levels which indicates apoptotic cells (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / result-01 :ARG1 (t2 / treat-04 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01) :ARG1-of (i4 / include-91 :ARG2 (m2 / molecular-physical-entity :quant "2" :mod (t3 / this))) :mod (e / either))) :ARG2 (i2 / increase-01 :ARG1 (a / and :op1 (p / population :mod (e2 / event :name (n / name :op1 "sub-G0"))) :op2 (p4 / population :mod (e3 / event :name (n3 / name :op1 "G1"))) :op3 (l / level :quant-of (p3 / protein :name (n2 / name :op1 "PARP") :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :ARG1-of (c2 / cleave-01)) :ARG0-of (i3 / indicate-01 :ARG1 (c / cell :mod (a2 / apoptosis))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id a_pmid_2514_2146.214 # ::date 2015-06-13T16:12:03 # ::file a_pmid_2514_2146_214.txt # ::snt A modest increase of 3-10% was seen in the sub-G0 population for all cell lines treated with vemurafenib, SCH772984 or the combination. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / see-01 :ARG1 (i / increase-01 :ARG2 (v / value-interval :op1 (p2 / percentage-entity :value "3") :op2 (p / percentage-entity :value "10")) :mod (m / modest)) :location (p3 / populate-01 :ARG1 (c / cell-line :mod (a / all) :ARG1-of (t / treat-04 :ARG2 (o / or :op1 (s3 / small-molecule :name (n2 / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s2 / small-molecule :name (n / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :op3 (c3 / combine-01 :ARG1 s3 :ARG2 s2)))) :time (e / event :name (n3 / name :op1 "sub-GO")))) # ::id a_pmid_2514_2146.215 # ::date 2015-06-13T16:17:37 # ::file a_pmid_2514_2146_215.txt # ::snt The amount of subG1 increase did not correlate with sensitivity or resistance to the MAPK pathway inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / correlate-01 :polarity "-" :ARG1 (a / amount-01 :ARG1 (i2 / increase-01 :time (e / event :name (n2 / name :op1 "subG1")))) :ARG2 (o / or :op1 (s / sensitive-03 :ARG1 (m / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / pathway :name (n3 / name :op1 "MAPK"))))) :op2 (r / resist-01 :ARG1 m))) # ::id a_pmid_2514_2146.216 # ::date 2015-06-14T02:35:28 # ::file a_pmid_2514_2146_216.txt # ::snt In contrast, for the G0-G1 populations, there was a correlation with sensitivity, with an up to 40% increase in G0-G1 population seen in the sensitive cell lines M238 and M792, while the resistant cell lines M233 and M299 demonstrated only a 10% increase in the G0-G1 population for the combination treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (c2 / correlate-01 :ARG1 (p / population :mod (e / event :name (n3 / name :op1 "G0-G1"))) :ARG2 (s3 / sensitive-03) :prep-with (i / increase-01 :ARG1 p :ARG2 (u / up-to :op1 (p3 / percentage-entity :value "40")) :ARG1-of (s / see-01 :location (a / and :op1 (c3 / cell-line :name (n / name :op1 "M238")) :op2 (c4 / cell-line :name (n2 / name :op1 "M792")) :ARG0-of (s2 / sensitive-03))))) :ARG2 (d / demonstrate-01 :ARG0 (a2 / and :op1 (c5 / cell-line :name (n4 / name :op1 "M233")) :op2 (c6 / cell-line :name (n5 / name :op1 "M299")) :ARG1-of (t / treat-04 :ARG2 (c7 / combine-01)) :ARG0-of (r / resist-01)) :ARG1 (i2 / increase-01 :ARG1 p :ARG2 (p4 / percentage-entity :value "10")))) # ::id a_pmid_2514_2146.217 # ::date 2015-06-15T16:21:56 # ::file a_pmid_2514_2146_217.txt # ::snt Concomitant with the increase in G0-G1, a decreased proportion of cells were observed in S-phase, with the largest decreases of over 20% seen in the sensitive cell lines M792 and M238 (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (o / observe-01 :ARG1 (a2 / and :op1 (p3 / proportion-01 :ARG1 (c / cell) :ARG1-of (d2 / decrease-01 :time (e / event :name (n5 / name :op1 "S-phase")))) :op2 (i / increase-01 :time (e2 / event :name (n / name :op1 "G0-G1"))) :op3 (d3 / decrease-01 :ARG2 (o2 / over :op1 (p5 / percentage-entity :value "20")) :mod (l2 / large :degree (m2 / most)) :ARG1-of (s / see-01 :location (a / and :op1 (c2 / cell-line :name (n3 / name :op1 "M792")) :op2 (c3 / cell-line :name (n4 / name :op1 "M238")) :ARG0-of (s2 / sensitive-03))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B")) :mod (c4 / concomitant)) # ::id a_pmid_2514_2146.218 # ::date 2015-06-14T00:01:32 # ::file a_pmid_2514_2146_218.txt # ::snt Treatment of the sensitive cell lines, M238 and M792, with SCH772984 alone or in combination with vemurafenib resulted in a dramatic increase in cleaved PARP reaching induced percentages around 40-50%. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG1 (a2 / and :op1 (c2 / cell-line :name (n / name :op1 "M238")) :op2 (c3 / cell-line :name (n2 / name :op1 "M792")) :ARG0-of (s / sensitive-03)) :ARG2 (o / or :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984") :mod (a3 / alone) :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :op2 (c / combine-01 :ARG1 s2 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056"))))) :ARG2 (i / increase-01 :ARG1 (p2 / protein :name (n5 / name :op1 "PARP") :ARG1-of (c4 / cleave-01) :ARG0-of (r2 / reach-01 :ARG1 (p3 / percentage :ARG2-of (i2 / induce-01) :ARG1-of (e2 / equal-01 :ARG2 (a4 / around :op1 (v / value-interval :op1 (p4 / percentage-entity :value "40") :op2 (p5 / percentage-entity :value "50") :mod (a / around)))))) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :degree (d / dramatic))) # ::id a_pmid_2514_2146.219 # ::date 2015-06-14T00:39:07 # ::file a_pmid_2514_2146_219.txt # ::snt In comparison, the resistant cell lines (M233 and M299) had cleaved PARP at 20-25% (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (c / compare-01 :ARG2 (h / have-03 :ARG0 (a / and :op1 (c3 / cell-line :name (n / name :op1 "M233")) :op2 (c4 / cell-line :name (n2 / name :op1 "M299")) :ARG0-of (r / resist-01)) :ARG1 (p2 / protein :name (n3 / name :op1 "PARP") :ARG1-of (c2 / cleave-01) :quant (v / value-interval :op1 (p / percentage-entity :value "20") :op2 (p3 / percentage-entity :value "25")) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id a_pmid_2514_2146.220 # ::date 2015-06-14T00:46:28 # ::file a_pmid_2514_2146_220.txt # ::snt With the exception of M299, a statistically significant increase in cleaved PARP was seen in all cell lines treated with SCH772984, or the combination of SCH772984 and vemurafenib, compared to vemurafenib alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (s / see-01 :ARG1 (i / increase-01 :ARG1 (p / protein :name (n / name :op1 "PARP") :ARG1-of (c / cleave-01) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :ARG2 (s2 / significant-02 :mod (s3 / statistics)) :location (c2 / cell-line :ARG1-of (t / treat-04 :ARG2 (o / or :op1 (s4 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :op2 (c3 / combine-01 :ARG1 s4 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056"))))) :ARG2-of (e3 / except-01 :ARG1 (c4 / cell-line :name (n5 / name :op1 "M299"))) :mod (a2 / all)) :compared-to (t2 / treat-04 :ARG2 s5 :mod (a / alone)))) # ::id a_pmid_2514_2146.221 # ::date 2015-06-14T01:02:18 # ::file a_pmid_2514_2146_221.txt # ::snt Combinatorial treatment offered a statistically significant increase in cleaved PARP compared to vemurafenib alone in all cell lines (20% increase in sensitive cell lines and 10% increase in resistant cell lines compared to vemurafenib alone). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (o / offer-01 :ARG0 (t / treat-04 :mod (c / combine-01)) :ARG1 (i / increase-01 :ARG1 (p3 / protein :name (n / name :op1 "PARP") :ARG1-of (c2 / cleave-01) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :ARG2 (s / significant-02 :mod (s2 / statistics)) :compared-to (o2 / offer-01 :ARG0 (t2 / treat-04 :ARG2 (s4 / small-molecule :name (n2 / name :op1 "vemurafenib") :mod (a2 / alone) :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")))) :location (c3 / cell-line :mod (a / all)) :ARG1-of (e2 / equal-01 :ARG2 (a3 / and :op1 (i3 / increase-01 :ARG2 (p4 / percentage-entity :value "20") :location (c4 / cell-line :ARG1-of (s3 / sensitive-03))) :op2 (i4 / increase-01 :ARG2 (p5 / percentage-entity :value "10") :location (c5 / cell-line :ARG0-of (r / resist-01))))))) # ::id a_pmid_2514_2146.222 # ::date 2015-06-14T01:16:42 # ::file a_pmid_2514_2146_222.txt # ::snt However only a trend towards increased cleaved PARP fractions was observed comparing combinatorial treatment with SCH772984 alone without reaching statistical significance.

Effect of SCH722984, vemurafenib or the combination on cell cycle progression and apoptosis in BRAF-mutant melanoma cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (c8 / contrast-01 :ARG2 (o / observe-01 :ARG1 (t / trend-01 :ARG2 (f / fraction-01 :ARG1 (p / protein :name (n / name :op1 "PARP") :ARG1-of (c / cleave-01) :xref (x1 / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :ARG1-of (i / increase-01 :ARG0-of (r / reach-01 :polarity "-" :ARG1 (s2 / significant-02 :mod (s3 / statistics))))) :mod (o3 / only)) :condition (c2 / compare-01 :ARG1 (t2 / treat-04 :mod (c3 / combine-01)) :ARG2 (t3 / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "SCH772984") :mod (a3 / alone) :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134")))))) :snt2 (a / affect-01 :ARG0 (o2 / or :op1 (s4 / small-molecule :name (n3 / name :op1 "SCH722984")) :op2 (s5 / small-molecule :name (n4 / name :op1 "vemurafenib") :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op3 (c4 / combine-01 :ARG1 s4 :ARG2 s5)) :ARG1 (a2 / and :op1 (p2 / progress-01 :ARG1 (c5 / cycle-02 :ARG1 (c6 / cell))) :op2 (a4 / apoptosis)) :location (c7 / cell-line :mod (m3 / medical-condition :name (n6 / name :op1 "melanoma") :mod (e2 / enzyme :name (n7 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6")))) # ::id a_pmid_2514_2146.223 # ::date 2015-06-14T01:36:07 # ::file a_pmid_2514_2146_223.txt # ::snt Two sensitive cell lines (M238 and M792) and two resistant cell lines (M233 and M299) were exposed to DMSO as vehicle control (Unst, control unstained: Control, control stained), 1 μM vemurafenib (Vem), SCH722984 (ERKi), the combination (V + E) or 1 μM staurosporine for 48 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a4 / and :op1 (e / expose-01 :ARG1 (a / and :op1 (c2 / cell-line :name (n / name :op1 "M238")) :op2 (c3 / cell-line :name (n2 / name :op1 "M792")) :ARG0-of (s / sensitive-03)) :ARG2 (o / or :op1 (s2 / small-molecule :name (n5 / name :op1 "DMSO") :ARG0-of (c5 / control-01 :ARG1 (v / vehicle) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (s3 / stain-01 :ARG1 c5) :op2 (s8 / stain-01 :polarity "-" :ARG1 c5)))) :xref (x / xref :value "PUBCHEM:679" :prob "16.740406")) :op2 (s4 / small-molecule :name (n7 / name :op1 "vemurafenib") :quant (c7 / concentration-quantity :quant "1" :unit (m2 / micromolar)) :xref (x2 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op3 (s6 / small-molecule :name (n9 / name :op1 "SCH722984") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n6 / name :op1 "ERK")))) :op4 (c8 / combine-01 :ARG1 s4 :ARG2 s6 :ARG1-of (l / label-01 :ARG2 (s5 / string-entity :value "V+E"))) :op5 (s7 / small-molecule :name (n10 / name :op1 "staurosporine") :quant (c9 / concentration-quantity :quant "1" :unit (m3 / micromolar)) :xref (x1 / xref :value "PUBCHEM:5279" :prob "16.295719"))) :duration (t2 / temporal-quantity :quant "48" :unit (h2 / hour))) :op2 (e3 / expose-01 :ARG1 (a3 / and :op1 (c / cell-line :name (n3 / name :op1 "M233")) :op2 (c4 / cell-line :name (n4 / name :op1 "M299")) :ARG0-of (r / resist-01)) :ARG2 (o2 / or :op1 s2 :op2 s4 :op3 s6 :op4 c8 :op5 s7) :duration t2)) # ::id a_pmid_2514_2146.224 # ::date 2015-06-14T03:37:23 # ::file a_pmid_2514_2146_224.txt # ::snt A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "A") # ::id a_pmid_2514_2146.225 # ::date 2015-06-14T03:41:22 # ::file a_pmid_2514_2146_225.txt # ::snt Cell cycle progression was tested by DAPI staining solution and induced apoptosis by cleaved PARP (PARP-Ax700). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (t / test-01 :ARG0 (s / solution :mod (s2 / stain-01 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "DAPI") :xref (x2 / xref :value "PUBCHEM:2954" :prob "18.167522")))) :ARG1 (p / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)))) :op2 (i / induce-01 :ARG0 p :ARG2 (a2 / apoptosis) :instrument (p2 / protein :name (n2 / name :op1 "PARP") :ARG1-of (c3 / cleave-01) :ARG1-of (e / equal-01 :ARG2 (p3 / protein :name (n3 / name :op1 "PARP") :mod (s4 / small-molecule :name (n5 / name :op1 "Ax700")) :xref (x1 / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352"))) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")))) # ::id a_pmid_2514_2146.226 # ::date 2015-06-14T03:48:25 # ::file a_pmid_2514_2146_226.txt # ::snt Figures are representative of triplicate experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (r2 / represent-01 :ARG0 (f / figure) :ARG1 (e / experiment :quant "3")) # ::id a_pmid_2514_2146.227 # ::date 2015-06-14T03:54:47 # ::file a_pmid_2514_2146_227.txt # ::snt B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "B") # ::id a_pmid_2514_2146.228 # ::date 2015-06-14T03:55:13 # ::file a_pmid_2514_2146_228.txt # ::snt Quantitative analysis of the cell cycle progression by DAPI staining using flow cytometry shows the percentage of cells in sub-G0 (blue), G0/G1 (red), S phase (yellow), or G2/M (green). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (p / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :instrument (s2 / stain-01 :ARG2 (s5 / small-molecule :name (n / name :op1 "DAPI") :xref (x / xref :value "PUBCHEM:2954" :prob "18.167522")) :ARG0-of (u / use-01 :ARG1 (c3 / cytometry :mod (f / flow))))) :mod (q / quantitative)) :ARG1 (o / or :op1 (p2 / percentage :quant-of (c4 / cell :ARG1-of (c5 / color-01 :ARG2 (b / blue)) :mod (e / event :name (n2 / name :op1 "sub-G0")))) :op2 (p3 / percentage :quant-of (c6 / cell :ARG1-of (c7 / color-01 :ARG2 (r / red-02)) :mod (s3 / slash :op1 (e2 / event :name (n6 / name :op1 "G0")) :op2 (e3 / event :name (n7 / name :op1 "G1"))))) :op3 (p4 / percentage :quant-of (c8 / cell :ARG1-of (c9 / color-01 :ARG2 (y / yellow-02)) :mod (e4 / event :name (n5 / name :op1 "S" :op2 "phase")))) :op4 (p5 / percentage :quant-of (c10 / cell :ARG1-of (c11 / color-01 :ARG2 (g / green-02)) :mod (s4 / slash :op1 (e5 / event :name (n3 / name :op1 "G2")) :op2 (e6 / event :name (n8 / name :op1 "M"))))))) # ::id a_pmid_2514_2146.229 # ::date 2015-06-14T04:05:29 # ::file a_pmid_2514_2146_229.txt # ::snt Numbers on the bar graph represent percentage of cells in G0/G1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / represent-01 :ARG0 (n / number :mod (g / graph :mod (b / bar))) :ARG1 (p / percentage :quant-of (c / cell) :mod (s / slash :op1 (e / event :name (n2 / name :op1 "G0")) :op2 (e2 / event :name (n3 / name :op1 "G1"))))) # ::id a_pmid_2514_2146.230 # ::date 2015-06-14T04:08:39 # ::file a_pmid_2514_2146_230.txt # ::snt Columns represent mean values of three independent experiments (n = 3); bars, SEM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (r / represent-01 :ARG0 (c / column) :ARG1 (v / value :mod (m / mean) :poss (e / experiment :quant "3" :ARG0-of (d / depend-01 :polarity "-"))) :ARG1-of (m2 / mean-01 :ARG2 (e2 / equal-01 :ARG1 (v2 / variable :name (n / name :op1 "n")) :ARG2 "3"))) :op2 (b / bar) :op3 (m3 / mean :mod (e3 / error :ARG1-of (s / standard-02)))) # ::id a_pmid_2514_2146.231 # ::date 2015-06-14T04:15:19 # ::file a_pmid_2514_2146_231.txt # ::snt C. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / string-entity :value "C") # ::id a_pmid_2514_2146.232 # ::date 2015-06-14T04:15:39 # ::file a_pmid_2514_2146_232.txt # ::snt Apoptosis in response to MAPK inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / respond-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "MAPK")))) :ARG2 (a / apoptosis)) # ::id a_pmid_2514_2146.233 # ::date 2015-06-14T04:19:53 # ::file a_pmid_2514_2146_233.txt # ::snt Percentage of apoptotic cells positive for cleaved PARP (PARP-Ax700) in this four melanoma cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (p6 / percentage :quant-of (c / cell :mod (p5 / positive :topic (p3 / protein :name (n2 / name :op1 "PARP") :ARG1-of (c2 / cleave-01 :ARG2 (p4 / protein :name (n3 / name :op1 "PARP") :mod (s / small-molecule :name (n5 / name :op1 "Ax700")) :xref (x1 / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352"))) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352"))) :mod (a / apoptosis)) :location (c3 / cell-line :quant "4" :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma")) :mod (t2 / this))) # ::id a_pmid_2514_2146.234 # ::date 2015-06-14T04:26:25 # ::file a_pmid_2514_2146_234.txt # ::snt Columns represent mean values of three independent experiments (n = 3); bars, SEM; *, P < 0.05.

# ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (r / represent-01 :ARG0 (c / column) :ARG1 (v / value :mod (m / mean) :poss (e / experiment :quant "3" :ARG0-of (d / depend-01 :polarity "-")))) :op2 (b / bar) :op3 (m2 / mean-01 :mod (e2 / error :ARG1-of (s / standard-02))) :op3 (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) # ::id a_pmid_2514_2146.235 # ::date 2015-06-14T04:29:49 # ::file a_pmid_2514_2146_235.txt # ::snt To address whether there are differences in MEK inhibition or ERK inhibition on apoptosis, we performed cell cycle analysis on three melanoma cell lines with distinct sensitivity profile to SCH772984: M263 (sensitive), M255 (intermediately sensitive) and M370 (resistant). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / perform-01 :ARG0 (w / we) :ARG1 (a / analyze-01 :ARG0 w :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :location (c3 / cell-line :quant "3" :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma")) :ARG0-of (h / have-03 :ARG1 (p2 / profile-01 :ARG1 (s / sensitive-03 :ARG0 c3 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :mod (d2 / distinct)))) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (c4 / cell-line :name (n5 / name :op1 "M263") :ARG0-of (s3 / sensitive-03 :ARG1 s2)) :op2 (c5 / cell-line :name (n6 / name :op1 "M255") :ARG0-of (s4 / sensitive-03 :ARG1 s2 :mod (i / intermediate))) :op3 (c6 / cell-line :name (n7 / name :op1 "M370") :ARG0-of (r / resist-01 :ARG1 s2)))))) :purpose (a3 / address-02 :ARG0 w :ARG1 (d3 / differ-02 :mode "interrogative" :ARG1 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2 (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG3 (a4 / apoptosis)))) # ::id a_pmid_2514_2146.236 # ::date 2015-06-14T04:43:33 # ::file a_pmid_2514_2146_236.txt # ::snt All three cell lines demonstrated good synergy for the combination of vemurafenib and SCH772984. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (d / demonstrate-01 :ARG0 (c / cell-line :quant "3" :mod (a / all)) :ARG1 (s / synergize-01 :ARG1-of (g / good-02)) :condition (c2 / combine-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134")))) # ::id a_pmid_2514_2146.237 # ::date 2015-06-14T04:53:50 # ::file a_pmid_2514_2146_237.txt # ::snt Cell lines treated with SCH772984 or the combination of vemurafenib + SCH772984 had the highest levels of cleaved PARP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h2 / have-03 :ARG0 (c / cell-line :ARG1-of (t / treat-04 :ARG2 (o / or :op1 (s / small-molecule :name (n / name :op1 "SCH772984") :xref (x2 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :op2 (c2 / combine-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 s)))) :ARG1 (l / level :ARG1-of (h / high-02 :degree (m / most)) :quant-of (p / protein :name (n3 / name :op1 "PARP") :ARG1-of (c3 / cleave-01) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")))) # ::id a_pmid_2514_2146.238 # ::date 2015-06-14T04:58:07 # ::file a_pmid_2514_2146_238.txt # ::snt In comparison, trametinib, did not induce the same levels of apoptosis in any case. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / compare-01 :ARG2 (i / induce-01 :polarity "-" :ARG0 (s2 / small-molecule :name (n / name :op1 "trametinib") :xref (x / xref :value "PUBCHEM:11707110" :prob "17.561386")) :ARG2 (l / level :ARG2-of (s / same-01) :degree-of (a2 / apoptosis)) :prep-in (c2 / case-04 :mod (a / any)))) # ::id a_pmid_2514_2146.239 # ::date 2015-06-14T05:03:37 # ::file a_pmid_2514_2146_239.txt # ::snt In terms of effects on the cell cycle, G0-G1 arrest was maximally induced by ERK inhibition also (Additional file 6: Figure S6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a3 / affect-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :ARG2 (i / induce-01 :ARG0 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2 (a / arrest-02 :time (v / value-interval :op1 (e2 / event :name (n2 / name :op1 "G0")) :op2 (e3 / event :name (n3 / name :op1 "G1")))) :mod (a2 / also) :manner (m / maximal)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S6" :location (f2 / file :mod "6" :ARG1-of (a4 / add-02))))) # ::id a_pmid_2514_2146.240 # ::date 2015-06-14T05:11:13 # ::file a_pmid_2514_2146_240.txt # ::snt This data support the potent activity of SCH772984 both as a single agent and in combination. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / support-01 :ARG0 (d / data :mod (t / this)) :ARG1 (a / activity-06 :ARG0 (a2 / and :op1 (s2 / small-molecule :name (n / name :op1 "SCH772984") :mod (a3 / agent :ARG1-of (s3 / single-02)) :xref (x / xref :value "PUBCHEM:24866313" :prob "19.266134")) :op2 (c / combine-01 :ARG1 s2)) :mod (p / potent))) # ::id a_pmid_2514_2146.241 # ::date 2015-06-14T05:15:34 # ::file a_pmid_2514_2146_241.txt # ::snt Combining BRAF and ERK inhibition delays the development of resistance # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / delay-01 :ARG0 (c / combine-01 :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (d2 / develop-01 :ARG2 (r / resist-01))) # ::id a_pmid_2514_2146.242 # ::date 2015-06-14T05:33:13 # ::file a_pmid_2514_2146_242.txt # ::snt Given the potent synergistic inhibition seen when combining vemurafenib and SCH772984, we hypothesized that chronic exposure to dual inhibition would significantly delay the development of resistance compared to either single agent alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (d2 / delay-01 :ARG0 (e / expose-01 :ARG2 (i / inhibit-01 :mod (d / dual)) :mod (c / chronic)) :ARG1 (d3 / develop-01 :ARG2 (r / resist-01)) :ARG1-of (s / significant-02 :compared-to (a / agent :mod (e3 / either) :ARG1-of (s5 / single-02)))) :ARG1-of (c2 / cause-01 :ARG0 (i2 / inhibit-01 :ARG0-of (s2 / synergize-01) :mod (p / potent) :ARG1-of (s3 / see-01 :time (c3 / combine-01 :ARG1 (s6 / small-molecule :name (n / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 (s4 / small-molecule :name (n2 / name :op1 "SCH772984") :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134"))))))) # ::id a_pmid_2514_2146.243 # ::date 2015-06-14T05:46:37 # ::file a_pmid_2514_2146_243.txt # ::snt To test this hypothesis, long term cultures were established in 96-well plates to allow both qualitative and quantitative assessment of the effect of each drug alone or their combination on M238 and M792, which are highly sensitive to both inhibitors and for which dual therapy was highly synergistic (Figure 7A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (e / establish-01 :ARG1 (c / culture :ARG1-of (l / long-03)) :location (p / plate :quant "96" :mod (w / well)) :purpose (a / allow-01 :ARG1 (a8 / and :op1 (a2 / assess-01 :ARG1 (a4 / affect-01 :ARG0 (o / or :op1 (d / drug :mod (e2 / each) :mod (a5 / alone)) :op2 (c2 / combine-01 :ARG1 d :ARG2 d)) :ARG1 (a6 / and :op1 (c3 / cell-line :name (n / name :op1 "M238")) :op2 (c4 / cell-line :name (n2 / name :op1 "M792")) :ARG0-of (s / sensitive-03 :ARG1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01) :mod (b / both))) :ARG0-of (h2 / have-03 :ARG1 (t3 / therapy :mod (d2 / dual) :ARG0-of (s2 / synergize-01 :ARG1-of (h3 / high-02)))))) :mod (q / qualitative)) :op2 (a9 / assess-01 :ARG1 a4 :mod (q2 / quantitative)))) :purpose (t4 / test-01 :ARG1 (h / hypothesize-01 :mod (t5 / this))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "7A"))) # ::id a_pmid_2514_2146.244 # ::date 2015-06-14T06:08:25 # ::file a_pmid_2514_2146_244.txt # ::snt Treatment with 500nM vemurafenib initially suppressed growth of M238 and M792, however, by 42 days of treatment, several wells were confluent and cells had normal morphology, indicating development of BRAFi-resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (h / have-concession-91 :ARG1 (a2 / and :op1 (c4 / confluent :domain (w / well :quant (s2 / several))) :op2 (h2 / have-03 :ARG0 (c5 / cell) :ARG1 (m / morphology :ARG1-of (n5 / normal-02))) :ARG0-of (i2 / indicate-01 :ARG1 (d2 / develop-01 :ARG2 (r / resist-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n6 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) :time (a3 / after :op1 (t4 / treat-04) :quant (t3 / temporal-quantity :quant "42" :unit (d3 / day)))) :ARG2 (s / suppress-01 :ARG0 (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n / name :op1 "vemurafenib") :quant (c / concentration-quantity :quant "500" :unit (n2 / nanomolar)) :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :ARG1 (g / grow-01 :ARG1 (a / and :op1 (c2 / cell-line :name (n3 / name :op1 "M238")) :op2 (c3 / cell-line :name (n4 / name :op1 "M792")))) :time (i / initial))) # ::id a_pmid_2514_2146.245 # ::date 2015-06-14T06:17:35 # ::file a_pmid_2514_2146_245.txt # ::snt In contrast, very few cells were seen in plates treated with ERKi alone or in combination at 42 days (Figure 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG2 (s / see-01 :ARG1 (c2 / cell :mod (f / few :mod (v / very))) :location (p / plate :ARG1-of (t2 / treat-04 :ARG2 (o / or :op1 (m / molecular-physical-entity :mod (a / alone) :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "ERK")))) :op2 (c3 / combine-01 :ARG1 m)))) :time (a2 / after :quant (t3 / temporal-quantity :quant "42" :unit (d2 / day)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "7B"))) # ::id a_pmid_2514_2146.246 # ::date 2015-06-14T06:22:24 # ::file a_pmid_2514_2146_246.txt # ::snt For ERKi-treated M792 plates, confluent wells were not seen until 84 days. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (s / see-01 :polarity "-" :ARG1 (w / well :mod (c / confluent)) :time (u / until :quant (t2 / temporal-quantity :quant "84" :unit (d2 / day))) :location (p / plate :part (c2 / cell-line :name (n / name :op1 "M792")) :ARG1-of (t3 / treat-04 :ARG2 (e / enzyme :name (n2 / name :op1 "ERKi") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.263"))))) # ::id a_pmid_2514_2146.247 # ::date 2015-06-14T06:26:12 # ::file a_pmid_2514_2146_247.txt # ::snt When cell viability was quantified at day 44 for BRAFi-treated cells, over 90% of the wells had >10,000 viable cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :ARG0 (w / well :ARG1-of (i / include-91 :ARG2 (w2 / well)) :quant (o2 / over :op1 (p / percentage-entity :value "90"))) :ARG1 (c / cell :mod (v / viable) :quant (m / more-than :op1 "10000")) :time (q / quantify-01 :ARG1 (v2 / viable :domain (c2 / cell)) :time (a / after :quant (t / temporal-quantity :quant "44" :unit (d / day))) :beneficiary (c3 / cell :ARG1-of (t2 / treat-04 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))))) # ::id a_pmid_2514_2146.248 # ::date 2015-06-14T06:37:23 # ::file a_pmid_2514_2146_248.txt # ::snt In contrast, many fewer viable cells were seen for M792 treated with ERKi alone or in combination with BRAFi measured at day 84. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (s / see-01 :ARG1 (c2 / cell :mod (f / few :mod (m / more) :mod (m2 / many)) :mod (v / viable)) :location (c3 / cell-line :name (n / name :op1 "M792") :ARG1-of (t / treat-04 :ARG2 (o / or :op1 (e / enzyme :name (n2 / name :op1 "ERKi") :mod (a / alone) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.263")) :op2 (c4 / combine-01 :ARG1 e :ARG2 (m4 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) :ARG1-of (m3 / measure-01 :time (a2 / after :quant (t2 / temporal-quantity :quant "84" :unit (d / day))))))) # ::id a_pmid_2514_2146.249 # ::date 2015-06-14T06:42:56 # ::file a_pmid_2514_2146_249.txt # ::snt Only 20% of the wells treated with ERKi alone and <5% of wells treated with the combination had >10,000 cells (Figure 7C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (h / have-03 :ARG0 (a / and :op1 (w / well :quant (p2 / percentage-entity :value "20" :ARG1-of (i / include-91 :ARG2 (w2 / well :ARG1-of (t / treat-04 :ARG2 (e / enzyme :name (n / name :op1 "ERKi") :mod (a2 / alone) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.263")))))) :mod (o2 / only)) :op2 (w3 / well :quant (l / less-than :op1 (p3 / percentage-entity :value "5")) :ARG1-of (i2 / include-91 :ARG2 (w4 / well :ARG1-of (t2 / treat-04 :ARG2 (c / combine-01 :ARG1 e)))))) :ARG1 (c2 / cell :quant (m / more-than :op1 "10000")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7C"))) # ::id a_pmid_2514_2146.250 # ::date 2015-06-14T06:49:59 # ::file a_pmid_2514_2146_250.txt # ::snt For M238, similar data were seen, though in this case, treatment with 500nM ERKi alone delayed the development of resistance until 140 days. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (s / see-01 :ARG1 (d / data :ARG2-of (r2 / resemble-01)) :location (c / cell-line :name (n / name :op1 "M238")) :concession (d3 / delay-01 :ARG0 (t2 / treat-04 :ARG2 (e / enzyme :name (n2 / name :op1 "ERKi") :quant (c2 / concentration-quantity :quant "500" :unit (n3 / nanomolar)) :mod (a / alone) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.263"))) :ARG1 (d4 / develop-01 :ARG2 (r3 / resist-01)) :ARG2 (u / until :quant (t3 / temporal-quantity :quant "140" :unit (d5 / day))) :condition (c3 / case-04 :ARG1 (t4 / this)))) # ::id a_pmid_2514_2146.251 # ::date 2015-06-14T07:33:27 # ::file a_pmid_2514_2146_251.txt # ::snt Most strikingly, for M238, 280 days, twice that for SCH772984 alone, were required for resistance to the combination of vemurafenib and SCH772984 to develop (Figure 7D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (r / require-01 :ARG0 (d3 / develop-01 :ARG1 (c / cell-line :name (n / name :op1 "M238")) :ARG2 (r3 / resist-01 :ARG1 (c2 / combine-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :ARG2 "s"))) :ARG1 (t2 / temporal-quantity :quant "280" :unit (d2 / day) :ARG1-of (e / equal-01 :ARG2 (p / product-of :op1 "2" :op2 (t / temporal-quantity :ARG1-of (r2 / require-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "SCH772984") :mod (a / alone) :xref (x1 / xref :value "PUBCHEM:24866313" :prob "19.266134"))))))) :ARG1-of (s2 / strike-04 :degree (m2 / most)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "7D"))) # ::id a_pmid_2514_2146.252 # ::date 2015-06-14T07:47:36 # ::file a_pmid_2514_2146_252.txt # ::snt Taken together, these data provide preliminary in vitro evidence that SCH772984 may more potently and more durably inhibit BRAF-mutant melanoma compared to single agent vemurafenib, and that the combination of BRAF and ERK inhibition results in better inhibition than either alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / provide-01 :ARG0 (d2 / data :mod (t / this) :ARG1-of (t2 / take-01 :manner (t3 / together))) :ARG1 (e2 / evidence-01 :ARG1 (a2 / and :op1 (p3 / possible-01 :ARG1 (i2 / inhibit-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "SCH772984") :xref (x3 / xref :value "PUBCHEM:24866313" :prob "19.266134")) :ARG1 (m5 / medical-condition :name (n2 / name :op1 "melanoma") :mod (g2 / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m4 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :mod (p4 / potent :degree (m2 / more) :compared-to (i3 / inhibit-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "vemurafenib") :ARG1-of (s / single-02) :mod (a / agent) :xref (x4 / xref :value "PUBCHEM:42611257" :prob "17.762056")))) :mod (d3 / durable :degree (m3 / more)))) :op2 (r / result-01 :ARG1 (c / combine-01 :ARG1 (i4 / inhibit-01 :ARG1 (e / enzyme :name (n5 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (i5 / inhibit-01 :ARG1 (e3 / enzyme :name (n6 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG2 (i6 / inhibit-01 :ARG1-of (g / good-02 :degree (m / more) :compared-to (i7 / inhibit-01 :ARG0 (o / or :op1 e :op2 e3) :mod (a3 / alone)))))) :mod (p2 / preliminary) :mod (i / in-vitro))) # ::id a_pmid_2514_2146.253 # ::date 2015-06-14T07:59:49 # ::file a_pmid_2514_2146_253.txt # ::snt These data are intriguing and should be further validated in vivo.

Effect of combined MAPK inhibition on long-term melanoma cultures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m / multi-sentence :snt1 (a / and :op1 (i / intrigue-01 :ARG0 (d / data :mod (t / this))) :op2 (r2 / recommend-01 :ARG1 (v / validate-01 :ARG1 d :manner (f / further) :manner (i2 / in-vivo))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "7"))) :snt2 (a2 / affect-01 :ARG0 (i3 / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :ARG1-of (c / combine-01)) :ARG1 (c2 / culture-01 :ARG1 (m2 / medical-condition :name (n2 / name :op1 "melanoma")) :ARG1-of (l / long-03)))) # ::id a_pmid_2514_2146.254 # ::date 2015-06-14T08:06:35 # ::file a_pmid_2514_2146_254.txt # ::snt M238 and M792, two MAPK inhibitor-sensitive cell lines, were chronically exposed to 500nM of Vemurafenib (V), SCH722984 (E) or combination (V + E) in 96-well plates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / expose-01 :ARG1 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "M238")) :op2 (c3 / cell-line :name (n3 / name :op1 "M792")) :ARG0-of (s / sensitive-03 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MAPK")))))) :ARG2 (o / or :op1 (s3 / small-molecule :name (n4 / name :op1 "Vemurafenib") :quant (c4 / concentration-quantity :quant "500" :unit (n5 / nanomolar)) :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :op2 (s2 / small-molecule :name (n6 / name :op1 "SCH722984")) :op3 (c5 / combine-01 :ARG1 s3 :ARG2 s2)) :manner (c / chronic) :location (p2 / plate :quant "96" :mod (w / well))) # ::id a_pmid_2514_2146.255 # ::date 2015-06-14T08:12:39 # ::file a_pmid_2514_2146_255.txt # ::snt A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "A") # ::id a_pmid_2514_2146.256 # ::date 2015-06-14T08:13:07 # ::file a_pmid_2514_2146_256.txt # ::snt Schematic. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (s / schematic) # ::id a_pmid_2514_2146.257 # ::date 2015-06-14T08:14:07 # ::file a_pmid_2514_2146_257.txt # ::snt For each cell line, 20,000 cells/well were plated on 96-well plates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (p / plate-00 :ARG1 (o / or :op1 (c / cell :quant "20000") :op2 (w / well :quant "20000")) :condition (c2 / cell-line :mod (e / each)) :location (p2 / plate :quant "96" :mod (w2 / well))) # ::id a_pmid_2514_2146.258 # ::date 2015-06-14T08:18:50 # ::file a_pmid_2514_2146_258.txt # ::snt The following day, all cells on the plate were treated with 500nM of each drug or combination. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (t / treat-04 :ARG1 (c / cell :location (p / plate) :mod (a / all)) :ARG2 (o / or :op1 (d / drug :mod (e / each) :quant (c2 / concentration-quantity :quant "500" :unit (n / nanomolar))) :op2 (c3 / combine-01 :ARG1 d)) :time (d2 / day :ARG1-of (f / follow-01))) # ::id a_pmid_2514_2146.259 # ::date 2015-06-14T08:35:34 # ::file a_pmid_2514_2146_259.txt # ::snt Fresh media containing the appropriate inhibitor(s) was added weekly. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / add-02 :ARG1 (m / medium :ARG1-of (f / fresh-04) :ARG0-of (c / contain-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01) :ARG1-of (a2 / appropriate-02)))) :frequency (r / rate-entity-91 :ARG1 "1" :ARG2 (t / temporal-quantity :quant "1" :unit (w / week)))) # ::id a_pmid_2514_2146.260 # ::date 2015-06-14T08:42:36 # ::file a_pmid_2514_2146_260.txt # ::snt When cells in several wells were confluent, viable cells were quantified by MTS assay and cell numbers were determined by comparing with a standard curve of known cell numbers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a2 / and :op1 (q / quantify-01 :ARG0 (a / assay-01 :instrument (s3 / small-molecule :name (n / name :op1 "MTS") :xref (x / xref :value "PUBCHEM:65521" :prob "10.885861"))) :ARG1 (c / cell :mod (v / viable))) :op2 (d / determine-01 :ARG1 (n2 / number :quant-of (c2 / cell)) :instrument (c3 / compare-01 :ARG1 n2 :ARG2 (c4 / curve :ARG1-of (s / standard-02) :quant-of (n3 / number :mod (c5 / cell) :ARG1-of (k / know-01))))) :time (c6 / confluent :domain (c7 / cell :location (w / well :quant (s2 / several))))) # ::id a_pmid_2514_2146.261 # ::date 2015-06-14T08:48:36 # ::file a_pmid_2514_2146_261.txt # ::snt B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "B") # ::id a_pmid_2514_2146.262 # ::date 2015-06-14T08:49:00 # ::file a_pmid_2514_2146_262.txt # ::snt Microscopic imaging of treated M238 cells photographed at 14 days (top) or 44 days (bottom) of treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / image-101 :ARG1 (a3 / and :op1 (c / cell-line :name (n / name :op1 "M238") :ARG1-of (t3 / treat-04) :ARG1-of (p / photograph-01 :time (a / after :op1 (t7 / treat-04) :quant (t4 / temporal-quantity :quant "14" :unit (d3 / day)))) :location (t5 / top)) :op2 (c2 / cell-line :name (n2 / name :op1 "M238") :ARG1-of t3 :ARG1-of (p2 / photograph-01 :time (a2 / after :op1 (t / treat-04) :quant (t6 / temporal-quantity :quant "44" :unit (d4 / day)))) :location (b / bottom))) :mod (m / microscopic)) # ::id a_pmid_2514_2146.263 # ::date 2015-06-14T08:57:44 # ::file a_pmid_2514_2146_263.txt # ::snt C. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "C") # ::id a_pmid_2514_2146.264 # ::date 2015-06-14T08:58:08 # ::file a_pmid_2514_2146_264.txt # ::snt Quantitative analysis of viable cells for M792 at 44 days (V) or 84 days (E and V + E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / analyze-01 :ARG1 (c / cell :mod (v / viable)) :mod (q / quantitative) :purpose (a5 / and :op1 (c2 / cell-line :name (n / name :op1 "M792") :ARG1-of (e / expose-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :duration (t3 / temporal-quantity :quant "44" :unit (d3 / day)))) :op1 (c4 / cell-line :name (n4 / name :op1 "M792") :ARG1-of (e3 / expose-01 :ARG2 (a3 / and :op1 (s / small-molecule :name (n3 / name :op1 "SCH722984")) :op2 (c3 / combine-01 :ARG1 s2 :ARG2 s)) :duration (t4 / temporal-quantity :quant "84" :unit (d4 / day)))))) # ::id a_pmid_2514_2146.265 # ::date 2015-06-14T09:06:59 # ::file a_pmid_2514_2146_265.txt # ::snt D. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (h / have-li-91 :ARG2 "D") # ::id a_pmid_2514_2146.266 # ::date 2015-06-14T09:07:22 # ::file a_pmid_2514_2146_266.txt # ::snt Quantitative analysis of viable cells for M238 at 44 days (V), 140 days (E) or 280 days (V + E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a3 / analyze-01 :ARG1 (o2 / or :op1 (c / cell :mod (v / viable))) :mod (q / quantitative) :purpose (a / and :op1 (c2 / cell-line :name (n / name :op1 "M238") :ARG1-of (e / expose-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Vemurafenib") :xref (x / xref :value "PUBCHEM:42611257" :prob "17.762056")) :duration (t4 / temporal-quantity :quant "44" :unit (d4 / day)))) :op2 (c3 / cell-line :name (n6 / name :op1 "M238") :ARG1-of (e3 / expose-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "SCH722984")) :duration (t5 / temporal-quantity :quant "140" :unit (d5 / day)))) :op3 (c6 / cell-line :name (n7 / name :op1 "M238") :ARG1-of (e4 / expose-01 :ARG2 (a6 / and :op1 s2 :op2 s) :duration (t6 / temporal-quantity :quant "280" :unit (d6 / day)))))) # ::id a_pmid_2514_2146.267 # ::date 2015-06-14T09:19:57 # ::file a_pmid_2514_2146_267.txt # ::snt The percentage of wells with 1–1,000 (white), 2,000-3,999 (tan), 4,000-5,999 (yellow), 6,000-7,999 (orange), 8,000-9,999 (red) and >10,000 (brown) viable cells are shown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG1 (p2 / percentage :quant-of (w / well :ARG0-of (h / have-03 :ARG1 (a / and :op1 (c / cell :mod (v / viable) :quant (v2 / value-interval :op1 "1" :op2 "1000") :ARG1-of (c2 / color-01 :ARG2 (w2 / white-03))) :op2 (c3 / cell :mod v :quant (v3 / value-interval :op1 "2000" :op2 "3999") :ARG1-of (c4 / color-01 :ARG2 (t / tan))) :op3 (c5 / cell :mod v :quant (v4 / value-interval :op1 "4000" :op2 "5999") :ARG1-of (c6 / color-01 :ARG2 (y / yellow-02))) :op4 (c7 / cell :mod v :quant (v5 / value-interval :op1 "6000" :op2 "7999") :ARG1-of (c8 / color-01 :ARG2 (o / orange))) :op5 (c9 / cell :mod v :quant (v6 / value-interval :op1 "8000" :op2 "9999") :ARG1-of (c10 / color-01 :ARG2 (r / red-02))) :op6 (c11 / cell :mod v :quant (m / more-than :op1 "10000") :ARG1-of (c12 / color-01 :ARG2 (b4 / brown)))))))) # ::id a_pmid_2514_2146.268 # ::date 2015-06-14T09:32:03 # ::file a_pmid_2514_2146_268.txt # ::snt Data are representative of triplicate independent experiments.

# ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (r2 / represent-01 :ARG0 (d / data) :ARG1 (e / experiment :quant "3" :ARG0-of (d2 / depend-01 :polarity "-"))) # ::id bel_pmid_1088_2715.4484 # ::date 2015-04-16T13:40:07 # ::file bel_pmid_1088_2715_4484.txt # ::snt GEF activity of Ras-GRF1 toward Ha-Ras, as defined by in vitro GDP binding and release assays, was augmented after tyrosine phosphorylation by ACK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / augment-01 :ARG1 (a3 / activity-06 :ARG0 (p3 / protein :name (n3 / name :op1 "GEF") :xref (x2 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (p2 / protein :name (n4 / name :op1 "Ras-GRF1") :xref (x1 / xref :value "UNIPROT:RGRF1_HUMAN" :prob "1.003")) :beneficiary (e2 / enzyme :name (n5 / name :op1 "Ha-Ras") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :manner (d / define-01 :ARG0 (a4 / and :op1 (b / bind-01 :ARG1 (s2 / small-molecule :name (n6 / name :op1 "GDP") :xref (x4 / xref :value "PUBCHEM:8977" :prob "14.712257")) :manner (i / in-vitro)) :op2 (a5 / assay-01 :ARG1 (r / release-01))) :ARG1 a3)) :time (a6 / after :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (e / enzyme :name (n / name :op1 "ACK1") :xref (x3 / xref :value "UNIPROT:ACK1_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1088_2715.4486 # ::date 2015-04-16T14:49:15 # ::file bel_pmid_1088_2715_4486.txt # ::snt Ras-GRF1 acts as a GEF for Rac when tyrosine-phosphorylated following G protein-coupled receptor stimulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / act-01 :ARG0 (p / protein :name (n / name :op1 "Ras-GRF1") :xref (x3 / xref :value "UNIPROT:RGRF1_HUMAN" :prob "1.003")) :ARG1 (p2 / protein :name (n2 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :time (p3 / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of p :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (f / follow-01 :ARG2 (s2 / stimulate-01 :ARG1 (r / receptor :ARG1-of (c / couple-01 :ARG2 (p4 / protein :name (n5 / name :op1 "G") :xref (x2 / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601")))))) :beneficiary (e / enzyme :name (n3 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) # ::id bel_pmid_1088_2715.21490 # ::date 2015-04-16T11:11:33 # ::file bel_pmid_1088_2715_21490.txt # ::snt We show here that activated ACK1, a nonreceptor tyrosine kinase that belongs to the focal adhesion kinase family, causes tyrosine phosphorylation of Ras-GRF1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (c / cause-01 :ARG0 (n5 / nonreceptor-tyrosine-kinase :name (n4 / name :op1 "ACK1") :ARG0-of (b / belong-01 :ARG1 (p3 / protein-family :name (n3 / name :op1 "focal" :op2 "adhesion" :op3 "kinase"))) :ARG0-of (r / receive-01 :polarity "-") :ARG1-of (a2 / activate-01)) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "Ras-GRF1") :xref (x / xref :value "UNIPROT:RGRF1_HUMAN" :prob "1.003")) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :location (h / here)) # ::id bel_pmid_1090_3731.2472 # ::date 2015-04-16T11:23:52 # ::file bel_pmid_1090_3731_2472.txt # ::snt Stimulation by IL-18 strongly enhanced tyrosine phosphorylation of STAT3 and of the mitogen-activated protein kinases (MAPK) p44erk-1and p42erk-2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / enhance-01 :ARG0 (s2 / stimulate-01 :ARG2 (p5 / protein :name (n4 / name :op1 "IL-18") :xref (x3 / xref :value "UNIPROT:IL18_HUMAN" :prob "1.003"))) :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (p6 / protein :name (n5 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a2 / and :op1 (a4 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (a6 / and :op1 (e3 / enzyme :name (n / name :op1 "p44" :op2 "ERK-1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.653")) :op2 (e4 / enzyme :name (n2 / name :op1 "p44" :op2 "ERK-2") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "0.283")) :ARG1-of (m3 / mean-01 :ARG2 (p2 / protein-family :name (n8 / name :op1 "MAPK")))) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :ARG1-of (s / strong-02)) # ::id bel_pmid_1090_3731.37032 # ::date 2015-04-16T21:53:29 # ::file bel_pmid_1090_3731_37032.txt # ::snt MAPK activation appears to play a prominent role in IL-18 signaling, being involved in transcription and translation of IL-18-induced IFN-gamma mRNA and IL-18-induced cytolytic effects. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / cause-01 :ARG0 (i / involve-01 :ARG1 "a2" :ARG2 (a3 / and :op1 (t / transcribe-01 :ARG0 "a2" :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA") :mod (p5 / protein :name (n4 / name :op1 "IFN-gamma") :xref (x1 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")) :ARG2-of (i2 / induce-01 :ARG0 "p4"))) :op2 (t2 / translate-01 :ARG0 "a2" :ARG1 n5) :op3 (a4 / affect-01 :ARG2 (c2 / cytolysis) :ARG1-of i2))) :ARG1 (a / appear-01 :ARG1 (p2 / play-02 :ARG0 (a2 / activate-01 :ARG0 (p / pathway :name (n / name :op1 "MAPK"))) :ARG1 (r / role :mod (p3 / prominent)) :topic (s / signal-07 :ARG0 (p4 / protein :name (n2 / name :op1 "IL-18") :xref (x / xref :value "UNIPROT:IL18_HUMAN" :prob "1.003")))))) # ::id bel_pmid_1090_3734.4380 # ::date 2015-04-16T22:01:39 # ::file bel_pmid_1090_3734_4380.txt # ::snt Moreover, cord blood T cells cultured with IGF-1 and PHA had a higher resistance to anti-Fas-induced apoptosis as compared with PHA-activated cord blood T cells. IGF-1 also significantly inhibited PHA-induced Fas expression on cord blood T cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (a2 / and :op2 (r / resist-01 :ARG0 (c4 / cell :name (n4 / name :op1 "T") :ARG1-of (c3 / culture-01 :ARG0 (a6 / and :op1 (p2 / protein :name (n5 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :op2 (p3 / protein :name (n6 / name :op1 "PHA") :xref (x1 / xref :value "UNIPROT:PHAX_HUMAN" :prob "0.262"))) :mod (b2 / blood :location (c5 / cord)))) :ARG1 (a4 / apoptosis :ARG0-of (c6 / counter-01 :ARG1 "p5") :ARG2-of (i3 / induce-01)) :compared-to (c7 / cell :name (n7 / name :op1 "T") :ARG1-of (a5 / activate-01 :ARG0 p3) :mod b2) :ARG1-of (h / high-02 :degree (m2 / more)))) :snt2 (i / inhibit-01 :ARG0 (p4 / protein :name (n8 / name :op1 "IGF-1") :xref (x2 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (e / express-03 :ARG1 (p5 / protein :name (n2 / name :op1 "Fas") :xref (x3 / xref :value "UNIPROT:FAS_HUMAN" :prob "0.603")) :ARG3 (c / cell :name (n3 / name :op1 "T") :mod (b / blood :location (c2 / cord))) :ARG2-of (i2 / induce-01 :ARG0 (p / protein :name (n / name :op1 "PHA") :xref (x4 / xref :value "UNIPROT:PHAX_HUMAN" :prob "0.262")))) :mod (a / also) :ARG1-of (s / significant-02))) # ::id bel_pmid_1090_3734.23408 # ::date 2015-04-16T10:37:26 # ::file bel_pmid_1090_3734_23408.txt # ::snt Our previous study indicated that IGF-1 could significantly increase IL-6 mRNA expression and protein production in PHA- activated cord blood MNC ( 12 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (i / indicate-01 :ARG0 (s / study-01 :ARG0 (w / we) :time (p / previous)) :ARG1 (p5 / possible-01 :ARG1 (i2 / increase-01 :ARG0 (p2 / protein :name (n3 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")) :ARG1 (a / and :op1 (e / express-03 :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA") :mod (p4 / protein :name (n / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :op2 (p3 / produce-01 :ARG1 (p6 / protein) :ARG3 (c3 / cell :name (n4 / name :op1 "MNC") :ARG1-of (a2 / activate-01 :ARG0 (p7 / protein :name (n5 / name :op1 "PHA") :xref (x1 / xref :value "UNIPROT:PHAX_HUMAN" :prob "0.262"))) :mod (b / blood :location (c / cord))))) :ARG2 (s2 / significant-02))) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 "12")))) # ::id bel_pmid_1091_2795.5930 # ::date 2015-04-16T10:59:04 # ::file bel_pmid_1091_2795_5930.txt # ::snt constitutively active kinases within the ERK1/2 pathway (MEKK1, MEK1) or the p38 pathway (ASK1, MEKK1, MKK3) are potent activators of the MMP-1 promoter # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (a / activate-01 :ARG0 (o / or :op1 (k / kinase :ARG0-of (a2 / activity-06 :manner (c / constitutive)) :location (o2 / or :op1 (p4 / pathway :name (n3 / name :op1 "ERK1/2") :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (e5 / enzyme :name (n5 / name :op1 "MEKK1") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :op2 (e6 / enzyme :name (n6 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))))) :op2 (p3 / pathway :name (n2 / name :op1 "p38") :ARG1-of (m3 / mean-01 :ARG2 (a4 / and :op1 (e2 / enzyme :name (n7 / name :op1 "ASK1") :xref (x3 / xref :value "UNIPROT:M3K5_HUMAN" :prob "1.003")) :op2 e5 :op3 (e4 / enzyme :name (n9 / name :op1 "MKK3") :xref (x1 / xref :value "UNIPROT:MP2K3_HUMAN" :prob "1.003")))))))) :ARG1 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "MMP-1") :xref (x4 / xref :value "UNIPROT:MMP1_HUMAN" :prob "1.002")))) :mod (p / potent)) # ::id bel_pmid_1092_5306.24430 # ::date 2015-04-16T18:32:24 # ::file bel_pmid_1092_5306_24430.txt # ::snt TGF-b1 also stimulates H2O2 production in bovine pulmonary artery endothelial cells (22), vascular endothelial cells (23), mouse osteoblastic cells (24), and human lung fibroblast (HLF) cells (25, 26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (s / stimulate-01 :ARG0 (p5 / protein :name (n / name :op1 "TGF-b1") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.653")) :ARG1 (p / produce-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "H2O2") :xref (x1 / xref :value "PUBCHEM:784" :prob "17.186693"))) :mod (a / also) :location (a2 / and :op1 (c / cell :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c8 / cite-01 :ARG2 "22"))) :mod (e / endothelium) :part-of (a3 / artery :mod (l2 / lung) :mod (c9 / cattle))) :op2 (c2 / cell :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 "23"))) :mod e :part-of (v / vessel)) :op3 (c3 / cell :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 "24"))) :mod (o / osteoblast) :part-of (m3 / mouse)) :op4 (c4 / cell :ARG1-of (d5 / describe-01 :ARG0 (p6 / publication :ARG1-of (c5 / cite-01 :ARG2 (a4 / and :op1 "25" :op2 "26")))) :part-of (l / lung :mod (h / human)) :mod (f / fibroblast)))) # ::id bel_pmid_1092_5306.24432 # ::date 2015-04-16T22:45:07 # ::file bel_pmid_1092_5306_24432.txt # ::snt TGF-b1 (1 ng/ml)-induced intracellular ROS levels in HLF cells were measured with DCFH-DA and laser-scanning confocal microscopy...As shown in Fig. 1, A and B, DCF fluorescence displayed a rapid increase with maximal intensity at 5 min after treatment and was followed by a decline in fluorescence to the basal level by 20 min. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (m2 / measure-01 :ARG1 (l / level :quant-of (s3 / small-molecule :name (n / name :op1 "ROS") :xref (x1 / xref :value "PUBCHEM:128351" :prob "11.468653")) :location (c / cell :name (n2 / name :op1 "HLF")) :mod (i / intracellular) :ARG2-of (i2 / induce-01 :ARG0 (p / protein :name (n3 / name :op1 "TGF-b1") :quant (c2 / concentration-quantity :quant "1" :unit (n4 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.653")))) :ARG2 (a / and :op1 (s4 / small-molecule :name (n5 / name :op1 "DCFH-DA") :xref (x3 / xref :value "PUBCHEM:104913" :prob "18.152187")) :op2 (m6 / microscope :mod (c3 / confocal) :ARG2-of (s / scan-01 :ARG0 (l2 / laser))))) :snt2 (a2 / and :op1 (d / display-01 :ARG1 (i3 / increase-01 :ARG1 (f4 / fluoresce-01 :ARG1 (s5 / small-molecule :name (n6 / name :op1 "DCF") :xref (x2 / xref :value "PUBCHEM:4739" :prob "13.838984"))) :mod (r / rapid) :ARG1-of (i4 / intense-02 :degree (m8 / maximal)) :time (a4 / after :op1 (t2 / treat-04 :ARG1 f4 :ARG2 s5) :quant (t / temporal-quantity :quant "5" :unit (m4 / minute))))) :op2 (f / follow-01 :ARG1 (d3 / decline-01 :ARG1 (f5 / fluoresce-01) :degree (l3 / level :mod (b / basal)) :time (a5 / after :op1 (t3 / treat-04) :quant (t4 / temporal-quantity :quant "20" :unit (m3 / minute)))) :ARG2 f4) :ARG1-of (s2 / show-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "1A") :op2 (f3 / figure :mod "1B"))))) # ::id bel_pmid_1092_5306.24450 # ::date 2015-04-16T12:56:04 # ::file bel_pmid_1092_5306_24450.txt # ::snt Also, stimulation with TGF-b1 (1 ng/ml) caused a time-dependent increase in IL-6 protein accumulation in the culture supernatants (Fig. 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 23, 2015 (c / cause-01 :ARG0 (s / stimulate-01 :ARG2 (p2 / protein :name (n / name :op1 "TGF-b1") :quant (c2 / concentration-quantity :quant "1" :unit (n2 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.653"))) :ARG1 (i / increase-01 :ARG1 (a2 / accumulate-01 :ARG0 (p / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG0-of (d2 / depend-01 :ARG1 (t / time)) :location (s2 / supernatant :mod (c3 / culture))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2C")) :mod (a / also)) # ::id bel_pmid_1092_5306.24464 # ::date 2015-04-16T22:23:36 # ::file bel_pmid_1092_5306_24464.txt # ::snt The amount of 1 ng/ml TGF-b1 was sufficient to induce the IL-6 mRNA (Fig. 2A). TGF-b1 (1 ng/ml) treatment produced a progressive increase in IL-6 mRNA concentrations, beginning as early as 30 min, peaking at 12 h, and decreasing after 24 h (Fig. 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (s / suffice-01 :ARG0 (a / amount-01 :ARG1 (p6 / protein :name (n / name :op1 "TGF-b1") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.653")) :ARG2 (c / concentration-quantity :quant "1" :unit (n2 / nanogram-per-milliliter))) :ARG1 (i / induce-01 :ARG0 a :ARG2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA") :mod (p / protein :name (n3 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) :snt2 (p2 / produce-01 :ARG0 (t / treat-04 :ARG2 (p7 / protein :name (n6 / name :op1 "TGF-b1") :quant (c2 / concentration-quantity :quant "1" :unit (n5 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.653"))) :ARG1 (i2 / increase-01 :ARG1 (c3 / concentrate-02 :ARG1 (n10 / nucleic-acid :name (n7 / name :op1 "mRNA") :mod (p3 / protein :name (n8 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG0-of (b / begin-01 :time (e / early :op1 (t2 / temporal-quantity :quant "30" :unit (m4 / minute)))) :ARG1-of (p4 / peak-01 :time (a3 / after :op1 (t3 / temporal-quantity :quant "12" :unit (h / hour)))) :ARG1-of (d3 / decrease-01 :time (a2 / after :op1 (t4 / temporal-quantity :quant "24" :unit (h2 / hour)))) :ARG1-of (p5 / progress-01)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2B")))) # ::id bel_pmid_1093_8266.21268 # ::date 2015-04-16T13:43:02 # ::file bel_pmid_1093_8266_21268.txt # ::snt Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (a / and :op1 (s / stimulate-01 :ARG0 (s3 / secrete-01 :ARG0 (a2 / autocrine) :ARG1 (p4 / protein :name (n / name :op1 "PRL") :xref (x3 / xref :value "UNIPROT:PRL_HUMAN" :prob "1.003"))) :ARG1 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n3 / name :op1 "ErbB-2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.593")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (e / enzyme :name (n4 / name :op1 "Jak2") :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "0.604")))) :op2 (p / provide-01 :ARG0 a2 :ARG1 (s4 / site :ARG0-of (d / dock-01)) :ARG2 (p7 / protein :name (n5 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :op3 (s2 / stimulate-01 :ARG0 a2 :ARG1 (p6 / pathway :name (n7 / name :op1 "Ras-MAP" :op2 "kinase"))) :ARG0-of (c / cause-01 :ARG1 (p2 / proliferate-01 :ARG0 (c2 / cell) :ARG1-of (r2 / restrict-01 :polarity "-"))))) # ::id bel_pmid_1094_3842.21324 # ::date 2015-04-16T14:11:14 # ::file bel_pmid_1094_3842_21324.txt # ::snt inhibition of MAPK14 activity also interfered with stabilization of EPO mRNA in human hepatoma cells undergoing hypoxic stress # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / interfere-01 :ARG0 (i2 / inhibit-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "MAPK14") :xref (x / xref :value "UNIPROT:MK14_HUMAN" :prob "1.002")))) :ARG1 (s / stabilize-01 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA") :mod (s3 / small-molecule :name (n3 / name :op1 "EPO") :xref (x1 / xref :value "PUBCHEM:5288169" :prob "16.321695"))) :location (c / cell :mod (h / hepatoma) :mod (h2 / human) :ARG1-of (s2 / stress-02 :ARG0 (h3 / hypoxia)))) :mod (a2 / also)) # ::id bel_pmid_1094_5974.21384 # ::date 2015-04-16T15:21:00 # ::file bel_pmid_1094_5974_21384.txt # ::snt Consistent with the earlier results, p42/44 MAPK and its upstream kinase MEK1/2 were activated in a time-dependent manner by the induction of Pak1 (Fig. 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a3 / activate-01 :ARG0 (i / induce-01 :ARG2 (e2 / enzyme :name (n / name :op1 "Pak1") :xref (x4 / xref :value "UNIPROT:PAK1_HUMAN" :prob "0.604"))) :ARG1 (a2 / and :op1 (s / slash :op1 (e3 / enzyme :name (n3 / name :op1 "p42" :op2 "MAPK") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.683")) :op2 (e4 / enzyme :name (n4 / name :op1 "p44" :op2 "MAPK") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.683"))) :op2 (s2 / slash :op1 (k5 / kinase :name (n2 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (k6 / kinase :name (n6 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :location (u / upstream) :poss s)) :manner (d / depend-01 :ARG1 (t2 / time)) :ARG1-of (c / consistent-01 :ARG2 (t / thing :ARG2-of (r / result-01 :time (e / early :degree (m / more)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3C")))) # ::id bel_pmid_1097_1465.18050 # ::date 2015-04-16T14:25:55 # ::file bel_pmid_1097_1465_18050.txt # ::snt Jaffe et al. [22,23] reported IL-5 and IL-13 production from human lung mast cells following IgE-mediated activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / report-01 :ARG0 (a / and :op1 (p / person :name (n / name :op1 "Jaffe")) :op2 (p2 / person :mod (o / other))) :ARG1 (p4 / produce-01 :ARG1 (a3 / and :op1 (p5 / protein :name (n2 / name :op1 "IL-5") :xref (x1 / xref :value "UNIPROT:IL5_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n3 / name :op1 "IL-13") :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003"))) :ARG2 (c2 / cell :mod (m / mast) :part-of (l / lung :mod (h / human))) :ARG1-of (f / follow-01 :ARG2 (a4 / activate-01 :ARG1-of (m2 / mediate-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "IgE") :xref (x2 / xref :value "PUBCHEM:19920" :prob "17.561386")))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 "22" :op2 "23"))))) # ::id bel_pmid_1097_1465.18052 # ::date 2015-04-16T14:48:41 # ::file bel_pmid_1097_1465_18052.txt # ::snt Using immunocytochemistry, Bradding et al. [1±4] reported that interleukin (IL)-4, IL-5, IL-6, and tumour necrosis factor (TNF)-a were present within mast cells in nasal and bronchial mucosa taken from both normal subjects and patients with allergic perennial rhinitis, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / cause-01 :ARG0 (u / use-01 :ARG0 "a" :ARG1 (i / immunocytochemistry) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 (o2 / or :op1 "1" :op2 (a6 / and :op1 "1" :op2 "4")))))) :ARG1 (r / report-01 :ARG0 (a / and :op1 (p / person :name (n / name :op1 "Bradding")) :op2 (p2 / person :mod (o / other))) :ARG1 (p9 / present-02 :ARG1 (a2 / and :op1 (p4 / protein :name (n4 / name :op1 "IL-4") :xref (x2 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :op2 (p5 / protein :name (n5 / name :op1 "IL-5") :xref (x3 / xref :value "UNIPROT:IL5_HUMAN" :prob "1.003")) :op3 (p6 / protein :name (n6 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op4 (p7 / protein :name (n7 / name :op1 "tumour" :op2 "necrosis" :op3 "factor-a") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.382"))) :ARG2 (c2 / cell :mod (m / mast :location (a4 / and :op1 (m2 / mucosa :mod (n8 / nose)) :op2 (m3 / mucosa :mod (b3 / bronchus)) :ARG1-of (t / take-01 :ARG2 (a3 / and :op1 (s / subject :ARG1-of (n2 / normal-02)) :op2 (p3 / patient :ARG1-of (a5 / allergic-01 :ARG2 (m4 / medical-condition :name (n3 / name :op1 "perennial" :op2 "rhinitis")))))))))))) # ::id bel_pmid_1099_3906.5890 # ::date 2015-04-16T16:35:07 # ::file bel_pmid_1099_3906_5890.txt # ::snt STAM2 is downstream of the Jak family of kinases since coexpression of STAM2 with Jak1 or Jak2 but not an unrelated Tec family kinase, Etk, resulted in its tyrosine phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c4 / cause-01 :ARG0 (c5 / contrast-01 :ARG1 (r / result-01 :ARG1 (e3 / express-03 :ARG2 (a2 / and :op1 (p5 / protein :name (n3 / name :op1 "STAM2") :xref (x3 / xref :value "UNIPROT:STAM2_HUMAN" :prob "1.003")) :op2 (o / or :op1 (e / enzyme :name (n / name :op1 "Jak1") :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.604")) :op2 (e2 / enzyme :name (n2 / name :op1 "Jak2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "0.604"))))) :ARG2 (p4 / phosphorylate-01 :ARG1 (a / amino-acid :name (n5 / name :op1 "tyrosine") :part-of p5 :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :ARG2 (r2 / result-01 :polarity "-" :ARG1 (k2 / kinase :name (n7 / name :op1 "Etk") :ARG1-of (r3 / relate-01 :polarity "-") :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n6 / name :op1 "Tec"))) :xref (x / xref :value "UNIPROT:EPHA3_HUMAN" :prob "0.603")) :ARG2 p4)) :ARG1 (b / be-located-at-91 :ARG1 p5 :ARG2 (r4 / relative-position :op1 (p / protein-family :name (n4 / name :op1 "Jak")) :direction (d / downstream)))) # ::id bel_pmid_1099_3906.6852 # ::date 2015-04-16T16:07:43 # ::file bel_pmid_1099_3906_6852.txt # ::snt Tyrosine phosphorylation of STAM2 is induced by growth factors such as epidermal growth factor and platelet-derived growth factor as well as by cytokines like IL-3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (i / induce-01 :ARG0 (g / growth-factor :example (a2 / and :op1 (p3 / protein :name (n7 / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703")) :op2 (p4 / protein :name (n6 / name :op1 "platelet-derived" :op2 "growth" :op3 "factor") :xref (x2 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.393")) :op2 (p5 / protein :name (n5 / name :op1 "cytokine") :example (p6 / protein :name (n4 / name :op1 "IL-3") :xref (x1 / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003")) :xref (x3 / xref :value "UNIPROT:RED_HUMAN" :prob "0.342")))) :ARG2 (p8 / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (p / protein :name (n2 / name :op1 "STAM2") :xref (x4 / xref :value "UNIPROT:STAM2_HUMAN" :prob "1.003")) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")))) # ::id bel_pmid_1099_3906.7612 # ::date 2015-04-16T15:51:09 # ::file bel_pmid_1099_3906_7612.txt # ::snt Finally, overexpression of wild type STAM2 led to an increase in IL-2-mediated induction of c-Myc promoter activation indicating that it potentiates cytokine receptor signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (l / lead-03 :li "-1" :ARG0 (o / overexpress-01 :ARG1 (p5 / protein :name (n / name :op1 "STAM2") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:STAM2_HUMAN" :prob "1.003"))) :ARG2 (i / increase-01 :ARG1 (i2 / induce-01 :ARG2 (a / activate-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p6 / protein :name (n3 / name :op1 "c-Myc") :xref (x / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.661"))))) :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "IL-2") :xref (x3 / xref :value "UNIPROT:IL2_HUMAN" :prob "1.003"))))) :ARG0-of (i3 / indicate-01 :ARG1 (p3 / potentiate-01 :ARG1 (s / signal-07 :ARG0 (r / receptor :mod (p4 / protein :name (n4 / name :op1 "cytokine") :xref (x1 / xref :value "UNIPROT:RED_HUMAN" :prob "0.342")))) :ARG2 o))) # ::id bel_pmid_1101_5448.8236 # ::date 2015-04-19T13:37:46 # ::file bel_pmid_1101_5448_8236.txt # ::snt Additionally, T cells from CCR2(-/)- immunized mice showed decreased antigen-induced proliferation and production of IFN-gamma compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op2 (s / show-01 :ARG0 (c / cell :name (n / name :op1 "T") :source (m / mouse :ARG1-of (i / immunize-01) :mod (p / protein :name (n2 / name :op1 "CCR2") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:CCR2_HUMAN" :prob "1.003")))) :ARG1 (a2 / and :op1 (p2 / proliferate-01 :ARG2-of (i2 / induce-01 :ARG0 (a3 / antigen))) :op2 (p3 / produce-01 :ARG1 (p4 / protein :name (n3 / name :op1 "IFN-gamma") :xref (x / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002"))) :ARG1-of (d / decrease-01 :ARG1-of (c2 / compare-01 :ARG2 (m3 / mouse :ARG2-of (c3 / control-01) :ARG1-of i :mod (w / wild-type)) :ARG0-of (s2 / suggest-01 :ARG1 (e / enhance-01 :ARG0 p :ARG1 (r / respond-01 :ARG0 (c4 / cell :name (n4 / name :op1 "T-helper") :ARG1-of (t2 / type-03)) :ARG1-of (i3 / immune-02 :ARG2 (d2 / disease :name (n6 / name :op1 "experimental" :op2 "autoimmune" :op3 "encephalomyelitis"))))))))))) # ::id bel_pmid_1101_5448.18896 # ::date 2015-04-19T14:24:47 # ::file bel_pmid_1101_5448_18896.txt # ::snt At days 8, 11, 20, 23, and 26 after disease induction, splenocytes from CCR2-deficient mice also proliferated less robustly to Ag and secreted lower levels of IFN-{gamma} and IL-6 than splenocytes from wild-type controls # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (p / proliferate-01 :ARG0 (c / cell :name (n / name :op1 "splenocyte") :source (m / mouse :mod (p2 / protein :name (n2 / name :op1 "CCR2") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:CCR2_HUMAN" :prob "1.003")))) :manner (r / robust :degree (l / less)) :mod (a2 / also) :ARG1-of (r2 / result-01 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "Ag") :xref (x3 / xref :value "PUBCHEM:23954" :prob "6.73862")))) :op2 (s / secrete-01 :ARG0 c :ARG1 (a4 / and :op1 (l2 / level :quant-of (p3 / protein :name (n3 / name :op1 "IFN-γ") :xref (x1 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.232")) :ARG1-of (l3 / low-04 :degree (m4 / more) :compared-to (c2 / cell :name (n6 / name :op1 "splenocyte") :source (m5 / mouse :mod (c3 / control) :mod (w / wild-type))))) :op2 (l4 / level :quant-of (p4 / protein :name (n4 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of l3))) :time (a5 / after :op1 (i / induce-01 :ARG2 (d2 / disease)) :quant (a3 / and :op1 (t / temporal-quantity :quant "8" :unit (d3 / day)) :op2 (t2 / temporal-quantity :quant "11" :unit (d4 / day)) :op3 (t3 / temporal-quantity :quant "20" :unit (d5 / day)) :op4 (t4 / temporal-quantity :quant "23" :unit (d6 / day)) :op5 (t5 / temporal-quantity :quant "26" :unit (d7 / day))))) # ::id bel_pmid_1102_9459.7644 # ::date 2015-04-19T15:49:48 # ::file bel_pmid_1102_9459_7644.txt # ::snt The wild-type Ki-ras transfectants lack functional TGF-beta receptors, whereas all three Ki-ras(G12V) transfectants expressed functional TGF-beta receptors that bound (125)I-TGF-beta1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (l / lack-01 :ARG0 (c2 / cell :ARG1-of (t / transfect-01 :ARG2 (p / protein :name (n / name :op1 "Ki-ras") :mod (w / wild-type) :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.673")))) :ARG1 (p4 / protein :name (n6 / name :op1 "TGF-β" :op2 "receptor") :mod (f / function-01) :xref (x1 / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.293"))) :ARG2 (e / express-03 :ARG2 (p5 / protein :name (n2 / name :op1 "TGF-β" :op2 "receptor") :mod f :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n4 / name :op1 "(125)I-TGF-β1"))) :xref (x2 / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.293")) :ARG3 (c3 / cell :quant "3" :ARG1-of (t2 / transfect-01 :ARG2 (p3 / protein :name (n5 / name :op1 "Ki-ras") :ARG2-of (m / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.673"))) :mod (a / all)))) # ::id bel_pmid_1102_9459.20858 # ::date 2015-04-19T16:12:26 # ::file bel_pmid_1102_9459_20858.txt # ::snt GnT-V transcription was stimulated by several oncogenes including src , her -2/ neu , H- ras , and v- sis (9 , 10 , 11) , and this overexpression was regulated through the ras-raf-ets pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op1 (s / stimulate-01 :ARG0 (o / oncogene :mod (s2 / several) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (g / gene :name (n / name :op1 "src") :xref (x2 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :op2 (g2 / gene :name (n2 / name :op1 "her-2/neu")) :op3 (g3 / gene :name (n3 / name :op1 "H-ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.601")) :op4 (g4 / gene :name (n4 / name :op1 "v-sis")) :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")))))) :ARG1 (t / transcribe-01 :ARG1 (e / enzyme :name (n5 / name :op1 "GnT-V") :xref (x1 / xref :value "UNIPROT:MGT5A_HUMAN" :prob "0.662"))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "9") :op2 (f2 / figure :mod "10") :op3 (f3 / figure :mod "11")))) :op2 (r / regulate-01 :ARG0 (p / pathway :name (n6 / name :op1 "ras-raf-ets")) :ARG1 (o2 / overexpress-01 :mod (t2 / this)))) # ::id bel_pmid_1102_9459.21486 # ::date 2015-04-19T16:37:10 # ::file bel_pmid_1102_9459_21486.txt # ::snt Each of three Ki-ras(G12V) transfectants responded to TGF-beta1 by an increase in proliferation and by decreasing the abundance of the Cdk inhibitor p21 and the tumor suppressor PTEN, whereas each of three wild-type Ki-ras transfectants remained unresponsive to TGF-beta1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (r / respond-01 :ARG0 (c2 / cell :quant "3" :ARG1-of (t / transfect-01 :ARG2 (e5 / enzyme :name (n / name :op1 "Ki-ras") :ARG2-of (m / mutate-01 :value "G12V") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.673"))) :mod (e / each)) :ARG1 (p2 / protein :name (n3 / name :op1 "TGF-β1") :xref (x4 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.283")) :ARG2 (a / and :op1 (i / increase-01 :ARG1 (p3 / proliferate-01)) :op2 (d / decrease-01 :ARG1 (a2 / abound-01 :ARG1 (a3 / and :op1 (p4 / protein :name (n4 / name :op1 "p21") :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Cdk") :xref (x3 / xref :value "UNIPROT:CDK4_HUMAN_DNA" :prob "0.22"))) :xref (x5 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")) :op2 (s / suppress-01 :ARG0 (g / gene :name (n6 / name :op1 "PTEN") :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG1 (t2 / tumor))))))) :ARG2 (r2 / remain-01 :ARG1 (c3 / cell :quant "3" :ARG1-of (t3 / transfect-01 :ARG2 (e4 / enzyme :name (n7 / name :op1 "Ki-ras") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.673"))) :mod (e3 / each) :mod (w / wild-type)) :ARG3 (r3 / respond-01 :polarity "-" :ARG0 c3 :ARG1 p2))) # ::id bel_pmid_1103_6942.20042 # ::date 2015-04-19T16:58:12 # ::file bel_pmid_1103_6942_20042.txt # ::snt SIRP is a transmembrane protein that is now known to bind to integrin-associated protein. It appears to bind directly to JAK2 by a process that does not require tyrosyl phosphorylation, although is itself highly phosphorylated on tyrosines in response to GH. The phosphorylated SIRP recruits one or more molecules of the tyrosine phosphatase SHP2 that, in turn, de-phosphorylates SIRP and most likely JAK2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (k / know-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "SIRP") :mod (t / transmembrane) :xref (x6 / xref :value "UNIPROT:SHPS1_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :ARG1-of (a / associate-01 :ARG2 (p3 / protein :name (n2 / name :op1 "integrin") :xref (x3 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311"))))) :time (n3 / now)) :snt2 (a2 / appear-02 :ARG1 (b2 / bind-01 :ARG1 (p4 / protein :name (n5 / name :op1 "SIRP") :xref (x5 / xref :value "UNIPROT:SHPS1_HUMAN" :prob "1.002")) :ARG2 (e / enzyme :name (n4 / name :op1 "JAK2") :xref (x4 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :ARG1-of (d / direct-02) :ARG1-of (p5 / process-02 :ARG0-of (r / require-01 :polarity "-" :ARG1 (p6 / phosphorylate-01 :ARG1 (a6 / amino-acid :name (n6 / name :op1 "tyrosine") :xref (x8 / xref :value "PUBCHEM:1153" :prob "11.081481")))))) :concession (p7 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n7 / name :op1 "tyrosine") :part-of p4 :xref (x7 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (h / high-02) :ARG2-of (r2 / respond-01 :ARG1 (p10 / protein :name (n8 / name :op1 "GH") :xref (x1 / xref :value "UNIPROT:GGH_HUMAN" :prob "1.002"))))) :snt3 (r3 / recruit-01 :ARG0 (p8 / protein :name (n9 / name :op1 "SIRP") :ARG1-of (p9 / phosphorylate-01) :xref (x / xref :value "UNIPROT:SHPS1_HUMAN" :prob "1.002")) :ARG1 (m4 / molecule :mod (t2 / tyrosine-phosphatase :name (n10 / name :op1 "SHP2") :ARG1-of (r4 / respond-01 :ARG2 (d2 / dephosphorylate-01 :ARG0 t2 :ARG1 (a4 / and :op1 p8 :op2 (e3 / enzyme :name (n11 / name :op1 "JAK2") :ARG1-of (l / likely-01 :degree (m5 / most)) :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :mod (i / in-turn)))) :quant (a5 / at-least :op1 "1")))) # ::id bel_pmid_1104_3579.5226 # ::date 2015-04-19T17:48:52 # ::file bel_pmid_1104_3579_5226.txt # ::snt Consistent with acting through a G protein-coupled receptor, estradiol signaling to Erk-1/-2 occurred via a Gbetagamma-dependent, pertussis toxin-sensitive pathway that required Src-related tyrosine kinase activity and tyrosine phosphorylation of tyrosine 317 of the Shc adapter protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (s / signal-07 :ARG0 (s3 / small-molecule :name (n / name :op1 "estradiol") :xref (x5 / xref :value "PUBCHEM:5757" :prob "13.090267")) :ARG2 (e / enzyme :name (n2 / name :op1 "Erk-1/-2")) :manner (p / pathway :ARG0-of (d / depend-01 :ARG1 (m2 / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "Gβ") :xref (x3 / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.58")) :part (p3 / protein :name (n4 / name :op1 "Gγ") :xref (x4 / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.58")))) :ARG0-of (s2 / sensitive-03 :ARG1 (s4 / small-molecule :name (n5 / name :op1 "pertussis" :op2 "toxin") :xref (x6 / xref :value "PUBCHEM:135154" :prob "3.65835"))) :ARG0-of (r / require-01 :ARG1 (a / and :op1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n6 / name :op1 "tyrosine" :op2 "kinase") :xref (x2 / xref :value "UNIPROT:FER_HUMAN" :prob "0.392")) :ARG1-of (r2 / relate-01 :ARG2 (p4 / protein :name (n7 / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")))) :op2 (p5 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "317" :name (n8 / name :op1 "tyrosine") :part-of (p6 / protein :name (n9 / name :op1 "Shc" :op2 "adapter")) :xref (x7 / xref :value "PUBCHEM:1153" :prob "11.081481")))))) :ARG1-of (c / consistent-01 :ARG2 (a4 / act-01 :instrument (r3 / receptor :ARG1-of (c2 / couple-01 :ARG2 (p7 / protein :name (n10 / name :op1 "G") :xref (x / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601"))))))) # ::id bel_pmid_1104_3579.5228 # ::date 2015-04-19T18:40:01 # ::file bel_pmid_1104_3579_5228.txt # ::snt Reinforcing this idea, estradiol signaling to Erk-1/-2 was dependent upon trans-activation of the epidermal growth factor (EGF) receptor via release of heparan-bound EGF (HB-EGF). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / depend-01 :ARG0 (s / signal-07 :ARG0 (s2 / small-molecule :name (n / name :op1 "estradiol") :xref (x2 / xref :value "PUBCHEM:5757" :prob "13.090267")) :ARG2 (e / enzyme :name (n2 / name :op1 "Erk-1/-2"))) :ARG1 (a / activate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.703")) :mod (t / trans) :manner (r3 / release-01 :ARG1 (b / bind-01 :ARG1 (r2 / receptor) :ARG2 (h / heparin) :ARG1-of (d3 / describe-01 :ARG0 (p / protein :name (n5 / name :op1 "HB-EGF") :xref (x1 / xref :value "UNIPROT:HBEGF_HUMAN" :prob "1.003")))))) :ARG2-of (r4 / reinforce-01 :ARG1 (i / idea :mod (t2 / this)))) # ::id bel_pmid_1104_3579.19856 # ::date 2015-04-19T19:00:20 # ::file bel_pmid_1104_3579_19856.txt # ::snt Estrogen rapidly activates the mitogen-activated protein kinases, Erk-1 and Erk-2, via an as yet unknown mechanism. requires the expression of the G protein-coupled receptor homolog, GPR30. We show that 17beta-estradiol activates Erk-1/-2 not only in MCF-7 cells, which express both estrogen receptor alpha (ER alpha) and ER beta, but # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (a / activate-01 :ARG0 (e / estrogen) :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "Erk-1") :xref (x4 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.633")) :op2 (e3 / enzyme :name (n2 / name :op1 "Erk-2") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.633")) :domain (e4 / enzyme :name (n3 / name :op1 "protein" :op2 "kinase") :ARG1-of (a3 / activate-01 :ARG0 (m2 / mitogen)) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393"))) :manner (r / rapid) :manner (m3 / mechanism :ARG1-of (k / know-01 :polarity "-" :mod (y / yet)))) :snt2 (r2 / require-01 :ARG1 (e5 / express-03 :ARG2 (p / protein :name (n4 / name :op1 "G" :op2 "protein-coupled" :op3 "receptor" :op4 "homolog") :ARG1-of (d / describe-01 :ARG0 (p2 / protein :name (n5 / name :op1 "GPR30") :xref (x1 / xref :value "UNIPROT:GPER1_HUMAN" :prob "1.002"))) :xref (x7 / xref :value "UNIPROT:ACKR3_HUMAN" :prob "0.392")))) :snt3 (s / show-01 :ARG0 (w / we) :ARG1 (a4 / activate-01 :ARG0 (s2 / small-molecule :name (n6 / name :op1 "17β-estradiol") :xref (x8 / xref :value "PUBCHEM:67083" :prob "10.238353")) :ARG1 (e6 / enzyme :name (n7 / name :op1 "Erk-1/-2")) :location (c / cell-line :name (n8 / name :op1 "MCF-7") :mod (o / only :polarity "-") :ARG2-of (e7 / express-03 :ARG1 (a5 / and :op1 (p3 / protein :name (n9 / name :op1 "estrogen" :op2 "receptor" :op3 "α") :ARG1-of (d2 / describe-01 :ARG0 (p4 / protein :name (n10 / name :op1 "ERα") :xref (x / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623"))) :xref (x5 / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.693")) :op2 (p5 / protein :name (n11 / name :op1 "ERβ") :xref (x6 / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623")))))))) # ::id bel_pmid_1106_2502.20878 # ::date 2015-04-21T12:35:44 # ::file bel_pmid_1106_2502_20878.txt # ::snt Correspondingly, in vitro kinase assays showed that N17Rac1 inhibited the kinase activities of MEK1/2 and ERK1/2 stimulated by target signals (Fig. 4b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (a / assay-01 :ARG1 (k / kinase) :manner (i / in-vitro)) :ARG1 (i2 / inhibit-01 :ARG0 (e3 / enzyme :name (n / name :op1 "N17Rac1")) :ARG1 (a2 / activity-06 :ARG0 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "MEK1/2")) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"))) :ARG1 k :ARG1-of (s2 / stimulate-01 :ARG0 (s3 / signal-07 :ARG1-of (t / target-01))))) :ARG1-of (c / correspond-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4b"))) # ::id bel_pmid_1106_2502.20880 # ::date 2015-04-21T13:13:15 # ::file bel_pmid_1106_2502_20880.txt # ::snt Introduction of N17Rac1 into NK92 cells totally blocked PAK1 activation triggered by target ligation, whereas introduction of V12Rac1 strongly stimulated PAK1 activity even in the absence of target cells (Fig. 7d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (b / block-01 :ARG0 (i / introduce-02 :ARG1 (e3 / enzyme :name (n / name :op1 "N17Rac1")) :ARG2 (c2 / cell :name (n2 / name :op1 "NK92"))) :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "PAK1") :xref (x / xref :value "UNIPROT:PAK1_HUMAN" :prob "1.004")) :ARG1-of (t / trigger-01 :ARG0 (l / ligate-01 :ARG1 (t2 / target-01)))) :degree (t3 / total)) :ARG2 (s / stimulate-01 :ARG0 (i2 / introduce-02 :ARG1 (e2 / enzyme :name (n4 / name :op1 "V12Rac1")) :ARG2 c2) :ARG1 (a2 / activity-06 :ARG1 e) :ARG1-of (s2 / strong-02) :concession (a3 / absent-01 :ARG1 (c3 / cell :ARG1-of (t4 / target-01)) :ARG2 s)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7d"))) # ::id bel_pmid_1106_2502.21386 # ::date 2015-04-21T17:24:36 # ::file bel_pmid_1106_2502_21386.txt # ::snt Examination of whole cell lysates from the same NK92 cells showed that kinase-deficient (KD) PAK1, unlike control CD56, also effectively suppressed MEK and ERK activation by target ligation (Fig. 7b). Thus, PAK1 is upstream of both MEK and ERK in the NK lytic process. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG0 (e / examine-01 :ARG1 (l / lysate :mod (c / cell) :source (c2 / cell :name (n / name :op1 "NK92") :ARG1-of (s2 / same-01)) :mod (w / whole))) :ARG1 (c3 / contrast-01 :ARG1 (s3 / suppress-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PAK1") :mod (k / kinase :ARG2-of (m2 / mutate-01 :mod "-/-")) :xref (x5 / xref :value "UNIPROT:PAK1_HUMAN" :prob "1.004")) :ARG1 (a / activate-01 :ARG0 (l2 / ligate-01 :ARG1 (t / target-01)) :ARG1 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "MEK") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e4 / enzyme :name (n4 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :mod (a3 / also) :manner (e5 / effective-04)) :ARG2 (s4 / suppress-01 :polarity "-" :ARG0 (p / protein :name (n5 / name :op1 "CD56") :ARG2-of (c4 / control-01) :xref (x6 / xref :value "UNIPROT:NCAM1_HUMAN" :prob "1.003")) :ARG1 a)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7b"))) :snt2 (c5 / cause-01 :ARG1 (b / be-located-at-91 :ARG1 (e6 / enzyme :name (n6 / name :op1 "PAK1") :xref (x3 / xref :value "UNIPROT:PAK1_HUMAN" :prob "1.004")) :ARG2 (r / relative-position :op1 (a4 / and :op1 (e7 / enzyme :name (n7 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e8 / enzyme :name (n8 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :direction (u / upstream)) :time (p2 / process-02 :ARG1 (l3 / lyse-00 :ARG1 (c6 / cell :name (n9 / name :op1 "NK"))))))) # ::id bel_pmid_1111_7534.6206 # ::date 2015-04-21T18:11:37 # ::file bel_pmid_1111_7534_6206.txt # ::snt PRL enhanced tyrosine phosphorylation of NKCC1, and this effect was attenuated by the JAK2 inhibitor AG490. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (e / enhance-01 :ARG0 (p3 / protein :name (n / name :op1 "PRL") :xref (x1 / xref :value "UNIPROT:PRL_HUMAN" :prob "1.003")) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (p2 / protein :name (n3 / name :op1 "NKCC1") :xref (x / xref :value "UNIPROT:S12A2_HUMAN" :prob "1.002")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG2-of (a4 / affect-01)) :op2 (a3 / attenuate-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "AG490") :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "JAK2") :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :xref (x3 / xref :value "PUBCHEM:5328779" :prob "18.349844")) :ARG1 e)) # ::id bel_pmid_1111_7534.6208 # ::date 2015-04-21T18:22:31 # ::file bel_pmid_1111_7534_6208.txt # ::snt PRL treatment of HC11 cells increased phosphorylation of STAT5. The JAK2 inhibitor AG490 blocked phosphorylation of STAT5 and PRL-induced, but not PGE1-induced, Cl- transport # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (i / increase-01 :ARG0 (t / treat-04 :ARG1 (c / cell :name (n / name :op1 "HC11")) :ARG2 (p5 / protein :name (n2 / name :op1 "PRL") :xref (x3 / xref :value "UNIPROT:PRL_HUMAN" :prob "1.003"))) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "STAT5") :xref (x / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")))) :snt2 (b / block-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "AG490") :ARG0-of (i2 / inhibit-01 :ARG1 (e / enzyme :name (n5 / name :op1 "JAK2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :xref (x5 / xref :value "PUBCHEM:5328779" :prob "18.349844")) :ARG1 (a / and :op1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n6 / name :op1 "STAT5") :xref (x2 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003"))) :op2 (t2 / transport-01 :ARG1 (s3 / small-molecule :name (n7 / name :op1 "Cl") :xref (x4 / xref :value "PUBCHEM:312" :prob "11.306334")) :ARG2-of (i3 / induce-01 :ARG0 (s4 / small-molecule :name (n8 / name :op1 "PRL") :xref (x6 / xref :value "PUBCHEM:7099" :prob "17.879841"))) :ARG1-of (c2 / contrast-01 :ARG2 (b2 / block-01 :polarity "-" :ARG1 (t3 / transport-01 :ARG1 s3 :ARG2-of (i4 / induce-01 :ARG0 (s / small-molecule :name (n10 / name :op1 "PGE1") :xref (x7 / xref :value "PUBCHEM:5280723" :prob "15.415987")))))))))) # ::id bel_pmid_1112_3332.21962 # ::date 2015-04-21T18:40:34 # ::file bel_pmid_1112_3332_21962.txt # ::snt These results suggest that ERK2 has a regulatory role in activating CREB in vivo in lung neutrophils after hemorrhage or endotoxemia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Apr 25, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (r2 / role :topic (r3 / regulate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "CREB") :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :manner (i / in-vivo) :location (c / cell :name (n2 / name :op1 "neutrophil") :part-of (l / lung)) :time (a2 / after :mod (o / or :op1 (h / hemorrhage-01) :op2 (e2 / endotoxemia))))) :poss e)) # ::id bel_pmid_1112_3332.37042 # ::date 2015-04-21T18:56:11 # ::file bel_pmid_1112_3332_37042.txt # ::snt These results suggest that ERK2 has a regulatory role in activating CREB in vivo in lung neutrophils after hemorrhage or endotoxemia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Apr 25, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (r2 / role :topic (r3 / regulate-01 :ARG0 (e / enzyme :name (n / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1 (a / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "CREB") :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :manner (i / in-vivo) :location (c / cell :name (n3 / name :op1 "neutrophil") :part-of (l / lung)) :time (a2 / after :mod (o / or :op1 (h / hemorrhage-01) :op2 (e2 / endotoxemia))))) :poss e)) # ::id bel_pmid_1112_7821.23468 # ::date 2015-04-21T19:02:13 # ::file bel_pmid_1112_7821_23468.txt # ::snt Tyrosine phosphorylation of JAK1 was detected at a very low concentration of IL-4 (1 ng/ml), while IL-13 induced phosphorylation only at concentrations of 50 ng/ml and above, both in normal (Figure 2a,b, upper blots) and tumor lung myo®broblasts (Figure 2c,d, upper blots). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (d / detect-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "JAK1") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :condition (p2 / protein :name (n3 / name :op1 "IL-4") :quant (c2 / concentration-quantity :quant "1" :unit (n4 / nanogram-per-milliliter) :ARG1-of (l / low-04 :degree (v / very))) :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003"))) :ARG2 (d2 / detect-01 :ARG1 (p3 / phosphorylate-01 :ARG2-of (i / induce-01 :ARG0 "p4")) :condition (p4 / protein :name (n5 / name :op1 "IL-13") :quant (a2 / and :op1 (c3 / concentration-quantity :quant "50" :unit n4) :op2 (a3 / above :op1 c3) :mod (o / only)) :xref (x2 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003"))) :location (a4 / and :op1 (m / myofibroblast :part-of (l2 / lung) :ARG1-of (n6 / normal-02) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "2a") :op2 (f2 / figure :mod "2b") :op3 (b / blot :mod (u / upper))))) :op2 (m2 / myofibroblast :part-of l2 :mod (t / tumor) :ARG1-of (d4 / describe-01 :ARG0 (a6 / and :op1 (f3 / figure :mod "2c") :op2 (f4 / figure :mod "2d") :op3 b))))) # ::id bel_pmid_1112_7821.23470 # ::date 2015-04-21T19:39:15 # ::file bel_pmid_1112_7821_23470.txt # ::snt the constitutive phosphorylation of STAT3 was observed repeatedly in tumor myo®bro- blasts (Figure 6f), but only occasionally in normal ®broblasts (Figure 6e). In the latter cells, IL-4 and IL- 13 induced (Figure 6d) or increased (Figure 6e) the tyrosine phosphorylation of STAT3, whereas in tumor myo®broblasts the two cytokines only caused an increase in the phosphorylation of STAT3 (Figure 6f). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (o / observe-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :mod (c2 / constitute-01)) :ARG1-of (r / repeat-01) :location (m2 / myofibroblast :mod (t / tumor)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6f"))) :ARG2 (o2 / observe-01 :ARG1 p :frequency (o3 / occasional :mod (o4 / only)) :location (f2 / fibroblast :ARG1-of (n2 / normal-02)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "6e")))) :snt2 (c3 / contrast-01 :ARG1 (o5 / or :op1 (i / induce-01 :ARG0 (a / and :op1 (c4 / cytokine :name (n3 / name :op1 "IL-4")) :op2 (c5 / cytokine :name (n4 / name :op1 "IL-13"))) :ARG2 (p3 / phosphorylate-01 :ARG0 (a2 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (p4 / protein :name (n5 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (d3 / describe-01 :ARG0 (f4 / figure :mod "6d"))) :op2 (i2 / increase-01 :ARG0 a :ARG1 p3 :ARG1-of (d4 / describe-01 :ARG0 (f5 / figure :mod "6e"))) :location (c6 / cell :mod (l / latter))) :ARG2 (c7 / cause-01 :ARG0 a :ARG1 (i3 / increase-01 :ARG0 a :ARG1 p3) :mod (o6 / only) :location (m3 / myofibroblast :mod (t2 / tumor)) :ARG1-of (d5 / describe-01 :ARG0 (f6 / figure :mod "6f"))))) # ::id bel_pmid_1112_7821.23472 # ::date 2015-04-21T20:05:26 # ::file bel_pmid_1112_7821_23472.txt # ::snt In normal lung ®broblasts and in tumor myo®broblasts, STAT6 was indeed phosphorylated on tyrosine residues in response to IL-4 and IL-13 (Figure 4a,b, upper blots). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (p / phosphorylate-01 :ARG1 (r / residue :mod (a / amino-acid :name (n / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :part-of (p2 / protein :name (n2 / name :op1 "STAT6") :xref (x / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")) :location (a2 / and :op1 (f / fibroblast :ARG1-of (n3 / normal-02) :part-of (l / lung)) :op2 (m / myofibroblast :mod (t / tumor)))) :ARG2-of (r2 / respond-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "IL-4") :xref (x1 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n5 / name :op1 "IL-13") :xref (x2 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")))) :mod (i / indeed) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "4a") :op2 (f3 / figure :mod "4b") :op3 (b / blot :mod (u / upper))))) # ::id bel_pmid_1112_7821.23474 # ::date 2015-04-21T20:17:49 # ::file bel_pmid_1112_7821_23474.txt # ::snt Finally, Tyk2, the fourth member of the JAK family, was found to be constitutively tyrosine-phosphorylated in these cells. However, IL-4 and IL-13 increased its phosphorylation level in lung myo®broblasts (Figure 2j), but not in normal cells, where both cytokines appear to slightly decrease its extent of phosphoryla- tion (Figure 2i). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (f / find-01 :li "-1" :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "Tyk2") :ARG1-of (m2 / mean-01 :ARG2 (m3 / member :ord (o / ordinal-entity :value "4") :ARG1-of (i / include-91 :ARG2 (p3 / protein-family :name (n3 / name :op1 "JAK"))))) :xref (x / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :manner (c / constitutive) :location (c2 / cell :mod (t / this)))) :snt2 (c3 / contrast-01 :ARG1 (i2 / increase-01 :ARG0 (a2 / and :op1 (c4 / cytokine :name (n4 / name :op1 "IL-4")) :op2 (c5 / cytokine :name (n5 / name :op1 "IL-13"))) :ARG1 (l / level :degree-of (p2 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine") :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :location (m4 / myofibroblast :part-of (l2 / lung)) :ARG1-of (d / describe-01 :ARG0 (f4 / figure :mod "2j"))) :ARG2 (i3 / increase-01 :polarity "-" :ARG0 a2 :ARG1 l :location (c6 / cell :ARG1-of (n7 / normal-02) :location-of (d2 / decrease-01 :ARG0 a2 :ARG1 (e3 / extent :degree-of p2) :ARG1-of (a4 / appear-02) :degree (s / slight))) :ARG1-of (d3 / describe-01 :ARG0 (f5 / figure :mod "2i"))))) # ::id bel_pmid_1112_7821.23486 # ::date 2015-04-21T20:18:17 # ::file bel_pmid_1112_7821_23486.txt # ::snt IL-4 and IL-13 induced tyrosine phosphorylation of STAT6 (green cytoplasmic staining) but probably also nuclear translocation of some phosphorylated STAT6 mole- cules, accounting for the yellow signal detected. Similar results were obtained with normal lung ®broblasts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (i / induce-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "IL-4") :xref (x2 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "IL-13") :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003"))) :ARG2 (a2 / and :op1 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (p4 / protein :name (n4 / name :op1 "STAT6") :xref (x1 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (d / describe-01 :ARG0 (s / stain-01 :ARG2 (c / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (g / green-02)))) :op2 (t / translocate-01 :ARG1 (m2 / molecule :mod p4 :ARG1-of p3 :quant (s2 / some)) :ARG2 (n5 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8")) :mod (p5 / probable) :mod (a4 / also) :ARG2-of (a5 / account-01 :ARG1 (s3 / signal-07 :ARG1-of (d2 / detect-01) :ARG1-of (y / yellow-02)))))) :snt2 (o / obtain-01 :ARG1 (t2 / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :ARG2 (f / fibroblast :part-of (l / lung) :ARG1-of (n6 / normal-02)))) # ::id bel_pmid_1113_4016.21280 # ::date 2015-04-17T07:07:34 # ::file bel_pmid_1113_4016_21280.txt # ::snt Using purified wild-type and mutant c-Raf-1 proteins, we demonstrate that Thr(269) is the major c-Raf-1 site phosphorylated by KSR in vitro and that phosphorylation of this site is essential for c-Raf-1 activation by KSR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p2 / protein-segment :part-of (e5 / enzyme :name (n2 / name :op1 "c-Raf-1") :xref (x / xref :value "UNIPROT:TRAF3_HUMAN" :prob "0.592")) :domain (a2 / amino-acid :mod "269" :name (n / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1-of (m / major-02) :ARG1-of (p / phosphorylate-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "KSR") :xref (x2 / xref :value "UNIPROT:KSR1_HUMAN" :prob "1.003")) :manner (i / in-vitro))) :op1 (e3 / essential :domain (p5 / phosphorylate-01 :ARG1 a2 :mod (e / essential) :purpose (a3 / activate-01 :ARG0 e2 :ARG1 e5) :mod a2))) :manner (u / use-01 :ARG0 w :ARG1 (a4 / and :op1 (p6 / protein :mod (w2 / wild-type) :ARG1-of (p8 / purify-01)) :op2 (e4 / enzyme :name (n4 / name :op1 "c-Raf-1") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:TRAF3_HUMAN" :prob "0.592"))))) # ::id bel_pmid_1113_4016.22950 # ::date 2015-04-21T05:59:02 # ::file bel_pmid_1113_4016_22950.txt # ::snt In vivo, low physiologic doses of EGF (0.001-0.1 ng/ml) stimulated KSR activation and induced Thr(269) phosphorylation and activation of c-Raf-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "EGF") :quant (d / dose :ARG1-of (l / low-04) :mod (p2 / physiology)) :quant (v / value-interval :op1 "0.001" :op1 "0.1" :unit (n3 / nanogram-per-milliliter)) :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "KSR") :xref (x / xref :value "UNIPROT:KSR1_HUMAN" :prob "1.003")))) :op2 (i / induce-01 :ARG0 p :ARG2 (a3 / and :op1 (p4 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "269" :name (n5 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (e2 / enzyme :name (n4 / name :op1 "c-Raf-1") :xref (x2 / xref :value "UNIPROT:TRAF3_HUMAN" :prob "0.592"))) :op2 (a5 / activate-01 :ARG1 e2))) :manner (i2 / in-vivo)) # ::id bel_pmid_1114_5587.7292 # ::date 2015-04-21T06:16:53 # ::file bel_pmid_1114_5587_7292.txt # ::snt In conclusion , our results show that IL-6 stimulates hepatic IGFBP-4 gene expression and production in vitro and in vivo , thereby suggesting another mechanism by which cytokines could control IGF-I action. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 23, 2015 (c / conclude-02 :ARG0 "w" :ARG1 (s / show-01 :ARG0 (t / thing :ARG1-of (r / result-01) :poss (w / we)) :ARG1 (s2 / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (a / and :op1 (e / express-03 :ARG1 (g / gene :name (n2 / name :op1 "IGFBP-4") :mod (h / hepatic) :xref (x / xref :value "UNIPROT:IBP4_HUMAN" :prob "1.002"))) :op2 (p2 / produce-01 :ARG1 g) :manner (a2 / and :op1 (i / in-vitro) :op2 (i2 / in-vivo)))) :ARG0-of (s3 / suggest-01 :ARG1 (p5 / possible-01 :ARG1 (c2 / control-01 :ARG0 (c3 / cytokine) :ARG1 (a3 / act-02 :ARG0 (p4 / protein :name (n4 / name :op1 "IGF-I") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "1.003"))) :manner (m / mechanism :mod (a4 / another))))))) # ::id bel_pmid_1115_4060.8844 # ::date 2015-04-21T06:30:49 # ::file bel_pmid_1115_4060_8844.txt # ::snt GAGA box of the rat serine protease inhibitor 2 (spi 2) genes not only acts as a basal promoter element, but also mediates transcriptional activation by growth hormone and interleukin-6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (a2 / act-02 :ARG0 (d2 / dna-sequence :name (n3 / name :op1 "GAGA" :op2 "box") :part-of (g2 / gene :name (n / name :op1 "serine" :op2 "protease" :op3 "inhibitor" :op4 "2") :mod (r / rat) :xref (x1 / xref :value "UNIPROT:ISK2_HUMAN" :prob "0.382"))) :ARG1 (e2 / element :ARG0-of (p / promote-01 :mod (b2 / basal)))) :op2 (m / mediate-01 :ARG0 d2 :ARG1 (a3 / activate-01 :ARG0 (a4 / and :op1 (h / hormone :ARG0-of (g / grow-01)) :op2 (p2 / protein :name (n2 / name :op1 "interleukin-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))) :mod (t / transcribe-01)) :mod (a5 / also))) # ::id bel_pmid_1116_0334.6798 # ::date 2015-04-21T06:51:13 # ::file bel_pmid_1116_0334_6798.txt # ::snt SDF-1alpha treatment induced expression of the chemokines monocyte chemoattractant protein-1, IL-8, and IFN-gamma-inducible protein-10. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / induce-01 :ARG0 (t / treat-04 :ARG2 (p / protein :name (n / name :op1 "SDF-1" :op2 "alpha") :xref (x4 / xref :value "UNIPROT:SDF1_HUMAN" :prob "0.323"))) :ARG2 (e / express-03 :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "monocyte" :op2 "chemoattractant" :op3 "protein-1") :xref (x / xref :value "UNIPROT:CCL2_HUMAN" :prob "0.692")) :op2 (p3 / protein :name (n4 / name :op1 "IL-8") :xref (x2 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n3 / name :op1 "IFN-gamma-inducible" :op2 "protein-10") :xref (x1 / xref :value "UNIPROT:SG1D4_HUMAN" :prob "0.312")) :mod (p5 / protein :name (n5 / name :op1 "chemokine") :xref (x3 / xref :value "UNIPROT:CCL15_HUMAN" :prob "0.332"))))) # ::id bel_pmid_1116_0334.7176 # ::date 2015-04-21T07:44:10 # ::file bel_pmid_1116_0334_7176.txt # ::snt CXCR4 protein expression was also enhanced upon treatment with TNF-alpha and IL-1beta (2- to 3-fold). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (e / enhance-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "CXCR4") :xref (x2 / xref :value "UNIPROT:CXCR4_HUMAN" :prob "1.004"))) :mod (a / also) :condition (t / treat-04 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "TNF-alpha") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n3 / name :op1 "IL-1beta") :xref (x1 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :quant (p4 / product-of :op1 (v / value-interval :op1 "2" :op2 "3"))))) # ::id bel_pmid_1116_0334.7194 # ::date 2015-04-21T07:55:30 # ::file bel_pmid_1116_0334_7194.txt # ::snt Enhancement of CXC chemokine receptor 4 (CXCR4) mRNA expression was observed upon treatment with the cytokines TNF-alpha and IL-1beta. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (o / observe-01 :ARG1 (e / enhance-01 :ARG1 (e2 / express-03 :ARG1 (n6 / nucleic-acid :name (n5 / name :op1 "mRNA")) :ARG2 (p / protein :name (n / name :op1 "CXC" :op2 "chemokine" :op3 "receptor" :op4 "4") :ARG1-of (d / describe-01 :ARG2 (p2 / protein :name (n4 / name :op1 "CXCR4") :xref (x / xref :value "UNIPROT:CXCR4_HUMAN" :prob "1.004"))) :xref (x1 / xref :value "UNIPROT:CXCR4_HUMAN" :prob "0.393")))) :condition (t / treat-04 :ARG2 (a / and :op1 (c / cytokine :name (n2 / name :op1 "TNF-alpha")) :op2 (c2 / cytokine :name (n3 / name :op1 "IL-1beta"))))) # ::id bel_pmid_1116_0334.22876 # ::date 2015-04-21T08:01:25 # ::file bel_pmid_1116_0334_22876.txt # ::snt Stimulation of cells with the ligand for CXCR4, stromal cell-derived factor-1alpha (SDF-1alpha), resulted in an elevation in intracellular Ca(2+) concentration # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / result-01 :ARG1 (s / stimulate-01 :ARG0 (p2 / protein :name (n / name :op1 "stromal" :op2 "cell-derived" :op3 "factor-1alpha") :ARG1-of (b / bind-01 :ARG2 (p / protein :name (n2 / name :op1 "CXCR4") :xref (x1 / xref :value "UNIPROT:CXCR4_HUMAN" :prob "1.004"))) :xref (x / xref :value "UNIPROT:SDF1_HUMAN" :prob "0.383")) :ARG1 (c / cell)) :ARG2 (e / elevate-01 :ARG1 (c2 / concentrate-02 :ARG1 (c3 / calcium :mod (i / intracellular) :ARG1-of (i2 / ionize-01 :value "2+"))))) # ::id bel_pmid_1116_0334.22880 # ::date 2015-04-21T08:03:27 # ::file bel_pmid_1116_0334_22880.txt # ::snt resulted in an elevation in intracellular Ca(2+) concentration and activation of the mitogen-activated protein kinase cascade, specifically, extracellular signal-regulated kinase 2 (ERK2) mitogen-activated protein kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / result-01 :ARG1 (a3 / and :op1 (e / elevate-01 :ARG1 (c2 / concentrate-02 :ARG1 (c / calcium :mod (i / intracellular) :ARG1-of (i2 / ionize-01 :value "2+")))) :op2 (a2 / activate-01 :ARG1 (c3 / cascade :mod (p / pathway :name (n / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase") :ARG1-of (m / mean-01 :ARG2 (p2 / pathway :name (n2 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase" :op4 "2" :op5 "mitogen-activated" :op6 "protein" :op7 "kinase")) :ARG1-of (s / specific-02))))))) # ::id bel_pmid_1116_0334.23556 # ::date 2015-04-21T08:12:32 # ::file bel_pmid_1116_0334_23556.txt # ::snt IL-1beta stimulation also enhanced CXCR4 expression (28.8% for CRT-J and 41.6% for U87-MG cells). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "IL-1beta") :xref (x1 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :ARG0-of (e / enhance-01 :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "CXCR4") :ARG0-of (m / mean-01 :ARG1 (a / and :op1 (c / cell :name (n3 / name :op1 "CRT-J") :mod (p3 / percentage-entity :value "28.8")) :op2 (c2 / cell :name (n5 / name :op1 "U87-MG") :mod (p4 / percentage-entity :value "41.6")))) :xref (x / xref :value "UNIPROT:CXCR4_HUMAN" :prob "1.004"))) :mod (a2 / also))) # ::id bel_pmid_1116_0334.37038 # ::date 2015-04-21T08:18:07 # ::file bel_pmid_1116_0334_37038.txt # ::snt SDF-1alpha-induced chemokine expression was abrogated upon inclusion of U0126, a pharmacological inhibitor of ERK1/2, indicating that the ERK signaling cascade is involved in this response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / abrogate-01 :ARG1 (e / express-03 :ARG2 (c / chemokine) :ARG2-of (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "SDF-1" :op2 "alpha") :xref (x2 / xref :value "UNIPROT:SDF1_HUMAN" :prob "0.323")))) :time (i2 / include-01 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "U0126") :ARG0-of (i3 / inhibit-01 :ARG1 (s / slash :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :mod (p2 / pharmacology)) :xref (x3 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG0-of (i4 / indicate-01 :ARG1 (i5 / involve-01 :ARG1 (p3 / pathway :name (n4 / name :op1 "ERK") :ARG0-of (s2 / signal-07)) :ARG2 (r / respond-01 :mod (t / this))))) # ::id bel_pmid_1119_6191.2576 # ::date 2015-04-21T08:39:33 # ::file bel_pmid_1119_6191_2576.txt # ::snt In T47D cells, IL-6 stimulated the activation of Janus-activated kinase 1 tyrosine kinase and signal transducers and activators of transcription (STAT) 1 and STAT3 transcription factors. Expression of dominant negative STAT3 in the cells strongly reduced IL-6-mediated growth inhibition but did not prevent IL-6-induced cell migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m / multi-sentence :snt1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "Janus-activated" :op2 "kinase" :op3 "1" :op4 "tyrosine" :op5 "kinase")) :op2 (p2 / protein :name (n3 / name :op1 "signal" :op2 "transducers" :op3 "activator" :op4 "transcription") :xref (x / xref :value "UNIPROT:A8K4S9_HUMAN" :prob "0.381")) :op3 (e2 / enzyme :name (n4 / name :op1 "STAT3" :op2 "transcription" :op3 "factors")))) :location (c4 / cell :name (n8 / name :op1 "T47D"))) :snt2 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (e3 / express-03 :ARG2 (p3 / protein :name (n5 / name :op1 "STAT3") :ARG2-of (m4 / mutate-01 :mod "-/-") :ARG0-of (d / dominate-01) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :location (c2 / cell)) :ARG1 (i / inhibit-01 :ARG1 (g / grow-01) :ARG1-of (m2 / mediate-01 :ARG0 p)) :ARG1-of (s2 / strong-02)) :ARG2 (p4 / prevent-01 :polarity "-" :ARG0 e3 :ARG1 (m3 / migrate-01 :ARG0 (c3 / cell) :ARG2-of (i2 / induce-01 :ARG0 p))))) # ::id bel_pmid_1119_6191.23672 # ::date 2015-04-21T09:38:51 # ::file bel_pmid_1119_6191_23672.txt # ::snt The IL-6-type cytokines, IL-6 and oncostatin M, simultaneously inhibited cell proliferation and increased cell migration # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / inhibit-01 :ARG0 (a / and :op1 (p2 / protein :name (n3 / name :op1 "IL-6-type" :op2 "cytokine")) :op2 (p3 / protein :name (n4 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n5 / name :op1 "oncostatin" :op2 "M") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "0.682"))) :ARG1 (a2 / and :op1 (p / proliferate-01 :ARG0 (c3 / cell)) :op2 (i2 / increase-01 :ARG1 (m / migrate-01 :ARG0 (c4 / cell)))) :manner (s / simultaneous)) # ::id bel_pmid_1119_6191.38528 # ::date 2015-04-21T09:44:41 # ::file bel_pmid_1119_6191_38528.txt # ::snt Pretreatment of cells with EGF receptor specific inhibitor CGP59326 or with the bispecific EGF receptor/ERBB2 inhibitor PD153035, diminished IL6 induced MAPK activation. Even the PKB phosphorylation was also affected by these two inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (d / diminish-01 :ARG0 (o / or :op1 (p / pretreat-01 :ARG1 (c / cell) :ARG3 (s4 / small-molecule :name (n / name :op1 "CGP59326") :ARG0-of (i / inhibit-01) :ARG1-of (s / specific-02 :ARG2 (e2 / enzyme :name (n7 / name :op1 "EGF" :op2 "receptor") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.213"))))) :op2 (p3 / pretreat-01 :ARG1 c :ARG3 (s3 / small-molecule :name (n3 / name :op1 "PD153035") :ARG0-of (i2 / inhibit-01) :mod (b / bispecific :prep-to (s2 / slash :op1 e2 :op2 (p2 / protein :name (n2 / name :op1 "ERBB2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.004")))) :xref (x5 / xref :value "PUBCHEM:4705" :prob "15.816147")))) :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "MAPK") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2-of (i3 / induce-01 :ARG0 (p5 / protein :name (n5 / name :op1 "il6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624"))))) :snt2 (a2 / affect-01 :ARG1 (p6 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n6 / name :op1 "PKB") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003"))) :ARG2 (t / thing :quant "2" :ARG0-of (i4 / inhibit-01) :mod (t2 / this)) :mod (a3 / also))) # ::id bel_pmid_1120_8678.16854 # ::date 2015-04-21T09:56:46 # ::file bel_pmid_1120_8678_16854.txt # ::snt Tissue factor (TF) can be induced in monocytes by external signals such as growth factors, inflammatory cytokines (interleukin [IL]-1b and tumor necrosis factor [TNF]-a), oxidized LDLs, and endotoxin. 2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (p6 / possible-01 :ARG1 (i / induce-01 :ARG2 (p5 / protein :name (n6 / name :op1 "tissue" :op2 "factor") :xref (x2 / xref :value "UNIPROT:TF_HUMAN" :prob "0.702")) :location (m / monocyte) :manner (s / signal-07 :mod (e / external) :example (a / and :op1 (g / growth-factor) :op2 (c / cytokine :ARG1-of (i2 / inflame-01) :ARG0-of (m2 / mean-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "interleukin" :op2 "IL-1b") :xref (x3 / xref :value "UNIPROT:IL17B_HUMAN" :prob "0.342")) :op2 (p4 / protein :name (n3 / name :op1 "tumor" :op2 "necrosis" :op3 "factor") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.702"))))) :op3 (p2 / protein :name (n4 / name :op1 "LDL") :ARG1-of (o / oxidize-01) :xref (x / xref :value "UNIPROT:COG1_HUMAN" :prob "0.262")) :op4 (s2 / small-molecule :name (n5 / name :op1 "endotoxin") :xref (x4 / xref :value "PUBCHEM:44268108" :prob "17.762056")))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "2"))))) # ::id bel_pmid_1120_8678.23564 # ::date 2015-04-21T10:07:33 # ::file bel_pmid_1120_8678_23564.txt # ::snt Incubation of monocytes with LPS or IL-1b resulted in a 10- and 5-fold increase of TF activity, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / result-01 :ARG1 (i / incubate-01 :ARG1 (m / monocyte) :ARG2 (o / or :op1 (l / lipopolysaccharide) :op2 (p / protein :name (n2 / name :op1 "IL-1b") :xref (x1 / xref :value "UNIPROT:O43645_HUMAN" :prob "0.671")))) :ARG2 (i2 / increase-01 :ARG1 (a / activity-06 :ARG0 (p3 / protein :name (n3 / name :op1 "TF") :xref (x / xref :value "UNIPROT:TF_HUMAN" :prob "1.003"))) :ARG2 (p2 / product-of :op1 "10" :op2 "5"))) # ::id bel_pmid_1120_8678.24148 # ::date 2015-04-21T10:55:26 # ::file bel_pmid_1120_8678_24148.txt # ::snt In human aortic smooth muscle cells, fibrates inhibit the IL-1b?induced expression of cyclooxygenase (COX)-2 and IL-6 by inhibiting the NF-kB and AP-1 signaling pathway.9,10 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG0 (f / fibrate) :ARG1 (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "cyclooxygenase" :op2 "2") :xref (x1 / xref :value "UNIPROT:PGH2_HUMAN" :prob "0.693")) :op2 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2-of (i2 / induce-01 :ARG0 (p / protein :name (n2 / name :op1 "IL-1b") :xref (x3 / xref :value "UNIPROT:O43645_HUMAN" :prob "0.671")))) :manner (i3 / inhibit-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "NF-kB") :xref (x2 / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272")) :op2 (p4 / pathway :name (n5 / name :op1 "AP-1") :ARG0-of (s / signal-07)))) :location (c / cell :mod (m / muscle :ARG1-of (s2 / smooth-06)) :mod (a3 / aortic :mod (h / human))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG0-of (c2 / cite-01 :ARG2 (a4 / and :op1 "9" :op2 "10"))))) # ::id bel_pmid_1120_8678.24150 # ::date 2015-04-22T04:19:37 # ::file bel_pmid_1120_8678_24150.txt # ::snt PPARa activators prevent TNF-a?induced VCAM-1 expression in human saphenous vein endothelial cells, partly via inhibition of the NF-kB pathway.14 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p / prevent-01 :ARG0 (a / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "PPARa") :xref (x / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.664"))) :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "VCAM-1") :xref (x1 / xref :value "UNIPROT:VCAM1_HUMAN" :prob "1.002")) :ARG2-of (i / induce-01 :ARG0 (p4 / protein :name (n3 / name :op1 "TNF-a") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :location (c / cell :mod (e2 / endothelium) :mod (v / vein :mod (s / saphenous)) :mod (h / human)) :degree (p5 / part) :manner (i2 / inhibit-01 :ARG1 (p6 / pathway :name (n5 / name :op1 "NF-kB"))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 "14")))) # ::id bel_pmid_1120_8678.24166 # ::date 2015-04-22T05:04:52 # ::file bel_pmid_1120_8678_24166.txt # ::snt In human vascular endothelial cells, PPARa inhibits the thrombin-mediated activation of endothelin-1 via negative interference with the AP-1 signaling pathway.13 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "PPARa") :xref (x2 / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.664")) :ARG1 (a / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "endothelin-1") :xref (x / xref :value "UNIPROT:EDN1_HUMAN" :prob "0.703")) :ARG1-of (m / mediate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "thrombin") :xref (x1 / xref :value "UNIPROT:THRB_HUMAN" :prob "0.292")))) :manner (i2 / interfere-01 :ARG0 p :ARG1 (p3 / pathway :name (n5 / name :op1 "AP-1") :ARG0-of (s / signal-07)) :ARG0-of (n4 / negative-02)) :location (c / cell :name (n6 / name :op1 "human" :op2 "vascular" :op3 "endothelial")) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "13")))) # ::id bel_pmid_1120_8678.24170 # ::date 2015-04-22T05:15:01 # ::file bel_pmid_1120_8678_24170.txt # ::snt Incubation of THP-1 cells with PPARa activators 1 hour before LPS stimulation for 2 hours resulted in a decreased level of TF mRNA compared with cells incubated with only LPS (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / result-01 :ARG1 (i / incubate-01 :ARG1 (c / cell :name (n / name :op1 "THP-1")) :ARG2 (a / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "PPARa") :xref (x1 / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.664"))) :time (b / before :op1 (s / stimulate-01 :ARG1 (l2 / lipopolysaccharide) :duration (t2 / temporal-quantity :quant "2" :unit (h2 / hour))) :quant (t / temporal-quantity :quant "1" :unit (h / hour)))) :ARG2 (d / decrease-01 :ARG1 (l / level :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n6 / name :op1 "TF") :xref (x / xref :value "UNIPROT:TF_HUMAN" :prob "1.003"))))) :compared-to (c2 / cell :ARG1-of (i2 / incubate-01 :ARG2 l2 :mod (o / only)))) :ARG1-of (d2 / describe-01 :ARG2 (f / figure :mod "2A"))) # ::id bel_pmid_1123_1577.20122 # ::date 2015-04-22T05:51:53 # ::file bel_pmid_1123_1577_20122.txt # ::snt Bag1, a co-chaperone for heat-shock protein 70 (Hsp70), coordinates signals for cell growth in response to cell stress, by downregulating the activity of Raf-1 kinase. Raf-1 and Hsp70 compete for binding to Bag1, such that Bag1 binds to and activates Raf-1, subsequently activating the downstream extracellular signal-related kinases # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (c / coordinate-01 :ARG1 (p / protein :name (n / name :op1 "Bag1") :ARG0-of (m2 / mean-01 :ARG1 (p2 / protein :name (n2 / name :op1 "co-chaperone") :beneficiary (p3 / protein :name (n3 / name :op1 "heat-shock") :mod (m3 / molecular-mass :mod "70") :xref (x3 / xref :value "UNIPROT:HS90A_HUMAN" :prob "0.293")))) :xref (x6 / xref :value "UNIPROT:BAG1_HUMAN" :prob "0.603")) :ARG2 (s / signal-07 :beneficiary (g / grow-01 :ARG1 (c2 / cell)) :ARG0-of (r / respond-01 :ARG1 (s2 / stress-02 :ARG1 (c3 / cell)))) :manner (d / downregulate-01 :ARG1 (a / activity-06 :ARG0 (e3 / enzyme :name (n4 / name :op1 "Raf-1") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))))) :snt2 (c4 / compete-01 :ARG0 (e / enzyme :name (n5 / name :op1 "Raf-1") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1 (p4 / protein :name (n6 / name :op1 "Hsp70") :xref (x / xref :value "UNIPROT:CH10_HUMAN" :prob "0.282")) :ARG2 (b / bind-01 :ARG1 (p5 / protein :name (n7 / name :op1 "Bag1") :xref (x5 / xref :value "UNIPROT:BAG1_HUMAN" :prob "0.603"))) :ARG1-of (c5 / cause-01 :ARG0 (a3 / and :op1 (b2 / bind-01 :ARG0 p5 :ARG1 e) :op2 (a4 / activate-01 :ARG0 p5 :ARG1 e))) :time (s3 / subsequent :op1 (a5 / activate-01 :ARG1 (e2 / enzyme :name (n8 / name :op1 "extracellular" :op2 "signal-related" :op3 "kinase") :mod (d2 / downstream) :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.393")))))) # ::id bel_pmid_1123_9409.20136 # ::date 2015-04-21T10:39:53 # ::file bel_pmid_1123_9409_20136.txt # ::snt Phosphorylation of Shc produces its binding to the adaptor protein Grb2, causing activation of the protooncogene ras, which is also upstream of the MAP kinase pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 22, 2015 (c / cause-01 :ARG0 (p / produce-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :ARG1 (b / bind-01 :ARG1 p3 :ARG2 (p4 / protein :name (n2 / name :op1 "grb2") :mod (a / adaptor) :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")))) :ARG1 (a2 / activate-01 :ARG1 (p5 / protooncogene :name (n3 / name :op1 "ras") :ARG1-of (b2 / be-located-at-91 :ARG2 (p6 / pathway :name (n4 / name :op1 "MAP" :op2 "kinase")) :direction (u / upstream) :mod (a3 / also))))) # ::id bel_pmid_1123_9409.21258 # ::date 2015-04-21T10:48:33 # ::file bel_pmid_1123_9409_21258.txt # ::snt insulin receptor phosphorylates a number of intracellular substrates on tyrosine including members of the insulin receptor substrate family (IRS1/2/3/4), the Shc adaptor... # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (n / number :quant-of (s / substrate :mod (i2 / intracellular))) :op2 (i4 / include-01 :ARG1 (m / member :ARG1-of (m2 / mean-01 :ARG2 (s2 / slash :op1 (p4 / protein :name (n5 / name :op1 "IRS1") :xref (x2 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.004")) :op2 (p5 / protein :name (n6 / name :op1 "IRS2") :xref (x3 / xref :value "UNIPROT:IRS2_HUMAN" :prob "1.004")) :op3 (p6 / protein :name (n7 / name :op1 "IRS3") :xref (x / xref :value "UNIPROT:BAIP2_HUMAN" :prob "0.282")) :op4 (p7 / protein :name (n8 / name :op1 "IRS4") :xref (x1 / xref :value "UNIPROT:IRS4_HUMAN" :prob "1.003"))))) :ARG2 (p2 / protein-family :name (n3 / name :op1 "insulin" :op2 "receptor" :op3 "substrate"))) :op3 (p3 / protein :name (n4 / name :op1 "Shc" :op2 "adaptor"))) :ARG2 (r / receptor :mod (i / insulin)) :location (a / amino-acid :name (n2 / name :op1 "tyrosine") :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) # ::id bel_pmid_1123_9409.23154 # ::date 2015-04-22T04:49:02 # ::file bel_pmid_1123_9409_23154.txt # ::snt Insulin stimulates the tyrosine kinase activity of its receptor, leading to the phosphorylation of a number of cellular substrates, including Gab1, Shc, IRS 1 - 4, and Cbl. Gab1 appears to interact with the SH2 containing tyrosine phosphatase SHP2, leading to the activation of the MAP kinase pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / multi-sentence :snt1 (s / stimulate-01 :ARG0 (i / insulin) :ARG1 (a / activity-06 :ARG0 (r / receptor :poss i) :ARG1 (e / enzyme :name (n / name :op1 "tyrosine" :op2 "kinase") :xref (x3 / xref :value "UNIPROT:FER_HUMAN" :prob "0.392"))) :ARG0-of (l / lead-03 :ARG2 (p / phosphorylate-01 :ARG1 (n2 / number :quant-of (s2 / substrate :mod (c / cell) :ARG2-of (i2 / include-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n3 / name :op1 "Gab1") :xref (x / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n4 / name :op1 "Shc") :xref (x2 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :op3 (p4 / protein :name (n5 / name :op1 "IRS") :mod (v / value-interval :op1 "1" :op2 "4") :xref (x4 / xref :value "UNIPROT:SYIC_HUMAN" :prob "1.002")) :op4 (p5 / protein :name (n6 / name :op1 "Cbl") :xref (x5 / xref :value "UNIPROT:CBL_HUMAN" :prob "0.604"))))))))) :snt2 (a3 / appear-02 :ARG1 (p6 / protein :name (n7 / name :op1 "Gab1") :xref (x1 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.604")) :ARG2 (i3 / interact-01 :ARG0 p6 :ARG1 (t / tyrosine-phosphatase :name (n8 / name :op1 "SHP2") :ARG1-of (c2 / contain-01 :ARG0 (p8 / protein :name (n9 / name :op1 "Sh2") :xref (x6 / xref :value "UNIPROT:SH2B2_HUMAN" :prob "0.233")))) :ARG0-of (l2 / lead-03 :ARG2 (a4 / activate-01 :ARG1 (p9 / pathway :name (n10 / name :op1 "MAP" :op2 "kinase"))))))) # ::id bel_pmid_1123_9409.24744 # ::date 2015-04-21T10:08:31 # ::file bel_pmid_1123_9409_24744.txt # ::snt Overexpression of these enzymes [LAR and PTP1B] in cultured cells prevents insulin receptor kinase activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (p / prevent-01 :ARG0 (o / overexpress-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "LAR") :xref (x1 / xref :value "UNIPROT:PTPRF_HUMAN" :prob "1.002")) :op2 (e2 / enzyme :name (n2 / name :op1 "PTP1B") :xref (x2 / xref :value "UNIPROT:PTN1_HUMAN" :prob "1.003"))) :location (c / cell :ARG1-of (c2 / culture-01))) :ARG1 (a2 / activate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "insulin" :op2 "receptor" :op3 "kinase") :xref (x / xref :value "UNIPROT:INSR_HUMAN" :prob "0.353")))) # ::id bel_pmid_1123_9409.32116 # ::date 2015-04-21T10:11:51 # ::file bel_pmid_1123_9409_32116.txt # ::snt The translocation of phosphorylated cbl recruits additional signaling proteins to the lipid raft, resulting in the activation of the G protein TC10. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / recruit-01 :ARG0 (t / translocate-01 :ARG1 (p / protein :name (n / name :op1 "cbl") :ARG1-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:CBL_HUMAN" :prob "0.604"))) :ARG1 (p3 / protein :ARG0-of (s / signal-07) :mod (a / additional)) :ARG2 (r2 / raft :mod (l / lipid)) :ARG2-of (r3 / result-01 :ARG1 (a2 / activate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "G" :op2 "TC10") :xref (x / xref :value "UNIPROT:COG5_HUMAN" :prob "0.232"))))) # ::id bel_pmid_1125_0916.23582 # ::date 2015-04-21T10:19:34 # ::file bel_pmid_1125_0916_23582.txt # ::snt Contrary to the hypothesis, both IL-1beta and IL-6 treatment resulted in a significant decrease in OT receptor messenger RNA measured by ribonuclease protection analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / result-01 :ARG1 (t / treat-04 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "IL-1beta") :xref (x1 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :op2 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG2 (d / decrease-01 :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "messeger" :op2 "RNA") :ARG0-of (e / encode-01 :ARG1 (r5 / receptor :name (n4 / name :op1 "OT")))) :ARG2 (s / significant-02) :ARG1-of (m / measure-01 :manner (a2 / analyze-01 :ARG1 (p3 / protection :mod (r3 / ribonuclease))))) :ARG0-of (c / counter-01 :ARG1 (t2 / thing :ARG1-of (h / hypothesize-01)))) # ::id bel_pmid_1125_2722.32494 # ::date 2015-04-22T01:33:42 # ::file bel_pmid_1125_2722_32494.txt # ::snt We demonstrated that ROR alpha is expressed in human primary smooth-muscle cells and that ectopic expression of ROR alpha1 inhibits TNFalpha-induced IL-6, IL-8 and COX-2 expression in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (a / and :op1 (e / express-03 :ARG2 (p4 / protein :name (n2 / name :op1 "ROR" :op2 "alpha" :op3 "receptor")) :location (c / cell :mod (m / muscle :ARG1-of (s / smooth-06 :mod (p / primary))) :mod (h / human))) :op2 (i / inhibit-01 :ARG0 (e2 / express-03 :ARG2 (p2 / protein :name (n7 / name :op1 "ROR" :op2 "alpha1" :op3 "receptor")) :manner (e3 / ectopic)) :ARG1 (a2 / and :op1 (p5 / protein :name (n3 / name :op1 "IL-6") :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "TNFalpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.692"))) :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n5 / name :op1 "IL-8") :xref (x1 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003")) :op3 (e4 / express-03 :ARG2 (e5 / enzyme :name (n6 / name :op1 "COX-2") :xref (x / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")))) :location (c4 / cell :mod (t / this))))) # ::id bel_pmid_1127_9172.6266 # ::date 2015-04-20T09:43:50 # ::file bel_pmid_1127_9172_6266.txt # ::snt SB203580, a specific p38 MAPK inhibitor, attenuated these effects, further confirming that both MMK6 and MMK3 act via p38 MAPK, whereas they had no effect on the increase in glucose transport induced by a constitutively active MAPK kinase 1 (MEK1) mutant or by myristoylated Akt. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a6 / attenuate-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "SB203580") :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "p38" :op2 "MAPK"))) :ARG1-of (s / specific-02) :xref (x4 / xref :value "PUBCHEM:176155" :prob "18.572987")) :ARG1 (a2 / affect-01 :mod (t / this)) :ARG0-of (c / confirm-01 :ARG1 (a4 / act-01 :ARG0 (a7 / and :op1 (e / enzyme :name (n3 / name :op1 "MKK6") :xref (x3 / xref :value "UNIPROT:MP2K6_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "MKK3") :xref (x2 / xref :value "UNIPROT:MP2K3_HUMAN" :prob "1.003"))) :manner p :ARG1-of (c2 / contrast-01 :ARG2 (a3 / affect-01 :polarity "-" :ARG0 a7 :ARG1 (i3 / increase-01 :ARG1 (t2 / transport-01 :ARG1 (g / glucose)) :ARG2-of (i4 / induce-01 :ARG0 (o / or :op1 (e4 / enzyme :name (n5 / name :op1 "MAPK" :op2 "kinase" :op3 "1") :ARG2-of (m3 / mutate-01) :ARG0-of (a / activity-06 :mod (c3 / constitutive)) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.393")) :op2 (e5 / enzyme :name (n6 / name :op1 "Akt") :ARG1-of (m5 / myristoylate-00) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))))))) :degree (f / further))) # ::id bel_pmid_1127_9172.21850 # ::date 2015-04-21T10:58:48 # ::file bel_pmid_1127_9172_21850.txt # ::snt Constitutively active MKK6/3 mutants up-regulated GLUT1 expression and down-regulated GLUT4 expression, thereby significantly increasing basal glucose transport but diminishing transport induced by insulin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / cause-01 :ARG0 (a / and :op1 (u / upregulate-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n2 / name :op1 "GLUT1") :xref (x4 / xref :value "UNIPROT:GTR1_HUMAN" :prob "1.003"))) :ARG2 (s2 / slash :op1 (e4 / enzyme :name (n5 / name :op1 "MKK6") :ARG0-of (a2 / activity-06 :mod (c2 / constitutive)) :xref (x1 / xref :value "UNIPROT:MP2K6_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n6 / name :op1 "MKK3") :ARG1-of a2 :xref (x / xref :value "UNIPROT:MP2K3_HUMAN" :prob "1.003")) :ARG2-of (m / mutate-01))) :op2 (d / downregulate-01 :ARG1 (e3 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "GLUT4") :xref (x2 / xref :value "UNIPROT:GTR4_HUMAN" :prob "1.002"))) :ARG2 m)) :ARG1 (c3 / contrast-01 :ARG1 (i / increase-01 :ARG1 (t / transport-01 :ARG1 (g / glucose :mod (b / basal))) :ARG2 (s / significant-02)) :ARG2 (d2 / diminish-01 :ARG1 (t2 / transport-01 :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "insulin") :xref (x3 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))))))) # ::id bel_pmid_1128_2560.28384 # ::date 2015-04-21T11:14:00 # ::file bel_pmid_1128_2560_28384.txt # ::snt A similar 24P3 induction was observed in other T cell lymphomas (EL4 and TH201) in response to IL-9, as well as in EL4 cells stimulated with IL-6 or IL-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (o / observe-01 :ARG1 (i / induce-01 :ARG2 (p / protein :name (n / name :op1 "24P3") :xref (x / xref :value "UNIPROT:S22AH_HUMAN" :prob "0.232")) :ARG1-of (r / resemble-01)) :location (a2 / and :op1 (l / lymphoma :example (a / and :op1 (c2 / cell :name (n3 / name :op1 "EL4")) :op2 (c3 / cell :name (n4 / name :op1 "TH201"))) :mod (o2 / other) :ARG2-of (r2 / respond-01 :ARG1 (p2 / protein :name (n5 / name :op1 "IL-9") :xref (x1 / xref :value "UNIPROT:IL9_HUMAN" :prob "1.003"))) :mod (c5 / cell :name (n9 / name :op1 "T"))) :op2 (c4 / cell :name (n6 / name :op1 "EL4") :ARG1-of (s / stimulate-01 :ARG0 (o3 / or :op1 (p3 / protein :name (n7 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n8 / name :op1 "IL-1") :xref (x3 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382"))))))) # ::id bel_pmid_1128_2560.28446 # ::date 2015-04-21T11:39:29 # ::file bel_pmid_1128_2560_28446.txt # ::snt Searching for genes specifically modulated by IL-9, we observed that the 24P3 mRNA is strongly upregulated in BW5147 T lymphoma cells upon IL-9 stimulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (h / have-condition-91 :ARG1 (u / upregulate-01 :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n / name :op1 "24P3") :xref (x1 / xref :value "UNIPROT:S22AH_HUMAN" :prob "0.232")))) :location (c / cell :name (n2 / name :op1 "BW5147" :op2 "T") :mod (l / lymphoma)) :ARG1-of (s2 / strong-02)) :ARG2 (s / stimulate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "IL-9") :xref (x / xref :value "UNIPROT:IL9_HUMAN" :prob "1.003")))) :time (s3 / search-01 :ARG0 w :ARG1 (g / gene :ARG1-of (m2 / modulate-01 :ARG0 p2 :ARG1-of (s4 / specific-02))))) # ::id bel_pmid_1128_7618.22858 # ::date 2015-04-21T12:03:34 # ::file bel_pmid_1128_7618_22858.txt # ::snt ResnetDB sentence: Gadd45gamma expression is induced by several cytokines, including IL-3, IL-6, and GM-CSF (20). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (d / describe-01 :ARG0 (s / sentence :mod (t / thing :name (n / name :op1 "ResnetDB"))) :ARG1 (i / induce-01 :ARG0 (c / cytokine :ARG2-of (i2 / include-91 :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "IL-3") :xref (x / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n4 / name :op1 "GM-CSF") :xref (x2 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.003")))) :quant (s2 / several)) :ARG2 (e / express-03 :ARG2 (p7 / protein :name (n6 / name :op1 "Gadd45" :op2 "gamma") :xref (x1 / xref :value "UNIPROT:GA45A_HUMAN" :prob "0.242")))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "20")))) # ::id bel_pmid_1128_7618.23626 # ::date 2015-04-21T12:15:46 # ::file bel_pmid_1128_7618_23626.txt # ::snt Gadd45gamma, a family member of the growth arrest and DNA damage-inducible gene family 45 (Gadd45), is strongly induced by interleukin-2 (IL-2) in peripheral T cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (i / induce-01 :ARG0 (p2 / protein :name (n3 / name :op1 "interleukin-2") :xref (x / xref :value "UNIPROT:IL2_HUMAN" :prob "0.703")) :ARG2 (p / protein :name (n / name :op1 "Gadd45gamma") :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family :name (n2 / name :op1 "growth" :op2 "arrest" :op3 "and" :op4 "DNA" :op5 "damage-inducible" :op6 "gene" :op7 "45"))) :xref (x1 / xref :value "UNIPROT:GA45A_HUMAN" :prob "0.242")) :location (c / cell :name (n4 / name :op1 "T") :mod (p3 / peripheral)) :ARG1-of (s / strong-02)) # ::id bel_pmid_1128_9146.5754 # ::date 2015-04-21T12:47:25 # ::file bel_pmid_1128_9146_5754.txt # ::snt K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (i2 / involve-01 :ARG1 (a / activate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "protein" :op2 "kinase" :op3 "B1") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393"))) :ARG2 (i / increase-01 :ARG1 (s / stability :mod (n5 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "cyclooxygenase" :op2 "2") :xref (x2 / xref :value "UNIPROT:PGH2_HUMAN" :prob "0.693"))))) :ARG1-of (m / mediate-01 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) # ::id bel_pmid_1128_9146.7350 # ::date 2015-04-21T12:53:57 # ::file bel_pmid_1128_9146_7350.txt # ::snt Thus, Akt/PKB activity is involved in K-Ras-induced expression of COX-2 and stabilization of COX-2 mRNA largely depends on the activation of Akt/PKB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (a / and :op1 (i / involve-01 :ARG1 (a2 / activity-06 :ARG0 (p / pathway :name (n / name :op1 "Akt/PKB"))) :ARG2 (e3 / express-03 :ARG2 (e4 / enzyme :name (n3 / name :op1 "COX-2") :xref (x / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")) :ARG2-of (i2 / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) :op2 (d / depend-01 :ARG0 (s / stabilize-01 :ARG2 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e5 / encode-01 :ARG1 e4))) :ARG1 (a3 / activate-01 :ARG1 p) :degree (l / large)))) # ::id bel_pmid_1129_4897.21214 # ::date 2015-04-21T13:05:07 # ::file bel_pmid_1129_4897_21214.txt # ::snt Addition of a single tyrosine residue, Y724, restored its [Fgfr3] ability to stimulate cellular transformation, phosphatidylinositol 3-kinase activation, and phosphorylation of Shp2, MAPK, Stat1, and Stat3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 28, 2015 (r3 / restore-01 :ARG0 (a / add-02 :ARG1 (r / residue :mod (a2 / amino-acid :mod "724" :name (n / name :op1 "tyrosine") :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (s / single-02))) :ARG1 (c / capable-01 :ARG1 (p / protein :name (n3 / name :op1 "Fgfr3") :xref (x5 / xref :value "UNIPROT:FGFR3_HUMAN" :prob "0.604")) :ARG2 (s2 / stimulate-01 :ARG0 p :ARG1 (a4 / and :op1 (t / transform-01 :mod (c2 / cell)) :op2 (a5 / activate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "phosphatidylinositol" :op2 "3-kinase") :xref (x3 / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.701"))) :op3 (p2 / phosphorylate-01 :ARG1 (a6 / and :op1 (e2 / enzyme :name (n5 / name :op1 "Shp2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n6 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op3 (p3 / protein :name (n7 / name :op1 "Stat1") :xref (x2 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604")) :op4 (p4 / protein :name (n8 / name :op1 "Stat3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))))))) # ::id bel_pmid_1129_4897.23128 # ::date 2015-04-21T13:23:38 # ::file bel_pmid_1129_4897_23128.txt # ::snt We also found that Y770 may function as a negative regulatory site for FGFR3-stimulated transformation and PI 3-kinase activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (f2 / function-01 :ARG0 (a / amino-acid :mod "770" :name (n / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1 (p3 / protein-segment :ARG2-of (d / downregulate-01 :ARG1 (a2 / and :op1 (t / transform-01 :ARG1-of (s2 / stimulate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "FGFR3") :xref (x1 / xref :value "UNIPROT:FGFR3_HUMAN" :prob "1.004")))) :op2 (a3 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "PI" :op2 "3-kinase") :xref (x / xref :value "UNIPROT:PK3C3_HUMAN" :prob "0.313")))))))) :mod (a4 / also)) # ::id bel_pmid_1129_7520.6398 # ::date 2015-04-21T13:35:06 # ::file bel_pmid_1129_7520_6398.txt # ::snt The reintroduction of wild-type LKB1 into a cancer cell line that lacks LKB1 suppressed growth, but mutants of LKB1 in which Ser(431) was mutated to Ala to prevent phosphorylation of LKB1 were ineffective in inhibiting growth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (s / suppress-01 :ARG0 (r / reintroduce-01 :ARG1 (e / enzyme :name (n / name :op1 "LKB1") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:STK11_HUMAN" :prob "1.002")) :ARG2 (c4 / cell-line :ARG0-of (l2 / lack-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "LKB1") :xref (x1 / xref :value "UNIPROT:STK11_HUMAN" :prob "1.002"))) :mod (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))) :ARG1 (g / grow-01)) :ARG2 (e2 / effective-04 :polarity "-" :ARG0 (e4 / enzyme :name (n5 / name :op1 "LKB1") :part (a / amino-acid :mod "431" :name (n2 / name :op1 "serine") :ARG1-of (m2 / mutate-01 :ARG2 (a2 / amino-acid :name (n3 / name :op1 "Ala") :xref (x3 / xref :value "PUBCHEM:602" :prob "11.66124")) :ARG0-of (p / prevent-01 :ARG1 (p2 / phosphorylate-01 :ARG1 e))) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:STK11_HUMAN" :prob "1.002")) :ARG1 (i / inhibit-01 :ARG0 e4 :ARG1 g))) # ::id bel_pmid_1129_7520.22158 # ::date 2015-04-21T13:54:33 # ::file bel_pmid_1129_7520_22158.txt # ::snt We present pharmacological and genetic evidence that p90(RSK) mediated this phosphorylation in response to agonists that activate ERK1/2 and that cAMP-dependent protein kinase mediated this phosphorylation in response to agonists that activate adenylate cyclase # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / present-01 :ARG0 (w / we) :ARG1 (e / evidence-01 :ARG1 (a / and :op1 (m / mediate-01 :ARG0 (p7 / protein :name (n8 / name :op1 "p90" :op2 "RSK") :xref (x2 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.322")) :ARG1 (p4 / phosphorylate-01 :mod (t / this)) :ARG2-of (r / respond-01 :ARG1 (a5 / agonist :ARG0-of (a2 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2")))))) :op2 (m3 / mediate-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "protein" :op2 "kinase") :ARG0-of (d / depend-01 :ARG1 (s / small-molecule :name (n / name :op1 "cAMP") :xref (x3 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393")) :ARG1 p4 :ARG2-of (r2 / respond-01 :ARG1 (a4 / agonist :ARG0-of (a3 / activate-01 :ARG1 (e4 / enzyme :name (n6 / name :op1 "adenylate" :op2 "cyclase") :xref (x / xref :value "UNIPROT:ADCYA_HUMAN" :prob "0.362"))))))) :mod (g / genetics) :mod (p2 / pharmacology))) # ::id bel_pmid_1129_7530.22688 # ::date 2015-04-21T14:08:08 # ::file bel_pmid_1129_7530_22688.txt # ::snt Immunoblot analysis of extracts from control and HT15 cells showed an increase in the activated forms of ERK1/2 in the Sod2-overexpressing cells that was reversed upon coexpression of catalase (Fig. 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / show-01 :ARG0 (a / and :op1 (a2 / analyze-01 :ARG1 (t / thing :ARG1-of (e / extract-01 :ARG2 (c / control))) :manner (i / immunoblot-01)) :op2 (c2 / cell-line :name (n / name :op1 "HT15"))) :ARG1 (i2 / increase-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG1-of (a3 / activate-01)) :location (c3 / cell :location-of (o / overexpress-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Sod2") :xref (x1 / xref :value "UNIPROT:SODM_HUMAN" :prob "0.603")))) :ARG1-of (r / reverse-01 :ARG0 (c4 / coexpress-01 :ARG2 (e4 / enzyme :name (n4 / name :op1 "catalase") :xref (x / xref :value "UNIPROT:CATA_HUMAN" :prob "0.702"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5A"))) # ::id bel_pmid_1129_7530.22690 # ::date 2015-04-21T14:17:40 # ::file bel_pmid_1129_7530_22690.txt # ::snt Analysis of IL-1a levels in Sod2-overexpressing cells showed a 3-fold increase in basal IL-1a levels that was reversed when catalase was coexpressed in these cell lines (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "IL-1a") :xref (x1 / xref :value "UNIPROT:IL1A_HUMAN" :prob "0.593"))) :location (c / cell :location-of (o / overexpress-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Sod2") :xref (x2 / xref :value "UNIPROT:SODM_HUMAN" :prob "0.603"))))) :ARG1 (i / increase-01 :ARG1 (l2 / level :mod (b / basal) :quant-of p) :ARG2 (p3 / product-of :op1 "3") :ARG1-of (r / reverse-01 :time (c2 / coexpress-01 :ARG2 (e / enzyme :name (n4 / name :op1 "catalase") :xref (x / xref :value "UNIPROT:CATA_HUMAN" :prob "0.702")) :ARG3 (c4 / cell-line :mod (t / this))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id bel_pmid_1129_7530.24362 # ::date 2015-04-21T14:26:17 # ::file bel_pmid_1129_7530_24362.txt # ::snt Thus, a 15-fold increase in Sod2 levels, which is well within the range of activity observed in response to cytokines and growth factors, can enhance MMP-1 expression in an H2O2-dependent fashion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (c / cause-01 :ARG1 (p / possible-01 :ARG1 (e / enhance-01 :ARG0 (i / increase-01 :ARG1 (l / level :quant-of (e2 / enzyme :name (n / name :op1 "Sod2") :xref (x / xref :value "UNIPROT:SODM_HUMAN" :prob "0.603"))) :ARG2 (p2 / product-of :op1 "15") :part-of (r / range-01 :ARG1 (a / activity-06) :ARG1-of (o / observe-01 :ARG2-of (r2 / respond-01 :ARG1 (a2 / and :op1 (c2 / cytokine) :op2 (g / growth-factor)))) :degree (w / well))) :ARG1 (e3 / express-03 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MMP-1") :xref (x1 / xref :value "UNIPROT:MMP1_HUMAN" :prob "1.002"))) :manner (d / depend-01 :ARG0 e3 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "H2O2") :xref (x2 / xref :value "PUBCHEM:784" :prob "17.186693")))))) # ::id bel_pmid_1129_7530.24364 # ::date 2015-04-22T08:40:56 # ::file bel_pmid_1129_7530_24364.txt # ::snt In support of this hypothesis, the gelatinolytic activity of MMP-2 and the mRNA levels of MMP-3 and MMP-7 were increased in the Sod2 overexpressors compared with control cell lines (Fig. 5C, left panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (s / support-01 :ARG0 (i / increase-01 :ARG1 (a / and :op1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "MMP-2") :xref (x3 / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.002")) :ARG1 (g / gelatinolysis)) :op2 (l / level :quant-of (n6 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "MMP-3") :xref (x / xref :value "UNIPROT:MMP3_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "MMP-7") :xref (x2 / xref :value "UNIPROT:MMP7_HUMAN" :prob "1.003"))))))) :location (c3 / cell-line :location-of (o / overexpress-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "Sod2") :xref (x1 / xref :value "UNIPROT:SODM_HUMAN" :prob "0.603"))) :compared-to (c4 / cell-line :ARG2-of (c2 / control-01)))) :ARG1 (h / hypothesize-01 :mod (t / this)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C" :location (p / panel :ARG1-of (l2 / left-20))))) # ::id bel_pmid_1129_7530.24366 # ::date 2015-04-22T08:49:39 # ::file bel_pmid_1129_7530_24366.txt # ::snt The observed decline in MMP-9 activity in the HT15 cell line may represent a negative regulatory aspect of Sod2 in MMP expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (p / possible-01 :ARG1 (r / represent-01 :ARG0 (d / decline-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "MMP-9") :xref (x / xref :value "UNIPROT:MMP9_HUMAN" :prob "1.002")) :location (c2 / cell-line :name (n5 / name :op1 "HT15"))) :ARG1-of (o / observe-01)) :ARG1 (a2 / aspect :ARG0-of (d2 / downregulate-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Sod2") :xref (x2 / xref :value "UNIPROT:SODM_HUMAN" :prob "0.603")) :topic (e3 / express-03 :ARG2 (e4 / enzyme :name (n4 / name :op1 "MMP") :xref (x1 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263"))))))) # ::id bel_pmid_1129_7530.28094 # ::date 2015-04-22T09:11:29 # ::file bel_pmid_1129_7530_28094.txt # ::snt The induction of MMP-13 by IL-1a and phorbol myristate acetate was severely impaired in the Sod2-/+ fibroblasts compared with the Sod2+/+ fibroblasts (Fig. 3, A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / impair-01 :ARG1 (i2 / induce-01 :ARG0 (a / and :op1 (p / protein :name (n2 / name :op1 "IL-1a") :xref (x3 / xref :value "UNIPROT:IL1A_HUMAN" :prob "0.593")) :op2 (s2 / small-molecule :name (n3 / name :op1 "phorbol" :op2 "myristate" :op3 "acetate") :xref (x4 / xref :value "PUBCHEM:4792" :prob "10.650805"))) :ARG2 (e / enzyme :name (n / name :op1 "MMP-13") :xref (x2 / xref :value "UNIPROT:MMP13_HUMAN" :prob "1.002"))) :location (f / fibroblast :mod (e2 / enzyme :name (n4 / name :op1 "Sod2") :ARG2-of (m2 / mutate-01 :mod "-/+") :xref (x1 / xref :value "UNIPROT:SODM_HUMAN" :prob "0.603"))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f3 / figure :mod "3A") :op2 (f4 / figure :mod "3B"))) :degree (s / severe) :compared-to (f2 / fibroblast :mod (e3 / enzyme :name (n5 / name :op1 "Sod2") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:SODM_HUMAN" :prob "0.603")))) # ::id bel_pmid_1129_7530.30812 # ::date 2015-04-22T09:57:46 # ::file bel_pmid_1129_7530_30812.txt # ::snt the wild-type MEFs responded to the induction of MMP-13 by TNF, whereas the heterozygotes did not. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / respond-01 :ARG0 (c2 / cell :name (n / name :op1 "MEF") :mod (w / wild-type)) :ARG1 (i / induce-01 :ARG0 (p2 / protein :name (n3 / name :op1 "TNF") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG2 (e / enzyme :name (n2 / name :op1 "MMP-13") :xref (x1 / xref :value "UNIPROT:MMP13_HUMAN" :prob "1.002")))) :ARG2 (r2 / respond-01 :polarity "-" :ARG0 (h / heterozygote) :ARG1 i)) # ::id bel_pmid_1129_7548.19988 # ::date 2015-04-22T10:06:54 # ::file bel_pmid_1129_7548_19988.txt # ::snt Although the growth factors epidermal growth factor (EGF) and neuregulin (NRG) 1 similarly stimulated Erk1/2 in MDA-MB-361 cells, EGF acting through an EGF receptor/ErbB2 heterodimer preferentially stimulated protein kinase C, and NRG1beta acting through an ErbB2/ErbB3 heterodimer preferentially stimulated Akt. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (h / have-concession-91 :ARG1 (a2 / and :op1 (s2 / stimulate-01 :ARG0 (p3 / protein :name (n5 / name :op1 "EGF") :ARG0-of (a3 / act-01 :instrument (h2 / heterodimer :part (p4 / protein :name (n7 / name :op1 "ErbB2") :xref (x6 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.634")))) :xref (x4 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (e2 / enzyme :name (n8 / name :op1 "protein" :op2 "kinase" :op3 "C") :xref (x3 / xref :value "UNIPROT:A0A087X0I9_HUMAN" :prob "0.701")) :ARG1-of (p5 / prefer-01)) :op2 (s3 / stimulate-01 :ARG0 (p6 / protein :name (n9 / name :op1 "NRG1beta") :ARG0-of (a4 / act-01 :instrument (m / macro-molecular-complex :name (n13 / name :op1 "heterodimer") :part (p8 / protein :name (n11 / name :op1 "ErbB3") :xref (x7 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "0.634")) :part p4)) :xref (x5 / xref :value "UNIPROT:NRG1_HUMAN" :prob "0.253")) :ARG1 (e3 / enzyme :name (n14 / name :op1 "Akt") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of p5)) :ARG2 (s / stimulate-01 :ARG0 (g / growth-factor :example (a / and :op1 (p / protein :name (n / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703")) :op2 (p2 / protein :name (n2 / name :op1 "neuregulin" :op2 "1") :xref (x1 / xref :value "UNIPROT:NRG1_HUMAN" :prob "0.683")))) :ARG1 (e / enzyme :name (n3 / name :op1 "Erk1/2")) :manner (r / resemble-01) :location (c / cell :name (n4 / name :op1 "MDA-MB-361")))) # ::id bel_pmid_1129_7548.24054 # ::date 2015-04-22T10:33:08 # ::file bel_pmid_1129_7548_24054.txt # ::snt In MDA-MB-453 cells, NRG1beta acting through an ErbB2/ErbB3 heterodimer stimulated prolonged signaling of all pathways examined relative to NRG2beta acting through the same heterodimeric receptor species. Surprisingly, NRG1beta and NRG2beta also regulated partially overlapping but distinct sets of genes in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (m / multi-sentence :snt1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "NRG1beta") :ARG0-of (a / act-01 :instrument (h / heterodimer :part (p2 / protein :name (n3 / name :op1 "ErbB2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.634")) :part (p3 / protein :name (n4 / name :op1 "ErbB3") :xref (x3 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "0.634")))) :xref (x5 / xref :value "UNIPROT:NRG1_HUMAN" :prob "0.253")) :ARG1 (s2 / signal-07 :ARG0 (p5 / pathway :mod (a2 / all) :ARG1-of (e / examine-01)) :ARG1-of (p4 / prolong-01)) :ARG1-of (r / relative-05 :ARG3 (p6 / protein :name (n5 / name :op1 "NRG2beta") :ARG0-of (a3 / act-01 :instrument (s3 / specie :mod (r2 / receptor :ARG1-of (s5 / same-01) :mod (h2 / heterodimer)))) :xref (x1 / xref :value "UNIPROT:NRG2_HUMAN" :prob "0.253"))) :location (c / cell :name (n7 / name :op1 "MDA-MB-453"))) :snt2 (r3 / regulate-01 :ARG0 (a4 / and :op1 (p7 / protein :name (n8 / name :op1 "NRG1beta") :xref (x2 / xref :value "UNIPROT:NRG1_HUMAN" :prob "0.253")) :op2 (p8 / protein :name (n9 / name :op1 "NRG2beta") :xref (x4 / xref :value "UNIPROT:NRG2_HUMAN" :prob "0.253"))) :ARG1 (s4 / set :mod (g / gene) :ARG0-of (o / overlap-01 :degree (p9 / part) :ARG1-of (c3 / contrast-01 :ARG2 (d / distinct :domain s4)))) :location (c2 / cell :mod (t / this)) :ARG0-of (s6 / surprise-01) :mod (a5 / also))) # ::id bel_pmid_1129_7548.24056 # ::date 2015-04-22T12:33:36 # ::file bel_pmid_1129_7548_24056.txt # ::snt As expected, EGF preferentially stimulated the recruitment of the adaptor protein Grb2 to EGF receptor whereas NRG1beta preferentially stimulated the recruitment of this protein to ErbB3. NRG1beta also preferentially stimulated the association of p85, the 85-kDa subunit of PI3K, with ErbB3, as demonstrated previously (40). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "EGF") :xref (x7 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (r / recruit-01 :ARG1 (p4 / protein :name (n2 / name :op1 "Grb2") :mod (a / adaptor) :xref (x5 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2 (e3 / enzyme :name (n8 / name :op1 "EGF" :op2 "receptor") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.213"))) :ARG1-of (p2 / prefer-01)) :ARG2 (s2 / stimulate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "NRG1beta") :xref (x3 / xref :value "UNIPROT:NRG1_HUMAN" :prob "0.253")) :ARG1 (r3 / recruit-01 :ARG1 p4 :ARG2 (p5 / protein :name (n5 / name :op1 "ErbB3") :xref (x6 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "0.634"))) :ARG1-of p2) :ARG1-of (e / expect-01)) :snt2 (s3 / stimulate-01 :ARG0 (p7 / protein :name (n6 / name :op1 "NRG1beta") :xref (x4 / xref :value "UNIPROT:NRG1_HUMAN" :prob "0.253")) :ARG1 (a3 / associate-01 :ARG1 (p8 / protein-segment :name (n7 / name :op1 "p85") :ARG1-of (m2 / mean-01 :ARG2 (e2 / enzyme :name (n9 / name :op1 "PI3K") :quant (m3 / mass-quantity :quant "85" :unit (k / kilodalton)) :xref (x2 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :ARG2 (p11 / protein :name (n10 / name :op1 "ErbB3") :xref (x / xref :value "UNIPROT:ERBB3_HUMAN" :prob "0.634"))) :mod (a2 / also) :ARG1-of (p6 / prefer-01) :ARG1-of (d / demonstrate-01 :time (p12 / previous)) :ARG1-of (d2 / describe-01 :ARG0 (p13 / publication :ARG1-of (c2 / cite-01 :ARG2 "40"))))) # ::id bel_pmid_1129_7548.38074 # ::date 2015-04-22T13:02:54 # ::file bel_pmid_1129_7548_38074.txt # ::snt Although the growth factors epidermal growth factor (EGF) and neuregulin (NRG) 1 similarly stimulated Erk1/2 in MDA-MB-361 cells, EGF acting through an EGF receptor/ErbB2 heterodimer preferentially stimulated protein kinase C, and NRG1beta acting through an ErbB2/ErbB3 heterodimer preferentially stimulated Akt. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (h / have-concession-91 :ARG1 (a / and :op1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "EGF") :ARG0-of (a2 / act-01 :instrument (h2 / heterodimer :part (p2 / protein :name (n4 / name :op1 "ErbB2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.634")) :part (p7 / protein :name (n3 / name :op1 "EGF" :op2 "receptor") :xref (x5 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.213")))) :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (e / enzyme :name (n5 / name :op1 "protein" :op2 "kinase" :op3 "C") :xref (x4 / xref :value "UNIPROT:A0A087X0I9_HUMAN" :prob "0.701")) :ARG1-of (p3 / prefer-01)) :op2 (s2 / stimulate-01 :ARG0 (p4 / protein :name (n6 / name :op1 "NRG1beta") :ARG0-of (a3 / act-01 :instrument (h3 / heterodimer :part (p6 / protein :name (n9 / name :op1 "ErbB3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "0.634")) :part p2)) :xref (x6 / xref :value "UNIPROT:NRG1_HUMAN" :prob "0.253")) :ARG1 (e2 / enzyme :name (n10 / name :op1 "Akt") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of p3)) :ARG2 (s3 / stimulate-01 :ARG0 (g / growth-factor :example (a4 / and :op1 (p8 / protein :name (n11 / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x7 / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703")) :op2 (p9 / protein :name (n12 / name :op1 "neuregulin" :op2 "1") :xref (x8 / xref :value "UNIPROT:NRG1_HUMAN" :prob "0.683")))) :ARG1 (e3 / enzyme :name (n13 / name :op1 "Erk1/2")) :manner (r2 / resemble-01) :location (c / cell :name (n14 / name :op1 "MDA-MB-361")))) # ::id bel_pmid_1131_3931.5286 # ::date 2015-04-22T13:13:05 # ::file bel_pmid_1131_3931_5286.txt # ::snt We find that Cdk10 binds full length Ets2 in vitro and in vivo and inhibits Ets2 transactivation in mammalian cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (f3 / find-01 :ARG0 (w / we) :ARG1 (a3 / and :op1 (b / bind-01 :ARG0 (e / enzyme :name (n / name :op1 "Cdk10") :xref (x / xref :value "UNIPROT:CDK10_HUMAN" :prob "0.633")) :ARG1 (l / length :poss (p / protein :name (n2 / name :op1 "Ets2") :xref (x1 / xref :value "UNIPROT:ETS2_HUMAN" :prob "0.603")) :degree (f2 / full)) :manner (a2 / and :op1 (i / in-vitro) :op2 (i2 / in-vivo))) :op2 (i3 / inhibit-01 :ARG0 e :ARG1 (t / transactivate-01 :ARG1 p :location (c / cell :mod (m / mammal)))))) # ::id bel_pmid_1132_3411.1008 # ::date 2015-04-22T13:22:03 # ::file bel_pmid_1132_3411_1008.txt # ::snt Consistently, substrate-trapping experiments with a SHP2 catalytic inactive mutant suggested that Gab1 was a SHP2 PTPase substrate in the cells. Therefore, Gab1 not only is a SHP2 activator but also is a target of its PTPase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (m / multi-sentence :snt1 (s / suggest-01 :ARG0 (a / and :op1 (e / experiment-01 :ARG1 (s2 / substrate :ARG1-of (t / trap-01 :ARG0 (e2 / enzyme :name (n / name :op1 "SHP2") :ARG2-of (m2 / mutate-01) :ARG1-of (a2 / activate-01 :polarity "-" :mod (c / catalysis)) :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673")))))) :ARG1 (s3 / substrate :domain (p / protein :name (n2 / name :op1 "Gab1") :xref (x5 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.604")) :mod (e3 / enzyme :name (n3 / name :op1 "SHP2" :op2 "PTPase") :xref (x4 / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.243")) :location (c2 / cell)) :manner (c4 / consistent-02)) :snt2 (c3 / cause-01 :ARG1 (a3 / and :op1 (a4 / activate-01 :ARG0 (p2 / protein :name (n5 / name :op1 "Gab1") :xref (x3 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.604")) :ARG1 (e4 / enzyme :name (n4 / name :op1 "SHP2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673"))) :op2 (t2 / target-01 :ARG0 (e5 / enzyme :name (n6 / name :op1 "PTPase") :part-of e4 :xref (x / xref :value "UNIPROT:PTPRO_HUMAN" :prob "0.322")) :ARG1 p2)))) # ::id bel_pmid_1132_3411.6960 # ::date 2015-04-22T13:40:51 # ::file bel_pmid_1132_3411_6960.txt # ::snt We found that both Tyr-627 and Tyr-659 of Gab1 were required for SHP2 binding to Gab1 and for ERK2 activation by EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (r / require-01 :ARG0 (a4 / and :op1 (b / bind-01 :ARG1 (e / enzyme :name (n4 / name :op1 "SHP2") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673")) :ARG2 (p2 / protein :name (n5 / name :op1 "Gab1") :xref (x / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.604"))) :op2 (a5 / activate-01 :ARG0 (p3 / protein :name (n6 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (e2 / enzyme :name (n7 / name :op1 "ERK2") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :ARG1 (a / and :op1 (a2 / amino-acid :mod "627" :name (n / name :op1 "tyrosine") :part-of p2 :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a3 / amino-acid :mod "659" :name (n3 / name :op1 "tyrosine") :part-of p2 :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) # ::id bel_pmid_1134_1776.3378 # ::date 2015-04-22T13:47:25 # ::file bel_pmid_1134_1776_3378.txt # ::snt We demonstrated that lung myofibroblasts, incubated in the presence of E2, showed a rapid phosphorylation on serine-259 of Raf1 and tyrosine-204 of ERK1/2 MAP kinase at 15 min, by approximately 3- and 5-fold, respectively # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (s / show-01 :ARG0 (m2 / myofibroblast :mod (l / lung) :ARG1-of (i / incubate-01 :condition (p / present-02 :ARG1 (e / enzyme :name (n3 / name :op1 "E2"))))) :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG0 (a2 / amino-acid :mod "259" :name (n4 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1 (e2 / enzyme :name (n5 / name :op1 "Raf1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.674")) :mod (r2 / rapid) :quant (a4 / approximately :op1 (p4 / product-of :op1 "3"))) :op2 (p3 / phosphorylate-01 :ARG0 (a3 / amino-acid :mod "204" :name (n6 / name :op1 "tyrosine") :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1 (e3 / enzyme :name (n7 / name :op1 "ERK1/2" :op2 "MAP" :op3 "kinase")) :quant (a5 / approximately :op1 (p5 / product-of :op1 "5"))) :mod (r / respective) :time (a6 / after :quant (t / temporal-quantity :quant "15" :unit (m / minute)))))) # ::id bel_pmid_1135_0938.21662 # ::date 2015-04-21T04:51:58 # ::file bel_pmid_1135_0938_21662.txt # ::snt since in PKR-null MEFs there is a marked defect in Erk1 and Erk2 activation by PDGF (Figure1D), it appears that PKR is involved in serine phosphorylation of Stat3 through the activation of Erks. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / appear-02 :ARG1 (i / involve-01 :ARG0 (e / enzyme :name (n / name :op1 "PKR") :xref (x5 / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002")) :ARG2 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "serine") :part-of (p2 / protein :name (n2 / name :op1 "Stat3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (a2 / activate-01 :ARG1 "a5"))) :ARG1-of (c / cause-01 :ARG0 (d / defect :prep-in (a4 / activate-01 :ARG0 (p3 / protein :name (n5 / name :op1 "PDGF") :xref (x4 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :ARG1 (a5 / and :op1 (e3 / enzyme :name (n6 / name :op1 "Erk1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n7 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :mod (m2 / marked) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1D")) :location (c2 / cell :name (n8 / name :op1 "MEF") :ARG3-of (e6 / express-03 :ARG2 (e5 / enzyme :name (n9 / name :op1 "PKR") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002"))))))) # ::id bel_pmid_1135_0938.21664 # ::date 2015-04-21T05:27:58 # ::file bel_pmid_1135_0938_21664.txt # ::snt Whereas PKR+/+ cells exhibited a clear induction in phospho-Ser727 Stat3, PKR-null cells were defective in this process (Figure1B) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (e3 / exhibit-01 :polarity "-" :ARG0 (c4 / cell :ARG3-of (e5 / express-03 :ARG2 (e4 / enzyme :name (n4 / name :op1 "PKR") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002")))) :ARG1 (i2 / induce-01 :ARG2 (p3 / phosphorylate-01 :ARG1 "a"))) :ARG2 (e / exhibit-01 :ARG0 (c2 / cell :ARG3-of (e6 / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "PKR") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002")))) :ARG1 (i / induce-01 :ARG2 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "727" :name (n2 / name :op1 "serine") :part-of (p2 / protein :name (n3 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1-of (c3 / clear-06))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id bel_pmid_1135_0938.21666 # ::date 2015-04-21T05:41:20 # ::file bel_pmid_1135_0938_21666.txt # ::snt Accordingly, nuclear extracts prepared from PDGF-treated PKR- null cells were severely deficient in Stat3 containing DNA-binding complexes compared with wild-type MEFs (data not shown). Taken together, we conclude that PDGF-induced activation of Stat3 DNA binding is PKR dependent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (l / lack-01 :ARG0 (e / extract :mod (n / nucleus :xref (x6 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (p / prepare-01 :ARG2 (c / cell :ARG1-of (t / treat-04 :ARG2 (p2 / protein :name (n2 / name :op1 "PDGF") :xref (x2 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313"))) :ARG2-of (e5 / express-03 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PKR") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002")))))) :ARG1 (m3 / macro-molecular-complex :ARG0-of (b / bind-01 :ARG1 (n9 / nucleic-acid :wiki "DNA" :name (n10 / name :op1 "DNA"))) :ARG0-of (c3 / contain-01 :ARG1 (p3 / protein :name (n4 / name :op1 "Stat3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :ARG1-of (s / show-01 :polarity "-") :degree (s2 / severe) :manner (a2 / accordingly) :compared-to (c2 / cell :name (n8 / name :op1 "MEF") :mod (w2 / wild-type))) :snt2 (c4 / conclude-01 :ARG0 (w / we) :ARG1 (d2 / depend-01 :ARG0 (a / activate-01 :ARG0 (p4 / protein :name (n6 / name :op1 "PDGF") :xref (x4 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :ARG1 (b2 / bind-01 :ARG1 (n11 / nucleic-acid :wiki "DNA" :name (n12 / name :op1 "DNA") :mod (p5 / protein :name (n7 / name :op1 "Stat3") :xref (x5 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))))) :ARG1 (e3 / enzyme :name (n5 / name :op1 "PKR") :xref (x / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002"))) :ARG1-of (t2 / take-01 :mod (t3 / together)))) # ::id bel_pmid_1135_0938.26648 # ::date 2015-04-21T05:57:48 # ::file bel_pmid_1135_0938_26648.txt # ::snt PDGF treatment induced two Tyr705-phosphorylated forms of Stat3 in PKR+/+ cells, a faster migrating species termed Stat3fm and a slower migrating species termed Stat3sm (Figure1A).....Importantly, PDGF treatment did not induce either form of tyrosine-phosphorylated Stat3 in PKR-null cells (Figure1A), implicating a requirement for PKR in both tyrosine and serine phosphorylation of Stat3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (m2 / multi-sentence :snt1 (i / induce-01 :ARG0 (t / treat-04 :ARG1 (p2 / protein :name (n2 / name :op1 "PDGF") :xref (x3 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313"))) :ARG2 (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "Stat3") :ARG0-of (m3 / migrate-01 :ARG1-of (f2 / fast-02 :degree (m4 / more))) :ARG1-of (t2 / term-01 :ARG3 (s2 / string-entity :value "Stat3fm")) :part (a3 / amino-acid :mod "705" :name (n4 / name :op1 "tyrosine") :ARG1-of (p3 / phosphorylate-01) :xref (x8 / xref :value "PUBCHEM:1153" :prob "11.081481")) :xref (x5 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :op2 (p5 / protein :name (n6 / name :op1 "Stat3") :ARG0-of (m5 / migrate-01 :ARG1-of (s3 / slow-05 :degree (l / less))) :ARG1-of (t3 / term-01 :ARG3 (s / string-entity :value "Stat3sm")) :part a3 :xref (x6 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :location (c / cell :ARG2-of (e4 / express-03 :ARG1 (e / enzyme :name (n3 / name :op1 "PKR") :mod (w / wild-type) :xref (x4 / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002")))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "1A"))) :snt2 (i2 / induce-01 :polarity "-" :ARG0 (t4 / treat-04 :ARG1 (p6 / protein :name (n7 / name :op1 "PDGF") :xref (x7 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313"))) :ARG2 (f / form :quant "2" :mod (p7 / protein :name (n8 / name :op1 "Stat3") :part (a4 / amino-acid :name (n9 / name :op1 "tyrosine") :ARG1-of (p8 / phosphorylate-01) :xref (x10 / xref :value "PUBCHEM:1153" :prob "11.081481")) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :mod (e2 / either)) :location (c2 / cell :ARG2-of (e5 / express-03 :ARG1 (e3 / enzyme :name (n10 / name :op1 "PKR") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002")))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure :mod "1A")) :ARG0-of (i3 / imply-01 :ARG1 (r / require-01 :ARG0 (p9 / phosphorylate-01 :ARG1 (a / and :op1 (a5 / amino-acid :name (n11 / name :op1 "tyrosine") :part-of (p10 / protein :name (n13 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :xref (x9 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a6 / amino-acid :name (n12 / name :op1 "serine") :part-of p10 :xref (x11 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :ARG1 e3)) :mod (i4 / important))) # ::id bel_pmid_1135_0938.26650 # ::date 2015-04-21T06:29:03 # ::file bel_pmid_1135_0938_26650.txt # ::snt The results (Figure4A and B) showed a 16-fold induction in PKR wild-type cells in contrast to a 0.8-fold induction in c-fos message in PKR-null cells at 15 min of PDGF treatment # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Apr 28, 2015 (s / show-01 :ARG0 (t / thing :ARG1-of (r / result-01 :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B"))))) :ARG1 (c / contrast-01 :ARG1 (i / induce-01 :location (c2 / cell :ARG3-of (e5 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "PKR") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002")))) :mod (p2 / product-of :op1 "16")) :ARG2 (i2 / induce-01 :ARG1 (e4 / express-03 :ARG1 (g / gene :name (n4 / name :op1 "c-fos"))) :location (c3 / cell :ARG2-of (e3 / express-03 :ARG1 (e2 / enzyme :name (n2 / name :op1 "PKR") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002")))) :mod (p3 / product-of :op1 "0.8")) :time (a / after :op1 (t2 / treat-04 :ARG2 (p / protein :name (n3 / name :op1 "PDGF") :xref (x2 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313"))) :quant (t3 / temporal-quantity :quant "15" :unit (m2 / minute))))) # ::id bel_pmid_1135_0938.29866 # ::date 2015-04-21T06:47:48 # ::file bel_pmid_1135_0938_29866.txt # ::snt Immunoblotting with anti-Stat3 as well as anti-PKR anti bodies (Figure2E) showed an increase in interaction within 5-15 min of treatment with the growth factor, followed by a decrease to below basal level at later time points. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (s2 / show-01 :ARG0 (i / immunoblot-01 :ARG3 (a / and :op1 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n2 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :op2 (a3 / antibody :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n3 / name :op1 "PKR") :xref (x / xref :value "UNIPROT:E2AK2_HUMAN" :prob "1.002"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2E"))) :ARG1 (i2 / increase-01 :ARG1 (i3 / interact-01) :time (a4 / after :op1 (t / treat-04 :ARG2 (g / growth-factor)) :quant (t2 / temporal-quantity :quant (b / between :op1 "5" :op2 "15") :unit (m2 / minute))) :ARG2-of (f2 / follow-01 :ARG1 (d2 / decrease-01 :ARG4 (b3 / below :op1 (l2 / level :mod (b2 / basal))) :time (l / late :degree (m / more)))))) # ::id bel_pmid_1140_4390.9676 # ::date 2015-04-21T07:10:14 # ::file bel_pmid_1140_4390_9676.txt # ::snt The induction of TNF-alpha production by NGF was blocked by K252a, an inhibitor of the TrkA receptor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (b / block-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "K252a") :ARG0-of (i / inhibit-01 :ARG1 (r / receptor :name (n4 / name :op1 "TrkA"))) :xref (x2 / xref :value "PUBCHEM:127357" :prob "18.349844")) :ARG1 (i2 / induce-01 :ARG0 (p / protein :name (n / name :op1 "NGF") :xref (x1 / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :ARG2 (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "TNF-alpha") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))))) # ::id bel_pmid_1140_4390.22028 # ::date 2015-04-21T07:22:21 # ::file bel_pmid_1140_4390_22028.txt # ::snt To examine the role of TrkA in NGF's effects, we used K252a, which inhibits the tyrosine kinase activity of this receptor. Pretreatment of the cells with K252a (50 ng/mL) inhibited the production of TNF-a by NGF # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (u / use-01 :ARG0 (w / we) :ARG1 (s / small-molecule :name (n / name :op1 "K252a") :ARG0-of (i / inhibit-01 :ARG1 (a / activity-06 :ARG0 "r2" :ARG1 (e2 / enzyme :name (n9 / name :op1 "tyrosine" :op2 "kinase") :xref (x1 / xref :value "UNIPROT:FER_HUMAN" :prob "0.392")))) :xref (x5 / xref :value "PUBCHEM:127357" :prob "18.349844")) :ARG2 (e / examine-01 :ARG0 w :ARG1 (r / role :poss (r2 / receptor :name (n2 / name :op1 "TrkA")) :topic (t / thing :ARG2-of (a2 / affect-01 :ARG0 (p2 / protein :name (n3 / name :op1 "NGF") :xref (x / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004"))))))) :snt2 (i2 / inhibit-01 :ARG0 (p / pretreat-01 :ARG1 (c / cell) :ARG3 (s2 / small-molecule :name (n5 / name :op1 "K252a") :quant (m2 / mass-quantity :quant "50" :unit (n8 / nanogram-per-milliliter)) :xref (x4 / xref :value "PUBCHEM:127357" :prob "18.349844"))) :ARG1 (p3 / produce-01 :ARG0 (p4 / protein :name (n6 / name :op1 "NGF") :xref (x2 / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :ARG1 (p5 / protein :name (n7 / name :op1 "TNF-a") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))))) # ::id bel_pmid_1140_4390.29562 # ::date 2015-04-21T11:30:05 # ::file bel_pmid_1140_4390_29562.txt # ::snt NGF activates Erk1/Erk2 and JNK but not p38MAPK in J774 cells... NGF also induced phosphorylation of JNK # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (a / activate-01 :ARG0 (p2 / protein :name (n / name :op1 "NGF") :xref (x / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "Erk1") :xref (x6 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2") :xref (x4 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")) :op3 (e3 / enzyme :name (n4 / name :op1 "JNK") :xref (x3 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :location (c2 / cell-line :name (n6 / name :op1 "J774"))) :ARG2 (a2 / activate-01 :polarity "-" :ARG0 p2 :ARG1 (e4 / enzyme :name (n5 / name :op1 "p38MAPK") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203")) :location c2)) :snt2 (i / induce-01 :ARG0 (p3 / protein :name (n7 / name :op1 "NGF") :xref (x5 / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :ARG2 (p4 / phosphorylate-01 :ARG1 (e5 / enzyme :name (n8 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :mod (a4 / also))) # ::id bel_pmid_1140_4390.29566 # ::date 2015-04-21T11:49:11 # ::file bel_pmid_1140_4390_29566.txt # ::snt The MAP kinase-Erk kinase (MEK) inhibitor PD 098059 inhibits the production of TNF-alpha induced by NGF # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i2 / inhibit-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "PD098059") :ARG0-of (i / inhibit-01 :ARG1 (a / and :op1 (p4 / protein-family :name (n6 / name :op1 "MAP" :op2 "kinase")) :op2 (p5 / protein-family :name (n3 / name :op1 "Erk"))))) :ARG1 (p / produce-01 :ARG1 (p2 / protein :name (n5 / name :op1 "TNF-alpha") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG2-of (i3 / induce-01 :ARG0 (p3 / protein :name (n / name :op1 "NGF") :xref (x1 / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004"))))) # ::id bel_pmid_1140_8560.1760 # ::date 2015-04-21T12:06:06 # ::file bel_pmid_1140_8560_1760.txt # ::snt Both early passage and immortalized MEF cells from GSTpi(-/-) animals expressed significantly elevated activity of extracellular signal-regulated kinases ERK1/ERK2, kinases linked to cell proliferation pathways # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (e / exhibit-01 :ARG0 (a / and :op1 (c / cell :mod (p / passage :mod (e2 / early)) :source (c4 / cell :name (n4 / name :op1 "MEF") :ARG3-of (e4 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "GSTpi") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:GSTP1_HUMAN" :prob "0.252"))))) :op2 (c2 / cell :ARG1-of (i / immortalize-03) :source c4)) :ARG1 (a2 / activity-06 :ARG0 (a3 / and :op1 (e3 / enzyme :name (n / name :op1 "ERK1") :ARG1-of (l / link-01 :ARG2 (p3 / pathway :mod (p4 / proliferate-01 :ARG0 (c3 / cell)))) :ARG1-of (i2 / include-91 :ARG2 (p5 / protein-family :name (n5 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase"))) :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e6 / enzyme :name (n2 / name :op1 "ERK2") :ARG1-of l :ARG1-of i2 :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1-of (e5 / elevate-01 :ARG1-of (s / significant-02)))) # ::id bel_pmid_1143_8543.2568 # ::date 2015-04-22T02:04:21 # ::file bel_pmid_1143_8543_2568.txt # ::snt A tetrameric Stat3 complex was found to be essential in transfection experiments for maximal interleukin-6-inducible activation of alpha2-macroglobulin gene promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (f / find-01 :ARG1 (e / essential :domain (m3 / macro-molecular-complex :mod (t / tetrameric) :mod (p / protein :name (n / name :op1 "Stat3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :purpose (a / activate-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (g / gene :ARG0-of (e3 / encode-01 :ARG1 (p5 / protein :name (n3 / name :op1 "alpha2-macroglobulin") :xref (x1 / xref :value "UNIPROT:A2MG_HUMAN" :prob "0.692")))))) :degree (m / maximum) :ARG2-of (i / induce-01 :ARG0 (p3 / protein :name (n2 / name :op1 "interleukin-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703")) :ARG1-of (p2 / possible-01))) :prep-in (e2 / experiment-01 :ARG2 (t2 / transfect-01)))) # ::id bel_pmid_1144_7289.27070 # ::date 2015-04-22T02:22:20 # ::file bel_pmid_1144_7289_27070.txt # ::snt We have previously demonstrated that complex formation between the SH2 domain of Grb2 and FRS2a is mediated via Y196-, Y306-, Y349-, and Y392-designated Grb2 binding sites (4, 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / demonstrate-01 :ARG0 (w2 / we) :ARG1 (m / mediate-01 :ARG0 (b / bind-01 :ARG2 (a2 / and :op1 (a4 / amino-acid :mod "196" :name (n8 / name :op1 "tyrosine") :part-of "p2" :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a5 / amino-acid :mod "306" :name (n9 / name :op1 "tyrosine") :part-of "p2" :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op3 (a6 / amino-acid :mod "349" :name (n10 / name :op1 "tyrosine") :part-of "p2" :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :ARG1 (f / form-01 :ARG0 (a / and :op1 (p4 / protein-segment :name (n4 / name :op1 "SH2" :op2 "domain") :part-of (p2 / protein :name (n2 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :op2 (p3 / protein :name (n3 / name :op1 "FRS2a") :xref (x1 / xref :value "UNIPROT:FRS2_HUMAN" :prob "0.313"))) :ARG1 (m2 / macro-molecular-complex))) :time (p / previous) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "4" :op2 "5"))))) # ::id bel_pmid_1144_7289.27072 # ::date 2015-04-22T02:53:10 # ::file bel_pmid_1144_7289_27072.txt # ::snt In addition, FRS2a recruits Grb2 indirectly by means of two binding sites for the SH2 domains of the protein tyrosine phosphatase Shp2 at Y436- and Y471-designated Shp2 binding sites (5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op2 (r / recruit-01 :ARG0 (p / protein :name (n / name :op1 "FRS2a") :xref (x1 / xref :value "UNIPROT:FRS2_HUMAN" :prob "0.313")) :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG1-of (d / direct-02 :polarity "-") :manner (b / bind-01) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 "5"))) :instrument (a3 / and :op1 (a4 / amino-acid :mod "436" :name (n7 / name :op1 "tyrosine") :part-of (p3 / protein-segment :name (n5 / name :op1 "SH2" :op2 "domain") :part-of (p4 / protein-tyrosine-phosphatase :name (n6 / name :op1 "Shp2")) :ARG1-of (b2 / bind-01)) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a5 / amino-acid :mod "471" :name (n8 / name :op1 "tyrosine") :part-of p3 :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) # ::id bel_pmid_1149_0023.3486 # ::date 2015-04-22T03:18:07 # ::file bel_pmid_1149_0023_3486.txt # ::snt Serum amyloid A-activating factor-1 (SAF-1) is a zinc finger transcription factor that is activated by many mediators of inflammation including IL-1, IL-6, and bacterial LPS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / activate-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (m3 / mediate-01 :ARG1 (i / inflame-01)) :quant (m4 / many) :ARG2-of (i2 / include-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "IL-1") :xref (x / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382")) :op2 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (l / lipopolysaccharide :mod (b / bacteria))))) :ARG1 (p / protein :name (n / name :op1 "serum" :op2 "amyloid" :op3 "A-activating" :op4 "factor-1") :ARG0-of (t / transcribe-01 :ARG1 (p4 / protein :name (n5 / name :op1 "zinc" :op2 "finger") :xref (x2 / xref :value "UNIPROT:CHD3_HUMAN" :prob "0.302"))) :xref (x3 / xref :value "UNIPROT:MAZ_HUMAN" :prob "0.702"))) # ::id bel_pmid_1149_0023.22070 # ::date 2015-04-22T03:28:06 # ::file bel_pmid_1149_0023_22070.txt # ::snt We further show that SAF-1 is phosphorylated in vitro by PKA-Calpha and that addition of cAMP markedly induces in vivo phosphorylation of SAF-1 and transcription of SAF-regulated reporter genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op2 (s / show-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "SAF-1") :xref (x1 / xref :value "UNIPROT:MAZ_HUMAN" :prob "1.002")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKA-Calpha") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.672")) :manner (i2 / in-vitro)) :op2 (i / induce-01 :ARG0 (a3 / add-02 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "cAMP") :xref (x2 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :ARG2 (a4 / and :op1 (p5 / phosphorylate-01 :ARG1 p4 :manner (i3 / in-vivo)) :op2 (t / transcribe-01 :ARG1 (g / gene :ARG1-of (r2 / regulate-01 :ARG0 p4) :ARG0-of (r3 / report-01)) :manner i3)) :manner (m / marked))) :mod (f / further))) # ::id bel_pmid_1149_3654.6262 # ::date 2015-04-22T03:38:36 # ::file bel_pmid_1149_3654_6262.txt # ::snt Inhibition of p38 MAPK by SB203580 in differentiating C2C12 myoblasts blocks MyoD expression, SHPS-1 tyrosyl phosphorylation and the association of SHPS-1 with SHP-2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (b / block-01 :ARG0 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "SB203580") :xref (x5 / xref :value "PUBCHEM:176155" :prob "18.572987")) :ARG1 (e / enzyme :name (n3 / name :op1 "p38MAPK") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203")) :location (m / myoblast :part-of (c / cell-line :name (n4 / name :op1 "C2C12") :ARG1-of (d / differentiate-101)))) :ARG1 (a / and :op1 (e2 / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "MyoD") :xref (x2 / xref :value "UNIPROT:MYOD1_HUMAN" :prob "0.602"))) :op2 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (p5 / protein :name (n7 / name :op1 "SHPS-1") :xref (x3 / xref :value "UNIPROT:SHPS1_HUMAN" :prob "1.002")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op3 (a2 / associate-01 :ARG1 p5 :ARG2 (p6 / protein :name (n8 / name :op1 "SHP-2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1149_3654.11578 # ::date 2015-04-22T04:02:12 # ::file bel_pmid_1149_3654_11578.txt # ::snt Either constitutive expression or inducible activation of MyoD in 10T(1/2) fibroblasts promotes SHPS-1 tyrosyl phosphorylation and its association with SHP-2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p2 / promote-01 :ARG0 (a / and :op1 (e / express-03 :ARG2 "p" :ARG3 (f / fibroblast :part-of (c2 / cell-line :name (n2 / name :op1 "10T(1/2)"))) :mod (c / constitutive)) :op2 (a2 / activate-01 :ARG1 (p / protein :name (n / name :op1 "MyoD") :xref (x2 / xref :value "UNIPROT:MYOD1_HUMAN" :prob "0.602")) :ARG2-of (i / induce-01 :ARG1-of (p3 / possible-01)) :location f)) :ARG1 (a3 / and :op1 (p5 / phosphorylate-01 :ARG1 (a4 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (p6 / protein :name (n4 / name :op1 "SHPS-1") :xref (x1 / xref :value "UNIPROT:SHPS1_HUMAN" :prob "1.002")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (a5 / associate-01 :ARG1 p6 :ARG2 (p7 / protein :name (n5 / name :op1 "SHP-2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1149_3654.30640 # ::date 2015-04-22T04:11:16 # ::file bel_pmid_1149_3654_30640.txt # ::snt We have identified that the 120 kDa complex consists of the SHP-2 substrate-1 (SHPS-1) and the Grb2-associated binder-1 (Gab-1). SHPS-1, but not Gab-1, undergoes tyrosyl phosphorylation and association with SHP-2 during myogenesis, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (i / identify-01 :ARG0 (w2 / we) :ARG1 (c / consist-01 :ARG1 (m4 / macro-molecular-complex :ARG1-of (e / equal-01 :ARG2 (m2 / mass-quantity :quant "120" :unit (k / kilodalton)))) :ARG2 (a / and :op1 (p2 / protein :name (n / name :op1 "SHP-2" :op2 "substrate-1") :xref (x / xref :value "UNIPROT:SHPS1_HUMAN" :prob "0.382")) :op2 (p3 / protein :name (n2 / name :op1 "Grb2-associated" :op2 "binder-1") :xref (x1 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.693"))))) :snt2 (c3 / contrast-01 :ARG1 (a3 / and :op1 (p4 / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (p / protein :name (n6 / name :op1 "SHP-2" :op2 "substrate-1") :xref (x4 / xref :value "UNIPROT:SHPS1_HUMAN" :prob "0.382")) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :time (m3 / myogenesis)) :op2 (a4 / associate-01 :ARG1 p :ARG2 (p5 / protein :name (n4 / name :op1 "SHP-2") :xref (x3 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :time m3)) :ARG2 (a5 / and :op1 (p6 / phosphorylate-01 :polarity "-" :ARG1 (a6 / amino-acid :name (n5 / name :op1 "tyrosine") :part-of (p7 / protein :name (n7 / name :op1 "Grb2-associated" :op2 "binder-1") :xref (x2 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.693")) :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481")) :time m3) :op2 (a7 / associate-01 :ARG1 p7 :ARG2 p5 :time m3)))) # ::id bel_pmid_1150_0506.8864 # ::date 2015-04-23T00:37:06 # ::file bel_pmid_1150_0506_8864.txt # ::snt The expression and activity of the protein-tyrosine phosphatase 1B (PTP1B), but not protein-tyrosine phosphatases SHP-1, SHP-2, and LAR, were constitutively decreased in tissues expressing the Q205L Galpha(i2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c2 / contrast-01 :ARG1 (d / decrease-01 :ARG1 (a / and :op1 (e / express-03 :ARG2 (e4 / enzyme :name (n6 / name :op1 "protein" :op2 "tyrosyne" :op3 "phosphatase" :op4 "1B") :xref (x / xref :value "UNIPROT:PTN1_HUMAN" :prob "0.383")) :ARG3 (t / tissue :ARG3-of (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Galpha(i2)") :ARG1-of (m / mutate-01 :value "Q205L"))))) :op2 (a2 / activity-06 :ARG0 e4 :location t)) :mod (c / constitutive)) :ARG2 (d2 / decrease-01 :polarity "-" :ARG1 (a3 / and :op1 (e3 / express-03 :ARG2 (a4 / and :op1 (p3 / protein-tyrosine-phophatase :name (n3 / name :op1 "SHP-1")) :op2 (p4 / protein-tyrosine-phosphatase :name (n4 / name :op1 "SHP-2")) :op3 (p5 / protein-tyrosine-phosphatase :name (n5 / name :op1 "LAR"))) :ARG3 t) :op2 (a5 / activity-06 :ARG0 a4 :location t)))) # ::id bel_pmid_1153_6047.16526 # ::date 2015-04-23T01:01:38 # ::file bel_pmid_1153_6047_16526.txt # ::snt IL-6 induced STAT3 transactivation was reduced from sixfold to 2.5-fold when cells were pre-treated with the JAK2 inhibitor (Figure 2b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (r / reduce-01 :ARG1 (t / transactivate-01 :ARG1 (p / protein :name (n / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG3 (p4 / product-of :op1 "6") :ARG4 (p5 / product-of :op1 "2.5") :condition (p3 / pretreat-01 :ARG1 (c / cell) :ARG3 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "JAK2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")))) :time (b / before)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2b"))) # ::id bel_pmid_1153_6047.22124 # ::date 2015-04-23T01:26:41 # ::file bel_pmid_1153_6047_22124.txt # ::snt Overexpression of both MEN2A-RET and STAT3 strongly enhanced reporter activation, indicating that MEN2A-RET induces cyclin-D1 gene expression via STAT3 (Figure 4a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (e / enhance-01 :ARG0 (o / overexpress-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "MEN2A-RET") :xref (x / xref :value "UNIPROT:MENT_HUMAN" :prob "0.222")) :op2 (p3 / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :mod (b / both))) :ARG1 (a2 / activate-01 :ARG1 (g / gene :ARG0-of (r2 / report-01))) :ARG1-of (s / strong-02) :ARG0-of (i / indicate-01 :ARG1 (i2 / induce-01 :ARG0 p2 :ARG2 (e2 / express-03 :ARG1 (g2 / gene :name (n3 / name :op1 "cyclin-D1") :xref (x2 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.691"))) :instrument p3)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4a"))) # ::id bel_pmid_1153_6047.22126 # ::date 2015-04-23T01:39:46 # ::file bel_pmid_1153_6047_22126.txt # ::snt These data indicate that MEN2A-RET enhances proliferation via STAT3, and that a full length STAT3 is required to mediate the MEN2A-RET induced proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / indicate-01 :ARG0 (d / data :mod (t / this)) :ARG1 (a / and :op1 (e / enhance-01 :ARG0 (p / protein :name (n / name :op1 "MEN2A-RET") :xref (x2 / xref :value "UNIPROT:MENT_HUMAN" :prob "0.222")) :ARG1 (p2 / proliferate-01) :ARG2 (p3 / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :op2 (r / require-01 :ARG0 (m / mediate-01 :ARG0 "p4" :ARG1 (p5 / proliferate-01 :ARG2-of (i2 / induce-01 :ARG0 p))) :ARG1 (p4 / protein :name (n3 / name :op1 "STAT3") :ARG1-of (l / long-03 :degree (f / full)) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))))) # ::id bel_pmid_1153_6047.30396 # ::date 2015-04-23T01:45:44 # ::file bel_pmid_1153_6047_30396.txt # ::snt Over-expression of MEN2A-RET mutants reduced STAT3 ser727 phosphorylation to basal levels, suggesting that STAT3 tyr705 phosphorylation is a prerequisite for maximal MEN2A-RET induced STAT3 ser727 phosphorylation (Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / reduce-01 :ARG0 (o / overexpress-01 :ARG1 (p3 / protein :name (n / name :op1 "MEN2A-RET") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:MENT_HUMAN" :prob "0.222"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod "727" :name (n2 / name :op1 "serine") :part-of (p4 / protein :name (n3 / name :op1 "STAT-3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.683")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG4 (l / level :mod (b / basal)) :ARG0-of (s / suggest-01 :ARG1 (r2 / require-01 :ARG0 (p5 / phosphorylate-01 :ARG1 a :degree (m2 / maximum) :ARG2-of (i / induce-01 :ARG0 p3)) :ARG1 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "705" :name (n6 / name :op1 "tyrosine") :part-of p4 :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id bel_pmid_1153_6047.30398 # ::date 2015-04-23T02:16:27 # ::file bel_pmid_1153_6047_30398.txt # ::snt STAT3 tyr705 phosphorylation was reduced when the MEN2A-RET single mutants tyr752phe or tyr928phe were overexpressed, while no STAT3 tyr705 phosphorylation was observed in the presence of the MEN2A-RET double mutant (Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG1 (r / reduce-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod "705" :name (n / name :op1 "tyrosine") :part-of (p3 / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :condition (o / overexpress-01 :ARG1 (o2 / or :op1 (p / protein :name (n4 / name :op1 "MEN2A-RET") :ARG2-of (m2 / mutate-01 :value "tyr752phe") :ARG1-of (s / single-02) :xref (x / xref :value "UNIPROT:MENT_HUMAN" :prob "0.222")) :op2 (p5 / protein :name (n9 / name :op1 "MEN2A-RET") :ARG2-of (m5 / mutate-01 :value "tyr928phe") :ARG1-of s :xref (x3 / xref :value "UNIPROT:MENT_HUMAN" :prob "0.222"))))) :ARG2 (o3 / observe-01 :polarity "-" :ARG1 p2 :condition (p4 / present-02 :ARG1 (p7 / protein :name (n5 / name :op1 "MEN2A-RET") :ARG1-of (m3 / mutate-01 :mod (d / double)) :xref (x2 / xref :value "UNIPROT:MENT_HUMAN" :prob "0.222")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id bel_pmid_1153_6047.30400 # ::date 2015-04-23T02:24:21 # ::file bel_pmid_1153_6047_30400.txt # ::snt As depicted in Figure 3a, mutation of tyr928 (RET) reduced STAT3 transactivation approximately 1.5-fold, indicating that other STAT3 docking sites must be present in MEN2A-RET as well. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / reduce-01 :ARG0 (m / mutate-01 :ARG1 (a / amino-acid :mod "928" :name (n / name :op1 "tyrosine") :part-of (p / protein :name (n2 / name :op1 "RET") :xref (x2 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1 (t / transactivate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :ARG2 (p5 / product-of :op1 "1.5" :mod (a3 / approximate)) :ARG0-of (i / indicate-01 :ARG1 (o / obligate-01 :ARG2 (p6 / present-02 :ARG1 (p4 / protein-segment :ARG2-of (d / dock-01 :ARG1 p2) :mod (o2 / other)) :ARG2 (p3 / protein :name (n4 / name :op1 "MEN2A-RET") :xref (x1 / xref :value "UNIPROT:MENT_HUMAN" :prob "0.222")) :mod (a2 / as-well)))) :ARG1-of (d2 / depict-01 :ARG0 (f / figure :mod "3a"))) # ::id bel_pmid_1153_6047.30402 # ::date 2015-04-23T02:37:07 # ::file bel_pmid_1153_6047_30402.txt # ::snt As depicted in Figure 1a,b, over-expression of both MEN2A-RET and STAT3 strongly enhanced IRE transactivation, while overexpression of STAT3 alone did not affect reporter activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (c / contrast-01 :ARG1 (e / enhance-01 :ARG0 (o / overexpress-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "MEN2A-RET") :xref (x / xref :value "UNIPROT:MENT_HUMAN" :prob "0.222")) :op2 (p3 / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :ARG1 (t / transactivate-01 :ARG1 (p4 / protein-segment :name (n3 / name :op1 "IRE"))) :ARG1-of (s / strong-02)) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 (o2 / overexpress-01 :ARG1 p3) :ARG1 (a4 / activate-01 :ARG1 (g / gene :ARG0-of (r2 / report-01)))) :ARG1-of (d / depict-01 :ARG0 (a5 / and :op1 (f / figure :mod "1a") :op2 (f2 / figure :mod "1b")))) # ::id bel_pmid_1155_7580.38186 # ::date 2015-04-22T05:07:19 # ::file bel_pmid_1155_7580_38186.txt # ::snt After bFGF was added to pulmonary fibroblasts, the kinase activities of p44/p42 ERK1/2 were determined by an in-gel assay at various times after exposure (Fig. 1). The data demonstrate that the addition of bFGF results in activation of ERK1/2 within 5 min, with the highest activity at 30 min, followed by a lower level of activity that persists for 8-12 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m3 / multi-sentence :snt1 (d / determine-01 :ARG1 (a14 / and :op1 (a / activity-06 :ARG0 (k2 / kinase :name (n / name :op1 "p44" :op2 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.683"))) :op2 (a13 / activity-06 :ARG0 (k3 / kinase :name (n3 / name :op1 "p42" :op2 "ERK2") :xref (x2 / xref :value "UNIPROT:NUP43_HUMAN" :prob "0.262")))) :manner (a3 / assay-01 :manner (i / in-gel)) :time (a5 / after :op1 (a6 / add-02 :ARG1 (p3 / protein :name (n2 / name :op1 "bFGF") :xref (x4 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.003")) :ARG2 (f3 / fibroblast :part-of (l3 / lung)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1")) :frequency (v / various :time (a4 / after :op1 (e2 / expose-01)))) :snt2 (d3 / demonstrate-01 :ARG0 (d4 / data) :ARG1 (r / result-01 :ARG1 (a7 / add-02 :ARG1 (p / protein :name (n5 / name :op1 "bFGF") :xref (x5 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.003"))) :ARG2 (a8 / activate-01 :ARG1 (a9 / and :op1 (e4 / enzyme :name (n6 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n7 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG0-of (a2 / activity-06 :ARG2-of (f2 / follow-01 :ARG1 (a12 / activity-06 :ARG0 a9 :ARG1-of (l / low-04 :degree (m2 / more)) :ARG1-of (p2 / persist-01 :duration (b2 / between :op1 (t4 / temporal-quantity :quant "8" :unit (h3 / hour)) :op2 (t5 / temporal-quantity :quant "12" :unit (h4 / hour)))))) :ARG1-of (h / high-02 :degree (m / most) :time (a11 / after :op1 a7 :quant (t2 / temporal-quantity :quant "30" :unit "m4"))))) :time (a10 / after :op1 a7 :quant (u / up-to :op1 (t / temporal-quantity :quant "5" :unit (m4 / minute)))))))) # ::id bel_pmid_1155_7774.11824 # ::date 2015-04-22T05:39:51 # ::file bel_pmid_1155_7774_11824.txt # ::snt PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (a / and :op1 (c / control-01 :ARG0 (p / protein :name (n / name :op1 "PPARalpha") :ARG1-of (d2 / describe-01 :ARG2 (p4 / protein :name (n5 / name :op1 "NR1C1") :xref (x1 / xref :value "UNIPROT:PPARA_HUMAN" :prob "1.003"))) :xref (x3 / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.693")) :ARG1 (a2 / and :op1 (o / oxidize-01 :ARG1 (l / lipid)) :op2 (c2 / clear-01 :ARG2 l)) :location (h / hepatocyte)) :op2 (p2 / promote-02 :ARG0 (p3 / protein :name (n3 / name :op1 "PPARgamma") :ARG1-of (d3 / describe-01 :ARG2 (p5 / protein :name (n6 / name :op1 "NR1C3") :xref (x2 / xref :value "UNIPROT:PPARG_HUMAN" :prob "1.002"))) :xref (x / xref :value "UNIPROT:PPARG_HUMAN" :prob "0.692")) :ARG1 (a3 / and :op1 (d / differentiate-01 :ARG1 (p6 / preadipocyte)) :op2 (l2 / lipogenesis :location p6)))) # ::id bel_pmid_1155_7774.16262 # ::date 2015-04-22T05:52:03 # ::file bel_pmid_1155_7774_16262.txt # ::snt Furthermore, it has been shown that activation of PPARg by the thiozolidinedione, rosiglitazaone, decreased scavenger receptor class A expresion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 22, 2015 (a / and :op2 (s / show-01 :ARG1 (d / decrease-01 :ARG0 (a2 / activate-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "rosiglitazone") :ARG1-of (i / include-91 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "thiazolidinedione") :xref (x3 / xref :value "PUBCHEM:5437" :prob "12.610051"))) :xref (x2 / xref :value "PUBCHEM:77999" :prob "15.898837")) :ARG1 (p / protein :name (n / name :op1 "PPARgamma") :xref (x1 / xref :value "UNIPROT:PPARG_HUMAN" :prob "0.692"))) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "scavenger" :op2 "receptor" :op3 "class" :op4 "A") :xref (x / xref :value "UNIPROT:MSRE_HUMAN" :prob "0.382")))))) # ::id bel_pmid_1155_7774.16418 # ::date 2015-04-22T06:04:25 # ::file bel_pmid_1155_7774_16418.txt # ::snt Pparg, which is activated by 15-deoxy-D12,14-prostaglandin J2 and the thiazolidione class of insulin-sensitizing drugs,...Among its known target genes are adipocyte factty-acid binidng protein and fatty acid synthase, which are efeeectors of lipid accumulaiton during adipogeesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (m / multi-sentence :snt1 (a / activate-01 :ARG0 (a2 / and :op1 (s / small-molecule :name (n2 / name :op1 "15-deoxy-D12" :op2 "14-prostaglandin" :op3 "J2") :xref (x5 / xref :value "PUBCHEM:5311211" :prob "4.098453")) :op2 (c / class :mod (s2 / small-molecule :name (n3 / name :op1 "thiazolidione")) :ARG1-of (i / include-91 :ARG2 (d / drug :ARG0-of (s3 / sensitize-01 :ARG2 (p4 / protein :name (n4 / name :op1 "insulin") :xref (x2 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))))))) :ARG1 (p / protein :name (n / name :op1 "PPAR-gamma") :xref (x4 / xref :value "UNIPROT:PPARG_HUMAN" :prob "1.002"))) :snt2 (i2 / include-91 :ARG1 (a3 / and :op1 (g2 / gene :ARG0-of (e3 / encode-01 :ARG1 (p5 / protein :name (n8 / name :op1 "adipocyte" :op2 "fatty-acid" :op3 "biniding" :op4 "protein") :xref (x3 / xref :value "UNIPROT:FABP4_HUMAN" :prob "0.372")))) :op2 (g3 / gene :ARG0-of (e4 / encode-01 :ARG1 (e / enzyme :name (n7 / name :op1 "fatty" :op2 "acid" :op3 "synthase") :xref (x1 / xref :value "UNIPROT:FAS_HUMAN" :prob "0.702")))) :mod (e2 / effector :ARG0-of (c2 / cause-01 :ARG1 (a4 / accumulate-01 :ARG1 (l / lipid)) :time (a5 / adipogenesis))) :part-of (a6 / adipocyte)) :ARG2 (g / gene :ARG1-of (t / target-01 :ARG2 (p2 / protein :name (n5 / name :op1 "PPARgamma") :xref (x / xref :value "UNIPROT:PPARG_HUMAN" :prob "0.692"))) :ARG1-of (k / know-01)))) # ::id bel_pmid_1155_7774.30036 # ::date 2015-04-22T06:23:11 # ::file bel_pmid_1155_7774_30036.txt # ::snt Therefore the profound repression of CYP27 and apoE expressoin by activatoin or overexpression of PPARd might contribute to the lipid accumulation observed in these cells in culture # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (i / infer-01 :ARG1 (p / possible-01 :ARG1 (c / contribute-01 :ARG0 (r / repress-01 :ARG0 (o / or :op1 (a3 / activate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "PPARdelta") :xref (x1 / xref :value "UNIPROT:PPARD_HUMAN" :prob "0.692"))) :op2 (o2 / overexpress-01 :ARG1 p2)) :ARG1 (e / express-03 :ARG1 (a2 / and :op1 (g / gene :name (n / name :op1 "CYP27") :xref (x2 / xref :value "UNIPROT:CP27A_HUMAN" :prob "1.002")) :op2 (g2 / gene :name (n2 / name :op1 "apoE") :xref (x / xref :value "UNIPROT:APOE_HUMAN" :prob "0.633")))) :mod (p3 / profound)) :ARG2 (a / accumulate-01 :ARG1 (l / lipid) :ARG1-of (o3 / observe-01 :location (c2 / cell :mod (t / this)) :manner (i2 / in-culture)))))) # ::id bel_pmid_1155_7774.33822 # ::date 2015-04-22T06:40:44 # ::file bel_pmid_1155_7774_33822.txt # ::snt However, plaque formation is also appreciated to be an inflammoratory response and it has been shown that activators of Pparg inhibit the production of inflammoratory cytokines such as TNFa, Il6 and Il1b. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c2 / contrast-01 :ARG2 (a2 / and :op1 (u / understand-01 :ARG1 (f / form-01 :ARG1 (p / plaque)) :ARG2 (r / respond-01 :ARG2 (i / inflame-01)) :mod (a4 / also)) :op2 (s / show-01 :ARG1 (i2 / inhibit-01 :ARG0 (t / thing :ARG0-of (a / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "PPARgamma") :xref (x / xref :value "UNIPROT:PPARG_HUMAN" :prob "0.692")))) :ARG1 (p3 / produce-01 :ARG1 (c / cytokine :example (a3 / and :op1 (p5 / protein :name (n3 / name :op1 "TNFa") :xref (x3 / xref :value "UNIPROT:Q9UBM5_HUMAN" :prob "1.001")) :op2 (p6 / protein :name (n4 / name :op1 "Il6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :op3 (p7 / protein :name (n5 / name :op1 "Il6b") :xref (x2 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "0.233"))) :ARG0-of i)))))) # ::id bel_pmid_1155_7774.33878 # ::date 2015-04-22T06:56:30 # ::file bel_pmid_1155_7774_33878.txt # ::snt These studies started with the observation that Pparg up-regulates CD36 (savenger receptor calss-B) expression in macrophages. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (s / start-01 :ARG1 (s2 / study-01 :mod (t / this)) :ARG2 (o / observe-02 :ARG1 (u / upregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "CD36") :ARG1-of (d / describe-01 :ARG2 (p3 / protein :name (n3 / name :op1 "savenger" :op2 "receptor" :op3 "class" :op4 "B"))) :xref (x / xref :value "UNIPROT:CD36_HUMAN" :prob "1.003")) :ARG3 (m / macrophage)) :ARG2 (p / protein :name (n / name :op1 "PPARgamma") :xref (x1 / xref :value "UNIPROT:PPARG_HUMAN" :prob "0.692"))))) # ::id bel_pmid_1158_3971.7986 # ::date 2015-04-22T07:00:57 # ::file bel_pmid_1158_3971_7986.txt # ::snt Exogenous ANXA1 but not ANXA5, administered to IL-6 KO mice before LPS challenge inhibited TNF-alpha release. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "ANXA1") :mod (e / exogenous) :ARG1-of (c / contrast-01 :ARG2 (p2 / protein :name (n2 / name :op1 "ANXA5") :xref (x / xref :value "UNIPROT:ANXA5_HUMAN" :prob "1.003"))) :ARG1-of (a / administer-01 :ARG2 (m / mouse :mod (p3 / protein :name (n3 / name :op1 "IL-6") :ARG2-of (m2 / mutate-01 :mod "-/+") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :time (b / before :op1 (c2 / challenge-01 :ARG2 (l / lipopolysaccharide)))) :xref (x3 / xref :value "UNIPROT:ANXA1_HUMAN" :prob "1.003")) :ARG1 (r / release-01 :ARG1 (p4 / protein :name (n5 / name :op1 "TNF-alpha") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) # ::id bel_pmid_1158_3971.9278 # ::date 2015-04-22T07:13:20 # ::file bel_pmid_1158_3971_9278.txt # ::snt recombinant IL-6 to IL-6 KO animals before LPS or TNF-alpha challenge, replenished ANXA1 liver synthesis to that of WT animals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / replenish-01 :ARG0 (p / protein :name (n / name :op1 "IL-6") :ARG1-of (r2 / recombine-01) :ARG1-of (a / administer-01 :ARG2 (a2 / animal :mod (p4 / protein :name (n5 / name :op1 "IL-6") :ARG2-of (m / mutate-01 :mod "-/+") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :time (b / before :op1 (c / challenge-01 :ARG2 (o / or :op1 (l3 / lipopolysaccharide) :op2 (p2 / protein :name (n3 / name :op1 "TNF-alpha") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))))) :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (s2 / synthesize-01 :ARG0 (l / liver) :ARG1 (p3 / protein :name (n4 / name :op1 "ANXA1") :xref (x1 / xref :value "UNIPROT:ANXA1_HUMAN" :prob "1.003"))) :extent (s3 / synthesize-01 :ARG0 (l2 / liver :part-of (a3 / animal :mod (w / wild-type))) :ARG1 p3)) # ::id bel_pmid_1159_1769.19228 # ::date 2015-04-22T07:21:10 # ::file bel_pmid_1159_1769_19228.txt # ::snt Here we show that IL-10 directly affects progenitor myeloid cells by protecting them from death following the removal of growth factors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (p2 / protein :name (n / name :op1 "IL-10") :xref (x / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :ARG1 (c / cell :mod (p3 / progenitor) :mod (m / myeloid)) :ARG2 (p4 / protect-01 :ARG0 p2 :ARG1 c :ARG2 (d / die-01 :ARG1-of (f / follow-01 :ARG2 (r / remove-01 :ARG1 (g / growth-factor))))) :ARG1-of (d2 / direct-02)) :medium (h / here)) # ::id bel_pmid_1159_1769.21788 # ::date 2015-04-22T07:26:19 # ::file bel_pmid_1159_1769_21788.txt # ::snt Following ligand binding to the IL-10R, Jak1 and Tyk2, which are constitutively associated with IL-10R1 and IL-10R2, respectively (3, 14), are phosphorylated on tyrosine The phosphorylated IL-10R/Jak1/Tyk2 complex serves as a docking site for the transcription factors Stat-1 and Stat-3 Jak1, which is required for the biological activity of IL-10 (20), also tyrosine phosphorylates the insulin receptor substrate-1 (IRS-1) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (m / multi-sentence :snt1 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (e / enzyme :name (n / name :op1 "Jak1") :ARG1-of (a4 / associate-01 :ARG2 (r2 / receptor :name (n6 / name :op1 "IL-10R1")) :manner (c / constitutive) :manner (r4 / respective) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a6 / and :op1 "3" :op2 "14"))))) :xref (x8 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.604")) :xref (x12 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a3 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n2 / name :op1 "Tyk2") :ARG1-of (a5 / associate-01 :ARG2 (r3 / receptor :name (n7 / name :op1 "IL-10R2")) :manner c :ARG1-of d :manner r4) :xref (x7 / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603")) :xref (x11 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (f / follow-01 :ARG2 (b / bind-01 :ARG1 (l / ligand) :ARG2 (r / receptor :name (n5 / name :op1 "IL-10R"))))) :snt2 (s / serve-01 :ARG0 (m2 / macro-molecular-complex :part (r5 / receptor :name (n8 / name :op1 "IL-10R")) :part (e3 / enzyme :name (n9 / name :op1 "Jak1") :xref (x6 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.604")) :part (e4 / enzyme :name (n10 / name :op1 "Tyk2") :xref (x2 / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603")) :ARG1-of (p3 / phosphorylate-01)) :ARG1 (s2 / site :ARG2-of (d2 / dock-01 :ARG1 (a7 / and :op1 (p4 / protein :name (n11 / name :op1 "Stat-1") :xref (x3 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.593")) :op2 (p5 / protein :name (n12 / name :op1 "Stat-3") :xref (x5 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.593")) :mod (f2 / factor :ARG0-of (t / transcribe-01)))))) :snt3 (p6 / phosphorylate-01 :ARG1 (a9 / amino-acid :name (n14 / name :op1 "tyrosine") :part-of (p7 / protein :name (n15 / name :op1 "insulin" :op2 "receptor" :op3 "substrate" :op4 "1") :ARG1-of (d3 / describe-01 :ARG2 (p8 / protein :name (n16 / name :op1 "IRS-1") :xref (x9 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003"))) :xref (x / xref :value "UNIPROT:IRS1_HUMAN" :prob "0.703")) :xref (x10 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (e5 / enzyme :name (n13 / name :op1 "Jak1") :ARG1-of (r6 / require-01 :ARG0 (a10 / activity-06 :ARG0 (p9 / protein :name (n17 / name :op1 "IL-10") :xref (x4 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :mod (b2 / biology)) :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication :ARG1-of (c3 / cite-01 :ARG2 "20")))) :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.604")) :mod (a8 / also))) # ::id bel_pmid_1159_1769.27658 # ::date 2015-04-23T23:45:22 # ::file bel_pmid_1159_1769_27658.txt # ::snt We and others have shown that activation of IL-4 (23) and IFN-{alpha} receptors stimulates tyrosyl phosphorylation of IRS docking proteins, which depends upon Jak, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 24, 2015 (s / show-01 :ARG0 (a / and :op1 (w / we) :op2 (p2 / person :mod (o / other))) :ARG1 (s2 / stimulate-01 :ARG0 (a2 / activate-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n / name :op1 "IL-4") :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "23"))) :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :op2 (r / receptor :name (n2 / name :op1 "IFN-alpha")))) :ARG1 (p / phosphorylate-01 :ARG1 (a4 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (p5 / protein :name (n4 / name :op1 "IRS") :ARG1-of (d2 / dock-01) :xref (x2 / xref :value "UNIPROT:SYIC_HUMAN" :prob "1.002")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG0-of (d3 / depend-01 :ARG1 (e / enzyme :name (n5 / name :op1 "Jak") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.203")))))) # ::id bel_pmid_1159_1769.27854 # ::date 2015-04-24T00:24:51 # ::file bel_pmid_1159_1769_27854.txt # ::snt IL-10 can directly promote the death of inflammatory cells, including activated macrophages (4), neutrophils (5), and T cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (p / possible-01 :ARG1 (p2 / promote-02 :ARG0 (p3 / protein :name (n / name :op1 "IL-10") :xref (x / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :ARG1 (d2 / die-01 :ARG1 (c / cell :ARG0-of (i / inflame-01) :ARG2-of (i2 / include-01 :ARG1 (a / and :op1 (m / macrophage :ARG1-of (a2 / activate-01) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "4")))) :op2 (n2 / neutrophil :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "5")))) :op3 (c4 / cell :name (n3 / name :op1 "T")))))) :ARG1-of (d / direct-02))) # ::id bel_pmid_1159_1769.27880 # ::date 2015-04-24T00:31:14 # ::file bel_pmid_1159_1769_27880.txt # ::snt In contrast, IL-10 increases the survival of some types of human cancer cells, such as Burkitt lymphoma (7). Non-Hodgkin s lymphoma cells secrete IL-10, and inhibition of this autocrine IL-10 has recently been shown to promote cell death and reduce expression of the anti-apoptotic protein Bcl-2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (m / multi-sentence :snt1 (c / contrast-01 :ARG2 (i / increase-01 :ARG0 (p / protein :name (n2 / name :op1 "IL-10") :xref (x2 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :ARG1 (s / survive-01 :ARG0 (c2 / cell :ARG1-of (t / type-03 :quant (s2 / some)) :mod (d5 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :mod (h / human) :mod (d / disease :name (n / name :op1 "Burkitt" :op2 "lymphoma")))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 "7")))) :snt2 (a / and :op1 (s3 / secrete-01 :ARG0 (c5 / cell :mod (d4 / disease :name (n4 / name :op1 "non-Hodgkin" :op2 "lymphoma"))) :ARG1 (p3 / protein :name (n3 / name :op1 "IL-10") :mod (a3 / autocrine) :xref (x / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003"))) :op2 (s4 / show-01 :ARG1 (a2 / and :op1 (p4 / promote-01 :ARG0 (i2 / inhibit-01 :ARG1 p3) :ARG1 (d3 / die-01 :ARG1 (c6 / cell))) :op2 (r / reduce-01 :ARG0 i2 :ARG1 (e / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "Bcl-2") :ARG0-of (c7 / counter-01 :ARG1 (a4 / apoptosis)) :xref (x1 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.701"))))) :time (r2 / recent)))) # ::id bel_pmid_1159_1769.27882 # ::date 2015-04-24T00:47:49 # ::file bel_pmid_1159_1769_27882.txt # ::snt Similarly, IL-10 increases the expression of Bcl-xL in thyrocytes from patients with Graves disease # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 14, 2015 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "IL-10") :xref (x1 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Bcl-xL") :xref (x / xref :value "UNIPROT:BCL9_HUMAN" :prob "0.232")) :ARG3 (t / thyrocyte :source (p3 / person :ARG0-of (s / suffer-01 :ARG1 (d / disease :name (n5 / name :op1 "Graves"))) :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient))))) :ARG1-of (r / resemble-01)) # ::id bel_pmid_1160_6453.38354 # ::date 2015-04-24T00:52:35 # ::file bel_pmid_1160_6453_38354.txt # ::snt LDL, in pathophysiological concentrations, affect the IGF-I signaling pathway at multiple levels: 1) they induce phosphorylation of IGF-I receptor beta and IRS-1 in a time- and dose-dependent manner; 2) they up-regulate IRS-1-associated PI3 kinase/Akt activation in response to IGF-I at early times; and 3) they show additive effects with IGF-I on extracellular signal-regulated MAPK 1/2 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (p6 / protein :name (n2 / name :op1 "LDL") :quant (c / concentration :mod (p2 / pathophysiology)) :xref (x3 / xref :value "UNIPROT:COG1_HUMAN" :prob "0.262")) :ARG1 (p4 / pathway :name (n3 / name :op1 "IGF-I") :ARG0-of (s2 / signal-07)) :manner (l / level :quant (m / multiple) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (i / induce-01 :li "1" :ARG0 p6 :ARG2 (p / phosphorylate-01 :ARG2 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "IGF-I" :op2 "receptor" :op3 "beta") :xref (x2 / xref :value "UNIPROT:IGF1R_HUMAN" :prob "0.373")) :op2 (p7 / protein :name (n5 / name :op1 "IRS-1") :xref (x4 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")))) :manner (d / depend-01 :ARG0 p :ARG1 (a4 / and :op1 (t / time) :op2 (d2 / dose)))) :op2 (u / upregulate-01 :li "2" :ARG1 (a5 / activate-01 :ARG1 (p8 / pathway :name (n6 / name :op1 "PI3-kinase/Akt")) :ARG1-of (a6 / associate-01 :ARG2 p7)) :ARG2 p6 :ARG2-of (r / respond-01 :ARG1 (p5 / protein)) :time (e / early)) :op3 (s3 / show-01 :li "3" :ARG0 p6 :ARG1 (a7 / affect-01 :ARG0 p6 :ARG1 (p9 / phosphorylate-01 :ARG1 (a9 / and :op1 (e3 / enzyme :name (n / name :op1 "MAPK1") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n7 / name :op1 "MAPK2") :xref (x / xref :value "UNIPROT:MAPK2_HUMAN" :prob "1.003"))) :ARG1-of (r2 / regulate-01 :ARG0 (s4 / signal-07 :mod (e2 / extracellular)))) :ARG1-of (a8 / add-02 :ARG2 p5))))))) # ::id bel_pmid_1168_9697.19254 # ::date 2015-04-24T01:17:44 # ::file bel_pmid_1168_9697_19254.txt # ::snt identification of an acidic domain of gp130 as a binding region for Hck, which mediates proliferative signaling the deletion of this region of gp130 resulted in a significant reduction of Hck kinase activity and cell proliferation upon stimulation of gp130 compared to wild-type gp130 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (m / multi-sentence :snt1 (i / identify-01 :ARG1 (p / protein-segment :mod (a / acid) :part-of (p2 / protein :name (n / name :op1 "gp130") :xref (x3 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))) :ARG2 (r / region :ARG2-of (b / bind-01 :ARG1 (k2 / kinase :name (n2 / name :op1 "Hck") :xref (x1 / xref :value "UNIPROT:HCK_HUMAN" :prob "0.604"))) :ARG0-of (m2 / mediate-01 :ARG1 (s / signal-07 :mod (p3 / proliferate-01))))) :snt2 (r2 / result-01 :ARG1 (d / delete-01 :ARG1 (p4 / protein-segment :mod (t / this) :part-of (p5 / protein :name (n3 / name :op1 "gp130") :xref (x4 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")))) :ARG2 (r3 / reduce-01 :ARG1 (a4 / and :op1 (a2 / activity-06 :ARG0 (k3 / kinase :name (n4 / name :op1 "Hck") :xref (x / xref :value "UNIPROT:HCK_HUMAN" :prob "0.604"))) :op2 (p6 / proliferate-01 :ARG0 (c / cell))) :ARG2 (s2 / significant-02) :compared-to (p7 / protein :name (n5 / name :op1 "gp130") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")) :condition (s3 / stimulate-01 :ARG1 p5)))) # ::id bel_pmid_1168_9697.28350 # ::date 2015-04-24T01:34:59 # ::file bel_pmid_1168_9697_28350.txt # ::snt Il6 induces the activation of the Src family kinase Hck, which is associated with the Il6 receptor beta-chain, gp130 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (a / activate-01 :ARG1 (k2 / kinase :name (n2 / name :op1 "Hck") :ARG1-of (i2 / include-91 :ARG2 (p4 / protein-family :name (n3 / name :op1 "Src"))) :ARG1-of (a2 / associate-01 :ARG2 (p3 / protein :name (n4 / name :op1 "IL-6" :op2 "receptor" :op3 "beta-chain") :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n5 / name :op1 "gp130") :xref (x1 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))) :xref (x / xref :value "UNIPROT:IL6RB_HUMAN" :prob "0.313"))) :xref (x2 / xref :value "UNIPROT:HCK_HUMAN" :prob "0.604")))) # ::id bel_pmid_1168_9697.28396 # ::date 2015-04-24T02:02:24 # ::file bel_pmid_1168_9697_28396.txt # ::snt this acidic domain of gp130 is responsible for the activation of Hck, Erk, Pyk2 and signals cell proliferation upon growth factor stimulation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a / and :op1 (r / responsible-01 :ARG0 (p / protein-segment :mod (a3 / acid) :part-of (p2 / protein :name (n3 / name :op1 "gp130") :xref (x / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")) :mod (t / this)) :ARG1 (a2 / activate-01 :ARG1 (a4 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Hck") :xref (x1 / xref :value "UNIPROT:HCK_HUMAN" :prob "0.604")) :op2 (e3 / enzyme :name (n5 / name :op1 "Erk") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :op3 (e4 / enzyme :name (n6 / name :op1 "Pyk2") :xref (x3 / xref :value "UNIPROT:FAK2_HUMAN" :prob "0.603"))))) :op2 (s2 / signal-07 :ARG0 p :ARG1 (p3 / proliferate-01 :ARG0 (c / cell)) :condition (s3 / stimulate-01 :ARG2 (g / growth-factor)))) # ::id bel_pmid_1169_8287.20332 # ::date 2015-04-24T02:08:19 # ::file bel_pmid_1169_8287_20332.txt # ::snt It hasrecently been reported that a cytosolic isoform of PTPepsilon (PTPepsilonC) whenover-expressed in murine M1 myeloid cells inhibits interleukin-6 (IL-6)- and leukemia inhibitory factor-induced activation of Janus kinases (JAKs), thereby suppressing STAT3 tyrosine phosphorylation and STAT3 signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / report-01 :ARG1 (i / inhibit-01 :ARG0 (i2 / isoform :part-of (c / cytosol :xref (x5 / xref :value "GO:0005829" :prob "0.8")) :mod (e / enzyme :name (n2 / name :op1 "PTPepsilon")) :ARG1-of (d2 / describe-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "PTPepsilonC")))) :ARG1 (a / activate-01 :ARG1 (e3 / enzyme :name (n6 / name :op1 "Janus" :op2 "kinase") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.393")) :ARG2-of (i3 / induce-01 :ARG0 (a3 / and :op1 (p2 / protein :name (n7 / name :op1 "interleukin-6") :ARG1-of (d4 / describe-01 :ARG2 (p3 / protein :name (n8 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703")) :op2 (p5 / protein :name (n / name :op1 "leukemia" :op2 "inhibitory" :op3 "factor") :xref (x4 / xref :value "UNIPROT:LIF_HUMAN" :prob "0.702"))))) :condition (o / overexpress-01 :ARG1 i2 :location (c2 / cell-line :name (n4 / name :op1 "M1") :mod (m / myeloid) :part-of (m2 / mouse))) :ARG0-of (c3 / cause-01 :ARG1 (s / suppress-01 :ARG0 i2 :ARG1 (a5 / and :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n11 / name :op1 "tyrosine") :part-of (p4 / protein :name (n10 / name :op1 "STAT3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (s2 / signal-07 :ARG2 p4))))) :time (r2 / recent)) # ::id bel_pmid_1174_2412.20342 # ::date 2015-04-24T02:25:46 # ::file bel_pmid_1174_2412_20342.txt # ::snt Others are themselves enzymes, including the phosphotyrosine phosphatase SHP2 and the cytoplasmic tyrosine kinase Fyn. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (e / enzyme :ARG2-of (i / include-01 :ARG1 (a / and :op1 (t2 / tyrosine-phosphatase :name (n3 / name :op1 "SHP2") :ARG3-of (p / phosphorylate-01)) :op2 (t3 / tyrosine-kinase :name (n4 / name :op1 "Fyn") :part-of (c / cytoplasm :xref (x / xref :value "GO:0005737" :prob "0.8")))))) # ::id bel_pmid_1174_2412.25070 # ::date 2015-04-24T02:40:40 # ::file bel_pmid_1174_2412_25070.txt # ::snt Blockade of the pathway with dominant negative mutants or pharmacological inhibitors prevents the stimulation of cell growth by insulin, but has no effect on the metabolic actions of the hormone deletion of Akt2 produces hepatic insulin resistance in mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m2 / multi-sentence :snt1 (c / contrast-01 :ARG1 (p / prevent-01 :ARG0 (b / block-01 :ARG1 (p2 / pathway) :ARG3 (o / or :op1 (g2 / gene :ARG2-of (m / mutate-01 :mod "-/-") :ARG0-of (d / dominate-01)) :op2 (m5 / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (p3 / pharmacological)))) :ARG1 (s / stimulate-01 :ARG1 (g / grow-01 :ARG1 (c2 / cell)) :ARG2 (p6 / protein :name (n / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")))) :ARG2 (a / affect-01 :polarity "-" :ARG0 b :ARG1 (a2 / act-01 :ARG0 (h / hormone :ARG1-of (m6 / mean-01 :ARG2 p6)) :ARG1 (m3 / metabolize-01)))) :snt2 (p4 / produce-01 :ARG0 (d2 / delete-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Akt2") :xref (x2 / xref :value "UNIPROT:AKT2_HUMAN" :prob "0.604"))) :ARG1 (r / resist-01 :ARG0 (l / liver) :ARG1 (p5 / protein :name (n3 / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :location (m4 / mouse))) # ::id bel_pmid_1174_2412.38246 # ::date 2015-04-24T02:59:06 # ::file bel_pmid_1174_2412_38246.txt # ::snt Upon its activation downstream of PI(3)K, Akt phosphorylates and inactivates GSK-3, decreasing the rate of phosphorylation of glycogen synthase, thus increasing its activity state59. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (p / phosphorylate-01 :ARG1 (e4 / enzyme :name (n2 / name :op1 "GSK-3") :xref (x / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.262")) :ARG2 (e / enzyme :name (n / name :op1 "Akt") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :op2 (i / inactivate-00 :ARG0 e :ARG1 e4) :ARG0-of (c / cause-01 :ARG1 (d / decrease-01 :ARG1 (r / rate :degree-of (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "glycogen" :op2 "synthase") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.322")))) :ARG0-of (c2 / cause-01 :ARG1 (i2 / increase-01 :ARG1 (s / state :mod (a2 / activity-06 :ARG0 e2)))))) :condition (a3 / activate-01 :ARG1 e :location (r2 / relative-position :op1 (e3 / enzyme :name (n4 / name :op1 "PI(3)K")) :direction (d2 / downstream))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "59")))) # ::id bel_pmid_1175_3615.28390 # ::date 2015-04-24T03:16:55 # ::file bel_pmid_1175_3615_28390.txt # ::snt interleukin-6 (IL-6) or leukemia inhibitory factor (LIF)-induced differentiation of the myeloid cell line M1 was associated with a rapid increase in the level of mRNA encoding the signaling adaptor protein, SKAP55R # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / associate-01 :ARG1 (d2 / differentiate-01 :ARG1 (c / cell-line :name (n2 / name :op1 "M1") :mod (m / myeloid)) :ARG2-of (i / induce-01 :ARG0 (o / or :op1 (p / protein :name (n3 / name :op1 "interleukin-6") :ARG1-of (d3 / describe-01 :ARG2 (p2 / protein :name (n4 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703")) :op2 (p5 / protein :name (n5 / name :op1 "leukemia" :op2 "inhibitory" :op3 "factor") :ARG1-of (d4 / describe-01 :ARG2 (p3 / protein :name (n6 / name :op1 "LIF") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003"))) :xref (x3 / xref :value "UNIPROT:LIF_HUMAN" :prob "0.702"))))) :ARG2 (i2 / increase-01 :ARG1 (l / level :quant-of (n / nucleic-acid :name (n7 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p4 / protein :name (n9 / name :op1 "SKAP55R") :mod (a2 / adaptor) :ARG0-of (s3 / signal-07) :xref (x2 / xref :value "UNIPROT:SKAP2_HUMAN" :prob "1.002"))))) :mod (r / rapid))) # ::id bel_pmid_1177_9161.28386 # ::date 2015-04-24T08:55:26 # ::file bel_pmid_1177_9161_28386.txt # ::snt inflammatory cytokines, notably Tnf-alpha, and Il6, induce the expression of Cox2 and the secretion of Pge2 in human prostate cancer cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / induce-01 :ARG0 (c3 / cytokine :ARG2-of (i2 / include-91 :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Tnf-alpha") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.682")) :op2 (p3 / protein :name (n4 / name :op1 "Il6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG1-of (n / notable-04))) :ARG0-of (i3 / inflame-01)) :ARG2 (a / and :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n5 / name :op1 "Cox2") :xref (x2 / xref :value "UNIPROT:X2D3Z6_HUMAN" :prob "0.701"))) :op2 (s / secrete-01 :ARG1 (s2 / small-molecule :name (n6 / name :op1 "Pge2") :xref (x3 / xref :value "PUBCHEM:5280360" :prob "15.07648"))) :location (c / cell-line :mod (h / human) :mod (d / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer"))))) # ::id bel_pmid_1177_9161.28388 # ::date 2015-04-24T09:59:40 # ::file bel_pmid_1177_9161_28388.txt # ::snt the human COx2 gene contains a putative NF-IL-6 element in the 5'-flanking promoter region which can be activated by Il6 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (c / contain-01 :ARG0 (g / gene :name (n / name :op1 "COx2") :mod (h / human) :xref (x / xref :value "UNIPROT:COX2_HUMAN" :prob "0.653")) :ARG1 (e2 / element :mod (p / protein :name (n2 / name :op1 "NF-IL-6") :xref (x2 / xref :value "UNIPROT:CEBPD_HUMAN" :prob "0.252")) :ARG1-of (t / think-01) :ARG1-of (p3 / possible-01) :ARG1-of (a2 / activate-01 :ARG0 (p5 / protein :name (n4 / name :op1 "Il6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG1-of (p4 / possible-01))) :location (r / region :mod (d / dna-sequence :name (n3 / name :op1 "5'-flanking")) :ARG0-of (p2 / promote-01))) # ::id bel_pmid_1177_9161.34138 # ::date 2015-04-24T10:48:11 # ::file bel_pmid_1177_9161_34138.txt # ::snt events lead to activation of Stat signaling and result in the induction of proteins, such as bcl-2 and cMyc, both of which are critical regulators of cell cycle progression and apoptosis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (l / lead-03 :ARG0 (e / event) :ARG2 (a2 / activate-01 :ARG1 (s / signal-07 :ARG0 (p / protein :name (n / name :op1 "Stat") :xref (x2 / xref :value "UNIPROT:STAT_HUMAN" :prob "0.603"))))) :op2 (r / result-01 :ARG1 e :ARG2 (i / induce-01 :ARG2 (p2 / protein :example (a3 / and :op1 (p3 / protein :name (n2 / name :op1 "bcl-2") :xref (x / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "1.001")) :op2 (p4 / protein :name (n3 / name :op1 "cMyc") :xref (x1 / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.631")) :ARG0-of (r2 / regulate-01 :ARG1 (a4 / and :op1 (p5 / progress-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell))) :op2 (a5 / apoptosis :mod c2)) :mod (b / both)) :ARG1-of (c / critical-02)))))) # ::id bel_pmid_1179_0801.20476 # ::date 2015-04-24T11:25:29 # ::file bel_pmid_1179_0801_20476.txt # ::snt Further work revealed that TGF-R signaling (Massague and Wotton, 2000) was required for EMT, invasion in vitro, and metastasis in vivo, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reveal-01 :ARG0 (w / work-01 :degree (f / further)) :ARG1 (r2 / require-01 :ARG0 (a2 / and :op1 (e / event :name (n4 / name :op1 "epithelial−mesenchymal" :op2 "transition")) :op2 (i / invade-01 :manner (i2 / in-vitro)) :op3 (m / metastasis :manner (i3 / in-vivo))) :ARG1 (s / signal-07 :ARG1 (p / pathway :name (n / name :op1 "TGF-R")))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n2 / name :op1 "Massague")) :op2 (p4 / person :name (n3 / name :op1 "Wotton"))) :time (d2 / date-entity :year "2000")))) # ::id bel_pmid_1179_0801.21076 # ::date 2015-04-24T12:09:36 # ::file bel_pmid_1179_0801_21076.txt # ::snt Raf/mitogen-activated protein kinase (MAPK) is required for EMT, whereas activation of phosphatidylinositol 3-kinase (PI3K) causes scattering and protects from TGFbeta-induced apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / require-01 :ARG0 (e2 / event :name (n / name :op1 "epithelial−mesenchymal" :op2 "transition")) :ARG1 (p3 / pathway :name (n6 / name :op1 "Raf/MAPK")) :ARG1-of (c / contrast-01 :ARG2 (a2 / and :op1 (c2 / cause-01 :ARG0 (a3 / activate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "phosphatidylinositol" :op2 "3-kinase") :xref (x / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.701"))) :ARG1 (s / scatter-01)) :op2 (p5 / protect-01 :ARG0 a3 :ARG2 (a4 / apoptosis :ARG2-of (i / induce-01 :ARG0 (p6 / protein :name (n5 / name :op1 "TGFbeta") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.333")))))))) # ::id bel_pmid_1179_0801.26880 # ::date 2015-04-25T01:06:29 # ::file bel_pmid_1179_0801_26880.txt # ::snt In addition to oncogenic Ras (Oft et al., 1996), hepatocyte growth factor (HGF)/scatter factor (SF), fibroblast growth factor (FGF), and TGF alone induce mesenchymal features in diverse epithelial cell systems (Brinkmann et al., 1995; Piek et al., 1999; Thiery and Chopin, 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / induce-01 :ARG0 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d7 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n3 / name :op1 "Oft")) :op2 (p4 / person :mod (o / other))) :time (d2 / date-entity :year "1996"))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (s / slash :op1 (s4 / small-molecule :name (n2 / name :op1 "hepatocyte" :op2 "growth" :op3 "factor") :xref (x3 / xref :value "PUBCHEM:42785" :prob "4.83839"))) :op3 (s2 / small-molecule :name (n5 / name :op1 "scatter" :op2 "factor") :ARG1-of "d3" :xref (x2 / xref :value "PUBCHEM:34469" :prob "3.784401")) :op4 (p13 / protein-family :name (n8 / name :op1 "fibroblast" :op2 "growth" :op3 "factor")) :op5 (p12 / protein :name (n6 / name :op1 "TGF") :mod (a3 / alone) :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.263"))) :ARG2 (f / feature :mod (m4 / mesenchyme)) :location (s5 / system :consist-of (c6 / cell :mod (e / epithelium)) :mod (d6 / diverse)) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p5 / publication-91 :ARG0 (a5 / and :op1 (p6 / person :name (n9 / name :op1 "Brinkmann")) :op2 (p14 / person :mod (o2 / other)) :time (d4 / date-entity :year "1995"))) :op2 (p7 / publication-91 :ARG0 (a6 / and :op1 (p8 / person :name (n11 / name :op1 "Piek")) :op2 (p15 / person :mod (o3 / other)) :time (d5 / date-entity :year "1999"))) :op3 (p9 / publication-91 :ARG0 (a7 / and :op1 (p10 / person :name (n13 / name :op1 "Thiery")) :op2 (p11 / person :name (n10 / name :op1 "Chopin"))) :time d5)))) # ::id bel_pmid_1179_0801.27514 # ::date 2015-04-25T03:01:02 # ::file bel_pmid_1179_0801_27514.txt # ::snt Ha-Ras cooperates with transforming growth factor beta (TGFbeta) to cause epithelial mesenchymal transition (EMT) characterized by spindle-like cell morphology, loss of epithelial markers, and induction of mesenchymal markers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cooperate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "Ha-Ras") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG1 (p / protein :name (n3 / name :op1 "transforming" :op2 "growth" :op3 "factor" :op4 "beta") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.393")) :ARG2 (c2 / cause-01 :ARG0 (a2 / and :op1 e2 :op2 p) :ARG1 (t2 / transition-01 :ARG2 "m4" :ARG3 "e" :ARG1-of (c3 / characterize-01 :ARG2 (a / and :op1 (m / morphology :mod (c4 / cell) :ARG1-of (r / resemble-01 :ARG2 (s / spindle))) :op2 (l / lose-02 :ARG1 (m2 / marker :mod (e / epithelium))) :op3 (i / induce-01 :ARG2 (m3 / marker :mod (m4 / mesenchyme)))))))) # ::id bel_pmid_1179_0801.31150 # ::date 2015-04-25T05:52:40 # ::file bel_pmid_1179_0801_31150.txt # ::snt the spindle-like phenotype induced by TGF treatment (Fig. 1 A, inset) persisted after factor removal (Fig. 1 B, inset) and involved loss of E-cadherin/4-integrin, whereas vimentin was strongly induced # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (p / persist-01 :ARG1 (p2 / phenotype :ARG1-of (r / resemble-01 :ARG2 (s / spindle)) :ARG1-of (i2 / induce-01 :ARG0 (t / treat-04 :ARG2 (p5 / protein :name (n3 / name :op1 "TGF") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.263"))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1A" :location (i3 / inset))))) :time (a2 / after :op1 (r2 / remove-01 :ARG1 p5 :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "1B" :location i3))))) :op2 (i / involve-01 :ARG0 p2 :ARG1 (l / lose-02 :ARG1 (s2 / slash :op1 (p3 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n2 / name :op1 "4-integrin"))))) :ARG1-of (c / contrast-01 :ARG2 (i4 / induce-01 :ARG2 (p6 / protein :name (n4 / name :op1 "vimentin") :xref (x1 / xref :value "UNIPROT:VIME_HUMAN" :prob "0.702")) :ARG1-of (s3 / strong-02)))) # ::id bel_pmid_1179_8191.15678 # ::date 2015-04-25T11:24:44 # ::file bel_pmid_1179_8191_15678.txt # ::snt Two peroxisome proliferator-activated receptor a agonsists: Wy-14643 and a marketed fribrate drug, fenofibrate # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (a / and :op1 (s / small-molecule :name (n / name :op1 "Wy-14643") :xref (x2 / xref :value "PUBCHEM:5694" :prob "19.069792")) :op3 (s2 / small-molecule :name (n2 / name :op1 "fenofibrate") :domain (d / drug :ARG1-of (m / market-01) :mod (f / fibrate)) :xref (x1 / xref :value "PUBCHEM:3339" :prob "16.375763")) :domain (a2 / agonist :quant "2" :mod (p / protein :name (n3 / name :op1 "peroxisome" :op2 "proliferator-activated" :op3 "receptor" :op4 "alpha") :xref (x / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.703")))) # ::id bel_pmid_1179_8191.28334 # ::date 2015-04-25T11:30:27 # ::file bel_pmid_1179_8191_28334.txt # ::snt Several pro-inflammatory mediators up-regulate SAA transcription, including Il1, Il6, TNFalpha, and Lif. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 3, 2015 (u / upregulate-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (m / mediate-01 :quant (s / several)) :ARG0-of (f / favor-01 :ARG1 (i / inflame-01)) :ARG2-of (i2 / include-91 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "Il1") :xref (x4 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.282")) :op2 (p2 / protein :name (n3 / name :op1 "Il6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :op3 (p3 / protein :name (n4 / name :op1 "TNFalpha") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.692")) :op4 (p4 / protein :name (n5 / name :op1 "Lif") :xref (x2 / xref :value "UNIPROT:LIF_HUMAN" :prob "0.603")))) :quant (s2 / several)) :ARG1 (t / transcribe-01 :ARG1 (g / gene :name (n / name :op1 "SAA") :xref (x1 / xref :value "UNIPROT:SAA1_HUMAN" :prob "1.002")))) # ::id bel_pmid_1179_8191.33678 # ::date 2015-04-25T11:47:11 # ::file bel_pmid_1179_8191_33678.txt # ::snt Fibrates induce the peroxisomal b-oxidation system of fatty acids in rodents, resulting in proliferation of peroxisomes, hepatomegaly and eventually hepatocarcinoma. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (i / induce-01 :ARG0 (f / fibrate) :ARG2 (s / system :mod (o / oxidize-01 :ARG1 (a / acid :ARG1-of (f2 / fat-03)) :mod (b / beta) :mod (p / peroxisome))) :ARG1-of (r / result-01 :ARG2 (a2 / and :op1 (p2 / proliferate-01 :ARG0 p) :op2 (h / hepatomegaly) :op3 (h2 / hepatocarcinoma :time (e / eventual)))) :location (r2 / rodent)) # ::id bel_pmid_1180_3570.9290 # ::date 2015-04-25T12:10:20 # ::file bel_pmid_1180_3570_9290.txt # ::snt We note a marked and differential increase in Itih-4 labeling in proliferating hepatocytes, compared with bile duct cells in liver explant cultures treated with interleukin-6 (IL-6) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (n / note-01 :ARG1 (w / we) :ARG2 (i / increase-01 :ARG1 (l / label-01 :ARG1 (p / protein :name (n2 / name :op1 "Itih-4") :xref (x1 / xref :value "UNIPROT:ITIH4_HUMAN" :prob "0.592"))) :location (h / hepatocyte :ARG0-of (p2 / proliferate-01)) :compared-to (c2 / cell :mod (d2 / duct :mod (b / bile)) :location (c3 / culture :mod (e / explant) :mod (l2 / liver) :ARG1-of (t / treat-04 :ARG2 (p3 / protein :name (n4 / name :op1 "interleukin-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))))) :ARG2-of (m / mark-02) :ARG1-of (d / differ-02))) # ::id bel_pmid_1180_3570.9376 # ::date 2015-04-26T00:04:28 # ::file bel_pmid_1180_3570_9376.txt # ::snt Inter-alpha-trypsin inhibitor-4 (Itih-4) is a liver-restricted member of the serine protease inhibitor family with diverse functions as an anti-apoptotic and matrix stabilizing molecule that are important throughout development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / include-91 :ARG1 (p2 / protein :name (n4 / name :op1 "Inter-alpha-trypsin" :op2 "inhibitor-4") :ARG1-of (r / restrict-01 :ARG2 (l / liver)) :ARG0-of (f2 / function-01 :ARG1 (a2 / and :op1 (c / counter-01 :ARG1 (a3 / apoptosis)) :op2 (s / stabilize-01 :ARG0 (m / molecule) :ARG1 (m2 / matrix))) :mod (i3 / important :time (d / develop-01)) :mod (d2 / diverse)) :xref (x / xref :value "UNIPROT:ITIH4_HUMAN" :prob "0.372")) :ARG2 (p3 / protein-family :name (n3 / name :op1 "serine" :op2 "protease" :op3 "inhibitor"))) # ::id bel_pmid_1182_0727.27898 # ::date 2015-04-26T00:58:40 # ::file bel_pmid_1182_0727_27898.txt # ::snt tryosine phosphorylation of gp130 was observed in fibroblasts after stimulation with all the cytokines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (o / observe-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (p2 / protein :name (n / name :op1 "gp130") :xref (x / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :location (f / fibroblast) :time (a2 / after :op1 (s / stimulate-01 :ARG2 (c / cytokine :mod (a3 / all))))) # ::id bel_pmid_1183_2424.8080 # ::date 2015-04-26T01:10:58 # ::file bel_pmid_1183_2424_8080.txt # ::snt We have previously shown that B cell lymphoma/leukemia-2 (bcl-2) -/- mice develop cystic kidneys and exhibit sustained phosphorylation of FAK and paxillin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (a / and :op1 (d / develop-01 :ARG1 (m / mouse :mod (p5 / protein :name (n3 / name :op1 "bcl-2") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "1.001"))) :ARG2 (k2 / kidney :mod (c / cyst))) :op2 (e / exhibit-01 :ARG0 m :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "FAK") :xref (x2 / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n2 / name :op1 "paxillin") :xref (x / xref :value "UNIPROT:PAXI_HUMAN" :prob "0.703"))) :ARG1-of (s2 / sustain-01)))) :time (p4 / previous)) # ::id bel_pmid_1183_2424.8082 # ::date 2015-04-26T02:25:04 # ::file bel_pmid_1183_2424_8082.txt # ::snt Cystic kidneys from postnatal day 20 bcl-2 -/- mice demonstrate a reduced expression, sixfold decrease in activity, and altered distribution of SHP-2 and PTP 1B # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (d / demonstrate-01 :ARG0 (k / kidney :mod (c / cyst) :time (d2 / day :value "20") :source (m / mouse :mod (p2 / protein :name (n / name :op1 "bcl-2") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "1.001"))) :time (a5 / after :op1 (b / bear-02))) :ARG1 (a / and :op1 (r2 / reduce-01 :ARG1-of (e / express-03)) :op2 (d3 / decrease-01 :ARG1 (a2 / activity-06) :ARG2 (p / product-of :op1 "6")) :op3 (d4 / distribute-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n2 / name :op1 "SHP-2") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "PTP" :op2 "1B") :xref (x / xref :value "UNIPROT:PTN1_HUMAN" :prob "0.683"))) :ARG1-of (a4 / alter-01)))) # ::id bel_pmid_1183_2424.8084 # ::date 2015-04-26T03:04:37 # ::file bel_pmid_1183_2424_8084.txt # ::snt Cystic kidneys from postnatal day 20 bcl-2 -/- mice demonstrate a reduced expression, sixfold decrease in activity, and altered distribution of SHP-2 and PTP 1B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (d / demonstrate-01 :ARG0 (k / kidney :mod (c / cyst) :time (d2 / day :value "20") :source (m / mouse :mod (p2 / protein :name (n / name :op1 "bcl-2") :ARG0-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "1.001"))) :time (a5 / after :op1 (b / bear-02))) :ARG1 (a / and :op1 (r / reduce-01 :ARG1 (e / express-03)) :op2 (d3 / decrease-01 :ARG1 (a2 / activity-06) :ARG2 (p / product-of :op1 "6")) :op3 (d4 / distribute-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "SHP-2") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "PTP" :op2 "1B") :xref (x / xref :value "UNIPROT:PTN1_HUMAN" :prob "0.683"))) :ARG1-of (a4 / alter-01)))) # ::id bel_pmid_1190_2577.36732 # ::date 2015-04-26T03:15:51 # ::file bel_pmid_1190_2577_36732.txt # ::snt The primary substrates of CDK4/6 and CDK2 in G1 progression are the members of the retinoblastoma protein family RB,p107 and p130 The activity of the RB proteins is modulated by sequential phosphorylation by CDK4/6cyclinD and CDK2cyclinE complexes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (i / include-91 :ARG1 (s5 / substrate :poss (a5 / and :op1 (e3 / enzyme :name (n9 / name :op1 "CDK4/6")) :op2 (e4 / enzyme :name (n10 / name :op1 "CDK2") :xref (x1 / xref :value "UNIPROT:CDK2_HUMAN" :prob "1.003"))) :time (p9 / progress-01 :ARG1 (e5 / event :name (n12 / name :op1 "G1"))) :mod (p10 / primary)) :ARG2 (p / protein-family :name (n / name :op1 "retinoblastoma") :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "RB") :xref (x / xref :value "UNIPROT:RB_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n3 / name :op1 "p107") :xref (x3 / xref :value "UNIPROT:RBL1_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n4 / name :op1 "p130") :xref (x5 / xref :value "UNIPROT:RBL2_HUMAN" :prob "1.002")))))) :snt2 (m3 / modulate-01 :ARG0 (p5 / phosphorylate-01 :ARG2 (a2 / and :op1 (m4 / macro-molecular-complex :op1 (e / enzyme :name (n5 / name :op1 "CDK4/6")) :op2 (p7 / protein :name (n7 / name :op1 "cyclinD") :xref (x4 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.341"))) :op2 (m5 / macro-molecular-complex :op1 (e2 / enzyme :name (n11 / name :op1 "CDK2") :xref (x2 / xref :value "UNIPROT:CDK2_HUMAN" :prob "1.003")) :op2 (p8 / protein :name (n8 / name :op1 "cyclinE") :xref (x7 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.332")))) :mod (s3 / sequence)) :ARG1 (a3 / activity-06 :ARG0 (p6 / protein :name (n6 / name :op1 "RB") :xref (x6 / xref :value "UNIPROT:RB_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1190_2577.37122 # ::date 2015-04-26T04:19:24 # ::file bel_pmid_1190_2577_37122.txt # ::snt Inhibitory phosphorylation of adjacent threonine and tyrosine residues (T14/Y15 in CDK1) is mediated by dualspecificity kinases (such as WEE1 and MYT1). This inhibition is relieved when the CDC25 phosphatases (CDC25A,CDC25B and CDC25C) dephosphorylate these residues, which triggers entry into mitosis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / multi-sentence :snt1 (m2 / mediate-01 :ARG0 (k / kinase :mod (d / dualspecificity) :example (a5 / and :op1 (k2 / kinase :name (n4 / name :op1 "WEE1") :xref (x1 / xref :value "UNIPROT:WEE1_HUMAN" :prob "1.003")) :op2 (k3 / kinase :name (n5 / name :op1 "MYT1") :xref (x / xref :value "UNIPROT:MYT1_HUMAN" :prob "1.003")))) :ARG1 (p / phosphorylate-01 :ARG1 (a7 / and :op1 (r / residue :mod (a / amino-acid :name (n / name :op1 "threonine") :part-of (e5 / enzyme :name (n3 / name :op1 "CDK1") :xref (x2 / xref :value "UNIPROT:CDK1_HUMAN" :prob "1.003")) :xref (x7 / xref :value "PUBCHEM:205" :prob "11.848252"))) :op2 (r3 / residue :mod (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of e5 :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :mod (a4 / adjacent)) :ARG0-of (i / inhibit-01))) :snt2 (r2 / relieve-01 :ARG1 (i2 / inhibit-01 :mod (t / this)) :time (d2 / dephosphorylate-01 :ARG1 (r4 / residue :mod (t2 / this)) :ARG2 (p3 / phosphatase :name (n6 / name :op1 "CDC25") :ARG2-of (i3 / include-91 :ARG1 (a3 / and :op1 (e / enzyme :name (n7 / name :op1 "CDC25A") :xref (x5 / xref :value "UNIPROT:MPIP1_HUMAN" :prob "1.002")) :op2 (e2 / enzyme :name (n8 / name :op1 "CDC25B") :xref (x4 / xref :value "UNIPROT:MPIP2_HUMAN" :prob "1.002")) :op3 (e3 / enzyme :name (n9 / name :op1 "CDC25C") :xref (x3 / xref :value "UNIPROT:MPIP3_HUMAN" :prob "1.003"))))) :ARG0-of (t4 / trigger-01 :ARG1 (e4 / enter-01 :ARG1 (m4 / mitosis)))))) # ::id bel_pmid_1190_2577.37858 # ::date 2015-04-26T04:55:20 # ::file bel_pmid_1190_2577_37858.txt # ::snt CDK2 is sequentially activated by the E-type cyclins cyclin E1 and E2 during the G1/S transition, and the A-type cyclins cyclin A1 and A2 during S phase # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a / activate-01 :ARG0 (a2 / and :op1 (p5 / protein :name (n4 / name :op1 "cyclin" :op2 "E") :time (t / transition-01 :ARG2 (e3 / event :name (n9 / name :op1 "S")) :ARG3 (e / event :name (n7 / name :op1 "G1"))) :ARG2-of (t4 / type-03 :ARG1 (a3 / and :op1 (p7 / protein :name (n11 / name :op1 "cyclin" :op2 "E1") :xref (x3 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361")) :op2 (p8 / protein :name (n12 / name :op1 "cyclin" :op2 "E2") :xref (x6 / xref :value "UNIPROT:CCNA2_HUMAN" :prob "0.312")))) :xref (x4 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")) :op2 (p / protein :name (n2 / name :op1 "cyclin" :op2 "A") :ARG2-of (t2 / type-03 :ARG1 (a4 / and :op1 (p2 / protein :name (n / name :op1 "cyclin" :op2 "A1") :xref (x1 / xref :value "UNIPROT:CCNA1_HUMAN" :prob "0.672")) :op2 (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "A2") :xref (x2 / xref :value "UNIPROT:CCNA2_HUMAN" :prob "0.672")))) :time e3 :xref (x5 / xref :value "UNIPROT:CCNA2_HUMAN" :prob "0.662"))) :ARG1 (e2 / enzyme :name (n8 / name :op1 "CDK2") :xref (x / xref :value "UNIPROT:CDK2_HUMAN" :prob "1.003")) :manner (s / sequence)) # ::id bel_pmid_1190_2577.37928 # ::date 2015-04-26T05:17:56 # ::file bel_pmid_1190_2577_37928.txt # ::snt CKIs are of two types(reviewed in REF. 17). The four members of the INK4 family INK4A (also known as p16),INK4B(also known as p15),INK4C (also known as p18) and INK4D (also known as p19) exert their inhibitory activity by binding to the CDK4 and CDK6 kinases and preventing their association with D-type cyclins # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt2 (e2 / exert-01 :ARG0 (a / and :op1 (p / protein :name (n2 / name :op1 "INK4A") :ARG1-of (k / know-02 :ARG2 (p5 / protein :name (n6 / name :op1 "p16") :xref (x5 / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262")) :mod (a5 / also))) :op2 (p2 / protein :name (n3 / name :op1 "INK4B") :ARG1-of (k2 / know-02 :ARG2 (p6 / protein :name (n7 / name :op1 "p15") :xref (x3 / xref :value "UNIPROT:P13986_HUMAN" :prob "1.001")) :mod a5)) :op3 (p3 / protein :name (n4 / name :op1 "INK4C") :ARG1-of (k3 / know-02 :ARG2 (p7 / protein :name (n8 / name :op1 "p18") :xref (x4 / xref :value "UNIPROT:ARAID_HUMAN" :prob "1.002")) :mod a5)) :op4 (p4 / protein :name (n5 / name :op1 "INK4D") :ARG1-of (k4 / know-02 :ARG2 (p8 / protein-family :name (n9 / name :op1 "p19")) :mod a5)) :ARG1-of (i2 / include-91 :ARG2 (p10 / protein :name (n12 / name :op1 "INK4")))) :ARG1 (a3 / activity-06 :ARG0 a :ARG1 (i / inhibit-01 :ARG0 a)) :manner (a4 / and :op1 (b / bind-01 :ARG1 (a2 / and :op1 (k5 / kinase :name (n10 / name :op1 "CDK4") :xref (x1 / xref :value "UNIPROT:CDK4_HUMAN" :prob "1.003")) :op2 (k6 / kinase :name (n11 / name :op1 "CDK6") :xref (x / xref :value "UNIPROT:CDK6_HUMAN" :prob "1.003")))) :op2 (p9 / prevent-01 :ARG1 (a6 / associate-01 :ARG1 a2 :ARG2 (p13 / protein :name (n13 / name :op1 "cyclin" :op2 "D") :xref (x6 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.371")))))) :snt1 (t / type-03 :quant "2" :ARG1 (e / enzyme :name (n / name :op1 "CKI") :xref (x2 / xref :value "UNIPROT:CHKA_HUMAN" :prob "1.002")) :ARG1-of (r / review-02 :medium (r2 / ref :mod "17")))) # ::id bel_pmid_1190_9529.24784 # ::date 2015-04-24T06:45:50 # ::file bel_pmid_1190_9529_24784.txt # ::snt Cotransfection of JAK1 or JAK3 with TCPTP-WT resulted in substantial dephosphorylation of the kinases # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / result-01 :ARG1 (c / cotransfect-01 :ARG2 (a / and :op1 (o / or :op1 (e2 / enzyme :name (n / name :op1 "JAK1") :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :op2 (e / enzyme :name (n2 / name :op1 "JAK3") :xref (x1 / xref :value "UNIPROT:JAK3_HUMAN" :prob "1.004"))) :op2 (p3 / protein :name (n3 / name :op1 "TCPTP") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:PTN2_HUMAN" :prob "1.002")))) :ARG2 (d / dephosphorylate-01 :ARG1 o :degree (s / substantial))) # ::id bel_pmid_1190_9529.30256 # ::date 2015-04-25T08:44:14 # ::file bel_pmid_1190_9529_30256.txt # ::snt Immunoblotting with a phospho-STAT1 antibody revealed an increase in STAT1 phosphorylation in TCPTP-deficient thymocytes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / reveal-01 :ARG0 (i / immunoblot-01 :ARG3 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "STAT1") :ARG3-of (p5 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))))) :ARG1 (i2 / increase-01 :ARG1 (p2 / phosphorylate-01 :ARG1 p) :location (c2 / cell :name (n4 / name :op1 "thymocyte") :ARG0-of (l2 / lack-01 :ARG1 (p4 / protein :name (n3 / name :op1 "TCPTP") :xref (x / xref :value "UNIPROT:PTN2_HUMAN" :prob "1.002")))))) # ::id bel_pmid_1197_1957.1966 # ::date 2015-04-26T02:39:36 # ::file bel_pmid_1197_1957_1966.txt # ::snt PKA also decreased Raf-1 serine 338 phosphorylation of Raf-1, previously shown to be required for Raf-1 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (d / decrease-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "338" :name (n3 / name :op1 "serine") :part-of (e / enzyme :name (n / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 e :ARG1-of (r / require-01 :purpose (a4 / activate-01 :ARG1 e) :ARG1-of (s2 / show-01 :time (p2 / previous)))) :mod (a2 / also)) # ::id bel_pmid_1197_1957.37446 # ::date 2015-04-26T04:55:14 # ::file bel_pmid_1197_1957_37446.txt # ::snt The cyclic AMP (cAMP)-dependent protein kinase (PKA) can inhibit Raf-1 by direct phosphorylation. We have mapped all cAMP-induced phosphorylation sites in Raf-1, showing that serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (p2 / possible-01 :ARG1 (i / inhibit-01 :ARG0 (e5 / enzyme :name (n5 / name :op1 "protein" :op2 "kinase") :ARG0-of (d2 / depend-01 :ARG1 "s") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393")) :ARG1 (e / enzyme :name (n / name :op1 "Raf-1") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :manner (p4 / phosphorylate-01 :ARG1-of (d / direct-02)))) :snt2 (m3 / map-01 :ARG0 (w / we) :ARG1 (p3 / protein-segment :location (e2 / enzyme :name (n4 / name :op1 "Raf-1") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1-of (p / phosphorylate-01) :ARG2-of (i2 / induce-01 :ARG0 (s / small-molecule :name (n10 / name :op1 "cAMP") :xref (x7 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :mod (a / all)) :ARG0-of (c2 / cause-01 :ARG1 (s2 / show-01 :ARG0 w :ARG1 (a7 / and :op1 (p6 / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "43" :name (n6 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "259" :name (n7 / name :op1 "serine") :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op3 (a5 / amino-acid :mod "621" :name (n8 / name :op1 "serine") :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG2 (e3 / enzyme :name (n9 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :manner (i3 / in-vitro)) :op2 (i4 / induce-01 :ARG0 s :ARG2 a2 :manner (i5 / in-vivo))))))) # ::id bel_pmid_1202_1251.10412 # ::date 2015-04-26T07:44:27 # ::file bel_pmid_1202_1251_10412.txt # ::snt In contrast, LPS from Escherichia coli stimulated mast cells in a TLR4-dependent manner to produce TNF-alpha, IL-1beta, IL-6, and IL-13, but not IL-4 nor IL-5. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / contrast-01 :ARG2 (s / stimulate-01 :ARG0 (l / lipopolysaccharide :source (o / organism :name (n2 / name :op1 "Escherichia" :op2 "coli"))) :ARG1 (c3 / cell :mod (m2 / mast)) :manner (d / depend-01 :ARG1 (p / protein :name (n3 / name :op1 "TLR4") :xref (x6 / xref :value "UNIPROT:TLR4_HUMAN" :prob "1.004"))) :purpose (c4 / contrast-01 :ARG1 (p8 / produce-01 :ARG0 c3 :ARG1 (a / and :op1 (p2 / protein :name (n4 / name :op1 "TNF-alpha") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n5 / name :op1 "IL-1beta") :xref (x2 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :op3 (p4 / protein :name (n6 / name :op1 "IL-6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op4 (p5 / protein :name (n7 / name :op1 "IL-13") :xref (x5 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")))) :ARG2 (p9 / produce-01 :polarity "-" :ARG0 c3 :ARG1 (a2 / and :op1 (p6 / protein :name (n8 / name :op1 "IL-4") :xref (x3 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :op2 (p7 / protein :name (n9 / name :op1 "IL-5") :xref (x / xref :value "UNIPROT:IL5_HUMAN" :prob "1.003"))))))) # ::id bel_pmid_1202_3369.1246 # ::date 2015-04-24T10:00:31 # ::file bel_pmid_1202_3369_1246.txt # ::snt Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rbeta1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (b / bind-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-23") :ARG1-of (r / resemble-01 :ARG2 (p2 / protein :name (n / name :op1 "IL-12") :xref (x / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343"))) :xref (x3 / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.312")) :ARG2 (p4 / protein :name (n3 / name :op1 "IL-12Rbeta1") :ARG1-of (i / include-91 :ARG2 (p3 / protein :name (n4 / name :op1 "IL-12R") :xref (x1 / xref :value "UNIPROT:I12R1_HUMAN" :prob "0.683"))) :xref (x2 / xref :value "UNIPROT:I12R1_HUMAN" :prob "0.683"))) # ::id bel_pmid_1202_3369.35656 # ::date 2015-04-24T10:27:04 # ::file bel_pmid_1202_3369_35656.txt # ::snt IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (h / have-concession-91 :ARG1 (a3 / and :op1 (w / weak-02 :ARG1 (a4 / activate-01 :ARG1 "p12") :degree (m2 / more) :degree (s / substantial)) :op2 (f / form-01 :ARG1 (m3 / macro-molecular-complex :ARG1-of (b / bind-01 :ARG2 (n14 / nucleic-acid :wiki "DNA" :name (n15 / name :op1 "DNA"))) :mod (p7 / protein :name (n13 / name :op1 "stat") :xref (x8 / xref :value "UNIPROT:STAT_HUMAN" :prob "0.603")) :ARG1-of (d3 / differ-02)) :ARG2-of (r2 / respond-01 :ARG1 (p5 / protein :name (n5 / name :op1 "IL-23") :xref (x9 / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.312"))) :compared-to (p6 / protein :name (n6 / name :op1 "IL-12") :xref (x7 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343")))) :ARG2 (a2 / activate-01 :ARG0 p5 :ARG1 (m4 / molecule :ARG0-of (s3 / signal-07 :ARG1 (p4 / pathway :name (n7 / name :op1 "Jak-stat"))) :ARG1-of (m5 / mean-01 :ARG2 (a5 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Jak2") :xref (x5 / xref :value "UNIPROT:JAK2_HUMAN" :prob "0.604")) :op2 (e3 / enzyme :name (n12 / name :op1 "Tyk2") :xref (x4 / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603")) :op3 (p10 / protein :name (n8 / name :op1 "stat1") :xref (x2 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604")) :op4 (p11 / protein :name (n9 / name :op1 "stat3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :op5 (p12 / protein :name (n10 / name :op1 "stat4") :xref (x10 / xref :value "UNIPROT:STAT4_HUMAN" :prob "0.604")) :op6 (p13 / protein :name (n11 / name :op1 "stat5") :xref (x11 / xref :value "UNIPROT:STA5A_HUMAN" :prob "0.603")))) :ARG1-of (r3 / resemble-01 :ARG2 (m6 / molecule :ARG1-of (a8 / activate-01 :ARG0 p6))) :ARG1-of (s2 / same-01)))) :snt2 (a / and :op1 (a6 / associate-01 :ARG1 (p / protein :name (n / name :op1 "IL-23R") :xref (x1 / xref :value "UNIPROT:IL23R_HUMAN" :prob "1.002")) :ARG2 (e / enzyme :name (n2 / name :op1 "Jak2") :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "0.604")) :manner (c / constitutive)) :op2 (a7 / associate-01 :ARG1 p :ARG2 (p3 / protein :name (n3 / name :op1 "stat3") :xref (x6 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :manner (d / depend-01 :ARG0 (l / ligand))))) # ::id bel_pmid_1207_7275.28056 # ::date 2015-04-28T00:47:26 # ::file bel_pmid_1207_7275_28056.txt # ::snt At day 7 following infection, lung tissue from mice given hIL-17F Ad showed substantial increases in the mRNA for inflammatory cytokines and chemokines, including IL-6, IFN-g, inflammatory protein 10, and monokine induced by IFN-g (Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG0 (t / tissue :location (l / lung) :source (m / mouse :ARG2-of (g / give-01 :ARG1 (g2 / gene :name (n / name :op1 "Ad") :ARG3-of (e / express-03 :ARG2 (p6 / protein :name (n8 / name :op1 "hil-17F"))))))) :ARG1 (i2 / increase-01 :ARG1 (a2 / and :op1 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA") :purpose (a3 / and :op1 (c / cytokine) :op2 (c2 / chemokine) :ARG0-of (i3 / inflame-01) :ARG2-of (i4 / include-91 :ARG1 (a4 / and :op1 (p3 / protein :name (n5 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n6 / name :op1 "IFN-g") :xref (x1 / xref :value "UNIPROT:IFNG_HUMAN" :prob "0.632")) :op3 (p5 / protein :name (n7 / name :op1 "inflammatory" :op2 "protein" :op3 "10") :xref (x2 / xref :value "UNIPROT:TP8L2_HUMAN" :prob "0.312")) :op4 (m2 / monokine :ARG2-of (i5 / induce-01 :ARG0 p4))))))) :degree (s2 / substantial)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3")) :time (a / after :op1 (i / infect-01 :ARG1 t) :quant (t2 / temporal-quantity :quant "7" :unit (d / day)))) # ::id bel_pmid_1207_7275.28070 # ::date 2015-04-26T03:07:16 # ::file bel_pmid_1207_7275_28070.txt # ::snt We cultured sorted mast cells and basophils with IL-25, IL-18, or IL-25 IL-18 and detected both IL-5 and IL-13 from IL-18 cultured cell supernatants # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (a / and :op1 (c / culture-01 :ARG0 (w / we) :ARG1 (o / or :op1 (a3 / and :op1 (p / protein :name (n / name :op1 "IL-25") :xref (x3 / xref :value "UNIPROT:IL25_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "IL-18") :xref (x / xref :value "UNIPROT:IL18_HUMAN" :prob "1.003"))) :op2 (a4 / and :op1 p :op2 p2)) :location (a2 / and :op1 (c2 / cell :mod (m / mast) :ARG1-of (s2 / sort-01)) :op2 (c5 / cell :name (n3 / name :op1 "basophil")))) :op2 (d / detect-01 :ARG0 w :ARG1 (a5 / and :op1 (p3 / protein :name (n4 / name :op1 "IL-5") :xref (x1 / xref :value "UNIPROT:IL5_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n5 / name :op1 "IL-13") :xref (x2 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :source (s / supernatant :mod (c3 / cell) :location-of (c4 / culture-01 :ARG0 w :ARG1 p2))))) # ::id bel_pmid_1208_2107.1700 # ::date 2015-04-26T03:32:14 # ::file bel_pmid_1208_2107_1700.txt # ::snt The dual phosphorylation of Thr-183 and Tyr-185 in ERK2 is catalyzed by MAPK/ERK kinase 1 (MEK1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (c / catalyze-01 :ARG0 (e2 / enzyme :name (n / name :op1 "MAPK/ERK" :op2 "kinase" :op3 "1")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "183" :name (n2 / name :op1 "threonine") :part-of (e / enzyme :name (n4 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a3 / amino-acid :mod "185" :name (n3 / name :op1 "tyrosine") :part-of e :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :mod (d / dual))) # ::id bel_pmid_1208_7097.38812 # ::date 2015-04-26T04:42:38 # ::file bel_pmid_1208_7097_38812.txt # ::snt the phosphorylation of Raf-1 on Ser-259 induced by paclitaxel he region surrounding Ser-259 in Raf-1 conforms to a consensus sequence for phosphorylation by Akt # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / conform-01 :ARG1 (p / phosphorylate-01 :ARG2 (a / amino-acid :mod "259" :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2-of (i / induce-01 :ARG0 (p3 / paclitaxel :location (r / region :ARG0-of (s2 / surround-01 :ARG1 a))))) :ARG2 (s / sequence :mod (c2 / consensus) :purpose (p2 / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))))) # ::id bel_pmid_1208_9357.6280 # ::date 2015-04-26T09:01:03 # ::file bel_pmid_1208_9357_6280.txt # ::snt The MAPK kinase inhibitors did not affect Nur77 and Nurr1 mRNA induction but blocked CRH or cAMP-stimulated Nur transcriptional activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / contrast-01 :ARG1 (a / affect-01 :polarity "-" :ARG0 (m / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p3 / protein-family :name (n8 / name :op1 "MAPK" :op2 "kinase")))) :ARG1 (i / induce-01 :ARG2 (a2 / and :op1 (n9 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n / name :op1 "Nur77") :xref (x2 / xref :value "UNIPROT:NR4A1_HUMAN" :prob "1.002")))) :op2 (n10 / nucleic-acid :name (n7 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Nurr1") :xref (x / xref :value "UNIPROT:NR4A2_HUMAN" :prob "0.602"))))))) :ARG2 (b / block-01 :ARG0 m :ARG1 (a3 / activity-06 :ARG0 (p6 / protein :name (n5 / name :op1 "Nur") :xref (x1 / xref :value "UNIPROT:NR4A1_HUMAN" :prob "0.232")) :ARG1 (t2 / transcribe-01) :ARG1-of (s / stimulate-01 :ARG0 (o / or :op1 (s2 / small-molecule :name (n3 / name :op1 "CRH") :xref (x4 / xref :value "PUBCHEM:16130996" :prob "9.430335")) :op2 (s3 / small-molecule :name (n4 / name :op1 "cAMP") :xref (x3 / xref :value "PUBCHEM:6076" :prob "15.374314"))))))) # ::id bel_pmid_1208_9357.19824 # ::date 2015-04-26T09:21:30 # ::file bel_pmid_1208_9357_19824.txt # ::snt calcium-independent pathways are accounted for in part by MAPK activation (Rap1/B-Raf/MAPK-ERK kinase/ERK1/2) AtT-20 corticotrophs express B-Raf, as do other cells in which cAMP stimulates MAPK. CRH/cAMP stimulated ERK2 (Mapk1) activity and increased transcriptional activity of a Gal4-Elk1 protein, which was blocked by overexpression of dominant negative mutants and kinase inhibitors and stimulated by expression of B-Raf. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (a5 / account-01 :ARG1 (p / pathway :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 (c / calcium)) :example (p4 / pathway :name (n16 / name :op1 "Rap1/B-Raf/MAPK-ERK-kinase/ERK1/2"))) :ARG2 (a6 / activate-01 :ARG1 (e7 / enzyme :name (n3 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :degree (p3 / part)) :snt2 (e / express-03 :ARG1 (c2 / corticotroph :name (n / name :op1 "AtT-20")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :xref (x4 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1-of (r / resemble-01 :ARG2 (e11 / express-03 :ARG1 (c3 / cell :mod (o2 / other) :location-of (s4 / stimulate-01 :ARG0 (s6 / small-molecule :name (n10 / name :op1 "cAMP") :xref (x7 / xref :value "PUBCHEM:6076" :prob "15.374314")) :ARG1 (e4 / enzyme :name (n14 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))))))) :snt3 (a / and :op1 (s / stimulate-01 :ARG0 (s2 / slash :op1 (s7 / small-molecule :name (n4 / name :op1 "CRH") :xref (x6 / xref :value "PUBCHEM:16130996" :prob "9.430335")) :op2 (s5 / small-molecule :name (n5 / name :op1 "cAMP") :xref (x8 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :ARG1 (a2 / activity-06 :ARG0 (e3 / enzyme :name (n6 / name :op1 "ERK2") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :op2 (i2 / increase-01 :ARG0 s2 :ARG1 (a3 / activity-06 :ARG0 (p5 / protein :name (n8 / name :op1 "Gal4-Elk1") :ARG1-of (b / block-01 :ARG0 (a4 / and :op1 (o / overexpress-01 :ARG1 (p6 / protein :ARG2-of (m3 / mutate-01 :mod "-/-"))) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (k / kinase))))) :ARG1-of (s3 / stimulate-01 :ARG0 (e5 / express-03 :ARG2 (e6 / enzyme :name (n9 / name :op1 "B-Raf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :xref (x5 / xref :value "UNIPROT:LEG1_HUMAN" :prob "0.223")) :ARG1 (t2 / transcribe-01))))) # ::id bel_pmid_1208_9357.26116 # ::date 2015-04-28T02:24:41 # ::file bel_pmid_1208_9357_26116.txt # ::snt CRH and cAMP induce Nur77 and Nurr1 expression and transcription at the NurRE site by protein kinase A (PKA) and calcium-dependent and -independent mechanisms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / induce-01 :ARG0 (a / and :op1 (s / small-molecule :name (n / name :op1 "CRH") :xref (x4 / xref :value "PUBCHEM:16130996" :prob "9.430335")) :op2 (s2 / small-molecule :name (n2 / name :op1 "cAMP") :xref (x3 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :ARG2 (a4 / and :op1 (e / express-03 :ARG2 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "Nur77") :xref (x1 / xref :value "UNIPROT:NR4A1_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n4 / name :op1 "Nurr1") :xref (x2 / xref :value "UNIPROT:NR4A2_HUMAN" :prob "0.602")))) :op2 (t / transcribe-01 :ARG0 (a3 / and :op1 (e2 / enzyme :name (n6 / name :op1 "protein" :op2 "kinase" :op3 "A") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393")) :op2 (m / mechanism :ARG0-of (d / depend-01 :ARG1 (c / calcium))) :op3 (m2 / mechanism :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 (c2 / calcium)))) :ARG1 a2 :location (p / protein-segment :name (n5 / name :op1 "NurRE"))))) # ::id bel_pmid_1210_1242.29522 # ::date 2015-04-27T12:13:10 # ::file bel_pmid_1210_1242_29522.txt # ::snt The levels of collagen alpha1 (I), alpha1 (III), and fibronectin mRNAs were reduced in 1-day wounds of Nrf2 knockout mice compared to control littermates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / reduce-01 :ARG1 (a / and :op1 (l2 / level :quant-of (p2 / protein :name (n3 / name :op1 "collagen" :op2 "alpha1(I)"))) :op2 (l3 / level :quant-of (p3 / protein :name (n / name :op1 "alpha1(III)"))) :op3 (l4 / level :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA") :mod (f / fibronectin)))) :location (w / wound-01 :ARG1 (m / mouse :ARG1-of (k / knock-out-03 :ARG0 (p / protein :name (n2 / name :op1 "Nrf2") :xref (x / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602")))) :age (t / temporal-quantity :quant "1" :unit (d / day)) :compared-to (l / littermate :ARG1-of (c / control-01)))) # ::id bel_pmid_1210_1242.29526 # ::date 2015-04-27T12:37:21 # ::file bel_pmid_1210_1242_29526.txt # ::snt Interestingly, the normally observed induction of IL-1beta and TNF-alpha expression (22) was delayed in the knockout mice. The levels of IL-1beta mRNA were 50% lower in the 1-day wounds of Nrf2-/- mice than for control littermates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m2 / multi-sentence :snt1 (d2 / delay-01 :ARG1 (i / induce-01 :ARG2 (e / express-03 :ARG2 (a / and :op1 (p4 / protein :name (n5 / name :op1 "IL-1beta") :xref (x2 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :op2 (p5 / protein :name (n6 / name :op1 "TNF-alpha") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :ARG1-of (o / observe-01 :ARG1-of (n4 / normal-02)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "22")))) :ARG2-of (i2 / interest-01) :location (m5 / mouse :ARG2-of (m6 / mutate-01 :mod "+/-"))) :snt2 (l2 / low-04 :ARG1 (l / level :quant-of (n7 / nucleic-acid :name (n / name :op1 "mRNA") :mod (p2 / protein :name (n2 / name :op1 "IL-1beta") :xref (x / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")))) :degree (m / more) :quant (p / percentage-entity :value "50") :location (w / wound-01 :ARG1 (m3 / mouse :ARG1-of (k / knock-out-03 :ARG0 (p3 / protein :name (n3 / name :op1 "Nrf2") :xref (x1 / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602")))) :age (t / temporal-quantity :quant "1" :unit (d / day))) :compared-to (l3 / littermate :ARG1-of (c / control-01)))) # ::id bel_pmid_1210_1242.29528 # ::date 2015-04-26T07:11:09 # ::file bel_pmid_1210_1242_29528.txt # ::snt Expression of IL-6 was also lower in 1-day wounds of Nrf2 null mice, but in contrast to IL-1beta the mRNA of this cytokine was no longer detectable at later stages of repair. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (h / have-concession-91 :ARG1 (c2 / contrast-01 :ARG1 (p3 / protein :name (n3 / name :op1 "IL1-beta") :xref (x1 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.652")) :ARG2 (p4 / possible-01 :ARG1 (d2 / detect-01 :ARG1 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA") :poss "p") :time (n6 / no-longer) :time (s / stage :mod (l / late :degree (m3 / more)) :subevent-of (r2 / repair-01))))) :ARG2 (l2 / low-04 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :degree (m / more) :mod (a / also) :location (w / wound-01 :ARG1 (m2 / mouse :mod (p2 / protein :name (n2 / name :op1 "Nrf2") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602"))) :age (t / temporal-quantity :quant "1" :unit (d / day))))) # ::id bel_pmid_1210_1242.29532 # ::date 2015-04-24T10:28:50 # ::file bel_pmid_1210_1242_29532.txt # ::snt Indeed, TGF-beta1 mRNA was present at lower levels in unwounded back skin and in 1-day wounds of Nrf2-/- mice (Fig.7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (p3 / present-02 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA") :mod (p / protein :name (n3 / name :op1 "TGF-beta1") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.693")) :quant (l / level :ARG1-of (l2 / low-04 :degree (m / more)))) :ARG2 (a2 / and :op1 (s / skin :location (b2 / back) :ARG1-of (w / wound-01 :polarity "-")) :op2 (w2 / wound-01 :ARG1 (m2 / mouse :mod (p2 / protein :name (n / name :op1 "Nrf2") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602")) :age (t / temporal-quantity :quant "1" :unit (d / day))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7")) :mod (i / indeed)) # ::id bel_pmid_1210_1242.29534 # ::date 2015-04-24T10:41:23 # ::file bel_pmid_1210_1242_29534.txt # ::snt Expression of VEGF, a major regulator of angiogenesis, was also reduced in nonwounded skin and in 1-day wounds of Nrf2 null mice (Fig.7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (r2 / reduce-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "VEGF") :ARG0-of (r / regulate-01 :ARG1 (a4 / angiogenesis) :ARG1-of (m3 / major-02)) :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003"))) :mod (a2 / also) :location (a3 / and :op1 (s / skin :ARG1-of (w / wound-01 :polarity "-")) :op2 (m / mouse :mod (p2 / protein :name (n3 / name :op1 "Nrf2") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602")) :age (t / temporal-quantity :quant "1" :unit (d / day)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7"))) # ::id bel_pmid_1211_0143.268 # ::date 2015-04-26T05:25:35 # ::file bel_pmid_1211_0143_268.txt # ::snt binding of Il6 to Il6R induces homodimerization ofgp130, activating JAK associated with gp130 at Box1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / induce-01 :ARG0 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Il6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG2 (p2 / protein :name (n2 / name :op1 "Il6R") :xref (x / xref :value "UNIPROT:IL6RA_HUMAN" :prob "0.653"))) :ARG2 (h2 / homodimerize-01 :ARG1 (p3 / protein :name (n3 / name :op1 "gp130") :xref (x1 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))) :ARG0-of (a / activate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "JAK") :ARG1-of (a2 / associate-01 :ARG2 p3 :location (p5 / protein-segment :name (n5 / name :op1 "Box1") :part-of p3)) :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")))) # ::id bel_pmid_1211_0143.20340 # ::date 2015-04-26T06:48:31 # ::file bel_pmid_1211_0143_20340.txt # ::snt in Il6 signal cascade, the SHP2 interaction site of gp130 has also been shown to be a Socs3 contact site so that Socs3 may compete for the SHP2-gp130 interaction site # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (s / show-01 :ARG1 (p5 / protein-segment :location-of (i / interact-01 :ARG1 (e / enzyme :name (n / name :op1 "SHP2") :xref (x3 / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673"))) :domain (p6 / protein-segment :ARG0-of (c / contact-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Socs3") :purpose (p3 / possible-01 :ARG1 (c2 / compete-01 :ARG0 p2 :ARG1 p5)) :xref (x / xref :value "UNIPROT:SOCS3_HUMAN" :prob "0.604")))) :part-of (p / protein :name (n2 / name :op1 "gp130") :xref (x2 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))) :location (c3 / cascade :mod (s2 / signal-07 :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :mod (a / also)) # ::id bel_pmid_1211_0143.28372 # ::date 2015-04-26T08:13:52 # ::file bel_pmid_1211_0143_28372.txt # ::snt nonreceptor tyrosine kinases, such as Btk, Tec, Fes, and Hck are activated through the Il6R receptor # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG0 (r / receptor :name (n / name :op1 "IL-6R")) :ARG1 (e5 / enzyme :name (n2 / name :op1 "nonreceptor" :op2 "tyrosine" :op3 "kinase") :example (a3 / and :op1 (k / kinase :name (n3 / name :op1 "Btk") :xref (x / xref :value "UNIPROT:BTK_HUMAN" :prob "0.604")) :op2 (k2 / kinase :name (n4 / name :op1 "Tec") :xref (x2 / xref :value "UNIPROT:Q14219_HUMAN" :prob "0.671")) :op3 (k3 / kinase :name (n5 / name :op1 "Fes") :xref (x1 / xref :value "UNIPROT:FES_HUMAN" :prob "0.603")) :op4 (k4 / kinase :name (n6 / name :op1 "Hck") :xref (x3 / xref :value "UNIPROT:HCK_HUMAN" :prob "0.604"))) :xref (x4 / xref :value "UNIPROT:TNK1_HUMAN" :prob "0.342"))) # ::id bel_pmid_1211_0143.28412 # ::date 2015-04-26T08:19:58 # ::file bel_pmid_1211_0143_28412.txt # ::snt tyrosine phosphorylation of SHP2, a phosphotyrosine phosphatase, and that of STAT3 depend on the second tyrosine residue Y2 from the membrane in gp130 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (d / depend-01 :ARG0 (a / and :op1 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (e / enzyme :name (n4 / name :op1 "SHP2") :ARG1-of (m / mean-01 :ARG2 (p3 / phosphatase :mod (p5 / phosphotyrosine))) :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (p4 / phosphorylate-01 :ARG1 (a4 / amino-acid :name (n7 / name :op1 "tyrosine") :part-of (p6 / protein :name (n5 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :ARG1 (r / residue :name (n2 / name :op1 "Y2") :mod (a2 / amino-acid :name (n / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :mod (o / ordinal-entity :value "2") :location (m2 / membrane :part-of (p2 / protein :name (n3 / name :op1 "gp130") :xref (x / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")) :xref (x3 / xref :value "GO:0016020" :prob "0.8")))) # ::id bel_pmid_1211_0143.32746 # ::date 2015-04-27T11:48:31 # ::file bel_pmid_1211_0143_32746.txt # ::snt presence of type 1 Il6R, which is a binding site for NF-IL-6, IL-6DBP, and CEBPbeta has been confirmed in the genes for CRP, hemoplexin A and haptoglobin binding activity of NF-IL-6 is probably induced by Il6 through the increased expression of the NF-IL-6 gene # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (c / confirm-01 :ARG1 (p3 / present-02 :ARG1 (p4 / protein :name (n3 / name :op1 "IL-6R") :ARG1-of (t / type-03 :mod "1") :domain (p8 / protein-segment :ARG1-of (b2 / bind-01 :ARG2 (a3 / and :op1 (p5 / protein :name (n / name :op1 "NF-IL-6") :xref (x6 / xref :value "UNIPROT:CEBPD_HUMAN" :prob "0.252")) :op2 (p6 / protein :name (n4 / name :op1 "IL-6DBP") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.233")) :op3 (p7 / protein :name (n5 / name :op1 "CEBPbeta") :xref (x4 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.673"))))) :xref (x5 / xref :value "UNIPROT:IL6RA_HUMAN" :prob "0.673"))) :ARG2 (a / and :op1 (p9 / protein :name (n6 / name :op1 "CRP") :xref (x7 / xref :value "UNIPROT:CRP_HUMAN" :prob "1.003")) :op2 (p10 / protein :name (n7 / name :op1 "hemoplexin" :op2 "A") :xref (x1 / xref :value "UNIPROT:HEMO_HUMAN" :prob "0.302")) :op3 (p11 / protein :name (n9 / name :op1 "haptoglobin") :xref (x2 / xref :value "UNIPROT:HPT_HUMAN" :prob "0.702"))) :location (g2 / gene)) :snt2 (i / induce-01 :ARG0 (p2 / protein :name (n10 / name :op1 "Il6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG2 (a2 / activity-06 :ARG0 (p12 / protein :name (n8 / name :op1 "NF-IL-6") :xref (x8 / xref :value "UNIPROT:CEBPD_HUMAN" :prob "0.252")) :ARG1 (b / bind-01)) :mod (p / probable) :manner (e / express-03 :ARG2 (g / gene :ARG0-of (e2 / encode-01 :ARG1 p12)) :ARG1-of (i2 / increase-01)))) # ::id bel_pmid_1211_0143.35664 # ::date 2015-04-27T12:38:01 # ::file bel_pmid_1211_0143_35664.txt # ::snt binding of Il6 to Il6R induces homodimerization ofgp130, activating JAK associated with gp130 at Box1.......Our group and others found that JAK1, JAK2, and Tky-2 are activated and are tyrosine-phosphorylated in response to IL-6, CNTF, LIF, and OSM [14] # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (i / induce-01 :ARG0 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Il6") :xref (x9 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG2 (p2 / protein :name (n2 / name :op1 "Il6R") :xref (x5 / xref :value "UNIPROT:IL6RA_HUMAN" :prob "0.653"))) :ARG2 (h / homodimerize-01 :ARG1 (p3 / protein :name (n3 / name :op1 "gp130") :xref (x6 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))) :ARG0-of (a / activate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "JAK") :ARG1-of (a2 / associate-01 :ARG2 p3 :location (p5 / protein-segment :name (n5 / name :op1 "Box1"))) :xref (x4 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")))) :snt2 (f / find-01 :ARG0 (a3 / and :op1 (g / group :poss (w / we)) :op2 (g2 / group :mod (o / other))) :ARG1 (a4 / and :op1 (a5 / activate-01 :ARG1 (a6 / and :op1 (e3 / enzyme :name (n6 / name :op1 "JAK1") :xref (x3 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n7 / name :op1 "JAK2") :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :op3 (p9 / protein :name (n8 / name :op1 "Tky2")))) :op2 (p6 / phosphorylate-01 :ARG1 (a9 / and :op1 (a7 / amino-acid :name (n9 / name :op1 "tyrosine") :part-of e3 :xref (x12 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a10 / amino-acid :name (n14 / name :op1 "tyrosine") :part-of e4 :xref (x10 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op3 (a11 / amino-acid :name (n15 / name :op1 "tyrosine") :part-of (e / enzyme :name (n16 / name :op1 "Tky-2")) :xref (x11 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG2-of (r / respond-01 :ARG1 (a8 / and :op1 (p10 / protein :name (n10 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p11 / protein :name (n11 / name :op1 "CNTF") :xref (x1 / xref :value "UNIPROT:CNTF_HUMAN" :prob "1.003")) :op3 (p12 / protein :name (n12 / name :op1 "LIF") :xref (x8 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :op4 (p7 / protein :name (n13 / name :op1 "OSM") :xref (x7 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")))))) :ARG1-of (d2 / describe-01 :ARG0 (p14 / publication :ARG1-of (c2 / cite-01 :ARG2 "14"))))) # ::id bel_pmid_1211_0143.38318 # ::date 2015-04-26T06:48:54 # ::file bel_pmid_1211_0143_38318.txt # ::snt Socs1 is essential for inhibition of IFN-gamma-induced inhibition of STAT6 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (e / essential :domain (p / protein :name (n / name :op1 "Socs1") :xref (x2 / xref :value "UNIPROT:SOCS1_HUMAN" :prob "0.604")) :purpose (i / inhibit-01 :ARG1 (i2 / inhibit-01 :ARG1 (p3 / protein :name (n3 / name :op1 "STAT6") :xref (x1 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")) :ARG2-of (i3 / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "IFN-gamma") :xref (x / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")))))) # ::id bel_pmid_1211_0143.38516 # ::date 2015-04-24T06:57:38 # ::file bel_pmid_1211_0143_38516.txt # ::snt Socs1 inhibits activation of STAT6 by Il4 stimulation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 1, 2015 (i / inhibit-01 :ARG0 (p3 / protein :name (n / name :op1 "Socs1") :xref (x / xref :value "UNIPROT:SOCS1_HUMAN" :prob "0.604")) :ARG1 (a / activate-01 :ARG0 (s / stimulate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IL-4") :xref (x2 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003"))) :ARG1 (p / protein :name (n2 / name :op1 "STAT6") :xref (x1 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")))) # ::id bel_pmid_1211_0143.38548 # ::date 2015-04-24T07:11:00 # ::file bel_pmid_1211_0143_38548.txt # ::snt Il6 activates STAT1 and STAT5 in addition to STAT3 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Apr 28, 2015 (a / activate-01 :ARG0 (p / protein :name (n5 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "STAT1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n3 / name :op1 "STAT5") :xref (x1 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n4 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) # ::id bel_pmid_1214_7685.34134 # ::date 2015-04-24T09:59:30 # ::file bel_pmid_1214_7685_34134.txt # ::snt the down-regulation of D1 and D2 cyclins by OSM was mediated by STAT3 but not by SHP2/Ras STAT3 activation is necessary and sufficient for down-regulation of D1 and D2 cyclins in fetal hepatocytes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (m3 / multi-sentence :snt1 (c4 / contrast-01 :ARG1 (m / mediate-01 :ARG0 (p7 / protein :name (n10 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1 (d2 / downregulate-01 :ARG1 (a5 / and :op1 (p5 / protein :name (n8 / name :op1 "D1" :op2 "cyclin")) :op2 (p6 / protein :name (n9 / name :op1 "D2" :op2 "cyclin"))) :ARG2 (e / enzyme :name (n4 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")))) :ARG2 (m2 / mediate-01 :polarity "-" :ARG0 (p4 / pathway :name (n7 / name :op1 "SHP2/Ras")) :ARG1 d2)) :snt2 (a / and :op1 (n / need-01 :ARG0 (d / downregulate-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "D1" :op2 "cyclin")) :op2 (p3 / protein :name (n3 / name :op1 "D2" :op2 "cyclin")) :location (h / hepatocyte :mod (f / fetus)))) :ARG1 (a4 / activate-01 :ARG1 (p / protein :name (n6 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :op2 (s / suffice-01 :ARG0 a2 :ARG1 d))) # ::id bel_pmid_1217_7059.29876 # ::date 2015-04-24T13:12:00 # ::file bel_pmid_1217_7059_29876.txt # ::snt Substitution of Arg-238, equivalent to conserved Arg in the 14-3-3 binding motif, with Glu (R238E) decreased 14-3-3theta binding to PDK1 (Fig. 3 C, upper panel, lane 4). In contrast, substitution of Val-243 with Pro (V243P), a residue conserved in many 14-3-3 targets, such as Raf-1 and Bad (Fig.3 A), dramatically increased the amount of 14-3-3theta bound to PDK1 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (d / decrease-01 :ARG0 (s / substitute-01 :value "R238E" :ARG1 (a8 / amino-acid :name (n14 / name :op1 "glutamic" :op2 "acid") :xref (x11 / xref :value "PUBCHEM:611" :prob "7.558843")) :ARG3 (a / amino-acid :mod "238" :name (n2 / name :op1 "arginine") :ARG1-of (e / equal-01 :ARG2 (a2 / amino-acid :name (n3 / name :op1 "arginine") :ARG1-of (c / conserve-01 :location (p9 / protein-segment :ARG1-of (b2 / bind-01 :ARG2 (p / protein :name (n / name :op1 "14-3-3") :xref (x7 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))))) :xref (x8 / xref :value "PUBCHEM:232" :prob "11.348415"))) :xref (x12 / xref :value "PUBCHEM:232" :prob "11.348415"))) :ARG1 (b3 / bind-01 :ARG1 (p2 / protein :name (n5 / name :op1 "14-3-3theta") :xref (x / xref :value "UNIPROT:1433T_HUMAN" :prob "0.253")) :ARG2 (e3 / enzyme :name (n6 / name :op1 "PDK1") :xref (x3 / xref :value "UNIPROT:PDK1_HUMAN" :prob "1.003"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3C") :location (l / lane :mod "4" :location (p8 / panel :mod (u2 / upper))))) :snt2 (c2 / contrast-01 :ARG2 (i / increase-01 :ARG0 (s2 / substitute-01 :value "V243P" :ARG1 (a4 / amino-acid :name (n7 / name :op1 "proline") :xref (x10 / xref :value "PUBCHEM:614" :prob "10.45396")) :ARG2 (a5 / amino-acid :mod "243" :name (n8 / name :op1 "valine") :ARG1-of (m3 / mean-01 :ARG2 (r / residue :ARG1-of (c3 / conserve-01 :location (m2 / molecular-physical-entity :ARG1-of (t / target-01 :ARG0 (p4 / protein :name (n9 / name :op1 "14-3-3") :xref (x5 / xref :value "UNIPROT:OXDA_HUMAN" :prob "0.572"))) :example (a6 / and :op1 (e2 / enzyme :name (n10 / name :op1 "Raf-1") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (p5 / protein :name (n11 / name :op1 "Bad") :xref (x1 / xref :value "UNIPROT:BAD_HUMAN" :prob "0.604"))) :quant (m4 / many))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "3A")))) :xref (x9 / xref :value "PUBCHEM:6287" :prob "10.890044"))) :ARG1 (a7 / amount :quant-of (p6 / protein :name (n12 / name :op1 "14-3-3theta") :ARG1-of (b4 / bind-01 :ARG2 (e4 / enzyme :name (n13 / name :op1 "PDK1") :xref (x2 / xref :value "UNIPROT:PDK1_HUMAN" :prob "1.003"))) :xref (x6 / xref :value "UNIPROT:1433T_HUMAN" :prob "0.253"))) :manner (d4 / dramatic)))) # ::id bel_pmid_1217_7059.29878 # ::date 2015-04-24T14:04:14 # ::file bel_pmid_1217_7059_29878.txt # ::snt Co-immunoprecipitation analysis indicated that mutation at Ser-241 impairs the PDK1 binding ability for 14-3-3theta and 14-3-3eta (Fig. 3 B, upper panel, lane 3, and data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (a / analyze-01 :manner (c / coimmunoprecipitate-01)) :ARG1 (i2 / impair-01 :ARG0 (m / mutate-01 :ARG1 (a2 / amino-acid :mod "241" :name (n2 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (c2 / capable-01 :ARG1 (e / enzyme :name (n3 / name :op1 "PDK1") :xref (x1 / xref :value "UNIPROT:PDK1_HUMAN" :prob "1.003")) :ARG2 (b2 / bind-01 :ARG1 e :ARG2 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "14-3-3theta") :xref (x / xref :value "UNIPROT:1433T_HUMAN" :prob "0.253")) :op2 (p4 / protein :name (n5 / name :op1 "14-3-3eta") :xref (x2 / xref :value "UNIPROT:1433E_HUMAN" :prob "0.303")))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "3B" :location (l / lane :mod "3" :location (p5 / panel :mod (u2 / upper)))) :op2 (d2 / data :ARG1-of (s / show-01 :polarity "-"))))) # ::id bel_pmid_1219_8646.11798 # ::date 2015-04-25T00:40:31 # ::file bel_pmid_1219_8646_11798.txt # ::snt Hepatic expression of Ccnd1, cMyc, IL-1r1, and IL-6r was induced in wild-type mice, but not Pparalpha-null mice, after acute exposure to the potent Pparalpha agonist Wy-14,643, indicating a role for Pparalpha in regulating the expression of these genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG2 (e / express-03 :ARG2 (a / and :op1 (g / gene :name (n / name :op1 "Ccnd1") :xref (x4 / xref :value "UNIPROT:CCND1_HUMAN" :prob "0.604")) :op2 (g2 / gene :name (n2 / name :op1 "cMyc") :xref (x2 / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.631")) :op3 (g3 / gene :name (n3 / name :op1 "IL-1r1") :xref (x1 / xref :value "UNIPROT:IL1R1_HUMAN" :prob "0.652")) :op4 (g4 / gene :name (n4 / name :op1 "IL-6r") :xref (x / xref :value "UNIPROT:IL6RA_HUMAN" :prob "0.593"))) :mod (h / hepatic)) :location (m / mouse :mod (w / wild-type) :ARG1-of (c / contrast-01 :ARG2 (m2 / mouse :polarity "-" :ARG3-of (e4 / express-03 :ARG2 (p5 / protein :name (n6 / name :op1 "Pparalpha") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x5 / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.653")))))) :time (a2 / after :op1 (e2 / expose-01 :ARG2 (a4 / agonist :name (n7 / name :op1 "Wy-14,643") :mod (p6 / potent) :mod (p7 / protein :name (n8 / name :op1 "Pparalpha") :xref (x3 / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.653"))) :mod (a3 / acute) :ARG0-of (i2 / indicate-01 :ARG1 (r / role :topic (r2 / regulate-01 :ARG0 p7 :ARG1 (e3 / express-03 :ARG2 a))))))) # ::id bel_pmid_1220_4103.24772 # ::date 2015-04-25T02:16:02 # ::file bel_pmid_1220_4103_24772.txt # ::snt Jak1 phosphorylation was reduced in wildtype indivduals after Il13 treatement, implying that SHP-2 is responsible for this effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reduce-01 :ARG1 (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "Jak1") :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.604"))) :location (i / individual :mod (w / wild-type)) :time (a / after :op1 (t / treat-04 :ARG2 (p3 / protein :name (n2 / name :op1 "Il13") :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "0.654")))) :ARG0-of (i2 / imply-01 :ARG1 (r2 / responsible-01 :ARG0 (p2 / protein :name (n3 / name :op1 "SHP-2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :ARG1 (a2 / affect-01 :ARG0 p2 :ARG2 "r")))) # ::id bel_pmid_1220_4103.27950 # ::date 2015-04-25T02:40:16 # ::file bel_pmid_1220_4103_27950.txt # ::snt as for Jak1, the phosphoryaltions of Tyk2 and IRS-2 were reduced after IL13 stimulaiton in wildtype cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (r / reduce-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Tyk2") :xref (x1 / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n2 / name :op1 "IRS-2") :xref (x / xref :value "UNIPROT:IRS2_HUMAN" :prob "1.003")))) :topic (e2 / enzyme :name (n3 / name :op1 "Jak1") :xref (x3 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.604")) :time (a2 / after :op1 (s / stimulate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "IL13") :xref (x2 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.004")) :location (c / cell :mod (w / wild-type))))) # ::id bel_pmid_1220_4103.27958 # ::date 2015-04-25T02:48:28 # ::file bel_pmid_1220_4103_27958.txt # ::snt Results In cytoplasmic extracts, phosphoryalation of the p85alpha subunit of PI3-kinase was markedly increased after stimulation with Il13 in both groups of probands. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :name (n / name :op1 "p85alpha") :part-of (e / enzyme :name (n2 / name :op1 "PI3-kinase") :xref (x / xref :value "UNIPROT:PK3C3_HUMAN" :prob "0.323")))) :manner (m / marked) :time (a / after :op1 (s / stimulate-01 :ARG2 (p3 / protein :name (n3 / name :op1 "Il13") :xref (x1 / xref :value "UNIPROT:IL13_HUMAN" :prob "0.654")) :location (g / group :mod (b / both) :ARG2-of (i2 / include-91 :ARG1 (p4 / proband))))) :ARG2-of (r / result-01) :location (m2 / molecular-physical-entity :ARG1-of (e2 / extract-01 :ARG2 (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8"))))) # ::id bel_pmid_1221_8157.20330 # ::date 2015-04-25T03:11:24 # ::file bel_pmid_1221_8157_20330.txt # ::snt when Il6 and Il6R were combined, significant stimulation of both mineral and matrix release from bone explants was noted # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (n / note-02 :ARG1 (s / stimulate-01 :ARG1 (r / release-01 :ARG1 (a / and :op1 (m / mineral) :op2 (m2 / matrix)) :ARG2 (e / explant :mod (b / bone))) :ARG1-of (s2 / significant-02)) :time (c / combine-01 :ARG1 (p / protein :name (n2 / name :op1 "Il6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG2 (p2 / protein :name (n3 / name :op1 "Il6R") :xref (x / xref :value "UNIPROT:IL6RA_HUMAN" :prob "0.653")))) # ::id bel_pmid_1221_8157.20336 # ::date 2015-04-25T03:25:27 # ::file bel_pmid_1221_8157_20336.txt # ::snt Il6 plus Il6R enhanced the expression of RANKL and OPG in calvarial bones, but decreased RANK expression # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Apr 25, 2015 (c / contrast-01 :ARG1 (e / enhance-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "Il6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :op2 (p2 / protein :name (n2 / name :op1 "Il6R") :xref (x / xref :value "UNIPROT:IL6RA_HUMAN" :prob "0.653"))) :ARG1 (e2 / express-03 :ARG2 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "RANKL") :xref (x2 / xref :value "UNIPROT:TNF11_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n4 / name :op1 "OPG") :xref (x1 / xref :value "UNIPROT:TR11B_HUMAN" :prob "1.002")))) :location (b / bone :mod (c2 / calvarial))) :ARG2 (d / decrease-01 :ARG0 a :ARG1 (e3 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "RANK") :xref (x3 / xref :value "UNIPROT:TNR11_HUMAN" :prob "1.002"))))) # ::id bel_pmid_1221_8157.28344 # ::date 2015-04-25T03:37:06 # ::file bel_pmid_1221_8157_28344.txt # ::snt Il6, leukemia inhibitory factor [LIF}, and oncostatin M [OSM] are Il6-type cytokines that stimulate osteoclast formation and function # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (t2 / type-03 :ARG1 (a3 / and :op1 (p / protein :name (n2 / name :op1 "Il6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :op2 (p2 / protein :name (n3 / name :op1 "leukemia" :op2 "inhibitory" :op3 "factor") :xref (x / xref :value "UNIPROT:LIF_HUMAN" :prob "0.702")) :op3 (p3 / protein :name (n4 / name :op1 "oncostatin" :op2 "M") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "0.682"))) :ARG2 (c / cytokine :ARG0-of (s / stimulate-01 :ARG1 (a2 / and :op1 (f / form-01 :ARG1 (o / osteoclast)) :op2 (f2 / function-01 :ARG0 o))) :mod p)) # ::id bel_pmid_1221_8157.29756 # ::date 2015-04-25T04:19:56 # ::file bel_pmid_1221_8157_29756.txt # ::snt OSM also stimulated Ca release and enhanced the mRNA expression of RANKL and OPG in mouse calcaria, but have no effect on the expression of RANK # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (c / contrast-01 :ARG1 (a / and :op1 (s2 / stimulate-01 :ARG0 (p / protein :name (n2 / name :op1 "OSM") :xref (x3 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (r / release-01 :ARG1 (c3 / calcium)) :mod (a2 / also)) :op2 (e / enhance-01 :ARG0 p :ARG1 (e2 / express-03 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "mRNA")) :ARG2 (a3 / and :op1 (p2 / protein :name (n4 / name :op1 "RANKL") :xref (x / xref :value "UNIPROT:TNF11_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n5 / name :op1 "OPG") :xref (x1 / xref :value "UNIPROT:TR11B_HUMAN" :prob "1.002"))) :ARG3 (c2 / calcaria :mod (m2 / mouse))))) :ARG2 (a4 / affect-01 :polarity "-" :ARG0 p :ARG1 (e3 / express-03 :ARG2 (p4 / protein :name (n6 / name :op1 "RANK") :xref (x2 / xref :value "UNIPROT:TNR11_HUMAN" :prob "1.002"))))) # ::id bel_pmid_1221_9085.28406 # ::date 2015-04-25T04:35:46 # ::file bel_pmid_1221_9085_28406.txt # ::snt functions of the 2 major signaling pathways, the signal transducers and activators of transcription 1 and 3 [STAT1/3] and the Src-homology tyrosine phosphatase 2 [SHP2]-Ras-ERK [Ptpn11], emanating from the common signal transducer, gp130, in the gastrointestinal tract # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (f2 / function-01 :ARG0 (p / pathway :quant "2" :ARG0-of (s / signal-07) :ARG1-of (m / major-02) :example (a2 / and :op1 (a / and :op1 (p3 / pathway :name (n2 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "1")) :op2 (p6 / pathway :name (n5 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "3"))) :op2 (p4 / pathway :name (n3 / name :op1 "Src-homology" :op2 "tyrosine" :op3 "phosphatase" :op4 "2-Ras-ERK")))) :ARG1-of (e / emanate-01 :ARG2 (m3 / molecular-physical-entity :ARG2-of (t / transduce-01 :ARG1 (s2 / signal-07) :ARG1-of (m2 / mean-01 :ARG2 (p2 / protein :name (n / name :op1 "gp130") :xref (x / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")))) :mod (c / common)) :location (t3 / tract :mod (g / gastrointestinal)))) # ::id bel_pmid_1222_0517.8134 # ::date 2015-04-25T05:15:59 # ::file bel_pmid_1222_0517_8134.txt # ::snt Sp1-mediated transcription is one of the mechanisms, which is responsible for BMP2-induced up-regulation of Erk2 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (t2 / transcribe-01 :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n / name :op1 "Sp1") :xref (x1 / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001"))) :ARG1-of (i / include-91 :ARG2 (m2 / mechanism)) :ARG0-of (r / responsible-01 :ARG1 (e / express-03 :ARG2 (u / upregulate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "BMP2") :xref (x / xref :value "UNIPROT:BMP2_HUMAN" :prob "1.004"))))))) # ::id bel_pmid_1222_0517.25504 # ::date 2015-04-25T07:05:16 # ::file bel_pmid_1222_0517_25504.txt # ::snt increased Erk2 protein level under BMP2 inducement comes from BMP2-up-regulated Erk2 mRNA expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / come-01 :ARG1 (l / level :quant-of (e3 / enzyme :name (n / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")) :ARG1-of (i / increase-01) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "BMP2") :xref (x / xref :value "UNIPROT:BMP2_HUMAN" :prob "1.004")))) :ARG3 (e / express-03 :ARG2 (n3 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG1-of (u / upregulate-01 :ARG2 p2) :ARG0-of (e2 / encode-01 :ARG1 e3)))) # ::id bel_pmid_1222_6756.17890 # ::date 2015-04-25T11:00:20 # ::file bel_pmid_1222_6756_17890.txt # ::snt NIH3T3 cells expressing either Raf :ER-DD or Raf : ER-YY synthesized RALT upon stimulation with Tamoxifen for 4 ± 8 h in serum-deprived medium (Figure 4b). The effect of tamoxifen was as strong as serum stimulation and was reverted by the administra- tion of U0126 (Figure 4b) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (s2 / synthesize-01 :ARG0 (c / cell-line :name (n3 / name :op1 "NIH3T3") :ARG3-of (e2 / express-03 :ARG2 (o / or :op1 (p2 / protein :name (n / name :op1 "Raf:ER-DD")) :op2 (p3 / protein :name (n4 / name :op1 "Raf:ER-YY"))))) :ARG1 (p / protein :name (n8 / name :op1 "RALT") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.263")) :time (s3 / stimulate-01 :ARG2 (s9 / small-molecule :name (n9 / name :op1 "tamoxifen") :xref (x1 / xref :value "PUBCHEM:2733526" :prob "14.823483")) :duration (b / between :op1 (t / temporal-quantity :quant "4" :unit (h / hour)) :op2 (t2 / temporal-quantity :quant "8" :unit (h2 / hour))) :location (m5 / medium :ARG1-of (d / deprive-01 :ARG2 (s4 / serum)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4b"))) :snt2 (a / and :op1 (s5 / strong-02 :ARG1 (a2 / affect-01 :ARG0 (s7 / small-molecule :name (n10 / name :op1 "tamoxifen") :xref (x2 / xref :value "PUBCHEM:2733526" :prob "14.823483"))) :degree (e3 / equal) :compared-to (s6 / stimulate-01 :ARG0 (s8 / serum))) :op2 (r / revert-01 :ARG0 (a3 / administrate-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "U0126") :xref (x3 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 a2) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "4b")))) # ::id bel_pmid_1222_6756.17894 # ::date 2015-04-25T10:26:29 # ::file bel_pmid_1222_6756_17894.txt # ::snt Ablation of RALT expression by MEK- 1 inhibitors is caused by suppression of RALT transcription, as indicated by the Northern blot analysis presented in Figure 3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (c2 / cause-01 :ARG0 (s / suppress-01 :ARG1 (t2 / transcribe-01 :ARG1 "p")) :ARG1 (a / ablate-01 :ARG1 (e3 / express-03 :ARG2 (p / protein :name (n3 / name :op1 "RALT") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.263"))) :ARG3 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK-1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.673"))))) :ARG1-of (i3 / indicate-01 :ARG0 (a2 / analyze-01 :instrument (t3 / thing :name (n4 / name :op1 "Northern" :op2 "blot")) :ARG1-of (p2 / present-01 :location (f / figure :mod "3"))))) # ::id bel_pmid_1222_6756.26554 # ::date 2015-04-25T11:52:45 # ::file bel_pmid_1222_6756_26554.txt # ::snt Upon stimulation with EGF (0.3 ng/ml) or bFGF (0.3 ng/ml) about 20% of uninjected EGFR/ErbB-2 cells entered S phase (data not shown). We observed a similar rate of entrance into S phase when counting cells microinjected with a control antiserum (RAM, Figure 1e). Cells micro- injected with anti-RALT antibodies and stimulated with EGF progressed to S phase at a frequency which was 2.8-fold higher than control cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / multi-sentence :snt1 (e / enter-01 :ARG0 (a / about :op1 (p2 / percentage-entity :value "20" :quant-of (c3 / cell :ARG2-of (i / inject-01 :polarity "-") :mod (s4 / slash :op1 (e6 / enzyme :name (n8 / name :op1 "EGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e7 / enzyme :name (n9 / name :op1 "ErbB-2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.593")))))) :ARG1 (e4 / event :name (n10 / name :op1 "S" :op2 "phase")) :time (s / stimulate-01 :ARG2 (o / or :op1 (p3 / protein :name (n / name :op1 "EGF") :quant (c / concentration-quantity :quant "0.3" :unit (n2 / nanogram-per-milliliter)) :xref (x4 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (p5 / protein :name (n3 / name :op1 "bFGF") :quant (c2 / concentration-quantity :quant "0.3" :unit (n4 / nanogram-per-milliliter)) :xref (x5 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity "-")))) :snt2 (o2 / observe-01 :ARG0 (w / we) :ARG1 (r / rate :degree-of (e2 / enter-01 :ARG1 (e5 / event :name (n11 / name :op1 "S" :op2 "phase"))) :ARG1-of (r2 / resemble-01)) :time (c4 / count-01 :ARG1 (c5 / cell :ARG2-of (m2 / microinject-01 :ARG1 (a2 / antiserum :mod (c6 / control-01) :ARG1-of (l / label-01 :ARG2 (s5 / string-entity :value "RAM")))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1e"))) :snt3 (p4 / progress-01 :ARG1 (a4 / and :op1 (m3 / microinject-01 :ARG1 (a5 / antibody :ARG0-of (c10 / counter-01 :ARG1 (p9 / protein :name (n5 / name :op1 "RALT") :xref (x1 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.263")))) :ARG2 (c7 / cell)) :op2 (s3 / stimulate-01 :ARG1 c7 :ARG2 (p / protein :name (n7 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG4 (e3 / event :name (n6 / name :op1 "S" :op2 "phase")) :ARG1-of (h2 / have-frequency-91 :ARG2 (p6 / product-of :op1 "2.8") :ARG1-of (h / high-02) :compared-to (c8 / cell :mod (c9 / control-01))))) # ::id bel_pmid_1222_6756.26768 # ::date 2015-04-26T03:21:14 # ::file bel_pmid_1222_6756_26768.txt # ::snt We conclude that endogenous RALT protein behaves as a bonafide feedback inhibitor of the ErbB-2 kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / conclude-01 :ARG0 (w / we) :ARG1 (b / behave-01 :ARG0 (p / protein :name (n / name :op1 "RALT") :mod (m / monocot) :xref (x1 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.263")) :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ErbB-2" :op2 "kinase") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.203")) :mod (f / feedback :mod (b2 / bonafide)))))) # ::id bel_pmid_1222_6756.29724 # ::date 2015-04-26T03:28:58 # ::file bel_pmid_1222_6756_29724.txt # ::snt These observations were extended to HC-11 cells, a murine cell line derived from breast epithelium. In these cells TGF-a, an activator of EGFR, and HRG- 1b, which triggers ErbB-2/ErbB-3 dimers (Marte et al., 1995a,b), are able to induce RALT expression (Fiorentino et al., 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (e2 / extend-01 :ARG1 (t / thing :ARG1-of (o / observe-01) :mod (t2 / this)) :ARG4 (c / cell :name (n2 / name :op1 "HC-11") :ARG1-of (m2 / mean-01 :ARG2 (c3 / cell-line :mod (o4 / organism :name (n / name :op1 "Muridae")) :ARG1-of (d3 / derive-01 :ARG2 (e3 / epithelium :mod (b / breast))))))) :snt2 (p / possible-01 :ARG1 (i / induce-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n3 / name :op1 "TGF-a") :ARG0-of (a3 / activate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :xref (x3 / xref :value "UNIPROT:TGFA_HUMAN" :prob "0.632")) :op2 (p3 / protein :name (n5 / name :op1 "HRG-1b") :xref (x4 / xref :value "UNIPROT:HRG1_HUMAN" :prob "0.312")) :ARG0-of (t3 / trigger-01 :ARG1 (a6 / and :op1 (e / enzyme :name (n10 / name :op1 "ErbB-2") :xref (x5 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.593")) :op2 (e6 / enzyme :name (n11 / name :op1 "ErbB-3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "0.593")) :ARG3-of (d4 / dimerize-01)) :ARG1-of (d5 / describe-01 :ARG0 (a7 / and :op1 (p4 / publication-91 :li "a" :ARG0 (a4 / and :op1 (p5 / person :name (n7 / name :op1 "Marte")) :op2 (p6 / person :mod (o2 / other)))) :op2 (p12 / publication-91 :li "b" :ARG0 a4) :time (d / date-entity :year "1995"))))) :ARG2 (e5 / express-03 :ARG2 (p7 / protein :name (n8 / name :op1 "RALT") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.263"))) :ARG1-of (d6 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n9 / name :op1 "Fiorentino")) :op2 (p10 / person :mod (o3 / other))) :time (d2 / date-entity :year "2000"))) :location (c2 / cell :mod (t4 / this))))) # ::id bel_pmid_1223_7173.1150 # ::date 2015-04-26T04:17:21 # ::file bel_pmid_1223_7173_1150.txt # ::snt We tested if human coronary artery endothelial cells (HCAEC) may become a source of cytokine and adhesion molecule expression when stimulated with bacterial lipopolysaccharide (LPS). Analysis of HCAEC supernatants by ELISA identified enhanced secretion of IL-6, IL-8, and MCP-1 while # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (t / test-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (b / become-01 :mode "interrogative" :ARG1 (c / cell :mod (e3 / endothelium) :mod (a / artery :mod (c4 / coronary)) :mod (h / human)) :ARG2 (s / source-02 :ARG1 (e / express-03 :ARG2 (a5 / and :op1 (c2 / cytokine) :op2 (p5 / protein :name (n8 / name :op1 "adhesion" :op2 "molecule") :xref (x3 / xref :value "UNIPROT:AT1B2_HUMAN" :prob "0.362"))))) :time (s2 / stimulate-01 :ARG1 c :ARG2 (l / lipopolysaccharide :mod (b2 / bacteria)))))) :snt2 (i / identify-01 :ARG1 (a3 / analyze-01 :ARG1 (s3 / supernatant :mod (c3 / cell :name (n3 / name :op1 "HCAEC"))) :instrument (t2 / thing :name (n4 / name :op1 "ELISA"))) :ARG2 (s4 / secrete-01 :ARG1 (a4 / and :op1 (p2 / protein :name (n5 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n6 / name :op1 "IL-8") :xref (x1 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n7 / name :op1 "MCP-1") :xref (x2 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002"))) :ARG1-of (e2 / enhance-01)))) # ::id bel_pmid_1223_7173.1152 # ::date 2015-04-26T04:40:04 # ::file bel_pmid_1223_7173_1152.txt # ::snt IL-1beta and TNF-alpha but not IL-10. FACS analysis showed an LPS-induced upregulation of ICAM-1, VCAM, and ELAM-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "IL-1beta") :xref (x5 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :op2 (p2 / protein :name (n2 / name :op1 "TNF-alpha") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))) :ARG2 (p3 / protein :polarity "-" :name (n3 / name :op1 "IL-10") :xref (x1 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003"))) :snt2 (s / show-01 :ARG0 (a2 / analyze-01 :instrument (t / thing :name (n4 / name :op1 "FACS"))) :ARG1 (u / upregulate-01 :ARG1 (a3 / and :op1 (p4 / protein :name (n6 / name :op1 "ICAM-1") :xref (x3 / xref :value "UNIPROT:ICAM1_HUMAN" :prob "1.002")) :op2 (p5 / protein :name (n7 / name :op1 "VCAM") :xref (x4 / xref :value "UNIPROT:VCAM1_HUMAN" :prob "0.312")) :op3 (p6 / protein :name (n8 / name :op1 "ELAM-1") :xref (x2 / xref :value "UNIPROT:LYAM2_HUMAN" :prob "1.002"))) :ARG2-of (i / induce-01 :ARG0 (l / lipopolysaccharide))))) # ::id bel_pmid_1227_0932.7862 # ::date 2015-04-26T04:51:12 # ::file bel_pmid_1227_0932_7862.txt # ::snt SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p3 / phosphatase :domain (p / protein :name (n2 / name :op1 "SHP-2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :ARG1-of (i / involve-01 :ARG2 (d2 / dephosphorylate-01 :ARG1 (a2 / and :op1 (r2 / residue :mod (a3 / amino-acid :name (n4 / name :op1 "tyrosine") :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (r3 / residue :mod (a / amino-acid :name (n / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :part-of (p2 / protein :name (n3 / name :op1 "Stat1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604"))) :location (n5 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")))) :ARG1-of (s / specific-02 :mod (d / dual))) # ::id bel_pmid_1227_0932.9942 # ::date 2015-04-26T05:39:35 # ::file bel_pmid_1227_0932_9942.txt # ::snt In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) by IFNgamma was enhanced and prolonged. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (e / enhance-01 :ARG1 (p / phosphorylate-01 :ARG1 (a3 / and :op1 (r / residue :mod (a4 / amino-acid :mod "701" :name (n3 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (r2 / residue :mod (a / amino-acid :mod "727" :name (n / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :part-of (p2 / protein :name (n2 / name :op1 "Stat1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604"))) :ARG2 (p3 / protein :name (n4 / name :op1 "IFNgamma") :xref (x1 / xref :value "UNIPROT:IFNG_HUMAN" :prob "0.692")))) :op2 (p4 / prolong-01 :ARG1 p) :location (c2 / cell :name (n5 / name :op1 "fibroblast") :mod (m / mouse) :mod (p5 / protein :name (n6 / name :op1 "SHP-2") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")))) # ::id bel_pmid_1227_0932.39476 # ::date 2015-04-26T05:53:40 # ::file bel_pmid_1227_0932_39476.txt # ::snt Consistently, purified GST-SHP-2 dephosphorylated Stat1 at both tyrosine and serine residues when immunoprecipitated phospho-Stat1 or a peptide corresponding to the sequence surrounding Tyr(P)(701) or Ser(P)(727) of Stat1 was used as the substrate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (d / dephosphorylate-01 :ARG1 (a2 / and :op1 (r / residue :mod (a3 / amino-acid :name (n3 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (r2 / residue :mod (a4 / amino-acid :name (n4 / name :op1 "serine") :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :part-of (p2 / protein :name (n5 / name :op1 "Stat1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604"))) :ARG2 (e / enzyme :name (n2 / name :op1 "GST-SHP-2") :ARG1-of (p / purify-01) :xref (x2 / xref :value "UNIPROT:GSTO2_HUMAN" :prob "0.252")) :time (u / use-01 :ARG1 (o / or :op1 (p3 / protein :name (n6 / name :op1 "Stat1") :ARG1-of (i / immunoprecipitate-01) :ARG3-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604")) :op2 (p5 / peptide :ARG1-of (c / correspond-02 :ARG2 (s / sequence :ARG1-of (s2 / surround-01 :ARG2 (o2 / or :op1 (a5 / amino-acid :mod "701" :name (n7 / name :op1 "tyrosine") :part-of p2 :ARG3-of p4 :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a6 / amino-acid :mod "727" :name (n8 / name :op1 "serine") :part-of p2 :ARG3-of p4 :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784")))))))) :ARG2 (s3 / substrate)) :manner (c2 / consistent-02)) # ::id bel_pmid_1240_2043.4190 # ::date 2015-04-26T08:18:35 # ::file bel_pmid_1240_2043_4190.txt # ::snt Here we show that after stimulation by growth factors Spry1 and Spry2 translocate to the plasma membrane and become phosphorylated on a conserved tyrosine. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (a / and :op1 (t / translocate-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "Spry1") :xref (x1 / xref :value "UNIPROT:SPY1_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n2 / name :op1 "Spry2") :xref (x / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682"))) :ARG2 (m / membrane :mod (p3 / plasma) :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :op2 (b / become-01 :ARG1 a2 :ARG2 (p4 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine") :ARG1-of (c / conserve-01) :part-of a2 :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :time (a4 / after :op1 (s2 / stimulate-01 :ARG0 (g / growth-factor) :ARG1 a2))) :location (h / here)) # ::id bel_pmid_1240_2043.10224 # ::date 2015-04-26T08:42:25 # ::file bel_pmid_1240_2043_10224.txt # ::snt Next, they bind to the adaptor protein Grb2 and inhibit the recruitment of the Grb2-Sos complex either to the fibroblast growth factor receptor (FGFR) docking adaptor protein FRS2 or to Shp2. Membrane translocation of Spry is necessary for its phosphorylation, which is essential for its inhibitor activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / multi-sentence :snt1 (a / and :op1 (b / bind-01 :ARG1 (t2 / they) :ARG2 (p2 / protein :name (n3 / name :op1 "adaptor" :op2 "protein" :op3 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.373"))) :op2 (i2 / inhibit-01 :ARG0 t2 :ARG1 (r / recruit-01 :ARG1 (m2 / macro-molecular-complex :part (p3 / protein :name (n4 / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :part (p4 / protein :name (n5 / name :op1 "Sos") :xref (x4 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203")))) :location (o / or :op1 (p5 / protein :name (n6 / name :op1 "fibroblast" :op2 "growth" :op3 "factor" :op4 "receptor") :ARG0-of (d / dock-01 :ARG1 (p6 / protein :name (n7 / name :op1 "adaptor" :op2 "protein" :op3 "FRS2") :xref (x3 / xref :value "UNIPROT:TIRAP_HUMAN" :prob "0.332"))) :xref (x5 / xref :value "UNIPROT:A0A024R7P8_HUMAN" :prob "0.701")) :op2 (e2 / enzyme :name (n8 / name :op1 "Shp2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")))) :time (n / next)) :snt2 (n2 / need-01 :ARG0 (t / translocate-01 :ARG1 (p8 / protein :name (n9 / name :op1 "Spry") :xref (x6 / xref :value "UNIPROT:SPY1_HUMAN" :prob "0.292")) :ARG2 (m3 / membrane :xref (x7 / xref :value "GO:0016020" :prob "0.8"))) :ARG1 (p9 / phosphorylate-01 :ARG1 p8 :mod (e / essential) :purpose (a2 / activity-06 :ARG0 p8 :ARG1 (i3 / inhibit-01))))) # ::id bel_pmid_1240_2043.26582 # ::date 2015-04-26T09:09:57 # ::file bel_pmid_1240_2043_26582.txt # ::snt Using an antibody against Spry2, we showed that endogenous Spry2 becomes phosphorylated on tyrosine in response to EGF or FGF stimulation in C2C12 cells (Fig. 4b, left) and in COS7 cells (Fig. 4b, right). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (b / become-01 :ARG1 (p / protein :name (n / name :op1 "Spry2") :mod (m / monocot) :xref (x3 / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682")) :ARG2 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "tyrosine") :part-of p :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2-of (r / respond-01 :ARG1 (s2 / stimulate-01 :ARG1 p :ARG2 (o / or :op1 (p3 / protein :name (n3 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (p4 / protein :name (n4 / name :op1 "FGF") :xref (x1 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001"))) :location (a2 / and :op1 (c / cell-line :name (n5 / name :op1 "C2C12") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4b" :ARG1-of (l / left-20)))) :op2 (c2 / cell :name (n6 / name :op1 "COS7") :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4b" :ARG1-of (r2 / right-04))))))))) :manner (u / use-01 :ARG1 (a3 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p5 / protein :name (n7 / name :op1 "Spry2") :xref (x2 / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682")))))) # ::id bel_pmid_1240_2043.26584 # ::date 2015-04-26T09:36:05 # ::file bel_pmid_1240_2043_26584.txt # ::snt In addition, neither xSpry1Y53F nor mSpry2Y55F was tyrosine phosphorylated in cells stimulated with EGF (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (a / and :op2 (p / phosphorylate-01 :polarity "-" :ARG1 (a6 / and :op1 (a5 / amino-acid :name (n5 / name :op1 "tyrosine") :part-of (p4 / protein :name (n7 / name :op1 "xSpry1Y53F")) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a7 / amino-acid :name (n8 / name :op1 "tyrosine") :part-of (p5 / protein :name (n9 / name :op1 "mSpry2Y55F")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :location (c / cell :ARG1-of (s / stimulate-01 :ARG0 (p2 / protein :name (n6 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s3 / show-01 :polarity "-")))) # ::id bel_pmid_1240_2043.26602 # ::date 2015-04-26T10:28:50 # ::file bel_pmid_1240_2043_26602.txt # ::snt When Myc-tagged mSpry2 and haemagluttinin A (HA)- tagged Grb2 were expressed in cultured cells, both molecules translocated to the ruffling membrane region in response to stimulation with FGF or EGF and colocalized there (Fig. 1c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a5 / and :op1 (t3 / translocate-01 :ARG1 "a2" :ARG2 (r / region :part-of (m / membrane :xref (x5 / xref :value "GO:0016020" :prob "0.8")) :ARG0-of (r2 / ruffle-02)) :ARG2-of (r3 / respond-01 :ARG1 (s / stimulate-01 :ARG0 (o / or :op1 (p5 / protein :wiki "Fibroblast_growth_factor" :name (n5 / name :op1 "FGF") :xref (x3 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001")) :op2 (p6 / protein :wiki "Epidermal_growth_factor" :name (n6 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))))) :op2 (c3 / colocalize-01 :ARG1 "a2" :ARG2 r) :time (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :wiki "SPRY2" :name (n2 / name :op1 "Spry2") :ARG1-of (t / tag-01 :ARG2 (p / protein :wiki "-" :name (n / name :op1 "Myc") :xref (x4 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604"))) :mod (m2 / mouse) :xref (x / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682")) :op2 (p4 / protein :wiki "GRB2" :name (n4 / name :op1 "Grb2") :ARG1-of (t2 / tag-01 :ARG0 (p3 / protein :wiki "-" :name (n3 / name :op1 "haemagluttinin" :op2 "A"))) :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :ARG3 (c / cell :ARG1-of (c2 / culture-01))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1c"))) # ::id bel_pmid_1240_2043.30896 # ::date 2015-04-26T10:50:14 # ::file bel_pmid_1240_2043_30896.txt # ::snt both xSpry1Y53F and mSpry2Y55F were unable to inhibit the binding of Grb2 to FRS2 or Shp2 in response to FGF stimulation (Fig. 2a, b) or the recruitment of Grb2–Sos complex to FRS2 (Fig. 2c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (p / possible-01 :polarity "-" :ARG1 (i / inhibit-01 :ARG0 (a / and :op1 (p3 / protein :name (n12 / name :op1 "xSpry1") :ARG2-of (m2 / mutate-01 :value "Y53F")) :op2 (p8 / protein :name (n / name :op1 "Spry2") :ARG1-of (t / tag-01 :ARG2 (p10 / protein :name (n3 / name :op1 "myc") :xref (x1 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604"))) :ARG2-of (m3 / mutate-01 :value "Y55F") :xref (x6 / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682"))) :ARG1 (a5 / and :op1 (b / bind-01 :ARG1 (p4 / protein :name (n5 / name :op1 "Grb2") :xref (x4 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2 (o / or :op1 (p5 / protein :name (n6 / name :op1 "FRS2") :xref (x5 / xref :value "UNIPROT:FRS2_HUMAN" :prob "1.004")) :op2 (e / enzyme :name (n7 / name :op1 "Shp2") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003"))) :ARG2-of (r / respond-01 :ARG1 (o2 / or :op1 (s / stimulate-01 :ARG0 (p7 / protein :name (n8 / name :op1 "FGF") :xref (x3 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001")) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2a") :op2 (f2 / figure :mod "2b"))))))) :op2 (r2 / recruit-01 :ARG1 (m / macro-molecular-complex :part p4 :part (p9 / protein :name (n10 / name :op1 "Sos") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))) :ARG2 p5 :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "2c")))))) # ::id bel_pmid_1240_2043.30898 # ::date 2015-04-26T11:02:37 # ::file bel_pmid_1240_2043_30898.txt # ::snt We investigated the ability of the Spry mutants to bind to Grb2. Both xSpry1Y53F and mSpry2Y55F failed to bind to Grb2 in response to FGF stimulation (Fig. 5c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (i / investigate-01 :ARG0 (w / we) :ARG1 (c / capable-01 :ARG1 (p / protein :name (n / name :op1 "Spry") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:SPY1_HUMAN" :prob "0.292")) :ARG2 (b / bind-01 :ARG1 p :ARG2 (p2 / protein :name (n2 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))) :snt2 (f / fail-01 :ARG1 (a / and :op1 (p4 / protein :name (n9 / name :op1 "xSpry1") :ARG2-of (m3 / mutate-01 :value "Y53F")) :op2 (p7 / protein :name (n3 / name :op1 "Spry2") :ARG2-of (m4 / mutate-01 :value "Y55F") :ARG1-of (t / tag-01 :ARG2 (p3 / protein :name (n5 / name :op1 "myc") :xref (x2 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604"))) :xref (x4 / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682"))) :ARG2 (b2 / bind-01 :ARG1 a :ARG2 (p5 / protein :name (n7 / name :op1 "Grb2") :xref (x5 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2-of (r / respond-01 :ARG1 (s / stimulate-01 :ARG0 (p6 / protein :name (n8 / name :op1 "FGF") :xref (x3 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5c")))) # ::id bel_pmid_1240_2043.30900 # ::date 2015-04-26T11:10:13 # ::file bel_pmid_1240_2043_30900.txt # ::snt We also found that the tyrosine- phosphorylated, endogenous Spry2 binds to endogenous Grb2 in a manner dependent on FGF stimulation (Fig. 4c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (b / bind-01 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine") :ARG1-of (p / phosphorylate-01) :part-of (p2 / protein :name (n2 / name :op1 "Spry2") :mod (m / monocot) :xref (x / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (p3 / protein :name (n3 / name :op1 "Grb2") :mod m :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :manner (d / depend-01 :ARG1 (s / stimulate-01 :ARG0 (p4 / protein :name (n4 / name :op1 "FGF") :xref (x1 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001"))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4c")) :mod (a2 / also)) # ::id bel_pmid_1242_3677.2596 # ::date 2015-06-13T07:11:54 # ::file bel_pmid_1242_3677_2596.txt # ::snt gp130-mediated Stat1/3 activation is required to maintain the normal balance of hematopoietic progenitors during fetal and adult hematopoiesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (r / require-01 :ARG0 (m / maintain-01 :ARG1 (b / balance-01 :ARG1 (p / progenitor :mod (h / hematopoiesis)) :ARG1-of (n2 / normal-02))) :ARG1 (a / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "Stat1/3")) :ARG1-of (m2 / mediate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "gp130") :xref (x / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")))) :time (a2 / and :op1 (h2 / hematopoiesis :mod (f / fetus)) :op2 (h3 / hematopoiesis :mod (a3 / adult)))) # ::id bel_pmid_1244_4555.28358 # ::date 2015-06-13T07:41:17 # ::file bel_pmid_1244_4555_28358.txt # ::snt Immunoblots using antibodies to BATF detected an increase in BATF protein in response to LIF/IL-6 stimulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (d / detect-01 :ARG0 (i / immunoblot-01 :ARG0-of (u / use-01 :ARG1 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "BATF") :xref (x / xref :value "UNIPROT:BATF_HUMAN" :prob "1.003")))))) :ARG1 (i2 / increase-01 :ARG1 p :ARG2-of (r / respond-01 :ARG1 (s / stimulate-01 :ARG2 (p2 / protein :name (n2 / name :op1 "LIF/IL-6")))))) # ::id bel_pmid_1247_9220.29758 # ::date 2015-06-13T08:15:28 # ::file bel_pmid_1247_9220_29758.txt # ::snt These data demonstrate that OSM induces up-regulation of C/EBPdelta via a Stat3-dependent pathway in mammary epithelial cells and that the growth inhibition induced by OSM depends on the presence of C/EBPdelta. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / demonstrate-01 :ARG0 (d2 / data :mod (t / this)) :ARG1 (a / and :op1 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG2 (u / upregulate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "C/EBPδ"))) :instrument (p3 / pathway :ARG0-of (d3 / depend-01 :ARG1 (p4 / protein :name (n3 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :location (c / cell :mod (e / epithelium :mod (m / mammary)))) :op2 (d4 / depend-01 :ARG0 (i2 / inhibit-01 :ARG1 (g / grow-01) :ARG2-of (i3 / induce-01 :ARG0 p)) :ARG1 (p5 / present-02 :ARG1 p2)))) # ::id bel_pmid_1247_9220.29764 # ::date 2015-06-13T08:28:54 # ::file bel_pmid_1247_9220_29764.txt # ::snt Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up-regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "Oncostatin" :op2 "M") :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n2 / name :op1 "interleukin" :op2 "6-type" :op3 "cytokine") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.273"))) :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "0.692")) :ARG2 (u / upregulate-01 :ARG1 (a / and :op1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "CCAAT/enhancer-binding" :op2 "protein" :op3 "δ")))) :op2 p2) :ARG1-of (s / sustain-01))) # ::id bel_pmid_1247_9220.29772 # ::date 2015-06-13T08:38:16 # ::file bel_pmid_1247_9220_29772.txt # ::snt % Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up-regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein in nonneoplastic HC11 mouse mammary epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "Oncostatin" :op2 "M") :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n2 / name :op1 "interleukin" :op2 "6-type" :op3 "cytokine") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.273"))) :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "0.692")) :ARG2 (u / upregulate-01 :ARG1 (a / and :op1 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "CCAAT/enhancer-binding" :op2 "protein" :op3 "δ")))) :op2 p2) :ARG1-of (s / sustain-01)) :location (c2 / cell :name (n5 / name :op1 "HC11") :mod (e2 / epithelium :mod (m2 / mammary :part-of (m3 / mouse))) :mod (n6 / neoplasm :polarity "-"))) # ::id bel_pmid_1247_9220.29776 # ::date 2015-06-13T09:28:48 # ::file bel_pmid_1247_9220_29776.txt # ::snt This up-regulation is dependent on signaling by phospho-Stat3 (signal transducers and activators of transcription). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (d / depend-01 :ARG0 (u / upregulate-01 :mod (t / this)) :ARG1 (s / signal-07 :ARG0 (p / protein :name (n / name :op1 "Stat3") :ARG3-of (p2 / phosphorylate-01) :ARG2-of (t2 / transduce-01 :ARG1 (s2 / signal-07)) :ARG0-of (a / activate-01 :ARG1 (t3 / transcribe-01)) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) # ::id bel_pmid_1249_6442.9810 # ::date 2015-06-13T09:47:21 # ::file bel_pmid_1249_6442_9810.txt # ::snt Recombinant murine OSM stimulated eotaxin protein production and mRNA levels in the NIH 3T3 fibroblast cell line # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 14, 2015 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "OSM") :part-of (o / organism :name (n2 / name :op1 "Muridae")) :ARG3-of (r / recombine-01) :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (a / and :op1 (p2 / produce-01 :ARG1 (p3 / protein :name (n3 / name :op1 "eotaxin") :xref (x / xref :value "UNIPROT:CCL11_HUMAN" :prob "0.703"))) :op2 (l / level :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA")))) :location (c / cell-line :name (n5 / name :op1 "NIH-3T3") :mod (f / fibroblast))) # ::id bel_pmid_1249_6442.19422 # ::date 2015-06-13T10:00:22 # ::file bel_pmid_1249_6442_19422.txt # ::snt overexpression of Osm in lungs of mice resulted in a vigorous inflammatory response strongly supports a role of Osm in lung inflammatory responses that involve eosinophil infiltration # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (m / multi-sentence :snt1 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :location (l / lung :part-of (m2 / mouse))) :ARG2 (r2 / respond-01 :ARG0-of (i / inflame-01) :mod (v / vigorous))) :snt2 (s / support-01 :ARG1 (r3 / role :poss (p2 / protein :name (n2 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :topic (r4 / respond-01 :ARG0-of (i2 / inflame-01 :ARG1 (l2 / lung)) :ARG2-of (i3 / involve-01 :ARG1 (i4 / infiltrate-01 :ARG0 (c / cell :name (n3 / name :op1 "eosinophil")))))) :ARG1-of (s2 / strong-02))) # ::id bel_pmid_1249_6442.19424 # ::date 2015-06-13T10:56:22 # ::file bel_pmid_1249_6442_19424.txt # ::snt Osm stimluated eotaxin protein prudction and mRNA levels in fibroblasts Il6 could regulate a small induction of eotaxin, but other Il6/Lif cytokines [Lif, cariotrophin-1] had no effect # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (a / and :op1 (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "eotaxin") :xref (x2 / xref :value "UNIPROT:CCL11_HUMAN" :prob "0.703"))) :op2 (l / level :quant-of (n9 / nucleic-acid :name (n3 / name :op1 "mRNA")))) :location (f / fibroblast)) :snt2 (c / contrast-01 :ARG1 (p4 / possible-01 :ARG1 (r2 / regulate-01 :ARG0 (p5 / protein :name (n4 / name :op1 "Il6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG1 (i / induce-01 :ARG2 (p6 / protein :name (n5 / name :op1 "eotaxin") :xref (x3 / xref :value "UNIPROT:CCL11_HUMAN" :prob "0.703")) :degree (s2 / small)))) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 (c2 / cytokine :name (n6 / name :op1 "Il6/Lif") :mod (o / other) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (p7 / protein :name (n7 / name :op1 "Lif") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "0.603")) :op2 (p8 / protein :name (n8 / name :op1 "cariotrophin-1") :xref (x4 / xref :value "UNIPROT:CTF1_HUMAN" :prob "0.392")))))))) # ::id bel_pmid_1249_6958.18008 # ::date 2015-06-13T11:22:49 # ::file bel_pmid_1249_6958_18008.txt # ::snt GSK3-beta is also phosphorylated in response to hormonal stimuli not involving mechanical stress, such as insulin28; this pathway, however, was unaffected in the melusin-null background. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (p2 / pathway :name (n / name :op1 "GSK-3β")) :mod (a / also) :ARG2-of (r / respond-01 :ARG1 (s / stimulate-01 :ARG0 (h / hormone :example (p3 / protein :name (n2 / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :ARG2-of (i / involve-01 :polarity "-" :ARG1 (s2 / stress-02 :mod (m / mechanics))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "28"))))) :ARG1-of (c / contrast-01 :ARG2 (a2 / affect-01 :polarity "-" :ARG1 p2 :location (b / background :mod (p4 / protein :name (n3 / name :op1 "melusin") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:ITBP2_HUMAN" :prob "0.702")))))) # ::id bel_pmid_1249_6958.19264 # ::date 2015-06-13T12:32:13 # ::file bel_pmid_1249_6958_19264.txt # ::snt but did not substantially affect phosphorylation of p38 and ERK 1/2. In addition, phosphorylation of AKT was greatly impaired in aortic-banded heart of melusin-null mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jun 13, 2015 (m / multi-sentence :snt1 (c / contrast-01 :ARG2 (a / affect-01 :polarity "-" :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "p38") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")))) :degree (s / substantial))) :snt2 (a3 / and :op2 (i / impair-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :location (h / heart :ARG1-of (b / band-01 :ARG2 (a4 / aorta)) :part-of (m2 / mouse :mod (p3 / protein :name (n4 / name :op1 "melusin") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:ITBP2_HUMAN" :prob "0.702")))) :degree (g / great)))) # ::id bel_pmid_1249_6958.19266 # ::date 2015-06-13T12:55:08 # ::file bel_pmid_1249_6958_19266.txt # ::snt Analysis of intracellular signaling events induced by pressure overload indicated that phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was specifically blunted in melusin-null hearts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (i / indicate-01 :ARG0 (a / analyze-01 :ARG1 (e / event :mod (s / signal-07) :mod (i2 / intracellular) :ARG2-of (i3 / induce-01 :ARG0 (o / overload-01 :ARG2 (p / pressure-01))))) :ARG1 (b / blunt-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "glycogen" :op2 "synthase" :op3 "kinase-3β") :xref (x1 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.392"))) :location (h / heart :mod (p3 / protein :name (n2 / name :op1 "melusin") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:ITBP2_HUMAN" :prob "0.702"))) :ARG1-of (s2 / specific-02))) # ::id bel_pmid_1252_4227.38280 # ::date 2015-06-13T13:07:03 # ::file bel_pmid_1252_4227_38280.txt # ::snt HGF induced activation of ERK1 and ERK2 was shown to be dependent on the presence of HS moieties. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (s / show-01 :ARG1 (d / depend-01 :ARG0 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG2-of (i / induce-01 :ARG0 (p / protein :name (n3 / name :op1 "HGF") :xref (x1 / xref :value "UNIPROT:HGF_HUMAN" :prob "1.004")))) :ARG1 (p2 / present-02 :ARG1 (m / moiety :mod (s2 / small-molecule :name (n4 / name :op1 "HS") :xref (x3 / xref :value "PUBCHEM:24842" :prob "14.387128")))))) # ::id bel_pmid_1254_0842.9294 # ::date 2015-06-13T13:15:45 # ::file bel_pmid_1254_0842_9294.txt # ::snt STAP-2 mRNA was strongly induced in the liver in response to lipopolysaccharide and in isolated hepatocytes in response to interleukin-6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (i / induce-01 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "STAP-2") :xref (x1 / xref :value "UNIPROT:STAP2_HUMAN" :prob "1.002")))) :location (l / liver) :ARG1-of (s / strong-02) :ARG0-of (r2 / respond-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "lipopolysaccharide") :xref (x2 / xref :value "PUBCHEM:11970143" :prob "17.879841")))) :op2 (i2 / induce-01 :ARG2 n5 :degree s :location (h / hepatocyte :ARG1-of (i3 / isolate-01)) :ARG0-of (r3 / respond-01 :ARG1 (p2 / protein :name (n4 / name :op1 "interleukin-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))))) # ::id bel_pmid_1254_0842.10250 # ::date 2015-06-13T13:21:32 # ::file bel_pmid_1254_0842_10250.txt # ::snt These data suggest that STAP-2 is a new class of adaptor molecule that modulates STAT3 activity through its YXXQ motif. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (p / protein :name (n / name :op1 "STAP-2") :domain (c / class :mod (m / molecule :ARG0-of (a / adapt-01)) :ARG1-of (n2 / new-01)) :ARG0-of (m2 / modulate-01 :ARG1 (a2 / activity-06 :ARG0 (p2 / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :instrument (m3 / motif :name (n4 / name :op1 "YXXQ") :part-of p2)) :xref (x1 / xref :value "UNIPROT:STAP2_HUMAN" :prob "1.002"))) # ::id bel_pmid_1254_0842.28154 # ::date 2015-06-13T13:50:15 # ::file bel_pmid_1254_0842_28154.txt # ::snt Because STAP-2 expression is induced by proinflammatory cytokines such as IL-6 or IL-1beta, STAP-2 may play a role in the regulation of inflammation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / cause-01 :ARG0 (i / induce-01 :ARG0 (c2 / cytokine :ARG0-of (f / favor-01 :ARG1 (i2 / inflame-01)) :example (o / or :op1 (c3 / cytokine :name (n / name :op1 "IL-6")) :op2 (c4 / cytokine :name (n2 / name :op1 "IL-1β")))) :ARG2 (e / express-03 :ARG2 (p / protein :name (n3 / name :op1 "STAP-2") :xref (x / xref :value "UNIPROT:STAP2_HUMAN" :prob "1.002")))) :ARG1 (p2 / possible-01 :ARG1 (p3 / play-08 :ARG0 p :ARG1 (r / regulate-01 :ARG1 i2)))) # ::id bel_pmid_1258_6835.2750 # ::date 2015-06-13T14:05:55 # ::file bel_pmid_1258_6835_2750.txt # ::snt conditional inactivation of Cdc2 reduces phosphorylation of S6K1 at S/TP sites while simultaneously increasing phosphorylation of Thr(389) and of the S6K1 substrate, RPS6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (a / activate-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "Cdc2") :xref (x / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :mod (c2 / conditional)) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :name (n2 / name :op1 "S/TP") :part-of (e2 / enzyme :name (n3 / name :op1 "S6K1") :xref (x1 / xref :value "UNIPROT:KS6B1_HUMAN" :prob "1.003"))))) :ARG2 (i / increase-01 :ARG0 a :ARG1 (p3 / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "389" :name (n4 / name :op1 "threonine") :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (s / substrate :name (n5 / name :op1 "RPS6") :part-of e2))) :manner (s2 / simultaneous))) # ::id bel_pmid_1259_5539.28136 # ::date 2015-06-13T15:11:52 # ::file bel_pmid_1259_5539_28136.txt # ::snt iNOS protein was undetectable at 1 h but was increased after 2, 4, and 24 h of incubation with IL-6. The iNOS expression induced by a 2-h incubation with 10 ng/ml IL-1beta, a well known inducer of iNOS in cardiac myocytes (38), was used as a positive control in these experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (p / possible-01 :polarity "-" :ARG1 (d / detect-01 :ARG1 (e3 / enzyme :name (n / name :op1 "iNOS") :xref (x1 / xref :value "UNIPROT:NOS2_HUMAN" :prob "1.002"))) :time (a / after :op1 (t / temporal-quantity :quant "1" :unit (h / hour)))) :ARG2 (i / increase-01 :ARG1 e3 :time (a2 / after :op1 (i2 / incubate-01 :ARG2 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :duration (t2 / temporal-quantity :quant (a3 / and :op1 "2" :op2 "4" :op3 "24") :unit h))))) :snt2 (u / use-01 :ARG1 (e / express-03 :ARG2 (e4 / enzyme :name (n3 / name :op1 "iNOS") :xref (x / xref :value "UNIPROT:NOS2_HUMAN" :prob "1.002")) :ARG2-of (i3 / induce-01 :ARG0 (i4 / incubate-01 :ARG2 (p5 / protein :name (n4 / name :op1 "IL-1β") :quant (c2 / concentration-quantity :quant "10" :unit (n5 / nanogram-per-milliliter)) :ARG0-of (i5 / induce-01 :ARG1 e4 :location (m2 / myocyte :part-of (h2 / heart)) :ARG1-of (k / know-02 :degree (w / well)) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "38")))) :xref (x3 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.332")) :duration (t3 / temporal-quantity :quant "2" :unit (h3 / hour))))) :ARG2 (c4 / control-01 :mod (p7 / positive)) :location (e2 / experiment-01 :mod (t4 / this)))) # ::id bel_pmid_1259_5539.28352 # ::date 2015-06-13T15:48:28 # ::file bel_pmid_1259_5539_28352.txt # ::snt Fig.3 A shows that an increase in phosphorylation of ERK2 at Tyr204 was detected after 5 min of exposure to 10 ng/ml IL-6; this effect peaked at 30 min and was followed by a decline to basal levels by 2 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG0 (f / figure :mod "3A") :ARG1 (d / detect-01 :ARG1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "204" :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :time (a2 / after :op1 (e2 / expose-01 :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6") :quant (c / concentration-quantity :quant "10" :unit (n4 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :duration (t / temporal-quantity :quant "5" :unit (m2 / minute)))))) :snt2 (a3 / and :op1 (p3 / peak-01 :ARG1 (a4 / affect-01 :mod (t2 / this)) :time (a5 / after :quant (t3 / temporal-quantity :quant "30" :unit m2))) :op2 (f2 / follow-01 :ARG1 (d2 / decline-01 :ARG4 (l / level :mod (b / basal)) :time (a6 / after :quant (u / up-to :op1 (t4 / temporal-quantity :quant "2" :unit (h / hour))))) :ARG2 a4))) # ::id bel_pmid_1259_5539.28364 # ::date 2015-06-13T16:03:45 # ::file bel_pmid_1259_5539_28364.txt # ::snt IL-6 increased phosphorylation of STAT3 (at Tyr(705)) and ERK1/2 (at Tyr(204)) within 5 min that peaked at 15-30 min and returned to basal levels at 2 h # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "705" :name (n2 / name :op1 "tyrosine") :part-of (p3 / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a3 / amino-acid :mod "204" :name (n4 / name :op1 "tyrosine") :part-of (e / enzyme :name (n5 / name :op1 "ERK1/2")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :time (a4 / after :quant (u / up-to :op1 (t / temporal-quantity :quant "5" :unit (m / minute)))) :ARG1-of (p4 / peak-01 :time (a5 / after :quant (t2 / temporal-quantity :quant (v / value-interval :op1 "15" :op2 "30") :unit m))) :ARG1-of (r / return-01 :ARG4 (l / level :mod (b / basal)) :time (a6 / after :quant (t3 / temporal-quantity :quant "2" :unit (h / hour))))) # ::id bel_pmid_1259_5539.28368 # ::date 2015-06-13T16:16:01 # ::file bel_pmid_1259_5539_28368.txt # ::snt Fig. 1 Ashows that phosphorylation of STAT3 at Tyr705 was detected after 5 min of exposure to 10 ng/ml IL-6, reached a maximum at 15 min, and then declined within 1 h. These results demonstrate that IL-6 activates a STAT3 signaling in adult rat ventricular myocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG0 (f / figure :mod "1A") :ARG1 (a / and :op1 (d / detect-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "705" :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :time (a3 / after :op1 (e / expose-01 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-6") :quant (c / concentration-quantity :quant "10" :unit (n4 / nanogram-per-milliliter)) :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :duration (t / temporal-quantity :quant "5" :unit (m2 / minute))))) :op2 (r / reach-01 :ARG0 p :ARG1 (m3 / maximum) :time (a4 / after :quant (t2 / temporal-quantity :quant "15" :unit m2))) :op3 (d2 / decline-01 :ARG1 p :time (a5 / after :quant (u / up-to :op1 (t3 / temporal-quantity :quant "1" :unit (h / hour)))) :mod (t4 / then)))) :snt2 (d3 / demonstrate-01 :ARG0 (t5 / thing :ARG2-of (r2 / result-01) :mod (t6 / this)) :ARG1 (a6 / activate-01 :ARG0 (p4 / protein :name (n5 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (s2 / signal-07 :ARG0 (p5 / protein :name (n6 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :location (m4 / myocyte :mod (v / ventricle) :part-of (r3 / rat :mod (a7 / adult)))))) # ::id bel_pmid_1259_5539.38542 # ::date 2015-06-13T16:31:28 # ::file bel_pmid_1259_5539_38542.txt # ::snt Fig. 1 Ashows that phosphorylation of STAT3 at Tyr705 was detected after 5 min of exposure to 10 ng/ml IL-6, reached a maximum at 15 min, and then declined within 1 h. These results demonstrate that IL-6 activates a STAT3 signaling in adult rat ventricular myocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG0 (f / figure :mod "1A") :ARG1 (a / and :op1 (d / detect-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "705" :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :time (a3 / after :op1 (e / expose-01 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-6") :quant (c / concentration-quantity :quant "10" :unit (n4 / nanogram-per-milliliter)) :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :duration (t / temporal-quantity :quant "5" :unit (m2 / minute))))) :op2 (r / reach-01 :ARG0 p :ARG1 (m3 / maximum) :time (a4 / after :op1 (t2 / temporal-quantity :quant "15" :unit m2))) :op3 (d2 / decline-01 :ARG1 p :time (a5 / after :op1 (u / up-to :op1 (t3 / temporal-quantity :quant "1" :unit (h / hour)))) :mod (t4 / then)))) :snt2 (d3 / demonstrate-01 :ARG0 (t5 / thing :ARG2-of (r2 / result-01) :mod (t6 / this)) :ARG1 (a6 / activate-01 :ARG0 (p4 / protein :name (n5 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (s2 / signal-07 :ARG0 (p5 / protein :name (n6 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :location (m4 / myocyte :mod (v / ventricle) :part-of (r3 / rat :mod (a7 / adult)))))) # ::id bel_pmid_1260_4616.9184 # ::date 2015-06-13T16:43:55 # ::file bel_pmid_1260_4616_9184.txt # ::snt Overexpression of mSef in NIH3T3 cells results in a decrease in FGF-induced cell proliferation associated with a decrease in Tyr phosphorylation of FGFR1 and FRS2. As a consequence, there is a reduction in the phosphorylation of Raf-1 at Ser(338), MEK1/2 at Ser(217) and Ser(221), and ERK1/2 at Thr(202) and Tyr(204). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "Sef") :part-of (m2 / mouse) :xref (x4 / xref :value "UNIPROT:I17RD_HUMAN" :prob "0.602")) :location (c / cell-line :name (n2 / name :op1 "NIH3T3"))) :ARG2 (a / associate-01 :ARG1 (d / decrease-01 :ARG1 (p2 / proliferate-01 :ARG0 (c2 / cell) :ARG2-of (i / induce-01 :ARG0 (p3 / protein :name (n3 / name :op1 "FGF") :xref (x2 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001"))))) :ARG2 (d2 / decrease-01 :ARG1 (p4 / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (e4 / enzyme :name (n5 / name :op1 "FGFR1") :xref (x1 / xref :value "UNIPROT:FGFR1_HUMAN" :prob "1.004")) :xref (x7 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a4 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (p6 / protein :name (n7 / name :op1 "FRS2") :xref (x3 / xref :value "UNIPROT:FRS2_HUMAN" :prob "1.004")) :xref (x8 / xref :value "PUBCHEM:1153" :prob "11.081481"))))))) :snt2 (c3 / cause-01 :ARG1 (r2 / reduce-01 :ARG1 (p7 / phosphorylate-01 :ARG1 (a5 / and :op1 (a6 / amino-acid :mod "338" :name (n8 / name :op1 "serine") :part-of (e / enzyme :name (n9 / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :xref (x10 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a7 / amino-acid :mod "217" :name (n10 / name :op1 "serine") :part-of (e2 / enzyme :name (n11 / name :op1 "MEK1/2")) :xref (x9 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op3 (a8 / amino-acid :mod "221" :name (n12 / name :op1 "serine") :part-of e2 :xref (x11 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op4 (a9 / amino-acid :mod "202" :name (n13 / name :op1 "threonine") :part-of (e3 / enzyme :name (n14 / name :op1 "ERK1/2")) :xref (x6 / xref :value "PUBCHEM:205" :prob "11.848252")) :op5 (a10 / amino-acid :mod "204" :name (n15 / name :op1 "tyrosine") :part-of e3 :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481"))))))) # ::id bel_pmid_1260_4616.26900 # ::date 2015-06-14T06:27:27 # ::file bel_pmid_1260_4616_26900.txt # ::snt These data indicate that adenovirus-mediated expression of mSef reduced FGF-induced tyrosine phosphorylation of FGFR without affecting the overall level of FGFR expression (Fig.4 A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (i / indicate-01 :ARG0 (d / data :mod (t / this)) :ARG1 (r / reduce-01 :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Sef") :part-of (m / mouse) :xref (x2 / xref :value "UNIPROT:I17RD_HUMAN" :prob "0.602")) :ARG1-of (m2 / mediate-01 :ARG0 (a / adenovirus))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (p3 / protein :name (n3 / name :op1 "FGFR") :xref (x / xref :value "UNIPROT:FGFR1_HUMAN" :prob "0.313")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2-of (i2 / induce-01 :ARG0 (p4 / protein :name (n4 / name :op1 "FGF") :xref (x1 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001")))) :manner (a3 / affect-01 :polarity "-" :ARG1 (l / level :quant-of (e2 / express-03 :ARG2 p3) :mod (o / overall)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id bel_pmid_1260_4616.28060 # ::date 2015-06-14T06:38:51 # ::file bel_pmid_1260_4616_28060.txt # ::snt Adenovirus-mediated expression of mSef but not GFP resulted in a reduction in the levels of activated ERK1/2, whereas overall levels of ERK1/2 were unaffected (Fig. 2 A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (c / contrast-01 :ARG1 (r / result-01 :ARG1 (c2 / contrast-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Sef") :part-of (m / mouse) :xref (x1 / xref :value "UNIPROT:I17RD_HUMAN" :prob "0.602")) :ARG1-of (m2 / mediate-01 :ARG0 (a / adenovirus))) :ARG2 (e2 / express-03 :polarity "-" :ARG2 (p2 / protein :name (n2 / name :op1 "GFP") :xref (x / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")) :ARG1-of m2)) :ARG2 (r2 / reduce-01 :ARG1 (l / level :quant-of (e3 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG1-of (a2 / activate-01))))) :ARG2 (a3 / affect-01 :polarity "-" :ARG1 (l2 / level :quant-of (e4 / enzyme :name (n4 / name :op1 "ERK1/2")) :mod (o / overall))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id bel_pmid_1261_2908.9036 # ::date 2015-06-14T06:46:00 # ::file bel_pmid_1261_2908_9036.txt # ::snt We found that liver from ICAM-1-deficient mice exhibited impaired regeneration after partial hepatectomy. This finding is associated with dramatic decrease in leukocyte recruitment and tissue TNF-alpha and IL-6 levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (f / find-01 :ARG0 (w / we) :ARG1 (e / exhibit-01 :ARG0 (l / liver :source (m2 / mouse :mod (p / protein :name (n / name :op1 "ICAM-1") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:ICAM1_HUMAN" :prob "1.002")))) :ARG1 (r / regenerate-01 :ARG1-of (i / impair-01)) :time (a / after :op1 (h / hepatectomy :degree (p2 / part))))) :snt2 (a2 / associate-01 :ARG1 (f2 / find-01 :mod (t / this)) :ARG2 (d / decrease-01 :ARG1 (a3 / and :op1 (r2 / recruit-01 :ARG1 (c / cell :name (n2 / name :op1 "leukocyte"))) :op2 (l2 / level :quant-of (a4 / and :op1 (p3 / protein :name (n3 / name :op1 "TNF-α") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :op2 (p4 / protein :name (n4 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (t2 / tissue)))) :degree (d2 / dramatic)))) # ::id bel_pmid_1261_8892.1630 # ::date 2015-04-27T11:37:26 # ::file bel_pmid_1261_8892_1630.txt # ::snt The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (m / multi-sentence :snt1 (r / result-01 :ARG1 (t / treat-04 :ARG1 (c / cell :name (n / name :op1 "NCI-N87")) :ARG2 (p / protein :name (n2 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG2 (i / increase-01 :ARG0 t :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "Erk1/2")) :op2 (e2 / enzyme :name (n4 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op3 (e3 / enzyme :name (n5 / name :op1 "P38") :xref (x / xref :value "UNIPROT:GRAP2_HUMAN" :prob "1.003")))))) :snt2 (b / blockade-01 :ARG1 (o / or :op1 (p3 / pathway :name (n6 / name :op1 "Erk")) :op2 (p4 / pathway :name (n7 / name :op1 "phosphatidylinositol-3-kinase/Akt")) :op3 (p5 / pathway :name (n8 / name :op1 "P38"))) :location (c2 / cell-line :mod (t2 / this)))) # ::id bel_pmid_1262_9177.8352 # ::date 2015-04-28T03:44:03 # ::file bel_pmid_1262_9177_8352.txt # ::snt ciliary neurotrophic factor, CNTF, activation of gp130 in NSCs rapidly increased Notch1 expression # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (i / increase-01 :ARG0 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "ciliary" :op2 "neurotrophic" :op3 "factor") :xref (x2 / xref :value "UNIPROT:CNTF_HUMAN" :prob "0.702")) :ARG1 (p2 / protein :name (n2 / name :op1 "gp130") :xref (x / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")) :location (c / cell :name (n3 / name :op1 "NSC"))) :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "Notch1") :xref (x1 / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.693"))) :manner (r / rapid)) # ::id bel_pmid_1262_9177.26086 # ::date 2015-04-28T05:12:11 # ::file bel_pmid_1262_9177_26086.txt # ::snt infusion of EGF and CNTF into adult forebrain lateral ventricles increased periventricular NOTCH1 compared with EGF alone # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 23, 2015 (i / increase-01 :ARG0 (i2 / infuse-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (p2 / protein :name (n2 / name :op1 "CNTF") :xref (x / xref :value "UNIPROT:CNTF_HUMAN" :prob "1.003"))) :ARG2 (v / ventricle :location (l / lateral) :part-of (f / forebrain :mod (a2 / adult)))) :ARG1 (p3 / protein :name (n3 / name :op1 "NOTCH1") :location (p4 / periventricular) :xref (x1 / xref :value "UNIPROT:NOTC1_HUMAN" :prob "1.003")) :compared-to (i3 / infuse-01 :ARG1 p :ARG2 v)) # ::id bel_pmid_1262_9177.28408 # ::date 2015-04-28T05:53:24 # ::file bel_pmid_1262_9177_28408.txt # ::snt NOTCH1 activation, indicated by tumor necrosis factor alpha-converting enzyme, TACE [Adam17], and presenilin-mediated processing, also increased # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (i / increase-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "NOTCH1") :xref (x2 / xref :value "UNIPROT:NOTC1_HUMAN" :prob "1.003")) :ARG1-of (i2 / indicate-01 :ARG0 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha-converting" :op5 "enzyme") :xref (x / xref :value "UNIPROT:IL32_HUMAN" :prob "0.312")) :op2 (p2 / process-01 :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "presenilin") :xref (x1 / xref :value "UNIPROT:A0A024R6A3_HUMAN" :prob "0.701"))))))) :mod (a4 / also)) # ::id bel_pmid_1268_6512.15962 # ::date 2015-04-28T07:07:22 # ::file bel_pmid_1268_6512_15962.txt # ::snt We used a murine macrophage-like cell line, RAW264.7, to demonstrate that Janus kinase (JAK)2 is tyrosine phosphorylated immediately after LPS stimulation. Anti-Toll-like receptor (TLR)4 neutralization antibody inhibits the phosphorylation of JAK2 and the c-Jun NH2-terminal protein kinase (JNK). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (u / use-01 :ARG0 (w / we) :ARG1 (c / cell-line :name (n / name :op1 "RAW264.7") :ARG1-of (r / resemble-01 :ARG2 (c2 / cell :name (n2 / name :op1 "macrophage"))) :part-of (o / organism :name (n3 / name :op1 "Muridae"))) :ARG2 (d / demonstrate-01 :ARG0 w :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (e / enzyme :name (n5 / name :op1 "Janus" :op2 "kinase" :op3 "2") :xref (x3 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.003")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :time (a2 / after :op1 (s / stimulate-01 :ARG0 (l / lipopolysaccharide) :ARG1 e) :mod (i / immediate))))) :snt2 (i2 / inhibit-01 :ARG0 (a3 / antibody :ARG0-of (n7 / neutralize-01 :ARG1 (p2 / protein :name (n8 / name :op1 "Toll-like" :op2 "receptor" :op3 "4") :xref (x / xref :value "UNIPROT:TLR4_HUMAN" :prob "1.003")))) :ARG1 (p3 / phosphorylate-01 :ARG1 (a4 / and :op1 (e2 / enzyme :name (n9 / name :op1 "JAK2") :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n10 / name :op1 "c-Jun" :op2 "NH2-terminal" :op3 "protein" :op4 "kinase") :xref (x1 / xref :value "UNIPROT:MK08_HUMAN" :prob "0.313")))))) # ::id bel_pmid_1268_7404.28336 # ::date 2015-04-28T07:57:00 # ::file bel_pmid_1268_7404_28336.txt # ::snt Il6 can elicit proinflammatory or anti-inflammatory effects, depending on the in vivo environmental circumstances # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (p / possible-01 :ARG1 (e / elicit-01 :ARG0 (p2 / protein :name (n / name :op1 "Il6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG1 (a / and :op1 (a2 / affect-01 :ARG0-of (f / favor-01 :ARG1 (i / inflame-01))) :op2 (a3 / affect-01 :ARG0-of (c / counter-01 :ARG1 i)))) :ARG0-of (d / depend-01 :ARG1 (c2 / circumstance :manner (i2 / in-vivo) :mod (e4 / environment)))) # ::id bel_pmid_1268_7404.38564 # ::date 2015-04-28T08:21:02 # ::file bel_pmid_1268_7404_38564.txt # ::snt Il6 promotes the growth arrest and differentiation of M1 cells through gp130-mediated Stat3 activation, whereas the Y759/SHP-2-mediated cascade by gp130 stimulation has growth-enhancing effects # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (p / promote-01 :ARG0 (p2 / protein :name (n / name :op1 "Il6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :ARG1 (a / and :op1 (a2 / arrest-02 :ARG1 (g / grow-01 :ARG1 (c2 / cell :name (n2 / name :op1 "M1")))) :op2 (d / differentiate-01 :ARG1 c2)) :manner (a3 / activate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Stat3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1-of (m / mediate-01 :ARG0 (p4 / protein :name (n4 / name :op1 "gp130") :xref (x / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))))) :ARG2 (a5 / affect-01 :ARG0 (c3 / cascade :ARG1-of (m2 / mediate-01 :ARG0 (a4 / amino-acid :mod "759" :name (n5 / name :op1 "tyrosine") :part-of (p5 / protein :name (n6 / name :op1 "SHP-2") :xref (x3 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (s / stimulate-01 :ARG0 p4)) :ARG2 (e3 / enhance-01 :ARG0 c3 :ARG1 (g2 / grow-01)))) # ::id bel_pmid_1276_9686.36092 # ::date 2015-04-28T12:26:18 # ::file bel_pmid_1276_9686_36092.txt # ::snt Mutational inactivation of the MYCantagonist Mxi-1 in prostate carcinoma may be another mechanism of MYC activation [54]. Mxi-1 inactivation would presumably shift the equilibrium between Mxi-1/MAX and c-MYC/MAX in prostate cells towards c- MYC/MAX hetero-dimers, and therefore lead to elevated expression of c-MYC-target genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (m / multi-sentence :snt1 (m2 / mechanism :ARG1-of (p / possible-01) :ARG0-of (a / activate-01 :ARG1 (p10 / protein :name (n / name :op1 "MYC") :xref (x / xref :value "UNIPROT:MYC_HUMAN" :prob "1.004"))) :domain (a2 / activate-01 :polarity "-" :ARG1 (p11 / protein :name (n2 / name :op1 "Mxi-1") :ARG1-of (a3 / antagonize-02 :ARG2 p10) :xref (x1 / xref :value "UNIPROT:MXI1_HUMAN" :prob "0.592")) :ARG1-of (m3 / mutate-01) :location (m6 / medical-condition :name (n3 / name :op1 "carcinoma") :location (p2 / prostate))) :mod (a4 / another) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "54")))) :snt2 (a5 / and :op1 (s / shift-01 :ARG0 (a6 / activate-01 :polarity "-" :ARG1 (p9 / protein :name (n4 / name :op1 "Mxi-1") :xref (x5 / xref :value "UNIPROT:MXI1_HUMAN" :prob "0.592"))) :ARG1 (e / equilibrium :mod (b / between :op1 (m4 / macro-molecular-complex :part p9 :part (p4 / protein :name (n5 / name :op1 "MAX") :xref (x3 / xref :value "UNIPROT:MAX_HUMAN" :prob "1.004"))) :op2 (m5 / macro-molecular-complex :part (p8 / protein :name (n6 / name :op1 "c-MYC") :xref (x4 / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.601")) :part p4))) :ARG2 (h / heterodimer :mod m5) :location (c2 / cell :part-of (p5 / prostate)) :ARG1-of (p6 / presume-01)) :op2 (c3 / cause-01 :ARG0 s :ARG1 (l / lead-03 :ARG2 (e2 / express-03 :ARG1 (p7 / protein :name (n7 / name :op1 "c-MYC") :ARG1-of (t / target-01) :xref (x2 / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.601")) :ARG1-of (e3 / elevate-01)))))) # ::id bel_pmid_1276_9686.37908 # ::date 2015-04-28T14:08:29 # ::file bel_pmid_1276_9686_37908.txt # ::snt The encoded protein (CDKN1A) binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a / and :op1 (b / bind-01 :ARG1 (p / protein :ARG1-of (e / encode-01 :ARG0 (g / gene :name (n / name :op1 "CDKN1A") :xref (x1 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")))) :ARG2 (o / or :op1 (m / macro-molecular-complex :part (p2 / protein :name (n2 / name :op1 "cyclin") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.702")) :part (e2 / enzyme :name (n3 / name :op1 "CDK2") :xref (x3 / xref :value "UNIPROT:CDK2_HUMAN" :prob "1.003"))) :op2 (m2 / macro-molecular-complex :part p2 :part (e3 / enzyme :name (n4 / name :op1 "CDK4") :xref (x2 / xref :value "UNIPROT:CDK4_HUMAN" :prob "1.003"))))) :op2 (i / inhibit-01 :ARG0 p :ARG1 (a2 / activity-06 :ARG0 o))) # ::id bel_pmid_1276_9686.37918 # ::date 2015-04-28T14:29:04 # ::file bel_pmid_1276_9686_37918.txt # ::snt The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Apr 28, 2015 (a / and :op1 (b / bind-01 :ARG1 (p / protein :ARG1-of (e / encode-01)) :ARG2 (o / or :op1 (m / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "cyclin" :op2 "E") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")) :part (e2 / enzyme :name (n2 / name :op1 "CDK2") :xref (x3 / xref :value "UNIPROT:CDK2_HUMAN" :prob "1.003"))) :op2 (m2 / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.371")) :part (e3 / enzyme :name (n4 / name :op1 "CDK4") :xref (x2 / xref :value "UNIPROT:CDK4_HUMAN" :prob "1.003"))))) :op2 (p4 / prevent-01 :ARG0 p :ARG1 (a2 / activate-01 :ARG1 o))) # ::id bel_pmid_1281_2976.37028 # ::date 2015-04-28T14:42:22 # ::file bel_pmid_1281_2976_37028.txt # ::snt In many cells PKA inhibits the extracellular receptor kinase (ERK1/2) cascade of the mitogen-activated protein kinase (MAPK) pathway leading to inhibition of cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (i / inhibit-01 :ARG0 (e / enzyme :name (n / name :op1 "PKA") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1 (c / cascade :mod (e2 / enzyme :name (n2 / name :op1 "extracellular" :op2 "receptor" :op3 "kinase") :xref (x1 / xref :value "UNIPROT:CD44_HUMAN" :prob "0.313")) :poss (p / pathway :name (n3 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase"))) :location (c2 / cell :quant (m / many)) :ARG0-of (l / lead-03 :ARG2 (i2 / inhibit-01 :ARG1 (p2 / proliferate-01 :ARG0 (c3 / cell))))) # ::id bel_pmid_1288_1425.6346 # ::date 2015-04-28T14:55:56 # ::file bel_pmid_1288_1425_6346.txt # ::snt Here we demonstrate that Ser311 accounts for zetaPKC phosphorylation of RelA and that this site is phosphorylated in vivo in response to TNF-alpha. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (a / and :op1 (a2 / account-01 :ARG0 (a3 / amino-acid :mod "311" :name (n / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "RelA") :xref (x / xref :value "UNIPROT:TF65_HUMAN" :prob "0.603")) :ARG2 (e / enzyme :name (n3 / name :op1 "zetaPKC") :xref (x1 / xref :value "UNIPROT:AP5Z1_HUMAN" :prob "0.222")))) :op2 (p3 / phosphorylate-01 :ARG1 (p4 / protein-segment :mod (t / this)) :manner (i / in-vivo) :ARG2-of (r / respond-01 :ARG1 (p5 / protein :name (n4 / name :op1 "TNF-alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))))) :location (h / here)) # ::id bel_pmid_1288_1425.9992 # ::date 2015-04-28T15:29:15 # ::file bel_pmid_1288_1425_9992.txt # ::snt Also, an inactivating mutation of that residue severely impairs RelA transcriptional activity, blocks its anti-apoptotic function and abrogates the interaction of RelA with the co-activator CBP as well as its recruitment, and that of RNA polymerase II (Pol II) with the interleukin-6 (IL-6) promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a2 / and :op1 (i / impair-01 :ARG0 (m / mutate-01 :ARG1 (r / residue :mod (t / that)) :ARG1-of (a3 / activate-01 :polarity "-")) :ARG1 (a4 / activity-06 :ARG0 (p / protein :name (n / name :op1 "RelA") :xref (x3 / xref :value "UNIPROT:TF65_HUMAN" :prob "0.603")) :ARG1 (t2 / transcribe-01))) :op2 (b / block-01 :ARG0 m :ARG1 (f / function-01 :ARG0 r :ARG1 (o / oppose-01 :ARG1 (a5 / apoptosis)))) :op3 (a6 / abrogate-01 :ARG0 m :ARG1 (a7 / and :op1 (i2 / interact-01 :ARG0 p :ARG1 (a8 / and :op1 (p2 / protein :name (n2 / name :op1 "CBP") :ARG0-of (c / coactivate-01) :xref (x / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :op2 (r2 / recruit-01 :ARG0 p2))) :op2 (i3 / interact-01 :ARG0 (e / enzyme :name (n3 / name :op1 "RNA" :op2 "polymerase" :op3 "II") :xref (x1 / xref :value "UNIPROT:RPB2_HUMAN" :prob "0.352")) :ARG1 (m2 / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (p4 / protein :name (n4 / name :op1 "interleukin-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))))))) :manner (s / severe) :mod (a9 / also)) # ::id bel_pmid_1292_3167.9944 # ::date 2015-04-28T16:21:04 # ::file bel_pmid_1292_3167_9944.txt # ::snt Immunoblot analyses confirm that Tyr-542 and Tyr-580 are the major sites of Shp2 tyrosyl phosphorylation and that Tyr-542 is the major Grb2 binding site. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / confirm-01 :ARG0 (a / analyze-01 :manner (i / immunoblot-01)) :ARG1 (a2 / and :op1 (p / protein-segment :domain (a3 / and :op1 (a4 / amino-acid :mod "542" :name (n / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a5 / amino-acid :mod "580" :name (n2 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (m / major-02) :location-of (p2 / phosphorylate-01 :ARG1 (a6 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (e / enzyme :name (n4 / name :op1 "Shp2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :op2 (p3 / protein-segment :domain a4 :ARG1-of m :ARG1-of (b / bind-01) :part-of (p4 / protein :name (n5 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))) # ::id bel_pmid_1292_3167.29880 # ::date 2015-04-28T16:44:44 # ::file bel_pmid_1292_3167_29880.txt # ::snt Y542F-expressing cells exhibited an ?50% decrease in Tyr-580 phosphorylation (Fig. 3C, right panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (e / exhibit-01 :ARG0 (c / cell :ARG3-of (e2 / express-03 :ARG2 (a / amino-acid :ARG2-of (m / mutate-01 :value "Y542F")))) :ARG1 (d / decrease-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "580" :name (n / name :op1 "tyrosine") :xref (x / xref :value "PUBCHEM:1153" :prob "11.081481"))) :quant (a3 / approximately :op1 (p2 / percentage-entity :value "50"))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "3C" :part (p3 / panel :ARG1-of (r / right-04)))))) # ::id bel_pmid_1293_4012.314 # ::date 2015-04-28T16:59:56 # ::file bel_pmid_1293_4012_314.txt # ::snt Therefore, the cell cycle progression from S to M phase was impaired during liver regeneration in Cry-deficient mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / cause-01 :ARG1 (i / impair-01 :ARG1 (p / progress-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell)) :ARG3 (e / event :name (n / name :op1 "S" :op2 "phase")) :ARG4 (e2 / event :name (n2 / name :op1 "M" :op2 "phase"))) :time (r / regenerate-01 :ARG1 (l / liver) :location (m / mouse :mod (p2 / protein :name (n3 / name :op1 "Cry") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:CRYL1_HUMAN" :prob "0.602")))))) # ::id bel_pmid_1293_4012.20242 # ::date 2015-04-28T17:14:59 # ::file bel_pmid_1293_4012_20242.txt # ::snt from full text - Three E-box elements were found within 1.2 kb of the mouse wee1 gene 5-upstream region (Fig. 3B). CLOCK and BMAL1 together, but neither of them alone, produced a major increase in transcriptional activity through this fragment in transfected NIH3T3 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (f / find-01 :ARG1 (e / element :quant "3" :mod (d / dna-sequence :name (n / name :op1 "E-box"))) :location (r / region :direction (u / upstream :mod "5") :location (g / gene :name (n2 / name :op1 "wee1") :part-of (m2 / mouse) :quant (d2 / distance-quantity :quant "1.2" :unit (k / kilo-base-pair)) :xref (x2 / xref :value "UNIPROT:WEE1_HUMAN" :prob "0.603"))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "3B"))) :snt2 (p / produce-01 :ARG0 (c / contrast-01 :ARG1 (a / and :op1 (g2 / gene :name (n3 / name :op1 "CLOCK") :xref (x1 / xref :value "UNIPROT:CLOCK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n4 / name :op1 "BMAL1") :xref (x / xref :value "UNIPROT:BMAL1_HUMAN" :prob "1.003")) :mod (t / together)) :ARG2 (o / or :op1 g2 :op2 g3 :mod (a2 / alone))) :ARG1 (i / increase-01 :ARG1 (a3 / activity-06 :ARG0 a :ARG1 (t2 / transcribe-01)) :medium (f3 / fragment :mod (t3 / this)) :location (c2 / cell-line :name (n5 / name :op1 "NIH3T3") :ARG1-of (t4 / transfect-01)) :ARG1-of (m3 / major-02))) :source (t5 / text :ARG1-of (f4 / full-09))) # ::id bel_pmid_1293_4012.22244 # ::date 2015-04-29T03:31:21 # ::file bel_pmid_1293_4012_22244.txt # ::snt from full text - The wee1 gene product phosphorylates Cdc2 on Tyr-15 [p-Cdc2(Tyr 15)] and keeps it in an inactive form # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "15" :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "Cdc2") :xref (x / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (p2 / product :poss (g / gene :name (n3 / name :op1 "wee1") :xref (x1 / xref :value "UNIPROT:WEE1_HUMAN" :prob "0.603")))) :op2 (k / keep-01 :ARG0 p2 :ARG1 (a4 / amino-acid :mod "15" :name (n5 / name :op1 "tyrosine") :part-of e :ARG3-of (p3 / phosphorylate-01) :mod (f / form :ARG1-of (a3 / activate-01 :polarity "-")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :source (t / text :ARG1-of (f2 / full-09))) # ::id bel_pmid_1293_4012.26132 # ::date 2015-04-29T04:38:56 # ::file bel_pmid_1293_4012_26132.txt # ::snt from full text - Furthermore, Cdc2 kinase activity was reduced (Figs. 2B and 1C). Therefore, the cell cycle progression from S to M phase was impaired during liver regeneration in Cry-deficient mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (a / and :op2 (r / reduce-01 :ARG1 (a2 / activity-06 :ARG1 (k / kinase :name (n / name :op1 "Cdc2") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "2B") :op2 (f2 / figure :mod "1C")))) :snt2 (c / cause-01 :ARG1 (i / impair-01 :ARG1 (p / progress-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell)) :ARG3 (e / event :name (n2 / name :op1 "S" :op2 "phase")) :ARG4 (e2 / event :name (n3 / name :op1 "M" :op2 "phase"))) :time (r2 / regenerate-01 :ARG1 (l / liver) :location (m2 / mouse :mod (p2 / protein :name (n4 / name :op1 "Cry") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:CRYL1_HUMAN" :prob "0.602")))))) :source (t3 / text :ARG1-of (f3 / full-09))) # ::id bel_pmid_1293_4012.26134 # ::date 2015-04-29T05:11:30 # ::file bel_pmid_1293_4012_26134.txt # ::snt from full text - The expression profiles of cyclin D1 and wee1 transcripts were markedly different between Cry-deficient and wildtype mice throughout the liver regeneration process: cyclin D1 expression decreased up to 86% and wee1 expression increased up to 4.6-fold # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / differ-02 :ARG1 (p / profile-01 :ARG1 (p2 / protein :name (n / name :op1 "cyclin" :op2 "D1") :ARG1-of (t / transcribe-01) :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001"))) :ARG2 (p3 / profile-01 :ARG1 (p4 / protein :name (n2 / name :op1 "wee1") :ARG1-of t :xref (x1 / xref :value "UNIPROT:WEE1_HUMAN" :prob "0.603"))) :degree (e / express-03 :ARG2 (a / and :op1 p2 :op2 p4)) :degree (m / marked) :location (b / between :op1 (m2 / mouse :mod (p5 / protein :name (n3 / name :op1 "Cry") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:CRYL1_HUMAN" :prob "0.602"))) :op2 (m4 / mouse :mod (w / wild-type))) :time (p6 / process-02 :ARG1 (r / regenerate-01 :ARG1 (l / liver))) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and :op1 (d2 / decrease-01 :ARG1 (e2 / express-03 :ARG1 p2) :ARG2 (u / up-to :op1 (p7 / percentage-entity :value "86"))) :op2 (i / increase-01 :ARG1 (e3 / express-03 :ARG1 p4) :ARG2 (u2 / up-to :op1 (p8 / product-of :op1 "4.6"))))) :source (t2 / text :ARG1-of (f / full-09))) # ::id bel_pmid_1293_4012.32782 # ::date 2015-04-29T06:50:16 # ::file bel_pmid_1293_4012_32782.txt # ::snt from full text - However, in Clock mutant (Clock/Clock) mice (26), which carry dominantnegative Clock mutations (27), wee1 expression was low at both ZTs # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (h / have-concession-91 :ARG1 (l / low-04 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "wee1") :xref (x2 / xref :value "UNIPROT:WEE1_HUMAN" :prob "0.603"))) :time (z / zeitgeber-time :mod (b / both)) :location (m / mouse :mod (g / gene :name (n2 / name :op1 "Clock") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:Q8N757_HUMAN" :prob "0.701")) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "26"))) :ARG0-of (c2 / carry-01 :ARG1 (g2 / gene :name (n3 / name :op1 "Clock") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:Q8N757_HUMAN" :prob "0.701")) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "27")))))) :source (t / text :ARG1-of (f / full-09))) # ::id bel_pmid_1295_7325.25184 # ::date 2015-04-29T07:11:28 # ::file bel_pmid_1295_7325_25184.txt # ::snt Studies crossing PPAR-–deficient mice with apolipoprotein E atherosclerosis-prone mice and placing them on high-fat diets found less atherosclerosis, despite the PPAR- null mice having higher atherogenic lipids.101 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (f / find-01 :ARG0 (s / study-01 :ARG0-of (c / cross-01 :ARG1 (a / and :op1 (m / mouse :mod (p / protein :name (n / name :op1 "PPAR") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:PPARA_HUMAN" :prob "1.003"))) :op2 (m3 / mouse :ARG1-of (p2 / prone-01 :ARG2 (d / disease :name (n2 / name :op1 "atherosclerosis"))) :mod (p3 / protein :name (n3 / name :op1 "apolipoprotein" :op2 "E") :xref (x / xref :value "UNIPROT:APOE_HUMAN" :prob "0.702"))))) :ARG0-of (p4 / place-01 :ARG1 a :ARG2 (d2 / diet :instrument (f2 / fat :ARG1-of (h / high-02))))) :ARG1 (d3 / disease :name (n4 / name :op1 "atherosclerosis") :quant (l / less)) :concession (h3 / have-03 :ARG0 m :ARG1 (l2 / lipid :mod (a2 / atherogenic) :ARG1-of (h4 / high-02 :degree (m4 / more)))) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "101")))) # ::id bel_pmid_1295_7325.30032 # ::date 2015-04-29T07:44:00 # ::file bel_pmid_1295_7325_30032.txt # ::snt These investigators went on to demonstrate that interleukin-6 production is increased in aortic explants of PPAR-–deficient mice.95 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (g / go-on-15 :ARG1 (p / person :ARG0-of (i / investigate-01) :mod (t / this)) :purpose (d / demonstrate-01 :ARG0 p :ARG1 (i2 / increase-01 :ARG1 (p2 / produce-01 :ARG1 (p3 / protein :name (n / name :op1 "interleukin-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))) :location (e / explant :part-of (a / aorta :part-of (m / mouse :mod (p4 / protein :name (n2 / name :op1 "PPAR") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:PPARA_HUMAN" :prob "1.003"))))))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "95")))) # ::id bel_pmid_1463_5034.19774 # ::date 2015-04-29T07:59:03 # ::file bel_pmid_1463_5034_19774.txt # ::snt As demonstrated in Fig. 3A, blockade of the OX40/OX40L interaction significantly reduced the Th1-specific transcription factor T-bet to 30.8% compared with controls (p=0.007). On the other hand, expression of IL-10, a cytokine that was shown to be protective in chronic DSS-induced colitis [29], increased 3.6-fold (p=0.008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (r / reduce-01 :ARG0 (b / blockade-01 :ARG1 (i / interact-01 :ARG0 (p8 / protein :name (n / name :op1 "OX40") :xref (x3 / xref :value "UNIPROT:TNFL4_HUMAN" :prob "0.312")) :ARG1 (p9 / protein :name (n2 / name :op1 "OX40L") :xref (x4 / xref :value "UNIPROT:TNFL4_HUMAN" :prob "1.002")))) :ARG1 (p2 / protein :name (n3 / name :op1 "T-bet") :ARG0-of (t / transcribe-01) :ARG1-of (s / specific-02 :ARG2 (p7 / protein :name (n4 / name :op1 "Th1") :xref (x2 / xref :value "UNIPROT:NELFD_HUMAN" :prob "0.622"))) :xref (x / xref :value "UNIPROT:TBX21_HUMAN" :prob "0.592")) :ARG2 (s2 / significant-02) :ARG4 (p / percentage-entity :value "30.8") :ARG1-of (c2 / compare-01 :ARG2 (c3 / control-01)) :ARG1-of (d / demonstrate-01 :ARG0 (f2 / figure :mod "3A")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.007")) :snt2 (c4 / contrast-01 :ARG2 (i2 / increase-01 :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n5 / name :op1 "IL-10") :ARG1-of (m4 / mean-01 :ARG2 (c5 / cytokine :ARG0-of (p4 / protect-01 :ARG1-of (s3 / show-01) :location (d2 / disease :name (n6 / name :op1 "colitis") :mod (c6 / chronic) :ARG2-of (i3 / induce-01 :ARG0 (s6 / small-molecule :name (n7 / name :op1 "DSS") :xref (x5 / xref :value "PUBCHEM:2955" :prob "11.1749")))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c7 / cite-01 :ARG2 "29")))) :xref (x1 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003"))) :ARG2 (p6 / product-of :op1 "3.6") :ARG1-of (s5 / statistical-test-91 :ARG2 "0.008")))) # ::id bel_pmid_1463_5034.19776 # ::date 2015-04-29T09:15:18 # ::file bel_pmid_1463_5034_19776.txt # ::snt IL- 10 secretion increased 20-fold (p X 0.0001). This was accompanied by a significant, 18-fold, increase of IL-5 secretion. IFNG levels were not altered, but IL-6 secretion was reduced to 60% compared with controls. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (m / multi-sentence :snt1 (i / increase-01 :ARG1 (s / secrete-01 :ARG1 (p / protein :name (n / name :op1 "IL-10") :xref (x3 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003"))) :ARG2 (p2 / product-of :op1 "20") :ARG1-of (s5 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001"))) :snt2 (a / accompany-01 :ARG0 (i2 / increase-01 :ARG1 (s2 / secrete-01 :ARG1 (p4 / protein :name (n2 / name :op1 "IL-5") :xref (x1 / xref :value "UNIPROT:IL5_HUMAN" :prob "1.003"))) :ARG2 (p5 / product-of :op1 "18") :ARG1-of (s3 / significant-02)) :ARG1 (t / this)) :snt3 (c / contrast-01 :ARG1 (r / reduce-01 :ARG1 (s4 / secrete-01 :ARG1 (p6 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG4 (p7 / percentage-entity :value "60") :ARG1-of (c2 / compare-01 :ARG2 (c3 / control-01))) :ARG2 (a2 / alter-01 :polarity "-" :ARG1 (l2 / level :quant-of (p8 / protein :name (n4 / name :op1 "IFN-γ") :xref (x2 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.232")))))) # ::id bel_pmid_1465_6721.15754 # ::date 2015-04-29T09:38:46 # ::file bel_pmid_1465_6721_15754.txt # ::snt In neutrophils challenged with LPS, IkB-a underwent time-dependent degradation (Fig. 8C). However, in neutrophils incubated with both LPS and H2O2, no degradation of IkB-a was apparent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (u / undergo-28 :ARG1 (p / protein :name (n / name :op1 "IκB-α")) :ARG2 (d / degrade-01 :ARG1 p :ARG0-of (d2 / depend-01 :ARG1 (t / time))) :location (c / cell :name (n2 / name :op1 "neutrophil") :ARG1-of (c2 / challenge-01 :ARG0 (l / lipopolysaccharide))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "8C"))) :snt2 (h / have-concession-91 :ARG1 (a / appear-02 :polarity "-" :ARG1 (d4 / degrade-01 :ARG1 (p2 / protein :name (n4 / name :op1 "IκB-α"))) :location (c3 / cell :name (n5 / name :op1 "neutrophil") :ARG1-of (i / incubate-01 :ARG2 (a2 / and :op1 (l2 / lipopolysaccharide) :op2 (s / small-molecule :name (n7 / name :op1 "H2O2") :xref (x / xref :value "PUBCHEM:784" :prob "17.186693")))))))) # ::id bel_pmid_1465_6721.15758 # ::date 2015-04-29T11:45:21 # ::file bel_pmid_1465_6721_15758.txt # ::snt neutrophils stimulated with LPS demonstrated increased TNF-a secretion (Fig. 6A). The response was significantly attenuated by concurrent incubation of neutrophils with H2O2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (m / multi-sentence :snt1 (d / demonstrate-01 :ARG0 (c / cell :name (n / name :op1 "neutrophil") :ARG1-of (s / stimulate-01 :ARG2 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS") :xref (x2 / xref :value "PUBCHEM:53481794" :prob "9.905254")))) :ARG1 (s2 / secrete-01 :ARG1 (p / protein :name (n3 / name :op1 "TNF-α") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :ARG1-of (i / increase-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6A"))) :snt2 (a / attenuate-01 :ARG0 (i2 / incubate-01 :ARG1 (c2 / cell :name (n4 / name :op1 "neutrophil")) :ARG2 (s4 / small-molecule :name (n5 / name :op1 "H2O2") :ARG1-of (c3 / concurrent-02) :xref (x1 / xref :value "PUBCHEM:784" :prob "17.186693"))) :ARG1 (t / thing :ARG2-of (r / respond-01)) :ARG1-of (s3 / significant-02))) # ::id bel_pmid_1465_6721.15794 # ::date 2015-04-29T11:59:04 # ::file bel_pmid_1465_6721_15794.txt # ::snt As was the case for p38, ERK1/2 was both rapidly and persistently activated in neutrophils exposed to H2O2 (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (c / cell :name (n2 / name :op1 "neutrophil") :ARG1-of (e2 / expose-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "H2O2") :xref (x1 / xref :value "PUBCHEM:784" :prob "17.186693")))) :manner (a2 / and :op1 (r / rapid) :op2 (p / persistent)) :ARG1-of (r2 / resemble-01 :ARG2 (e3 / enzyme :name (n4 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id bel_pmid_1465_6721.15796 # ::date 2015-04-29T12:10:44 # ::file bel_pmid_1465_6721_15796.txt # ::snt Similar to the patterns seen with ERK1/2 and p38, JNK activation in neutrophils exposed to H2O2 was both rapid and persistent (Fig. 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (a / and :op1 (r / rapid) :op2 (p / persistent) :domain (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :location (c / cell :name (n2 / name :op1 "neutrophil") :ARG1-of (e2 / expose-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "H2O2") :xref (x2 / xref :value "PUBCHEM:784" :prob "17.186693"))))) :ARG1-of (r2 / resemble-01 :ARG2 (p2 / pattern :ARG1-of (s / see-01) :poss (a3 / and :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1/2")) :op2 (e4 / enzyme :name (n5 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id bel_pmid_1465_6721.15930 # ::date 2015-04-29T12:36:46 # ::file bel_pmid_1465_6721_15930.txt # ::snt whereas exposure of neutrophils to LPS or TNF-a resulted in increased levels of the transcriptionally active serine 133-phosphorylated form of CREB # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (c / contrast-01 :ARG2 (r / result-01 :ARG1 (e / expose-01 :ARG1 (c2 / cell :name (n / name :op1 "neutrophil")) :ARG2 (o / or :op1 (m / molecular-physical-entity :name (n2 / name :op1 "LPS") :xref (x3 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :op2 (p / protein :name (n3 / name :op1 "TNF-α") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")))) :ARG2 (l / level :ARG1-of (i / increase-01) :quant-of (p2 / protein :name (n4 / name :op1 "CREB") :part (a / amino-acid :mod "133" :name (n5 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (p3 / phosphorylate-01) :ARG0-of (a2 / activity-06 :manner (t / transcribe-01)) :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))))) # ::id bel_pmid_1465_6721.15966 # ::date 2015-04-29T13:03:52 # ::file bel_pmid_1465_6721_15966.txt # ::snt Exposure of neutrophils to LPS resulted in persistence of p38 activation that was similar to that produced by H2O2, but the increase in phosphorylated p38 was less rapid, rising above baseline values more than 5 min after LPS was added to the neutrophils. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (r / result-01 :ARG1 (e / expose-01 :ARG1 (c2 / cell :name (n / name :op1 "neutrophil")) :ARG2 (m / molecular-physical-entity :name (n2 / name :op1 "LPS") :xref (x2 / xref :value "PUBCHEM:53481794" :prob "9.905254"))) :ARG2 (p / persist-01 :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))) :ARG1-of (r2 / resemble-01 :ARG2 (p2 / produce-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "H2O2") :xref (x3 / xref :value "PUBCHEM:784" :prob "17.186693")) :ARG1 p)))) :ARG2 (r3 / rapid :degree (l / less) :domain (i / increase-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "p38") :ARG1-of (r4 / rise-01 :ARG4 (a2 / above :op1 (v / value :mod (b / baseline))) :time (a3 / after :op1 (a4 / add-02 :ARG1 m :ARG2 c2) :op1 (m2 / more-than :op1 (t / temporal-quantity :quant "5" :unit (m3 / minute))))) :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1465_6721.15968 # ::date 2015-04-29T14:02:07 # ::file bel_pmid_1465_6721_15968.txt # ::snt Phosphorylation of ERK1/2 after exposure of neutrophils with LPS was only apparent after 20-min incubation and was less intense than that produced by stimulation of neutrophils with H2O2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (a / and :op1 (a2 / appear-02 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :time (a3 / after :op1 (e2 / expose-01 :ARG1 (c / cell :name (n2 / name :op1 "neutrophil")) :ARG2 (m / molecular-physical-entity :name (n3 / name :op1 "LPS") :xref (x1 / xref :value "PUBCHEM:53481794" :prob "9.905254"))))) :mod (o / only) :time (a4 / after :op1 (i / incubate-01 :duration (t / temporal-quantity :quant "20" :unit (m2 / minute))))) :op2 (i2 / intense-02 :ARG1 p :degree (l / less) :compared-to (p2 / phosphorylate-01 :ARG1 e :ARG1-of (p3 / produce-01 :ARG0 (s / stimulate-01 :ARG1 c :ARG2 (s2 / small-molecule :name (n4 / name :op1 "H2O2") :xref (x / xref :value "PUBCHEM:784" :prob "17.186693"))))))) # ::id bel_pmid_1465_6721.15970 # ::date 2015-04-29T14:28:20 # ::file bel_pmid_1465_6721_15970.txt # ::snt JNK activation induced by LPS only became apparent 20 min after LPS was added to the cells and was of a lesser degree than that induced by H2O2 at all time points. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (a / and :op1 (b / become-01 :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG2-of (i / induce-01 :ARG0 (m / molecular-physical-entity :name (n2 / name :op1 "LPS") :xref (x1 / xref :value "PUBCHEM:53481794" :prob "9.905254")))) :ARG2 (a3 / appear-02 :ARG1 a2) :mod (o / only) :time (a4 / after :op1 (a5 / add-02 :ARG1 m :ARG2 (c / cell)) :quant (t / temporal-quantity :quant "20" :unit (m2 / minute)))) :op2 (a8 / activate-01 :ARG1 e :ARG2-of i :degree (l / less :degree (m3 / more) :time (a7 / always)) :compared-to (a6 / activate-01 :ARG1 e :ARG2-of (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "H2O2") :xref (x2 / xref :value "PUBCHEM:784" :prob "17.186693")))))) # ::id bel_pmid_1465_7354.10332 # ::date 2015-04-28T09:21:19 # ::file bel_pmid_1465_7354_10332.txt # ::snt Further, evidence is presented for TGF-beta-stimulated p160ROCK translocation to the nucleus and inhibitory phosphorylation of the cyclin-dependent kinase-activating phosphatase, Cdc25A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p / present-01 :ARG1 (e / evidence-01 :ARG1 (a / and :op1 (t / translocate-01 :ARG1 (p2 / protein :name (n / name :op1 "p160ROCK") :ARG1-of (s / stimulate-01 :ARG0 (p4 / protein :name (n2 / name :op1 "TGF-beta") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.373"))) :xref (x / xref :value "UNIPROT:ROCK1_HUMAN" :prob "1.003")) :ARG2 (n3 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8"))) :op2 (p3 / phosphorylate-01 :ARG1 (p6 / phosphatase :name (n4 / name :op1 "Cdc25A")) :ARG0-of (d / depend-01 :ARG1 (c / cyclin :ARG0-of (a2 / activate-01 :ARG1 (k / kinase)))) :ARG0-of (i / inhibit-01)))) :mod (f / further)) # ::id bel_pmid_1467_1317.33588 # ::date 2015-04-28T10:31:00 # ::file bel_pmid_1467_1317_33588.txt # ::snt p57Kip2 (Cdkn1c) is expressed in postmitotic differentiating midbrain dopamine cells. Induction of p57Kip2 expression depends on Nurr1, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m3 / multi-sentence :snt1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "p57Kip2") :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Cdkn1c") :xref (x / xref :value "UNIPROT:CDN1C_HUMAN" :prob "0.602"))) :xref (x3 / xref :value "UNIPROT:CDN1C_HUMAN" :prob "1.002")) :ARG3 (c / cell :mod (d / dopamine) :mod (m2 / midbrain) :mod (p3 / postmitotic) :ARG0-of (d2 / differentiate-01))) :snt2 (d3 / depend-01 :ARG0 (i / induce-01 :ARG2 (e2 / express-03 :ARG2 (p5 / protein :name (n4 / name :op1 "p57Kip2") :xref (x2 / xref :value "UNIPROT:CDN1C_HUMAN" :prob "1.002")))) :ARG1 (p4 / protein :name (n3 / name :op1 "Nurr1") :xref (x1 / xref :value "UNIPROT:NR4A2_HUMAN" :prob "0.602")))) # ::id bel_pmid_1475_9523.36890 # ::date 2015-04-30T02:40:11 # ::file bel_pmid_1475_9523_36890.txt # ::snt The expression of MUP2 is known to be stimulated by growth hormone (GH), through the GH receptor (GHR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signal transduction pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (k / know-01 :ARG1 (s / stimulate-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "growth" :op2 "hormone") :xref (x2 / xref :value "PUBCHEM:16129681" :prob "10.609655")) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "MUP2") :xref (x / xref :value "UNIPROT:TPC_HUMAN" :prob "0.222"))) :ARG2 (a / and :op1 (r / receptor :name (n2 / name :op1 "GH")) :op2 (e2 / enzyme :name (n4 / name :op1 "Janus" :op2 "kinase" :op3 "2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.003")) :op3 (p2 / pathway :name (n5 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "5") :ARG0-of (s3 / signal-07 :ARG1-of (t / transduce-01)))))) # ::id bel_pmid_1496_3018.30938 # ::date 2015-04-30T04:12:05 # ::file bel_pmid_1496_3018_30938.txt # ::snt Phosphorylation at Ser727 in signal transducer and activator of transcription 1 (STAT1) is essential for its activation and signal transduction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (e / essential :domain (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "727" :name (n / name :op1 "serine") :part-of (p2 / protein :name (n2 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.393")) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :purpose (a2 / and :op1 (a3 / activate-01 :ARG1 p2) :op2 (t / transduce-01 :ARG1 (s / signal-07)))) # ::id bel_pmid_1496_3018.37018 # ::date 2015-05-04T01:46:14 # ::file bel_pmid_1496_3018_37018.txt # ::snt In vitro kinase assays using the combined STAT1 proteins as substrates from immunoprecipitation and glutathione S-transferase pull down show that active ERK1, JNK1, p38 kinase, MEK1 and MSK1 stimulated phosphorylation of STAT1 (Ser727) indirectly through an unidentified factor or a downstream kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (a / assay-01 :ARG1 (k / kinase) :manner (i / in-vitro) :ARG0-of (u / use-01 :ARG1 (p / protein :name (n / name :op1 "STAT1") :ARG3-of (c / combine-01) :xref (x5 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG2 (s2 / substrate :source (a2 / and :op1 (i2 / immunoprecipitate-01) :op2 (p2 / pull-down-08 :ARG1 (e / enzyme :name (n2 / name :op1 "glutathione" :op2 "S-transferase") :xref (x4 / xref :value "UNIPROT:HPGDS_HUMAN" :prob "0.702"))))))) :ARG1 (s3 / stimulate-01 :ARG0 (a3 / and :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "JNK1") :xref (x2 / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003")) :op3 (e6 / enzyme :name (n5 / name :op1 "p38" :op2 "kinase")) :op4 (e4 / enzyme :name (n6 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op5 (e5 / enzyme :name (n7 / name :op1 "MSK1") :xref (x / xref :value "UNIPROT:KS6A5_HUMAN" :prob "1.002"))) :ARG1 (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "727" :name (n8 / name :op1 "serine") :part-of p :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (o / or :op1 (f / factor :ARG1-of (i4 / identify-01 :polarity "-")) :op2 (k3 / kinase :mod (d / downstream)))) :ARG1-of (d2 / direct-02 :polarity "-") :ARG0-of (a5 / activity-06))) # ::id bel_pmid_1496_6563.336 # ::date 2015-05-03T08:25:01 # ::file bel_pmid_1496_6563_336.txt # ::snt Inactivation of Icmt inhibited cell growth and K-Ras-induced oncogenic transformation, both in soft agar assays and in a nude mice model. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a2 / and :op1 (a / activate-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "Icmt") :xref (x / xref :value "UNIPROT:ICMT_HUMAN" :prob "0.603")) :ARG0-of (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (c / cell)) :location (a5 / and :op1 (a3 / assay-01 :ARG1 (a4 / agar :ARG1-of (s / soft-02))) :op2 (m / model :topic (m2 / mouse) :mod (n3 / nude))))) :op2 (t / transform-01 :ARG1 c :ARG2-of (i2 / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))) # ::id bel_pmid_1496_6563.338 # ::date 2015-05-03T09:28:45 # ::file bel_pmid_1496_6563_338.txt # ::snt The effect of inactivating Icmt was not limited to the inhibition of K-Ras-induced transformation: inactivation of Icmt blocked transformation by an oncogenic form of B-Raf # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a3 / and :op1 (l / limit-01 :polarity "-" :ARG1 (a / affect-01 :ARG0 (a2 / activate-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "Icmt") :xref (x / xref :value "UNIPROT:ICMT_HUMAN" :prob "0.603")))) :ARG2 (i / inhibit-01 :ARG1 (t / transform-01 :ARG2-of (i2 / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))))) :op2 (b / block-01 :ARG0 a2 :ARG1 (t2 / transform-01) :ARG3 (f / form :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :mod (e3 / enzyme :name (n3 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) # ::id bel_pmid_1496_6563.4878 # ::date 2015-05-03T10:41:41 # ::file bel_pmid_1496_6563_4878.txt # ::snt In the case of the Ras proteins, carboxyl methylation is important for targeting of the proteins to the plasma membrane. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / important :purpose (t / target-01 :ARG0 (p / protein :name (n / name :op1 "carboxyl" :op2 "methylation") :xref (x / xref :value "UNIPROT:CEL_HUMAN" :prob "0.212")) :ARG1 (p3 / protein-family :name (n2 / name :op1 "Ras")) :direction (m / membrane :part-of (p2 / plasma) :xref (x1 / xref :value "GO:0016020" :prob "0.8")))) # ::id bel_pmid_1496_6563.4882 # ::date 2015-05-10T10:29:07 # ::file bel_pmid_1496_6563_4882.txt # ::snt levels of RhoA were greatly reduced as a consequence of accelerated protein turnover. In addition, there was a large Ras/Erk1/2-dependent increase in p21(Cip1), which was probably a consequence of the reduced levels of RhoA. Deletion of p21(Cip1) restored the ability of K-Ras-Icmt(Delta/Delta) fibroblasts to grow in soft agar. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (m / multi-sentence :snt1 (r / reduce-01 :ARG1 (l / level :degree-of (p / protein :name (n / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :ARG2 (g / great) :ARG1-of (c / cause-01 :ARG0 (t / turnover :mod (p2 / protein) :ARG1-of (a / accelerate-01)))) :snt3 (r2 / restore-01 :ARG0 (d2 / delete-01 :ARG1 (p6 / protein :name (n5 / name :op1 "p21(Cip1)"))) :ARG1 (c3 / capable-01 :ARG1 (f / fibroblast :ARG0-of (c4 / contain-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "K-Ras-Icmt(Delta/Delta)")))) :ARG2 (g2 / grow-01 :ARG1 f :location (a3 / agar :ARG1-of (s / soft-02))))) :snt2 (a2 / and :op2 (i / increase-01 :ARG1 (p3 / protein :name (n2 / name :op1 "p21(Cip1)")) :ARG2 (l2 / large) :ARG0-of (d / depend-01 :ARG1 (p7 / pathway :name (n3 / name :op1 "Ras/Erk1/2"))) :ARG1-of (c2 / cause-01 :ARG0 (r3 / reduce-01 :ARG1 (l3 / level :quant-of (p5 / protein :name (n4 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")))) :mod (p4 / probable))))) # ::id bel_pmid_1496_6572.18984 # ::date 2015-05-04T00:31:42 # ::file bel_pmid_1496_6572_18984.txt # ::snt The increase in IL-6 in septic DPPI(-/-) mice, which appears to protect these mice from death, may be related to reduced DPPI-mediated activation of mast cell tryptase and other peptidases, which we show cleave IL-6 in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 20, 2015 (p / possible-01 :ARG1 (r / relate-01 :ARG1 (i / increase-01 :ARG1 (p2 / protein :name (n / name :op1 "IL-6") :ARG0-of (p3 / protect-01 :ARG1 "m" :ARG2 (d / die-01 :ARG1 "m") :ARG1-of (a2 / appear-02)) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (m / mouse :mod (s / septic) :mod (e / enzyme :name (n2 / name :op1 "DPPI") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:CATC_HUMAN" :prob "1.002")))) :ARG2 (a / activate-01 :ARG1 (a3 / and :op1 (e3 / enzyme :name (n4 / name :op1 "tryptase") :mod (c2 / cell) :mod (m4 / mast) :xref (x / xref :value "UNIPROT:Q96RZ7_HUMAN" :prob "0.371")) :op2 (p4 / peptidase :mod (o / other)) :ARG0-of (c / cleave-01 :ARG1 p2 :manner (i2 / in-vitro) :ARG1-of (s2 / show-01 :ARG0 (w / we)))) :ARG1-of (m3 / mediate-01 :ARG0 e) :ARG1-of (r2 / reduce-01)))) # ::id bel_pmid_1503_9780.28646 # ::date 2015-05-03T23:41:52 # ::file bel_pmid_1503_9780_28646.txt # ::snt Importantly, over-expression of c-Jun rescued the defects in proliferation and premature senescence observed in mkk7-/- MEFs (Fig. 7b-d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / rescue-01 :ARG0 (o2 / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "c-Jun"))) :ARG1 (d / defect :topic (a / and :op1 (p2 / proliferate-01) :op2 (s / senescence :mod (p3 / premature)) :ARG1-of (o / observe-01 :location (c / cell :name (n2 / name :op1 "MEF") :part (e2 / enzyme :name (n3 / name :op1 "mkk7") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MP2K7_HUMAN" :prob "0.603")))))) :mod (i / important) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "7b") :op2 (f3 / figure :mod "7c") :op3 (f2 / figure :mod "7d")))) # ::id bel_pmid_1503_9780.29004 # ::date 2015-05-06T00:16:11 # ::file bel_pmid_1503_9780_29004.txt # ::snt Moreover, genetic inactivation of MKK4 in MEFs resulted in reduced proliferation doubling times and premature senescence, indicating that both MKK4 and MKK7 are essential for these cellular processes (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (a4 / and :op2 (r / result-01 :ARG1 (a / activate-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "MKK4") :location (c / cell :name (n2 / name :op1 "MEF")) :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003")) :mod (g / genetic) :location c) :ARG2 (a2 / and :op1 (t2 / time :ARG1-of (r2 / reduce-01) :duration-of (d / double-01 :ARG1 (p / proliferate-01 :ARG0 c))) :op2 (s / senescence :mod (p3 / premature))) :ARG0-of (i / indicate-01 :ARG1 (e2 / essential :purpose (p2 / process-02 :location (c2 / cell) :mod (t / this)) :domain (a3 / and :op1 e :op2 (e3 / enzyme :name (n3 / name :op1 "MKK7") :xref (x / xref :value "UNIPROT:MP2K7_HUMAN" :prob "1.003"))) :ARG1-of (s2 / show-01 :polarity "-"))))) # ::id bel_pmid_1503_9780.29010 # ::date 2015-05-07T07:22:31 # ::file bel_pmid_1503_9780_29010.txt # ::snt In contrast, proliferation of hepatocytes was markedly impaired in E11.5 mkk7-/- embryos, as determined by BrdU in vivo labelling (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / contrast-01 :ARG2 (i / impair-01 :ARG1 (p / proliferate-01 :ARG0 (c / cell :name (n / name :op1 "hepatocyte"))) :manner (m / marked) :location (e / embryo :mod (e2 / enzyme :name (n2 / name :op1 "mkk7") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MP2K7_HUMAN" :prob "0.603")) :age (t2 / temporal-quantity :quant "11.5" :unit (d2 / day))) :ARG1-of (d / determine-01 :ARG0 (l / label-01 :instrument (s2 / small-molecule :name (n4 / name :op1 "BrdU") :xref (x1 / xref :value "PUBCHEM:6035" :prob "18.013371")) :manner (i2 / in-vivo))) :ARG1-of (s / show-01 :polarity "-"))) # ::id bel_pmid_1503_9780.29012 # ::date 2015-05-06T01:38:47 # ::file bel_pmid_1503_9780_29012.txt # ::snt Re-expression of wild-type MKK7 (Fig. 2c) restored the reduced proliferation of mkk7- /- MEFs to levels observed in wild-type MEFs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 10, 2015 (r / restore-01 :ARG0 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MKK7") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:MP2K7_HUMAN" :prob "1.003")) :mod (a / again) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2c"))) :ARG1 (p / proliferate-01 :ARG0 (c / cell :name (n2 / name :op1 "MEF") :part (e3 / enzyme :name (n3 / name :op1 "mkk7") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MP2K7_HUMAN" :prob "0.603"))) :ARG1-of (r2 / reduce-01)) :ARG2 (l / level :ARG1-of (o / observe-01 :location c))) # ::id bel_pmid_1503_9780.29014 # ::date 2015-05-07T07:21:47 # ::file bel_pmid_1503_9780_29014.txt # ::snt loss of MKK7 expression resulted in impaired JNK activation in MEFs at the basal level and after stimulation with tumour necrosis factor alpha (TNF-alpha) or UV irradiation (Fig. 2a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (r / result-01 :ARG1 (l / lose-02 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MKK7") :xref (x1 / xref :value "UNIPROT:MP2K7_HUMAN" :prob "1.003")))) :ARG2 (a / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG1-of (i / impair-01) :location (c / cell :name (n3 / name :op1 "MEF")) :location (l2 / level :mod (b / basal)) :time (a2 / after :op1 (s / stimulate-01 :ARG1 e3 :ARG2 (o / or :op1 (p / protein :name (n4 / name :op1 "tumour" :op2 "necrosis" :op3 "factor" :op4 "alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.352")) :op2 (i2 / irradiate-01 :ARG2 (l3 / light :mod (u / ultraviolet))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2a"))) # ::id bel_pmid_1503_9780.29016 # ::date 2015-05-11T22:59:07 # ::file bel_pmid_1503_9780_29016.txt # ::snt Importantly, cyclin B1-associated CDC2 kinase activity was markedly reduced in mkk7-/- MEFs (Fig. 4d), indicating that reduced CDC2 expression correlates with impaired cyclin B1/CDC2 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (r / reduce-01 :ARG1 (a / activity-06 :ARG0 (k / kinase :name (n / name :op1 "CDC2") :ARG1-of (a2 / associate-01 :ARG2 (p / protein :name (n2 / name :op1 "cyclin" :op2 "B1") :xref (x2 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361"))) :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "1.002"))) :mod (i / important) :manner (m / marked) :location (c / cell :name (n3 / name :op1 "MEF") :part (e / enzyme :name (n4 / name :op1 "mkk7") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MP2K7_HUMAN" :prob "0.603"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4d")) :ARG0-of (i2 / indicate-01 :ARG1 (c2 / correlate-01 :ARG1 (e2 / express-03 :ARG2 k :ARG1-of (r2 / reduce-01)) :ARG2 (a3 / activity-06 :ARG0 (s / slash :op1 p :op2 k) :ARG1-of (i3 / impair-01))))) # ::id bel_pmid_1503_9780.29022 # ::date 2015-05-07T10:01:03 # ::file bel_pmid_1503_9780_29022.txt # ::snt Similarly to mkk7-/- MEFs, cdc2 mRNA expression was downregulated in primary mkk7-/- hepatocytes (Fig. 4g). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / downregulate-01 :ARG1 (e / express-03 :ARG1 (n6 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (e5 / enzyme :name (n2 / name :op1 "cdc2") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602"))))) :location (c / cell :name (n3 / name :op1 "hepatocyte") :mod (p2 / primary) :mod (e3 / enzyme :name (n4 / name :op1 "mkk7") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MP2K7_HUMAN" :prob "0.603"))) :ARG1-of (r2 / resemble-01 :ARG2 (e4 / express-03 :ARG3 (c2 / cell :name (n5 / name :op1 "MEF") :part e3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4g"))) # ::id bel_pmid_1503_9780.29098 # ::date 2015-05-08T10:53:52 # ::file bel_pmid_1503_9780_29098.txt # ::snt These results are consistent with previous data showing that loss of JNK1/JNK2 in MEFs results in reduced proliferation17 and that inactivation of c-Jun in MEFs results in premature senescence and impaired proliferation19. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / consistent-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (d / data :time (p / previous) :ARG0-of (s / show-01 :ARG2 (a / and :op1 (r2 / result-01 :ARG1 (l / lose-02 :ARG1 (s2 / slash :op1 (e / enzyme :name (n / name :op1 "JNK1") :xref (x1 / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "JNK2") :xref (x / xref :value "UNIPROT:MK09_HUMAN" :prob "1.003")) :location (c2 / cell :name (n3 / name :op1 "MEF"))) :ARG2 (p2 / proliferate-01 :ARG1-of (r4 / reduce-01))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 "17")))) :op2 (r3 / result-01 :ARG1 (a2 / activate-01 :polarity "-" :ARG1 (p7 / protein :name (n4 / name :op1 "c-Jun") :location c2)) :ARG2 (a3 / and :op1 (s3 / senescence :mod (p3 / premature)) :op2 (p5 / proliferate-01 :ARG1-of (i2 / impair-01))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "19")))))))) # ::id bel_pmid_1503_9780.33214 # ::date 2015-05-09T04:14:05 # ::file bel_pmid_1503_9780_33214.txt # ::snt Over-expression of c-Jun in mkk7-/- MEFs restored CDC2 expression (Fig. 6c) and transactivation of the cdc2 AP-1 promoter construct to levels observed in wild-type MEFs (Fig. 6d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / restore-01 :ARG0 (o2 / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "c-Jun")) :location (c / cell :name (n2 / name :op1 "MEF") :part (e2 / enzyme :name (n3 / name :op1 "mkk7") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MP2K7_HUMAN" :prob "0.603")))) :ARG1 (a / and :op1 (e3 / express-03 :ARG2 (e / enzyme :name (n4 / name :op1 "CDC2") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "1.002")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6c"))) :op2 (t / transactivate-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (p4 / protein :name (n5 / name :op1 "cdc2" :op2 "AP-1") :ARG1-of (c2 / construct-01) :xref (x2 / xref :value "UNIPROT:MCM4_HUMAN" :prob "0.222")))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6d")))) :ARG2 (l / level :ARG1-of (o / observe-01 :location (c3 / cell :name (n6 / name :op1 "MEF") :mod (w / wild-type))))) # ::id bel_pmid_1511_5616.1726 # ::date 2015-05-05T00:21:55 # ::file bel_pmid_1511_5616_1726.txt # ::snt In this study, we found that H-Ras interacted with ASK1 to cause the inhibition of both ASK1 activity and ASK1-induced apoptosis in vivo # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "ASK1") :xref (x1 / xref :value "UNIPROT:M3K5_HUMAN" :prob "1.003")) :purpose (c / cause-01 :ARG0 e :ARG1 (i2 / inhibit-01 :ARG1 (a2 / and :op1 (a / activity-06 :ARG0 e2) :op2 (a3 / apoptosis :ARG2-of (i3 / induce-01 :ARG0 e2 :manner (i4 / in-vivo))))))) :medium (s / study-01 :mod (t / this))) # ::id bel_pmid_1512_8871.1604 # ::date 2015-05-13T22:27:24 # ::file bel_pmid_1512_8871_1604.txt # ::snt In this report, we demonstrate that the CDC25B phosphatase, an activator of cyclin dependent kinases at mitosis, is phosphorylated both in vitro and in vivo by Aurora-A on serine 353 and that this phosphorylated form of CDC25B is located at the centrosome during mitosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 25, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (a4 / and :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "353" :name (n2 / name :op1 "serine") :part-of (p3 / phosphatase :name (n4 / name :op1 "CDC25B") :ARG0-of (a / activate-01 :ARG1 (k / kinase :ARG0-of (d2 / depend-01 :ARG1 (c / cyclin))) :time (m / mitosis))) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e / enzyme :name (n3 / name :op1 "Aurora-A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.312")) :manner (a3 / and :op1 (i / in-vitro) :op2 (i2 / in-vivo))) :op2 (b2 / be-located-at-91 :ARG1 (p2 / protein) :ARG2 (c2 / centrosome) :time m)) :medium (r / report :mod (t / this))) # ::id bel_pmid_1514_3158.1864 # ::date 2015-05-09T03:18:32 # ::file bel_pmid_1514_3158_1864.txt # ::snt PTPD1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (EGF) signaling. EGF receptor phosphorylation and downstream activation of ERK 1/2 and Elk1-dependent gene transcription are enhanced by PTPD1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (a / and :op1 (a2 / activate-01 :ARG0 (p / protein :name (n / name :op1 "PTPD1") :xref (x4 / xref :value "UNIPROT:PTN21_HUMAN" :prob "1.002")) :ARG1 (p2 / protein :name (n3 / name :op1 "src" :op2 "tyrosine" :op3 "kinase") :xref (x / xref :value "UNIPROT:FYN_HUMAN" :prob "0.263"))) :op2 (i / increase-01 :ARG0 p :ARG1 (a3 / and :op1 (m2 / magnitude :poss (s / signal-07 :ARG0 (p3 / protein :name (n2 / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703")))) :op2 (d / duration :poss s)))) :snt2 (e / enhance-01 :ARG0 (p4 / protein :name (n4 / name :op1 "PTPD1") :xref (x3 / xref :value "UNIPROT:PTN21_HUMAN" :prob "1.002")) :ARG1 (a4 / and :op1 (p5 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n8 / name :op1 "EFG" :op2 "rececptor"))) :op2 (a5 / activate-01 :ARG1 (t / transcribe-01 :ARG1 (g / gene) :ARG0-of (d3 / depend-01 :ARG1 (a6 / and :op1 (e2 / enzyme :name (n6 / name :op1 "ERK" :op2 "1/2")) :op2 (p6 / protein :name (n7 / name :op1 "Elk1") :xref (x1 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.603"))))) :mod (d2 / downstream))))) # ::id bel_pmid_1515_6153.27354 # ::date 2015-05-11T23:49:03 # ::file bel_pmid_1515_6153_27354.txt # ::snt Importantly, expression of Myc–Hes1 greatly increased the amount of endogenous JAK2 coprecipitated with endogenous STAT3 (Fig. 4e), suggesting that Hes1 facilitates the interaction between JAK2 and its substrate STAT3 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / increase-01 :ARG0 (e / express-03 :ARG2 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "Myc") :xref (x3 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")) :part (p3 / protein :name (n5 / name :op1 "Hes1") :xref (x2 / xref :value "UNIPROT:HES1_HUMAN" :prob "0.603")))) :ARG1 (a / amount :quant-of (e2 / enzyme :name (n2 / name :op1 "JAK2") :mod (e3 / endogenous) :op1-of (a2 / and :op2 (p2 / protein :name (n3 / name :op1 "STAT3") :mod e3 :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (c / coprecipitate-01)) :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :ARG2 (g / great) :mod (i2 / important) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4e")) :ARG0-of (s / suggest-01 :ARG1 (f2 / facilitate-01 :ARG0 p3 :ARG1 (i3 / interact-01 :ARG0 e2 :ARG1 p2)))) # ::id bel_pmid_1515_6153.27358 # ::date 2015-05-08T12:10:25 # ::file bel_pmid_1515_6153_27358.txt # ::snt Expression of either Hes1 or Hes5 significantly activated the STAT reporter gene construct in both E13 neuroepithelial cells and MNS-70 cells, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (a / activate-01 :ARG0 (e / express-03 :ARG2 (o / or :op1 (p / protein :name (n / name :op1 "Hes1") :xref (x2 / xref :value "UNIPROT:HES1_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n2 / name :op1 "Hes5") :xref (x / xref :value "UNIPROT:HES5_HUMAN" :prob "0.603")))) :ARG1 (g / gene :name (n3 / name :op1 "STAT") :ARG0-of (r / report-01) :ARG1-of (c / construct-01) :xref (x1 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")) :ARG1-of (s / significant-02) :location (a2 / and :op1 (c3 / cell :name (n5 / name :op1 "E13") :part-of (n4 / neuroepithelium)) :op2 (c2 / cell :name (n6 / name :op1 "MNS-70")))) # ::id bel_pmid_1515_6153.29634 # ::date 2015-05-14T00:03:24 # ::file bel_pmid_1515_6153_29634.txt # ::snt Expression of an active form of Notch (Notch?E; the transmembrane and intracellular domains of mouse Notch1, comprising residues 1,704–2,531)15, significantly induced activation of a STAT-dependent reporter gene (APRE-Luc)16 in mouse cortical neuroepithelial cells derived on embryonic day (E) 13 or in the rat neural precursor MNS-70 cells17 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / induce-01 :ARG0 (e / express-03 :ARG2 (f / form :mod (p2 / protein :name (n3 / name :op1 "Notch") :ARG1-of (m3 / mean-01 :ARG2 (p9 / protein :name (n4 / name :op1 "Notch" :op2 "Delta" :op3 "E") :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (p3 / protein-segment :mod (t / transmembrane) :part-of (p5 / protein :name (n6 / name :op1 "Notch1") :mod (m2 / mouse) :xref (x3 / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.693"))) :op2 (p10 / protein-segment :mod (c2 / cell :part-of p5)) :ARG1-of (c / comprise-01 :ARG2 (v2 / value-interval :op1 (r2 / residue :mod "1704") :op2 (r4 / residue :mod "2531"))))) :xref (x / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.243"))) :xref (x2 / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.323")) :ARG0-of (a3 / activity-06)) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c6 / cite-01 :ARG2 "15")))) :ARG2 (a / activate-01 :ARG1 (g / gene :name (n / name :op1 "APRE-Luc") :ARG0-of (d / depend-01 :ARG1 (p / protein :name (n2 / name :op1 "STAT") :ARG1-of (a2 / activate-01) :xref (x4 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))) :ARG0-of (r / report-01) :xref (x1 / xref :value "UNIPROT:APR_HUMAN" :prob "0.202")) :location (o / or :op1 (c3 / cell :part-of (n7 / neuroepithelium) :mod (c4 / cortex) :ARG1-of (d2 / derive-01 :ARG1-of (d6 / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c8 / cite-01 :ARG2 "17"))) :time (d3 / day :ord (o2 / ordinal-entity :value "13") :mod (e2 / embryo)))) :op2 (c5 / cell :name (n8 / name :op1 "MNS-70") :mod (p6 / precursor) :mod (r3 / rat) :mod (n9 / neural)))) :ARG1-of (s / significant-02) :ARG1-of (d5 / describe-01 :ARG0 (p7 / publication-91 :ARG1-of (c7 / cite-01 :ARG2 "16")))) # ::id bel_pmid_1516_6036.20904 # ::date 2015-04-29T02:41:57 # ::file bel_pmid_1516_6036_20904.txt # ::snt Following depletion of both serum and Epo for 2 hours, p44/42 ERK (Phospho ERK1 (Thr202/Tyr204); phospho-ERK2 (Thr185/Tyr187)) remained active in H-ras.V12-transduced cells but not in the control cells. No difference was seen in the expression of total p44/42 ERK in the 2 populations of cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m3 / multi-sentence :snt1 (r / remain-01 :ARG1 (s2 / slash :op1 (e6 / enzyme :name (n10 / name :op1 "p44ERK") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.323")) :op2 (e7 / enzyme :name (n11 / name :op1 "p42ERK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.213")) :ARG1-of (m / mean-01 :ARG2 (a5 / and :op1 (s3 / slash :op1 (a6 / amino-acid :mod "202" :name (n / name :op1 "threonine") :part-of "e" :ARG3-of (p / phosphorylate-01) :xref (x8 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a7 / amino-acid :mod "204" :name (n2 / name :op1 "tyrosine") :part-of (e / enzyme :name (n6 / name :op1 "ERK1") :xref (x4 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :ARG1-of p :xref (x7 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (s4 / slash :op1 (a8 / amino-acid :mod "185" :name (n7 / name :op1 "threonine") :part-of "e4" :ARG3-of p :xref (x9 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a9 / amino-acid :name (n8 / name :op1 "tyrosine") :part-of (e4 / enzyme :name (n9 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG3-of p :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")))))) :ARG3 (c / contrast-01 :ARG1 (r2 / remain-01 :ARG1 s2 :ARG2 (a3 / activity-06 :ARG0 s2) :location (c5 / cell :ARG2-of (m2 / mutate-01 :value "V12") :ARG1-of (t / transduce-01 :ARG2 (e2 / enzyme :name (n5 / name :op1 "H-Ras") :xref (x3 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :ARG2 (a4 / activity-06 :polarity "-" :ARG0 s2 :location (c2 / cell :ARG0-of (c3 / control-01)))) :time (a / after :op1 (d / deplete-01 :ARG1 (a2 / and :op1 (s / serum) :op2 (s7 / small-molecule :name (n3 / name :op1 "Epo") :xref (x6 / xref :value "PUBCHEM:5288169" :prob "16.321695"))) :duration (t2 / temporal-quantity :quant "2" :unit (h2 / hour))))) :snt2 (s5 / see-01 :ARG0 (d2 / differ-02 :polarity "-" :ARG1 (e5 / express-03 :ARG2 (s6 / slash :op1 e6 :op2 e7 :mod (t3 / total)) :ARG3 (p2 / population :quant "2" :consist-of (c4 / cell)))))) # ::id bel_pmid_1519_6705.1680 # ::date 2015-04-29T02:59:12 # ::file bel_pmid_1519_6705_1680.txt # ::snt Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a2 / and :op2 (i / induce-01 :ARG0 (p / protein :name (n2 / name :op1 "GH") :xref (x2 / xref :value "UNIPROT:GGH_HUMAN" :prob "1.002")) :ARG2 (e / event :mod (s / signal-07 :ARG0-of (d / depend-01 :ARG1 (a / and :op1 (t / time) :op2 (d2 / dose))) :mod (r / rapid)) :location (c / cell-line :name (n3 / name :op1 "LNCaP")) :ARG2-of (i2 / include-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a3 / and :op1 (t2 / tyrosine-kinase :name (n / name :op1 "JAK2")) :op2 (p2 / protein :name (n5 / name :op1 "GHR") :xref (x / xref :value "UNIPROT:GHR_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n6 / name :op1 "STAT5A") :xref (x1 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :op4 (e5 / enzyme :name (n7 / name :op1 "p42/p44" :op2 "MAPK")) :op5 (e4 / enzyme :name (n8 / name :op1 "Akt/PKB")))))))) # ::id bel_pmid_1528_4181.1506 # ::date 2015-04-29T03:16:10 # ::file bel_pmid_1528_4181_1506.txt # ::snt COX-2 protein and activity measured as prostaglandin E(2) level were up-regulated in cells expressing mutant K-ras(V12); # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / upregulate-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n / name :op1 "COX-2") :xref (x / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")) :op2 (a2 / activity-06 :ARG0 e3 :ARG1-of (m / measure-01 :ARG3 (l / level :quant-of (s / small-molecule :name (n2 / name :op1 "prostaglandin" :op2 "E2") :xref (x2 / xref :value "PUBCHEM:5280360" :prob "11.978638")))))) :location (c / cell :ARG1-of (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "K-ras") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "1.001"))))) # ::id bel_pmid_1528_4181.19506 # ::date 2015-04-29T03:22:44 # ::file bel_pmid_1528_4181_19506.txt # ::snt In conclusion, the results suggest that ROS generation, through COX-2 up-regulation, may contribute to the active oncogenicity of mutant K-ras in the lung as a result of DNA damage # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c / conclude-02 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG0-of (s / suggest-01 :ARG1 (p / possible-01 :ARG1 (c2 / contribute-01 :ARG0 (g / generate-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "ROS") :xref (x2 / xref :value "PUBCHEM:128351" :prob "11.468653")) :instrument (u / upregulate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "COX-2") :xref (x1 / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")))) :ARG2 (o / oncogenicity :ARG0-of (a / activate-01) :poss (e3 / enzyme :name (n4 / name :op1 "K-ras") :ARG1-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "1.001")) :location (l / lung) :ARG2-of (r2 / result-01 :ARG1 (d2 / damage-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")))))))))) # ::id bel_pmid_1528_4181.28764 # ::date 2015-04-30T01:12:43 # ::file bel_pmid_1528_4181_28764.txt # ::snt Constitutively active mutant K-ras(V12) in E10 cells led to a highly significant (P < 0.001) increased level of peroxides, and a corresponding increase in the amount of DNA strand-break damage, compared with the parental line E10 and the vector control # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (l / lead-03 :ARG0 (e / enzyme :name (n / name :op1 "K-ras") :ARG0-of (a / activity-06 :manner (c / constitutive)) :ARG2-of (m / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "1.001")) :ARG1 (c2 / cell-line :name (n2 / name :op1 "E10")) :ARG2 (a2 / and :op1 (i / increase-01 :ARG1 (l2 / level :quant-of (p / peroxide)) :ARG2 (s2 / significant-02 :ARG1-of (h / high-02)) :ARG1-of (s3 / statistical-test-91 :ARG2 (l3 / less-than :op1 "0.001"))) :op2 (i2 / increase-01 :ARG1 (a3 / amount :degree-of (d / damage-01 :ARG1-of (c3 / cause-01 :ARG0 (b / break-01 :ARG1 (s / strand :part-of (n5 / nucleic-acid :name (n3 / name :op1 "DNA"))))))) :ARG2-of (c4 / correspond-02 :ARG1 i))) :ARG1-of (c5 / compare-01 :ARG2 (a4 / and :op1 (c6 / cell-line :name (n4 / name :op1 "E10") :mod (p2 / parent)) :op2 (c7 / control-01 :ARG0 (v / vector))))) # ::id bel_pmid_1528_4232.30936 # ::date 2015-04-30T01:33:09 # ::file bel_pmid_1528_4232_30936.txt # ::snt STAT3 activation is much stronger and more prolonged in STAT1-null mouse embryo fibroblasts than in wild-type cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a3 / and :op1 (s / strong-02 :ARG1 (a2 / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :mod (m5 / much :degree (m6 / more)) :location (f / fibroblast :mod (p3 / protein :name (n2 / name :op1 "STAT1") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :part-of (e / embryo :mod (m4 / mouse)))) :op2 (p / prolong-01 :ARG1 a2 :degree (m2 / more) :location f) :ARG1-of (c / compare-01 :ARG2 (c2 / cell :mod (w / wild-type)))) # ::id bel_pmid_1528_4232.36882 # ::date 2015-05-03T01:48:03 # ::file bel_pmid_1528_4232_36882.txt # ::snt In response to IFNgamma, SRC-family kinases are required to activate STAT3 (but not STAT1) through tyrosine phosphorylation, whereas the receptor-bound kinases JAK1 and JAK2 are required to activate both STATs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (r2 / require-01 :ARG1 (c / contrast-01 :ARG1 (a / activate-01 :ARG0 (k / kinase :ARG1-of (i / include-91 :ARG2 (p / protein-family :name (n7 / name :op1 "SRC")))) :ARG1 (p5 / protein :name (n2 / name :op1 "STAT3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :instrument (p3 / phosphorylate-01 :ARG1 (a6 / amino-acid :name (n4 / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :ARG2 (a2 / activate-01 :polarity "-" :ARG0 k :ARG1 (p6 / protein :name (n3 / name :op1 "STAT1") :xref (x3 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :instrument p3)) :ARG1-of (c2 / contrast-01 :ARG2 (r3 / require-01 :ARG1 (a3 / activate-01 :ARG0 (a4 / and :op1 (k4 / kinase :name (n6 / name :op1 "JAK1") :ARG1-of (b / bind-01 :ARG2 (r4 / receptor)) :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :op2 (k3 / kinase :name (n5 / name :op1 "JAK2") :ARG1-of b :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :ARG1 (a5 / and :op1 p5 :op2 p6)))) :ARG2-of (r / respond-01 :ARG1 (p2 / protein :name (n / name :op1 "IFNgamma") :xref (x / xref :value "UNIPROT:IFNG_HUMAN" :prob "0.692")))) # ::id bel_pmid_1529_2179.378 # ::date 2015-05-03T02:08:31 # ::file bel_pmid_1529_2179_378.txt # ::snt hyperoxia stimulated ERK-1 and ERK-2 phosphorylation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (s / stimulate-01 :ARG0 (h / hyperoxia) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "ERK-1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK-2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1529_2179.380 # ::date 2015-05-03T02:12:40 # ::file bel_pmid_1529_2179_380.txt # ::snt Collectively, these results indicate that ERK-1 regulates hyperoxia-stimulated Nrf2 phosphorylation and the subsequent ARE-driven transcriptional response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t3 / this)) :ARG1 (r2 / regulate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK-1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (p / protein :name (n / name :op1 "Nrf2") :ARG1-of (s / stimulate-01 :ARG0 (h / hyperoxia)) :xref (x2 / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602"))) :op2 (r3 / respond-01 :mod (s2 / subsequent) :mod (t2 / transcribe-01) :ARG1-of (d / drive-02 :ARG0 (p3 / protein :name (n2 / name :op1 "ARE") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "0.262")))))) :mod (c / collective)) # ::id bel_pmid_1529_2179.382 # ::date 2015-05-03T02:28:16 # ::file bel_pmid_1529_2179_382.txt # ::snt As was seen for wild-type MEFs, hyperoxia enhanced the phosphorylation of endogenous Nrf2 (lane 6) when compared with room air-exposed controls (lane 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 10, 2015 (e5 / enhance-01 :ARG0 (h / hyperoxia) :ARG1 (p2 / phosphorylate-01 :ARG1 (p / protein :name (n / name :op1 "Nrf2") :mod (e2 / endogene) :ARG1-of (d / describe-01 :ARG0 (l / lane :ARG1-of (l2 / label-01 :ARG2 "6"))) :xref (x / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602"))) :condition (c3 / compare-01 :ARG1 h :ARG2 (c2 / control :ARG1-of (e3 / expose-01 :ARG2 (a / air :mod (r / room))) :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane :ARG1-of (l4 / label-01 :ARG2 "5"))))) :ARG1-of (r2 / resemble-01 :ARG2 (t / thing :ARG1-of (s2 / see-01 :location (f / fibroblast :part-of (e4 / embryo :mod (m / mouse)) :mod (w / wild-type)))))) # ::id bel_pmid_1529_2179.384 # ::date 2015-05-03T03:11:55 # ::file bel_pmid_1529_2179_384.txt # ::snt In ERK-1+/+ MEFs, hyperoxia stimulated phosphorylation of Nrf2 (lane 4), when compared with room air-exposed controls (lane 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (s2 / stimulate-01 :ARG0 (h / hyperoxia) :ARG1 (p2 / phosphorylate-01 :ARG1 (p / protein :name (n / name :op1 "Nrf2") :xref (x1 / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602"))) :ARG1-of (d / describe-01 :ARG0 (l / lane :ARG1-of (l2 / label-01 :ARG2 "4"))) :location (f2 / fibroblast :part-of (e / embryo :mod (m / mouse)) :mod (e3 / enzyme :name (n2 / name :op1 "ERK-1") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))) :condition (c / compare-01 :ARG1 "s2" :ARG2 (c2 / control :ARG1-of (e2 / expose-01 :ARG2 (a / air :mod (r / room))) :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane :ARG1-of (l4 / label-01 :ARG2 "3")))))) # ::id bel_pmid_1529_2179.386 # ::date 2015-05-03T03:19:46 # ::file bel_pmid_1529_2179_386.txt # ::snt However, a high proportion of Nrf2 accumulated in the nucleus of both cell types following the exposure of cells to hyperoxia (Fig. 1A, right panels). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h3 / have-concession-91 :ARG1 (a / accumulate-01 :ARG1 (p / proportion :ARG1-of (h / high-02) :quant-of (p3 / protein :name (n / name :op1 "Nrf2") :xref (x / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602"))) :location (n2 / nucleus :part-of (c2 / cell :ARG1-of (t / type-03 :mod (b / both))) :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :time (a2 / after :op1 (e / expose-01 :ARG1 c2 :ARG2 (h2 / hyperoxia)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A" :location (p2 / panel :ARG1-of (r / right-04))))) # ::id bel_pmid_1529_2179.388 # ::date 2015-05-03T03:25:25 # ::file bel_pmid_1529_2179_388.txt # ::snt hyperoxia caused the translocation of Nrf2 from the cytoplasm to the nucleus within 30-60 min of exposure # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (c / cause-01 :ARG0 (h / hyperoxia) :ARG1 (t / translocate-01 :ARG1 (p / protein :name (n / name :op1 "Nrf2") :xref (x / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602")) :ARG2 (n2 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :ARG3 (c2 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :time (a / after :op1 (e / expose-01) :quant (u / up-to :op1 (v / value-interval :op1 (t2 / temporal-quantity :quant "30" :unit (m2 / minute)) :op2 (t3 / temporal-quantity :quant "60" :unit (m3 / minute))))))) # ::id bel_pmid_1529_2179.16234 # ::date 2015-05-03T05:07:08 # ::file bel_pmid_1529_2179_16234.txt # ::snt Taken together, these observations strongly support a role for NADPH oxidase-generated ROS in mediating hyperoxia-induced Nrf2 activation in pulmonary epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s4 / support-01 :ARG0 (t3 / thing :ARG1-of (o / observe-02) :ARG0-of (s / support-01 :ARG1-of (s2 / strong-02)) :mod (t4 / this)) :ARG1 (r / role :topic (m4 / mediate-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n3 / name :op1 "Nrf2") :xref (x / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602")) :ARG2-of (i / induce-01 :ARG0 (h2 / hyperoxia)) :location (c / cell :part-of (e2 / epithelium :part-of (l / lung))))) :beneficiary (s3 / small-molecule :name (n / name :op1 "ROS") :ARG1-of (g / generate-01 :ARG0 (m2 / macro-molecular-complex :part (o2 / oxidase) :part (s5 / small-molecule :name (n4 / name :op1 "NADPH") :xref (x2 / xref :value "PUBCHEM:5884" :prob "16.493546")))) :xref (x1 / xref :value "PUBCHEM:128351" :prob "11.468653"))) :condition (t6 / take-01 :ARG1 t3 :mod (t2 / together))) # ::id bel_pmid_1529_2179.22402 # ::date 2015-05-03T05:23:49 # ::file bel_pmid_1529_2179_22402.txt # ::snt hyperoxia stimulated ERK-1 and ERK-2 phosphorylation {SE: Canonical ERK phosphorylation leading directly to activation} # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (m / multi-sentence :snt1 (s / stimulate-01 :ARG0 (h / hyperoxia) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "ERK-1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK-2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))))) :snt2 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :mod (c2 / canon) :ARG0-of (l / lead-03 :ARG2 (a2 / activate-01) :ARG1-of (d / direct-02)))) # ::id bel_pmid_1529_2179.37048 # ::date 2015-05-03T05:29:47 # ::file bel_pmid_1529_2179_37048.txt # ::snt Overexpression of the ERK-1 mutant, but not the ERK-2 mutant, significantly inhibited hyperoxia-induced ARE transcription, suggesting that ERK-1 at least in part mediates Nrf2 translocation and its downstream target expression (Fig. 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (o / overexpress-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK-1") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))) :ARG1 (t3 / transcribe-01 :ARG1 (p3 / protein :name (n3 / name :op1 "ARE") :xref (x2 / xref :value "UNIPROT:AREG_HUMAN" :prob "0.262")) :ARG2-of (i3 / induce-01 :ARG0 (h / hyperoxia))) :ARG1-of (s2 / significant-02)) :ARG2 (i2 / inhibit-01 :polarity "-" :ARG0 (o2 / overexpress-01 :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK-2") :ARG1-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1 t3) :ARG0-of (s / suggest-01 :ARG1 (m3 / mediate-01 :ARG0 e2 :ARG1 (a2 / and :op1 (t2 / translocate-01 :ARG1 (p / protein :name (n4 / name :op1 "Nrf2") :xref (x3 / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.602"))) :op2 (e5 / express-03 :ARG2 p :location (d / downstream) :mod (t / target-01))) :degree (a / at-least :op1 (p2 / part)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7B"))) # ::id bel_pmid_1529_2206.19252 # ::date 2015-05-03T05:43:20 # ::file bel_pmid_1529_2206_19252.txt # ::snt The interleukin-6 (IL6) family of cytokines signals through the common receptor subunit gp130, and subsequently activates Stat3, MAPK, and PI3K. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (s / signal-07 :ARG0 (p / protein-family :name (n2 / name :op1 "interleukin-6")) :instrument (p4 / protein :name (n3 / name :op1 "gp130") :mod (s2 / subunit :part-of (r2 / receptor :mod (c2 / common))) :xref (x2 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003"))) :op2 (a2 / activate-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :op2 (e / enzyme :name (n / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op3 (e2 / enzyme :name (n5 / name :op1 "PI3K") :xref (x3 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :manner (s4 / subsequent))) # ::id bel_pmid_1529_2206.21658 # ::date 2015-05-03T05:58:35 # ::file bel_pmid_1529_2206_21658.txt # ::snt Experiments in primary mammary epithelial cells and transfected COS-7 cells revealed a p44/42 MAPK and EGFR-dependent Stat3 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / reveal-01 :ARG0 (e / experiment-01 :ARG1 (a / and :op1 (c / cell :part-of (e2 / epithelium) :mod (p2 / primary) :mod (m / mammary)) :op2 (c2 / cell-line :name (n2 / name :op1 "COS-7") :ARG1-of (t / transfect-01)))) :ARG1 (a2 / activate-01 :ARG1 (p / protein :name (n3 / name :op1 "Stat3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG0-of (d / depend-01 :ARG1 (a3 / and :op1 (e5 / enzyme :name (n4 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (s / slash :op1 (e3 / enzyme :name (n / name :op1 "p44MAPK") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.693")) :op2 (e4 / enzyme :name (n5 / name :op1 "p42MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.693"))))))) # ::id bel_pmid_1529_2206.28426 # ::date 2015-05-03T06:07:23 # ::file bel_pmid_1529_2206_28426.txt # ::snt Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution, which is partially induced by IL6 and LIF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / control-01 :ARG0 (p2 / protein :name (n / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1 (a / and :op1 (d / die-01 :ARG1 (c2 / cell)) :op2 (r / remodel-01 :ARG1 (t / tissue))) :location (g2 / gland :mod (m / mammary) :part-of (m2 / mouse)) :time (i / involution :ARG2-of (i2 / induce-01 :ARG0 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "IL6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")) :op2 (p4 / protein :name (n3 / name :op1 "LIF") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003"))) :degree (p / part)))) # ::id bel_pmid_1532_0963.2798 # ::date 2015-05-03T06:17:45 # ::file bel_pmid_1532_0963_2798.txt # ::snt We found that the Tyr701 phosphorylation kinetics of Stat1 mediated by IFN stimulation was higher when cells were incubated with IFN-alpha5 than when using IFN-alpha2. Similarly, Tyr(1054/1055) phosphorylation kinetics of Tyk2 were more intense after exposure to IFN-alpha5 than when using IFN-alpha2. Concomitantly, Tyr705 phosphorylation of Stat3 was higher after stimulation with IFN-alpha5 than with IFN-alpha2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (m / multi-sentence :snt1 (f / find-01 :ARG0 (w / we) :ARG1 (h2 / high-02 :ARG1 (k / kinetics :mod (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod "701" :name (n / name :op1 "tyrosine") :part-of (p / protein :name (n12 / name :op1 "Stat1") :xref (x9 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604")) :xref (x10 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (m2 / mediate-01 :ARG0 (s / stimulate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "IFN") :xref (x4 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.262"))))) :degree (m3 / more) :condition (i / incubate-01 :ARG1 (c / cell) :ARG2 (p4 / protein :name (n4 / name :op1 "IFN-alpha5") :xref (x6 / xref :value "UNIPROT:IFNA5_HUMAN" :prob "0.692"))) :compared-to (u / use-01 :ARG1 (p5 / protein :name (n7 / name :op1 "IFN-alpha2") :xref (x7 / xref :value "UNIPROT:IFNA2_HUMAN" :prob "0.692"))))) :snt2 (i2 / intense-02 :ARG1 (k3 / kinetics :mod (p6 / phosphorylate-01 :ARG1 (s2 / slash :op1 (a4 / amino-acid :mod "1054" :name (n2 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n6 / name :op1 "Tyk2") :xref (x3 / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603")) :xref (x12 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a5 / amino-acid :mod "1055" :name (n5 / name :op1 "tyrosine") :part-of e2 :xref (x11 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :degree (m4 / more) :compared-to (u2 / use-01 :ARG1 (p7 / protein :name (n8 / name :op1 "IFN-alpha2") :xref (x5 / xref :value "UNIPROT:IFNA2_HUMAN" :prob "0.692"))) :time (a3 / after :op1 (e / expose-01 :ARG1 (p8 / protein :name (n9 / name :op1 "IFN-alpha5") :xref (x / xref :value "UNIPROT:IFNA5_HUMAN" :prob "0.692")))) :ARG1-of (r / resemble-01)) :snt3 (h / high-02 :ARG1 (p9 / phosphorylate-01 :ARG1 (a6 / amino-acid :mod "705" :name (n13 / name :op1 "tyrosine") :part-of (p10 / protein :name (n14 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :xref (x13 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :degree (m5 / more) :time (a7 / after :op1 (s3 / stimulate-01 :ARG0 (p11 / protein :name (n15 / name :op1 "IFN-alpha5") :xref (x2 / xref :value "UNIPROT:IFNA5_HUMAN" :prob "0.692")))) :compared-to (s4 / stimulate-01 :ARG0 (p12 / protein :name (n16 / name :op1 "IFN-alpha2") :xref (x8 / xref :value "UNIPROT:IFNA2_HUMAN" :prob "0.692"))) :mod (c2 / concomitant))) # ::id bel_pmid_1535_5339.5770 # ::date 2015-05-03T08:26:03 # ::file bel_pmid_1535_5339_5770.txt # ::snt The accumulation of the ST6Gal I transcript in response to activated Ras was accompanied by an increase of alpha2,6-sialyltransferase activity and of Neu5Acalpha2,6Gal at the cell surface. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a6 / accompany-01 :ARG0 (i / increase-01 :ARG1 (a2 / activity-06 :ARG0 (a5 / and :op1 (e3 / enzyme :name (n4 / name :op1 "alpha2,6-sialyltransferase") :xref (x1 / xref :value "UNIPROT:SIA8E_HUMAN" :prob "0.382")) :op2 (e4 / enzyme :name (n5 / name :op1 "Neu5Acalpha2,6Gal"))) :location (s / surface :part-of (c / cell)))) :ARG1 (a / accumulate-01 :ARG1 (m / molecular-physical-entity :ARG0-of (t / transcribe-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ST6Gal-I") :xref (x / xref :value "UNIPROT:SIAT1_HUMAN" :prob "0.692")))) :ARG2-of (r / respond-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG1-of (a3 / activate-01) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) # ::id bel_pmid_1535_5339.19518 # ::date 2015-05-03T08:35:23 # ::file bel_pmid_1535_5339_19518.txt # ::snt Results obtained with H-RasV12 partial loss of function mutants H-RasV12S35 (Raf signal only), H-RasV12C40 (PI3-kinase signal only) and H-RasV12G37 (RalGEFs signal only) suggest that the H-Ras induction of the mouse ST6Gal I gene (Siat1) transcription is primarily routed through RalGEFs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :ARG1-of (o / obtain-01 :instrument (a / and :op1 (e / enzyme :name (n3 / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :value "V12S35") :ARG1-of (m5 / mean-01 :ARG2 (e2 / enzyme :name (n / name :op1 "H-Ras") :ARG2-of (m6 / mutate-01 :value "V12") :ARG0-of (l2 / lose-02 :ARG1 (f2 / function) :degree (p / part)) :xref (x4 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :ARG1-of (s2 / signal-07 :ARG0 (e5 / enzyme :name (n2 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :xref (x5 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e3 / enzyme :name (n4 / name :op1 "H-Ras") :ARG2-of (m2 / mutate-01 :value "V12C40") :ARG1-of (s3 / signal-07 :ARG0 (k / kinase :name (n6 / name :op1 "P13") :xref (x7 / xref :value "UNIPROT:RBL2_HUMAN" :prob "0.222"))) :xref (x3 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op3 (e4 / enzyme :name (n5 / name :op1 "H-Ras") :ARG2-of (m3 / mutate-01 :value "V12G37") :ARG1-of (s4 / signal-07 :ARG0 (p2 / pathway :name (n9 / name :op1 "RalGEF")) :mod (o2 / only)) :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :ARG1 (r2 / route-01 :ARG0 p2 :ARG1 (i / induce-01 :ARG0 (e6 / enzyme :name (n7 / name :op1 "H-Ras") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG2 (t2 / transcribe-01 :ARG1 (g / gene :name (n8 / name :op1 "ST6Gal" :op2 "I") :mod (m4 / mouse) :xref (x6 / xref :value "UNIPROT:SIAT1_HUMAN" :prob "1.002")))) :mod (p3 / primary))) # ::id bel_pmid_1535_5339.20914 # ::date 2015-05-03T09:52:19 # ::file bel_pmid_1535_5339_20914.txt # ::snt Transformation by human K-Ras or H-Ras (S12 and V12 point mutations, respectively) results in a 10-fold increase in ST6Gal I mRNA, but no alteration in the expression of related sialyltransferases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 10, 2015 (r / result-01 :ARG1 (t / transform-01 :ARG0 (o / or :op1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG2-of (m / mutate-01 :value "S2") :mod (h / human) :xref (x3 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :ARG2-of (m2 / mutate-01 :value "V12") :mod h :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))) :ARG2 (c / contrast-01 :ARG1 (i / increase-01 :ARG1 (n6 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e5 / encode-01 :ARG1 (e6 / enzyme :name (n3 / name :op1 "ST6Gal" :op2 "I") :xref (x1 / xref :value "UNIPROT:SIAT1_HUMAN" :prob "1.002")))) :ARG2 (p / product-of :op1 "10")) :ARG2 (a / alter-01 :polarity "-" :ARG1 (e3 / express-03 :ARG2 (e4 / enzyme :name (n5 / name :op1 "sialyltransferase") :ARG1-of (r3 / relate-01) :xref (x / xref :value "UNIPROT:SIA10_HUMAN" :prob "0.392")))))) # ::id bel_pmid_1536_9798.8104 # ::date 2015-05-03T10:01:46 # ::file bel_pmid_1536_9798_8104.txt # ::snt Survivin disruption by DN T34A Survivin blocked CA-Ras-induced IL-3-independent cell survival and proliferation; however, it did not affect CA-Ras-mediated enhancement of S-phase, indicating that the anti-apoptotic activity of CA-Ras is Survivin dependent while its S-phase enhancing effect is not. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG1 (a2 / affect-01 :polarity "-" :ARG0 "d" :ARG1 (e2 / enhance-01 :ARG1 (e5 / event :name (n / name :op1 "S-phase")) :ARG1-of (m / mediate-01 :ARG0 "e")) :ARG0-of (i2 / indicate-01 :ARG1 (c3 / contrast-01 :ARG1 (a3 / activity-06 :ARG0 "e" :ARG1 (o / oppose-01 :ARG1 (a4 / apoptosis)) :ARG0-of (d4 / depend-01 :ARG1 "p")) :ARG2 (d5 / depend-01 :polarity "-" :ARG0 (a5 / affect-01 :ARG2 (e4 / enhance-01 :ARG0 e5)) :ARG1 "p2")))) :ARG2 (b / block-01 :ARG0 (d / disrupt-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Survivin") :ARG2-of (m2 / mutate-01 :value "T34A" :mod "-/-")) :ARG1 (p / protein :name (n5 / name :op1 "Survivin"))) :ARG1 (a / and :op1 (s / survive-01 :ARG0 (c / cell) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n3 / name :op1 "CA-Ras") :xref (x / xref :value "UNIPROT:SYCC_HUMAN" :prob "0.222"))) :ARG0-of (d3 / depend-01 :ARG1 (p5 / protein :name (n4 / name :op1 "IL-3") :xref (x1 / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003")))) :op2 (p3 / proliferate-01 :ARG0 c :ARG1-of i :ARG0-of d3)))) # ::id bel_pmid_1536_9798.9254 # ::date 2015-05-03T10:28:07 # ::file bel_pmid_1536_9798_9254.txt # ::snt Survivin expression is up-regulated by IL-3 in Ba/F3 and CD34+ cells and inhibited by the Ras inhibitor, farnesylthiosalicylic acid. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a2 / and :op1 (u / upregulate-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :wiki "Survivin" :name (n2 / name :op1 "Survivin"))) :ARG2 (p2 / protein :wiki "Interleukin_3" :name (n3 / name :op1 "IL-3") :xref (x / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003")) :location (a / and :op1 (c2 / cell-line :wiki "-" :name (n4 / name :op1 "Ba/F3")) :op2 (c / cell-line :wiki "CD34" :name (n5 / name :op1 "CD34+")))) :op2 (i2 / inhibit-01 :ARG0 (s / small-molecule :wiki "-" :name (n7 / name :op1 "farnesylthiosalicylic" :op2 "acid") :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :wiki "Ras_subfamily" :name (n6 / name :op1 "Ras"))) :xref (x1 / xref :value "PUBCHEM:5469318" :prob "12.130847")) :ARG1 e2)) # ::id bel_pmid_1536_9798.27516 # ::date 2015-05-03T10:41:10 # ::file bel_pmid_1536_9798_27516.txt # ::snt Over-expression of constitutively activated H-Ras (CA-Ras) in Ba/F3 cells blocked down-modulation of Survivin expression, G0/G1 arrest, and apoptosis induced by IL-3 withdrawal, while dominant-negative (DN) H-Ras down-regulated Survivin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (c4 / contrast-01 :ARG1 (b / block-01 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "H-Ras") :ARG1-of (a / activate-01 :manner (c / constitutive)) :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :location (c5 / cell-line :name (n7 / name :op1 "Ba/F3"))) :ARG1 (a2 / and :op1 (d2 / downmodulate-01 :ARG1 (e3 / express-03 :ARG2 (p / protein :name (n3 / name :op1 "Survivin")))) :op2 (a3 / arrest-02 :ARG1 (c3 / cell-line :name (n4 / name :op1 "G0/G1"))) :op3 (a4 / apoptosis :ARG2-of (i / induce-01 :ARG0 (w / withdraw-01 :ARG1 (p2 / protein :name (n5 / name :op1 "IL-3") :xref (x / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003"))))))) :ARG2 (d / downregulate-01 :ARG0 (e4 / enzyme :name (n6 / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG1 p)) # ::id bel_pmid_1538_3658.21950 # ::date 2015-05-03T11:25:23 # ::file bel_pmid_1538_3658_21950.txt # ::snt By contrast, serum- and glucocorticoid-inducible kinase 1 (SGK1) was significantly induced in a p53-dependent manner after DNA damage, and this induction was through extracellular signal-regulated kinase 1/2-mediated posttranslational regulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG2 (i / induce-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "SGK1") :xref (x1 / xref :value "UNIPROT:SGK1_HUMAN" :prob "1.004")) :manner (d / depend-01 :ARG1 (p / protein :name (n / name :op1 "p53") :xref (x3 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :time (a2 / after :op1 (d2 / damage-01 :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")))) :ARG1-of (s3 / significant-02) :instrument (r2 / regulate-01 :mod (e / extracellular) :ARG1-of (r / regulate-01 :ARG0 (s / signal-07)) :ARG1-of (m / mediate-01 :ARG0 (s2 / slash :op1 (e2 / enzyme :name (n2 / name :op1 "kinase" :op2 "1") :xref (x2 / xref :value "UNIPROT:CBPN_HUMAN" :prob "0.332")) :op2 (e4 / enzyme :name (n4 / name :op1 "kinase" :op2 "2") :xref (x / xref :value "UNIPROT:ITK_HUMAN" :prob "0.293")))) :time (a4 / after :op1 (t / translate-02))))) # ::id bel_pmid_1538_9879.2572 # ::date 2015-05-03T11:56:37 # ::file bel_pmid_1538_9879_2572.txt # ::snt IL-6 family cytokines (Interleukin-6 and Oncostatin M (OSM))-increase STAT3 phosphorylation (pSTAT3), increase CCAAT enhancer binding protein delta (C/EBPdelta) gene expression # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / increase-01 :ARG0 (c / cytokine :ARG1-of (i2 / include-91 :ARG2 (p3 / protein-family :name (n7 / name :op1 "IL-6"))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (p5 / protein :name (n8 / name :op1 "Interleukin-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n9 / name :op1 "Oncostatin-M") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002"))))) :ARG1 (a2 / and :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n5 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :op2 (e / express-03 :ARG2 (g3 / gene :name (n6 / name :op1 "C/EBPdelta"))))) # ::id bel_pmid_1550_7530.2578 # ::date 2015-05-03T12:22:05 # ::file bel_pmid_1550_7530_2578.txt # ::snt results indicate that BCL-6 negatively regulates proliferation of the monocytic/macrophage lineage by suppressing an autocrine IL-6/STAT3-mediated gene expression program. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 10, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01)) :ARG1 (d / downregulate-01 :ARG0 (p3 / protein :name (n / name :op1 "BCL-6") :xref (x / xref :value "UNIPROT:BCL6_HUMAN" :prob "1.002")) :ARG1 (p / proliferate-01 :ARG0 (s2 / slash :op1 (l2 / lineage :mod (m2 / monocyte)) :op2 (l3 / lineage :mod (m3 / macrophage)))) :manner (s / suppress-01 :ARG1 (p2 / program :mod (e / express-03 :ARG2 (g2 / gene)) :ARG1-of (m / mediate-01 :ARG0 (s3 / slash :op1 (p4 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p5 / protein :name (n4 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :mod (a / autocrine))))) # ::id bel_pmid_1550_7530.32694 # ::date 2015-05-03T12:31:46 # ::file bel_pmid_1550_7530_32694.txt # ::snt Crucial to this enhanced proliferation is spontaneous interleukin 6 (IL-6) production and signal transducer and activator of transcription 3 (STAT3) activation in BCL-6(-/-) macrophages. Gene expression studies demonstrate that BCL-6 binds to several sequence motifs scattered in the IL-6 locus and can repress IL-6 transcription both in 293T cells and in macrophages. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m3 / multi-sentence :snt1 (c / crucial :prep-to (p3 / proliferate-01 :ARG1-of (e / enhance-01) :mod (t2 / this)) :domain (a2 / and :op1 (p / produce-01 :ARG1 (p2 / protein :name (n / name :op1 "interleukin-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703")) :mod (s / spontaneous)) :op2 (a3 / activate-01 :ARG1 (p8 / protein :name (n9 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.703")) :location (m4 / macrophage :mod (p4 / protein :name (n4 / name :op1 "BCL-6") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:BCL6_HUMAN" :prob "1.002")))))) :snt2 (d / demonstrate-01 :ARG0 (s2 / study-01 :ARG1 (e2 / express-03 :ARG2 (g2 / gene))) :ARG1 (a4 / and :op1 (b / bind-01 :ARG0 (p7 / protein :name (n8 / name :op1 "BCL-6") :xref (x / xref :value "UNIPROT:BCL6_HUMAN" :prob "1.002")) :ARG1 (m2 / motif :mod (s4 / sequence) :quant (s5 / several) :ARG1-of (s6 / scatter-01 :ARG2 (l / locus :location-of (g3 / gene :name (n5 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))))) :op2 (p5 / possible-01 :ARG1 (r / repress-01 :ARG0 p7 :ARG1 (t4 / transcribe-01 :ARG1 g3) :location (a5 / and :op1 (c2 / cell-line :name (n2 / name :op1 "293T")) :op2 (c3 / cell :name (n3 / name :op1 "macrophage")))))))) # ::id bel_pmid_1559_0693.2660 # ::date 2015-04-29T06:45:16 # ::file bel_pmid_1559_0693_2660.txt # ::snt ERK1/2 and JNK inactivation was associated with Ets-like transcription factor-1 (ELK-1) dephosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (a / associate-01 :ARG1 (a3 / activate-01 :polarity "-" :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x4 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n3 / name :op1 "JNK") :xref (x3 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")))) :ARG2 (d / dephosphorylate-01 :ARG1 (p2 / protein :name (n6 / name :op1 "Ets-like" :op2 "transcription" :op3 "factor-1") :ARG1-of (d2 / describe-01 :ARG2 (p / protein :name (n5 / name :op1 "ELK-1") :xref (x2 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.672"))) :xref (x / xref :value "UNIPROT:ELF1_HUMAN" :prob "0.312")))) # ::id bel_pmid_1562_3503.11656 # ::date 2015-04-29T06:55:46 # ::file bel_pmid_1562_3503_11656.txt # ::snt Rev-erbbeta is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-alpha (RORalpha) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / receptor :mod (o / orphan) :mod (n / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :domain (p / protein :name (n2 / name :op1 "Rev-erbbeta") :xref (x1 / xref :value "UNIPROT:NR1D2_HUMAN" :prob "0.692")) :ARG0-of (b / block-01 :ARG1 (t / transactivate-01 :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "retinoic" :op2 "acid-related" :op3 "orphan" :op4 "receptor-alpha") :ARG1-of (d / describe-01 :ARG2 (r2 / receptor :name (n4 / name :op1 "RORalpha"))) :xref (x / xref :value "UNIPROT:RORA_HUMAN" :prob "0.382")))) :manner (s / selective))) # ::id bel_pmid_1562_3503.33508 # ::date 2015-04-29T07:05:29 # ::file bel_pmid_1562_3503_33508.txt # ::snt Exogenous expression of a dominant negative version of mouse Rev-erbbeta decreases the expression of many genes involved in fatty acid/lipid absorption (including Cd36, and Fabp-3 and -4). Interestingly, we observed a robust induction (15-fold) in mRNA expression of interleukin-6 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (m / multi-sentence :snt1 (d / decrease-01 :ARG0 (e / express-03 :ARG2 (v / version :ARG0-of (d2 / dominate-01) :mod (p / protein :name (n / name :op1 "Rev-erbbeta") :source (m2 / mouse) :xref (x4 / xref :value "UNIPROT:NR1D2_HUMAN" :prob "0.692")) :ARG2-of (m5 / mutate-01 :mod "-/-")) :mod (e2 / exogenous)) :ARG1 (e3 / express-03 :ARG1 (g / gene :quant (m3 / many) :ARG1-of (i / involve-01 :ARG2 (a / absorb-01 :ARG1 (s / slash :op1 (a2 / acid :ARG1-of (f / fat-03)) :op2 (l / lipid)))) :ARG2-of (i2 / include-01 :ARG1 (a4 / and :op1 (g2 / gene :name (n3 / name :op1 "Cd36") :xref (x2 / xref :value "UNIPROT:CD36_HUMAN" :prob "0.653")) :op2 (g3 / gene :name (n4 / name :op1 "Fabp-3") :xref (x1 / xref :value "UNIPROT:FABPH_HUMAN" :prob "0.592")) :op3 (g4 / gene :name (n5 / name :op1 "Fabp-4") :xref (x / xref :value "UNIPROT:FABP4_HUMAN" :prob "0.592"))))))) :snt2 (o / observe-01 :ARG0 (w / we) :ARG1 (i3 / induce-01 :ARG2 (e4 / express-03 :ARG2 (n8 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e5 / encode-01 :ARG1 (p3 / protein :name (n7 / name :op1 "interleukin-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))))) :mod (r / robust :ARG1-of (m4 / mean-01 :ARG2 (p2 / product-of :op1 "15")))) :ARG2-of (i4 / interest-01))) # ::id bel_pmid_1564_7320.19184 # ::date 2015-04-29T07:22:33 # ::file bel_pmid_1564_7320_19184.txt # ::snt We report here that loss of Lsh specifically alters expression of the Cdkn1c gene The reactivation of the silenced paternal Cdkn1c allele correlates closely with a loss of CpG methylation at the 5' DMR at the Cdkn1c promoter Chromatin immunoprecipitations demonstrate a direct association of Lsh with the 5' DMR at the Cdkn1c promoter # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (r / report-01 :ARG0 (w / we) :ARG1 (a / alter-01 :ARG0 (l / lose-01 :ARG1 (p2 / protein :name (n / name :op1 "Lsh") :xref (x / xref :value "UNIPROT:NRAM1_HUMAN" :prob "0.602"))) :ARG1 (e / express-03 :ARG1 (g / gene :name (n2 / name :op1 "Cdkn1c") :xref (x4 / xref :value "UNIPROT:CDN1C_HUMAN" :prob "0.602"))) :manner (s / specific-02)) :medium (h / here)) :snt2 (c / correlate-01 :ARG1 (r2 / reactivate-01 :ARG1 (a2 / allele :mod (g2 / gene :name (n3 / name :op1 "Cdkn1c") :xref (x2 / xref :value "UNIPROT:CDN1C_HUMAN" :prob "0.602")) :mod (p3 / paternal) :ARG1-of (s2 / silence-01))) :ARG2 (l2 / lose-02 :ARG1 (m2 / methylate-01 :ARG1 (d5 / dna-sequence :name (n8 / name :op1 "5'" :op2 "DMR") :part-of (m4 / molecular-physical-entity :ARG0-of (p4 / promote-02 :ARG1 g2)) :part-of (d / dna-sequence :name (n4 / name :op1 "CpG"))))) :ARG1-of (c2 / close-10)) :snt3 (d3 / demonstrate-01 :ARG0 (i / immunoprecipitate-01 :ARG1 (m3 / macro-molecular-complex :name (n6 / name :op1 "chromatin"))) :ARG1 (a4 / associate-01 :ARG1 (p6 / protein :name (n7 / name :op1 "Lsh") :xref (x3 / xref :value "UNIPROT:NRAM1_HUMAN" :prob "0.602")) :ARG2 (d6 / dna-sequence :name (n10 / name :op1 "5'" :op2 "DMR") :part-of (m5 / molecular-physical-entity :ARG0-of (p7 / promote-02 :ARG1 (g3 / gene :name (n9 / name :op1 "Cdkn1c") :xref (x1 / xref :value "UNIPROT:CDN1C_HUMAN" :prob "0.602"))))) :ARG1-of (d4 / direct-02)))) # ::id bel_pmid_1564_7320.25946 # ::date 2015-04-29T07:49:23 # ::file bel_pmid_1564_7320_25946.txt # ::snt Entrez gene: Cyclin-dependent kinase inhibitor 1C is a tight-binding inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a / and :op1 (i2 / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "cyclin-dependent" :op2 "kinase" :op3 "inhibitor" :op4 "1C") :ARG1-of (b / bind-01 :ARG0-of (t / tight-05)) :xref (x2 / xref :value "UNIPROT:CDN1C_HUMAN" :prob "0.702")) :ARG1 (m / macro-molecular-complex :part (p2 / protein :name (n2 / name :op1 "cyclin") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.702")) :part (e / enzyme :name (n3 / name :op1 "Cdk") :xref (x1 / xref :value "UNIPROT:CDK4_HUMAN_DNA" :prob "0.22")) :quant (s / several) :mod (e2 / event :name (n5 / name :op1 "G1")))) :op2 (d / downregulate-01 :ARG1 (p3 / proliferate-01 :ARG0 (c / cell)) :ARG2 p) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG8 (n4 / name :op1 "Entrez" :op2 "gene")))) # ::id bel_pmid_1566_5273.5396 # ::date 2015-04-29T08:04:11 # ::file bel_pmid_1566_5273_5396.txt # ::snt CDK2-cyclin A1/E1 and CDK1-cyclin B1 phosphorylate BARD1 on its NH(2) terminus in vivo and in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 3, 2015 (p / phosphorylate-01 :ARG1 (p5 / protein-segment :name (n7 / name :op1 "NH2-terminus") :part-of (p6 / protein :name (n8 / name :op1 "BARD1") :xref (x4 / xref :value "UNIPROT:BARD1_HUMAN" :prob "1.003"))) :ARG2 (a / and :op1 (m / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "CDK2") :xref (x1 / xref :value "UNIPROT:CDK2_HUMAN" :prob "1.003")) :part (p2 / protein :name (n3 / name :op1 "cyclin" :op2 "A1") :xref (x / xref :value "UNIPROT:CCNA1_HUMAN" :prob "0.672"))) :op2 (m2 / macro-molecular-complex :part (p3 / protein :name (n4 / name :op1 "cyclin" :op2 "E1") :xref (x3 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361")) :part e) :op3 (m3 / macro-molecular-complex :part (e3 / enzyme :name (n5 / name :op1 "CDK1") :xref (x2 / xref :value "UNIPROT:CDK1_HUMAN" :prob "1.003")) :part (p4 / protein :name (n6 / name :op1 "cyclin" :op2 "B1") :xref (x5 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361")))) :manner (a2 / and :op1 (i / in-vivo) :op2 (i2 / in-vitro))) # ::id bel_pmid_1566_5823.1056 # ::date 2015-04-29T08:15:10 # ::file bel_pmid_1566_5823_1056.txt # ::snt We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (p / provide-01 :ARG0 (w / we) :ARG1 (e / evidence :topic (a2 / and :op1 (i / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "IRF-5") :xref (x / xref :value "UNIPROT:IRF5_HUMAN" :prob "1.002")) :ARG1 (a3 / and :op1 (p3 / protein :name (n2 / name :op1 "MyD88") :xref (x1 / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663")) :op2 (p4 / protein :name (n3 / name :op1 "TRAF6") :xref (x2 / xref :value "UNIPROT:TRAF6_HUMAN" :prob "1.003")))) :op2 (a4 / activate-01 :ARG0 a3 :ARG1 p2))) :mod (a / also)) # ::id bel_pmid_1566_5823.33196 # ::date 2015-04-29T08:19:54 # ::file bel_pmid_1566_5823_33196.txt # ::snt Here, we demonstrate that the transcription factor IRF-5 is generally involved downstream of the TLR-MyD88 signalling pathway for gene induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 gene (Irf5-/- mice), the induction of these cytokines by various TLR ligands is severely impaired # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (i / involve-01 :ARG1 (p2 / protein :name (n / name :op1 "IRF-5") :mod (f / factor :ARG0-of (t2 / transcribe-01)) :xref (x3 / xref :value "UNIPROT:IRF5_HUMAN" :prob "1.002")) :ARG1-of (g / general-02) :location (r / relative-position :op1 (p3 / pathway :name (n2 / name :op1 "TLR-MyD88") :ARG0-of (s / signal-07 :ARG1 (i2 / induce-01 :ARG2 (g2 / gene :ARG0-of (e / encode-01 :ARG1 (c2 / cytokine :ARG0-of (f2 / favor-01 :ARG1 (i3 / inflame-01)) :example (a / and :op1 (p5 / protein :name (n4 / name :op1 "interleukin-6") :ARG1-of (d3 / describe-01 :ARG2 (p8 / protein :name (n7 / name :op1 "IL-6") :xref (x6 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703")) :op2 (p6 / protein :name (n5 / name :op1 "IL-12") :xref (x5 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343")) :op3 (p7 / protein :name (n6 / name :op1 "tumour-necrosis" :op2 "factor-alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.332"))))))))) :direction (d2 / downstream))) :medium (h2 / here)) :snt2 (i4 / impair-01 :ARG1 (i5 / induce-01 :ARG0 (l / ligand :name (n9 / name :op1 "TLR") :mod (v / various)) :ARG2 (c3 / cytokine :mod (t3 / this))) :manner (s2 / severe) :location (c / cell :mod (h / haematopoietic) :source (m2 / mouse :ARG0-of (l2 / lack-01 :ARG1 (g4 / gene :name (n3 / name :op1 "IRF5") :xref (x / xref :value "UNIPROT:IRF5_HUMAN" :prob "1.003"))) :ARG1-of (d4 / describe-01 :ARG2 (m3 / mouse :mod (g3 / gene :name (n10 / name :op1 "IRF5") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:IRF5_HUMAN" :prob "1.003")))))))) # ::id bel_pmid_1567_1526.28746 # ::date 2015-04-29T08:40:12 # ::file bel_pmid_1567_1526_28746.txt # ::snt Stable knockdown of mutant KRAS(D12) in murine C26 CRC cells by RNA interference lead to a dramatic reduction of COX-2 synthesis and prostaglandin E2 production. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (l / lead-03 :ARG0 (k / knock-down-02 :ARG1 (e2 / enzyme :name (n / name :op1 "KRAS") :ARG1-of (m / mutate-01 :value "D12") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG5 (i / interfere-01 :ARG0 (n5 / nucleic-acid :name (n6 / name :op1 "RNA"))) :ARG1-of (s / stable-03) :location (c / cell-line :name (n4 / name :op1 "C26") :source (m2 / mouse) :mod (d2 / disease :name (n7 / name :op1 "CRC")))) :ARG2 (r2 / reduce-01 :ARG1 (a2 / and :op1 (s2 / synthesize-01 :ARG1 (e / enzyme :name (n2 / name :op1 "COX-2") :xref (x1 / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003"))) :op2 (p2 / produce-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "prostaglandin" :op2 "E2") :xref (x2 / xref :value "PUBCHEM:5280360" :prob "11.978638")))) :degree (d / dramatic))) # ::id bel_pmid_1568_5173.4092 # ::date 2015-04-29T08:57:34 # ::file bel_pmid_1568_5173_4092.txt # ::snt These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (m / multi-sentence :snt1 (i / indicate-01 :ARG0 (t / thing :mod (t2 / this) :ARG1-of (f / find-01)) :ARG1 (l / lead-03 :ARG0 (a / accumulate-01 :ARG0 (l3 / liver) :ARG1 (l2 / lipid)) :ARG1 (i2 / inflame-01 :ARG0 (a2 / and :op1 (a3 / activate-01 :ARG1 (m2 / macro-molecular-complex :name (n / name :op1 "NF-kappaB"))) :op2 (p / produce-01 :ARG1 (c2 / cytokine) :location (d / downstream))) :ARG1 l3 :mod (s / subacute)))) :snt2 (c / cause-01 :ARG0 (t3 / this) :ARG1 (r / resist-01 :ARG1 (p2 / protein :name (n3 / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :manner (a4 / and :op1 (l4 / local-02 :ARG2 (l5 / liver)) :op2 (s2 / system)))) # ::id bel_pmid_1568_5173.6180 # ::date 2015-04-29T09:09:44 # ::file bel_pmid_1568_5173_6180.txt # ::snt Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (i / improve-01 :ARG0 (o / or :op1 (n2 / neutralize-01 :ARG1 (p / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (s2 / system)) :op2 (i2 / inhibit-01 :ARG0 (s3 / small-molecule :name (n5 / name :op1 "salicylate") :xref (x3 / xref :value "PUBCHEM:338" :prob "13.268439")) :ARG1 (e / enzyme :name (n4 / name :op1 "IKK-beta") :xref (x1 / xref :value "UNIPROT:IKKB_HUMAN" :prob "1.002")))) :ARG1 (r / resist-01 :ARG1 (p3 / protein :name (n / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")))) # ::id bel_pmid_1568_8424.11152 # ::date 2015-04-29T09:13:46 # ::file bel_pmid_1568_8424_11152.txt # ::snt We here report that the NFkappaB and C/EBP beta controlled gene IL6 is upregulated in DDIT3- and FUS-DDIT3-expressing fibrosarcoma cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (r / report-01 :ARG0 (w / we) :ARG1 (u / upregulate-01 :ARG1 (g / gene :name (n / name :op1 "IL6") :ARG1-of (c / control-01 :ARG0 (a / and :op1 (m / macro-molecular-complex :name (n2 / name :op1 "NF-kappaB")) :op2 (p2 / protein :name (n3 / name :op1 "C/EBP" :op2 "beta")))) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")) :location (c2 / cell-line :part-of (f / fibrosarcoma) :ARG3-of (e / express-03 :ARG1 (a2 / and :op1 (p / protein :name (n4 / name :op1 "DDIT3") :xref (x1 / xref :value "UNIPROT:DDIT3_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n5 / name :op1 "FUS-DDIT3")))))) :medium (h / here)) # ::id bel_pmid_1568_8424.11196 # ::date 2015-04-29T09:24:44 # ::file bel_pmid_1568_8424_11196.txt # ::snt Knockdown experiments using siRNA against CEBPB transcripts showed that the effect of FUS-DDIT3 on IL6 expression is C/EBP beta dependent # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (e / experiment-01 :ARG1 (k / knock-down-02) :ARG0-of (u / use-01 :ARG1 (n2 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (c / counter-01 :ARG1 (g / gene :name (n3 / name :op1 "CEBPB") :ARG1-of (t / transcribe-01) :xref (x / xref :value "UNIPROT:CEBPB_HUMAN" :prob "1.004")))))) :ARG1 (d / depend-01 :ARG0 (a / affect-01 :ARG0 (p2 / protein :name (n6 / name :op1 "FUS-DDIT3")) :ARG1 (e2 / express-03 :ARG2 (p3 / protein :name (n5 / name :op1 "IL6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")))) :ARG1 (p / protein :name (n4 / name :op1 "C/EBP" :op2 "beta")))) # ::id bel_pmid_1573_6430.6098 # ::date 2015-04-29T09:56:35 # ::file bel_pmid_1573_6430_6098.txt # ::snt Our results suggest that Chk1 associates with BAD and phosphorylates the BAD protein at serine-155 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (s / suggest-01 :ARG0 (t / thing :ARG1-of (r / result-01) :poss (w / we)) :ARG1 (a / and :op1 (a2 / associate-01 :ARG1 (e / enzyme :name (n / name :op1 "Chk1") :xref (x / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604")) :ARG2 (p / protein :name (n2 / name :op1 "BAD") :xref (x1 / xref :value "UNIPROT:BAD_HUMAN" :prob "1.004"))) :op2 (p2 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "155" :name (n3 / name :op1 "serine") :part-of p :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 e))) # ::id bel_pmid_1573_6430.6100 # ::date 2015-04-29T10:04:01 # ::file bel_pmid_1573_6430_6100.txt # ::snt Furthermore, Chk1 also phosphorylates Cdc25A on serine 123 which accelerates its degradation through the ubiquitin-proteasome pathway and arrests cells in late G2-phase after DNA damage. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a2 / and :op2 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "123" :name (n / name :op1 "serine") :part-of (e / enzyme :name (n3 / name :op1 "Cdc25A") :xref (x1 / xref :value "UNIPROT:MPIP1_HUMAN" :prob "0.652")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Chk1") :xref (x / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604")) :ARG0-of (a3 / accelerate-01 :ARG1 (d / degrade-01 :ARG1 e :ARG2 (p2 / pathway :name (n4 / name :op1 "ubiquitin-proteasome")))) :ARG0-of (a4 / arrest-02 :ARG1 (c / cell) :time (a5 / after :op1 (d2 / damage-01 :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")))) :time (e3 / event :name (n7 / name :op1 "phase" :op2 "G2") :mod (l / late))) :mod (a6 / also))) # ::id bel_pmid_1574_9903.11636 # ::date 2015-04-29T10:15:47 # ::file bel_pmid_1574_9903_11636.txt # ::snt IkappaBNS was recruited to the IL-6 promoter, but not to the TNF-alpha promoter, together with p50. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (r / recruit-01 :ARG1 (p / protein :name (n / name :op1 "IkappaBNS") :accompanier (p6 / protein :name (n4 / name :op1 "p50") :xref (x1 / xref :value "UNIPROT:E4F1_HUMAN" :prob "0.212")) :xref (x3 / xref :value "UNIPROT:IKBD_HUMAN" :prob "1.002")) :ARG2 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG1-of (c / contrast-01 :ARG2 (r2 / recruit-01 :polarity "-" :ARG1 p :ARG2 (m2 / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (p5 / protein :name (n3 / name :op1 "TNF-alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))))))) # ::id bel_pmid_1574_9903.11638 # ::date 2015-04-29T10:23:42 # ::file bel_pmid_1574_9903_11638.txt # ::snt IkappaBNS resulted in impaired LPS-induced IL-6 production, but not TNF-alpha production in the murine macrophage cell line RAW264.7. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / result-01 :ARG1 (p / protein :name (n / name :op1 "IkappaBNS") :xref (x2 / xref :value "UNIPROT:IKBD_HUMAN" :prob "1.002")) :ARG2 (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (i / impair-01) :ARG2-of (i2 / induce-01 :ARG0 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS") :xref (x3 / xref :value "PUBCHEM:53481794" :prob "9.905254"))) :location (c / cell-line :name (n5 / name :op1 "RAW264.7") :consist-of (m / macrophage :mod (m2 / mouse)))) :ARG1-of (c2 / contrast-01 :ARG2 (r2 / result-01 :polarity "-" :ARG1 p :ARG2 (p4 / produce-01 :ARG1 (p5 / protein :name (n4 / name :op1 "TNF-alpha") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :location c)))) # ::id bel_pmid_1574_9903.27884 # ::date 2015-04-29T10:30:48 # ::file bel_pmid_1574_9903_27884.txt # ::snt We compared CLPMphi gene expression profiles of wild-type mice with IL-10-deficient mice, and identified genes that are selectively expressed in wild-type CLPMphi. These genes included nuclear IkappaB proteins such as Bcl-3 and IkappaBNS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (m / multi-sentence :snt1 (a / and :op1 (c / compare-01 :ARG0 (w / we) :ARG1 (p / profile :mod (e / express-03 :ARG1 (g / gene :name (n / name :op1 "CLPMphi") :xref (x3 / xref :value "UNIPROT:CALL3_HUMAN" :prob "0.202"))) :poss (m2 / mouse :mod (w2 / wild-type))) :ARG2 (m3 / mouse :ARG0-of (l / lack-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-10") :xref (x / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003"))))) :op2 (i / identify-01 :ARG0 w :ARG1 (g2 / gene :ARG1-of (e2 / express-03 :ARG3 (m4 / mouse :mod w2 :mod g) :manner (s / selective))))) :snt2 (i2 / include-01 :ARG1 (p3 / protein :name (n3 / name :op1 "IkappaB") :mod (n4 / nucleus :xref (x5 / xref :value "GO:0005634" :prob "0.8")) :example (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "Bcl-3") :xref (x2 / xref :value "UNIPROT:BCL3_HUMAN" :prob "0.632")) :op2 (p5 / protein :name (n6 / name :op1 "IkappaBNS") :xref (x4 / xref :value "UNIPROT:IKBD_HUMAN" :prob "1.002"))) :xref (x1 / xref :value "UNIPROT:IKBL1_HUMAN" :prob "0.372")) :ARG2 (g3 / gene :mod (t / this)))) # ::id bel_pmid_1575_7894.10588 # ::date 2015-04-29T10:41:20 # ::file bel_pmid_1575_7894_10588.txt # ::snt One of the phenotypes of mice with targeted disruption of the uncoupling protein-2 gene (Ucp2-/-) is greater macrophage phagocytic activity and free radical production, resulting in a striking resistance to infectious microorganisms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / include-91 :ARG1 (a / and :op1 (a2 / activity-06 :ARG0 (m2 / macrophage) :ARG1 (p / phagocytosis) :mod (g / great :degree (m / more))) :op2 (p2 / produce-01 :ARG1 (r3 / radical :ARG1-of (f / free-04))) :ARG1-of (r / result-01 :ARG2 (r2 / resist-01 :ARG1 (m5 / microorganism :ARG0-of (i2 / infect-01)) :ARG1-of (s / strike-04))) :domain (p4 / phenotype)) :ARG2 (p3 / phenotype :poss (m3 / mouse :mod (d / disrupt-01 :ARG1 (g2 / gene :name (n2 / name :op1 "uncoupling" :op2 "protein-2") :ARG1-of (d2 / describe-01 :ARG2 (g3 / gene :name (n3 / name :op1 "Ucp-2") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:UCP2_HUMAN" :prob "0.592"))) :xref (x1 / xref :value "UNIPROT:UNC50_HUMAN" :prob "0.222")) :ARG1-of (t / target-01))))) # ::id bel_pmid_1575_7894.31794 # ::date 2015-04-29T12:24:04 # ::file bel_pmid_1575_7894_31794.txt # ::snt We found that levels of nitric oxide measured in either plasma or isolated macrophages from Ucp2-/- mice are significantly elevated in response to bacterial lipopolysaccharide challenge compared with similarly treated Ucp2+/+ mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (e / elevate-01 :ARG1 (l / level :quant-of (s2 / small-molecule :name (n / name :op1 "nitric" :op2 "oxide") :xref (x3 / xref :value "PUBCHEM:145068" :prob "9.213943")) :ARG1-of (m / measure-01 :location (o / or :op1 (p / plasma) :op2 (m2 / macrophage :ARG1-of (i / isolate-01)) :source (m3 / mouse :mod (g / gene :name (n2 / name :op1 "Ucp2") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:UCP2_HUMAN" :prob "0.603")))))) :ARG1-of (s / significant-02) :ARG2-of (r / respond-01 :ARG1 (c2 / challenge-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "lipopolysaccharide") :mod (b / bacterium) :xref (x2 / xref :value "PUBCHEM:11970143" :prob "17.879841")))) :compared-to (m5 / mouse :ARG1-of (t / treat-03 :manner (r2 / resemble-01)) :mod (g2 / gene :name (n4 / name :op1 "Ucp2") :mod (w2 / wild-type) :xref (x / xref :value "UNIPROT:UCP2_HUMAN" :prob "0.603"))))) # ::id bel_pmid_1575_7894.31802 # ::date 2015-04-29T12:33:58 # ::file bel_pmid_1575_7894_31802.txt # ::snt Protein levels of iNOS and {beta}-actin were measured by Western blotting. (increased Nos2 expression) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / measure-01 :ARG1 (a2 / and :op1 (l / level :quant-of (e3 / enzyme :name (n2 / name :op1 "iNOS") :xref (x1 / xref :value "UNIPROT:NOS2_HUMAN" :prob "1.002"))) :op2 (l2 / level :quant-of (p2 / protein :name (n3 / name :op1 "beta-actin") :xref (x / xref :value "UNIPROT:ACTB_HUMAN" :prob "0.702")))) :ARG3 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "Nos2") :xref (x2 / xref :value "UNIPROT:NOS2_HUMAN" :prob "0.603")) :ARG1-of (i / increase-01)) :manner (i2 / immunoblot-01)) # ::id bel_pmid_1575_7894.31804 # ::date 2015-04-29T12:43:40 # ::file bel_pmid_1575_7894_31804.txt # ::snt nduction of inflammatory cytokines by LPS is increased in Ucp2-/- mice. A, Northern blotting. Spleen total RNA was isolated from mice treated with 4 µg/g bw LPS or PBS. RNA for IFNg, IL1b, TNF and IL6 were elevated in Ucp2-/- mice in response to LPS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (i / increase-01 :ARG1 (i2 / induce-01 :ARG0 (m8 / molecular-physical-entity :name (n2 / name :op1 "LPS") :xref (x9 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :ARG2 (c4 / cytokine :ARG0-of (i3 / inflame-01))) :location (m2 / mouse :mod (g / gene :name (n3 / name :op1 "Ucp2") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x4 / xref :value "UNIPROT:UCP2_HUMAN" :prob "0.603")))) :snt2 (t / thing :name (n4 / name :op1 "Northern" :op2 "blotting") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"))) :snt3 (i4 / isolate-01 :ARG1 (n / nucleic-acid :name (n7 / name :op1 "RNA") :quant (t2 / total) :mod (s2 / spleen)) :ARG2 (m4 / mouse :ARG1-of (t3 / treat-03 :ARG3 (o / or :op1 (m9 / molecular-physical-entity :name (n5 / name :op1 "LPS") :quant (c2 / concentration-quantity :quant "4" :unit (m5 / microgram-per-gram) :mod (w / weight :mod (b / basis))) :xref (x8 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :op2 (m10 / molecular-physical-entity :name (n6 / name :op1 "PBS") :quant c2 :xref (x7 / xref :value "PUBCHEM:14819" :prob "11.035435")))))) :snt4 (e / elevate-01 :ARG1 (a / and :op1 (n14 / nucleic-acid :name (n15 / name :op1 "RNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n8 / name :op1 "IFNg") :xref (x1 / xref :value "UNIPROT:IFNG_HUMAN" :prob "0.653")))) :op2 (n16 / nucleic-acid :name (n17 / name :op1 "RNA") :ARG0-of (e3 / encode-01 :ARG1 (p3 / protein :name (n9 / name :op1 "IL-1b") :xref (x3 / xref :value "UNIPROT:O43645_HUMAN" :prob "0.671")))) :op3 (n18 / nucleic-acid :name (n19 / name :op1 "RNA") :ARG0-of (e4 / encode-01 :ARG1 (p4 / protein :name (n10 / name :op1 "TNF") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :op4 (n20 / nucleic-acid :name (n21 / name :op1 "RNA") :ARG0-of (e5 / encode-01 :ARG1 (p5 / protein :name (n11 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :location (m6 / mouse :mod (g2 / gene :name (n12 / name :op1 "Ucp2") :ARG2-of (m7 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:UCP2_HUMAN" :prob "0.603"))) :ARG2-of (r6 / respond-01 :ARG1 (m11 / molecular-physical-entity :name (n13 / name :op1 "LPS") :xref (x6 / xref :value "PUBCHEM:53481794" :prob "9.905254"))))) # ::id bel_pmid_1576_4709.2580 # ::date 2015-04-29T12:56:13 # ::file bel_pmid_1576_4709_2580.txt # ::snt Signal transducer and activator of transcription 3 (STAT3) is activated by the IL-6 family of cytokines and growth factors. STAT3 requires phosphorylation on Ser-727, in addition to tyrosine phosphorylation on Tyr-705, to be transcriptionally active. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (m / multi-sentence :snt1 (a2 / activate-01 :ARG0 (a3 / and :op1 (p4 / protein-family :name (n4 / name :op1 "IL-6")) :op2 (g / growth-factor)) :ARG1 (p2 / protein :name (n / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "3") :ARG1-of (d / describe-01 :ARG2 (p3 / protein :name (n2 / name :op1 "STAT-3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.683"))) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.703"))) :snt2 (r / require-01 :ARG1 (p / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "727" :name (n7 / name :op1 "serine") :part-of (p7 / protein :name (n6 / name :op1 "STAT-3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.683")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (a5 / add-02 :ARG2 (p8 / phosphorylate-01 :ARG1 (a6 / amino-acid :mod "705" :name (n8 / name :op1 "tyrosine") :part-of p7 :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :purpose (a / activity-06 :ARG0 p7 :ARG1 (t2 / transcribe-01)))) # ::id bel_pmid_1577_8365.952 # ::date 2015-04-29T13:23:12 # ::file bel_pmid_1577_8365_952.txt # ::snt We found that CCR7 induced a Gi-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m3 / multi-sentence :snt1 (f / find-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "CCR7") :xref (x3 / xref :value "UNIPROT:CCR7_HUMAN" :prob "1.003")) :ARG2 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n4 / name :op1 "ERK1") :xref (x4 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n6 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op4 (e5 / enzyme :name (n7 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n / name :op1 "MAPK")))) :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Gi"))) :manner (c / control-01 :ARG0 (a3 / and :op1 e :op2 e2 :op3 e5) :ARG1 e3)))) :snt2 (r / regulate-01 :ARG0 (m4 / member :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family :name (n8 / name :op1 "MAPK")))) :ARG1 (c2 / chemotaxis :mod (c3 / cell :name (n9 / name :op1 "DC"))) :ARG1-of (c4 / contrast-01 :ARG2 (r2 / regulate-01 :polarity "-" :ARG0 m4 :ARG1 (s / speed :mod (m6 / migrate-01 :ARG0 c3)))))) # ::id bel_pmid_1577_8365.1824 # ::date 2015-04-29T13:42:29 # ::file bel_pmid_1577_8365_1824.txt # ::snt Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (i2 / interfere-01 :ARG1 (o / or :op1 (p / protein :name (n / name :op1 "Rho") :xref (x2 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")) :op2 (e / enzyme :name (n2 / name :op1 "Pyk2") :xref (x1 / xref :value "UNIPROT:FAK2_HUMAN" :prob "0.603")))) :ARG1 (a3 / and :op1 (a2 / activate-01 :polarity "-" :ARG1 (p2 / protein :name (n3 / name :op1 "cofilin") :xref (x / xref :value "UNIPROT:COF1_HUMAN" :prob "0.342"))) :op2 (s / speed :mod (m / migrate-01 :ARG0 (c2 / cell :name (n4 / name :op1 "DC")))))) :ARG2 (a4 / affect-01 :polarity "-" :ARG0 i2 :ARG1 (c3 / chemotaxis))) # ::id bel_pmid_1579_3228.19202 # ::date 2015-04-29T13:47:26 # ::file bel_pmid_1579_3228_19202.txt # ::snt AdipoQ (23), has been suggested to serve as an insulin-sensitizing factor (24). The mRNA level in mesenteric fat from Tg mice was markedly decreased # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (m / multi-sentence :snt1 (s / suggest-01 :ARG1 (s2 / serve-01 :ARG0 (p / protein :name (n / name :op1 "AdipoQ") :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "23"))) :xref (x1 / xref :value "UNIPROT:ADIPO_HUMAN" :prob "0.602")) :ARG1 (f / factor :ARG0-of (s3 / sensitize-01 :ARG2 (p2 / protein :name (n2 / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "24")))) :snt2 (d / decrease-01 :ARG1 (l / level :quant-of (n4 / nucleic-acid :name (n3 / name :op1 "mRNA")) :location (f2 / fat :mod (m3 / mesentery) :source (m4 / mouse :mod (t / transgenic)))) :manner (m2 / marked))) # ::id bel_pmid_1579_3228.19204 # ::date 2015-04-30T05:45:29 # ::file bel_pmid_1579_3228_19204.txt # ::snt Angiotensinogen mRNA, which is up-regulated by glucocorticoids (26), was substantially increased in Tg mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 1, 2015 (i / increase-01 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "angiotensinogen") :xref (x / xref :value "UNIPROT:ANGT_HUMAN" :prob "0.702"))) :ARG1-of (u / upregulate-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "glucocorticoid") :xref (x1 / xref :value "PUBCHEM:9838147" :prob "9.430335")) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "26"))))) :degree (s / substantial) :location (m / mouse :mod (t / transgenic))) # ::id bel_pmid_1579_3228.19208 # ::date 2015-04-30T05:50:58 # ::file bel_pmid_1579_3228_19208.txt # ::snt The mRNA for resistin, which has been suggested to be involved in glucose homeostasis (25), was significantly decreased in Tg mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / decrease-01 :ARG1 (n3 / nucleic-acid :wiki "Messenger_RNA" :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :wiki "Resistin" :name (n2 / name :op1 "resistin") :xref (x / xref :value "UNIPROT:RETN_HUMAN" :prob "0.702"))) :ARG1-of (i / involve-01 :ARG2 (h / homeostasis :mod (g / glucose)) :ARG1-of (s / suggest-01) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "25"))))) :ARG2 (s2 / significant-02) :location (m / mouse :mod (t / transgenic))) # ::id bel_pmid_1579_3228.19210 # ::date 2015-04-30T06:05:49 # ::file bel_pmid_1579_3228_19210.txt # ::snt model. Tumor necrosis factor- alpha (TNF-a), a fat cell- derived cytokine that can cause insulin resistance (3, 22), was significantly elevated in serum of Tg mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (m2 / model) :snt2 (e / elevate-01 :ARG1 (p / protein :name (n / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha") :ARG1-of (d / describe-01 :ARG2 (p2 / protein :name (n2 / name :op1 "TNF-a") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))) :mod (c / cytokine :ARG1-of (d2 / derive-01 :ARG2 (c2 / cell :mod (f / fat))) :ARG0-of (c3 / cause-01 :ARG1 (r / resist-01 :ARG1 (p4 / protein :name (n3 / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :ARG1-of (p3 / possible-01)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 (a / and :op1 "3" :op2 "22"))))) :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.382")) :ARG1-of (s / significant-02) :location (s2 / serum :source (m3 / mouse :mod (t / transgenic))))) # ::id bel_pmid_1579_3228.21750 # ::date 2015-04-30T06:16:15 # ::file bel_pmid_1579_3228_21750.txt # ::snt Genetic disruption of these pathways improves insulin resistance (86,87). Heterozygous IKKbeta+/- mice, fed with a high-fat diet or crossed with obese ob/ob mice, showed a significant decrease in blood glucose levels and improved insulin resistance (87). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (i / improve-01 :ARG0 (d / disrupt-01 :ARG1 (p / pathway :mod (t / this)) :mod (g / gene)) :ARG1 (r / resist-01 :ARG1 (p2 / protein :name (n / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 "86" :op2 "87"))))) :snt2 (s / show-01 :ARG0 (m2 / mouse :mod (p6 / protein :name (n2 / name :op1 "IKKbeta") :ARG2-of (m3 / mutate-01 :mod "+/-") :xref (x2 / xref :value "UNIPROT:IKKB_HUMAN" :prob "0.692")) :ARG2-of (f / feed-01 :ARG1 (d5 / diet :ARG0-of (c3 / contain-01 :ARG1 (f2 / fat :ARG1-of (h2 / high-02)))) :op1-of (o / or :op2 (c4 / cross-01 :ARG1 (a3 / and :op1 m2 :op2 (m4 / mouse :mod (o2 / obese) :mod (o3 / ob-ob)))))) :mod (h / heterozygous)) :ARG1 (a2 / and :op1 (d3 / decrease-01 :ARG1 (l / level :quant-of (g3 / glucose) :location (b / blood)) :ARG2 (s2 / significant-02)) :op2 (r2 / resist-01 :ARG1 (p4 / protein :name (n3 / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :ARG1-of (i2 / improve-01))) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "87"))))) # ::id bel_pmid_1579_3228.21980 # ::date 2015-04-30T06:42:27 # ::file bel_pmid_1579_3228_21980.txt # ::snt JNK1 knockout mice gain less weight and are protected against diet-induced insulin resistance or insulin resistance associated with a genetic model of obesity (ob/ob) (86). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (g / gain-02 :ARG0 (m / mouse :ARG1-of (k / knock-out-03 :ARG0 (e / enzyme :name (n / name :op1 "JNK1") :xref (x1 / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003")))) :ARG1 (w / weight :quant (l / less))) :op2 (p / protect-01 :ARG1 m :ARG2 (o / or :op1 (r / resist-01 :ARG1 (p2 / protein :name (n2 / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :ARG2-of (i / induce-01 :ARG0 (d / diet))) :op2 (r2 / resist-01 :ARG1 p2 :ARG1-of (a2 / associate-01 :ARG2 (m3 / model :mod (g2 / genetic) :mod (o2 / obesity) :ARG1-of (d2 / describe-01 :ARG2 (s / string-entity :value "ob/ob"))))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "86")))) # ::id bel_pmid_1579_3228.28348 # ::date 2015-04-30T06:53:33 # ::file bel_pmid_1579_3228_28348.txt # ::snt and in mice, IL-6 treatment causes insulin resistance in skeletal muscle and in liver most likely due to defects in IRS-1 (and IRS-2, respectively)-associated PI 3-kinase activity (56). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op2 (c / cause-01 :ARG0 (t / treat-03 :ARG1 (m2 / mouse) :ARG3 (p / protein :name (n / name :op1 "IL-6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1 (r / resist-01 :ARG1 (p2 / protein :name (n2 / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :ARG1-of (c2 / cause-01 :ARG0 (d / defect-01 :ARG0 (a3 / activity-06 :ARG0 (e / enzyme :name (n3 / name :op1 "PI" :op2 "3-kinase") :xref (x2 / xref :value "UNIPROT:PK3C3_HUMAN" :prob "0.313")) :ARG1-of (a4 / associate-01 :ARG2 (a5 / and :op1 (p3 / protein :name (n4 / name :op1 "IRS-1") :xref (x1 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n5 / name :op1 "IRS-2") :xref (x3 / xref :value "UNIPROT:IRS2_HUMAN" :prob "1.003")) :manner (r2 / respective))))) :ARG1-of (l / likely-01 :degree (m / most))) :location (a2 / and :op1 (m3 / muscle :mod (s / skeleton)) :op2 (l2 / liver)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "56")))) # ::id bel_pmid_1583_1486.36764 # ::date 2015-04-30T07:03:23 # ::file bel_pmid_1583_1486_36764.txt # ::snt As previously reported, expression of Dok-R in EGF-stimulated cells resulted in a dramatic decrease in the induction of Erk-2 activation as well as a delay in the activation kinetics (Fig. 1), while Dok-R {Delta}PRR completely lost this Erk-2 attenuating capacity, which demonstrates that the key residues for mediating this attenuation are found within the PRR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / result-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Dok-R")) :ARG3 (c2 / cell :ARG1-of (s / stimulate-01 :ARG2 (p5 / protein :name (n2 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :ARG2 (a2 / and :op1 (d / decrease-01 :ARG1 (i / induce-01 :ARG2 (a / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk-2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.633")))) :degree (d2 / dramatic)) :op2 (d3 / delay-01 :ARG1 (k / kinetics :mod (a3 / activate-01)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "1"))) :ARG2 (l / lose-02 :ARG0 (p2 / protein :name (n4 / name :op1 "Dok-R" :op2 "delta" :op3 "PRR")) :ARG1 (c5 / capable-01 :ARG2 (a4 / attenuate-01 :ARG1 e2)) :ARG1-of (c3 / complete-02) :ARG0-of (d5 / demonstrate-01 :ARG1 (f2 / find-01 :ARG1 (r2 / residue :ARG1-of (k2 / key-02 :ARG2 (m / mediate-01 :ARG1 a4))) :location (p3 / protein :name (n5 / name :op1 "PRR") :xref (x1 / xref :value "UNIPROT:PRLHR_HUMAN" :prob "0.282"))))) :ARG1-of (r3 / report-01 :time (p4 / previous))) # ::id bel_pmid_1584_5922.27198 # ::date 2015-04-30T07:28:29 # ::file bel_pmid_1584_5922_27198.txt # ::snt The isoform SH2-Bbeta modulates JAK2 activity by binding to the phosphorylated enzyme, further increasing its activity. in an animal model of GH excess in which JAK2 is not phosphorylated, although it is increased in the membrane-fraction, both the level of SH2-Bbeta, and especially its association to membranes, are augmented. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (m / multi-sentence :snt1 (m2 / modulate-01 :ARG0 (p / protein :name (n / name :op1 "SH2-Bbeta") :mod (i / isoform) :xref (x4 / xref :value "UNIPROT:SH2B1_HUMAN" :prob "0.212")) :ARG1 (a / activity-06 :ARG0 "e") :manner (b / bind-01 :ARG1 p :ARG2 (e / enzyme :name (n2 / name :op1 "JAK2") :ARG1-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :ARG0-of (i2 / increase-01 :ARG1 a :degree (f / further)))) :snt2 (a2 / augment-01 :ARG1 (a3 / and :op1 (l / level :quant-of (p3 / protein :name (n3 / name :op1 "SH2-Bbeta") :xref (x1 / xref :value "UNIPROT:SH2B1_HUMAN" :prob "0.212"))) :op2 (a4 / associate-01 :ARG1 p3 :ARG2 (m3 / membrane :xref (x5 / xref :value "GO:0016020" :prob "0.8")) :mod (e3 / especially))) :location (m4 / model :mod (a5 / animal) :mod (e4 / exceed-01 :ARG0 (p4 / protein :name (n4 / name :op1 "GH") :xref (x3 / xref :value "UNIPROT:GGH_HUMAN" :prob "1.002"))) :location-of (p5 / phosphorylate-01 :polarity "-" :ARG1 (e5 / enzyme :name (n5 / name :op1 "JAK2") :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :concession (i3 / increase-01 :ARG1 e5 :location (f2 / fraction :mod m3)))))) # ::id bel_pmid_1587_9117.18042 # ::date 2015-04-30T07:47:15 # ::file bel_pmid_1587_9117_18042.txt # ::snt In response to IFN-gamma, C/EBP-beta undergoes phosphorylation at a critical ERK1/2 phosphorylation motif. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (u / undergo-28 :ARG1 (p2 / protein :name (n / name :op1 "C/EBP-beta")) :ARG2 (p / phosphorylate-01 :ARG1 (p4 / protein-segment :part-of p2 :ARG1-of (c / critical-02 :ARG2 p)) :ARG2 (a / and :op1 (e / enzyme :name (n3 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :ARG2-of (r / respond-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IFN-gamma") :xref (x1 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")))) # ::id bel_pmid_1596_4826.36122 # ::date 2015-04-30T07:55:26 # ::file bel_pmid_1596_4826_36122.txt # ::snt Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3theta but not 14-3-3beta or -sigma preventing Y15 phosphorylation of Cdc2 by WEE1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (m / multi-sentence :snt1 (i / identify-01 :ARG1 (a / amino-acid :mod "642" :name (n2 / name :op1 "serine") :xref (x15 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (s / site :ARG1-of (p / phosphorylate-01) :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Akt") :xref (x7 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))))) :snt2 (a2 / affect-01 :polarity "-" :ARG0 (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "642" :name (n5 / name :op1 "serine") :xref (x13 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (a3 / activity-06 :ARG0 (k / kinase :name (n4 / name :op1 "WEE1Hu") :xref (x8 / xref :value "UNIPROT:WEE1_HUMAN" :prob "0.672")))) :snt3 (r / reveal-01 :ARG0 (w / we) :ARG1 (p4 / promote-02 :ARG0 (p5 / phosphorylate-01 :ARG1 (a5 / amino-acid :mod "642" :name (n6 / name :op1 "serine") :xref (x12 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (b2 / be-located-at-91 :ARG1 (k2 / kinase :name (n7 / name :op1 "WEE1Hu") :xref (x3 / xref :value "UNIPROT:WEE1_HUMAN" :prob "0.672")) :ARG2 (c / cytoplasm :xref (x10 / xref :value "GO:0005737" :prob "0.8"))))) :snt4 (m2 / mediate-01 :ARG0 (b / bind-01 :ARG1 (k3 / kinase :name (n8 / name :op1 "WEE1Hu") :xref (x2 / xref :value "UNIPROT:WEE1_HUMAN" :prob "0.672")) :ARG2 (p6 / protein :name (n9 / name :op1 "14-3-3" :op2 "theta") :xref (x5 / xref :value "UNIPROT:1433T_HUMAN" :prob "0.313")) :ARG0-of (d2 / depend-01 :ARG1 (p2 / phosphorylate-01))) :ARG1 (t / translocate-01 :ARG2 (c2 / cytoplasm :xref (x9 / xref :value "GO:0005737" :prob "0.8")) :ARG3 (n / nucleus :xref (x11 / xref :value "GO:0005634" :prob "0.8"))) :ARG0-of (p9 / prevent-01 :ARG1 (p10 / phosphorylate-01 :ARG1 (a6 / amino-acid :mod "15" :name (n12 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n13 / name :op1 "Cdc2") :xref (x6 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :xref (x14 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (k4 / kinase :name (n14 / name :op1 "WEE1") :xref (x4 / xref :value "UNIPROT:WEE1_HUMAN" :prob "1.003")))) :ARG1-of (c3 / contrast-01 :ARG2 (m3 / mediate-01 :polarity "-" :ARG0 (b3 / bind-01 :ARG1 k3 :ARG2 (o / or :op1 (p7 / protein :name (n10 / name :op1 "14-3-3" :op2 "beta") :xref (x / xref :value "UNIPROT:1433F_HUMAN" :prob "0.273")) :op2 (p8 / protein :name (n11 / name :op1 "14-3-3" :op2 "sigma") :xref (x1 / xref :value "UNIPROT:1433S_HUMAN" :prob "0.303")))) :ARG1 t)))) # ::id bel_pmid_1610_2754.11486 # ::date 2015-04-30T08:14:02 # ::file bel_pmid_1610_2754_11486.txt # ::snt KLF5 accelerates mitotic entry in H-Ras-transformed cells by transcriptionally activating cyclin B1 and Cdc2, which leads to an increase in cyclin B1/Cdc2 kinase activity # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a / accelerate-01 :ARG0 (p / protein :name (n / name :op1 "KLF5") :xref (x2 / xref :value "UNIPROT:KLF5_HUMAN" :prob "1.003")) :ARG1 (e / enter-01 :ARG0 (m / mitosis) :ARG1 (c / cell :ARG1-of (t / transform-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :xref (x3 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :manner (a2 / activate-01 :ARG0 p :ARG1 (a3 / and :op1 (p2 / protein :name (n3 / name :op1 "cyclin" :op2 "B1") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361")) :op2 (k / kinase :name (n4 / name :op1 "Cdc2") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602"))) :mod (t2 / transcribe-01) :ARG0-of (l / lead-03 :ARG2 (i / increase-01 :ARG1 (a4 / activity-06 :ARG0 a3))))) # ::id bel_pmid_1613_9224.21092 # ::date 2015-04-30T08:30:42 # ::file bel_pmid_1613_9224_21092.txt # ::snt We report that phosphorylation-induced turnover of endogenous N-myc protein in CGNPs increases during mitosis, due to increased priming phosphorylation of N-myc for GSK-3beta. The priming phosphorylation requires the Cdk1 complex, whose cyclin subunits are indirect Sonic hedgehog targets # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / multi-sentence :snt1 (r / report-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG1 (t / turnover :ARG2-of (i2 / induce-01 :ARG0 (p / phosphorylate-01)) :mod (p2 / protein :name (n / name :op1 "N-myc") :mod (e / endogenous) :xref (x3 / xref :value "UNIPROT:Q9UMQ5_HUMAN" :prob "1.001")) :location (c2 / cell :name (n6 / name :op1 "CGNP"))) :time (m2 / mitosis) :ARG1-of (c / cause-01 :ARG0 (p3 / phosphorylate-01 :ARG1 p2 :ARG2 (e2 / enzyme :name (n2 / name :op1 "GSK-3beta") :xref (x2 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :mod (p4 / priming) :ARG1-of (i3 / increase-01))))) :snt2 (r2 / require-01 :ARG0 (p5 / phosphorylate-01 :mod (p6 / priming)) :ARG1 (m3 / macro-molecular-complex :part (p7 / protein :name (n4 / name :op1 "cyclin") :ARG1-of (t2 / target-01 :ARG2 (p8 / protein :name (n5 / name :op1 "Sonic" :op2 "hedgehog") :xref (x4 / xref :value "UNIPROT:SHH_HUMAN" :prob "0.352")) :mod (i4 / indirect)) :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.702")) :part (e3 / enzyme :name (n3 / name :op1 "Cdk1") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.603"))))) # ::id bel_pmid_1614_1211.1764 # ::date 2015-04-30T08:44:28 # ::file bel_pmid_1614_1211_1764.txt # ::snt We conclude that TNFalpha and IGF-I may additively contribute to fibrosis during intestinal inflammation. TNFR2 is a primary mediator of fibrogenic actions of TNFalpha acting through ERK1/2 to stimulate proliferation and through STAT3 to stimulate TIMP-1 and inhibit collagen degradation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m2 / multi-sentence :snt1 (c / conclude-01 :ARG0 (w / we) :ARG1 (p2 / possible-01 :ARG1 (c2 / contribute-01 :ARG0 (a / and :op1 (p3 / protein :name (n / name :op1 "TNF-alpha") :xref (x4 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n2 / name :op1 "IGF-I") :xref (x6 / xref :value "UNIPROT:IGF1_HUMAN" :prob "1.003"))) :ARG2 (f / fibrosis) :manner (a2 / add-02) :time (i / inflame-01 :ARG1 (i2 / intestine))))) :snt2 (m3 / mediate-01 :ARG0 (p5 / protein :name (n3 / name :op1 "TNFR2") :xref (x7 / xref :value "UNIPROT:TNR1B_HUMAN" :prob "1.002")) :ARG1 (a3 / act-01 :ARG0 (p7 / protein :name (n4 / name :op1 "TNF-alpha") :xref (x5 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG1 (f2 / fibrogenesis)) :mod (p6 / primary) :manner (a8 / and :op1 (a4 / act-02 :ARG0 p5 :path (a5 / and :op1 (e / enzyme :name (n5 / name :op1 "ERK1") :xref (x8 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n6 / name :op1 "ERK2") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :purpose (s / stimulate-01 :ARG0 p5 :ARG1 (p8 / proliferate-01))) :op2 (a6 / act-02 :ARG0 p5 :path (p9 / protein :name (n7 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :purpose (a7 / and :op1 (s2 / stimulate-01 :ARG0 p5 :ARG1 (p10 / protein :name (n8 / name :op1 "TIMP-1") :xref (x2 / xref :value "UNIPROT:TIMP1_HUMAN" :prob "1.002"))) :op2 (i3 / inhibit-01 :ARG0 p5 :ARG1 (d2 / degrade-01 :ARG1 (p11 / protein :name (n9 / name :op1 "collagen") :xref (x1 / xref :value "UNIPROT:COLLAGEN_I_HUMAN" :prob "1.002"))))))))) # ::id bel_pmid_1614_1211.2914 # ::date 2015-04-30T09:03:20 # ::file bel_pmid_1614_1211_2914.txt # ::snt Tumor necrosis factor (TNF) alpha has defined proinflammatory # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 3, 2015 (d / define-01 :ARG1 (p3 / protein :name (n3 / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha") :ARG1-of (d2 / describe-01 :ARG2 (p2 / protein :name (n2 / name :op1 "TNF") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))) :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.382")) :ARG2 (f / favor-01 :ARG0 (p / protein) :ARG1 (i / inflame-01))) # ::id bel_pmid_1614_1211.10448 # ::date 2015-04-30T09:03:46 # ::file bel_pmid_1614_1211_10448.txt # ::snt TNFalpha, but not IGF-I, induced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and reduced matrix metalloproteinases-2 activity and collagen degradation. TNFalpha also activated ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (a / and :op1 (i2 / induce-01 :ARG0 (p / protein :name (n / name :op1 "TNF-alpha") :ARG1-of (c / contrast-01 :ARG2 (p2 / protein :name (n2 / name :op1 "IGF-I") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "1.003"))) :xref (x8 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG2 (e / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "tissue" :op2 "inhibitor" :op3 "of" :op4 "metalloproteinase-1") :ARG1-of (d / describe-01 :ARG2 (p4 / protein :name (n4 / name :op1 "TIMP-1") :xref (x6 / xref :value "UNIPROT:TIMP1_HUMAN" :prob "1.002"))) :xref (x5 / xref :value "UNIPROT:TIMP1_HUMAN" :prob "0.392")))) :op2 (r / reduce-01 :ARG0 p :ARG1 (a2 / and :op1 (a3 / activity-06 :ARG0 (e2 / enzyme :name (n5 / name :op1 "matrix" :op2 "metalloproteinase-2") :xref (x4 / xref :value "UNIPROT:MMP2_HUMAN" :prob "0.702"))) :op2 (d2 / degrade-01 :ARG1 (p5 / protein :name (n6 / name :op1 "collagen") :xref (x7 / xref :value "UNIPROT:COLLAGEN_I_HUMAN" :prob "1.002")))))) :snt2 (a4 / activate-01 :ARG0 (p6 / protein :name (n7 / name :op1 "TNF-alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG1 (a6 / and :op1 (e3 / enzyme :name (n8 / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n9 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :mod (a5 / also))) # ::id bel_pmid_1614_1211.19760 # ::date 2015-04-30T09:12:07 # ::file bel_pmid_1614_1211_19760.txt # ::snt These responses to TNFalpha were absent in TNFR2-/- and TNFR1/2-/- myofibroblasts, whereas TNFR1-/- cells showed similar responses to WT. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu May 7, 2015 (c / contrast-01 :ARG1 (a3 / absent-01 :ARG1 (t / thing :ARG2-of (r2 / respond-01 :ARG1 (p / protein :name (n / name :op1 "TNF-alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))) :mod (t3 / this)) :ARG2 (a / and :op1 (m2 / myofibroblast :mod "p2") :op2 (m3 / myofibroblast :mod (p3 / protein :name (n3 / name :op1 "TNFR1") :ARG2-of "m" :xref (x1 / xref :value "UNIPROT:TNR1A_HUMAN" :prob "1.002")) :mod (p2 / protein :name (n2 / name :op1 "TNFR2") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:TNR1B_HUMAN" :prob "1.002"))))) :ARG2 (s / show-01 :ARG0 (c2 / cell :mod p3) :ARG1 (t2 / thing :ARG2-of (r3 / respond-01) :ARG1-of (r / resemble-01 :ARG2 (c3 / cell :mod (w / wild-type)))))) # ::id bel_pmid_1614_9052.2664 # ::date 2015-04-30T09:23:31 # ::file bel_pmid_1614_9052_2664.txt # ::snt Additionally, genistein enhanced RA-induced neuronal differentiation by increasing the activation of extracellular signal-related kinase 1/2 (ERK1/2) via phosphorylation at Thr183 and Tyr185 in 3-7 days. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (e / enhance-01 :ARG0 (s / small-molecule :name (n / name :op1 "genistein") :xref (x7 / xref :value "PUBCHEM:5280961" :prob "15.344161")) :ARG1 (d3 / differentiate-01 :ARG1 (n2 / neuron) :ARG2-of (i / induce-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "RA") :xref (x4 / xref :value "PUBCHEM:1533" :prob "9.432343")))) :manner (i2 / increase-01 :ARG1 (a / activate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n4 / name :op1 "extracellular" :op2 "signal-related" :op3 "kinase" :op4 "1") :ARG1-of (d4 / describe-01 :ARG2 (e4 / enzyme :name (n6 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))) :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.393")) :op2 (e3 / enzyme :name (n5 / name :op1 "extracellular" :op2 "signal-related" :op3 "kinase" :op4 "2") :ARG1-of (d5 / describe-01 :ARG2 (e5 / enzyme :name (n7 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.393")))) :manner (p / phosphorylate-01 :ARG1 (a3 / and :op1 (a4 / amino-acid :mod "183" :name (n8 / name :op1 "tyrosine") :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a5 / amino-acid :mod "185" :name (n9 / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :ARG1-of (a6 / add-02) :time (b / between :op1 (t / temporal-quantity :quant "3" :unit (d / day)) :op2 (t2 / temporal-quantity :quant "7" :unit (d2 / day)))) # ::id bel_pmid_1617_7098.35020 # ::date 2015-04-29T03:38:18 # ::file bel_pmid_1617_7098_35020.txt # ::snt Ag stimulation of Lyn unique domain transfectants was accompanied by enhanced phosphorylation of MEK and ERK-2, which are required for leukotriene C4 (LTC4) release, and production of LTC4 was increased 3- to 5-fold, compared with cells transfected with vector alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (a / and :op1 (a2 / accompany-01 :ARG0 (p / phosphorylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK-2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1-of (r / require-01 :ARG0 (r2 / release-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "leukotriene" :op2 "C4") :xref (x3 / xref :value "PUBCHEM:3907" :prob "12.681629"))))) :ARG1-of (e4 / enhance-01)) :ARG1 (s / stimulate-01 :ARG0 (a4 / antigen) :ARG1 (m / molecular-physical-entity :ARG1-of (t / transfect-01 :ARG2 (d / domain :mod (u / unique) :part-of (e3 / enzyme :name (n3 / name :op1 "Lyn") :xref (x / xref :value "UNIPROT:LYN_HUMAN" :prob "0.604"))))))) :op2 (i / increase-01 :ARG1 (p2 / produce-01 :ARG1 s2) :ARG2 (v / value-interval :op1 (p3 / product-of :op1 "3") :op2 (p4 / product-of :op1 "5")) :compared-to (c / cell :ARG1-of (t2 / transfect-01 :ARG2 (v2 / vector :mod (a5 / alone)))))) # ::id bel_pmid_1618_2244.3476 # ::date 2015-04-29T04:08:13 # ::file bel_pmid_1618_2244_3476.txt # ::snt Our analyses using epiregulin-deficient mice with mixed and inbred genetic backgrounds revealed that epiregulin deficiency results in the reduction of IL-6 production levels in both cell types upon peptidoglycan stimulation, and that the extent of this reduction is more evident under the BALB/c background compared with the C57BL/6J background. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 8, 2015 (r / reveal-01 :ARG0 (t / thing :ARG1-of (a / analyze-01 :ARG0 (w2 / we) :instrument (m / mouse :ARG0-of (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "epiregulin") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "0.703"))) :ARG0-of (h / have-03 :ARG1 (a2 / and :op1 (b / background :ARG3-of (m2 / mix-01) :mod (g / genetic)) :op2 (b2 / background :ARG1-of (i / inbreed-00) :mod g)))))) :ARG1 (a3 / and :op1 (r2 / result-01 :ARG1 l :ARG2 (r3 / reduce-01 :ARG1 (l2 / level :degree-of (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :prep-in a2 :condition (s / stimulate-01 :ARG1 (m3 / macro-molecular-complex :name (n3 / name :op1 "peptidoglycan"))))) :op2 (e / evident :domain (e2 / extent :degree-of r3) :degree (m4 / more) :prep-under (b3 / background :mod (c / cell-line :name (n4 / name :op1 "BALB/c"))) :compared-to (b4 / background :mod (c2 / cell-line :name (n5 / name :op1 "C57BL/6J")))))) # ::id bel_pmid_1618_2244.26736 # ::date 2015-04-29T04:26:09 # ::file bel_pmid_1618_2244_26736.txt # ::snt rmEP reduced IL-18 expression in WT- and EP –/–-derived keratinocytes at 8 h after stimulation, and there was no obvious difference between WT and EP –/– (Fig. 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 8, 2015 (a / and :op1 (r / reduce-01 :ARG0 (p / protein :name (n / name :op1 "rmEP")) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "IL-18") :xref (x / xref :value "UNIPROT:IL18_HUMAN" :prob "1.003")) :ARG3 (a2 / and :op1 (k / keratinocyte :mod (w / wild-type)) :op2 (k2 / keratinocyte :ARG3-of (e2 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "EP") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:ACBP_HUMAN" :prob "1.002")))))) :time (a3 / after :op1 (s / stimulate-01) :quant (t / temporal-quantity :quant "8" :unit (h / hour)))) :op2 (d / differ-02 :ARG1 a2 :ARG1-of (o2 / obvious-01 :polarity "-")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3D"))) # ::id bel_pmid_1620_4059.41796 # ::date 2015-04-29T04:42:35 # ::file bel_pmid_1620_4059_41796.txt # ::snt Here, we show that ras-transformed cancer cells can also induce TSP-1 down-regulation in their adjacent nontransformed stromal fibroblasts, but not in endothelial cells, in a paracrine and distance-dependent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (c3 / contrast-01 :ARG1 (p / possible-01 :ARG1 (i / induce-01 :ARG0 (c / cell :ARG1-of (t / transform-01 :ARG0 (e / enzyme :name (n / name :op1 "ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.203"))) :mod (d5 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :ARG2 (d / downregulate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "TSP-1") :xref (x / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672")) :location (f / fibroblast :mod (s2 / stroma) :ARG1-of (t2 / transform-01 :polarity "-") :ARG2-of (b / border-01) :poss e)) :mod (a / also) :manner (p5 / paracrine) :ARG0-of (d3 / depend-01 :ARG1 (d4 / distance)))) :ARG2 (p4 / possible-01 :polarity "-" :ARG1 (i2 / induce-01 :ARG0 c :ARG2 (d2 / downregulate-01 :ARG1 p3 :location (c4 / cell :mod (e2 / endothelium)))))) :location (h / here)) # ::id bel_pmid_1620_4059.41800 # ::date 2015-04-29T05:04:55 # ::file bel_pmid_1620_4059_41800.txt # ::snt Indeed, MDF528 nontransformed dermal fibroblasts, like many other types of normal nonangiogenic cells (12), express copious amounts of TSP-1 (Fig. 1B, lane 1), which becomes undetectable in their H-ras -expressing counterparts (528ras1 cells; Fig. 1B, lane 2; refs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / express-03 :ARG2 (a / amount :mod (c3 / copious) :quant-of (p / protein :name (n3 / name :op1 "TSP-1") :ARG1-of (b / become-01 :ARG2 (d3 / detect-01 :ARG1 p :ARG1-of (p4 / possible-01 :polarity "-")) :location (c4 / counterpart :ARG3-of (e2 / express-03 :ARG2 (e4 / enzyme :name (n4 / name :op1 "H-ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.601"))) :poss "f" :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "1B" :mod (l2 / lane :mod "2")) :ARG2 (n7 / name :op1 "528ras1" :op2 "cells")) :ARG1-of (d6 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01))))) :xref (x1 / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672"))) :ARG3 (f / fibrolast :mod (d / dermis) :ARG1-of (t / transform-01 :polarity "-") :mod (c / cell-line :name (n5 / name :op1 "MDF528"))) :mod (i / indeed) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1B" :mod (l / lane :mod "1"))) :ARG1-of (r / resemble-01 :ARG2 (e3 / express-03 :ARG3 (c2 / cell :mod (a2 / angiogenic :polarity "-") :ARG1-of (n / normal-02) :ARG1-of (t2 / type-03 :mod (m / many) :mod (o / other)))) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 "12"))))) # ::id bel_pmid_1620_4059.41802 # ::date 2015-04-29T05:36:03 # ::file bel_pmid_1620_4059_41802.txt # ::snt Down-regulation of thrombospondin-1 promoter activity in nontumorigenic dermal fibroblasts exposed to tumor cell-derived soluble mediator(s). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (e / expose-01 :ARG1 (d / downregulate-01 :ARG1 (a / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n / name :op1 "thrombospondin-1") :xref (x / xref :value "UNIPROT:TSP1_HUMAN" :prob "0.702")))) :location (f / fibroblast :mod (d2 / dermis) :ARG0-of (c2 / cause-01 :polarity "-" :ARG1 (t / tumor))))) :ARG2 (m2 / molecular-physical-entity :ARG0-of (m3 / mediate-01) :ARG1-of (d3 / derive-01 :ARG2 (c / cell :source t)) :mod (s / soluble))) # ::id bel_pmid_1620_4059.41804 # ::date 2015-04-29T05:55:09 # ::file bel_pmid_1620_4059_41804.txt # ::snt Interestingly, exposure of MDF-EGFP/TSP-1 fibroblasts to conditioned medium derived rom H-ras-expressing 528ras1 cancer cells (528ras1 conditioned medium) induced a near complete inhibition of GFP fluorescence as indicated by both confocal microscopy and flow cytometry (Fig. 2C, left). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / induce-01 :ARG0 (e / expose-01 :ARG1 (f / fibroblast :mod (c2 / cell-line :name (n2 / name :op1 "MDF-EGFP/TSP-1"))) :ARG2 (m / medium :ARG1-of (c / condition-01) :ARG1-of (d2 / derive-01 :ARG2 (c3 / cell :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "H-ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.601"))) :mod (c5 / cell-line :name (n4 / name :op1 "528ras1")) :mod (d4 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :ARG1-of (d / describe-01 :ARG2 (n9 / name :op1 "528ras1" :op2 "conditioned" :op3 "medium")))) :ARG2 (i3 / inhibit-01 :ARG1 (f2 / fluoresce-01 :ARG1 (p2 / protein :name (n6 / name :op1 "GFP") :xref (x1 / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342"))) :ARG1-of (c6 / complete-02 :degree (n5 / near))) :ARG2-of (i2 / interest-01) :ARG1-of (i4 / indicate-01 :instrument (a / and :op1 (m2 / microscopy :mod (c4 / cofocal)) :op2 (c7 / cytometry :mod (f4 / flow))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "2C" :ARG1-of (l / left-20))))) # ::id bel_pmid_1620_4059.41806 # ::date 2015-04-29T06:16:04 # ::file bel_pmid_1620_4059_41806.txt # ::snt Again, this effect was paralleled by comparable decreases in TSP-1 mRNA and protein expression in these cells exposed to 528ras1 conditioned medium (Fig. 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 8, 2015 (p / parallel-01 :ARG0 (e / effect :mod (t / this)) :ARG1 (d / decrease-01 :ARG1 (e2 / express-03 :ARG2 (a / and :op1 (n4 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 "p3")) :op2 (p3 / protein :name (n3 / name :op1 "TSP-1") :xref (x / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672"))) :ARG3 (c2 / cell :mod (t2 / this) :ARG1-of (e3 / expose-01 :ARG2 (m / medium :ARG1-of (c3 / condition-01) :mod (c4 / cell-line :name (n2 / name :op1 "528ras1")))))) :ARG1-of (c / comparable-03)) :mod (a2 / again) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2C"))) # ::id bel_pmid_1620_4059.41808 # ::date 2015-04-29T06:22:23 # ::file bel_pmid_1620_4059_41808.txt # ::snt In addition to the aforementioned paracrine properties of 528ras1 cells, we observed that also conditioned medium of human colorectal cancer cells harboring a mutant K-ras oncogene (DLD-1), but not that of a DLD-1 variant with genetically disrupted K-ras allele (DKO-3 cells), efficiently suppressed the activity of the TSP-1 reporter gene in MDF-EGFP/ TSP-1 cells (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p2 / property :mod (p3 / paracrine) :ARG1-of (m / mention-01 :time (b / before)) :poss (c2 / cell-line :name (n3 / name :op1 "528ras1"))) :op1 (c10 / contrast-01 :ARG1 (s / suppress-01 :ARG0 (m2 / medium :ARG1-of (c / condition-01) :mod (c5 / cell :source (h / human) :ARG0-of (h2 / harbor-01 :ARG1 (g4 / gene :name (n6 / name :op1 "K-ras") :ARG2-of (m3 / mutate-01) :ARG0-of (c6 / cause-01 :ARG1 (d6 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "1.001"))) :ARG1-of (d4 / describe-01 :ARG2 (n12 / name :op1 "DLD-1")) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :mod (a4 / also)) :ARG1 (a2 / activity-06 :ARG0 (g / gene :ARG0-of (r2 / report-01 :ARG1 (p4 / protein :name (n4 / name :op1 "TSP-1") :xref (x / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672"))))) :location (c3 / cell-line :name (n5 / name :op1 "MDF-EGFP/TSP-1")) :ARG2-of (e / efficient-01)) :ARG2 (s2 / suppress-01 :polarity "-" :ARG0 (m4 / medium :ARG1-of (c4 / condition-01) :mod (v / variant :poss (c9 / cell-line :name (n7 / name :op1 "DLD-1")) :ARG1-of (d5 / describe-01 :ARG2 (n10 / name :op1 "DKO-3" :op2 "cells")) :ARG0-of (h3 / have-03 :ARG1 (a5 / allele :mod (g3 / gene :name (n2 / name :op1 "K-ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "1.001")) :ARG1-of (d3 / disrupt-01 :mod (g2 / genetic)))))) :ARG1 a2 :location c3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id bel_pmid_1620_4059.41810 # ::date 2015-04-29T07:21:22 # ::file bel_pmid_1620_4059_41810.txt # ::snt Once again, we observed that expression of TSP-1 by the nontransformed MDFB6 fibroblasts was precipitously down-regulated when these cells were incubated with B6ras conditioned medium (Fig. 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (o2 / observe-01 :ARG0 (w / we) :ARG1 (d / downregulate-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :wiki "Thrombospondin_1" :name (n2 / name :op1 "TSP-1") :xref (x / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672")) :ARG3 (f / fibroblast :mod (c / cell-line :wiki "-" :name (n3 / name :op1 "MDFB6")) :ARG1-of (t / transform-01 :polarity "-"))) :manner (p2 / precipitous) :condition (i / incubate-01 :ARG1 f :ARG2 (m / medium :ARG1-of (c2 / condition-01) :mod (c3 / cell-line :wiki "-" :name (n4 / name :op1 "B6ras"))))) :mod (a / again :mod (o / once)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5A"))) # ::id bel_pmid_1620_4059.41812 # ::date 2015-04-29T07:46:33 # ::file bel_pmid_1620_4059_41812.txt # ::snt A, immortalized dermal fibroblasts (MDFB6) down-regulate TSP-1 protein expression in the presence of conditioned medium from their H-ras-transformed counterparts (B6ras CM); quantification of representative Western blot. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (m / multi-sentence :snt1 (d / downregulate-01 :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "TSP-1") :xref (x / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672"))) :location (f / fibroblast :mod (d2 / dermis) :ARG1-of (i / immortalize-03) :ARG1-of (d3 / describe-01 :ARG2 (n5 / name :op1 "MDFB6"))) :condition (p / present-02 :ARG1 (m2 / medium :ARG1-of (c / condition-01) :mod (c2 / counterpart :poss f :ARG1-of (t / transform-01 :ARG0 (e / enzyme :name (n6 / name :op1 "H-ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.601")))) :ARG1-of (d5 / describe-01 :ARG2 (n8 / name :op1 "B6ras" :op2 "CM"))))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "A")) :snt2 (q / quantify-01 :ARG1 (i2 / immunoblot-01 :ARG0-of (r2 / represent-01)))) # ::id bel_pmid_1620_4059.41814 # ::date 2015-04-29T07:53:25 # ::file bel_pmid_1620_4059_41814.txt # ::snt B, absence of TSP-1 down-regulation in Id1-deficient dermal fibroblasts exposed to conditioned medium of ras-transformed (528ras1 CM and B6ras CM) and neu-transformed (528neu CM) tumor cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 8, 2015 (a / absent-01 :ARG1 (d2 / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "TSP-1") :xref (x3 / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672")) :location (f2 / fibroblast :mod (d3 / dermis) :ARG0-of (l / lack-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Id1") :xref (x / xref :value "UNIPROT:ID1_HUMAN" :prob "0.623"))) :ARG1-of (e2 / expose-01 :ARG2 (m / medium :ARG1-of (c / condition-01) :mod (c2 / cell :source (t / tumor) :ARG1-of (t2 / transform-01 :ARG0 (e / enzyme :name (n / name :op1 "ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.203"))) :ARG1-of (t3 / transform-01 :ARG0 (p3 / protein :name (n4 / name :op1 "neu") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603")))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"))) # ::id bel_pmid_1620_4059.41816 # ::date 2015-04-29T08:22:53 # ::file bel_pmid_1620_4059_41816.txt # ::snt Paracrine effects of various ras-driven cancer cells were detected at the level of TSP-1 protein, mRNA, and promoter activity (Fig. 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (d2 / detect-01 :ARG1 (e / effect :mod (p / paracrine) :poss (c / cell :mod (v / various) :ARG1-of (d3 / drive-02 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.203"))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :location (a / and :op1 (p3 / protein :name (n3 / name :op1 "TSP-1") :xref (x / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672")) :op2 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 p3)) :op3 (a2 / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 p3)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "2C"))) # ::id bel_pmid_1620_4059.41820 # ::date 2015-04-29T08:37:24 # ::file bel_pmid_1620_4059_41820.txt # ::snt In contrast, abrogation of TSP-1 suppression was observed (Fig. 6C) when MDF528 cells were incubated with dimethylsphingosine, a specific inhibitor of sphingosine kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (a / abrogate-01 :ARG1 (s / suppress-01 :ARG1 (p / protein :name (n / name :op1 "TSP-1") :xref (x1 / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672"))) :condition (i2 / incubate-01 :ARG1 (c2 / cell-line :name (n2 / name :op1 "MDF528")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "dimethylsphingosine") :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "sphingosine" :op2 "kinase") :xref (x / xref :value "UNIPROT:SPHK1_HUMAN" :prob "0.393"))) :ARG1-of (s3 / specific-02) :xref (x2 / xref :value "PUBCHEM:4285" :prob "9.006685")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C")))) # ::id bel_pmid_1620_4059.41822 # ::date 2015-04-29T08:43:53 # ::file bel_pmid_1620_4059_41822.txt # ::snt Thus, suppression of TSP-1 promoter activity by fraction 2 of 528ras1 conditioned medium was moderately sensitive to pertussis toxin but was completely abolished by dimethylsphingosine. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / infer-01 :ARG1 (c / contrast-01 :ARG1 (s / sensitive-03 :ARG0 (s2 / suppress-01 :ARG0 (f / fraction :mod "2" :ARG1-of (i2 / include-91 :ARG2 (m2 / medium :ARG1-of (c2 / condition-01) :mod (c3 / cell-line :name (n2 / name :op1 "528ras1"))))) :ARG1 (a2 / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n / name :op1 "TSP-1") :xref (x / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672")))))) :ARG1 (s3 / small-molecule :name (n3 / name :op1 "pertussis" :op2 "toxin") :xref (x1 / xref :value "PUBCHEM:135154" :prob "3.65835")) :ARG1-of (m3 / moderate-03)) :ARG2 (a / abolish-01 :ARG0 (s4 / small-molecule :name (n4 / name :op1 "dimethylsphingosine") :xref (x2 / xref :value "PUBCHEM:4285" :prob "9.006685")) :ARG1 s2 :ARG1-of (c4 / complete-02)))) # ::id bel_pmid_1625_4190.34278 # ::date 2015-04-29T08:51:46 # ::file bel_pmid_1625_4190_34278.txt # ::snt Table 3. Alteration of Gene Expression Specially Associated with p53 and H-ras Status in Skin Tumorigenesis upregulated # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / alter-01 :ARG1 (e2 / express-03 :ARG1 (g / gene) :ARG1-of (a2 / associate-01 :ARG2 (a3 / and :op1 (s / status :mod (p / protein :name (n2 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :op2 (s2 / status :mod (e / enzyme :name (n3 / name :op1 "H-ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.601")))) :ARG1-of (s4 / special-02))) :subevent-of (c / create-01 :ARG1 (t / tumor :mod (s3 / skin))) :ARG1-of (d / describe-01 :ARG0 (t2 / table :mod "3"))) # ::id bel_pmid_1628_7813.37026 # ::date 2015-04-29T09:06:48 # ::file bel_pmid_1628_7813_37026.txt # ::snt It is known that there are two isoforms of ERK, ERK1 and ERK2, and they phosphorylate and activate various transcription factors, such as Elk-1 and Elk-2. These transcription factors regulate expression of diverse genes that relates to the proliferation and growth of the cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / multi-sentence :snt1 (k / know-01 :ARG1 (a4 / and :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :mod (i / isoform :mod (p5 / protein-family :name (n4 / name :op1 "ERK"))) :ARG0-of (p / phosphorylate-01 :ARG1 (f / factor :ARG0-of (t / transcribe-01) :example (a / and :op1 (p2 / protein :name (n5 / name :op1 "Elk-1") :xref (x / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :op2 (p3 / protein :name (n6 / name :op1 "Elk-2") :xref (x3 / xref :value "UNIPROT:KCNH3_HUMAN" :prob "0.592"))) :mod (v / various))) :ARG0-of (a3 / activate-01 :ARG1 f) :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2") :mod i :ARG0-of p :ARG0-of a3 :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :snt2 (r / regulate-01 :ARG0 (f2 / factor :ARG0-of (t2 / transcribe-01) :mod (t3 / this)) :ARG1 (e5 / express-03 :ARG1 (g / gene :mod (d / diverse)) :ARG1-of (r2 / relate-01 :ARG2 (a2 / and :op1 (p4 / proliferate-01 :ARG0 (c / cell)) :op2 (g2 / grow-01 :ARG1 c)))))) # ::id bel_pmid_1632_4152.36878 # ::date 2015-04-29T09:26:46 # ::file bel_pmid_1632_4152_36878.txt # ::snt IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "IL-12") :xref (x1 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343")) :ARG1 (a2 / and :op1 (t / tyrosine-kinase :name (n2 / name :op1 "JAK2")) :op2 (t2 / tyrosine-kinase :name (n3 / name :op1 "Tyk2")) :ARG2-of (p2 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "693" :name (n4 / name :op1 "tyrosine") :part-of (p3 / protein :name (n5 / name :op1 "STAT4") :xref (x / xref :value "UNIPROT:STAT4_HUMAN" :prob "1.004")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :mod (i / in-turn)) :ARG1-of (i2 / include-91 :ARG2 (p4 / protein-family :name (n6 / name :op1 "Janus"))))) # ::id bel_pmid_1633_9523.28962 # ::date 2015-04-30T01:24:04 # ::file bel_pmid_1633_9523_28962.txt # ::snt Among the cytokines expressed after 4 h of Ag stimulation in BMMCs, our data show that levels of mRNA and protein for IL-4, IL-6, and for IL-13 are all significantly higher in Lyn-/- than in WT BMMCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (s / show-01 :ARG0 (d / data :poss (w / we)) :ARG1 (h / high-02 :ARG1 (a4 / and :op1 (l2 / level :quant-of (p / protein :name (n / name :op1 "IL-4") :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003"))) :op2 (l3 / level :quant-of (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op3 (l4 / level :quant-of (p3 / protein :name (n3 / name :op1 "IL-13") :xref (x3 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003"))) :op4 (l5 / level :quant-of (n11 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 p))) :op5 (l6 / level :quant-of (n12 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e5 / encode-01 :ARG1 p2))) :op6 (l7 / level :quant-of (n13 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e6 / encode-01 :ARG1 p3))) :ARG1-of (i / include-91 :ARG2 (c / cytokine :ARG2-of (e / express-03 :time (a2 / after :op1 (s2 / stimulate-01 :ARG0 (a3 / antigen) :location (c2 / cell-line :name (n7 / name :op1 "BMMC"))) :quant (t / temporal-quantity :quant "4" :unit (h2 / hour))))))) :degree (m / more) :location (c3 / cell-line :name (n8 / name :op1 "BMMC") :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n9 / name :op1 "Lyn") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:LYN_HUMAN" :prob "0.604")))) :compared-to (c4 / cell-line :name (n10 / name :op1 "BMMC") :mod (w2 / wild-type)) :ARG1-of (s3 / significant-02))) # ::id bel_pmid_1633_9523.28966 # ::date 2015-04-30T01:39:23 # ::file bel_pmid_1633_9523_28966.txt # ::snt Our data show that mRNA coding for at least one transcription factor, the cytoplasmic NF-AT (NF-ATC, also known as NFATC1 and NFAT2) is induced 3-fold more in Lyn–/– BMMCs than in WT BMMCs (Table II). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s / show-01 :ARG0 (d / data :poss (w / we)) :ARG1 (i / induce-01 :ARG2 (c / code-01 :ARG1 (f / factor :ARG0-of (t / transcribe-01) :quant (a / at-least :op1 "1") :ARG1-of (m / mean-01 :ARG2 (p4 / protein :name (n2 / name :op1 "NF-AT") :mod (c2 / cytoplasm :xref (x4 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (k / know-02 :ARG2 (a4 / and :op1 (p2 / protein :name (n3 / name :op1 "NFATC1") :xref (x / xref :value "UNIPROT:NFAC1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n4 / name :op1 "NFAT2") :xref (x2 / xref :value "UNIPROT:NFAC1_HUMAN" :prob "1.003"))) :mod (a3 / also)) :xref (x3 / xref :value "UNIPROT:NFAC3_HUMAN" :prob "0.313")))) :instrument (n8 / nucleic-acid :name (n / name :op1 "mRNA"))) :degree (p / product-of :op1 "3") :location (c3 / cell-line :name (n5 / name :op1 "BMMC") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n6 / name :op1 "Lyn") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:LYN_HUMAN" :prob "0.604")))) :compared-to (c4 / cell-line :name (n7 / name :op1 "BMMC") :mod (w2 / wild-type)) :mod (m3 / more)) :ARG1-of (d2 / describe-01 :ARG0 (t2 / table :mod "II"))) # ::id bel_pmid_1633_9523.28968 # ::date 2015-04-30T01:49:54 # ::file bel_pmid_1633_9523_28968.txt # ::snt The 33-fold up-regulation of sphingosine kinase 1 in Ag-stimulated Lyn–/– BMMCs may also contribute to increased chemokine production # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p / possible-01 :ARG1 (c / contribute-01 :ARG0 (u / upregulate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "sphingosine" :op2 "kinase" :op3 "1") :xref (x / xref :value "UNIPROT:SPHK1_HUMAN" :prob "0.703")) :degree (p2 / product-of :op1 "33") :location (c2 / cell-line :name (n2 / name :op1 "BMMC") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Lyn") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:LYN_HUMAN" :prob "0.604"))) :ARG1-of (s / stimulate-01 :ARG0 (a / antigen)))) :ARG2 (p3 / produce-01 :ARG1 (c3 / chemokine) :ARG1-of (i / increase-01)) :mod (a2 / also))) # ::id bel_pmid_1637_4521.27952 # ::date 2015-04-30T01:53:14 # ::file bel_pmid_1637_4521_27952.txt # ::snt After 24 hours of IL-13 induction, phosphorylation of ERK1 (p44) and ERK2 (p42) but not JNK1/2 or p38 MAPK was observed (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (o / observe-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "p44ERK1") :xref (x5 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.693")) :op2 (e2 / enzyme :name (n4 / name :op1 "p42ERK2") :xref (x3 / xref :value "UNIPROT:NUP43_HUMAN" :prob "0.272"))))) :ARG2 (o2 / observe-01 :polarity "-" :ARG1 (p4 / phosphorylate-01 :ARG1 (o3 / or :op1 (e3 / enzyme :name (n5 / name :op1 "JNK1") :xref (x2 / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n6 / name :op1 "JNK2") :xref (x1 / xref :value "UNIPROT:MK09_HUMAN" :prob "1.003")) :op3 (e5 / enzyme :name (n7 / name :op1 "p38MAPK") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203"))))) :time (a / after :op1 (i / induce-01 :ARG2 (p3 / protein :name (n2 / name :op1 "IL-13") :xref (x4 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003"))) :quant (t / temporal-quantity :quant "24" :unit (h / hour))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1"))) # ::id bel_pmid_1637_4521.27960 # ::date 2015-04-30T02:06:26 # ::file bel_pmid_1637_4521_27960.txt # ::snt Our previous studies demonstrated that IL-13 causes MMP- and cathepsin-dependent lung remodeling and inhibits the expression of a1–AT (4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 8, 2015 (d / demonstrate-01 :ARG0 (s / study-01 :ARG0 (w / we) :time (p / previous)) :ARG1 (a / and :op1 (c / cause-01 :ARG0 (p2 / protein :name (n / name :op1 "IL-13") :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :ARG1 (r / remodel-01 :ARG1 (l / lung) :ARG0-of (d2 / depend-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "MMP") :xref (x3 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263")) :op2 (e2 / enzyme :name (n3 / name :op1 "cathepsin") :xref (x1 / xref :value "UNIPROT:PPGB_HUMAN" :prob "0.362")))))) :op2 (i / inhibit-01 :ARG1 (e3 / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "a1–AT") :xref (x2 / xref :value "UNIPROT:A1AT_HUMAN" :prob "0.632"))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "4")))) # ::id bel_pmid_1637_4521.27968 # ::date 2015-04-30T02:12:02 # ::file bel_pmid_1637_4521_27968.txt # ::snt IL-13 Tg can be inducibly expressed in the adult murine lung by the administration of doxycycline-containing (dox-containing) water. As expected, increased levels of phospho-STAT6 were readily detected by Western blot analysis after Tg activation (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (p / possible-01 :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "IL-13") :mod (t / transgenic) :xref (x1 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :ARG3 (l / lung :part-of (o / organism :name (n / name :op1 "Muridae") :mod (a2 / adult))) :manner (i / induce-01 :ARG1-of (p2 / possible-01)) :instrument (a3 / administer-01 :ARG1 (w2 / water :ARG0-of (c / contain-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "doxycycline") :xref (x3 / xref :value "PUBCHEM:54671203" :prob "15.91623"))))))) :snt2 (d / detect-01 :ARG1 (l2 / level :ARG1-of (i2 / increase-01) :quant-of (p4 / protein :name (n4 / name :op1 "STAT6") :ARG3-of (p5 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))) :ARG2 (a4 / analyze-01 :manner (i3 / immunoblot-01)) :ARG1-of (e2 / expect-01) :manner (r / ready) :time (a5 / after :op1 (a6 / activate-01 :ARG0 (p6 / protein :name (n6 / name :op1 "IL-6") :mod (t2 / transgenic) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1")))) # ::id bel_pmid_1637_4521.27988 # ::date 2015-04-30T02:32:06 # ::file bel_pmid_1637_4521_27988.txt # ::snt Tg IL-13 caused increases in lung volume, alveolar size, goblet cell number, and Gob-5, Muc-5ac, and Muc-1 gene expression in Tg+ ERK1/2 MAPK-sufficient animals (Figure 8, A–H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (c / cause-01 :ARG0 (p / protein :name (n / name :op1 "IL-13") :mod (t / transgenic) :xref (x2 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :ARG1 (i / increase-01 :ARG1 (a / and :op1 (v / volume :mod (l / lung)) :op2 (s / size :mod (a2 / alveolus)) :op3 (n2 / number :quant-of (c2 / cell :mod (g / goblet))) :op3 (e / express-03 :ARG1 (a3 / and :op1 (g2 / gene :name (n3 / name :op1 "Gob-5")) :op2 (g3 / gene :name (n4 / name :op1 "Muc-5ac") :xref (x1 / xref :value "UNIPROT:MUC5A_HUMAN" :prob "0.602")) :op3 (g4 / gene :name (n5 / name :op1 "Muc-1") :xref (x / xref :value "UNIPROT:MUC1_HUMAN" :prob "0.632"))))) :location (a4 / animal :ARG1-of (s2 / suffice-01 :ARG0 (p2 / pathway :name (n6 / name :op1 "ERK1/2" :op2 "MAPK"))) :mod (t2 / transgenic :mod (p3 / positive)))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "8A") :op2 (f3 / figure :mod "8B") :op3 (f4 / figure :mod "8C") :op4 (f5 / figure :mod "8D") :op5 (f6 / figure :mod "8E") :op6 (f7 / figure :mod "8F") :op7 (f8 / figure :mod "8G") :op8 (f9 / figure :mod "8H")))) # ::id bel_pmid_1643_0878.29026 # ::date 2015-04-30T02:39:09 # ::file bel_pmid_1643_0878_29026.txt # ::snt BMMCs from mice lacking Map3k2 showed reduced production (50-60%) of IL-6, IL-13, and TNF-alpha after stimulation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (s / show-01 :ARG0 (c / cell-line :name (n / name :op1 "BMMC") :source (m / mouse :ARG0-of (l / lack-01 :ARG1 (g / gene :name (n2 / name :op1 "Map3k2") :xref (x1 / xref :value "UNIPROT:M3K2_HUMAN" :prob "0.603"))))) :ARG1 (p2 / produce-01 :ARG1 (a / and :op1 (p4 / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p5 / protein :name (n4 / name :op1 "IL-13") :xref (x3 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :op3 (p6 / protein :name (n5 / name :op1 "TNF-alpha") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))) :ARG1-of (r / reduce-01 :ARG1-of (m2 / mean-01 :ARG2 (v / value-interval :op1 (p / percentage-entity :value "50") :op2 (p3 / percentage-entity :value "60"))))) :time (a2 / after :op1 (s2 / stimulate-01))) # ::id bel_pmid_1648_4683.21972 # ::date 2015-04-30T02:44:55 # ::file bel_pmid_1648_4683_21972.txt # ::snt In asbestos-associated transformation of rodent mesothelial cells, the use of dominant negative ERK1 or Fra-1 constructs reverses the phenotype of mesothelioma cells to that of normal mesothelial cells (12). Moreover, Fra-1 expression is increased in human mesotheliomas and in other tumor types. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m / multi-sentence :snt1 (r / reverse-01 :ARG0 (u / use-01 :ARG1 (o / or :op1 (m2 / molecular-physical-entity :ARG1-of (c / construct-01 :mod (e / enzyme :name (n / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))) :ARG2-of (m4 / mutate-01 :mod "-/-" :ARG0-of (d / dominate-01))) :op2 (m6 / molecular-physical-entity :ARG1-of (c5 / construct-01 :mod (p5 / protein :name (n2 / name :op1 "Fra-1") :xref (x2 / xref :value "UNIPROT:FOSL1_HUMAN" :prob "0.632"))) :mod m4))) :ARG1 (p / phenotype :poss (c2 / cell :mod (m3 / mesothelium) :source (r2 / rodent))) :prep-to (p2 / phenotype :poss (c3 / cell :ARG1-of (n4 / normal-02) :mod m3)) :prep-in (t / transform-01 :ARG1 c2 :ARG1-of (a / associate-01 :ARG2 (a2 / asbestos))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "12")))) :snt2 (a3 / and :op2 (i / increase-01 :ARG1 (e3 / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "Fra-1") :xref (x / xref :value "UNIPROT:FOSL1_HUMAN" :prob "0.632")) :ARG3 (a4 / and :op1 (m5 / mesothelioma :source (h / human)) :op2 (t2 / tumor :mod (o2 / other))))))) # ::id bel_pmid_1648_4683.26962 # ::date 2015-04-30T02:56:45 # ::file bel_pmid_1648_4683_26962.txt # ::snt We have used siRNA approaches to show that Fra-1 expression is critical to the expression of genes, such as cd44 and c-met, that are critical to migration and autocrine growth factor production in transformation and invasion of mesotheliomas (13). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (u / use-01 :ARG0 (w2 / we) :ARG1 (a / approach-02 :instrument (n6 / nucleic-acid :name (n2 / name :op1 "siRNA"))) :purpose (s2 / show-01 :ARG0 w2 :ARG1 (c / critical-02 :ARG1 (e / express-03 :ARG2 (p / protein :name (n3 / name :op1 "Fra-1") :xref (x1 / xref :value "UNIPROT:FOSL1_HUMAN" :prob "0.632"))) :ARG2 (e2 / express-03 :ARG1 (g / gene :ARG1-of (c2 / critical-02 :ARG2 (a3 / and :op1 (m2 / migrate-01) :op2 (p2 / produce-01 :ARG1 (g4 / growth-factor :mod (a4 / autocrine))) :prep-in (a5 / and :op1 (t / transform-01 :ARG1 (m3 / mesothelioma)) :op2 (i / invade-01 :ARG1 m3)))) :example (a2 / and :op1 (g2 / gene :name (n4 / name :op1 "cd44") :xref (x / xref :value "UNIPROT:CD44_HUMAN" :prob "0.654")) :op2 (g3 / gene :name (n5 / name :op1 "c-met"))))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "13")))) # ::id bel_pmid_1648_4683.37584 # ::date 2015-04-30T03:06:52 # ::file bel_pmid_1648_4683_37584.txt # ::snt In contrast, EGFR activation by gram-positive bacteria occurred through cleavage of the transmembrane ligand HBEGF by ADAM 10. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 9, 2015 (c / contrast-01 :ARG2 (a / activate-01 :ARG0 (b / bacteria :mod (g / gram-positive)) :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :manner (c2 / cleave-01 :ARG0 (p / protein :name (n3 / name :op1 "ADAM" :op2 "10") :xref (x1 / xref :value "UNIPROT:ADA10_HUMAN" :prob "1.003")) :ARG1 (l / ligand :name (n2 / name :op1 "HBEGF") :mod (t / transmembrane))))) # ::id bel_pmid_1649_2667.37650 # ::date 2015-04-30T03:12:47 # ::file bel_pmid_1649_2667_37650.txt # ::snt from full text - Furthermore, the decreased expression of either b-arrestin 1 or b-arrestin 2 (via siRNA) resulted in a decrease in ERK1/2 activity # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op2 (r / result-01 :ARG1 (e / express-03 :ARG2 (o / or :op1 (p / protein :name (n / name :op1 "b-arrestin" :op2 "1") :xref (x / xref :value "UNIPROT:CND2_HUMAN" :prob "0.202")) :op2 (p2 / protein :name (n2 / name :op1 "b-arrestin" :op2 "2"))) :ARG1-of (d / decrease-01) :instrument (n5 / nucleic-acid :name (n3 / name :op1 "siRNA"))) :ARG2 (d2 / decrease-01 :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"))))) :ARG1-of (d3 / describe-01 :ARG0 (t / text :ARG1-of (f / full-09)))) # ::id bel_pmid_1651_0581.41864 # ::date 2015-04-30T03:18:13 # ::file bel_pmid_1651_0581_41864.txt # ::snt FBLN-3 expression in MB114 cells also prevented their activation of p38 MAPK, but not that of extracellular signal-regulated kinase 1/2 (ERK1/2), stimulated by VEGF (Fig. 2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 2, 2015 (c / contrast-01 :ARG1 (p2 / prevent-01 :ARG0 (e / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "FBLN-3") :xref (x / xref :value "UNIPROT:FBLN3_HUMAN" :prob "0.682")) :ARG3 (c2 / cell-line :name (n3 / name :op1 "MB114"))) :ARG1 (a / activate-01 :ARG0 c2 :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38MAPK") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203"))) :mod (a2 / also)) :ARG2 (p4 / prevent-01 :polarity "-" :ARG1 (a3 / activate-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase" :op4 "1/2")) :ARG1-of (s / stimulate-01 :ARG0 (p5 / protein :name (n6 / name :op1 "VEGF") :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2E"))) # ::id bel_pmid_1651_0581.41866 # ::date 2015-05-02T11:07:17 # ::file bel_pmid_1651_0581_41866.txt # ::snt Figure 3A shows that relative to control cells, FBLN-3 and FBLN-5 both decreased MB114 cell expression of MMP-2 and MMP-3 while simultaneously increasing that of the MMP antagonists, TIMP-1 and TIMP-3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (f / figure :mod "3A") :ARG1 (a / and :op1 (d / decrease-01 :ARG0 (a2 / and :op1 (p / protein :name (n / name :op1 "FBLN-3") :xref (x6 / xref :value "UNIPROT:FBLN3_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5") :xref (x1 / xref :value "UNIPROT:FBLN5_HUMAN" :prob "0.682"))) :ARG1 (e / express-03 :ARG2 (a3 / and :op1 (e3 / enzyme :name (n4 / name :op1 "MMP-2") :xref (x3 / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.002")) :op2 (e4 / enzyme :name (n5 / name :op1 "MMP-3") :xref (x2 / xref :value "UNIPROT:MMP3_HUMAN" :prob "1.003"))) :ARG3 (c3 / cell-line :name (n3 / name :op1 "MB114")))) :op2 (i / increase-01 :ARG0 a2 :ARG2 (a4 / and :op1 (p5 / protein :name (n6 / name :op1 "TIMP-1") :ARG1-of (a5 / antagonize-02 :ARG2 (e2 / enzyme :name (n7 / name :op1 "MMP") :xref (x4 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263"))) :xref (x5 / xref :value "UNIPROT:TIMP1_HUMAN" :prob "1.002")) :op2 (p7 / protein :name (n8 / name :op1 "TIMP-3") :ARG1-of a5 :xref (x / xref :value "UNIPROT:TIMP3_HUMAN" :prob "1.002"))) :manner (s2 / simultaneous)) :compared-to (c / cell :mod (c2 / control-01)))) # ::id bel_pmid_1651_0581.41868 # ::date 2015-05-03T01:35:17 # ::file bel_pmid_1651_0581_41868.txt # ::snt Although MB114 cell expression of TIMP-2 was unaffected by either FBLN-3 or FBLN-5, both FBLNs induced MB114 cell expression of the angiostatic molecule, TSP-1 (Fig. 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG1 (i / induce-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "FBLN-3") :xref (x3 / xref :value "UNIPROT:FBLN3_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5") :xref (x / xref :value "UNIPROT:FBLN5_HUMAN" :prob "0.682"))) :ARG2 (e / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "TSP-1") :mod (a2 / angiostatic) :xref (x2 / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672")) :ARG3 (c2 / cell-line :name (n3 / name :op1 "MB114")))) :ARG2 (a3 / affect-01 :polarity "-" :ARG0 a :ARG1 (e2 / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "TIMP-2") :xref (x1 / xref :value "UNIPROT:TIMP2_HUMAN" :prob "1.002")) :ARG3 c2)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id bel_pmid_1651_0581.41870 # ::date 2015-05-03T02:32:05 # ::file bel_pmid_1651_0581_41870.txt # ::snt Interestingly, although TIMP-3 expression was elevated basally in FBLN-5-expressing MB114 cells, only FBLN-3 stimulated TIMP-3 expression in tubulating MB114 cells (Fig. 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (h / have-concession-91 :ARG1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "FBLN-3") :mod (o / only) :xref (x2 / xref :value "UNIPROT:FBLN3_HUMAN" :prob "0.682")) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "TIMP-3") :xref (x / xref :value "UNIPROT:TIMP3_HUMAN" :prob "1.002")) :ARG3 (c2 / cell-line :name (n2 / name :op1 "MB114") :ARG0-of (t / tubulate-01)))) :ARG2 (e2 / elevate-01 :ARG1 (e3 / express-03 :ARG2 p2 :ARG3 (c3 / cell-line :name (n4 / name :op1 "MB114") :ARG3-of (e4 / express-03 :ARG2 (p3 / protein :name (n5 / name :op1 "FBLN-5") :xref (x1 / xref :value "UNIPROT:FBLN5_HUMAN" :prob "0.682"))))) :manner (b / basal)) :ARG2-of (i / interest-01)) # ::id bel_pmid_1651_0581.41872 # ::date 2015-05-03T02:46:15 # ::file bel_pmid_1651_0581_41872.txt # ::snt Gelatin zymography of MB114 cell conditioned medium confirmed that expression of either FBLN-3 or FBLN-5 significantly reduced MMP-2 protease activity in tubulating MB114 cells (Fig. 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / confirm-01 :ARG1 (r / reduce-01 :ARG0 (e / express-03 :ARG2 (o / or :op1 (p / protein :name (n3 / name :op1 "FBLN-3") :xref (x1 / xref :value "UNIPROT:FBLN3_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n4 / name :op1 "FBLN-5") :xref (x / xref :value "UNIPROT:FBLN5_HUMAN" :prob "0.682")))) :ARG1 (a / activity-06 :ARG0 (p3 / protease :name (n5 / name :op1 "MMP-2")) :location (c4 / cell-line :name (n6 / name :op1 "MB114") :ARG0-of (t / tubulate-01))) :ARG2 (s / significant-02)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3C")) :mod (z / zymography :mod (g / gelatin) :topic (m / medium :ARG1-of (c2 / condition-01) :mod (c3 / cell-line :name (n2 / name :op1 "MB114"))))) # ::id bel_pmid_1651_0581.41874 # ::date 2015-05-03T02:52:43 # ::file bel_pmid_1651_0581_41874.txt # ::snt FBLN-3 and FBLN-5 antagonize angiogenesis in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 3, 2015 (a / antagonize-02 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "FBLN-3") :xref (x1 / xref :value "UNIPROT:FBLN3_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5") :xref (x / xref :value "UNIPROT:FBLN5_HUMAN" :prob "0.682"))) :ARG2 (a3 / angiogenesis) :manner (i / in-vivo)) # ::id bel_pmid_1651_0581.41878 # ::date 2015-05-03T02:57:26 # ::file bel_pmid_1651_0581_41878.txt # ::snt Moreover, recombinant FBLN-3 and FBLN-5 (Fig. 4B) both inhibited human HMEC-1 endothelial cell migration to fibronectin (Fig. 4C), whereas FBLN-5, but not FBLN-3, mediated their adhesion in an RGD-dependent manner (Fig. 4D; refs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a3 / and :op2 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "FBLN-3") :xref (x2 / xref :value "UNIPROT:FBLN3_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5") :xref (x / xref :value "UNIPROT:FBLN5_HUMAN" :prob "0.682")) :ARG3-of (r / recombine-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B"))) :ARG1 (m / migrate-01 :ARG0 (c2 / cell-line :name (n3 / name :op1 "HMEC-1") :mod (h / human)) :ARG1 (e / endothelium) :ARG2 (p3 / protein :name (n4 / name :op1 "fibronectin") :xref (x1 / xref :value "UNIPROT:FINC_HUMAN" :prob "0.703"))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4C"))) :ARG2 (c3 / contrast-01 :ARG1 (m2 / mediate-01 :ARG0 p2 :ARG1 (a2 / adhere-01 :ARG1 c2 :manner (d3 / depend-01 :ARG0 c2 :ARG1 (s / small-molecule :name (n5 / name :op1 "RGD") :xref (x3 / xref :value "PUBCHEM:104802" :prob "10.391923"))))) :ARG2 (m3 / mediate-01 :polarity "-" :ARG0 p :ARG1 a2) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "4D")) :ARG1-of (d5 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01)))))) # ::id bel_pmid_1651_0581.41880 # ::date 2015-05-03T06:29:52 # ::file bel_pmid_1651_0581_41880.txt # ::snt Figure 5A shows that bFGF stimulated significant vascularization of implanted Matrigel plugs, which was quantified by measuring plug hemoglobin contents (Fig. 5A) and microvessel densities (Fig. 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / show-01 :ARG0 (f / figure :mod "5A") :ARG1 (s2 / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "bFGF") :xref (x1 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.003")) :ARG1 (v / vascularize-01 :ARG1 (p2 / plug :ARG1-of (i / implant-01) :mod (p4 / protein :name (n2 / name :op1 "Matrigel") :xref (x / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.273"))) :ARG1-of (s3 / significant-02) :ARG1-of (q / quantify-01 :manner (m / measure-01 :ARG1 (a / and :op1 (c / content :mod (h / hemoglobin) :ARG1-of (d2 / describe-01 :ARG0 f) :location (p3 / plug)) :op2 (d / density :mod (m2 / microvessel) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "5B"))))))))) # ::id bel_pmid_1651_0581.41890 # ::date 2015-05-03T06:53:58 # ::file bel_pmid_1651_0581_41890.txt # ::snt More importantly, tumors derived from FBLN-expressing MCA102 fibrosarcoma cells also exhibited significantly reduced blood vessel densities compared with tumors derived from control cells (Fig. 6D ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (e / exhibit-01 :ARG0 (t / tumor :ARG1-of (d / derive-01 :ARG2 (c / cell-line :name (n / name :op1 "MCA102") :ARG3-of (e2 / express-03 :ARG2 (p / protein :name (n2 / name :op1 "FBLN") :xref (x / xref :value "UNIPROT:FBLN1_HUMAN" :prob "0.312"))) :mod (f2 / fibrosarcoma)))) :ARG1 (d2 / density :mod (v / vessel :mod (b / blood)) :ARG1-of (r / reduce-01 :ARG2 (s / significant-02) :compared-to (t2 / tumor :ARG1-of (d4 / derive-01 :ARG2 (c2 / cell :mod (c3 / control-01)))))) :mod (i / important :degree (m / more)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "6D")) :mod (a / also)) # ::id bel_pmid_1651_0581.41892 # ::date 2015-05-03T06:58:31 # ::file bel_pmid_1651_0581_41892.txt # ::snt In addition, FBLN-3-expressing MCA102 tumors contained significantly enlarged regions of central and peripheral necrosis that were typically absent in their control counterparts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (a / and :op2 (c / contain-01 :ARG0 (t / tumor :source (c2 / cell-line :name (n / name :op1 "MCA102")) :ARG3-of (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "FBLN-3") :xref (x / xref :value "UNIPROT:FBLN3_HUMAN" :prob "0.682")))) :ARG1 (r / region :ARG1-of (e2 / enlarge-01 :ARG2 (s / significant-02)) :ARG1-of (a3 / absent-01 :ARG2 (c4 / counterpart :poss r :mod (c5 / control-01)) :ARG1-of (t2 / typical-02)) :location-of (a2 / and :op1 (n3 / necrosis :mod (c3 / center)) :op2 (n4 / necrosis :mod (p2 / periphery)))))) # ::id bel_pmid_1651_0838.19670 # ::date 2015-05-03T07:03:40 # ::file bel_pmid_1651_0838_19670.txt # ::snt The TLR3 agonist poly (I:C) significantly increased bidirectional secretion of CCL2, IL6, TNFA and CSF2 and basolateral secretion of CSF3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / increase-01 :ARG0 (a / agonist :name (n / name :op1 "poly" :op2 "(I:C)") :mod (p / protein :name (n2 / name :op1 "TLR3") :xref (x5 / xref :value "UNIPROT:TLR3_HUMAN" :prob "1.003"))) :ARG1 (a3 / and :op1 (s2 / secrete-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "CCL2") :xref (x1 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n3 / name :op1 "IL6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")) :op3 (p4 / protein :name (n5 / name :op1 "TNFA") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.003")) :op4 (p5 / protein :name (n6 / name :op1 "CSF2") :xref (x4 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.004"))) :mod (b2 / bidirectional)) :op2 (s3 / secrete-01 :ARG1 (p6 / protein :name (n7 / name :op1 "CSF3") :xref (x2 / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.003")) :mod (b / basolateral))) :ARG2 (s / significant-02)) # ::id bel_pmid_1654_7273.28276 # ::date 2015-05-01T10:50:35 # ::file bel_pmid_1654_7273_28276.txt # ::snt To verify the absence of the STAT6-signaling cascade in STAT6-/- MLF, we assessed mOSM and mIL-4 induced responses with respect to STAT3 and STAT6 activation. Fig. 6 confirms the absence of STAT6 protein and STAT6 induction in STAT6-/- MLF but equivalent activation of STAT3 in both wt and STAT6-/- MLF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (a / assess-01 :ARG0 (w / we) :ARG1 (t / thing :ARG2-of (r / respond-01) :ARG2-of (i2 / induce-01 :ARG0 (a2 / and :op1 (p11 / protein :name (n8 / name :op1 "OSM") :mod (m2 / mouse) :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (p / protein :name (n / name :op1 "IL-4") :mod m2 :xref (x7 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003"))))) :purpose (v / verify-01 :ARG0 w :ARG1 (a5 / absent-01 :ARG1 (c / cascade :ARG0-of (s / signal-07 :ARG1 (p2 / protein :name (n7 / name :op1 "STAT6") :xref (x / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")))) :ARG2 (f2 / fibroblast :mod (l / lung :mod m2) :mod (p6 / protein :name (n9 / name :op1 "STAT6") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))))) :topic (a3 / activate-01 :ARG1 (a4 / and :op1 (p3 / protein :name (n5 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 p2))) :snt2 (c2 / confirm-01 :ARG0 (f / figure :mod "6") :ARG1 (c3 / contrast-01 :ARG1 (a6 / and :op1 (a7 / absent-01 :ARG1 (p7 / protein :name (n10 / name :op1 "STAT6") :xref (x4 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")) :ARG2 "f3") :op2 (i / induce-01 :ARG2 p7 :location (f3 / fibroblast :mod (l2 / lung :mod (m11 / mouse)) :mod (p8 / protein :name (n12 / name :op1 "STAT6") :ARG2-of (m5 / mutate-01 :mod "-/-") :xref (x5 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))))) :ARG2 (a8 / activate-01 :ARG1 (p9 / protein :name (n13 / name :op1 "STAT3") :xref (x6 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG2-of (e3 / equal-01) :location (a9 / and :op1 f3 :op2 (f5 / fibroblast :mod (w2 / wild-type) :mod l2)))))) # ::id bel_pmid_1654_7273.28294 # ::date 2015-05-03T05:58:43 # ::file bel_pmid_1654_7273_28294.txt # ::snt Twenty-four hour stimulation with 25.0 ng/ml mOSM induced detectable increases in eotaxin-1 expression at the mRNA and protein level in both wt and STAT6-/- MLF (Fig. 5, A and C). Stimulation of wt MLF using 10.0 ng/ml mIL-4 induced eotaxin mRNA expression and protein production that was nondetectable in STAT6-/- MLF (Fig. 5, A and C) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (i / induce-01 :ARG0 (s / stimulate-01 :ARG2 (p / protein :name (n2 / name :op1 "OSM") :mod (m5 / mouse) :quant (c / concentration-quantity :quant "25" :unit (n3 / nanogram-per-milliliter)) :xref (x5 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :duration (t3 / temporal-quantity :quant "24" :unit (h3 / hour))) :ARG2 (i2 / increase-01 :ARG1 (e2 / express-03 :ARG2 (p11 / protein :name (n / name :op1 "eotaxin-1") :xref (x1 / xref :value "UNIPROT:CCL11_HUMAN" :prob "0.343")) :manner (a4 / and :op1 (l6 / level :mod (n4 / nucleic-acid :name (n5 / name :op1 "mRNA"))) :op2 (l / level :mod (p2 / protein)))) :ARG3 (a2 / and :op1 (f5 / fibroblast :mod (l2 / lung :mod m5) :mod (p3 / protein :name (n7 / name :op1 "STAT6") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))) :op2 (f6 / fibroblast :mod (w / wild-type) :mod l2)) :ARG1-of (d / detect-01 :ARG1-of (p4 / possible-01))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "5A") :op2 (f2 / figure :mod "5C")))) :snt2 (i3 / induce-01 :ARG0 (s2 / stimulate-01 :ARG1 (f7 / fibroblast :mod (l4 / lung :mod (m4 / mouse)) :mod (w2 / wild-type)) :ARG2-of (u / use-01 :ARG1 (p5 / protein :name (n12 / name :op1 "IL-4") :quant (c2 / concentration-quantity :quant "10" :unit (n13 / nanogram-per-milliliter)) :mod m4 :xref (x4 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")))) :ARG2 (a / and :op1 (e5 / express-03 :ARG1 (n6 / nucleic-acid :name (n14 / name :op1 "mRNA") :ARG0-of (e6 / encode-01 :ARG1 (p6 / protein :name (n15 / name :op1 "eotaxin") :xref (x3 / xref :value "UNIPROT:CCL11_HUMAN" :prob "0.703"))))) :op2 (p7 / produce-01 :ARG1 (p8 / protein)) :ARG1-of (d3 / detect-01 :polarity "-" :location (f8 / fibroblast :mod (p10 / protein :name (n17 / name :op1 "STAT6") :ARG2-of (m8 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")) :mod l4) :ARG1-of (p9 / possible-01))) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and :op1 (f3 / figure :mod "5A") :op2 (f4 / figure :mod "5C"))))) # ::id bel_pmid_1654_7273.29762 # ::date 2015-05-03T09:42:42 # ::file bel_pmid_1654_7273_29762.txt # ::snt We and others have shown that OSM can induce eotaxin-1 in mouse lung fibroblasts (MLF) (28) and lung smooth muscle cells (29). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (s / show-01 :ARG0 (a / and :op1 (w / we) :op2 (p / person :mod (o / other))) :ARG1 (p2 / possible-01 :ARG1 (i / induce-01 :ARG0 (p3 / protein :name (n / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG2 (p6 / protein :name (n2 / name :op1 "eotaxin-1") :xref (x1 / xref :value "UNIPROT:CCL11_HUMAN" :prob "0.343")) :location (a2 / and :op1 (f / fibroblast :mod (l / lung :mod (m / mouse)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "28")))) :op2 (c2 / cell :mod (m2 / muscle :ARG1-of (s2 / smooth-06) :mod (l2 / lung)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "29")))))))) # ::id bel_pmid_1654_7273.29766 # ::date 2015-05-03T09:58:48 # ::file bel_pmid_1654_7273_29766.txt # ::snt We also compared the effects of mOSM on IL-6 expression in both wt and STAT6-/- MLF (Fig. 5, B and D) and show that STAT6-/- MLF respond similarly to wt MLF in IL-6 expression at both the mRNA and protein levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (a / and :op1 (c / compare-01 :ARG0 (w / we) :ARG1 (a3 / affect-01 :ARG0 (p / protein :name (n2 / name :op1 "OSM") :mod (m4 / mouse) :xref (x2 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG3 (a4 / and :op1 (f3 / fibroblast :mod (l2 / lung :mod m4) :mod (w2 / wild-type)) :op2 (f4 / fibroblast :mod (p3 / protein :name (n6 / name :op1 "STAT6") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")) :mod l2)))) :mod (a2 / also) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "5B") :op2 (f2 / figure :mod "5D")))) :op2 (s / show-01 :ARG0 w :ARG1 (r2 / respond-01 :ARG0 f4 :ARG1-of (r3 / resemble-01 :ARG2 f3) :condition (e3 / express-01 :ARG2 p2 :manner (a7 / and :op1 (l3 / level :mod (n / nucleic-acid :name (n7 / name :op1 "mRNA"))) :op2 (l / level :mod (p5 / protein))))))) # ::id bel_pmid_1654_7273.29768 # ::date 2015-05-03T10:26:47 # ::file bel_pmid_1654_7273_29768.txt # ::snt mOSM induced STAT1 (Y701), STAT3 (Y705), and STAT5 (Y694) phosphorylation as reported by others (57, 58, 59). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "OSM") :mod (m / mouse) :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG2 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "701" :name (n3 / name :op1 "tyrosine") :part-of (p3 / protein :name (n4 / name :op1 "STAT1") :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a3 / amino-acid :mod "705" :name (n5 / name :op1 "tyrosine") :part-of (p4 / protein :name (n6 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op3 (a4 / amino-acid :mod "694" :name (n7 / name :op1 "tyrosine") :part-of (p5 / protein :name (n8 / name :op1 "STAT5") :xref (x3 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :ARG1-of (r2 / report-01 :ARG0 (p6 / person :mod (o / other))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 (a5 / and :op1 "57" :op2 "58" :op3 "59"))))) # ::id bel_pmid_1654_7273.29770 # ::date 2015-05-03T10:35:40 # ::file bel_pmid_1654_7273_29770.txt # ::snt Levels of VCAM-1 in STAT-6-deficient MLF were somewhat reduced compared with those observed in wt MLF, however, the ability of mOSM or mTNF-{alpha} to induce VCAM-1 was maintained (Fig. 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG1 (r / reduce-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "VCAM-1") :xref (x3 / xref :value "UNIPROT:VCAM1_HUMAN" :prob "1.002")) :location (f / fibroblast :mod (l2 / lung :mod "m4") :mod (p2 / protein :name (n2 / name :op1 "STAT6") :ARG2-of (m6 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))) :ARG1-of (c / compare-01 :ARG2 (l3 / level :ARG1-of (o / observe-01 :location (f2 / fibroblast :mod (w / wild-type) :mod l2)) :quant-of p))) :ARG2 (s / somewhat)) :ARG2 (m3 / maintain-01 :ARG1 (c2 / capable-01 :ARG1 (o2 / or :op1 (p4 / protein :name (n4 / name :op1 "OSM") :mod (m4 / mouse) :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (p5 / protein :name (n5 / name :op1 "TNF-{alpha}") :mod m4 :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.672"))) :ARG2 (i / induce-01 :ARG0 o2 :ARG2 p))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "7B"))) # ::id bel_pmid_1654_7273.38510 # ::date 2015-05-03T11:31:22 # ::file bel_pmid_1654_7273_38510.txt # ::snt IL-4 has been documented to regulate the expression of eotaxin-1 (41), eotaxin-2 (42), and eotaxin-3 (34) in endothelial cells and fibroblasts in a STAT6-dependent manner (42, 43, 44, 45). IL-4 signal transduction includes activation of STAT6 (46, 47, 48, 49, 50). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (d / document-01 :ARG1 (p / protein :name (n / name :op1 "IL-4") :ARG0-of (r / regulate-01 :ARG1 (e / express-03 :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "eotaxin-1") :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "41"))) :xref (x / xref :value "UNIPROT:CCL11_HUMAN" :prob "0.343")) :op2 (p4 / protein :name (n3 / name :op1 "eotaxin-2") :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "42"))) :xref (x4 / xref :value "UNIPROT:CCL24_HUMAN" :prob "0.702")) :op3 (p6 / protein :name (n4 / name :op1 "eotaxin-3") :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 "34"))) :xref (x3 / xref :value "UNIPROT:CCL26_HUMAN" :prob "0.702"))) :ARG3 (a2 / and :op1 (c4 / cell :mod (e2 / endothelium)) :op2 (f / fibroblast))) :manner (d5 / depend-01 :ARG0 r :ARG1 (p8 / protein :name (n5 / name :op1 "STAT6") :xref (x5 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")))) :xref (x6 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :ARG1-of (d6 / describe-01 :ARG0 (p9 / publication :ARG1-of (c5 / cite-01 :ARG2 (a3 / and :op1 "42" :op2 "43" :op3 "44" :op4 "45"))))) :snt2 (i / include-01 :ARG1 (a4 / activate-01 :ARG1 (p11 / protein :name (n7 / name :op1 "STAT6") :xref (x2 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))) :ARG2 (t / transduce-01 :ARG1 (s / signal-07 :ARG0 (p10 / protein :name (n6 / name :op1 "IL-4") :xref (x1 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")))) :ARG1-of (d7 / describe-01 :ARG0 (p12 / publication :ARG1-of (c6 / cite-01 :ARG2 (a5 / and :op1 "46" :op2 "47" :op3 "48" :op4 "49" :op5 "50")))))) # ::id bel_pmid_1654_7273.38520 # ::date 2015-05-03T11:49:14 # ::file bel_pmid_1654_7273_38520.txt # ::snt To verify the absence of the STAT6-signaling cascade in STAT6-/- MLF, we assessed mOSM and mIL-4 induced responses with respect to STAT3 and STAT6 activation. Fig. 6 confirms the absence of STAT6 protein and STAT6 induction in STAT6-/- MLF but equivalent activation of STAT3 in both wt and STAT6-/- MLF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (a / assess-01 :ARG0 (w / we) :ARG1 (t / thing :ARG1-of (r / respond-01) :ARG2-of (i2 / induce-01 :ARG0 (a2 / and :op1 (p / protein :name (n / name :op1 "OSM") :mod (m2 / mouse) :xref (x7 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "IL-4") :mod m2 :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003"))))) :purpose (v / verify-01 :ARG0 w :ARG1 (a5 / absent-01 :ARG1 (c / cascade :ARG0-of (s / signal-07 :ARG1 (p4 / protein :name (n5 / name :op1 "STAT6") :xref (x4 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")))) :ARG2 (f / fibroblast :mod (l / lung :mod m2) :mod (p6 / protein :name (n6 / name :op1 "STAT6") :ARG2-of (m5 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))))) :topic (a3 / activate-01 :ARG1 (a4 / and :op1 (p3 / protein :name (n3 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 p4))) :snt2 (c2 / confirm-01 :ARG0 (f2 / figure :mod "6") :ARG1 (c3 / contrast-01 :ARG1 (a6 / and :op1 (a7 / absent-01 :ARG1 (p7 / protein :name (n7 / name :op1 "STAT6") :xref (x3 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")) :ARG2 "f3") :op2 (i / induce-01 :ARG2 p7 :location (f3 / fibroblast :mod (l2 / lung :mod (m6 / mouse)) :mod (p8 / protein :name (n8 / name :op1 "STAT6") :ARG2-of (m7 / mutate-01 :mod "-/-") :xref (x5 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))))) :ARG2 (a8 / activate-01 :ARG1 (p9 / protein :name (n9 / name :op1 "STAT3") :xref (x6 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (e / equal-01) :location (a9 / and :op1 (f4 / fibroblast :mod (w2 / wild-type) :mod l2) :op2 f3))))) # ::id bel_pmid_1654_7273.39184 # ::date 2015-05-03T12:04:56 # ::file bel_pmid_1654_7273_39184.txt # ::snt Levels of VCAM-1 in STAT-6-deficient MLF were somewhat reduced compared with those observed in wt MLF, however, the ability of mOSM or mTNF-{alpha} to induce VCAM-1 was maintained (Fig. 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG1 (r / reduce-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "VCAM-1") :xref (x3 / xref :value "UNIPROT:VCAM1_HUMAN" :prob "1.002")) :location (f / fibroblast :mod (l2 / lung :mod "m4") :mod (p2 / protein :name (n2 / name :op1 "STAT-6") :ARG2-of (m6 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:STAT6_HUMAN" :prob "0.683"))) :ARG1-of (c / compare-01 :ARG2 (l3 / level :ARG1-of (o / observe-01 :location (f2 / fibroblast :mod (w / wild-type) :mod l2)) :quant-of p))) :ARG2 (s / somewhat)) :ARG2 (m3 / maintain-01 :ARG1 (c2 / capable-01 :ARG1 (o2 / or :op1 (p4 / protein :name (n4 / name :op1 "OSM") :mod (m4 / mouse) :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (p5 / protein :name (n5 / name :op1 "TNF-{alpha}") :mod m4 :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.672"))) :ARG2 (i / induce-01 :ARG0 o2 :ARG2 p))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "7B"))) # ::id bel_pmid_1658_5161.22112 # ::date 2015-05-03T12:12:14 # ::file bel_pmid_1658_5161_22112.txt # ::snt Focus formation was consistently observed with both mutants. However, C-RAF mutant proteins caused the formation of much smaller cell aggregates (Fig. 5A) as compared with v-Raf. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (m / multi-sentence :snt1 (o / observe-01 :ARG1 (f / form-01 :ARG1 (f2 / focus)) :manner (c / consistent-02) :instrument (m5 / molecular-physical-entity :ARG2-of (m2 / mutate-01) :mod (b / both))) :snt2 (c5 / contrast-01 :ARG2 (c2 / cause-01 :ARG0 (e / enzyme :name (n / name :op1 "C-RAF") :ARG2-of (m3 / mutate-01) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.593")) :ARG1 (f3 / form-01 :ARG1 (a / aggregate-01 :ARG1 (c3 / cell) :mod (s2 / small :degree (m4 / much) :compared-to (e2 / enzyme :name (n2 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")))) :ARG1-of (d / describe-01 :ARG0 (f4 / figure :mod "5A")))))) # ::id bel_pmid_1658_5540.18258 # ::date 2015-05-03T12:23:36 # ::file bel_pmid_1658_5540_18258.txt # ::snt Wild-type MEFs induced Ifnb, Tnfa, and Il-6 in response to poly(I:C) {an viral mimetic activator of FADD signaling-SE}, whereas the induction was severely impaired in FADD-deficient MEFs as examined by RT-PCR analyses (Fig. 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (i / induce-01 :ARG0 (f / fibroblast :mod (e / embryo :mod (m / mouse)) :mod (w / wild-type)) :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "Ifnb") :xref (x4 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n2 / name :op1 "Tnfa") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.603")) :op3 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2-of (r / respond-01 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "poly(I:C)") :ARG1-of (m2 / mean-01 :ARG2 (m6 / molecular-physical-entity :ARG0-of (a3 / activate-01 :ARG1 (s / signal-07 :ARG0 (p4 / protein :name (n5 / name :op1 "FADD") :xref (x2 / xref :value "UNIPROT:FADD_HUMAN" :prob "1.003")) :ARG1 (t3 / thing :name (n6 / name :op1 "SE")))) :ARG0-of (m3 / mimic-01 :ARG1 (v / virus))))))) :ARG2 (i2 / impair-01 :ARG1 i :degree (s2 / severe) :location (f2 / fibroblast :mod (e2 / embryo :mod (m4 / mouse)) :mod (p5 / protein :name (n7 / name :op1 "FADD") :ARG2-of (m5 / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:FADD_HUMAN" :prob "1.003"))) :ARG1-of (e3 / examine-01 :ARG0 (a4 / analyze-01 :mod (t / thing :name (n8 / name :op1 "RT-PCR"))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "1A"))) # ::id bel_pmid_1658_5540.25628 # ::date 2015-05-03T12:54:08 # ::file bel_pmid_1658_5540_25628.txt # ::snt the induction of Tnfa and Il-6 was severely impaired after 2 h of poly(I:C) stimulation and reduced after 6 h of stimulation in caspase-8-deficient cells (Fig. 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (i / impair-01 :ARG1 (i2 / induce-01 :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "Tnfa") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :degree (s / severe) :time (a3 / after :op1 (s2 / stimulate-01 :ARG0 (s4 / small-molecule :name (n3 / name :op1 "poly(I:C)")) :duration (t / temporal-quantity :quant "2" :unit (h / hour))))) :op2 (r / reduce-01 :ARG1 i2 :time (a4 / after :op1 (s3 / stimulate-01 :duration (t2 / temporal-quantity :quant "6" :unit (h2 / hour)) :location (c / cell :mod (p4 / protein :name (n4 / name :op1 "caspase-8") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:CASP8_HUMAN" :prob "0.702")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id bel_pmid_1658_5540.25630 # ::date 2015-05-03T13:05:29 # ::file bel_pmid_1658_5540_25630.txt # ::snt nuclear translocation of p65, a component of NF-{kappa}B, was reduced in caspase-8-deficient cells (Fig. 4C) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / reduce-01 :ARG1 (t / translocate-01 :ARG1 (p / protein-segment :name (n / name :op1 "p65") :part-of (p2 / protein :name (n3 / name :op1 "NF-{kappa}B") :xref (x / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.352"))) :ARG2 (n2 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8"))) :location (c / cell :mod (p3 / protein :name (n4 / name :op1 "caspase-8") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:CASP8_HUMAN" :prob "0.702"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id bel_pmid_1663_6663.7850 # ::date 2015-05-03T13:12:25 # ::file bel_pmid_1663_6663_7850.txt # ::snt LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / suppress-01 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "LMW-DSP2") :xref (x1 / xref :value "UNIPROT:DUS22_HUMAN" :prob "1.002")) :location (c / cell-line :name (n2 / name :op1 "293T"))) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 "p3") :op2 (a2 / activate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :ARG2-of (i / induce-01 :ARG0 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1663_6663.24748 # ::date 2015-05-03T13:20:23 # ::file bel_pmid_1663_6663_24748.txt # ::snt In contrast, small-interfering RNA-mediated reduction of LMW-DSP2 expression enhanced IL-6-induced STAT3-dependent transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG2 (e / enhance-01 :ARG0 (r2 / reduce-01 :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "LMW-DSP2") :xref (x2 / xref :value "UNIPROT:DUS22_HUMAN" :prob "1.002"))) :ARG1-of (m / mediate-01 :ARG0 (n / nucleic-acid :name (n5 / name :op1 "small-interfering" :op2 "RNA")))) :ARG1 (t / transcribe-01 :ARG2-of (i / induce-01 :ARG0 (p / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG0-of (d / depend-01 :ARG1 (p2 / protein :name (n4 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))))) # ::id bel_pmid_1663_6672.36768 # ::date 2015-05-03T13:24:50 # ::file bel_pmid_1663_6672_36768.txt # ::snt Expression of wild-type (wt) Cbp remarkably suppressed EGF-induced activation of Src, ERK1/2, and Akt-1 enzymes, and NIH3T3 cell transformation, as well as colony formation of a breast cancer cell line (MDA-MB-468) in soft agar. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (s / suppress-01 :ARG0 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "Cbp") :mod (w / wild-type) :xref (x5 / xref :value "UNIPROT:CBP_HUMAN" :prob "0.603"))) :ARG1 (a2 / and :op1 (a4 / activate-01 :ARG1 (a / and :op1 (p3 / protein :name (n4 / name :op1 "Src") :xref (x4 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :op2 (s2 / slash :op1 (e4 / enzyme :name (n5 / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n6 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :op3 (e2 / enzyme :name (n7 / name :op1 "Akt-1") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.593"))) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n3 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :op2 (t / transform-01 :ARG1 (c / cell-line :name (n8 / name :op1 "NIH3T3"))) :op3 (f / form-01 :ARG1 (c3 / cell-line :name (n9 / name :op1 "MDA-MB-468") :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))) :mod (c2 / colony) :location (a3 / agar :ARG1-of (s3 / soft-02)))) :ARG1-of (r / remarkable-02)) # ::id bel_pmid_1671_3670.8846 # ::date 2015-05-03T13:34:06 # ::file bel_pmid_1671_3670_8846.txt # ::snt Interestingly, 500 ng/ml GH and 30 ng/ml IL-6 increased PAI-1 secretion five-fold and 3.6-fold, respectively. Furthermore, GH and IL-6 induced PAI-1 mRNA by up to 7.3-fold, and 3.6-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml GH and 10 ng/ml IL-6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (m / multi-sentence :snt1 (a2 / and :op1 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "GH") :quant (c / concentration-quantity :quant "500" :unit (n2 / nanogram-per-milliliter)) :xref (x7 / xref :value "UNIPROT:GGH_HUMAN" :prob "1.002")) :ARG1 (s / secrete-01 :ARG1 (p3 / protein :name (n5 / name :op1 "PAI-1") :xref (x2 / xref :value "UNIPROT:PAI1_HUMAN" :prob "1.002"))) :ARG2 (p4 / product-of :op1 "5")) :op2 (i2 / increase-01 :ARG0 (p2 / protein :name (n3 / name :op1 "IL-6") :quant (c2 / concentration-quantity :quant "30" :unit (n4 / nanogram-per-milliliter)) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 s :ARG2 (p6 / product-of :op1 "3.6")) :ARG2-of (i5 / interest-01)) :snt2 (a / and :op2 (a3 / and :op1 (i3 / induce-01 :ARG0 (p5 / protein :name (n6 / name :op1 "GH") :xref (x4 / xref :value "UNIPROT:GGH_HUMAN" :prob "1.002")) :ARG2 (n15 / nucleic-acid :name (n7 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p7 / protein :name (n8 / name :op1 "PAI-1") :xref (x3 / xref :value "UNIPROT:PAI1_HUMAN" :prob "1.002"))) :quant (u / up-to :op1 (p8 / product-of :op1 "7.3")))) :op2 (i4 / induce-01 :ARG0 (p9 / protein :name (n9 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (n16 / nucleic-acid :name (n10 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 p7) :quant (u2 / up-to :op1 (p10 / product-of :op1 "3.6")))) :mod (r4 / respective) :instrument (s3 / stimulate-01 :ARG1-of (s2 / significant-02)) :manner (a5 / and :op1 (d / depend-01 :ARG1 (t / time)) :op2 (s5 / see-01 :time (c3 / concentrate-02 :ARG1 (a4 / and :op1 (p11 / protein :name (n11 / name :op1 "GH") :quant (c4 / concentration-quantity :quant "5" :unit (n12 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:GGH_HUMAN" :prob "1.002")) :op2 (p12 / protein :name (n13 / name :op1 "IL-6") :quant (c5 / concentration-quantity :quant "10" :unit (n14 / nanogram-per-milliliter)) :xref (x6 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (l / low-04))))))) # ::id bel_pmid_1679_8732.4954 # ::date 2015-05-04T09:56:00 # ::file bel_pmid_1679_8732_4954.txt # ::snt RNA interference-mediated inhibition of TLR2 and MyD88 expression in C2C12 muscle cells resulted in a near complete inhibition of palmitate-induced insulin resistance and IL-6 production. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (r / result-01 :ARG1 (i2 / inhibit-01 :ARG1 (e / express-03 :ARG2 (a3 / and :op1 (p / protein :name (n / name :op1 "TLR2") :xref (x / xref :value "UNIPROT:TLR2_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "MyD88") :xref (x1 / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663"))) :ARG3 (c / cell :name (n3 / name :op1 "C2C12") :mod (m2 / muscle))) :ARG1-of (m / mediate-01 :ARG0 (i / interfere-01 :ARG0 (n8 / nucleic-acid :name (n9 / name :op1 "RNA"))))) :ARG2 (a / and :op1 (i3 / inhibit-01 :ARG1 (r3 / resist-01 :ARG1 (p5 / protein :name (n5 / name :op1 "insulin") :xref (x3 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :ARG2-of (i4 / induce-01 :ARG0 (s / small-molecule :name (n6 / name :op1 "palmitate") :xref (x4 / xref :value "PUBCHEM:985" :prob "13.507233")))) :ARG1-of (c2 / complete-02 :degree (n4 / near))) :op2 (p3 / produce-01 :ARG1 (p4 / protein :name (n7 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1679_8732.19654 # ::date 2015-05-04T10:46:23 # ::file bel_pmid_1679_8732_19654.txt # ::snt When compared with an equimolar concentration of palmitate, fibroblast-stimulating lipopeptide-1, a known TLR2 ligand, was a slightly more potent activator of signal transduction and interleukin (IL)-6 production. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a2 / activate-01 :ARG0 (p / protein :name (n / name :op1 "fibroblast-stimulating" :op2 "lipopeptide-1") :ARG1-of (k / know-01) :mod (p2 / potent :degree (m / more :degree (s / slight)) :compared-to (c2 / concentrate-02 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "palmitate") :xref (x2 / xref :value "PUBCHEM:985" :prob "13.507233")) :mod (e / equimolar))) :mod (l / ligand :name (n2 / name :op1 "TLR2")) :xref (x1 / xref :value "UNIPROT:PCD16_HUMAN" :prob "0.202")) :ARG1 (a3 / and :op1 (t / transduce-01 :ARG1 (s2 / signal-07)) :op2 (p3 / produce-01 :ARG1 (p4 / protein :name (n3 / name :op1 "interleukin-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))))) # ::id bel_pmid_167_9532.20916 # ::date 2015-05-04T11:02:09 # ::file bel_pmid_167_9532_20916.txt # ::snt When c-H-ras expression was induced with heavy metal ions there was a marked reduction in the expression of two glycosylphosphatidylinositol (GPI) anchored proteins, TAP/Ly-6A.2 and Thy-1, on the plasma membrane of the transformed cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r2 / reduce-01 :ARG1 (e / express-03 :ARG2 (p5 / protein :quant "2" :name (n5 / name :op1 "glycosylphosphatidylinositol" :op2 "anchored" :op3 "protein") :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "TAP/Ly-6A.2")) :op2 (p3 / protein :name (n3 / name :op1 "Thy-1") :xref (x1 / xref :value "UNIPROT:THY1_HUMAN" :prob "0.592")))) :xref (x2 / xref :value "UNIPROT:VNN2_HUMAN" :prob "0.392")) :ARG3 (m2 / membrane :mod (p / plasma) :part-of (c / cell :ARG1-of (t / transform-01)) :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :ARG1-of (m / mark-01) :time (i2 / induce-01 :ARG2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n / name :op1 "c-H-ras") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003"))) :instrument (i3 / ion :mod (m3 / metal :mod (h / heavy))))) # ::id bel_pmid_1688_7332.6142 # ::date 2015-05-04T11:13:18 # ::file bel_pmid_1688_7332_6142.txt # ::snt We demonstrate that siRNA targeting ULK2 in mouse P19 cells results in elevated FGFR1 mediated FRS3 and SHP2 tyrosyl phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 11, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (r2 / result-01 :ARG1 (t / target-01 :ARG0 (n9 / nucleic-acid :name (n / name :op1 "siRNA")) :ARG1 (e / enzyme :name (n2 / name :op1 "ULK2") :xref (x3 / xref :value "UNIPROT:ULK2_HUMAN" :prob "1.003")) :location (c / cell :name (n3 / name :op1 "P19") :mod (m / mouse))) :ARG2 (p / phosphorylate-01 :ARG1 (a3 / and :op1 (a2 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (e3 / enzyme :name (n7 / name :op1 "SHP2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a4 / amino-acid :name (n8 / name :op1 "tyrosine") :part-of (p2 / protein :name (n4 / name :op1 "FRS3") :xref (x2 / xref :value "UNIPROT:FRS3_HUMAN" :prob "1.004")) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (m2 / mediate-01 :ARG0 (e2 / enzyme :name (n5 / name :op1 "FGFR1") :xref (x1 / xref :value "UNIPROT:FGFR1_HUMAN" :prob "1.004"))) :ARG1-of (e4 / elevate-01 :ARG0 e2)))) # ::id bel_pmid_1692_4534.3554 # ::date 2015-05-04T11:22:59 # ::file bel_pmid_1692_4534_3554.txt # ::snt PGD(2) induced a reduction in adiponectin and leptin mRNA, and the secretion of these adipokines was also inhibited, the effect being greater with leptin (up to 10-fold) than with adiponectin (twofold). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (i / induce-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "PGD2") :xref (x2 / xref :value "PUBCHEM:448457" :prob "15.769626")) :ARG2 (r / reduce-01 :ARG1 (a2 / and :op1 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "adiponectin") :xref (x1 / xref :value "UNIPROT:ADIPO_HUMAN" :prob "0.702")))) :op2 (n7 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "leptin") :xref (x / xref :value "UNIPROT:LEP_HUMAN" :prob "0.702"))))))) :op2 (i2 / inhibit-01 :ARG1 (s / secrete-01 :ARG1 (a7 / and :op1 p :op2 p2)) :mod (a4 / also)) :op3 (g / great :degree (m / more) :domain (a3 / affect-01 :ARG1 p2 :quant (u / up-to :op1 (p3 / product-of :op1 "10"))) :compared-to (a8 / affect-01 :ARG1 p :quant (p4 / product-of :quant "2")))) # ::id bel_pmid_1692_4534.16206 # ::date 2015-05-04T11:41:07 # ::file bel_pmid_1692_4534_16206.txt # ::snt In contrast, PGD(2) induced a marked stimulation of IL-6 and MCP-1 expression; with IL-6, this was rapid, the mRNA level increasing by >50-fold by 1 h. The rise in mRNA was accompanied by an increase in IL-6 and MCP-1 release (up to 100- and 6.5-fold, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt2 (a2 / accompany-01 :ARG0 (a4 / and :op1 (i3 / increase-01 :ARG1 (r6 / release-01 :ARG1 (p4 / protein :name (n6 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (p6 / product-of :op1 "100")) :op2 (i4 / increase-01 :ARG1 (r7 / release-01 :ARG1 (p5 / protein :name (n7 / name :op1 "MCP-1") :xref (x2 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002"))) :ARG2 (p7 / product-of :op1 "6.5")) :mod (r8 / respective)) :ARG1 (r4 / rise-01 :ARG1 (n8 / nucleic-acid :name (n5 / name :op1 "mRNA")))) :snt1 (a3 / and :op1 (c / contrast-01 :ARG2 (i / induce-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "PGD2") :xref (x4 / xref :value "PUBCHEM:448457" :prob "15.769626")) :ARG2 (s / stimulate-01 :ARG1 (a5 / and :op1 (e3 / express-03 :ARG2 (p / protein :name (n2 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (r / rapid)) :op2 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "MCP-1") :xref (x / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002")))) :ARG1-of (m3 / mark-01)))) :op2 (i2 / increase-01 :ARG1 (l / level :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 p))) :ARG2 (m4 / more-than :op1 (p3 / product-of :quant "50")) :time (a / after :op1 (s2 / stimulate-01 :ARG1 e3) :quant (u / up-to :op1 (t / temporal-quantity :quant "1" :unit (h / hour))))))) # ::id bel_pmid_1695_1379.27948 # ::date 2015-05-04T12:04:35 # ::file bel_pmid_1695_1379_27948.txt # ::snt IL-13 increased Egr-1 mRNA levels in a biphasic manner in Stat6/ fibroblasts; early induction of Egr-1 mRNA was observed 30 min following exposure to IL-13 and declined after 3–6 h (Fig. 6A). Egr-1 protein was increased in Stat6/ fibroblasts as compared with Stat6/ fibroblasts from 30 min to 3 h after IL-13 treatment (Fig. 6, B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt2 (i3 / increase-01 :ARG1 (p6 / protein :name (n8 / name :op1 "Erg-1") :xref (x2 / xref :value "UNIPROT:KCNH2_HUMAN" :prob "0.632")) :location (f4 / fibroblast :mod (p7 / protein :name (n9 / name :op1 "Stat6") :xref (x3 / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001")) :compared-to (f5 / fibroblast :mod (p8 / protein :name (n10 / name :op1 "Stat6") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x6 / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001"))) :mod (w2 / wild-type)) :time (a3 / after :op1 (t6 / treat-04 :ARG1 f4 :ARG2 (p9 / protein :name (n11 / name :op1 "IL-13") :xref (x5 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003"))) :quant (b2 / between :op1 (t4 / temporal-quantity :quant "30" :unit (m4 / minute)) :op2 (t5 / temporal-quantity :quant "3" :unit (h3 / hour)))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (f6 / figure :mod "6B") :op2 (f7 / figure :mod "6C")))) :snt1 (a5 / and :op1 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "IL-13") :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :ARG1 (l / level :quant-of "n2") :manner (b / biphasic) :location (f / fibroblast :mod (p3 / protein :name (n4 / name :op1 "Stat6") :xref (x1 / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001")) :mod (w / wild-type))) :op2 (a / and :op1 (o / observe-01 :ARG1 (i2 / induce-01 :ARG2 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p4 / protein :name (n6 / name :op1 "Egr-1") :xref (x4 / xref :value "UNIPROT:A0A089VKS7_HUMAN" :prob "1.001")))) :time (e3 / early) :ARG1-of (f2 / follow-01 :ARG2 (e4 / expose-01 :ARG1 f :ARG2 p))) :duration (t / temporal-quantity :quant "30" :unit (m2 / minute))) :op2 (d / decline-01 :ARG1 i2 :time (a2 / after :op1 e4 :quant (b3 / between :op1 (t2 / temporal-quantity :quant "3" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "6" :unit (h2 / hour))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "6A"))))) # ::id bel_pmid_1695_1379.27954 # ::date 2015-05-04T12:40:26 # ::file bel_pmid_1695_1379_27954.txt # ::snt PDGF-AA immunostaining was strongly expressed in the lungs of IL-13 transgene-positive mice and localized to the airway epithelium, airway smooth muscle, and interstitial cells (Fig. 1, B–E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / and :op1 (e / express-03 :ARG2 (i / immunostain-01 :ARG3 (p / protein :name (n / name :op1 "PDGF-AA") :xref (x1 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.353"))) :ARG3 (l / lung :mod (m / mouse :mod (p3 / protein :name (n3 / name :op1 "IL-13") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :mod (p2 / positive))) :ARG1-of (s / strong-02)) :op2 (b / be-located-at-91 :ARG1 p :ARG2 (a2 / and :op1 (e2 / epithelium :mod (a3 / airway)) :op2 (m2 / muscle :ARG1-of (s2 / smooth-06) :mod a3) :op3 (c / cell :mod (i2 / interstice)))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "1E")))) # ::id bel_pmid_1695_1379.27956 # ::date 2015-05-04T12:52:03 # ::file bel_pmid_1695_1379_27956.txt # ::snt PDGF-CC immunostaining was strongly expressed in the lungs of IL-13 transgene-positive mice and localized to airway epithelium, type II pneumocytes, alveolar macrophages, and fibroblasts (Fig. 1G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / and :op1 (e / express-03 :ARG2 (i / immunostain-01 :ARG3 (p / protein :name (n / name :op1 "PDGF-CC") :xref (x1 / xref :value "UNIPROT:PDGFC_HUMAN" :prob "0.373"))) :ARG3 (l / lung :poss-of (m / mouse :mod (p3 / protein :name (n2 / name :op1 "IL-13") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :mod (p2 / positive))) :ARG1-of (s / strong-02)) :op2 (b / be-located-at-91 :ARG1 p :ARG2 (a2 / and :op1 (e2 / epithelium :mod (a3 / airway)) :op2 (c / cell :name (n3 / name :op1 "type" :op2 "II" :op3 "pneumocyte")) :op3 (c2 / cell :name (n4 / name :op1 "macrophage") :mod (a4 / alveolus)) :op4 (f / fibroblast))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1G"))) # ::id bel_pmid_1695_1379.27964 # ::date 2015-05-04T12:58:32 # ::file bel_pmid_1695_1379_27964.txt # ::snt we observed that IL-13 caused tyrosine phosphorylation of Stat1 in Stat6/ and Stat6/ fibroblasts (Fig. 3, A and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 11, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (c / cause-01 :ARG0 (p2 / protein :name (n / name :op1 "IL-13") :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (p3 / protein :name (n3 / name :op1 "Stat1") :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :location (a2 / and :op1 (f / fibroblast :mod (p4 / protein :name (n4 / name :op1 "Stat6") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001"))) :op2 (f2 / fibroblast :mod (p5 / protein :name (n5 / name :op1 "Stat6") :xref (x3 / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001")) :mod (w2 / wild-type))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f3 / figure :mod "3A") :op2 (f4 / figure :mod "3C")))) # ::id bel_pmid_1695_1379.27966 # ::date 2015-05-04T13:10:27 # ::file bel_pmid_1695_1379_27966.txt # ::snt Next, we observed that Stat6 was tyrosine phosphorylated in Stat1/ and Stat1/ fibroblasts (Fig. 3, B and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 11, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (p2 / phosphorylate-01 :ARG1 (p / protein :name (n / name :op1 "Stat6") :part (a / amino-acid :name (n2 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :xref (x2 / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001")) :location (a2 / and :op1 (f / fibroblast :mod (p3 / protein :name (n3 / name :op1 "Stat1") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604"))) :op2 (f2 / fibroblast :mod (p4 / protein :name (n4 / name :op1 "Stat1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604")) :mod (w2 / wild-type)))) :time (n5 / next) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f3 / figure :mod "3B") :op2 (f4 / figure :mod "3D")))) # ::id bel_pmid_1695_1379.27992 # ::date 2015-05-04T13:15:50 # ::file bel_pmid_1695_1379_27992.txt # ::snt A late peak of Egr-1 mRNA occurred 12–24 h after IL-13 treatment but was not accompanied by an increase in Egr-1 protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 15, 2015 (c / contrast-01 :ARG1 (p / peak :mod (l / late) :mod (n4 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Egr-1") :xref (x / xref :value "UNIPROT:A0A089VKS7_HUMAN" :prob "1.001")))) :time (a / after :op1 (t / treat-04 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-13") :xref (x1 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003"))) :quant (b / between :op1 (t2 / temporal-quantity :quant "12" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "24" :unit (h2 / hour))))) :ARG2 (a2 / accompany-01 :polarity "-" :ARG0 (i / increase-01 :ARG1 p2) :ARG1 p)) # ::id bel_pmid_1695_1379.28002 # ::date 2015-05-04T13:23:36 # ::file bel_pmid_1695_1379_28002.txt # ::snt IL-13-induced PDGF-A and PDGF-C mRNA levels were significantly reduced in fibroblasts isolated from the lungs of Stat6/ mice compared with fibroblasts isolated from the lungs of the wild-type Stat6/ mice (Fig. 2, A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / reduce-01 :ARG1 (a / and :op1 (l / level :quant-of (n8 / nucleic-acid :wiki "Messenger_RNA" :name (n2 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :wiki "PDGFA" :name (n / name :op1 "PDGF-A") :xref (x / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.683"))))) :op2 (l2 / level :quant-of (n9 / nucleic-acid :wiki "Messenger_RNA" :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p3 / protein :wiki "PDGFC" :name (n5 / name :op1 "PDGF-C") :xref (x2 / xref :value "UNIPROT:PDGFC_HUMAN" :prob "1.003"))))) :ARG2-of (i / induce-01 :ARG0 (p2 / protein :wiki "Interleukin_13" :name (n3 / name :op1 "IL-13") :xref (x1 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")))) :ARG2 (s / significant-02) :location (f / fibroblast :ARG1-of (i2 / isolate-01 :ARG2 (l3 / lung :mod (m / mouse :mod (p4 / protein :wiki "STAT6" :name (n6 / name :op1 "Stat6") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001"))))) :compared-to (f2 / fibroblast :ARG1-of (i3 / isolate-01 :ARG2 (l4 / lung :mod (m3 / mouse :mod (p5 / protein :wiki "STAT6" :name (n7 / name :op1 "Stat6") :mod (w / wild-type) :xref (x4 / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001"))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f3 / figure :mod "2A") :op2 (f4 / figure :mod "2B")))) # ::id bel_pmid_1695_1379.32888 # ::date 2015-05-04T13:32:44 # ::file bel_pmid_1695_1379_32888.txt # ::snt Egr-1 has been characterized as a transcriptional regulator of both PDGF-A and PDGF-C gene expression (18, 19). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 4, 2015 (c / characterize-01 :ARG1 (p / protein :name (n / name :op1 "Erg-1") :xref (x2 / xref :value "UNIPROT:KCNH2_HUMAN" :prob "0.632")) :ARG2 (r / regulate-01 :ARG1 (e / express-03 :ARG1 (a / and :op1 (g / gene :name (n2 / name :op1 "PDGF-A") :xref (x1 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.683")) :op2 (g2 / gene :name (n3 / name :op1 "PDGF-C") :xref (x / xref :value "UNIPROT:PDGFC_HUMAN" :prob "1.003")))) :mod (t / transcribe-01)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "18" :op2 "19"))))) # ::id bel_pmid_1695_1379.38388 # ::date 2015-05-04T13:35:59 # ::file bel_pmid_1695_1379_38388.txt # ::snt Western blot analysis demonstrated that PD98059 blocked IL-13-induced phosphorylation of ERK1/2 (Fig. 8A) yet enhanced the phosphorylation of Stat6 and increased protein expression of Egr-1 in a time-dependent manner after IL-13 treatment (Fig. 8, B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / demonstrate-01 :ARG0 (a / analyze-01 :manner (i3 / immunoblot-01)) :ARG1 (c / contrast-01 :ARG1 (b / block-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "PD98059") :xref (x3 / xref :value "PUBCHEM:4713" :prob "18.349844")) :ARG1 (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2")) :ARG2-of (i / induce-01 :ARG0 (p4 / protein :name (n6 / name :op1 "IL-13") :xref (x2 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "8A"))) :ARG2 (a2 / and :op1 (e / enhance-01 :ARG0 s :ARG1 (p5 / phosphorylate-01 :ARG1 (p6 / protein :name (n7 / name :op1 "Stat6") :xref (x / xref :value "UNIPROT:Q6LCD8_HUMAN" :prob "1.001")))) :op2 (i2 / increase-01 :ARG0 s :ARG1 (e2 / express-03 :ARG2 (p7 / protein :name (n8 / name :op1 "Erg-1") :xref (x1 / xref :value "UNIPROT:KCNH2_HUMAN" :prob "0.632"))) :time (a3 / after :op1 (t / treat-04 :ARG2 p4)) :manner (d3 / depend-01 :ARG0 i2 :ARG1 (t2 / time))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "8B") :op2 (f3 / figure :mod "8C")))))) # ::id bel_pmid_1698_7002.500 # ::date 2015-05-01T11:07:21 # ::file bel_pmid_1698_7002_500.txt # ::snt In cycling cells, the effects of Nox1 were dose dependent: levels of Nox1 that induced 3- to 10-fold increases in ROS promoted phosphorylation of ERK1/2 and expression of cyclin D1, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (d / depend-01 :ARG0 (a / affect-01 :ARG0 (e / enzyme :name (n / name :op1 "Nox1") :xref (x1 / xref :value "UNIPROT:NOX1_HUMAN" :prob "0.604"))) :ARG1 (d2 / dose) :location (c / cell :ARG1-of (c2 / cycle-02)) :ARG1-of (m / mean-01 :ARG2 (p / promote-01 :ARG0 (l / level :quant-of e :ARG0-of (i / induce-01 :ARG2 (i2 / increase-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "ROS") :xref (x2 / xref :value "PUBCHEM:128351" :prob "11.468653")) :ARG2 (b / between :op1 (p4 / product-of :op1 "3") :op2 (p5 / product-of :op1 "10"))))) :ARG1 (a2 / and :op1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"))) :op2 (e2 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D1") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001"))))))) # ::id bel_pmid_1700_8315.1518 # ::date 2015-05-01T11:14:03 # ::file bel_pmid_1700_8315_1518.txt # ::snt Induction of STAT3 Tyr705 and Ser727 phosphorylations by Galpha(s)QL was suppressed by inhibition of protein kinase A, Janus kinase 2/3, Rac1, c-Jun N-terminal kinase (JNK), or phosphatidylinositol 3-kinase, and a similar profile was observed in response to beta2-adrenergic receptor stimulation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (s / suppress-01 :ARG0 (i2 / inhibit-01 :ARG1 (o2 / or :op1 (e / enzyme :name (n5 / name :op1 "protein" :op2 "kinase" :op3 "A") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393")) :op2 (e2 / enzyme :name (n6 / name :op1 "Janus" :op2 "kinase" :op3 "2/3")) :op3 (p4 / protein :name (n7 / name :op1 "Rac1") :xref (x4 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604")) :op4 (e3 / enzyme :name (n8 / name :op1 "c-Jun" :op2 "N-terminal" :op3 "kinase") :xref (x1 / xref :value "UNIPROT:MK08_HUMAN" :prob "0.393")) :op5 (e4 / enzyme :name (n9 / name :op1 "phosphatidylinositol" :op2 "3-kinase") :xref (x / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.701")))) :ARG1 (i / induce-01 :ARG2 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "705" :name (n2 / name :op1 "tyrosine") :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a4 / amino-acid :mod "727" :name (n3 / name :op1 "serine") :xref (x7 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of (p2 / protein :name (n / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :ARG2 (p3 / protein :name (n4 / name :op1 "Galpha(s)QL"))))) :op2 (o / observe-01 :ARG1 (p5 / profile :ARG1-of (r2 / resemble-01) :ARG2-of (r / respond-01 :ARG1 (s3 / stimulate-01 :ARG1 (p6 / protein :name (n10 / name :op1 "beta2-adrenergic" :op2 "receptor") :xref (x5 / xref :value "UNIPROT:ADRB2_HUMAN" :prob "0.693"))))))) # ::id bel_pmid_1703_0180.5428 # ::date 2015-05-03T12:23:41 # ::file bel_pmid_1703_0180_5428.txt # ::snt Activated KRAS is known to induce tyrosine phosphorylation of beta-catenin, leading to its release from E-cadherin at the adherens junction # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "KRAS") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG2 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (p3 / protein :name (n2 / name :op1 "beta-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (l / lead-03 :ARG2 (r / release-01 :ARG1 p3 :ARG2 (p4 / protein :name (n3 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :location (m / macro-molecular-complex :name (n5 / name :op1 "adherens" :op2 "junction")))) :ARG1-of (k / know-01)) # ::id bel_pmid_1708_2637.21974 # ::date 2015-05-03T12:58:41 # ::file bel_pmid_1708_2637_21974.txt # ::snt TNF-a strongly stimulated FRA-1 promoter activity in WT MEFs as compared with the erk1-/- MEFs (Fig. 9B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "TNF-a") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG1 (a / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n2 / name :op1 "FRA-1") :xref (x1 / xref :value "UNIPROT:FOSL1_HUMAN" :prob "1.002")))) :location (f2 / fibroblast :source (e / embryo :mod (m3 / mouse)) :mod (w / wild-type) :ARG2-of (c / compare-01 :ARG1 (f3 / fibroblast :source (e2 / embryo :mod (m / mouse)) :mod (e3 / enzyme :name (n3 / name :op1 "erk1") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")))))) :ARG1-of (s2 / strong-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "9B"))) # ::id bel_pmid_1708_2637.21978 # ::date 2015-05-03T13:23:33 # ::file bel_pmid_1708_2637_21978.txt # ::snt the recruitment of c-Jun was strongly enhanced following TNF-a treatment (Fig. 10B, lanes 3 and 4). In contrast, the binding of c-Jun to the fra-1 promoter was significantly diminished in MEFS lacking the erk1-/- signaling (cf lanes 7 and 8 with lanes 3 and 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (e2 / enhance-01 :ARG1 (r / recruit-01 :ARG1 (p5 / protein :name (n / name :op1 "c-Jun"))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (l / lane :mod "3") :op2 (l5 / lane :mod "5") :part-of (f / figure :mod "10B"))) :ARG1-of (f2 / follow-01 :ARG2 (t / treat-04 :ARG2 (p / protein :name (n2 / name :op1 "TNF-a") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :ARG1-of (s / strong-02)) :snt2 (c / contrast-01 :ARG2 (d2 / diminish-01 :ARG1 (b / bind-01 :ARG1 (p4 / protein :name (n4 / name :op1 "c-Jun")) :ARG2 (m2 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n3 / name :op1 "fra-1") :xref (x1 / xref :value "UNIPROT:FOSL1_HUMAN" :prob "0.632"))))) :ARG2 (s2 / significant-02) :location (f3 / fibroblast :source (e4 / embryo :mod (m3 / mouse)) :ARG0-of (l2 / lack-01 :ARG1 (s3 / signal-07 :ARG0 (e5 / enzyme :name (n5 / name :op1 "erk1") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")))))) :ARG1-of (c2 / conform-01 :ARG0 (c3 / compare-01 :ARG1 (a2 / and :op1 (l3 / lane :mod "7") :op2 (l4 / lane :mod "8")) :ARG2 (a3 / and :op1 (l6 / lane :mod "3") :op2 (l7 / lane :mod "4")))))) # ::id bel_pmid_1708_2637.31490 # ::date 2015-05-03T14:04:15 # ::file bel_pmid_1708_2637_31490.txt # ::snt As shown in Fig. 9A, TNF-a strongly stimulated both ERK1 and ERK2 phosphorylation in WT cells (cf lanes 1 and 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "TNF-a") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :mod (b / both)) :location (c / cell :mod (w / wild-type))) :ARG1-of (c3 / conform-01 :ARG0 (c2 / compare-01 :ARG1 (l / lane :mod "1") :ARG2 (l2 / lane :mod "2"))) :ARG1-of (s2 / show-01 :location (f / figure :mod "9A")) :ARG1-of (s3 / strong-02)) # ::id bel_pmid_1708_2637.39256 # ::date 2015-05-03T14:17:15 # ::file bel_pmid_1708_2637_39256.txt # ::snt The -318 TRE mediates c-Jun-dependent, TNF-alpha-inducible FRA-1 promoter activity.....Consistent with this result, ectopic expression of a c-Jun mutant lacking the transactivation domain greatly reduced (~80%) TNF-alpha-stimulated promoter activity (Fig. 2B)....However, TNF-a induced the binding of c-Jun to the promoter as early as 30 min (Fig. 3A, lane 2), and it remained high through 60 min (Fig. 3A, lane 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (m2 / mediate-01 :ARG0 (d / dna-sequence :mod "-318" :name (n / name :op1 "TRE")) :ARG1 (a / activity-06 :ARG0 (m8 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n2 / name :op1 "FRA-1") :xref (x1 / xref :value "UNIPROT:FOSL1_HUMAN" :prob "1.002")))) :ARG0-of (d2 / depend-01 :ARG1 (p11 / protein :name (n3 / name :op1 "c-Jun"))) :ARG2-of (i / induce-01 :ARG0 (p4 / protein :name (n4 / name :op1 "TNF-alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG1-of (p12 / possible-01)))) :snt2 (r / reduce-01 :ARG0 (e / express-03 :ARG2 (e4 / enzyme :name (n5 / name :op1 "c-Jun") :ARG2-of (m3 / mutate-01) :ARG0-of (l / lack-01 :ARG1 (p7 / protein-segment :ARG2-of (t / transactivate-01)))) :mod (e2 / ectopic)) :ARG1 (a3 / activity-06 :ARG0 (m6 / molecular-physical-entity :ARG0-of (p3 / promote-01)) :ARG1-of (s / stimulate-01 :ARG0 (p8 / protein :name (n6 / name :op1 "TNF-alpha") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :ARG2 (a2 / approximately :op1 (p6 / percentage-entity :value "80")) :degree (g / great) :ARG1-of (c / consistent-01 :ARG2 (t5 / thing :mod (t2 / this) :ARG2-of (r2 / result-01))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "2B"))) :snt3 (c2 / contrast-01 :ARG2 (a4 / and :op1 (i2 / induce-01 :ARG0 (p9 / protein :name (n7 / name :op1 "TNF-a") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG2 (b / bind-01 :ARG1 (p10 / protein :name (n8 / name :op1 "c-Jun")) :ARG2 (m7 / molecular-physical-entity :ARG0-of (p5 / promote-01))) :time (a5 / after :mod (e3 / early) :quant (t3 / temporal-quantity :quant "30" :unit (m4 / minute))) :ARG1-of (d5 / describe-01 :ARG0 (l2 / lane :mod "2" :part-of (f2 / figure :mod "3A")))) :op2 (r3 / remain-01 :ARG1 b :ARG3 (h / high-02 :ARG1 b) :duration (t4 / temporal-quantity :quant "60" :unit (m5 / minute)) :ARG1-of (d6 / describe-01 :ARG0 (l3 / lane :mod "3" :part-of f2)))))) # ::id bel_pmid_1710_5652.28156 # ::date 2015-05-03T15:17:27 # ::file bel_pmid_1710_5652_28156.txt # ::snt Real-time RT-PCR revealed that IL-1beta induced SYN expression at the transcriptional level, because the mRNA level of SYN was upregulated by IL-1?. TNF-? had a weaker effect on SYN transcription, whereas IL-6 had no effect # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (r / reveal-01 :ARG0 (t3 / thing :name (n / name :op1 "RT-PCR") :mod (r2 / real-time)) :ARG1 (i / induce-01 :ARG0 (p / protein :name (n2 / name :op1 "IL-1beta") :xref (x1 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :ARG2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "SYN") :xref (x2 / xref :value "UNIPROT:SYNEM_HUMAN" :prob "1.002"))) :mod (l / level :mod (t / transcribe-01))) :ARG1-of (c / cause-01 :ARG0 (u / upregulate-01 :ARG1 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA") :mod (l2 / level) :ARG0-of (e5 / encode-01 :ARG1 e3)) :ARG2 (p2 / protein :name (n5 / name :op1 "IL1B") :xref (x3 / xref :value "UNIPROT:IL1B_HUMAN" :prob "1.003"))))) :snt2 (c2 / contrast-01 :ARG1 (a / affect-01 :ARG0 (p3 / protein :name (n6 / name :op1 "TNF-α") :xref (x4 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :ARG1 (t2 / transcribe-01 :ARG1 (e4 / enzyme :name (n7 / name :op1 "SYN") :xref (x / xref :value "UNIPROT:SYNEM_HUMAN" :prob "1.002"))) :ARG1-of (w / weak-02 :degree (m2 / more))) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 (p4 / protein :name (n8 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 t2))) # ::id bel_pmid_1711_8707.35424 # ::date 2015-05-03T16:06:50 # ::file bel_pmid_1711_8707_35424.txt # ::snt STAT3 is also able to prevent cell death through inhibition of the extrinsic apoptotic pathway. This pathway is activated upon binding of extracellular ligands such as FAS ligand (FAS-L) to cell-surface death receptors. Upon interaction with FAS-L, the FAS death receptor induces cell death through caspase-8 activation and truncation of the death agonist BID. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (p / possible-01 :ARG1 (p2 / prevent-01 :ARG0 (p3 / protein :name (n / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1 (d / die-01 :ARG1 (c / cell)) :ARG3 (i / inhibit-01 :ARG1 (p4 / pathway :mod (e2 / extrinsic) :mod (a5 / apoptosis))) :mod (a / also))) :snt2 (a2 / activate-01 :ARG1 (p5 / pathway :mod (t / this)) :time (b / bind-01 :ARG1 (l / ligand :mod (e / extracellular) :example (l2 / ligand :name (n3 / name :op1 "FAS"))) :ARG2 (r / receptor :location (s / surface :part-of (c2 / cell)) :ARG1-of (d2 / die-01)))) :snt3 (i2 / induce-01 :ARG0 (p6 / protein :name (n4 / name :op1 "FAS" :op2 "death" :op3 "receptor") :xref (x2 / xref :value "UNIPROT:TNR6_HUMAN" :prob "0.322")) :ARG2 (d3 / die-01 :ARG1 (c3 / cell)) :manner (a3 / and :op1 (a4 / activate-01 :ARG1 (p7 / protein :name (n5 / name :op1 "caspase-8") :xref (x / xref :value "UNIPROT:CASP8_HUMAN" :prob "0.702"))) :op2 (t2 / truncate-01 :ARG1 (p8 / protein :name (n6 / name :op1 "death" :op2 "agonist" :op3 "BID")))) :time (i3 / interact-01 :ARG1 (p9 / protein :name (n7 / name :op1 "FAS-L") :xref (x3 / xref :value "UNIPROT:TNFL6_HUMAN" :prob "0.672"))))) # ::id bel_pmid_1711_8707.37686 # ::date 2015-05-04T01:14:17 # ::file bel_pmid_1711_8707_37686.txt # ::snt These genes can be divided in three classes: one that controls cell-cycle arrest and senescence, one that controls apoptosis and one that regulates glucose metabolism and autophagy [42]. p53 is essentially known as a pro-apoptotic transcription factor that upregulates the expression of proteins such as BCL2-associated X protein (BAX), p53 upregulated modulator of apoptosis (PUMA) or NOXA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (m / multi-sentence :snt2 (k / know-02 :ARG1 (p2 / protein :name (n / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG2 (p3 / protein :name (n2 / name :op1 "transcription" :op2 "factor") :ARG0-of (f / favor-01 :ARG1 (a7 / apoptosis)) :ARG0-of (u / upregulate-01 :ARG1 (e / express-03 :ARG2 (p4 / protein :example (o2 / or :op1 (p5 / protein :name (n3 / name :op1 "Bcl-2-associated" :op2 "X") :xref (x4 / xref :value "UNIPROT:BAG1_HUMAN" :prob "0.322")) :op2 (p6 / protein :name (n4 / name :op1 "p53" :op2 "upregulated" :op3 "modulator" :op4 "of" :op5 "apoptosis") :xref (x / xref :value "UNIPROT:BBC3B_HUMAN" :prob "0.692")) :op3 (p7 / protein :name (n5 / name :op1 "NOXA") :xref (x3 / xref :value "UNIPROT:APR_HUMAN" :prob "1.002")))))) :xref (x2 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.393")) :manner (e2 / essential)) :snt1 (p8 / possible-01 :ARG1 (d / divide-02 :ARG1 (g / gene :mod (t / this)) :ARG2 (c / class :quant "3" :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (c3 / class :ARG0-of (c2 / control-01 :ARG1 (a2 / and :op1 (a3 / arrest-02 :ARG1 (c4 / cycle-02 :ARG1 (c7 / cell))) :op2 (s / senescence)))) :op2 (c8 / class :ARG0-of (c9 / control-01 :ARG1 (a4 / apoptosis))) :op3 (c10 / class :ARG0-of (r / regulate-01 :ARG1 (a5 / and :op1 (m3 / metabolize-01 :ARG1 (g2 / glucose)) :op2 (a6 / autophagy))))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 "42")))))) # ::id bel_pmid_1711_8707.38556 # ::date 2015-05-04T02:07:52 # ::file bel_pmid_1711_8707_38556.txt # ::snt that IL-6 and IL-10, two cytokines that are known to activate STAT3, confer a drug-resistant phenotype in renal carcinomas, which was subsequently confirmed in different cancer cell lines such as multiple myeloma [72,73]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / confer-02 :ARG0 (a / and :op1 (c9 / cytokine :name (n / name :op1 "IL-6")) :op2 (c10 / cytokine :name (n2 / name :op1 "IL-10")) :ARG0-of (a2 / activate-01 :ARG1 (p / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (k / know-01))) :ARG1 (p4 / phenotype :ARG0-of (r / resist-01 :ARG1 (d / drug)) :ARG1-of (c3 / confirm-01 :location (c6 / cell-line :ARG1-of (d3 / differ-02) :mod (d5 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :example (d4 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma")))) :time (s / subsequent))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c8 / cite-01 :ARG2 (a3 / and :op1 "72" :op2 "73")))) :location (m / medical-condition :name (n6 / name :op1 "carcinoma") :mod (k2 / kidney))) # ::id bel_pmid_1711_8707.39772 # ::date 2015-05-04T02:09:46 # ::file bel_pmid_1711_8707_39772.txt # ::snt Importantly, the expression of survivin correlates with STAT3 activation in breast tumors, and the inhibition of this signaling pathway induces apoptosis [47,48]. Finally, it has also been shown that AKT is a direct target gene of STAT3, which binds directly to its promoter to enhance its expression [49]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (a / and :op1 (c / correlate-01 :ARG1 (e / express-03 :ARG2 (p5 / protein :name (n4 / name :op1 "survivin") :ARG0-of (s / signal-07))) :ARG2 (a2 / activate-01 :ARG1 (p / protein :name (n / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :location (t / tumor :mod (b / breast))) :op2 (i / induce-01 :ARG0 (i2 / inhibit-01 :ARG1 (p7 / pathway :mod (t2 / this) :ARG0-of s)) :ARG2 (a3 / apoptosis)) :manner (i3 / important) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 "47" :op2 "48"))))) :snt2 (s3 / show-01 :li "-1" :ARG1 (t3 / target-01 :ARG0 (p4 / protein :name (n2 / name :op1 "STAT3") :ARG1-of (b2 / bind-01 :ARG2 (m2 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 "g")) :purpose (e2 / enhance-01 :ARG0 p4 :ARG1 (e3 / express-03 :ARG1 "g"))) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1 (g / gene :name (n3 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (d2 / direct-02)) :mod (a5 / also) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "49"))))) # ::id bel_pmid_1712_7443.3208 # ::date 2015-05-04T03:05:58 # ::file bel_pmid_1712_7443_3208.txt # ::snt Several transcription factors have also been implicated in megakaryopoiesis including, GATA-1, friend of GATA-1 (FOG-1), nuclear factor-erythroid 2 (NF-E2), and Fli-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 9, 2015 (i / implicate-01 :ARG1 (p / protein :name (n / name :op1 "transcription" :op2 "factor") :quant (s / several) :ARG2-of (i2 / include-91 :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "GATA-1") :xref (x / xref :value "UNIPROT:GATA1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n5 / name :op1 "friend" :op2 "of" :op3 "GATA-1") :xref (x1 / xref :value "UNIPROT:FOG1_HUMAN" :prob "0.693")) :op3 (p4 / protein :name (n3 / name :op1 "nuclear" :op2 "factor-erythroid" :op3 "2") :xref (x2 / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.342")) :op4 (p5 / protein :name (n4 / name :op1 "Fli-1") :xref (x3 / xref :value "UNIPROT:Q65ZP9_HUMAN" :prob "0.631")))) :xref (x4 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.393")) :ARG2 (m / megakaryopoiesis) :mod (a / also)) # ::id bel_pmid_1712_7443.21794 # ::date 2015-05-04T03:19:04 # ::file bel_pmid_1712_7443_21794.txt # ::snt Tyk2, along with JAK2, does appear to regulate TPO receptor localization at the plasma membrane by stimulating recycling and enhancing the stability of the receptor in Ba/F3 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / appear-02 :ARG1 (r / regulate-01 :ARG0 (a3 / and :op1 (e / enzyme :name (n / name :op1 "Tyk2") :xref (x / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n5 / name :op1 "JAK2") :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :ARG1 (b / be-located-at-91 :ARG1 (p / protein :name (n3 / name :op1 "TPO" :op2 "receptor") :xref (x1 / xref :value "UNIPROT:TPOR_HUMAN" :prob "0.232")) :ARG2 (m / membrane :mod (p2 / plasma) :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :manner (a2 / and :op1 (s / stimulate-01 :ARG0 a3 :ARG1 (r2 / recycle-01)) :op2 (e3 / enhance-01 :ARG0 a3 :ARG1 (s2 / stability :poss p :location (c / cell-line :name (n4 / name :op1 "Ba/F3"))))))) # ::id bel_pmid_1712_7443.27130 # ::date 2015-05-04T03:37:35 # ::file bel_pmid_1712_7443_27130.txt # ::snt Other notable genes downregulated with GATA-1 knockdown are the p45 subunit of nuclear factor erythroid-derived 2 (NF- E2), JAK2, and beta1-tubulin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 9, 2015 (i / include-91 :ARG1 (a / and :op1 (s / subunit :part-of (g4 / gene :name (n4 / name :op1 "nuclear" :op2 "factor" :op3 "erythroid-derived" :op4 "2") :xref (x1 / xref :value "UNIPROT:NF2L2_HUMAN" :prob "0.382")) :mod (p2 / protein :name (n6 / name :op1 "p45") :xref (x / xref :value "UNIPROT:CASP1_HUMAN" :prob "1.002"))) :op2 (g2 / gene :name (n2 / name :op1 "JAK2") :xref (x3 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :op3 (g3 / gene :name (n3 / name :op1 "beta1-tubulin") :xref (x2 / xref :value "UNIPROT:BTC_HUMAN" :prob "0.263"))) :ARG2 (g / gene :mod (o / other) :ARG1-of (n / notable-04) :ARG1-of (d / downregulate-01 :ARG2 (p / protein :name (n5 / name :op1 "GATA-1") :ARG1-of (k / knock-down-02) :xref (x4 / xref :value "UNIPROT:GATA1_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1712_7443.29536 # ::date 2015-05-04T04:45:39 # ::file bel_pmid_1712_7443_29536.txt # ::snt There are two isoforms of 3beta- HSD expressed in wild-type megakaryocytes (I and VI), but neither are expressed in NF-E2 null megakaryocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (e / express-03 :ARG2 (i / isoform :quant "2" :mod (e2 / enzyme :name (n / name :op1 "3beta-HSD") :xref (x3 / xref :value "UNIPROT:3BHS1_HUMAN" :prob "0.342")) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (e4 / enzyme :name (n2 / name :op1 "3beta-HSD" :op2 "I") :xref (x2 / xref :value "UNIPROT:3BHS1_HUMAN" :prob "0.692")) :op2 (e5 / enzyme :name (n3 / name :op1 "3beta-HSD" :op2 "IV") :xref (x1 / xref :value "UNIPROT:3BHS1_HUMAN" :prob "0.372"))))) :ARG3 (m4 / megakaryocyte :mod (w / wild-type))) :ARG2 (e3 / express-03 :polarity "-" :ARG2 i :ARG3 (m3 / megakaryocyte :mod (p / protein :name (n5 / name :op1 "NF-E2") :ARG1-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:NFE2_HUMAN" :prob "0.672"))))) # ::id bel_pmid_1712_7443.31646 # ::date 2015-05-04T05:09:18 # ::file bel_pmid_1712_7443_31646.txt # ::snt TPO is necessary for megakaryocyte maturation in that TPO deficient mice display greatly reduced megakaryocyte production as well as reduced numbers of mature megakaryocytes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (n / need-01 :ARG0 (m / mature-01 :ARG1 (m4 / megakaryocyte)) :ARG1 (p2 / protein :name (n2 / name :op1 "TPO") :xref (x / xref :value "UNIPROT:TPO_HUMAN" :prob "1.003")) :ARG1-of (c2 / cause-01 :ARG0 (d / display-01 :ARG0 (m2 / mouse :ARG0-of (l / lack-01 :ARG1 p2)) :ARG1 (a / and :op1 (p / produce-01 :ARG1 m4 :ARG1-of (r / reduce-01 :degree (g / great))) :op2 (n3 / number :ARG1-of (r2 / reduce-01) :quant-of (m5 / megakaryocyte :ARG1-of (m3 / mature-02))))))) # ::id bel_pmid_1712_7443.35706 # ::date 2015-05-04T05:30:39 # ::file bel_pmid_1712_7443_35706.txt # ::snt TPO to c-Mpl (a receptor tyrosine kinase) activates both Janus Kinase 2 (JAK2) and Tyk2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG0 (a3 / and :op1 (p / protein :name (n3 / name :op1 "TPO") :xref (x1 / xref :value "UNIPROT:TPO_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n4 / name :op1 "c-Mpl") :ARG1-of (m / mean-01 :ARG2 (e4 / enzyme :name (n5 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :xref (x2 / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392"))) :xref (x / xref :value "UNIPROT:MATN1_HUMAN" :prob "0.202"))) :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "Janus" :op2 "Kinase" :op3 "2") :xref (x4 / xref :value "UNIPROT:JAK2_HUMAN" :prob "0.703")) :op2 (e3 / enzyme :name (n2 / name :op1 "Tyk2") :xref (x3 / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603"))) :mod (b / both)) # ::id bel_pmid_1714_2955.38942 # ::date 2015-05-04T06:03:13 # ::file bel_pmid_1714_2955_38942.txt # ::snt . Furthermore, the bFGF-induced activation of ERK1/2 seems to enhance the transcriptional activity of STAT3. Co-stimulation of KMS-11 with bFGF and IL-6 leads to marked expression of STAT3 target genes, such as c-myc and bcl-2, further suggesting the relevance of STAT3 phosphorylated at both Tyr705 and Ser727 for the full activation as a transcription factor (Fig. 5). In addition, the # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (a / and :op2 (s / seem-01 :ARG1 (e / enhance-01 :ARG0 (a3 / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2")) :ARG2-of (i / induce-01 :ARG0 (p3 / protein :name (n3 / name :op1 "bFGF") :xref (x3 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.003")))) :ARG1 (a2 / activity-06 :ARG0 (p / protein :name (n / name :op1 "STAT3") :xref (x6 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1 (t / transcribe-01))))) :snt2 (l / lead-03 :ARG0 (s2 / stimulate-01 :ARG1 (c / cell-line :name (n4 / name :op1 "KMS-11")) :ARG2 (a4 / and :op1 (p4 / protein :name (n5 / name :op1 "bFGF") :xref (x4 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.003")) :op2 (p5 / protein :name (n6 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :manner (j / joint)) :ARG1 (e2 / express-03 :ARG1 (g4 / gene :ARG2-of (i2 / include-91 :ARG1 (a5 / and :op1 (g2 / gene :name (n8 / name :op1 "c-myc") :xref (x2 / xref :value "UNIPROT:Q16158_HUMAN" :prob "1.001")) :op2 (g3 / gene :name (n9 / name :op1 "bcl-2") :xref (x1 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "1.001")))) :ARG1-of (t2 / target-01 :ARG0 (p2 / protein :name (n7 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :ARG1-of (m2 / mark-01)) :ARG0-of (s3 / suggest-01 :ARG1 (r / relevant-01 :ARG1 (a8 / and :op1 (a6 / amino-acid :name (n11 / name :op1 "tyrosine") :ARG1-of (p7 / phosphorylate-01) :xref (x8 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a7 / amino-acid :name (n12 / name :op1 "serine") :ARG1-of p7 :xref (x7 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of p2) :ARG2 (a9 / activate-01 :ARG1 (f3 / factor :ARG0-of (t3 / transcribe-01)) :ARG1-of (f2 / full-09))) :degree (f / further)) :ARG1-of (d / describe-01 :ARG0 (f4 / figure :mod "5")))) # ::id bel_pmid_1714_3332.29844 # ::date 2015-05-04T06:55:31 # ::file bel_pmid_1714_3332_29844.txt # ::snt Expression of PGC-1?, PEPCK, and glucose-6-phosphatase mRNAs were also significantly increased in fasted KO compared with fasted WT livers (Table 2), consistent with enhanced glucose production in KO livers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (i / increase-01 :ARG1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "PGC-1a") :xref (x2 / xref :value "UNIPROT:PRGC1_HUMAN" :prob "0.622")) :op2 (e2 / enzyme :name (n2 / name :op1 "PEPCK") :xref (x1 / xref :value "UNIPROT:PCKGC_HUMAN" :prob "0.332")) :op3 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "glucose-6-phosphatase") :xref (x / xref :value "UNIPROT:G6PC_HUMAN" :prob "0.702")))))) :ARG2 (s / significant-02) :location (l2 / liver :ARG0-of (f / fast-01) :ARG1-of (c / compare-01 :ARG2 (l / liver :ARG0-of f :mod (w / wild-type))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "2")) :ARG2-of (m / mutate-01 :mod "-/-")) :ARG1-of (c2 / consistent-01 :ARG2 (p2 / produce-01 :ARG1 (g / glucose) :ARG1-of (e4 / enhance-01) :location l2)) :mod (a2 / also)) # ::id bel_pmid_1714_3332.29846 # ::date 2015-05-04T07:24:55 # ::file bel_pmid_1714_3332_29846.txt # ::snt As analyzed by real-time RT-PCR, levels of SOCS-3 mRNA and mRNAs of proinflammatory cytokines IL-1, IL-6, TNF-?, and plasminogen activator inhibitor–1 (PAI-1) were increased in fasted KO liver (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (i / increase-01 :ARG1 (a / and :op1 (l2 / level :quant-of (n9 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "SOCS-3") :xref (x4 / xref :value "UNIPROT:SOCS3_HUMAN" :prob "1.003"))))) :op2 (l3 / level :quant-of (n10 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (a2 / and :op1 (c / cytokine :ARG2-of (i2 / include-91 :ARG1 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "IL-1") :xref (x1 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382")) :op2 (p4 / protein :name (n5 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p5 / protein :name (n7 / name :op1 "TNF-a") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :ARG0-of (f2 / favor-01 :ARG1 (i3 / inflame-01))) :op2 (p2 / protein :name (n8 / name :op1 "plasminogen" :op2 "activator" :op3 "inhibitor–1") :xref (x / xref :value "UNIPROT:PAI1_HUMAN" :prob "0.692"))))))) :location (l / liver :ARG0-of (f / fast-01) :ARG1-of (k / knock-out-03)) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "2")) :ARG1-of (a4 / analyze-01 :instrument (t2 / thing :name (n6 / name :op1 "RT-PCR") :mod (r / real-time)))) # ::id bel_pmid_1714_3332.29848 # ::date 2015-05-04T07:31:47 # ::file bel_pmid_1714_3332_29848.txt # ::snt In addition, expression of tribbles 3 (TRB3) protein (Figure 8C) and mRNA (Table 2) was increased in fasted KO livers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (a / and :op2 (i / increase-01 :ARG1 (e / express-03 :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "tribbles" :op2 "3") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8C")) :xref (x / xref :value "UNIPROT:TRIB3_HUMAN" :prob "0.312")) :op2 (n3 / nucleic-acid :name (n2 / name :op1 "mrna") :ARG1-of (d2 / describe-01 :ARG0 (t / table :mod "2"))))) :location (l / liver :ARG0-of (f2 / fast-01) :ARG1-of (k / knock-out-03)))) # ::id bel_pmid_1720_0144.37610 # ::date 2015-05-04T10:52:25 # ::file bel_pmid_1720_0144_37610.txt # ::snt mTORC2 can be activated by PI3K directly and phosphorylates Akt at S473, which together with phosphorylation at T308 results in the full activation of Akt [12,13]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (p / possible-01 :ARG1 (a2 / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :ARG1 (m / macro-molecular-complex :part (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC2"))) :ARG1-of (d / direct-02))) :op2 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "473" :name (n4 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 m2 :accompanier (p5 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "308" :name (n5 / name :op1 "tyrosine") :part-of e2 :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (r / result-01 :ARG2 (a5 / activate-01 :ARG1 e2 :ARG1-of (f / full-09)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a6 / and :op1 "12" :op2 "13"))))) # ::id bel_pmid_1720_0144.38486 # ::date 2015-05-04T11:23:37 # ::file bel_pmid_1720_0144_38486.txt # ::snt The intracellular signaling induced by IL-4/IL-4R interactions on CD4 T cells has been characterized in great detail. The binding of IL-4 to the Type I receptor in CD4 T cells induces the activation of the nonreceptor tyrosine kinase Jak1, which promotes the phosphorylation of STAT6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (c / characterize-01 :ARG1 (s / signal-07 :mod (i / intracellular) :ARG2-of (i2 / induce-01 :ARG0 (i3 / interact-01 :ARG0 (p / protein :name (n / name :op1 "IL-4") :xref (x5 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :ARG1 (p2 / protein :name (n2 / name :op1 "IL-4R") :xref (x2 / xref :value "UNIPROT:IL4RA_HUMAN" :prob "0.673")) :location (c2 / cell :name (n3 / name :op1 "CD4T"))))) :manner (d / detail-01 :degree (g / great))) :snt2 (i4 / induce-01 :ARG0 (b / bind-01 :ARG1 (p3 / protein :name (n4 / name :op1 "IL-4") :xref (x3 / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :ARG2 (p4 / protein :name (n5 / name :op1 "Type" :op2 "I" :op3 "receptor") :xref (x / xref :value "UNIPROT:GNRR2_HUMAN" :prob "0.362")) :location (c3 / cell :name (n6 / name :op1 "CD4" :op2 "T"))) :ARG2 (a / activate-01 :ARG1 (e / enzyme :name (n7 / name :op1 "nonreceptor" :op2 "tyrosine" :op3 "kinase" :op4 "Jak1") :ARG0-of (p5 / promote-01 :ARG1 (p6 / phosphorylate-01 :ARG1 (p7 / protein :name (n8 / name :op1 "STAT6") :xref (x1 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")))) :xref (x4 / xref :value "UNIPROT:TNK1_HUMAN" :prob "0.342"))))) # ::id bel_pmid_1723_4180.3578 # ::date 2015-05-04T11:45:28 # ::file bel_pmid_1723_4180_3578.txt # ::snt Marimastat (100 mg/kg), dexamethasone (10 mg/kg) and rolipram (0.3 mg/kg) reduced significantly IL-6, KC/CXCL1, MIP-1alpha/CCL3 and MMP-9 levels in bronchoalveolar lavage fluid. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (r / reduce-01 :ARG0 (a / and :op1 (s2 / small-molecule :name (n5 / name :op1 "marimastat") :quant (c2 / concentration-quantity :quant "100" :unit (m / milligram-per-kilogram)) :xref (x3 / xref :value "PUBCHEM:119031" :prob "18.167522")) :op2 (s3 / small-molecule :name (n6 / name :op1 "dexamethasone") :quant (c / concentration-quantity :quant "10" :unit (m2 / milligram-per-kilogram)) :xref (x2 / xref :value "PUBCHEM:5743" :prob "14.701785")) :op3 (s4 / small-molecule :name (n7 / name :op1 "rolipram") :quant (c3 / concentration-quantity :quant "0.3" :unit (m3 / milligram-per-kilogram)) :xref (x4 / xref :value "PUBCHEM:5092" :prob "16.663445"))) :ARG1 (a2 / and :op1 (l / level :quant-of (p / protein :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op2 (l3 / level :quant-of (p2 / protein :name (n2 / name :op1 "KC/CXCL1"))) :op3 (l4 / level :quant-of (p3 / protein :name (n3 / name :op1 "MIP-1alpha/CCL3"))) :op4 (l5 / level :quant-of (e2 / enzyme :name (n4 / name :op1 "MMP-9") :xref (x / xref :value "UNIPROT:MMP9_HUMAN" :prob "1.002")))) :ARG2 (s / significant-02) :location (f / fluid :mod (l2 / lavage) :mod (b / bronchoalveolar))) # ::id bel_pmid_1729_2829.29076 # ::date 2015-05-05T10:38:03 # ::file bel_pmid_1729_2829_29076.txt # ::snt Nox1 and Nox4 mRNAs were upregulated in H-RasV12-transformed p38??/? MEFs, suggesting that these two NOX family members may be involved in H-RasV12-induced ROS production in fibroblasts (Figure S5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (u / upregulate-01 :ARG1 (a / and :op1 (n10 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e5 / encode-01 :ARG1 (e / enzyme :name (n6 / name :op1 "Nox1") :xref (x3 / xref :value "UNIPROT:NOX1_HUMAN" :prob "0.604")))) :op2 (n11 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e6 / encode-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "Nox4") :xref (x2 / xref :value "UNIPROT:NOX4_HUMAN" :prob "0.603"))))) :ARG0-of (s / suggest-01 :ARG1 (p / possible-01 :ARG1 (i / involve-01 :ARG1 (m / member :quant "2" :ARG1-of (m4 / mean-01 :ARG2 a) :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family :name (n / name :op1 "NOX")))) :ARG2 (p2 / produce-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "ROS") :xref (x4 / xref :value "PUBCHEM:128351" :prob "11.468653")) :ARG2-of (i2 / induce-01 :ARG0 (e4 / enzyme :name (n3 / name :op1 "H-Ras") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "S5B")) :location (c / cell :name (n8 / name :op1 "MEF") :mod (e3 / enzyme :name (n9 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG1-of (t2 / transform-01 :ARG0 e4))) # ::id bel_pmid_1729_9132.25542 # ::date 2015-05-06T06:23:16 # ::file bel_pmid_1729_9132_25542.txt # ::snt Papillary adenomas (1.2.1.2.2) were detected 6–8 wk after BRafVE expression and appeared to increase in number and size. These lesions were bronchiolocentric, but did not appear to involve the terminal bronchioles. Rather, the lesions appeared to arise in alveolar ducts and expand outward and around bronchioles (Fig. 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (m / multi-sentence :snt1 (a / and :op1 (d / detect-01 :ARG1 (m3 / medical-condition :name (n3 / name :op1 "adenoma") :mod (p / papilla) :ARG1-of (l2 / label-01 :ARG2 (s2 / string-entity :value "1.2.1.2.2"))) :time (a4 / after :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "BRaf") :ARG2-of (m2 / mutate-01 :value "VE") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.631"))) :quant (b5 / between :op1 (t / temporal-quantity :quant "6" :unit (w / week)) :op2 (t3 / temporal-quantity :quant "8" :unit (w2 / week))))) :op2 (a2 / appear-02 :ARG1 (i / increase-01 :ARG1 (a12 / and :op1 (n2 / number :quant-of (a3 / adenoma)) :op2 (s / size :poss-of a3))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B")) :snt2 (c / contrast-01 :ARG1 (b / bronchiolocentric :domain (l / lesion :mod (t5 / this))) :ARG2 (a5 / appear-02 :polarity "-" :ARG1 (i2 / involve-01 :ARG1 (b3 / bronchiole :mod (t2 / terminus)) :ARG2 l))) :snt3 (a6 / appear-02 :ARG1 (a8 / and :op1 (a7 / arise-02 :ARG1 (l3 / lesion) :location (d3 / duct :part-of (a9 / alveolus))) :op2 (e3 / expand-01 :ARG1 l3 :location (a10 / and :op1 (o / outward :op1 (b4 / bronchiole)) :op2 (a11 / around :op1 b4)))) :mod (r / rather)) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "4B"))) # ::id bel_pmid_1729_9132.25544 # ::date 2015-05-05T13:24:45 # ::file bel_pmid_1729_9132_25544.txt # ::snt At early times after induced BRafVE expression, we detected evidence of epithelial hyperplasia (classified as 1.1.1.1) arising within the terminal bronchioles and within the central lung parenchyma. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (d / detect-01 :ARG0 (w / we) :ARG1 (e / evidence-01 :ARG1 (h / hyperplasia :mod (e2 / epithelium) :ARG1-of (a / arise-02 :location (a2 / and :op1 (b / bronchiole :mod (t / terminal)) :op2 (p / parenchyma :mod (l / lung :mod (c / central))))) :ARG1-of (c2 / classify-01 :ARG2 (s / string-entity :value "1.1.1.1")))) :time (t2 / time :mod (e3 / early)) :time (a3 / after :op1 (e4 / express-03 :ARG2 (e5 / enzyme :name (n / name :op1 "BRafVE") :ARG2-of (m / mutate-01 :value "VE") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.223")) :ARG2-of (i / induce-01)))) # ::id bel_pmid_1729_9132.25548 # ::date 2015-05-05T13:33:29 # ::file bel_pmid_1729_9132_25548.txt # ::snt the majority of cells within BRafVE-induced tumors expressed SP-C, suggesting that they have properties of ATII pneumocytes (Fig. 2K,L). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (e / express-03 :ARG2 (p5 / protein :name (n4 / name :op1 "SP-C") :xref (x / xref :value "UNIPROT:PSPC_HUMAN" :prob "1.002")) :ARG3 (c2 / cell :quant (m / majority) :ARG1-of (i / include-91 :ARG2 (c3 / cell :location (t / tumor :ARG2-of (i2 / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "VE") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))))) :ARG0-of (s / suggest-01 :ARG1 (h / have-03 :ARG0 c2 :ARG1 (p / property :poss (c / cell :name (n / name :op1 "ATII" :op2 "pneumocyte"))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2K") :op2 (f2 / figure :mod "2L")))) # ::id bel_pmid_1729_9132.28748 # ::date 2015-05-05T13:43:53 # ::file bel_pmid_1729_9132_28748.txt # ::snt It is reported that KRasG12D-induced lung tumors do not routinely display elevated pERK1/2 but display stress-activated MAP kinase (SAPK/JNK) activation (Lee et al. 2002)... Interestingly, the major difference appears to be that expression of KRasG12D in the lung leads to more rapid and consistent progression to adenocarcinoma than that elicited by BRafVE. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (m / multi-sentence :snt2 (a / appear-01 :ARG1 (d / differ-02 :ARG1 (l2 / lead-03 :ARG0 (e2 / express-03 :ARG2 (e6 / enzyme :name (n2 / name :op1 "KRAS") :ARG2-of (m3 / mutate-01 :value "G12D") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG3 (l / lung)) :ARG2 (p / progress-01 :ARG4 (m8 / medical-condition :name (n6 / name :op1 "adenocarcinoma")) :mod (r / rapid :degree (m5 / more)) :ARG1-of (c / consistent-02 :degree m5))) :ARG2 (p6 / progress-01 :ARG4 (a3 / adenocarcinoma) :ARG1-of (e3 / elicit-01 :ARG0 (e4 / enzyme :name (n / name :op1 "Braf") :ARG2-of (m6 / mutate-01 :value "VE") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :ARG1-of (m2 / major-02)) :ARG2-of (i / interest-01)) :snt1 (r2 / report-01 :ARG1 (c3 / contrast-01 :ARG1 (d4 / display-01 :polarity "-" :ARG0 (t / tumor :location (l4 / lung) :ARG2-of (i2 / induce-01 :ARG0 (e7 / enzyme :name (n4 / name :op1 "KRAS") :ARG1-of (m4 / mutate-01 :value "G12D") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG1 (e / enzyme :name (n5 / name :op1 "ERK1/2") :ARG1-of (e5 / elevate-01) :ARG3-of (p4 / phosphorylate-01)) :mod (r3 / routine)) :ARG2 (d5 / display-01 :ARG1 (a5 / activate-01 :ARG1 (p9 / pathway :name (n8 / name :op1 "MAP" :op2 "kinase") :ARG1-of (a6 / activate-01 :ARG0 (s / stress-02)) :ARG1-of (m7 / mean-01 :ARG2 (p7 / pathway :name (n7 / name :op1 "SAPK/JNK"))))))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n3 / name :op1 "Lee")) :op2 (p3 / person :mod (o / other)))) :time (d3 / date-entity :year "2002")))) # ::id bel_pmid_1730_3558.25228 # ::date 2015-05-06T05:15:30 # ::file bel_pmid_1730_3558_25228.txt # ::snt from full text - As shown in Fig. 1A, ERK1/2 in wild-type MEFs is phosphorylated after IGF-1 stimulation with a peak at 5–10 min, after which pERK declined substantially. In b-arrestin1 KO MEFs, on the other hand, ERK1/2 remained essentially inactivated upon IGF-1 stimulation (Fig. 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt2 (c3 / contrast-01 :ARG2 (r / remain-01 :ARG1 (a / activate-01 :polarity "-" :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2")) :time (s / stimulate-01 :ARG0 (p3 / protein :name (n2 / name :op1 "IGF-1") :xref (x1 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))) :manner (e / essential) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A")) :location (c / cell :name (n8 / name :op1 "MEF") :mod (p4 / protein :name (n3 / name :op1 "b-arrestin1") :ARG2-of (m4 / mutate-01 :mod "-/-"))))) :source (t2 / text :ARG1-of (f3 / full-09)) :snt1 (a3 / and :op1 (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n7 / name :op1 "ERK1/2")) :ARG1-of (s2 / show-01 :ARG0 (f2 / figure :mod "1A")) :location (c2 / cell :name (n4 / name :op1 "MEF") :mod (w / wild-type)) :time (a2 / after :op1 (s3 / stimulate-01 :ARG0 (p5 / protein :name (n5 / name :op1 "IGF-1") :xref (x2 / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673")))) :ARG1-of (p6 / peak-01 :time (b / between :op1 (t / temporal-quantity :quant "5" :unit (m2 / minute)) :op2 (t3 / temporal-quantity :quant "10" :unit (m3 / minute))))) :op2 (d2 / decline-01 :ARG1 (e4 / enzyme :name (n6 / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :degree (s4 / substantial) :time (a4 / after :op1 p6)))) # ::id bel_pmid_1730_3558.27774 # ::date 2015-05-05T12:23:11 # ::file bel_pmid_1730_3558_27774.txt # ::snt from full text - Similarly, we find that both b-arrestin1 and 2 are ubiquitinated in IGF-1-stimulated WT MEF cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (u / ubiquitinate-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "b-arrestin1")) :op2 (p2 / protein :name (n2 / name :op1 "b-arrestin2"))) :location (c / cell :name (n3 / name :op1 "MEF") :mod (w2 / wild-type) :ARG1-of (s / stimulate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "IGF-1") :xref (x / xref :value "UNIPROT:IGF1_HUMAN" :prob "0.673"))))) :ARG1-of (r / resemble-01) :source (t / text :ARG1-of (f2 / full-09))) # ::id bel_pmid_1732_0860.11808 # ::date 2015-05-05T12:25:02 # ::file bel_pmid_1732_0860_11808.txt # ::snt the preincubation of RAW264.7 cells with a specific PPARalpha agonist, K-111 (2,2-dichloro-12-(4-chlorophenyl)dodecanoic acid). K-111 reduced both the IL-6 production and mRNA expression in RAW264.7 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (p4 / preincubate-01 :ARG1 (c / cell-line :name (n / name :op1 "RAW264.7")) :ARG2 (a / agonist :name (n3 / name :op1 "K-111") :mod (p / protein :name (n2 / name :op1 "PPARalpha") :xref (x / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.693")) :ARG1-of (s / specific-02))) :snt2 (r / reduce-01 :ARG0 (a2 / agonist :name (n4 / name :op1 "K-111") :ARG1-of (m2 / mean-01 :ARG2 (s2 / small-molecule :name (n8 / name :op1 "2,2-dichloro-12-(4-chlorophenyl)dodecanoic" :op2 "acid")))) :ARG1 (a3 / and :op1 (p2 / produce-01 :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op2 (e / express-03 :ARG1 (n9 / nucleic-acid :name (n6 / name :op1 "mRNA")) :ARG3 (c2 / cell-line :name (n7 / name :op1 "RAW264.7")))))) # ::id bel_pmid_1732_2026.36370 # ::date 2015-05-05T12:35:45 # ::file bel_pmid_1732_2026_36370.txt # ::snt Since activation of NF-B in A549 cells is dependent on IKK2, which phosphorylates serines 32 and 36 of IB as a prelude to IB degradation and activation of NF-B (Catley et al., 2005 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / depend-01 :ARG0 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "NF-B") :location (c / cell-line :name (n2 / name :op1 "A549")) :xref (x1 / xref :value "UNIPROT:RRP5_HUMAN" :prob "0.202"))) :ARG1 (e / enzyme :name (n3 / name :op1 "IKK2") :ARG2-of (p3 / phosphorylate-01 :ARG1 (a2 / and :op1 (a6 / amino-acid :mod "32" :name (n6 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a7 / amino-acid :mod "36" :name (n7 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of (e2 / enzyme :name (n4 / name :op1 "IB"))) :purpose (p4 / prelude :prep-to (a3 / and :op1 (d2 / degrade-01 :ARG1 e2) :op2 (a4 / activate-01 :ARG1 p)))) :xref (x / xref :value "UNIPROT:IKKB_HUMAN" :prob "1.002")) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a5 / and :op1 (p5 / person :name (n5 / name :op1 "Catley")) :op2 (p6 / person :mod (o / other)))) :time (d4 / date-entity :year "2005"))) # ::id bel_pmid_1732_2026.38418 # ::date 2015-05-05T13:24:14 # ::file bel_pmid_1732_2026_38418.txt # ::snt Thus, IL-6 release was substantially increased by both IL-1 and to a lesser extent by TNF. In each case, prior infection with the null adenovirus showed no significant effect, whereas dominant IBN reduced IL-6 release to near-background levels. Likewise, the dominant-negative IKK2 adenovirus prevented IL-6 release # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt3 (p / prevent-01 :ARG0 (a / adenovirus :mod (e2 / enzyme :name (n / name :op1 "IKK2") :ARG0-of (d2 / dominate-01) :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:IKKB_HUMAN" :prob "1.002"))) :ARG1 (r / release-01 :ARG1 (p2 / protein :name (n10 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :manner (l3 / likewise)) :snt2 (c2 / contrast-01 :ARG1 (s / show-01 :ARG0 (i2 / infect-01 :ARG0 (a2 / adenovirus :ARG2-of (m3 / mutate-01 :mod "-/-")) :time (p3 / prior)) :ARG1 (a3 / affect-01 :polarity "-" :ARG1-of (s3 / significant-02)) :prep-in (c / case-04 :mod (e / each))) :ARG2 (r3 / reduce-01 :ARG0 (p8 / protein :name (n2 / name :op1 "IκBαΔN") :ARG0-of (d / dominate-01)) :ARG1 (r4 / release-01 :ARG1 (p4 / protein :name (n3 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG4 (n4 / near :op1 (l / level :mod (b / background))))) :snt1 (c3 / cause-01 :ARG1 (a4 / and :op1 (i / increase-01 :ARG0 (p6 / protein :name (n6 / name :op1 "IL-1") :xref (x4 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382")) :ARG1 (r5 / release-01 :ARG1 (p5 / protein :name (n5 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (s2 / substantial)) :op2 (i3 / increase-01 :ARG0 (p7 / protein :name (n7 / name :op1 "TNF") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG1 r5 :ARG2 (l2 / less :degree (m4 / more)))))) # ::id bel_pmid_1732_2026.39144 # ::date 2015-05-06T08:24:53 # ::file bel_pmid_1732_2026_39144.txt # ::snt Similar levels of RANTES and MCP-1 release were induced by IL-1 and TNF treatments. However, the induction of IL-6, IL-8, and GMCSF by TNF was 50 to 80% lower than for IL-1, whereas TNF-induced GRO was some 35- to 40-fold lower than that for IL-1. In all instances, preincubation with PS-1145 or ML120B resulted in a significant attenuation of cytokine release (Fig. 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m2 / multi-sentence :snt1 (i / induce-01 :ARG0 (a / and :op1 (t / treat-04 :ARG2 (p2 / protein :name (n / name :op1 "TNF") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))) :op2 (t2 / treat-04 :ARG2 (p3 / protein :name (n2 / name :op1 "IL-1") :xref (x4 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382")))) :ARG2 (a2 / and :op1 (l2 / level :quant-of (p14 / protein :name (n3 / name :op1 "RANTES") :ARG1-of "r2" :xref (x2 / xref :value "UNIPROT:CCR1_HUMAN" :prob "0.352")) :ARG1-of (r3 / resemble-01 :ARG2 (l3 / level :quant-of (p4 / protein :name (n4 / name :op1 "MCP-1") :ARG1-of (r2 / release-01) :xref (x6 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002"))))))) :snt2 (c / contrast-01 :ARG1 (l / lower-05 :ARG1 (i2 / induce-01 :ARG0 (p9 / protein :name (n8 / name :op1 "TNF") :xref (x8 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG2 (a3 / and :op1 (p6 / protein :name (n5 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p7 / protein :name (n6 / name :op1 "IL-8") :xref (x3 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003")) :op3 (p8 / protein :name (n7 / name :op1 "GMCSF") :xref (x7 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.003")))) :ARG2 (b / between :op1 (p5 / percentage-entity :value "50") :op2 (p / percentage-entity :value "80")) :compared-to (i4 / induce-01 :ARG0 p9 :ARG2 (p10 / protein :name (n9 / name :op1 "IL-1") :xref (x1 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382")))) :ARG2 (l4 / lower-05 :ARG1 (p13 / protein :name (n10 / name :op1 "GRO") :ARG2-of (i3 / induce-01 :ARG0 p9) :xref (x9 / xref :value "UNIPROT:GROA_HUMAN" :prob "1.002")) :ARG2 (b2 / between :op1 (p11 / percentage-entity :value "35") :op2 (p12 / percentage-entity :value "40")) :compared-to i4) :ARG2-of (c2 / contrast-01)) :snt3 (r / result-01 :ARG1 (p15 / preincubate-01 :ARG2 (o / or :op1 (s3 / small-molecule :name (n11 / name :op1 "PS-1145") :xref (x10 / xref :value "PUBCHEM:9949093" :prob "16.097086")) :op2 (s2 / small-molecule :name (n12 / name :op1 "ML120B") :xref (x11 / xref :value "PUBCHEM:9929127" :prob "19.266134")))) :ARG2 (a5 / attenuate-01 :ARG1 (r4 / release-01 :ARG1 (c3 / cytokine)) :ARG1-of (s / significant-02)) :prep-in (i6 / instance :mod (a4 / all))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6"))) # ::id bel_pmid_1733_2487.25838 # ::date 2015-05-05T11:48:28 # ::file bel_pmid_1733_2487_25838.txt # ::snt Exposure of CD40L enhanced the constitutive production of IL-6 and MCP-1 protein (Figure 4A and 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (e / enhance-01 :ARG0 (e2 / expose-01 :ARG1 (p / protein :name (n / name :op1 "CD40L") :xref (x2 / xref :value "UNIPROT:CD40L_HUMAN" :prob "1.003"))) :ARG1 (p2 / produce-01 :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n3 / name :op1 "MCP-1") :xref (x1 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002"))) :mod (c / constitutive)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :name (n4 / name :op1 "4A")) :op2 (f2 / figure :name (n5 / name :op1 "4B"))))) # ::id bel_pmid_1739_6137.31084 # ::date 2015-05-05T11:58:09 # ::file bel_pmid_1739_6137_31084.txt # ::snt Figure 1 TRF2 (myc-tagged) induces telomere dysfunction and cellular senescence in p53 P/P primary mouse embryonic fibroblasts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "TRF2") :ARG1-of (t2 / tag-01 :ARG2 (p4 / protein :name (n2 / name :op1 "myc") :xref (x / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604"))) :xref (x2 / xref :value "UNIPROT:TBPL1_HUMAN" :prob "1.002")) :ARG2 (a / and :op1 (f2 / function-01 :polarity "-" :ARG0 (t / telomere)) :op2 (s / senescence :mod (c2 / cell))) :location (f3 / fibroblast :mod (e / embryo :source (m / mouse :mod (p2 / primary) :mod (p3 / protein :name (n3 / name :op1 "p35") :ARG2-of (m2 / mutate-01 :value "P/P") :xref (x1 / xref :value "UNIPROT:ANXA1_HUMAN" :prob "1.002"))))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure :mod "1"))) # ::id bel_pmid_1739_6137.31086 # ::date 2015-05-06T06:38:23 # ::file bel_pmid_1739_6137_31086.txt # ::snt overexpression of TRF2 in p53 P/P MEFs resulted in upregulation of p21 (Fig 1D). In addition, reduction of BrdU incorporation, induction of p21 level and increased number of SA-beta-gal-positive senescent cells were also observed when oncogenic H-Ras was overexpressed in p53 P/P MEFs (Fig 1A?C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (m / multi-sentence :snt1 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (p / protein :name (n2 / name :op1 "TRF2") :xref (x5 / xref :value "UNIPROT:TBPL1_HUMAN" :prob "1.002")) :location (c / cell :name (n3 / name :op1 "MEF") :mod (p2 / protein :name (n4 / name :op1 "p53") :ARG2-of (m3 / mutate-01 :value "P/P") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :ARG2 (u / upregulate-01 :ARG1 (p3 / protein :name (n5 / name :op1 "p21") :xref (x3 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1D"))) :snt2 (a / and :op2 (o2 / observe-01 :ARG1 (a2 / and :op1 (r2 / reduce-01 :ARG1 (i / incorporate-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU") :xref (x6 / xref :value "PUBCHEM:6035" :prob "18.013371")))) :op2 (i2 / induce-01 :ARG2 (l / level :degree-of (p6 / protein :name (n9 / name :op1 "p21") :xref (x4 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")))) :op3 (n10 / number :quant-of (c3 / cell :mod (s / senescent) :mod (p7 / positive :mod (e / enzyme :name (n11 / name :op1 "SA-beta-gal")))) :ARG1-of (i3 / increase-01))) :time (o3 / overexpress-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "H-Ras") :mod (o4 / oncogenic) :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :location (c2 / cell :name (n8 / name :op1 "MEF") :mod (p4 / protein :name (n7 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :mod (a3 / also))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f3 / figure :mod "1A") :op2 (f4 / figure :mod "1B") :op3 (f5 / figure :mod "1C")))) # ::id bel_pmid_1740_4266.3636 # ::date 2015-05-05T11:58:52 # ::file bel_pmid_1740_4266_3636.txt # ::snt In addition, i.p. administration of UA increased the levels of IL-1beta secretion and MPO activity in colonic mucosa of ICR mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a2 / and :op2 (i / increase-01 :ARG0 (a / administrate-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "UA") :xref (x2 / xref :value "PUBCHEM:2730" :prob "10.32831")) :mod (i2 / injection :mod (i3 / intraperitoneal))) :ARG1 (a3 / and :op1 (l / level :degree-of (s / secrete-01 :ARG1 (p / protein :name (n3 / name :op1 "IL-1beta") :xref (x1 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")))) :op2 (l2 / level :degree-of (a4 / activity-06 :ARG0 (e / enzyme :name (n4 / name :op1 "MPO") :xref (x / xref :value "UNIPROT:PERM_HUMAN" :prob "1.002")) :location (m2 / mucosa :part-of (c / colon) :source (o / organism :name (n2 / name :op1 "ICR" :op2 "mouse")))))))) # ::id bel_pmid_1740_4266.3638 # ::date 2015-05-05T12:13:49 # ::file bel_pmid_1740_4266_3638.txt # ::snt UA increased the protein release of IL-1beta, IL-6, and MIF, but not of TNF-alpha, in dose- and time-dependent manners. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (c / contrast-01 :ARG1 (i2 / increase-01 :ARG0 (s / small-molecule :name (n / name :op1 "UA") :xref (x4 / xref :value "PUBCHEM:2730" :prob "10.32831")) :ARG1 (r / release-01 :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "IL-1beta") :xref (x / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :op2 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n4 / name :op1 "MIF") :xref (x2 / xref :value "UNIPROT:MIF_HUMAN" :prob "1.003"))))) :ARG2 (i3 / increase-01 :polarity "-" :ARG0 s :ARG1 (r2 / release-01 :ARG1 (p5 / protein :name (n5 / name :op1 "TNF-alpha") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :manner (a2 / and :op1 (d / depend-01 :ARG0 i2 :ARG1 (d3 / dose)) :op2 (d2 / depend-01 :ARG0 i2 :ARG1 (t / time)))) # ::id bel_pmid_1740_4266.16378 # ::date 2015-05-05T12:22:29 # ::file bel_pmid_1740_4266_16378.txt # ::snt As shown in Fig. 3, A and B, IL-1B mRNA and proIL-1B protein were detected in a constitutive manner at low levels in nontreated pMphi. Those treated with 4 microM UA for 3 and 6 h were markedly up-regulated, whereas, intriguingly, the levels diminished after 12 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (m / multi-sentence :snt1 (d / detect-01 :ARG1 (a4 / and :op1 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA") :part (p3 / protein :name (n4 / name :op1 "IL-B1"))) :op2 (p2 / protein :name (n2 / name :op1 "proIL-1B") :xref (x / xref :value "UNIPROT:Q9NRZ3_HUMAN" :prob "0.201")) :quant (l2 / level :ARG1-of (l3 / low-04))) :ARG1-of (s / show-01 :ARG0 (a3 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B"))) :manner (c3 / constitutive) :location (c4 / cell :name (n5 / name :op1 "pMphi") :ARG1-of (t5 / treat-04 :polarity "-"))) :snt2 (c / contrast-01 :ARG1 (u / upregulate-01 :ARG1 (c5 / cell :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "UA") :quant (c2 / concentration-quantity :quant "4" :unit (m3 / micromolar)) :xref (x1 / xref :value "PUBCHEM:2730" :prob "10.32831")) :duration (a / and :op1 (t2 / temporal-quantity :quant "3" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "6" :unit (h2 / hour))))) :manner (m4 / marked)) :ARG2 (d2 / diminish-01 :ARG1 (l / level) :time (a2 / after :op1 (t4 / temporal-quantity :quant "12" :unit (h3 / hour))) :ARG0-of (i / intrigue-01)))) # ::id bel_pmid_1740_6055.15774 # ::date 2015-05-06T04:34:07 # ::file bel_pmid_1740_6055_15774.txt # ::snt JAK-2 activation and phosphorylation have been demonstrated in response to exogenous H2O2 in fibroblasts and VSMCs, respectively (27,63). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (d2 / demonstrate-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "JAK-2") :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.003"))) :op2 (p / phosphorylate-01 :ARG1 e2)) :ARG2-of (r / respond-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "H2O2") :mod (e / exogenous) :location (a3 / and :op1 (f / fibroblast) :op2 (c / cell :name (n3 / name :op1 "VSMC"))) :xref (x1 / xref :value "PUBCHEM:784" :prob "17.186693"))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "27")) :op2 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "63"))))) # ::id bel_pmid_1740_6055.15784 # ::date 2015-05-06T04:56:50 # ::file bel_pmid_1740_6055_15784.txt # ::snt in view of the ability of H2O2 to inhibit protein tyrosine phosphatases (PTPases), such as PTP-1B (68), and SH-2 domain-containing tyrosine phosphatase (SHP)-2 (69), # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (h / have-purpose-91 :ARG2 (c / capable-01 :ARG1 (s / small-molecule :name (n / name :op1 "H2O2") :xref (x3 / xref :value "PUBCHEM:784" :prob "17.186693")) :ARG2 (i / inhibit-01 :ARG0 s :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "protein" :op2 "tyrosine" :op3 "phosphatase") :example (e2 / enzyme :name (n3 / name :op1 "PTP-1B") :xref (x2 / xref :value "UNIPROT:PTN1_HUMAN" :prob "1.003")) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "68"))) :xref (x / xref :value "UNIPROT:A0A024R963_HUMAN" :prob "0.691")) :op2 (e3 / enzyme :name (n5 / name :op1 "tyrosine" :op2 "phosphatase") :ARG0-of (c4 / contain-01 :ARG1 (d3 / domain :name (n4 / name :op1 "SH-2"))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "69"))) :xref (x1 / xref :value "UNIPROT:UBS3B_HUMAN" :prob "0.302")))))) # ::id bel_pmid_1740_6055.34632 # ::date 2015-05-06T09:43:44 # ::file bel_pmid_1740_6055_34632.txt # ::snt c-Src has also been shown to be activated in response to ROS, including H2O2, in different cell types (19,20, 33,37,50). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (s / show-01 :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "c-Src") :xref (x / xref :value "UNIPROT:CSK_HUMAN" :prob "0.212")) :ARG2-of (r / respond-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "ROS") :ARG2-of (i / include-91 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "H2O2") :xref (x2 / xref :value "PUBCHEM:784" :prob "17.186693"))) :location (c6 / cell :ARG1-of (t / type-03 :ARG1-of (d2 / differ-02))) :xref (x1 / xref :value "PUBCHEM:128351" :prob "11.468653")))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (p / publication :ARG1-of (c / cite-01 :ARG2 "19")) :op2 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "20")) :op3 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "33")) :op4 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "37")) :op5 (p5 / publication :ARG1-of (c5 / cite-01 :ARG2 "50")))) :mod (a3 / also)) # ::id bel_pmid_1746_8755.1748 # ::date 2015-05-05T10:49:52 # ::file bel_pmid_1746_8755_1748.txt # ::snt deletion of p38alpha mitogen-activated protein (MAP) kinase in adult mice results in increased proliferation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (r / result-01 :ARG1 (d / delete-01 :ARG1 (e / enzyme :name (n / name :op1 "p38" :op2 "alpha" :op3 "mitogen-activated" :op4 "protein" :op5 "kinase") :xref (x / xref :value "UNIPROT:MAPK5_HUMAN" :prob "0.302")) :location (m / mouse :mod (a / adult))) :ARG2 (p / proliferate-01 :ARG1-of (i / increase-01))) # ::id bel_pmid_1746_8755.1750 # ::date 2015-05-05T11:47:19 # ::file bel_pmid_1746_8755_1750.txt # ::snt In addition, p38alpha controls self-renewal of the lung stem and progenitor cell population by inhibiting proliferation-inducing signals, most notably epidermal growth factor receptor # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op2 (c / control-01 :ARG0 (e / enzyme :name (n2 / name :op1 "P38" :op2 "Alpha")) :ARG1 (r / renew-01 :ARG0 (a2 / and :op1 (p2 / population :consist-of (c2 / cell :mod (s2 / stem :source (l / lung)))) :op2 (p / population :consist-of (c3 / cell :mod (p4 / progenitor)))) :ARG1 a2) :ARG2 (i / inhibit-01 :ARG0 e :ARG1 (s3 / signal :ARG0-of (i2 / induce-01 :ARG2 (p5 / proliferate-01)) :ARG2-of (i3 / include-91 :ARG1 (e2 / enzyme :name (n / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.703")))) :ARG1-of (n3 / notable-04 :degree (m / most))))) # ::id bel_pmid_1746_8755.1754 # ::date 2015-05-06T04:57:26 # ::file bel_pmid_1746_8755_1754.txt # ::snt We found that p38alpha positively regulates factors such as CCAAT/enhancer-binding protein that are required for lung cell differentiation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 17, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (r / regulate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "p38" :op2 "alpha")) :ARG1 (f2 / factor :example (p / protein :name (n3 / name :op1 "CCAAT/enhancer-binding" :op2 "protein") :ARG1-of (r2 / require-01 :ARG0 (d / differentiate-01 :ARG1 (c / cell :mod (l / lung)))))) :manner (p2 / positive))) # ::id bel_pmid_1746_8755.21936 # ::date 2015-05-06T05:15:05 # ::file bel_pmid_1746_8755_21936.txt # ::snt The reduction in C/EBPa could be accounted for by lower levels of phospho-C/EBPb (Fig. 3a), a known target for p38a (refs. 12,20), which in turn regulates the expression of C/EBPa (ref. 21). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (a / account-01 :ARG1 (r / reduce-01 :ARG1 (p2 / protein :name (n / name :op1 "C/EBPa"))) :ARG2 (l / level :ARG1-of (l2 / low-04 :degree (m / more)) :quant-of (p8 / protein :name (n3 / name :op1 "C/EBPa") :ARG3-of (p3 / phosphorylate-01) :ARG1-of (t / target-01 :ARG0 (p4 / protein :name (n2 / name :op1 "p38a") :ARG0-of (r2 / regulate-01 :ARG1 (e / express-03 :ARG2 p2) :manner (i / in-turn) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 "21")))) :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "0.263")) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "12")) :op2 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "20")))) :ARG1-of (k / know-01)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3a")))) # ::id bel_pmid_1746_8755.22008 # ::date 2015-05-06T07:47:34 # ::file bel_pmid_1746_8755_22008.txt # ::snt Mnk1 was also activated at lower levels in Mapk14-null mice (Fig. 3b). This p38a-activated protein kinase phosphorylates and stabilizes Sprouty2 (ref. 26), which in turn can negatively regulate tyrosine kinase receptor signaling in lung cells27. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m2 / multi-sentence :snt1 (a / activate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Mnk1") :xref (x2 / xref :value "UNIPROT:MKNK1_HUMAN" :prob "1.002")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3b")) :mod (a5 / also) :degree (l3 / level :ARG1-of (l / low-04 :degree (m / more))) :location (m3 / mouse :mod (e2 / enzyme :name (n5 / name :op1 "Mapk14") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MK14_HUMAN" :prob "0.622"))) :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure :mod "3b"))) :snt2 (a2 / and :op1 (p / phosphorylate-01 :ARG1 "e" :ARG2 "k") :op2 (s / stabilize-01 :ARG0 (k / kinase :mod (p6 / protein) :ARG1-of (a4 / activate-01 :ARG0 (p7 / protein :name (n4 / name :op1 "p38a") :xref (x3 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.263")))) :ARG1 (e / enzyme :name (n / name :op1 "Sprouty2") :ARG2-of (d2 / downregulate-01 :ARG1 (s2 / signal-07 :ARG0 (p4 / pathway :name (n2 / name :op1 "tyrosine" :op2 "kinase" :op3 "receptor")) :location (c2 / cell :source (l2 / lung))) :mod (i / in-turn) :ARG1-of (p3 / possible-01) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "27")))) :xref (x1 / xref :value "UNIPROT:SPRE2_HUMAN" :prob "0.203")) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "26")))))) # ::id bel_pmid_1746_8755.25974 # ::date 2015-05-06T09:42:50 # ::file bel_pmid_1746_8755_25974.txt # ::snt Our results indicated that the p38a-deficient lungs had hyperproliferative alveolar tissue with loss of differentiation markers. A similar but more marked lung phenotype, with hyperproliferation and defective cell maturation, has been described previously in CCAAT/ enhancer-binding protein (C/EBP)a knockout mice, which die shortly after birth because of respiratory failure16–18. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (m / multi-sentence :snt1 (i / indicate-01 :ARG0 (t3 / thing :poss (w / we) :ARG2-of (r / result-01)) :ARG1 (h / have-03 :ARG0 (l / lung :ARG0-of (l2 / lack-01 :ARG1 (p8 / protein :name (n / name :op1 "p38a") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "0.263")))) :ARG1 (t / tissue :ARG0-of (p6 / proliferate-01 :degree (h2 / hyper)) :mod (a / alveolus) :mod (l3 / lose-02 :ARG1 (m8 / marker :ARG1-of (d / differentiate-01)))))) :ARG1-of (d5 / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 (v / value-interval :op1 "16" :op2 "18")))) :snt2 (d2 / describe-01 :ARG1 (p4 / phenotype :mod (l4 / lung) :mod (p5 / proliferate-01 :ARG0 "c2" :degree (h3 / hyper)) :ARG0-of (m5 / maturate-03 :ARG1 (c2 / cell) :mod (d3 / defective)) :ARG1-of (r2 / resemble-01 :ARG1-of (c6 / contrast-01 :ARG2 (m3 / marked :degree (m4 / more) :domain p4)))) :time (p3 / previous) :location (m6 / mouse :ARG1-of (d4 / die-01 :time (a2 / after :op1 (b / bear-02 :ARG1 m6) :ARG1-of (s / short-07)) :ARG1-of (c3 / cause-01 :ARG0 (f / fail-01 :ARG1 m6 :ARG2 (r3 / respiration)))) :mod (p2 / protein :name (n4 / name :op1 "CCAAT/" :op2 "enhancer-binding" :op3 "protein") :ARG2-of (m7 / mutate-01 :mod "+/-") :ARG1-of (m2 / mean-01 :ARG2 (p / protein :name (n3 / name :op1 "C/EBP")))) :ARG1-of (k / knock-out-03)))) # ::id bel_pmid_1746_8755.25986 # ::date 2015-05-06T12:42:28 # ::file bel_pmid_1746_8755_25986.txt # ::snt the amount of Tgfb1 (TGFb) mRNA was higher in p38a-deficient lungs compared with Mapk14D/+ lungs (Fig. 3e). TGFb has been found to be overexpressed in C/EBPa knockout lungs17, so the reduced C/EBPa levels in the Mapk14-null lungs could account for the higher TGFb expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (m2 / multi-sentence :snt1 (h / high-02 :ARG1 (a / amount :quant-of (n8 / nucleic-acid :name (n4 / name :op1 "mRNA") :part-of (p2 / protein :name (n3 / name :op1 "Tgfb1") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.604")))) :degree (m / more) :location (l / lung :ARG0-of (l2 / lack-01 :ARG1 (p / protein :name (n / name :op1 "p38a") :xref (x4 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.263"))) :ARG1-of (c / compare-01 :ARG2 (l3 / lung :mod (e / enzyme :name (n2 / name :op1 "Mapk14D") :ARG2-of (m3 / mutate-01 :mod "-/+") :xref (x3 / xref :value "UNIPROT:MK14_HUMAN" :prob "0.262"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3e"))) :snt2 (c2 / cause-01 :ARG0 (f2 / find-01 :ARG1 (o / overexpress-01 :ARG1 (p3 / protein :name (n5 / name :op1 "Tgfb") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.603")) :location (l4 / lung :mod (p5 / protein :name (n6 / name :op1 "C/EBPa") :ARG2-of (m6 / mutate-01 :mod "-/-"))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :mod "17")))) :ARG1 (p6 / possible-01 :ARG1 (a2 / account-01 :ARG0 (l6 / level :ARG1-of (r2 / reduce-01) :quant-of p5 :location (l5 / lung :mod (e2 / enzyme :name (n7 / name :op1 "Mapk14") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:MK14_HUMAN" :prob "0.622")))) :ARG1 (e3 / express-03 :ARG2 p3 :ARG1-of (h2 / high-02 :degree (m5 / more))))))) # ::id bel_pmid_1746_8755.28766 # ::date 2015-05-06T12:58:04 # ::file bel_pmid_1746_8755_28766.txt # ::snt Expression of KrasG12V induced also a loss of epithelial markers (as assessed by E-cadherin staining, which was similar in Mapk14D/+ and Mapk14D/D alveoli; Fig. 6c) and an increase in SP-C+ cells (Fig. 6d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (e / express-03 :ARG2 (e5 / enzyme :name (n / name :op1 "KRAS") :ARG2-of (m / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG2 (a2 / and :op1 (l / lose-02 :ARG1 (m4 / marker :mod (e2 / epithelium)) :ARG1-of (a3 / assess-01 :ARG0 (s / stain-01 :ARG2 (p / protein :name (n3 / name :op1 "E-cadherin") :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :location (a5 / alveoli :mod (e3 / enzyme :name (n5 / name :op1 "Mapk14D") :xref (x1 / xref :value "UNIPROT:MK14_HUMAN" :prob "0.262")) :ARG2-of (m3 / mutate-01 :mod "+/-") :ARG1-of (r / resemble-01 :ARG2 (a6 / alveoli :mod (e4 / enzyme :name (n4 / name :op1 "Mapk14D/D")))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6c")))) :op2 (i2 / increase-01 :location (c / cell :mod (p2 / protein :name (n2 / name :op1 "SPC+") :xref (x2 / xref :value "UNIPROT:UCN3_HUMAN" :prob "0.652"))))) :mod (a / also) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6d"))) # ::id bel_pmid_1746_8755.29060 # ::date 2015-05-06T13:07:34 # ::file bel_pmid_1746_8755_29060.txt # ::snt However, the SP-C+ cells were more numerous in the Mapk14-/- lungs (with almost twice as many as in Mapk14-/+ lungs; Fig. 2c). Notably, immunohistological staining showed reduced levels of the epithelial marker E-cadherin in the alveolar cells (Fig. 2c), indicating defective differentiation of these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (c / contrast-01 :ARG2 (n / numerous :degree (m2 / more) :domain (c2 / cell :mod (p2 / protein :name (n2 / name :op1 "SPC+") :xref (x1 / xref :value "UNIPROT:UCN3_HUMAN" :prob "0.652"))) :location (l / lung :mod (e / enzyme :name (n3 / name :op1 "Mapk14") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:MK14_HUMAN" :prob "0.622")))) :ARG1-of (m5 / mean-01 :ARG2 (c4 / cell :quant (n6 / numerous :quant (p3 / product-of :op1 "2" :op2 (c5 / cell :location (l3 / lung :mod (e3 / enzyme :name (n7 / name :op1 "Mapk14") :ARG2-of (m6 / mutate-01 :mod "-/+") :xref (x / xref :value "UNIPROT:MK14_HUMAN" :prob "0.622")))) :mod (a2 / almost)))))) :snt2 (s / show-01 :ARG0 (s2 / stain-01 :mod (i2 / immunohistology)) :ARG1 (l2 / level :ARG1-of (r / reduce-01) :quant-of (m7 / marker :mod (e2 / epithelium) :mod (p / protein :name (n5 / name :op1 "E-cadherin") :location "c3" :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG0-of (i / indicate-01 :ARG1 (d / differentiate-01 :ARG1 (c3 / cell :mod (a / alveolus)) :mod (d2 / defective))) :ARG1-of (n4 / notable-04) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2c")))) # ::id bel_pmid_1746_8755.29062 # ::date 2015-05-06T13:09:51 # ::file bel_pmid_1746_8755_29062.txt # ::snt Notably, we found that p38a-deficient lungs contained lower levels of C/EBPa and HNF3b, another transcription factor involved in lung differentiation whose expression is controlled by C/EBPa (ref. 19) (Fig. 3a and Supplementary Fig. 1a online). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (c / contain-01 :ARG0 (l2 / lung :ARG0-of (l3 / lack-01 :ARG1 (p / protein :name (n2 / name :op1 "p38a") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.263")))) :ARG1 (a / and :op1 (l4 / level :quant-of (p2 / protein :name (n3 / name :op1 "C/EBPa"))) :op2 (l5 / level :quant-of (p3 / protein :name (n4 / name :op1 "HNF3b") :domain (p4 / protein :name (n5 / name :op1 "transcription" :op2 "factor") :ARG1-of (i / involve-01 :ARG2 (d / differentiate-01 :ARG1 (l6 / lung))) :ARG2-of (e / express-03 :ARG1-of (c2 / control-01 :ARG0 p2)) :mod (a2 / another) :xref (x1 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.393")) :xref (x / xref :value "UNIPROT:FOXA2_HUMAN" :prob "0.662"))) :ARG1-of (l / low-04 :degree (m / more)))) :ARG1-of (n / notable-04) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "19"))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "3a") :op2 (f3 / figure :mod "1a" :ARG2-of (s / supplement-01) :medium (o / online))))) # ::id bel_pmid_1746_8755.29066 # ::date 2015-05-06T10:17:52 # ::file bel_pmid_1746_8755_29066.txt # ::snt Furthermore, the higher number of AT2 cells correlated with an almost fivefold increase in Ki67+ cells in Mapk14-/- lungs compared with the number of Ki67+ cells in their heterozygous Mapk14D/+ counterparts (Fig. 2d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op2 (c / correlate-01 :ARG1 (n / number :quant-of (c3 / cell :name (n3 / name :op1 "AT2")) :ARG1-of (h / high-02 :degree (m / more))) :ARG2 (i / increase-01 :ARG1 (c4 / cell :name (n4 / name :op1 "Ki67+") :ARG2-of (m2 / mutate-01 :mod "+/-") :location (l / lung :mod (e / enzyme :name (n5 / name :op1 "Mapk14") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:MK14_HUMAN" :prob "0.622")))) :ARG2 (a2 / almost :op1 (p / product-of :op1 "5")) :ARG1-of (c2 / compare-01 :ARG2 (n2 / number :quant-of (c5 / cell :name (n6 / name :op1 "Ki67+") :location (l2 / lung :mod (e2 / enzyme :name (n7 / name :op1 "Mapk14D") :xref (x / xref :value "UNIPROT:MK14_HUMAN" :prob "0.262")) :mod (h2 / heterozygous) :ARG2-of (m4 / mutate-01 :mod "-/+"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2d"))) # ::id bel_pmid_1746_8755.29068 # ::date 2015-05-06T06:56:12 # ::file bel_pmid_1746_8755_29068.txt # ::snt We also detected a reduction in STAT3 protein in Mapk14D/D lungs (Fig. 3a) that correlated with the reduction in Il6 mRNA (Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (d / detect-01 :ARG0 (w / we) :ARG1 (r / reduce-01 :ARG1 (p / protein :name (n / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :location (l / lung :mod (p2 / pathway :name (n2 / name :op1 "Mapk14D/D"))) :ARG1-of (c / correlate-01 :ARG2 (r2 / reduce-01 :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA") :part (p3 / protein :name (n4 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3a"))) :mod (a / also) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "3"))) # ::id bel_pmid_1746_8755.29072 # ::date 2015-05-06T07:27:06 # ::file bel_pmid_1746_8755_29072.txt # ::snt three times as much Egfr mRNA was present in Mapk14D/D lungs (Fig. 3d) compared with Mapk14D/+ lungs, suggesting that EGFR expression was transcriptionally enhanced in the absence of p38a. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / present-02 :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "mRNA") :quant (p3 / product-of :quant "3") :ARG0-of (e6 / encode-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "Egfr") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.604")))) :ARG2 (l / lung :mod (e7 / enzyme :name (n3 / name :op1 "Mapk14D/D"))) :ARG1-of (c / compare-01 :ARG2 (l2 / lung :mod (e8 / enzyme :name (n5 / name :op1 "Mapk14D") :ARG2-of (m / mutate-01 :mod "+/+") :xref (x / xref :value "UNIPROT:MK14_HUMAN" :prob "0.262")))) :ARG0-of (s / suggest-01 :ARG1 (e / enhance-01 :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :manner (t / transcribe-01) :condition (a / absent-01 :ARG1 (p2 / protein :name (n2 / name :op1 "p38a") :xref (x3 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.263"))))) :mod e3 :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3d"))) # ::id bel_pmid_1746_8755.29082 # ::date 2015-05-06T08:49:21 # ::file bel_pmid_1746_8755_29082.txt # ::snt Notably, EGFR transcription is regulated by AP-1 (ref. 28), and we observed higher levels of phospho-c-Jun, one of the AP-1 components, in the p38a-deficient lungs (Fig. 3c), suggesting that p38a downregulation might activate AP-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (r / regulate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "AP-1") :xref (x1 / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652")) :ARG1 (t / transcribe-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "28"))) :ARG1-of (n2 / notable-04)) :op2 (o / observe-01 :ARG0 (w / we) :ARG1 (l / level :ARG1-of (h / high-02 :degree (m / more)) :quant-of (p / protein :name (n4 / name :op1 "c-Jun") :ARG1-of (i / include-91 :ARG2 (c2 / component :poss p3)) :ARG1-of (p4 / phosphorylate-01)) :location (l2 / lung :ARG0-of (l3 / lack-01 :ARG1 (p6 / protein :name (n5 / name :op1 "p38a") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "0.263"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3c"))) :ARG0-of (s / suggest-01 :ARG1 (p5 / possible-01 :ARG1 (a2 / activate-01 :ARG0 (d3 / downregulate-01 :ARG1 p6) :ARG1 p3)))) # ::id bel_pmid_1746_8757.6426 # ::date 2015-05-04T08:07:32 # ::file bel_pmid_1746_8757_6426.txt # ::snt Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 4, 2015 (a / and :op2 (s / suppress-01 :ARG0 (a2 / activate-01 :polarity "-" :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op2 (p / protein :name (n2 / name :op1 "c-Jun")))) :ARG1 (p2 / proliferate-01 :ARG0 (a3 / and :op1 (c / cell :name (n3 / name :op1 "hepatocyte") :ARG0-of (l / lack-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Mapk14") :xref (x1 / xref :value "UNIPROT:MK14_HUMAN" :prob "0.622")))) :op2 (c2 / cell :mod (t / tumor))) :ARG1-of (i / increase-01)))) # ::id bel_pmid_1750_7094.5814 # ::date 2015-05-04T11:03:32 # ::file bel_pmid_1750_7094_5814.txt # ::snt Upon stimulation with TLR ligands, p105 is phosphorylated by I kappa B kinase (IKK) complex and partially degraded, which releases TPL2. The free TPL2 is active and stimulates the ERK pathway via MEK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (a / and :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "p105") :xref (x / xref :value "UNIPROT:CASL_HUMAN" :prob "1.002")) :ARG2 (e4 / enzyme :name (n2 / name :op1 "IκB" :op2 "kinase"))) :op2 (d / degrade-01 :ARG1 p2 :degree (p3 / part)) :ARG0-of (r / release-01 :ARG1 (e / enzyme :name (n3 / name :op1 "TPL2") :xref (x2 / xref :value "UNIPROT:M3K8_HUMAN" :prob "0.672"))) :time (s / stimulate-01 :ARG2 (l / ligand :name (n4 / name :op1 "TLR")))) :snt2 (a2 / and :op1 (a3 / activity-06 :ARG0 (e2 / enzyme :name (n5 / name :op1 "TPL2") :ARG1-of (f / free-04) :xref (x1 / xref :value "UNIPROT:M3K8_HUMAN" :prob "0.672"))) :op2 (s2 / stimulate-01 :ARG0 e2 :ARG1 (p4 / pathway :name (n6 / name :op1 "ERK")) :ARG2 (e3 / enzyme :name (n7 / name :op1 "MEK1/2"))))) # ::id bel_pmid_1751_1588.20428 # ::date 2015-05-04T11:34:52 # ::file bel_pmid_1751_1588_20428.txt # ::snt Angiopoietin-1 stimulates association of SHP-2 to the phosphorylated Tie-2 receptor (47), which in turn inhibits PI3 kinase-dependent signaling pathways leading to EC migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "angiopoietin-1") :xref (x2 / xref :value "UNIPROT:ANGP1_HUMAN" :prob "0.703")) :ARG1 (a / associate-01 :ARG0 p :ARG1 (p5 / protein :name (n2 / name :op1 "SHP-2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :ARG2 (r / receptor :name (n3 / name :op1 "Tie-2") :ARG1-of (p2 / phosphorylate-01)) :ARG0-of (i / inhibit-01 :ARG1 (p3 / pathway :ARG0-of (s2 / signal-07) :ARG0-of (d / depend-01 :ARG1 (k / kinase :name (n4 / name :op1 "PI3") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "1.002")))) :ARG0-of (l / lead-03 :ARG2 (m / migrate-01 :ARG0 (c / cell :name (n5 / name :op1 "EC")))) :mod (i2 / in-turn))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "47")))) # ::id bel_pmid_1751_1588.36510 # ::date 2015-05-04T12:09:40 # ::file bel_pmid_1751_1588_36510.txt # ::snt Overexpression of dominant negative N17Rac1 significantly inhibits VEGF-induced ROS production that is involved in VEGFR2 activation, EC migration, and proliferation (100). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (i / inhibit-01 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "N17Rac1") :ARG0-of (d / dominate-01) :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1 (p / produce-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "ROS") :xref (x2 / xref :value "PUBCHEM:128351" :prob "11.468653")) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n4 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003"))) :ARG1-of (i3 / involve-01 :ARG2 (a / and :op1 (a2 / activate-01 :ARG1 (p3 / protein :name (n5 / name :op1 "VEGFR2") :xref (x1 / xref :value "UNIPROT:VGFR2_HUMAN" :prob "1.003"))) :op2 (a3 / and :op1 (m2 / migrate-01 :ARG0 (c / cell :name (n6 / name :op1 "EC"))) :op2 (p4 / proliferate-01 :ARG0 c))))) :ARG1-of (s / significant-02) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "100")))) # ::id bel_pmid_1751_1588.36636 # ::date 2015-05-04T12:37:52 # ::file bel_pmid_1751_1588_36636.txt # ::snt VEGFR2 forms a complex with VE-cadherin, -catenin, and PI3 kinase that is required for phosphorylation of Akt, which plays an important role in EC survival (15) and migration (27, 28, 80). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (f / form-01 :ARG0 (p / protein :name (n / name :op1 "VEGFR2") :xref (x4 / xref :value "UNIPROT:VGFR2_HUMAN" :prob "1.003")) :ARG1 (m / macro-molecular-complex :part p :part (p2 / protein :name (n2 / name :op1 "VE-cadherin") :xref (x / xref :value "UNIPROT:CADH5_HUMAN" :prob "1.002")) :part (p3 / protein :name (n3 / name :op1 "VE-catenin") :xref (x1 / xref :value "UNIPROT:CADH5_HUMAN" :prob "0.272")) :part (k / kinase :name (n4 / name :op1 "PI3") :xref (x3 / xref :value "UNIPROT:ELAF_HUMAN" :prob "1.002")) :ARG1-of (r / require-01 :ARG0 (p4 / phosphorylate-01 :ARG2 (e / enzyme :name (n5 / name :op1 "Akt") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG0-of (p5 / play-08 :ARG1 (a / and :op1 (s / survive-02 :ARG0 (c / cell :name (n6 / name :op1 "EC")) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "15")))) :op2 (m2 / migrate-01 :ARG0 c :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 "27" :op2 "28" :op3 "80"))))) :mod (i / important))))))) # ::id bel_pmid_1751_3865.31240 # ::date 2015-05-04T13:10:29 # ::file bel_pmid_1751_3865_31240.txt # ::snt FIGURE 9. TGF-beta1 induces snail-1 in hepatocytes in EMT state and lack of evidence for Akt/Erk1/2 activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / describe-01 :ARG0 (f / figure :mod "9") :ARG1 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "TGF-β1") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.283")) :ARG2 (p2 / protein :name (n2 / name :op1 "snail-1") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.242")) :location (c / cell :name (n3 / name :op1 "hepatocyte") :condition (a / and :op1 (e2 / event :name (n4 / name :op1 "epithelial−mesenchymal" :op2 "transition")) :op2 (l / lack-01 :ARG1 (e / evidence-01 :ARG1 (a2 / activate-01 :ARG1 (p3 / pathway :name (n5 / name :op1 "Akt/Erk1/2"))))))))) # ::id bel_pmid_1751_3865.39040 # ::date 2015-05-04T13:46:20 # ::file bel_pmid_1751_3865_39040.txt # ::snt FIGURE 11. TGF-beta1 induces activation of Smad2/3 pathway in AML12 cell line # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / describe-01 :ARG0 (f / figure :mod "11") :ARG1 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "TGF-β1") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.283")) :ARG2 (a / activate-01 :ARG0 p :ARG1 (p2 / pathway :name (n2 / name :op1 "Smad2/3")) :location (c / cell-line :name (n3 / name :op1 "AML12"))))) # ::id bel_pmid_1764_3885.30204 # ::date 2015-05-04T13:49:47 # ::file bel_pmid_1764_3885_30204.txt # ::snt Aortas from COX-2?/? mice on atherogenic diet after 3 weeks had significantly larger areas of neutral lipid content as measured by Oil Red O staining (Fig. 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (h / have-03 :ARG0 (a / aorta :source (m / mouse :mod (e / enzyme :name (n / name :op1 "COX-2") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")) :condition (d / diet :mod (a2 / atherogenic)))) :ARG1 (a3 / area :quant (l / large :degree (m3 / more) :ARG1-of (s / significant-02)) :ARG0-of (c / contain-01 :ARG1 (l2 / lipid :ARG0-of (n2 / neutral-02))) :ARG1-of (m4 / measure-01 :ARG2 (s2 / stain-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "Oil" :op2 "Red" :op3 "O") :xref (x1 / xref :value "PUBCHEM:6046885" :prob "9.669818"))))) :time (a4 / after :op1 (t / temporal-quantity :quant "3" :unit (w / week))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id bel_pmid_1764_3885.30206 # ::date 2015-05-05T06:50:17 # ::file bel_pmid_1764_3885_30206.txt # ::snt Serum TXB2 is significantly increased in COX-2?/? mice on chow compared to wild-type littermates (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (i / increase-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "TXB2") :mod (s / serum) :xref (x1 / xref :value "PUBCHEM:5283137" :prob "17.879841")) :ARG2 (s2 / significant-02) :location (m2 / mouse :mod (e / enzyme :name (n2 / name :op1 "COX-2") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")) :mod (d / diet :mod (c / chow))) :compared-to (l / littermate :mod (w / wild-type)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id bel_pmid_1764_3885.30216 # ::date 2015-05-05T07:17:24 # ::file bel_pmid_1764_3885_30216.txt # ::snt Interestingly, COX-2?/? mice on atherogenic diet showed more systemic inflammation with higher levels of TNF (Fig. 5B) and IL-6 (Fig. 5D) than wild-type controls. Furthermore, IL-12 was significantly increased by atherogenic diet in wild-type controls, while COX-2 depletion completely abolished this induction (Fig. 5E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG0 (m2 / mouse :mod (e / enzyme :name (n / name :op1 "COX-2") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")) :condition (d / diet :mod (a / atherogenic))) :ARG1 (i / inflame-01 :mod (s2 / systemic :degree (m4 / more)) :mod (l / level :quant-of (a2 / and :op1 (p / protein :name (n2 / name :op1 "TNF") :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5B")) :xref (x4 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n3 / name :op1 "IL-6") :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "5D")) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (h / high-02 :degree (m5 / more) :compared-to (c / control-01 :mod (w / wild-type))))) :manner (i2 / interesting)) :snt2 (a3 / and :op2 (c2 / contrast-01 :ARG1 (i3 / increase-01 :ARG0 (d4 / diet :mod (a4 / atherogenic)) :ARG1 (p3 / protein :name (n4 / name :op1 "IL-12") :xref (x2 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343")) :ARG2 (s3 / significant-02) :location (c3 / control-01 :mod (w2 / wild-type))) :ARG2 (a5 / abolish-01 :ARG0 (d5 / deplete-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "COX-2") :xref (x1 / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003"))) :ARG1 (i4 / induce-01 :mod (t / this)) :ARG1-of (c4 / complete-02))) :ARG1-of (d6 / describe-01 :ARG0 (f3 / figure :mod "5E")))) # ::id bel_pmid_1769_2569.37970 # ::date 2015-05-05T08:26:30 # ::file bel_pmid_1769_2569_37970.txt # ::snt Table 1. Production of pro- and anti-angiogenic mediators by DCs Pro-angiogenic mediators: VEGF, FGF2, TNF-a, IL-6, TGF-b, CXCL8, CXCL5, CXCL1, 2, 3, CCL2, GM-CSF, ET-1, OPN, Anti-angiogenic mediators: IL-12, IL-18, IL-10, TSP-1, PTX3, IFN-a/b, CXCL9, CXCL10, CXCL13, CCL21 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (d / describe-01 :ARG0 (t / table :mod "1") :ARG1 (p / produce-01 :ARG0 (c / cell :name (n / name :op1 "DC")) :ARG1 (a / and :op1 (m / molecular-physical-entity :ARG0-of (m2 / mediate-01) :ARG0-of (f / favor-01 :ARG1 (a2 / angiogenesis)) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "VEGF") :xref (x6 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n3 / name :op1 "FGF2") :xref (x14 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.004")) :op3 (p4 / protein :name (n4 / name :op1 "TNF-α") :xref (x17 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642")) :op4 (p5 / protein :name (n5 / name :op1 "IL-6") :xref (x20 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op5 (p6 / protein :name (n6 / name :op1 "TGF-β") :xref (x15 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233")) :op6 (p7 / protein :name (n7 / name :op1 "CXCL8") :xref (x16 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003")) :op7 (p8 / protein :name (n8 / name :op1 "CXCL5") :xref (x19 / xref :value "UNIPROT:CXCL5_HUMAN" :prob "1.003")) :op8 (p9 / protein :name (n9 / name :op1 "CXCL1") :xref (x / xref :value "UNIPROT:GROA_HUMAN" :prob "1.002")) :op9 (p10 / protein :name (n10 / name :op1 "CXCL2") :xref (x7 / xref :value "UNIPROT:CXCL2_HUMAN" :prob "1.003")) :op10 (p11 / protein :name (n11 / name :op1 "CXCL3") :xref (x8 / xref :value "UNIPROT:CXCL3_HUMAN" :prob "1.003")) :op11 (p12 / protein :name (n12 / name :op1 "CCL2") :xref (x21 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.003")) :op12 (p13 / protein :name (n13 / name :op1 "GM-CSF") :xref (x22 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.003")) :op13 (p14 / protein :name (n14 / name :op1 "ET-1") :xref (x9 / xref :value "UNIPROT:EDN1_HUMAN" :prob "1.003")) :op14 (p15 / protein :name (n15 / name :op1 "OPN") :xref (x10 / xref :value "UNIPROT:OSTP_HUMAN" :prob "1.002"))))) :op2 (m4 / molecular-physical-entity :ARG0-of m2 :ARG0-of (c2 / counter-01 :ARG1 a2) :ARG1-of (m5 / mean-01 :ARG2 (a4 / and :op1 (p16 / protein :name (n16 / name :op1 "IL-12") :xref (x11 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343")) :op2 (p17 / protein :name (n17 / name :op1 "IL-18") :xref (x12 / xref :value "UNIPROT:IL18_HUMAN" :prob "1.003")) :op3 (p18 / protein :name (n18 / name :op1 "IL-10") :xref (x13 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :op4 (p19 / protein :name (n19 / name :op1 "TSP-1") :xref (x4 / xref :value "UNIPROT:PRS55_HUMAN" :prob "0.672")) :op5 (p20 / protein :name (n20 / name :op1 "PTX3") :xref (x2 / xref :value "UNIPROT:PTX3_HUMAN" :prob "1.003")) :op6 (p21 / protein :name (n21 / name :op1 "IFN-α/β")) :op7 (p22 / protein :name (n22 / name :op1 "CXCL9") :xref (x5 / xref :value "UNIPROT:CXCL9_HUMAN" :prob "1.004")) :op8 (p23 / protein :name (n23 / name :op1 "CXCL10") :xref (x3 / xref :value "UNIPROT:CXL10_HUMAN" :prob "1.003")) :op9 (p24 / protein :name (n24 / name :op1 "CXCL13") :xref (x18 / xref :value "UNIPROT:CXL13_HUMAN" :prob "1.003")) :op10 (p25 / protein :name (n25 / name :op1 "CCL21") :xref (x1 / xref :value "UNIPROT:CCL21_HUMAN" :prob "1.003")))))))) # ::id bel_pmid_1770_9751.28596 # ::date 2015-05-05T09:44:50 # ::file bel_pmid_1770_9751_28596.txt # ::snt Flow cytometry confirmed that follicular B cells present in Itpkb ?/? and Itpkb ?/? E?-2–22 BCL-2 mice expressed a higher level of Bim protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / confirm-01 :ARG0 (c3 / cytometry :mod (f2 / flow)) :ARG1 (e / express-03 :ARG2 (l / level :quant-of (p / protein :name (n2 / name :op1 "Bim") :xref (x2 / xref :value "UNIPROT:BIM_HUMAN_PROMOTER_PROBE" :prob "0.671")) :ARG1-of (h / high-02 :degree (m / more))) :ARG3 (c2 / cell :name (n3 / name :op1 "B") :ARG1-of (p3 / present-02 :ARG2 (a / and :op1 (m2 / mouse :mod (e2 / enzyme :name (n4 / name :op1 "Itpkb") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:IP3KB_HUMAN" :prob "0.602"))) :op2 (m4 / mouse :mod (p2 / protein :name (n5 / name :op1 "BCL-2") :mod (d / dna-sequence :name (n6 / name :op1 "Eμ-2–22") :mod e2) :xref (x / xref :value "UNIPROT:BCL2_HUMAN" :prob "0.672"))))) :location (f / follicle)))) # ::id bel_pmid_1770_9751.28598 # ::date 2015-05-05T10:24:02 # ::file bel_pmid_1770_9751_28598.txt # ::snt Erk1 and Erk2 were found to be much less phosphorylated in Itpkb ?/? E?-2?22-BCL-2 B cells than in control B cells after BCR activation (Fig. 3 b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 23, 2015 (f / find-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Erk1") :xref (x4 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n2 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :quant (l / less :degree (m / much)) :location (c / cell :name (n3 / name :op1 "B") :mod (p2 / protein :name (n6 / name :op1 "BCL-2") :mod (d / dna-sequence :name (n4 / name :op1 "Eμ-2–22") :mod (e3 / enzyme :name (n5 / name :op1 "Itpkb") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:IP3KB_HUMAN" :prob "0.602"))) :xref (x / xref :value "UNIPROT:BCL2_HUMAN" :prob "0.672")) :compared-to (c2 / cell :name (n7 / name :op1 "B") :mod (c3 / control)))) :time (a2 / after :op1 (a3 / activate-01 :ARG1 (p3 / protein :name (n8 / name :op1 "BCR") :xref (x3 / xref :value "UNIPROT:BCR_HUMAN" :prob "1.004")))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3b"))) # ::id bel_pmid_1770_9751.28600 # ::date 2015-05-05T10:38:48 # ::file bel_pmid_1770_9751_28600.txt # ::snt Quantitative real-time RT-PCR analysis revealed a slight, but very significant, increase in Bim messenger RNA level in splenic resting follicular B cells persisting in Itpkb ?/? mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :mod (t / thing :name (n / name :op1 "RT-PCR")) :mod (r2 / real-time) :mod (q / quantitative)) :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (n6 / nucleic-acid :name (n2 / name :op1 "messenger" :op2 "RNA") :ARG1-of (e / express-03 :ARG2 (p / protein :name (n3 / name :op1 "Bim") :xref (x1 / xref :value "UNIPROT:BIM_HUMAN_PROMOTER_PROBE" :prob "0.671"))))) :ARG2 (s / slight :ARG1-of (c / contrast-01 :ARG2 (s2 / significant-02 :degree (v / very)))) :location (c2 / cell :name (n4 / name :op1 "B") :location (f / follicle) :ARG1-of (r4 / rest-01 :location (s3 / spleen)) :ARG1-of (p2 / persist-01 :location (m / mouse :mod (e2 / enzyme :name (n5 / name :op1 "Itpkb") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:IP3KB_HUMAN" :prob "0.602"))))))) # ::id bel_pmid_1780_4750.41494 # ::date 2015-05-05T11:23:50 # ::file bel_pmid_1780_4750_41494.txt # ::snt The forkhead transcription factor Foxp3 is highly expressed in CD4+CD25+ regulatory T cells (Treg) and was recently identified as a key player in mediating their inhibitory functions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "forkhead" :op2 "transcription" :op3 "factor") :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Foxp3") :xref (x / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603"))) :xref (x3 / xref :value "UNIPROT:FOXS1_HUMAN" :prob "0.362")) :ARG3 (c / cell :name (n3 / name :op1 "T") :mod (p3 / protein :name (n4 / name :op1 "CD4") :xref (x1 / xref :value "UNIPROT:CD4_HUMAN" :prob "1.003")) :mod (p4 / protein :name (n5 / name :op1 "CD25") :xref (x2 / xref :value "UNIPROT:IL2RA_HUMAN" :prob "1.003")) :ARG0-of (r / regulate-01)) :ARG2-of (h / high-02)) :op2 (i / identify-01 :ARG1 p :ARG2 (m2 / molecular-physical-entity :ARG0-of (p5 / play-08) :ARG1-of (k / key-02 :ARG2 (m3 / mediate-01 :ARG0 p :ARG1 (f / function-01 :ARG0 c :ARG1 (i2 / inhibit-01))))) :time (r2 / recent))) # ::id bel_pmid_1780_4750.41496 # ::date 2015-05-05T11:47:26 # ::file bel_pmid_1780_4750_41496.txt # ::snt Foxp3 expression was induced by transforming growth factor-(32 (TGF-(32), but not TGF-(31 stimulation in these cells, and was partially suppressed following antibody-mediated neutralization of TGF-(32. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (c / contrast-01 :ARG1 (i / induce-01 :ARG0 (s / stimulate-01 :ARG1 (p / protein :name (n / name :op1 "transforming" :op2 "growth" :op3 "factor-β2") :xref (x2 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.393"))) :ARG2 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Foxp3") :xref (x / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")))) :ARG2 (i2 / induce-01 :polarity "-" :ARG0 (s2 / stimulate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "TGF-β1") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.283")))) :location (c2 / cell :mod (t / this))) :op2 (s3 / suppress-01 :ARG1 e :degree (p4 / part) :ARG1-of (f / follow-01 :ARG2 (n4 / neutralize-01 :ARG1 p :ARG1-of (m / mediate-01 :ARG0 (a2 / antibody)))))) # ::id bel_pmid_1780_4750.41498 # ::date 2015-05-05T11:58:56 # ::file bel_pmid_1780_4750_41498.txt # ::snt Down-regulation of Foxp3 with small interfering RNA (siRNA) in pancreatic carcinoma cells resulted in the up-regulation of interleukin 6 (IL-6) and IL-8 expression, providing evidence for a negative transcriptional activity of Foxp3 also in these epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / result-01 :ARG1 (d / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "Foxp3") :xref (x2 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "small" :op2 "interfering" :op3 "RNA")) :location (c / cell :mod (m / medical-condition :name (n7 / name :op1 "carcinoma") :mod (p2 / pancreas)))) :ARG2 (u / upregulate-01 :ARG1 (e / express-03 :ARG2 (a / and :op1 (p3 / protein :name (n3 / name :op1 "interleukin" :op2 "6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.693")) :op2 (p4 / protein :name (n4 / name :op1 "IL-8") :xref (x1 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003"))))) :ARG0-of (p5 / provide-01 :ARG1 (e2 / evidence-01 :ARG0 u :ARG1 (a2 / activity-06 :ARG0 p :ARG1 (t / transcribe-01) :ARG2-of (n5 / negative-01) :location (c3 / cell :mod (e3 / epithelium) :mod (t2 / this) :mod (a3 / also)))))) # ::id bel_pmid_1780_4750.41500 # ::date 2015-05-05T12:29:41 # ::file bel_pmid_1780_4750_41500.txt # ::snt Coculture of Foxp3-expressing tumor cells with naive T cells completely inhibited T-cell proliferation, but not activation, and this antiproliferative effect was partially abrogated following specific inhibition of Foxp3 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (c2 / coculture-01 :ARG1 (a5 / and :op1 (c3 / cell :mod (t / tumor) :ARG3-of (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Foxp3") :xref (x / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")))) :op2 (c4 / cell :name (n2 / name :op1 "T") :mod (n3 / naive)))) :ARG1 (p2 / proliferate-01 :ARG0 (c5 / cell :name (n4 / name :op1 "T"))) :ARG1-of (c6 / complete-02)) :ARG2 (i2 / inhibit-01 :polarity "-" :ARG0 c2 :ARG1 (a2 / activate-01 :ARG0 c5))) :op2 (a3 / abrogate-01 :ARG1 (a4 / affect-01 :ARG2 i :mod (t2 / this)) :degree (p3 / part) :ARG1-of (f / follow-01 :ARG2 (i3 / inhibit-01 :ARG1 (e3 / express-03 :ARG2 p) :ARG1-of (s / specific-02))))) # ::id bel_pmid_1780_4750.41502 # ::date 2015-05-05T12:45:44 # ::file bel_pmid_1780_4750_41502.txt # ::snt In an initial analysis of microdissected pancreatic carcinoma tissue using Affymetrix chip technology, Foxp3 was among the up-regulated genes in some tumor samples (26); (Fig. 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / include-91 :ARG1 (g / gene :name (n / name :op1 "Foxp3") :xref (x / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :ARG2 (g2 / gene :ARG1-of (u / upregulate-01)) :location (t / tumor :ARG1-of (s / sample-01) :quant (s2 / some)) :time (a / analyze-01 :ARG1 (t2 / tissue :ARG1-of (m / microdissect-00) :mod (m2 / medical-condition :name (n3 / name :op1 "carcinoma") :mod (p / pancreas))) :ARG0-of (u2 / use-01 :ARG1 (t3 / technology :name (n2 / name :op1 "Affymetrix" :op2 "chip"))) :mod (i2 / initial)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "26"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id bel_pmid_1780_4750.41504 # ::date 2015-05-05T13:02:17 # ::file bel_pmid_1780_4750_41504.txt # ::snt In accordance with the immunohistochemistry data pointing to FoxP3 expression in tumor cells (see above), Foxp3 expression was clearly detectable in several pancreatic carcinoma cell lines at both mRNA (Fig. 2A) and protein levels (Fig. 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / possible-01 :ARG1 (d / detect-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "Foxp3") :xref (x / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603"))) :ARG1-of (c / clear-06) :location (c2 / cell-line :quant (s / several) :location-of (a / and :op1 (l / level :mod (n3 / nucleic-acid :name (n2 / name :op1 "mRNA")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) :op2 (l2 / level :mod (p4 / protein) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2B")))) :mod (m / medical-condition :name (n4 / name :op1 "carcinoma") :mod (p3 / pancreas)))) :ARG1-of (a3 / accord-02 :ARG2 (d4 / data :mod (i / immunohistochemistry) :ARG0-of (p5 / point-01 :ARG2 (e2 / express-03 :ARG2 p2 :ARG3 (c5 / cell :mod (t / tumor))))) :ARG1-of (s2 / see-01 :mode "imperative" :ARG0 (y / you) :location (a2 / above)))) # ::id bel_pmid_1780_4750.41506 # ::date 2015-05-05T13:22:54 # ::file bel_pmid_1780_4750_41506.txt # ::snt Treatment of PANC-89, Capan1, and Panc1 cells with TGF-h2 led to an up-regulation of the Foxp3 protein, which was moderate for PANC-89 and Capan1 and strong for Panc1 (Fig. 3A and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (l / lead-03 :ARG0 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "PANC-89")) :op2 (c2 / cell-line :name (n2 / name :op1 "Capan1")) :op3 (c3 / cell-line :name (n3 / name :op1 "Panc1"))) :ARG2 (p / protein :name (n4 / name :op1 "TGF-h2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.263"))) :ARG2 (a2 / and :op1 (u / upregulate-01 :ARG1 (p2 / protein :name (n5 / name :op1 "Foxp3") :xref (x / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :ARG1-of (m / moderate-03 :beneficiary (a3 / and :op1 c :op2 c2) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A")))) :op2 (u2 / upregulate-01 :ARG1 p2 :ARG1-of (s / strong-02 :beneficiary c3 :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3D")))))) # ::id bel_pmid_1780_4750.41508 # ::date 2015-05-05T13:35:38 # ::file bel_pmid_1780_4750_41508.txt # ::snt RT-PCR analysis detected a 13-fold (mean value of four independent experiments) increase of Foxp3 mRNA expression in PANC-89 cells after a 48-h stimulation with TGF-h2, whereas no such effect was evident after stimulation with TGF-h1 (Fig. 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (d / detect-01 :ARG0 (a / analyze-01 :instrument (t2 / thing :name (n3 / name :op1 "RT-PCR"))) :ARG1 (i / increase-01 :ARG1 (e / express-03 :ARG1 (n7 / nucleic-acid :name (n2 / name :op1 "mRNA") :part (p / protein :name (n / name :op1 "Foxp3") :xref (x2 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603"))) :ARG3 (c2 / cell-line :name (n4 / name :op1 "PANC-89"))) :ARG2 (p2 / product-of :op1 "13" :ARG1-of (d2 / describe-01 :ARG0 (v / value :mod (m / mean) :quant-of (e2 / experiment-01 :quant "4" :ARG0-of (d3 / depend-01 :polarity "-"))))) :time (a2 / after :op1 (s / stimulate-01 :ARG2 (p3 / protein :name (n5 / name :op1 "TGF-h2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.263")) :duration (t / temporal-quantity :quant "48" :unit (h / hour)))))) :ARG2 (e3 / evident :polarity "-" :domain (a4 / affect-01 :ARG2 (i2 / increase-01 :ARG1 e :ARG2 p2)) :time (a3 / after :op1 (s3 / stimulate-01 :ARG2 (p4 / protein :name (n6 / name :op1 "TGF-h1") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.263"))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id bel_pmid_1780_4750.41510 # ::date 2015-05-05T13:54:53 # ::file bel_pmid_1780_4750_41510.txt # ::snt Moreover, the incubation of PANC-89 and Capan1 cells with anti-TGF-h2 antibody for 48 h clearly suppressed the Foxp3 signal (Fig. 3A ), suggesting that endogenously produced TGF-h2 maintains Foxp3 expression in pancreatic cancer cell cultures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (s / suppress-01 :ARG0 (i / incubate-01 :ARG1 (a2 / and :op1 (c / cell-line :name (n / name :op1 "PANC-89")) :op2 (c2 / cell-line :name (n2 / name :op1 "Capan1"))) :ARG2 (a3 / antibody :ARG0-of (c6 / counter-01 :ARG1 (p4 / protein :name (n3 / name :op1 "TGF-h2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.263")))) :duration (t / temporal-quantity :quant "48" :unit (h / hour))) :ARG1 (s2 / signal-07 :ARG0 (p / protein :name (n4 / name :op1 "Foxp3") :xref (x2 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603"))) :ARG1-of (c3 / clear-06) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A")) :ARG0-of (s3 / suggest-01 :ARG1 (m / maintain-01 :ARG0 (p2 / protein :name (n5 / name :op1 "TGF-h2") :ARG1-of (p3 / produce-01 :manner (e / endogenous)) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.263")) :ARG1 (e2 / express-03 :ARG2 p :ARG3 (c4 / culture :mod (c5 / cell :mod (d2 / disease :wiki "Pancreatic_cancer" :name (n6 / name :op1 "pancreatic" :op2 "cancer"))))))))) # ::id bel_pmid_1780_4750.41512 # ::date 2015-05-05T14:09:07 # ::file bel_pmid_1780_4750_41512.txt # ::snt Specific down-regulation of Foxp3 in pancreatic carcinoma cells results in up-regulation of IL-6 and IL-8. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (r / result-01 :ARG1 (d / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "Foxp3") :xref (x2 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :location (c / cell :mod (m / medical-condition :name (n2 / name :op1 "carcinoma") :mod (p2 / pancreas))) :ARG1-of (s / specific-02)) :ARG2 (u / upregulate-01 :ARG1 (a / and :op1 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "IL-8") :xref (x / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1780_4750.41514 # ::date 2015-05-05T14:12:53 # ::file bel_pmid_1780_4750_41514.txt # ::snt A screen for changes in cytokine secretion in these cells using the Raybiotec Cytokine Array (Hoelzel Diagnostica) revealed an increase of IL-6 and IL-8 in the culture supernatant, whereas other cytokines remained unchanged (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (c / contrast-01 :ARG1 (r / reveal-01 :ARG0 (s / screen-01 :ARG2 (c2 / change-01 :ARG1 (s2 / secrete-01 :ARG1 (c3 / cytokine) :location (c4 / cell :mod (t / this)))) :ARG2-of (u / use-01 :ARG1 (p / product :name (n / name :op1 "Raybiotech" :op2 "Cytokine" :op3 "Array") :source (c5 / company :name (n2 / name :op1 "Hoelzel" :op2 "Diagnostika"))))) :ARG1 (i / increase-01 :ARG1 (a / and :op1 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n4 / name :op1 "IL-8") :xref (x1 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003"))) :location (s3 / supernatant :ARG1-of (c6 / culture-01)))) :ARG2 (r2 / remain-01 :ARG1 (c7 / cytokine :mod (o / other)) :ARG3 (c8 / change-01 :polarity "-") :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s4 / show-01 :polarity "-"))))) # ::id bel_pmid_1780_4750.41518 # ::date 2015-05-05T14:34:17 # ::file bel_pmid_1780_4750_41518.txt # ::snt In the cocultures, Colo357, PANC-89, and PancTu1 tumor cells strongly inhibited the proliferation of anti-CD3/anti-CD28-stimulated T cells (Fig. 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / inhibit-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "Colo357")) :op2 (c2 / cell-line :name (n2 / name :op1 "PANC-89")) :op3 (c3 / cell-line :name (n3 / name :op1 "PancTu1")) :mod (t / tumor)) :ARG1 (p / proliferate-01 :ARG0 (c4 / cell :name (n4 / name :op1 "T") :ARG1-of (s / stimulate-01 :ARG0 (a2 / and :op1 (m / molecular-physical-entity :ARG0-of (c5 / counter-01 :ARG1 (p2 / protein :name (n5 / name :op1 "CD3") :xref (x / xref :value "UNIPROT:CD33_HUMAN" :prob "0.342")))) :op2 (m2 / molecular-physical-entity :ARG0-of (c6 / counter-01 :ARG1 (p3 / protein :name (n6 / name :op1 "CD28") :xref (x1 / xref :value "UNIPROT:CD28_HUMAN" :prob "1.003")))))))) :ARG1-of (s2 / strong-02) :location (c7 / cell :ARG1-of (c8 / coculture-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4D"))) # ::id bel_pmid_1780_4750.41520 # ::date 2015-05-05T14:43:23 # ::file bel_pmid_1780_4750_41520.txt # ::snt As shown in Fig. 5B, CD25 GITR and CD69 were up-regulated after anti-CD3/anti-CD28 stimulation, irrespective of the presence or absence of tumor cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (u / upregulate-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "CD25") :xref (x4 / xref :value "UNIPROT:IL2RA_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "GITR") :xref (x / xref :value "UNIPROT:TNR18_HUMAN" :prob "1.002")) :op3 (p3 / protein :name (n3 / name :op1 "CD69") :xref (x1 / xref :value "UNIPROT:CD69_HUMAN" :prob "1.003"))) :time (a2 / after :op1 (s / stimulate-01 :ARG0 (a3 / and :op1 (m / molecular-physical-entity :ARG0-of (c / counter-01 :ARG1 (p4 / protein :name (n4 / name :op1 "CD3") :xref (x2 / xref :value "UNIPROT:CD33_HUMAN" :prob "0.342")))) :op2 (m2 / molecular-physical-entity :ARG0-of (c2 / counter-01 :ARG1 (p5 / protein :name (n5 / name :op1 "CD28") :xref (x3 / xref :value "UNIPROT:CD28_HUMAN" :prob "1.003"))))))) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "5B")) :ARG1-of (r / regardless-91 :ARG2 (o / or :op1 (p6 / present-02 :ARG1 (c3 / cell :mod (t / tumor))) :op2 (a4 / absent-01 :ARG1 c3)))) # ::id bel_pmid_1780_4750.41522 # ::date 2015-05-05T14:54:55 # ::file bel_pmid_1780_4750_41522.txt # ::snt When using these cells, we observed an ~ 45% recovery of T-cell proliferation in the coculture system (Fig. 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (r / recover-02 :ARG1 (p / proliferate-01 :ARG0 (c / cell :name (n / name :op1 "T"))) :quant (a / approximately :op1 (p2 / percentage-entity :value "45"))) :location (s / system :consist-of (c2 / coculture-01)) :time (u / use-01 :ARG0 w :ARG1 (c3 / cell :mod (t / this))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id bel_pmid_1794_2936.40216 # ::date 2015-05-09T23:23:27 # ::file bel_pmid_1794_2936_40216.txt # ::snt Results Tumor-associated inflammation is reduced in IL-1R—/— mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 16, 2015 (r / reduce-01 :ARG1 (i / inflame-01 :ARG1-of (a / associate-01 :ARG2 (t / tumor))) :location (m2 / mouse :mod (p / protein :name (n2 / name :op1 "IL-1R") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:IL1R1_HUMAN" :prob "0.672"))) :ARG2-of (r2 / result-01)) # ::id bel_pmid_1794_2936.40218 # ::date 2015-05-09T23:40:34 # ::file bel_pmid_1794_2936_40218.txt # ::snt Canonical proinflammatory cytokines, such as IL-6, MCP-1, TGFh, and IL-1h were significantly elevated in 4T1 tumor tissue. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (e / elevate-01 :ARG1 (c7 / cytokine :mod (c2 / canonical) :ARG0-of (p / promote-01 :ARG1 (i / inflame-01)) :example (a / and :op1 (p2 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n2 / name :op1 "MCP-1") :xref (x2 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002")) :op3 (p4 / protein :name (n3 / name :op1 "TGFh") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.223")) :op4 (p5 / protein :name (n4 / name :op1 "IL-1h") :xref (x3 / xref :value "UNIPROT:IL37_HUMAN" :prob "0.662")))) :ARG1-of (s / significant-02) :location (t / tissue :mod (t2 / tumor :mod (c / cell-line :name (n5 / name :op1 "4T1"))))) # ::id bel_pmid_1794_2936.40222 # ::date 2015-05-09T23:48:40 # ::file bel_pmid_1794_2936_40222.txt # ::snt Additionally, IL-1R—/— tumor tissue had less IL-12p70 and more TGFh and IFNg than tumor tissue from wild-type BALB/c mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (a / and :op2 (h / have-03 :ARG0 (t / tissue :part-of (t2 / tumor) :mod (p / protein :name (n / name :op1 "IL-1R") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:IL1R1_HUMAN" :prob "0.672"))) :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "IL-12p70") :degree (l / less) :xref (x / xref :value "UNIPROT:IL12A_HUMAN" :prob "0.262")) :op2 (p3 / protein :name (n3 / name :op1 "TGFh") :degree (m3 / more) :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.223")) :op3 (p4 / protein :name (n4 / name :op1 "IFNg") :degree m3 :xref (x2 / xref :value "UNIPROT:IFNG_HUMAN" :prob "0.653")) :compared-to (t3 / tissue :mod (t4 / tumor) :source (m4 / mouse :mod (c / cell-line :name (n5 / name :op1 "BALB/c") :mod (w / wild-type))))))) # ::id bel_pmid_1794_2936.40248 # ::date 2015-05-10T00:06:13 # ::file bel_pmid_1794_2936_40248.txt # ::snt A potential downstream candidate is the proinflammatory cytokine, IL-6, the production of which is reduced in IL-1R—/— tumor tissue (Fig. 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 18, 2015 (c / cytokine :name (n / name :op1 "IL-6") :domain (c2 / candidate :mod (p3 / potential) :location (d / downstream)) :ARG1-of (p / produce-01 :ARG1-of (r / reduce-01 :location (t / tissue :part-of (t2 / tumor) :mod (p4 / protein :name (n2 / name :op1 "IL-1R") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:IL1R1_HUMAN" :prob "0.672"))))) :ARG0-of (p2 / promote-01 :ARG1 (i / inflame-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id bel_pmid_1796_7787.34624 # ::date 2015-05-10T00:24:28 # ::file bel_pmid_1796_7787_34624.txt # ::snt These data demonstrate that it is the hemin-induced surge in cellular ROS levels, in particular the superoxide generated most likely from NADPH oxidase activity, and consequent oxidative stress which mediates Egr-1 upregulation via ERK-1/2 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (d3 / demonstrate-01 :ARG0 (d2 / data :mod (t2 / this)) :ARG1 (a / and :op1 (s / surge-01 :ARG1 (l2 / level :quant-of (s4 / small-molecule :name (n / name :op1 "ROS") :part-of (c / cell) :xref (x5 / xref :value "PUBCHEM:128351" :prob "11.468653"))) :ARG2-of (i / induce-01 :ARG0 (s5 / small-molecule :name (n2 / name :op1 "hemin") :xref (x4 / xref :value "PUBCHEM:455658" :prob "17.656696")))) :op2 (m4 / macro-molecular-complex :name (n3 / name :op1 "superoxide") :mod (p / particular) :ARG1-of (g / generate-01 :ARG2 (a2 / activity-06 :ARG0 (m5 / macro-molecular-complex :part (o / oxidase) :part (s6 / small-molecule :name (n4 / name :op1 "NADPH") :xref (x3 / xref :value "PUBCHEM:5884" :prob "16.493546")))) :ARG1-of (l / likely-01 :degree (m / most)))) :op3 (s2 / stress-02 :ARG2-of (r / result-01 :ARG1 o)) :ARG0-of (m2 / mediate-01 :ARG1 (u / upregulate-01 :ARG1 (p2 / protein :name (n5 / name :op1 "Egr-1") :xref (x / xref :value "UNIPROT:A0A089VKS7_HUMAN" :prob "1.001")) :ARG2 (a3 / activate-01 :ARG1 (s3 / slash :op1 (e / enzyme :name (n6 / name :op1 "ERK-1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n7 / name :op1 "ERK-2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))))))) # ::id bel_pmid_1798_2092.10006 # ::date 2015-05-10T00:47:28 # ::file bel_pmid_1798_2092_10006.txt # ::snt However, RELMbeta stimulated naive bone marrow-derived macrophages to secrete significant amounts of TNF-alpha, IL-6, and RANTES # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (h / have-concession-91 :ARG1 (s / stimulate-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "RELMbeta")) :ARG1 (s3 / secrete-01 :ARG0 (m2 / macrophage :ARG1-of (d / derive-01 :ARG2 (m / marrow :source (b / bone :mod (n3 / naive))))) :ARG1 (a / amount :quant-of (a2 / and :op1 (p / protein :name (n4 / name :op1 "TNF-alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n5 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n6 / name :op1 "RANTES") :xref (x1 / xref :value "UNIPROT:CCR1_HUMAN" :prob "0.352"))) :ARG1-of (s4 / significant-02))))) # ::id bel_pmid_1799_2263.15480 # ::date 2015-05-10T01:11:41 # ::file bel_pmid_1799_2263_15480.txt # ::snt MMP-2 (76 kDa) activity was elevated only at day 11 in C57BL/6 mice but not in MyD88–/– and IL-1R1–/– mice (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG1 (e / elevate-01 :ARG1 (a / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "MMP-2") :quant (m / mass-quantity :quant "76" :unit (k / kilodalton)) :xref (x1 / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.002"))) :time (a2 / after :op1 (t / temporal-quantity :quant "11" :unit (d / day))) :mod (o / only) :location (m6 / mouse :name (n4 / name :op1 "C57BL/6"))) :ARG2 (e3 / elevate-01 :polarity "-" :ARG1 (a3 / activity-06 :ARG0 e2) :time a2 :location (a4 / and :op1 (m2 / mouse :mod (p / protein :name (n2 / name :op1 "MyD88") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663"))) :op2 (m4 / mouse :mod (p2 / protein :name (n3 / name :op1 "IL-1R1") :ARG2-of (m5 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:IL1R1_HUMAN" :prob "0.682"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id bel_pmid_1799_2263.15482 # ::date 2015-05-10T01:27:07 # ::file bel_pmid_1799_2263_15482.txt # ::snt MMP-9 activity was significantly upregulated in BALF at day 1 in C57BL/6 mice but not in MyD88–/– mice, and only partially in IL-1R1–/– mice (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / contrast-01 :ARG1 (a3 / and :op1 (u / upregulate-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "MMP-9") :xref (x2 / xref :value "UNIPROT:MMP9_HUMAN" :prob "1.002"))) :ARG1-of (s / significant-02) :location (f2 / fluid :mod (l / lavage :mod (a4 / alveolus :mod (b / bronchus)))) :time (a2 / after :quant (u2 / up-to :op1 (t2 / temporal-quantity :quant "1" :unit (d / day)))) :location (m6 / mouse :name (n5 / name :op1 "C57BL/6"))) :op2 (u3 / upregulate-01 :ARG1 a :degree (p / part :mod (o / only)) :location (m2 / mouse :mod (p3 / protein :name (n3 / name :op1 "IL-1R1") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:IL1R1_HUMAN" :prob "0.682"))))) :ARG2 (u4 / upregulate-01 :polarity "-" :ARG1 a :location (m4 / mouse :mod (p2 / protein :name (n4 / name :op1 "MyD88") :ARG2-of (m5 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id bel_pmid_1799_2263.15488 # ::date 2015-05-10T01:51:51 # ::file bel_pmid_1799_2263_15488.txt # ::snt Latent TGF-?1 was detected after activation in BALF from WT mice 7 days after BLM administration, but was not detected in BALF from MyD88- or IL-1R1–deficient mice (Figure 5G) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / contrast-01 :ARG1 (d2 / detect-01 :ARG1 (p / protein :name (n / name :op1 "TGFβ-1") :mod (l / latent) :xref (x2 / xref :value "UNIPROT:TGFR1_HUMAN" :prob "0.303")) :time (a2 / after :op1 (a3 / activate-01 :location (f2 / fluid :source (m / mouse :mod (w / wild-type)) :mod (l2 / lavage :mod (a / alveolus :mod (b / bronchus)))))) :time (a4 / after :op1 (a5 / administer-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "BLM") :xref (x3 / xref :value "PUBCHEM:5360373" :prob "17.320225"))) :quant (t3 / temporal-quantity :quant "7" :unit (d3 / day)))) :ARG2 (d4 / detect-01 :polarity "-" :ARG1 p :location (o / or :op1 (f3 / fluid :source (m3 / mouse :ARG0-of (l3 / lack-01 :ARG1 (p3 / protein :name (n5 / name :op1 "MyD88") :xref (x / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663")))) :mod l2) :op2 (f4 / fluid :source (m4 / mouse :ARG0-of (l4 / lack-01 :ARG1 (p4 / protein :name (n9 / name :op1 "IL-1R1") :xref (x1 / xref :value "UNIPROT:IL1R1_HUMAN" :prob "0.682")))) :mod l2))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "5G"))) # ::id bel_pmid_1799_2263.28110 # ::date 2015-05-10T02:12:28 # ::file bel_pmid_1799_2263_28110.txt # ::snt 7 days of administration IL-1? caused tissue injury with marked tissue destruction, disruption of alveolar architecture, inflammation, and fibrosis (although less pronounced than that obtained after BLM treatment; Figure 7, D and E) that was absent in saline controls (Figure 7C) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (a2 / administer-01 :ARG1 (p / protein :name (n / name :op1 "IL-1β") :xref (x / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.332")) :duration (t2 / temporal-quantity :quant "7" :unit (d / day))) :ARG1 (i2 / injure-01 :ARG1 (t3 / tissue) :accompanier (a / and :op1 (d2 / destroy-01 :ARG1 t3 :ARG1-of (m / mark-01)) :op2 (d4 / disrupt-01 :ARG1 (a7 / architecture :poss (a8 / alveolus))) :op3 (i / inflame-01) :op4 (f2 / fibrosis)) :ARG2-of (h / have-concession-91) :ARG1-of (p2 / pronounced-02 :degree (l / less) :compared-to (i4 / injure-01 :ARG1 (t4 / tissue) :ARG1-of (o / obtain-01 :ARG2 (t5 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "BLM") :xref (x1 / xref :value "PUBCHEM:5360373" :prob "17.320225"))) :ARG1-of (d5 / describe-01 :ARG0 (a9 / and :op1 (f3 / figure :mod "7D") :op2 (f4 / figure :mod "7E")))))) :ARG1-of (a10 / absent-01 :ARG2 (c2 / control-01 :ARG0 (s / saline)))) :ARG1-of (d6 / describe-01 :ARG0 (f5 / figure :mod "7C"))) # ::id bel_pmid_1799_2263.30264 # ::date 2015-05-10T02:43:26 # ::file bel_pmid_1799_2263_30264.txt # ::snt IL-1? production into the lung was attenuated in ASC–/– in comparison with ASC+/+ control littermates 24 hours after BLM administration (Figure 9D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 18, 2015 (a2 / attenuate-01 :ARG1 (p / produce-01 :ARG1 (p2 / protein :wiki "IL1B" :name (n / name :op1 "IL-1β") :xref (x / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.332")) :location (l / lung)) :location (m / mouse :mod (l2 / littermate) :mod (p3 / protein :wiki "-" :name (n2 / name :op1 "ASC") :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of (c / control-01) :xref (x1 / xref :value "UNIPROT:ASC_HUMAN" :prob "1.003"))) :time (a4 / after :op1 (a5 / administer-01 :ARG1 (s / small-molecule :wiki "Bloom_syndrome_protein" :name (n4 / name :op1 "BLM") :xref (x3 / xref :value "PUBCHEM:5360373" :prob "17.320225"))) :quant (t3 / temporal-quantity :quant "24" :unit (h2 / hour))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "9D")) :compared-to (p4 / produce-01 :ARG1 p2 :location (m3 / mouse :mod (l3 / littermate) :mod (p5 / protein :wiki "-" :name (n3 / name :op1 "ASC") :mod (w / wild-type) :ARG0-of (c2 / control-01) :xref (x2 / xref :value "UNIPROT:ASC_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1799_2263.30266 # ::date 2015-05-10T02:58:29 # ::file bel_pmid_1799_2263_30266.txt # ::snt IL-6 production into the lung 24 hours after BLM treatment was attenuated in ASC–/– in comparison with ASC+/+ control littermates (Figure 9E). Comparable reductions of IL-1? and IL-6 were obtained in the BALF # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m4 / multi-sentence :snt1 (a / attenuate-01 :ARG1 (p / produce-01 :ARG1 (p2 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (l / lung)) :time (a2 / after :op1 (t2 / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "BLM") :xref (x5 / xref :value "PUBCHEM:5360373" :prob "17.320225"))) :quant (t4 / temporal-quantity :quant "24" :unit (h / hour))) :location (m / mouse :mod (l2 / littermate) :mod (p3 / protein :name (n3 / name :op1 "ASC") :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of (c / control-01) :xref (x2 / xref :value "UNIPROT:ASC_HUMAN" :prob "1.003"))) :compared-to (p4 / produce-01 :ARG1 p2 :location (m3 / mouse :mod (l3 / littermate) :mod (p5 / protein :name (n4 / name :op1 "ASC") :mod (w / wild-type) :ARG0-of (c2 / control-01) :xref (x4 / xref :value "UNIPROT:ASC_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "9E"))) :snt2 (o / obtain-01 :ARG1 (r / reduce-01 :ARG1 (a3 / and :op1 (p6 / protein :name (n5 / name :op1 "IL-1β") :xref (x3 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.332")) :op2 (p7 / protein :name (n6 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (c3 / comparable-03)) :location (f2 / fluid :mod (l4 / lavage :mod (a4 / alveolus :mod (b / bronchus)))))) # ::id bel_pmid_1803_2482.6302 # ::date 2015-05-10T03:10:59 # ::file bel_pmid_1803_2482_6302.txt # ::snt Studies using bone marrow-derived macrophages (BMDM) isolated from a spontaneous mouse model of Crohn's disease-like ileitis (SAMP1/YitFc strain) revealed significant inhibition by CGP57380 of the proinflammatory cytokines TNF, IL-6, and monocyte chemoattractant protein-1 at 4 and 24 h after LPS stimulation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (r / reveal-01 :ARG0 (s2 / study-01 :ARG0-of (u / use-01 :ARG1 (m5 / macrophage :ARG1-of (d / derive-01 :ARG2 (m / marrow :poss (b / bone))) :ARG1-of (i / isolate-01 :ARG2 (m2 / model :mod (m3 / mouse) :mod (s / spontaneity) :topic (m7 / medical-condition :name (n2 / name :op1 "ileitis") :ARG1-of (r2 / resemble-01 :ARG2 (d2 / disease :wiki "Crohn's_disease" :name (n / name :op1 "Crohn's")))) :ARG1-of (m6 / mean-01 :ARG2 (s5 / strain :name (n3 / name :op1 "SAMP1/YitFc")))))))) :ARG1 (i2 / inhibit-01 :ARG0 (s6 / small-molecule :name (n4 / name :op1 "CGP57380") :xref (x2 / xref :value "PUBCHEM:11644425" :prob "19.266134")) :ARG1 (a / and :op1 (c2 / cytokine :name (n5 / name :op1 "TNF") :ARG0-of (p2 / promote-01 :ARG1 (i3 / inflame-01))) :op2 (c3 / cytokine :name (n6 / name :op1 "IL-6") :ARG0-of p2) :op3 (p / protein :name (n7 / name :op1 "monocyte-chemoattractant-protein-1") :xref (x1 / xref :value "UNIPROT:CCL2_HUMAN" :prob "0.692")) :op4 (p3 / protein :name (n8 / name :op1 "monocyte-chemoattractant-protein-4") :xref (x / xref :value "UNIPROT:CCL13_HUMAN" :prob "0.692"))) :ARG1-of (s3 / significant-02)) :time (a2 / after :op1 (s4 / stimulate-01 :ARG0 (m4 / molecular-physical-entity :name (n9 / name :op1 "LPS") :xref (x3 / xref :value "PUBCHEM:53481794" :prob "9.905254"))) :quant (t2 / temporal-quantity :quant "24" :unit (h / hour)))) # ::id bel_pmid_1804_8363.10226 # ::date 2015-05-10T04:11:25 # ::file bel_pmid_1804_8363_10226.txt # ::snt Co-immunoprecipitation studies with H-Ras-transformed cells revealed that Spry2 and H-Ras interact and that H-Ras interacts with Spry2-binding partners, c-Cbl and CIN85, in a Spry2-dependent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / reveal-01 :ARG0 (s / study-01 :ARG1 (c / coimmunoprecipitate-01) :instrument (c2 / cell :ARG1-of (t / transform-01 :ARG0 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :ARG1 (a / and :op1 (i / interact-01 :ARG0 (p / protein :name (n2 / name :op1 "Spry2") :xref (x3 / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682")) :ARG1 e) :op2 (i2 / interact-01 :ARG0 e :ARG1 (a2 / and :op1 (p2 / partner :ARG2-of (b / bind-01 :ARG1 p) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (p4 / protein :name (n3 / name :op1 "c-Cbl") :xref (x2 / xref :value "UNIPROT:Q6LB30_HUMAN" :prob "0.601")) :op2 (p3 / protein :name (n4 / name :op1 "CIN85") :xref (x / xref :value "UNIPROT:SH3K1_HUMAN" :prob "1.002")))))) :ARG0-of (d / depend-01 :ARG1 p)))) # ::id bel_pmid_1804_8363.20908 # ::date 2015-05-10T04:23:06 # ::file bel_pmid_1804_8363_20908.txt # ::snt We compared human fibroblasts malignantly transformed by overexpression of H-Ras(V12) oncogene to their nontransformed parental cells and found that the malignant cells express a high level of Spry2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (c / compare-01 :ARG0 (w / we) :ARG1 (f / fibroblast :mod (h2 / human) :ARG1-of (t / transform-01 :ARG0 (o / overexpress-01 :ARG1 (g2 / gene :name (n / name :op1 "H-Ras") :ARG2-of (m2 / mutate-01 :value "V12") :ARG1-of (m / malignant-02) :ARG0-of (c4 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :ARG2 (c2 / cell :mod (p / parent) :ARG1-of (t2 / transform-01 :polarity "-") :poss f)) :op2 (f2 / find-01 :ARG1 (e / express-03 :ARG1 (c3 / cell :ARG1-of (m3 / malignant-02)) :ARG2 (l / level :ARG1-of (h / high-02) :quant-of (p2 / protein :name (n2 / name :op1 "Spry2") :xref (x1 / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682")))))) # ::id bel_pmid_1804_8363.30892 # ::date 2015-05-10T04:32:34 # ::file bel_pmid_1804_8363_30892.txt # ::snt When we decreased expression of Spry2, using a Spry2-specific shRNA, the H-Ras(V12)-transformed fibroblasts could no longer form large colonies in agarose, grow in reduced levels of serum, or form tumors in athymic mice. The level of active H-Ras in these cells remained unaltered. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m4 / multi-sentence :snt1 (o / or :op1 (p2 / possible-01 :ARG1 (f / form-01 :ARG0 (f2 / fibroblast :ARG1-of (t / transform-01 :ARG0 (e / enzyme :name (n2 / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))) :ARG1 (c / colony :mod (l / large)) :location (a4 / agarose))) :op2 (p / possible-01 :ARG1 (g / grow-01 :ARG0 f2 :location (l2 / level :quant-of (s / serum) :ARG1-of (r / reduce-01)))) :op3 (p3 / possible-01 :ARG1 (f3 / form-01 :ARG0 f2 :ARG1 (t2 / tumor) :location (m3 / mouse :mod (a / athymic)))) :time (d / decrease-01 :ARG0 (w / we) :ARG1 (e2 / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "Spry2") :xref (x / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682"))) :instrument (n3 / nucleic-acid :name (n6 / name :op1 "shRNA") :ARG1-of (s2 / specific-02 :ARG2 p4))) :time (n / no-longer)) :snt2 (r3 / remain-01 :ARG1 (l3 / level :quant-of (e3 / enzyme :name (n7 / name :op1 "H-Ras") :ARG0-of (a2 / activity-06) :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :ARG3 (a3 / alter-01 :polarity "-" :ARG1 l3) :location (c2 / cell :mod (t3 / this)))) # ::id bel_pmid_1806_0032.38560 # ::date 2015-05-10T04:49:29 # ::file bel_pmid_1806_0032_38560.txt # ::snt We next determined whether the ?EGFR-expressing MCF-10A cells produced high levels of IL-6, leading to activation of STAT3, as was observed in lung adenocarcinoma–derived cell lines harboring mutant EGFR. The ?EGFR–MCF-10A cells were treated with P6, gp130, and IL-6 blocking antibodies, which inhibited STAT3 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m2 / multi-sentence :snt1 (d / determine-01 :ARG0 (w / we) :ARG1 (p / produce-01 :mode "interrogative" :ARG0 (c2 / cell-line :name (n3 / name :op1 "MCF-10A") :ARG1-of (e2 / express-03 :ARG2 (e / enzyme :name (n2 / name :op1 "ΔEGFR") :xref (x6 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.693")))) :ARG1 (l / level :ARG1-of (h / high-02) :quant-of (p2 / protein :name (n4 / name :op1 "IL-6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG0-of (l2 / lead-03 :ARG1 (a / activate-01 :ARG1 (p3 / protein :name (n5 / name :op1 "STAT3") :xref (x5 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))))) :ARG2-of (r / resemble-01 :ARG1 (o / observe-01 :location (c / cell-line :ARG1-of (d2 / derive-01 :ARG2 (m3 / medical-condition :name (n6 / name :op1 "adenocarcinoma") :mod (l3 / lung))) :ARG0-of (h2 / harbor-01 :ARG1 (e4 / enzyme :name (n7 / name :op1 "EGFR") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))))) :time (n / next)) :snt2 (t / treat-04 :ARG1 (c3 / cell-line :name (n8 / name :op1 "MCF-10A") :ARG1-of (e5 / express-03 :ARG2 (e3 / enzyme :name (n9 / name :op1 "ΔEGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.693")))) :ARG2 (a2 / and :op1 (p4 / protein :name (n10 / name :op1 "P6") :xref (x7 / xref :value "UNIPROT:S10AC_HUMAN" :prob "0.652")) :op2 (p5 / protein :name (n11 / name :op1 "gp130") :xref (x8 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "1.003")) :op3 (a3 / antibody :ARG0-of (b / block-01 :ARG1 (p7 / protein :name (n13 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG0-of (i / inhibit-01 :ARG1 (a4 / activate-01 :ARG1 (p6 / protein :name (n12 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))))))) # ::id bel_pmid_1806_0035.1688 # ::date 2015-05-10T05:27:44 # ::file bel_pmid_1806_0035_1688.txt # ::snt In contrast, enhanced thrombopoietin signaling, conferred by enforced expression of constitutively active JAK2 or c-MPL, induced phosphorylation of STAT3 and STAT5, but not STAT1, and failed to rescue megakaryocyte maturation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (a2 / and :op1 (i / induce-01 :ARG0 (s / signal-07 :ARG1 (p2 / protein :name (n / name :op1 "thrombopoietin") :xref (x1 / xref :value "UNIPROT:TPO_HUMAN" :prob "0.702")) :ARG1-of (e / enhance-01) :ARG1-of (c2 / confer-02 :ARG0 (e2 / express-03 :ARG2 (o / or :op1 (e4 / enzyme :name (n2 / name :op1 "JAK2") :ARG0-of (a3 / activity-06 :mod (c5 / constitutive)) :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :op2 (p8 / protein :name (n3 / name :op1 "c-MPL") :xref (x5 / xref :value "UNIPROT:MATN1_HUMAN" :prob "0.202"))) :ARG1-of (e3 / enforce-01)))) :ARG2 (p / phosphorylate-01 :ARG1 (a / and :op1 (p3 / protein :name (n4 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (p4 / protein :name (n5 / name :op1 "STAT5") :xref (x3 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003"))) :ARG1-of (c3 / contrast-01 :ARG2 (i2 / induce-01 :polarity "-" :ARG0 s :ARG2 (p5 / phosphorylate-01 :ARG1 (p6 / protein :name (n6 / name :op1 "STAT1") :xref (x4 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))))))) :op2 (f / fail-01 :ARG0 s :ARG1 (r / rescue-01 :ARG0 s :ARG1 (m / maturate-03 :ARG1 (m2 / megakaryocyte)))))) # ::id bel_pmid_1806_0035.28492 # ::date 2015-05-10T05:39:08 # ::file bel_pmid_1806_0035_28492.txt # ::snt We show that ectopic expression of STAT1 or its downstream transcriptional target IRF-1 promotes features of megakaryocytic differentiation of G1ME cells, a Gata1-null erythromegakaryocytic cell line (25), # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s2 / show-01 :ARG0 (w / we) :ARG1 (p / promote-01 :ARG0 (o / or :op1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "STAT1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :mod (e2 / ectopic)) :op2 (p4 / protein :name (n2 / name :op1 "IRF-1") :poss p2 :location (d / downstream) :ARG0-of (t / transcribe-01) :ARG1-of (t2 / target-01) :xref (x1 / xref :value "UNIPROT:IRF1_HUMAN" :prob "1.002"))) :ARG1 (f / feature :topic (d2 / differentiate-01 :ARG0 (m5 / megakaryocyte) :ARG1 (c / cell-line :name (n4 / name :op1 "G1ME") :ARG1-of (m4 / mean-01 :ARG2 (c3 / cell-line :ARG3-of (e3 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "Gata1") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:GATA1_HUMAN" :prob "0.604"))) :mod (m2 / megakaryocyte) :mod (e4 / erythroid)))))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "25"))))) # ::id bel_pmid_1806_0035.31648 # ::date 2015-05-10T05:53:48 # ::file bel_pmid_1806_0035_31648.txt # ::snt In most cell types, STAT1 is primarily triggered by interferon signaling (21). However, TPO signaling phosphorylates STAT1 in WT megakaryocytes (10). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m2 / multi-sentence :snt1 (t / trigger-01 :ARG0 (s / signal-07 :ARG1 (p3 / protein :name (n2 / name :op1 "interferon") :xref (x / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.332"))) :ARG1 (p / protein :name (n / name :op1 "STAT1") :xref (x3 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :manner (p2 / primary) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "21"))) :location (c / cell :ARG1-of (t2 / type-03 :mod (m / most)))) :snt2 (h / have-concession-91 :ARG1 (p5 / phosphorylate-01 :ARG1 (p6 / protein :name (n4 / name :op1 "STAT1") :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG2 (s2 / signal-07 :ARG1 (p8 / protein :name (n3 / name :op1 "TPO") :xref (x2 / xref :value "UNIPROT:TPO_HUMAN" :prob "1.003"))) :location (m3 / megakaryocyte :mod (w / wild-type)) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 "10")))))) # ::id bel_pmid_1806_0035.33056 # ::date 2015-05-10T06:04:27 # ::file bel_pmid_1806_0035_33056.txt # ::snt Moreover, GATA-1 transactivated the Stat1 promoter in luciferase reporter assays (Supplemental Figure 1). STAT1 and IRF-1 reciprocally activated each other’s transcription, as previously reported (Figure ?(Figure1D1D and Supplemental Table 1; also reviewed in ref. 26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (a / and :op2 (t / transactivate-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Stat1") :xref (x2 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.604")))) :ARG2 (p / protein :name (n / name :op1 "GATA-1") :xref (x3 / xref :value "UNIPROT:GATA1_HUMAN" :prob "1.003")) :time (a2 / assay-01 :ARG0-of (r2 / report-01 :ARG1 (e / enzyme :name (n3 / name :op1 "luciferase")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1" :ARG2-of (s / supplement-01))))) :snt2 (a5 / and :op1 (a3 / activate-01 :ARG0 (p4 / protein :name (n4 / name :op1 "STAT1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG1 (t3 / transcribe-01 :ARG1 (p7 / protein :name (n5 / name :op1 "IRF-1") :xref (x1 / xref :value "UNIPROT:IRF1_HUMAN" :prob "1.002")))) :op2 (a4 / activate-01 :ARG0 p7 :ARG1 (t4 / transcribe-01 :ARG1 p4)) :ARG1-of (r3 / report-01 :time (p5 / previous)) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (f2 / figure :mod "1D") :op2 (t5 / table :mod "1" :ARG2-of (s2 / supplement-01)))) :ARG1-of (r / review-02 :ARG2 (p6 / publication :ARG1-of (c / cite-01 :ARG2 "26")) :mod (a7 / also)))) # ::id bel_pmid_1806_0035.33182 # ::date 2015-05-10T06:21:50 # ::file bel_pmid_1806_0035_33182.txt # ::snt In addition, STAT1 or IRF-1 induced the expression of CD42, a late marker of megakaryocyte maturation, albeit to a much lesser extent than GATA-1 (Figure ?(Figure1C).1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op2 (i / induce-01 :ARG0 (o / or :op1 (p / protein :name (n / name :op1 "STAT1") :xref (x3 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n2 / name :op1 "IRF-1") :xref (x1 / xref :value "UNIPROT:IRF1_HUMAN" :prob "1.002"))) :ARG2 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "CD42") :ARG0-of (m / mark-02 :ARG1 (m2 / maturate-03 :ARG1 (m4 / megakaryocyte))) :mod (l3 / late) :xref (x / xref :value "UNIPROT:GPIX_HUMAN" :prob "0.312")))) :concession (i2 / induce-01 :ARG0 o :ARG2 e :extent (l / less :degree (m3 / more :degree (m5 / much))) :compared-to (e2 / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "GATA-1") :xref (x2 / xref :value "UNIPROT:GATA1_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id bel_pmid_1806_0035.34122 # ::date 2015-05-10T06:32:34 # ::file bel_pmid_1806_0035_34122.txt # ::snt enforced STAT1 expression promoted several features of megakaryocytic differentiation of G1ME cells, as evidenced by increased cell size (forward scatter) and increased DNA content, reflecting polyploidization (Figure ?(Figure1,1, A and B). Similar effects were produced by enforced expression of IRF-1, a major STAT1 effector (reviewed in ref. 26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / multi-sentence :snt1 (p / promote-01 :ARG0 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "STAT1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG1-of (e2 / enforce-01)) :ARG1 (f / feature :quant (s / several) :topic (d / differentiate-01 :ARG0 (m3 / megakaryocyte) :ARG1 (c2 / cell-line :name (n3 / name :op1 "G1ME")))) :ARG1-of (e3 / evidence-01 :ARG0 (a2 / and :op1 (s2 / size :poss (c3 / cell) :ARG1-of (i / increase-01) :ARG1-of (s3 / show-01 :ARG0 (s4 / scatter-01 :direction (f4 / forward)))) :op2 (c4 / contain-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :ARG1-of (i2 / increase-01))))) :ARG1-of (r2 / reflect-01 :ARG2 (p3 / polyploidize-01)) :ARG1-of (d3 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "1.1.A") :op2 (f3 / figure :mod "1.1.B")))) :snt2 (p4 / produce-01 :ARG0 (e5 / express-03 :ARG2 (p6 / protein :name (n4 / name :op1 "IRF-1") :ARG0-of (a4 / affect-01 :ARG1 (p5 / protein :name (n5 / name :op1 "STAT1") :xref (x2 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG1-of (m2 / major-02)) :xref (x1 / xref :value "UNIPROT:IRF1_HUMAN" :prob "1.002")) :ARG1-of (e6 / enforce-01)) :ARG1 (a3 / affect-01 :ARG1-of (r3 / resemble-01)) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 "26"))))) # ::id bel_pmid_1806_0035.34154 # ::date 2015-05-10T06:49:57 # ::file bel_pmid_1806_0035_34154.txt # ::snt Second, mice deficient for both STAT5A and STAT5B are thrombocytopenic, likely due to a reduction in functional hematopoietic progenitors (18). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 10, 2015 (t / thrombocytopenic :domain (m / mouse :ARG0-of (l / lack-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "STAT1A") :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.333")) :op2 (g2 / gene :name (n2 / name :op1 "STAT1B") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "0.333"))))) :ARG1-of (c / cause-01 :ARG0 (r / reduce-01 :ARG1 (p / progenitor :mod (h / hematopoietic) :ARG0-of (f / function-01))) :ARG1-of (l2 / likely-01)) :mod (o / ordinal-entity :value "2") :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "18")))) # ::id bel_pmid_1806_0035.39068 # ::date 2015-05-10T07:07:40 # ::file bel_pmid_1806_0035_39068.txt # ::snt TPO functions through binding its receptor, c-Mpl, to activate JAK2, STAT1, STAT3, and STAT5 in megakaryocytes and other hematopoietic cells (10–12). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (f / function-01 :ARG0 (p5 / protein :name (n / name :op1 "TPO") :xref (x2 / xref :value "UNIPROT:TPO_HUMAN" :prob "1.003")) :instrument (b / bind-01 :ARG1 (p6 / protein :name (n7 / name :op1 "c-Mpl" :op2 "receptor") :poss p5) :ARG2 p5 :purpose (a / activate-01 :ARG0 p5 :ARG1 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "JAK2") :xref (x4 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :op2 (p / protein :name (n4 / name :op1 "STAT1") :xref (x3 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :op3 (p2 / protein :name (n5 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op4 (p3 / protein :name (n6 / name :op1 "STAT5") :xref (x1 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003"))) :location (a3 / and :op1 (m / megakaryocyte) :op2 (c2 / cell :mod (h / hematopoietic) :mod (o / other))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 "10" :op2 "12"))))) # ::id bel_pmid_1806_0035.39758 # ::date 2015-05-10T07:17:20 # ::file bel_pmid_1806_0035_39758.txt # ::snt enforced STAT1 expression promoted several features of megakaryocytic differentiation of G1ME cells, as evidenced by increased cell size (forward scatter) and increased DNA content, reflecting polyploidization (Figure ?(Figure1,1, A and B). Similar effects were produced by enforced expression of IRF-1, a major STAT1 effector (reviewed in ref. 26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / multi-sentence :snt1 (p / promote-01 :ARG0 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "STAT1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG1-of (e2 / enforce-01)) :ARG1 (f / feature :quant (s / several) :topic (d / differentiate-01 :ARG0 (m3 / megakaryocyte) :ARG1 (c2 / cell-line :name (n3 / name :op1 "G1ME")))) :ARG1-of (e3 / evidence-01 :ARG0 (a / and :op1 (s2 / size :poss (c3 / cell) :ARG1-of (i / increase-01) :ARG1-of (s3 / show-01 :ARG0 (s4 / scatter-01 :direction (f4 / forward)))) :op2 (c4 / contain-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :ARG1-of (i2 / increase-01))))) :ARG1-of (r2 / reflect-01 :ARG2 (p3 / polyploidize-01)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1.1.A") :op2 (f3 / figure :mod "1.1.B")))) :snt2 (p4 / produce-01 :ARG0 (e4 / express-03 :ARG2 (p6 / protein :name (n4 / name :op1 "IRF-1") :ARG0-of (a4 / affect-01 :ARG1 (p5 / protein :name (n5 / name :op1 "STAT1") :xref (x2 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG1-of (m2 / major-02)) :xref (x1 / xref :value "UNIPROT:IRF1_HUMAN" :prob "1.002")) :ARG1-of (e6 / enforce-01)) :ARG1 (a3 / affect-01 :ARG1-of (r3 / resemble-01)) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 "26"))))) # ::id bel_pmid_1807_7438.4108 # ::date 2015-05-08T07:50:45 # ::file bel_pmid_1807_7438_4108.txt # ::snt Although inhibitors of PKC had no effect on this suppression, MAPK inhibitors completely prevented the TPA effect. RasGRP1 activates the MAPK pathway through activation of the small G protein H-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (m / multi-sentence :snt1 (p / prevent-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / pathway :name (n / name :op1 "MAPK")))) :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "TPA") :xref (x4 / xref :value "PUBCHEM:27924" :prob "16.198082"))) :ARG1-of (c / complete-02) :concession (a2 / affect-01 :polarity "-" :ARG0 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PKC") :xref (x2 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")))) :ARG1 (s3 / suppress-01 :ARG1 a))) :snt2 (a3 / activate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "RasGRP1") :xref (x3 / xref :value "UNIPROT:GRP1_HUMAN" :prob "0.663")) :ARG1 (p4 / pathway :name (n5 / name :op1 "MAPK")) :manner (a4 / activate-01 :ARG0 p3 :ARG1 (e3 / enzyme :name (n7 / name :op1 "H-Ras") :mod (e4 / enzyme :name (n6 / name :op1 "small" :op2 "G" :op3 "protein") :xref (x / xref :value "UNIPROT:RAC2_HUMAN" :prob "0.703")) :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) # ::id bel_pmid_1807_7438.32114 # ::date 2015-05-08T08:04:50 # ::file bel_pmid_1807_7438_32114.txt # ::snt Functional assessment of NCC by using thiazide-sensitive (22)Na(+) uptakes revealed that TPA completely suppresses NCC function. Biotinylation experiments demonstrated that this result was primarily because of decreased surface expression of NCC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / multi-sentence :snt1 (r / reveal-01 :ARG0 (a / assess-01 :ARG1 "p2" :mod (f2 / function-01) :manner (u / use-01 :ARG1 (u2 / uptake :mod (s5 / small-molecule :name (n3 / name :op1 "22Na+") :xref (x4 / xref :value "PUBCHEM:23667643" :prob "18.86067")) :ARG1-of (s2 / sensitize-01 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "thiazide") :xref (x2 / xref :value "PUBCHEM:2720" :prob "18.86067")))))) :ARG1 (s / suppress-01 :ARG0 (s6 / small-molecule :name (n / name :op1 "TPA") :xref (x3 / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1 (f / function-01 :ARG0 (p2 / protein :name (n2 / name :op1 "NCC") :xref (x / xref :value "UNIPROT:S12A3_HUMAN" :prob "1.002"))) :ARG1-of (c / complete-02))) :snt2 (d / demonstrate-01 :ARG0 (e / experiment-01 :ARG1 (b / biotinylate-01)) :ARG1 (c2 / cause-01 :ARG0 (d2 / decrease-01 :ARG1 (e2 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "NCC") :xref (x1 / xref :value "UNIPROT:S12A3_HUMAN" :prob "1.002")) :ARG3 (s4 / surface))) :ARG1 (t / thing :ARG2-of (r2 / result-01) :mod (t2 / this)) :mod (p4 / primary)))) # ::id bel_pmid_1820_0061.27886 # ::date 2015-05-08T08:20:26 # ::file bel_pmid_1820_0061_27886.txt # ::snt Expression of all proinflammatory/profibrotic mediators as assessed by reverse transcriptase-PCR and densitometry was less in Lenti-IL-10-injected wounds compared with Lenti-GFP-injected wounds, with the difference in the expression of IL-6, MCP-1, and HSP47 reaching statistical significance (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a6 / and :op1 (e / express-03 :ARG2 (a / and :op1 (m2 / molecular-physical-entity :ARG0-of (f / favor-01 :ARG1 (i / inflame-01)) :ARG0-of (m / mediate-01)) :op2 (m3 / molecular-physical-entity :ARG0-of m :ARG0-of (f2 / favor-01 :ARG1 (f3 / fibrosis))) :mod (a2 / all)) :ARG3 (w / wound-01 :ARG2-of (i2 / inject-01 :ARG1 (p / protein :name (n / name :op1 "Lenti-IL-10")))) :mod (l / less) :compared-to (e5 / express-03 :ARG2 a :ARG3 (w2 / wound-01 :ARG2-of (i3 / inject-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Lenti-GFP"))))) :ARG1-of (a4 / assess-01 :instrument (a5 / and :op1 (r2 / react-01 :ARG0 (p6 / polymerase) :ARG1-of (c / chain-01) :mod (t2 / transcriptase :ARG1-of (r3 / reverse-01))) :op2 (d3 / densitometry)))) :op2 (r / reach-01 :ARG0 (d / differ-02 :ARG1 (a3 / and :op1 (e2 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op2 (e3 / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "MCP-1") :xref (x / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002"))) :op3 (e4 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "HSP47") :xref (x1 / xref :value "UNIPROT:SERPH_HUMAN" :prob "1.002"))))) :ARG1 (s3 / signify-01 :mod (s / statistics))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure :mod "5"))) # ::id bel_pmid_1826_8536.21638 # ::date 2015-05-08T08:36:28 # ::file bel_pmid_1826_8536_21638.txt # ::snt observations that inhibition of PI3K or EGF-R is sufficient to prevent terminal differentiation in keratinocytes in suspension (Rodeck et al., 1997; Nikolopoulos et al., 2005), and that function disrupting antibodies to E-cadherin abrogate Akt phosphorylation inducing growth arrest and terminal differentiation in conventional submerged mouse keratinocyte cultures at confluency (Calautti et al., 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (o / observe-02 :ARG1 (a / and :op1 (s / suffice-01 :ARG0 (i / inhibit-01 :ARG1 (o2 / or :op1 (e2 / enzyme :name (n2 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e / enzyme :name (n / name :op1 "EGF-R") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673")))) :ARG1 (p / prevent-01 :ARG0 i :ARG1 (d / differentiate-01 :ARG1 (c / cell :name (n3 / name :op1 "keratinocyte") :ARG1-of (s2 / suspend-02)) :mod (t / terminal))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p2 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n4 / name :op1 "Rodeck")) :op2 (p4 / person :mod (o3 / other))) :time (d7 / date-entity :year "1997")) :op2 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n5 / name :op1 "Nikolopoulos")) :op2 (p7 / person :mod (o4 / other))) :time "d6")))) :op2 (a5 / abrogate-01 :ARG0 (a6 / antibody :ARG0-of (d3 / disrupt-01 :ARG1 (f / function-01)) :ARG0-of (c2 / counter-01 :ARG1 (p8 / protein :name (n6 / name :op1 "E-cadherin") :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG1 (p9 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n7 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG0-of (i2 / induce-01 :ARG2 (a7 / and :op1 (a8 / arrest-02 :ARG1 (g / grow-01 :ARG1 "c3")) :op2 (d4 / differentiate-01 :ARG1 (c3 / culture :source (m / mouse) :mod c :ARG1-of (s3 / submerge-01 :manner (c4 / conventional))) :mod t)) :manner (c5 / confluency)) :ARG1-of (d5 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a9 / and :op1 (p11 / person :name (n8 / name :op1 "Calautti")) :op2 (p12 / person :mod (o5 / other))) :time (d6 / date-entity :year "2005")))))) # ::id bel_pmid_1826_8536.21660 # ::date 2015-05-08T08:55:37 # ::file bel_pmid_1826_8536_21660.txt # ::snt In vivo, b4-integrin amplifies proproliferative signals in basal epidermal keratinocytes (Nikolopoulos et al., 2005), where STAT3 is expressed and can be activated by EGF/EGF-R (Nishio et al., 2001; Chan et al., 2004; Li et al., 2007) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / amplify-01 :ARG0 (p / protein :name (n / name :op1 "b4-integrin") :xref (x3 / xref :value "UNIPROT:IF6_HUMAN" :prob "0.242")) :ARG1 (s / signal-07 :mod (p2 / proliferate-01)) :location (c / cell :name (n2 / name :op1 "keratinocyte") :mod (b / basal) :part-of (e / epidermis) :ARG3-of (e2 / express-03 :ARG2 (p6 / protein :name (n4 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :location-of (p7 / possible-01 :ARG1 (a3 / activate-01 :ARG0 (s3 / slash :op1 (p17 / protein :name (n5 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n6 / name :op1 "EGF-R") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673"))) :ARG1 p6) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (p8 / publication-91 :ARG0 (a6 / and :op1 (p9 / person :name (n7 / name :op1 "Nishio")) :op2 (p10 / person :mod (o2 / other))) :time (d3 / date-entity :year "2001")) :op2 (p11 / publication-91 :ARG0 (a7 / and :op1 (p12 / person :name (n8 / name :op1 "Chan")) :op2 (p13 / person :mod (o3 / other))) :time (d4 / date-entity :year "2004")) :op3 (p14 / publication-91 :ARG0 (a8 / and :op1 (p15 / person :name (n9 / name :op1 "Li")) :op2 (p16 / person :mod (o4 / other))) :time (d5 / date-entity :year "2007")))))) :manner (i / in-vivo) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n3 / name :op1 "Nikolopoulos")) :op2 (p5 / person :mod (o / other))) :time (d6 / date-entity :year "2005")))) # ::id bel_pmid_1826_8536.22176 # ::date 2015-05-08T09:08:29 # ::file bel_pmid_1826_8536_22176.txt # ::snt Src-family kinases then phosphorylate the plaque proteins b-catenin, plakoglobin, p120cnt, and acatenin, which is required for their association with the E-cadherin tail (Calautti et al., 1998, 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "b-catenin") :xref (x / xref :value "UNIPROT:ODB2_HUMAN" :prob "0.202")) :op2 (p3 / protein :name (n3 / name :op1 "plakoglobin")) :op3 (p4 / protein :name (n4 / name :op1 "p120cnt") :xref (x2 / xref :value "UNIPROT:BRD8_HUMAN" :prob "0.262")) :op4 (p5 / protein :name (n5 / name :op1 "acatenin") :xref (x3 / xref :value "UNIPROT:ACATN_HUMAN" :prob "0.222")) :part-of (p6 / plaque)) :ARG2 (k / kinase :ARG1-of (i / include-91 :ARG2 (p13 / protein-family :name (n / name :op1 "Src")))) :time (t / then) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (p9 / publication-91 :ARG0 (a3 / and :op1 (p10 / person :name (n7 / name :op1 "Calautti")) :op2 (p11 / person :mod (o / other))) :time (d2 / date-entity :year "1998")) :op2 (p12 / publication-91 :ARG0 a3 :time (d3 / date-entity :year "2005")))) :ARG1-of (r / require-01 :purpose (a2 / associate-01 :ARG1 a :ARG2 (p7 / protein-segment :part-of (p8 / protein :name (n6 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))))) # ::id bel_pmid_1826_8536.22182 # ::date 2015-05-10T13:33:31 # ::file bel_pmid_1826_8536_22182.txt # ::snt JNK2 might potentially be activated via Src kinasemediated phosphorylation of EGF-R on Tyr920 (Calautti et al., 2005), # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 13, 2015 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "920" :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n4 / name :op1 "EGF-R") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (m / mediate-01 :ARG0 (k / kinase :name (n2 / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")))) :ARG1 (e / enzyme :name (n / name :op1 "JNK2") :xref (x / xref :value "UNIPROT:MK09_HUMAN" :prob "1.003"))) :manner (p3 / potential) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and :op1 (p6 / person :name (n5 / name :op1 "Calautti")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "2005")))) # ::id bel_pmid_1826_8536.22186 # ::date 2015-05-10T13:43:09 # ::file bel_pmid_1826_8536_22186.txt # ::snt b1-integrin phosphorylation by Src results in EGF-R activation (Miranti and Brugge, 2002), and b1-integrin expression is required for the initiation of mouse mammary tumors expressing the polyoma virus middle T antigen (White et al., 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 13, 2015 (a / and :op1 (r / result-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "b1-integrin")) :ARG2 (p10 / protein :name (n2 / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) :ARG2 (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "EGF-R") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673"))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n4 / name :op1 "Miranti")) :op2 (p5 / person :name (n5 / name :op1 "Brugge"))) :time (d / date-entity :year "2002")))) :op2 (r2 / require-01 :ARG0 (i / initiate-01 :ARG1 (t / tumor :mod (m / mammary) :location (m2 / mouse) :ARG3-of (e3 / express-03 :ARG2 (p6 / protein :name (n6 / name :op1 "polyoma" :op2 "virus" :op3 "middle" :op4 "T" :op5 "antigen") :xref (x1 / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.212"))))) :ARG1 (e2 / express-03 :ARG2 p2) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n7 / name :op1 "White")) :op2 (p9 / person :mod (o / other))) :time (d2 / date-entity :year "2004"))))) # ::id bel_pmid_1826_8536.25888 # ::date 2015-05-10T13:50:50 # ::file bel_pmid_1826_8536_25888.txt # ::snt E-cadherin gene deletion, which results in some hyperproliferation in the epidermis (Young et al., 2003; Tinkle et al., 2004; Tunggal et al., 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d6 / delete-01 :ARG1 (g / gene :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG1-of (r / result-01 :ARG2 (p11 / proliferate-01 :location (e2 / epidermis) :mod (s / some) :degree (h / hyper))) :ARG1-of (d5 / describe-01 :ARG0 (a / and :op1 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n2 / name :op1 "Young")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2003")) :op2 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n3 / name :op1 "Tinkle")) :op2 (p7 / person :mod (o2 / other))) :time (d2 / date-entity :year "2004")) :op3 (p8 / publication-91 :ARG0 (a4 / and :op1 (p9 / person :name (n4 / name :op1 "Tunggal")) :op2 (p10 / person :mod (o3 / other))) :time (d3 / date-entity :year "2005"))))) # ::id bel_pmid_1826_8536.25890 # ::date 2015-05-10T13:56:10 # ::file bel_pmid_1826_8536_25890.txt # ::snt E-cadherinknockout epidermis displays some hyperproliferation, which however appears to be limited due to compensatory upregulation of P-cadherin (Young et al., 2003; Tinkle et al., 2004; Tunggal et al., 2005) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c2 / contrast-01 :ARG1 (d4 / display-01 :ARG0 (e / epidermis :mod (p / protein :wiki "CDH1_(gene)" :name (n / name :op1 "E-cadherin") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG1 (p12 / proliferate-01 :mod (s / some) :degree (h / hyper))) :ARG2 (a / appear-02 :ARG1 (p13 / proliferate-01 :ARG1-of (l / limit-01 :ARG0 (u / upregulate-01 :ARG1 (p2 / protein :wiki "CDH3_(gene)" :name (n2 / name :op1 "P-cadherin") :xref (x / xref :value "UNIPROT:CADH3_HUMAN" :prob "1.002")) :ARG0-of (c / compensate-01))) :degree h)) :ARG1-of (d5 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :wiki "-" :name (n3 / name :op1 "Young")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2003")) :op2 (p6 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :wiki "-" :name (n4 / name :op1 "Tinkle")) :op2 (p8 / person :mod (o2 / other))) :time (d2 / date-entity :year "2004")) :op3 (p9 / publication-91 :ARG0 (a5 / and :op1 (p10 / person :wiki "-" :name (n5 / name :op1 "Tunggal")) :op2 (p11 / person :mod (o3 / other))) :time (d3 / date-entity :year "2005"))))) # ::id bel_pmid_1826_8536.25892 # ::date 2015-05-10T14:08:54 # ::file bel_pmid_1826_8536_25892.txt # ::snt Recently reported in A431 cells, this can occur through E-cadherin-mediated inhibition of transphosphorylation on Tyr845EGF-R (Perrais et al., 2007), the site, which catalyzes EGF-induced mitogenesis (Ishizawar and Parsons, 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (p / possible-01 :ARG1 (t / this :ARG1-of (r / report-01 :time (r2 / recent) :location (c2 / cell-line :name (n8 / name :op1 "A431")))) :manner (i / inhibit-01 :ARG1 (t2 / transphosphorylate-01 :ARG1 (a3 / amino-acid :mod "845" :name (n3 / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "EGF-R") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673")) :ARG0-of (c / catalyze-01 :ARG1 (m2 / mitogenesis :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a / and :op1 (p6 / person :name (n5 / name :op1 "Ishizawar")) :op2 (p7 / person :name (n6 / name :op1 "Parsons"))) :time (d2 / date-entity :year "2004")))) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG1-of (d4 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a2 / and :op1 (p9 / person :name (n7 / name :op1 "Perrais")) :op2 (p10 / person :mod (o2 / other))) :time (d / date-entity :year "2007")))) # ::id bel_pmid_1826_8536.26244 # ::date 2015-05-10T21:25:06 # ::file bel_pmid_1826_8536_26244.txt # ::snt In mouse keratinocytes, Src kinase-mediated phosphorylation was found to generate a docking site for PI3K (p85) on plakoglobin in an EGF-R-dependent manner, to a minor extent on p120cnt, but not on b-catenin, which apparently lacks a PI3K (p85)-docking motive (Calautti et al., 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 13, 2015 (f / find-01 :ARG1 (g / generate-01 :ARG0 (p / phosphorylate-01 :ARG1-of (m2 / mediate-01 :ARG0 (k / kinase :name (n2 / name :op1 "Src") :xref (x4 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")))) :ARG1 (s / site :ARG2-of (d2 / dock-01 :ARG1 (p2 / protein-segment :name (n4 / name :op1 "p85") :part-of (e / enzyme :name (n3 / name :op1 "PI3K") :xref (x2 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :location (a / and :op1 (p3 / protein :name (n5 / name :op1 "plakoglobin")) :op2 (p5 / protein :name (n7 / name :op1 "p120cnt") :extent (m3 / minor) :xref (x3 / xref :value "UNIPROT:BRD8_HUMAN" :prob "0.262")) :ARG1-of (c2 / contrast-01 :ARG2 (p6 / protein :name (n8 / name :op1 "b-catenin") :ARG0-of (l / lack-01 :ARG1 (m4 / motive :ARG2-of d2) :ARG1-of (a2 / appear-02)) :xref (x / xref :value "UNIPROT:ODB2_HUMAN" :prob "0.202"))))) :manner (d3 / depend-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "EGF-R") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673")))) :location (c / cell :name (n / name :op1 "keratinocyte") :source (m / mouse)) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a3 / and :op1 (p8 / person :name (n9 / name :op1 "Calautti")) :op2 (p9 / person :mod (o / other))) :time (d / date-entity :year "2005")))) # ::id bel_pmid_1826_8536.28578 # ::date 2015-05-10T21:44:21 # ::file bel_pmid_1826_8536_28578.txt # ::snt Transgenic mice (both newborn and adult) expressing the signalingdefective b4-integrin mutant showed a twofold decrease in the epidermal proliferative index, confirming that b4-integrin actually contributes to proliferation (Nikolopoulos et al., 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (a4 / and :op1 (m / mouse :mod (t / transgenic) :ARG1-of (b / bear-02 :time (n / new-01)) :ARG3-of (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "b4-integrin") :ARG2-of (m2 / mutate-01) :ARG0-of (d2 / defect-01 :ARG1 (s2 / signal-07)) :xref (x / xref :value "UNIPROT:IF6_HUMAN" :prob "0.242")))) :op2 (m3 / mouse :mod t :mod (a / adult) :ARG3-of e)) :ARG1 (d3 / decrease-01 :ARG1 (i / index :mod (p3 / proliferate-01 :ARG0 (e2 / epidermis))) :ARG2 (p2 / product-of :op1 "2")) :ARG0-of (c / confirm-01 :ARG1 (c2 / contribute-01 :ARG0 p :ARG2 p3 :ARG1-of (a2 / actual-02))) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n3 / name :op1 "Nikolopoulos")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "2005")))) # ::id bel_pmid_1826_8536.28582 # ::date 2015-05-10T21:51:36 # ::file bel_pmid_1826_8536_28582.txt # ::snt b4-integrin mediates the phosphorylation of ErbB2 on Tyr877 by a Src-family kinase....(Ishizawar and Parsons, 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / mediate-01 :ARG0 (p2 / protein :name (n / name :op1 "b4-integrin") :xref (x / xref :value "UNIPROT:IF6_HUMAN" :prob "0.242")) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "877" :name (n2 / name :op1 "tyrosine") :part-of (p4 / protein :name (n3 / name :op1 "ErbB2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.634")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (k / kinase :ARG1-of (i / include-91 :ARG2 (p3 / protein-family :name (n4 / name :op1 "Src"))))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a / and :op1 (p6 / person :name (n5 / name :op1 "Ishizawar")) :op2 (p7 / person :name (n6 / name :op1 "Parsons"))) :time (d / date-entity :year "2004")))) # ::id bel_pmid_1826_8536.28586 # ::date 2015-05-10T21:54:53 # ::file bel_pmid_1826_8536_28586.txt # ::snt In parallel to JNK, two other MAPKs, ERK1 and ERK2, were also found to be targeted to the nucleus in a b4-integrindependent manner in keratinocytes (Nikolopoulos et al., 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (t / target-01 :ARG0 (n4 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8")) :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1-of (i / include-91 :ARG2 (p6 / protein-family :name (n3 / name :op1 "MAPK"))) :ARG0-of (p2 / parallel-01 :ARG1 (e4 / enzyme :name (n7 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")))) :manner (d2 / depend-01 :ARG1 (p / protein :name (n5 / name :op1 "b4-integrin") :xref (x3 / xref :value "UNIPROT:IF6_HUMAN" :prob "0.242"))) :location (c / cell :name (n6 / name :op1 "keratinocyte"))) :mod (a2 / also) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n8 / name :op1 "Nikolopoulos")) :op2 (p5 / person :mod (o2 / other))) :time (d / date-entity :year "2005")))) # ::id bel_pmid_1826_8536.28670 # ::date 2015-05-10T22:01:58 # ::file bel_pmid_1826_8536_28670.txt # ::snt plakoglobin-mediated suppression of the pro-proliferative proto-oncogene c-Myc, which is critical for growth inhibition in these cells (Arnold and Watt, 2001; Waikel et al., 2001; Kolly et al., 2005; Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / critical-02 :ARG1 (s / suppress-01 :ARG1 (g2 / gene :name (n2 / name :op1 "c-Myc") :ARG0-of (f / favor-01 :ARG1 (p2 / proliferate-01)) :mod (p3 / proto) :ARG0-of (c3 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.661")) :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n / name :op1 "plakoglobin")))) :ARG3 (i / inhibit-01 :ARG1 (g / grow-01) :location (c2 / cell :mod (t / this))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (p4 / publication-91 :ARG0 (a2 / and :op1 (p7 / person :name (n3 / name :op1 "Arnold")) :op2 (p8 / person :name (n4 / name :op1 "Watt"))) :time (d / date-entity :year "2001")) :op2 (p5 / publication-91 :ARG0 (a3 / and :op1 (p9 / person :name (n5 / name :op1 "Waikel")) :op2 (p10 / person :mod (o2 / other))) :time d) :op3 (p6 / publication-91 :ARG0 (a4 / and :op1 (p11 / person :name (n6 / name :op1 "Kolly")) :op2 (p12 / person :mod (o3 / other))) :time (d3 / date-entity :year "2005")) :op4 (f2 / figure :mod "2")))) # ::id bel_pmid_1826_8536.29114 # ::date 2015-05-10T22:08:43 # ::file bel_pmid_1826_8536_29114.txt # ::snt JNK2 was found to be necessary for cell-cycle arrest in keratinocytes, as exemplified by hyperproliferation of JNK2-knockout epidermis (Sabapathy and Wagner, 2004; Weston et al., 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (f / find-01 :ARG1 (n3 / need-01 :ARG0 (a / arrest-02 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :location (c3 / cell :name (n4 / name :op1 "keratinocyte"))) :ARG1 (e / enzyme :name (n2 / name :op1 "JNK2") :xref (x1 / xref :value "UNIPROT:MK09_HUMAN" :prob "1.003"))) :example (p7 / proliferate-01 :ARG0 (e3 / epidermis :mod (e4 / enzyme :name (n5 / name :op1 "JNK2") :ARG1-of (k / knock-out-03) :xref (x / xref :value "UNIPROT:MK09_HUMAN" :prob "1.003"))) :degree (h / hyper)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n / name :op1 "Sabapathy")) :op2 (p3 / person :name (n6 / name :op1 "Wagner"))) :time (d / date-entity :year "2004")) :op2 (p4 / publication-91 :ARG0 (a4 / and :op1 (p5 / person :name (n7 / name :op1 "Weston")) :op2 (p6 / person :mod (o / other))) :time d)))) # ::id bel_pmid_1826_8536.32064 # ::date 2015-05-10T22:16:59 # ::file bel_pmid_1826_8536_32064.txt # ::snt In mouse keratinocytes, it was however shown to result in Src kinase-mediated phosphorylation of EGF-R, presumably on Tyr920 (Calautti et al., 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 13, 2015 (c / contrast-01 :ARG2 (s / show-01 :ARG1 (r / result-01 :ARG1 (i / it) :ARG2 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "920" :name (n2 / name :op1 "tyrosine") :ARG1-of (p3 / presume-01) :part-of (e / enzyme :name (n3 / name :op1 "EGF-R") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (m / mediate-01 :ARG0 (k / kinase :name (n / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))))) :location (c2 / cell :name (n5 / name :op1 "keratinocyte") :source (m2 / mouse))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a / and :op1 (p6 / person :name (n4 / name :op1 "Calautti")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "2005")))) # ::id bel_pmid_1826_8536.36030 # ::date 2015-05-10T22:21:42 # ::file bel_pmid_1826_8536_36030.txt # ::snt In human HaCaT keratinocytes for instance, ERK1/2 phosphorylation increases in dependence of EGF-R recruitment to transadhering E-cadherin, and E-cadherin-mediated activation of MAPK was also reported in intestinal epithelial cells (Pece and Gutkind, 2000; Laprise et al., 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (a / and :op1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (s / slash :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :ARG0-of (d3 / depend-01 :ARG1 (r / recruit-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "EGF-R") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673")) :ARG2 (p3 / protein :name (n5 / name :op1 "E-cadherin") :ARG0-of (t / transadhere-00) :xref (x4 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :location (c / cell-line :name (n6 / name :op1 "HaCaT") :ARG0-of (e / exemplify-01) :mod (h / human) :part-of (c3 / cell :name (n10 / name :op1 "keratinocyte")))) :op2 (r2 / report-01 :ARG1 (a4 / activate-01 :ARG1 (e6 / enzyme :name (n / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1-of (m / mediate-01 :ARG0 p3)) :mod (a3 / also) :location (c2 / cell :part-of (e5 / epithelium :part-of (i2 / intestine)))) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and :op1 (p4 / publication-91 :ARG0 (a6 / and :op1 (p5 / person :name (n7 / name :op1 "Pece")) :op2 (p6 / person :name (n8 / name :op1 "Gutkind"))) :time (d / date-entity :year "2000")) :op2 (p7 / publication-91 :ARG0 (a7 / and :op1 (p8 / person :name (n9 / name :op1 "Laprise")) :op2 (p9 / person :mod (o / other))) :time (d2 / date-entity :year "2004"))))) # ::id bel_pmid_1828_5820.25080 # ::date 2015-05-10T22:29:47 # ::file bel_pmid_1828_5820_25080.txt # ::snt Similar to AlkB, ABH2 and ABH3 have the ability to repair 1meA and 3meC residues. However, whereas ABH2 prefers double-stranded DNA, ABH3 and AlkB favour single-stranded DNA and RNA (Aas et al, 2003; Falnes et al, 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 28, 2015 (m / multi-sentence :snt1 (c / capable-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "ABH2") :xref (x5 / xref :value "UNIPROT:ALKB2_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "ABH3") :xref (x1 / xref :value "UNIPROT:ALKB3_HUMAN" :prob "1.002")) :ARG1-of (r3 / resemble-01 :ARG2 (p5 / protein :name (n5 / name :op1 "AlkB") :xref (x4 / xref :value "UNIPROT:ALKB1_HUMAN" :prob "0.232")))) :ARG2 (r2 / repair-01 :ARG0 a :ARG1 (a2 / and :op1 (p3 / protein-segment :name (n3 / name :op1 "1meA")) :op2 (p4 / protein-segment :name (n4 / name :op1 "3meC"))))) :snt2 (h / have-concession-91 :ARG1 (c2 / contrast-01 :ARG1 (p6 / prefer-01 :ARG0 (p7 / protein :name (n6 / name :op1 "ABH2") :xref (x2 / xref :value "UNIPROT:ALKB2_HUMAN" :prob "1.002")) :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n13 / name :op1 "DNA") :mod (s3 / strand :mod (d4 / double)))) :ARG2 (f / favor-01 :ARG0 (a3 / and :op1 (p8 / protein :name (n7 / name :op1 "ABH3") :xref (x3 / xref :value "UNIPROT:ALKB3_HUMAN" :prob "1.002")) :op2 (p9 / protein :name (n8 / name :op1 "AlkB") :xref (x / xref :value "UNIPROT:ALKB1_HUMAN" :prob "0.232"))) :ARG1 (a4 / and :op1 (n14 / nucleic-acid :wiki "DNA" :name (n15 / name :op1 "DNA") :mod (s / strand :ARG1-of (s2 / single-02))) :op2 (n16 / nucleic-acid :name (n11 / name :op1 "RNA") :mod s))) :ARG1-of (d6 / describe-01 :ARG0 (a5 / and :op1 (p10 / publication-91 :ARG0 (a6 / and :op1 (p11 / person :name (n9 / name :op1 "Aas")) :op2 (p12 / person :mod (o / other))) :time (d / date-entity :year "2003")) :op2 (p13 / publication-91 :ARG0 (a7 / and :op1 (p14 / person :name (n10 / name :op1 "Falnes")) :op2 (p15 / person :mod (o2 / other))) :time (d2 / date-entity :year "2004"))))))) # ::id bel_pmid_1828_5820.25550 # ::date 2015-05-10T22:41:07 # ::file bel_pmid_1828_5820_25550.txt # ::snt A targeted Brca1-null mutation to the T-cell lineage resulted in increased genomic instability, apoptosis, cell-cycle arrest, and a drastic depletion of the T-cell lineage (Mak et al, 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (m / mutate-01 :mod "-/-" :ARG1 (p / protein :name (n / name :op1 "Brca1") :part-of (c / cell :name (n2 / name :op1 "T-cell")) :xref (x / xref :value "UNIPROT:BRCA1_HUMAN" :prob "0.603")) :ARG1-of (t / target-01)) :ARG2 (a / and :op1 (i / increase-01 :ARG1 (i2 / instability :mod (g / genome))) :op2 (a2 / apoptosis) :op3 (a3 / arrest-02 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell))) :op4 (d2 / deplete-01 :ARG2 c :degree (d3 / drastic))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a4 / and :op1 (p3 / person :name (n3 / name :op1 "Mak")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2000")))) # ::id bel_pmid_1828_5820.25554 # ::date 2015-05-10T22:48:13 # ::file bel_pmid_1828_5820_25554.txt # ::snt null mutations for Brca2 result in early mouse embryonic lethality and impaired HR (Ludwig et al, 1997; Suzuki et al, 1997; Moynahan et al, 2001). Furthermore, loss of Brca2 in murine cells resulted in increased genomic instability and activation of p53. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (r / result-01 :ARG1 (m2 / mutate-01 :mod "-/-" :ARG1 (p / protein :name (n / name :op1 "Brca2") :xref (x1 / xref :value "UNIPROT:BRCA2_HUMAN" :prob "0.603"))) :ARG2 (a / and :op1 (d2 / die-01 :ARG1 (e / embryo :mod (m3 / mouse)) :time (e2 / early)) :op2 (i / impair-01 :ARG1 (t / thing :name (n2 / name :op1 "HR")))) :ARG1-of (d4 / describe-01 :ARG0 (a2 / and :op1 (p2 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n3 / name :op1 "Ludwig")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "1997")) :op2 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n4 / name :op1 "Suzuki")) :op2 (p7 / person :mod (o2 / other))) :time d) :op3 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n5 / name :op1 "Moynahan")) :op2 (p10 / person :mod (o3 / other))) :time (d3 / date-entity :year "2001"))))) :snt2 (a6 / and :op2 (r2 / result-01 :ARG1 (l / lose-02 :ARG1 (p11 / protein :name (n6 / name :op1 "Brca2") :xref (x / xref :value "UNIPROT:BRCA2_HUMAN" :prob "0.603")) :location (c / cell :part-of (o4 / organism :name (n8 / name :op1 "Murinae")))) :ARG2 (a7 / and :op1 (i2 / increase-01 :ARG1 (i3 / instability :mod (g / genome))) :op2 (a8 / activate-01 :ARG1 (p12 / protein :name (n7 / name :op1 "p53") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))))))) # ::id bel_pmid_1828_5820.25556 # ::date 2015-05-10T22:58:30 # ::file bel_pmid_1828_5820_25556.txt # ::snt BRCA2 functions in the loading of the HR protein RAD51 during filament formation. It directly binds to RAD51 and its phosphorylation on Ser3291 inhibits this binding (Esashi et al, 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (m / multi-sentence :snt1 (f / function-01 :ARG0 (p2 / protein :name (n / name :op1 "BRCA2") :xref (x / xref :value "UNIPROT:BRCA2_HUMAN" :prob "1.003")) :ARG1 (l / load-01 :ARG2 (p3 / protein :name (n2 / name :op1 "RAD51") :ARG0-of (c / cause-01 :ARG1 (t / thing :name (n3 / name :op1 "HR"))) :xref (x1 / xref :value "UNIPROT:RAD51_HUMAN" :prob "1.003"))) :time (f2 / form-01 :ARG1 (f3 / filament))) :snt2 (a / and :op1 (b / bind-01 :ARG1 (i2 / it) :ARG2 (p5 / protein :name (n5 / name :op1 "RAD51") :xref (x2 / xref :value "UNIPROT:RAD51_HUMAN" :prob "1.003")) :ARG1-of (d2 / direct-02)) :op2 (i / inhibit-01 :ARG0 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "3291" :name (n6 / name :op1 "serine") :part-of i2 :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 b) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a2 / and :op1 (p8 / person :name (n7 / name :op1 "Esashi")) :op2 (p9 / person :mod (o / other))) :time (d / date-entity :year "2005"))))) # ::id bel_pmid_1828_5820.28866 # ::date 2015-05-10T23:11:39 # ::file bel_pmid_1828_5820_28866.txt # ::snt The death of mutants such as Xrcc1/, LigIII/ and Polb/ was preceded by elevated levels of apoptosis (Gu et al, 1994; Tebbs et al, 1999; Sugo et al, 2000; Puebla-Osorio et al, 2006). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 13, 2015 (p / precede-01 :ARG1 (l / level :ARG1-of (e / elevate-01) :degree-of (a2 / apoptosis)) :ARG2 (d5 / die-01 :ARG1 (p2 / protein :ARG2-of (m / mutate-01) :example (a / and :op1 (p3 / protein :name (n / name :op1 "Xrcc1") :xref (x / xref :value "UNIPROT:XRCC1_HUMAN" :prob "0.603")) :op2 (p4 / protein :name (n2 / name :op1 "LigIII")) :op3 (p5 / protein :name (n3 / name :op1 "Polb") :xref (x1 / xref :value "UNIPROT:DPOLB_HUMAN" :prob "0.602"))))) :ARG1-of (d6 / describe-01 :ARG0 (a3 / and :op1 (p6 / publication-91 :ARG0 (a4 / and :op1 (p10 / person :name (n4 / name :op1 "Gu")) :op2 (p11 / person :mod (o / other))) :time (d / date-entity :year "1994")) :op2 (p7 / publication-91 :ARG0 (a5 / and :op1 (p12 / person :name (n5 / name :op1 "Tebbs")) :op2 (p13 / person :mod (o2 / other))) :time (d2 / date-entity :year "1999")) :op3 (p8 / publication-91 :ARG0 (a6 / and :op1 (p14 / person :name (n6 / name :op1 "Sugo")) :op2 (p15 / person :mod (o3 / other))) :time (d3 / date-entity :year "2000")) :op4 (p9 / publication-91 :ARG0 (a7 / and :op1 (p16 / person :name (n7 / name :op1 "Puebla-Osorio")) :op2 (p17 / person :mod (o4 / other))) :time (d4 / date-entity :year "2006"))))) # ::id bel_pmid_1828_5820.29340 # ::date 2015-05-10T23:19:38 # ::file bel_pmid_1828_5820_29340.txt # ::snt (McPherson et al, 2004a). Heterozygous and homozygous Mus81 mutants show cancer predisposition, particularly to T- and B-cell lymphomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (a / and :op1 (e / enzyme :name (n2 / name :op1 "Mus81") :ARG2-of (m / mutate-01) :mod (h / heterozygous) :xref (x1 / xref :value "UNIPROT:MUS81_HUMAN" :prob "0.633")) :op2 (e2 / enzyme :name (n3 / name :op1 "Mus81") :ARG2-of m :mod (h2 / homozygous) :xref (x / xref :value "UNIPROT:MUS81_HUMAN" :prob "0.633"))) :ARG1 (a2 / and :op1 (p / predispose-01 :ARG1 a :ARG2 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :op2 (p2 / predispose-01 :ARG1 a :ARG2 (a3 / and :op1 (l / lymphoma :mod (c2 / cell :name (n4 / name :op1 "T-cell"))) :op2 (l2 / lymphoma :mod (c3 / cell :name (n5 / name :op1 "B-cell")))) :mod (p6 / particular))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :li "a" :ARG0 (a4 / and :op1 (p4 / person :name (n6 / name :op1 "McPherson")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2004")))) # ::id bel_pmid_1828_5820.29342 # ::date 2015-05-10T23:27:51 # ::file bel_pmid_1828_5820_29342.txt # ::snt after a long latency, Ung/ and Mutyh/ mice developed B-cell lymphomas and intestinal tumors, respectively (Nilsen et al, 2003; Sakamoto et al, 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (d3 / develop-01 :ARG1 (m / mouse :mod (g / gene :name (n / name :op1 "Ung") :xref (x1 / xref :value "UNIPROT:UNG_HUMAN" :prob "0.603"))) :ARG2 (l / lymphoma :mod (c / cell :name (n3 / name :op1 "B-cell")))) :op2 (d4 / develop-01 :ARG1 (m2 / mouse :mod (g2 / gene :name (n2 / name :op1 "Mutyh") :xref (x / xref :value "UNIPROT:MUTYH_HUMAN" :prob "0.603"))) :ARG2 (t / tumor :mod (i / intestine))) :manner (r / respective) :time (a2 / after :op1 (l2 / latency :ARG1-of (l3 / long-03))) :ARG1-of (d5 / describe-01 :ARG0 (a3 / and :op1 (p / publication-91 :ARG0 (a4 / and :op1 (p3 / person :name (n4 / name :op1 "Nilsen")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2003")) :op2 (p2 / publication-91 :ARG0 (a5 / and :op1 (p5 / person :name (n5 / name :op1 "Sakamoto")) :op2 (p6 / person :mod (o2 / other))) :time (d2 / date-entity :year "2007"))))) # ::id bel_pmid_1828_5820.31706 # ::date 2015-05-10T23:34:11 # ::file bel_pmid_1828_5820_31706.txt # ::snt Increased apoptosis and proliferative arrest of pro-B cells in Ku80/ mice were rescued by a p53-null background (Difilippantonio et al, 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (r / rescue-01 :ARG0 (b / background :mod (p3 / protein :name (n3 / name :op1 "p53") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG1 (a / and :op1 (a2 / apoptosis :ARG1-of (i / increase-01)) :op2 (a3 / arrest-02 :ARG1 (c / cell :name (n / name :op1 "B") :part-of (m / mouse :mod (p2 / protein :name (n2 / name :op1 "Ku80") :xref (x / xref :value "UNIPROT:XRCC5_HUMAN" :prob "1.002"))) :time (p7 / pro)) :ARG0-of (p / proliferate-01))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and :op1 (p5 / person :name (n4 / name :op1 "Difilippantonio")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "2000")))) # ::id bel_pmid_1828_5820.36136 # ::date 2015-05-10T23:43:36 # ::file bel_pmid_1828_5820_36136.txt # ::snt The consequential loss of CDC25A results in G1/S arrest, due to the inefficient loading of CDC45 at the origin of replication. In addition, activated ATM, ATR, DNA–PK, Chk2, and Chk1 all aid in the phosphorylation and activation of p53, a key player in DNA-damage checkpoints. Activated p53 transactivates p21, which inhibits two G1/S-promoting cyclin-dependent kinases (CDKs), CDK2 and CDK4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (r / result-01 :ARG1 (l / lose-02 :ARG1 (e11 / enzyme :name (n / name :op1 "CDC25A") :xref (x2 / xref :value "UNIPROT:MPIP1_HUMAN" :prob "1.002")) :mod (c / consequential)) :ARG2 (a / arrest-02 :ARG1 (e6 / event :name (n15 / name :op1 "G1/S")) :ARG1-of (c2 / cause-01 :ARG0 (l2 / load-01 :ARG2 (e10 / enzyme :name (n2 / name :op1 "CDC45") :xref (x3 / xref :value "UNIPROT:CDC45_HUMAN" :prob "1.003")) :ARG1-of (e / efficient-01 :polarity "-") :time (o / origin :mod (r2 / replicate-01)))))) :snt2 (a3 / and :op2 (a4 / aid-01 :ARG0 (a5 / and :op1 (e2 / enzyme :name (n3 / name :op1 "ATM") :xref (x8 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")) :op2 (e12 / enzyme :name (n4 / name :op1 "ATR") :xref (x4 / xref :value "UNIPROT:ATR_HUMAN" :prob "1.004")) :op3 (e3 / enzyme :name (n5 / name :op1 "DNA–PK") :xref (x7 / xref :value "UNIPROT:PRKDC_HUMAN" :prob "0.262")) :op4 (e4 / enzyme :name (n6 / name :op1 "Chk2") :xref (x / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603")) :op5 (e5 / enzyme :name (n7 / name :op1 "Chk1") :xref (x6 / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604")) :mod (a6 / all) :ARG1-of (a2 / activate-01)) :ARG1 (a7 / and :op1 (p / phosphorylate-01 :ARG1 (p7 / protein :name (n8 / name :op1 "p53") :ARG0-of (p2 / play-08 :ARG1-of (k / key-02 :ARG2 (c3 / checkpoint :mod (d / damage-01 :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n17 / name :op1 "DNA")))))) :xref (x10 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :op2 (a8 / activate-01 :ARG1 p7)))) :snt3 (t / transactivate-01 :ARG1 (p9 / protein :name (n10 / name :op1 "p21") :ARG0-of (i / inhibit-01 :ARG1 (k2 / kinase :quant "2" :ARG0-of (p10 / promote-02 :ARG1 (e7 / event :name (n16 / name :op1 "G1/S"))) :ARG1-of (m2 / mean-01 :ARG2 (a11 / and :op1 (e8 / enzyme :name (n13 / name :op1 "CDK2") :xref (x5 / xref :value "UNIPROT:CDK2_HUMAN" :prob "1.003")) :op2 (e9 / enzyme :name (n14 / name :op1 "CDK4") :xref (x12 / xref :value "UNIPROT:CDK4_HUMAN" :prob "1.003")))) :ARG0-of (d2 / depend-01 :ARG1 (p3 / protein :name (n11 / name :op1 "cyclin") :xref (x9 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.702"))))) :xref (x11 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")) :ARG2 (p8 / protein :name (n9 / name :op1 "p53") :ARG1-of (a9 / activate-01) :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) # ::id bel_pmid_1828_5820.36694 # ::date 2015-05-11T00:00:54 # ::file bel_pmid_1828_5820_36694.txt # ::snt Activated ATM and ATR mediate the phosphorylation and subsequent activation of Chk2 and Chk1, respectively; this process is necessary in the induction of phosphorylation of CDC25A, marking it for proteosomal degradation (Su, 2006). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (a5 / and :op1 (m2 / mediate-01 :ARG0 (e / enzyme :name (n2 / name :op1 "ATM") :ARG1-of (a / activate-01) :xref (x4 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")) :ARG1 (a2 / and :op1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Chk2") :xref (x3 / xref :value "UNIPROT:CHK2_HUMAN" :prob "0.603"))) :op2 (a3 / activate-01 :ARG1 e2 :mod (s / subsequent)))) :op2 (m3 / mediate-01 :ARG0 (e5 / enzyme :name (n3 / name :op1 "ATR") :ARG1-of a :xref (x / xref :value "UNIPROT:ATR_HUMAN" :prob "1.004")) :ARG1 (a6 / and :op1 (p3 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "Chk1") :xref (x2 / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604"))) :op2 (a7 / activate-01 :ARG1 e3 :mod s))) :manner (r / respective)) :snt2 (n / need-01 :ARG0 (i / induce-01 :ARG2 (p5 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n6 / name :op1 "CDC25A") :xref (x1 / xref :value "UNIPROT:MPIP1_HUMAN" :prob "1.002")) :ARG0-of (m4 / mark-02 :ARG1 e4 :purpose (d3 / degrade-01 :ARG1 e4 :ARG2 (p8 / protein :name (n8 / name :op1 "proteosome") :xref (x5 / xref :value "UNIPROT:VP113_HUMAN" :prob "0.262")))))) :ARG1 (p4 / process-02 :mod (t / this)) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (p7 / person :name (n7 / name :op1 "Su")) :time (d / date-entity :year "2006"))))) # ::id bel_pmid_1831_7950.3272 # ::date 2015-05-11T00:16:14 # ::file bel_pmid_1831_7950_3272.txt # ::snt Phosphorylation of 4E-BP1, S6k1(Thr(389)), and Erk 1/2 was reduced 2 h following IP injection of alcohol. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (r / reduce-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "4E-BP1") :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002")) :op2 (a4 / amino-acid :mod "389" :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n4 / name :op1 "S6k1") :xref (x3 / xref :value "UNIPROT:KS6B1_HUMAN" :prob "0.653")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op3 (e3 / enzyme :name (n5 / name :op1 "Erk1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op4 (e4 / enzyme :name (n6 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :time (a2 / after :op1 (i / inject-01 :ARG1 (a3 / alcohol) :ARG2 (p3 / peritoneum)) :quant (t / temporal-quantity :quant "2" :unit (h / hour)))) # ::id bel_pmid_1836_8049.20310 # ::date 2015-05-11T00:26:16 # ::file bel_pmid_1836_8049_20310.txt # ::snt TGF-beta-induced Foxp3 expression is inhibited by IL-6 (ref. 17), IL-21 (ref. 10) and IL-23 (Supplementary Fig. 8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / inhibit-01 :ARG0 (a / and :op1 (p3 / protein :name (n3 / name :op1 "IL-6") :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 "17"))) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "IL-21") :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 "10"))) :xref (x2 / xref :value "UNIPROT:IL21_HUMAN" :prob "1.003")) :op3 (p5 / protein :name (n5 / name :op1 "IL-23") :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "8" :ARG2-of (s / supplement-01))) :xref (x3 / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.312"))) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Foxp3") :xref (x4 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-beta") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.373"))))) # ::id bel_pmid_1836_8049.27060 # ::date 2015-05-11T00:30:21 # ::file bel_pmid_1836_8049_27060.txt # ::snt Forced expression of wild-type mouse Foxp3 inhibited IL-6/IL-21-induced Il23r expression, whereas Foxp3DeltaEx2 had less inhibitory activity (Fig. 4a) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Foxp3") :xref (x4 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :ARG3 (m / mouse :mod (w / wild-type)) :ARG1-of (f / force-02)) :ARG1 (e2 / express-03 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-23-R") :xref (x / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.692")) :ARG2-of (i2 / induce-01 :ARG0 (s / slash :op1 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "IL-21") :xref (x2 / xref :value "UNIPROT:IL21_HUMAN" :prob "1.003")))))) :ARG2 (a / activity-06 :ARG0 (p5 / protein :name (n5 / name :op1 "Foxp3ΔEx2") :xref (x3 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.222")) :ARG1 (i3 / inhibit-01) :degree (l / less)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4a"))) # ::id bel_pmid_1836_8049.27066 # ::date 2015-05-11T00:42:38 # ::file bel_pmid_1836_8049_27066.txt # ::snt Both mouse and human Foxp3 blocked RORgammat-directed IL-17 expression, but full suppression required the presence of the exon 2-encoded sequence in Foxp3, suggesting that the interaction between Foxp3 and RORgammat is essential (Fig. 3c and Supplementary Fig. 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG1 (b / block-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "Foxp3") :mod (m / mouse) :xref (x4 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n2 / name :op1 "Foxp3") :mod (h / human) :xref (x / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603"))) :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-17") :xref (x2 / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003")) :ARG1-of (d / direct-01 :ARG0 (p4 / protein :name (n4 / name :op1 "RORgammat") :xref (x3 / xref :value "UNIPROT:RORG_HUMAN" :prob "0.202"))))) :ARG2 (r / require-01 :ARG0 (s / suppress-01 :ARG1 e :ARG1-of (f / full-09)) :ARG1 (p7 / present-02 :ARG1 (p5 / protein-segment :name (n5 / name :op1 "exon" :op2 "2") :ARG1-of (e2 / encode-01) :part-of (p6 / protein :name (n6 / name :op1 "Foxp3") :xref (x1 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")))) :ARG0-of (s3 / suggest-01 :ARG1 (e3 / essential :domain (i / interact-01 :ARG0 p6 :ARG1 p4)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "3c") :op2 (f3 / figure :mod "5" :ARG2-of (s4 / supplement-01))))) # ::id bel_pmid_1836_8049.33032 # ::date 2015-05-11T01:13:05 # ::file bel_pmid_1836_8049_33032.txt # ::snt Examination of IL-17 expression in heterozygous RORgammat–GFP knock-in mice revealed that RORgammat+Foxp3+ lamina propria T cells produced much less IL-17 than RORgammat+Foxp3- cells, suggesting that Foxp3 may interfere with the ability of RORgammat to induce IL-17 (Fig. 1c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / reveal-01 :ARG0 (e / examine-01 :ARG1 (e2 / express-03 :ARG2 "p" :ARG3 (m / mouse :mod (h / heterozygous) :ARG3-of (e3 / express-03 :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "RORgammat") :xref (x / xref :value "UNIPROT:RORG_HUMAN" :prob "0.202")) :op2 (p3 / protein :name (n3 / name :op1 "GFP") :xref (x2 / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342"))))))) :ARG1 (p4 / produce-01 :ARG0 (c / cell :name (n4 / name :op1 "T") :part-of (l / lamina-propria) :mod (p5 / protein :name (n5 / name :op1 "RORgammat+") :xref (x4 / xref :value "UNIPROT:RORG_HUMAN" :prob "0.202")) :mod (p6 / protein :name (n6 / name :op1 "Foxp3+") :xref (x1 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.592"))) :ARG1 (p / protein :name (n / name :op1 "IL-17") :quant (l2 / less :degree (m2 / much)) :xref (x6 / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003")) :compared-to (c2 / cell :mod (p7 / protein :name (n7 / name :op1 "Foxp3-") :xref (x3 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.592")) :mod p5)) :ARG0-of (s / suggest-01 :ARG1 (p8 / possible-01 :ARG1 (i / interfere-01 :ARG0 (p9 / protein :name (n8 / name :op1 "Foxp3") :xref (x5 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :ARG1 (c3 / capable-01 :ARG1 p2 :ARG2 (i2 / induce-01 :ARG0 p2 :ARG2 p))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1c"))) # ::id bel_pmid_1842_3196.15956 # ::date 2015-05-11T01:32:44 # ::file bel_pmid_1842_3196_15956.txt # ::snt A) Increase in IL-6 production from baseline in WT, tlr4/, myd88/, and trif/ alveolar macrophages treated with LPS, BAL fluid from normal control, or BAL fluid from acid-treated WT mice. **p < 0.01. Data are from four separate experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt1 (i / increase-01 :li "A" :ARG1 (p / produce-01 :ARG1 (p2 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :location (a / and :op1 (b / baseline :source (m2 / macrophage :mod (w / wild-type) :mod (a2 / alveolus))) :op2 (m3 / macrophage :mod a2 :mod (p3 / protein :name (n2 / name :op1 "tlr4") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:TLR4_HUMAN" :prob "0.604"))) :op3 (m5 / macrophage :mod a2 :mod (p4 / protein :name (n3 / name :op1 "myd88") :ARG2-of m4 :xref (x2 / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.633"))) :op4 (m6 / macrophage :mod a2 :mod (p5 / protein :name (n4 / name :op1 "trif") :ARG2-of m4 :xref (x3 / xref :value "UNIPROT:TCAM1_HUMAN" :prob "0.602"))) :ARG1-of (t / treat-03 :ARG3 (o / or :op1 (m7 / molecular-physical-entity :name (n5 / name :op1 "LPS") :xref (x4 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :op2 (f / fluid :source (c / control :ARG1-of (n7 / normal-02)) :mod (l2 / lavage :mod (a4 / alveolus :mod (b2 / bronchus)))) :op3 (f2 / fluid :source (m10 / mouse :mod w :ARG1-of (t2 / treat-03 :ARG3 (a3 / acid))) :mod l2)))) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.01"))) :snt2 (d / data :source (e / experiment :quant "4" :ARG1-of (s / separate-02)))) # ::id bel_pmid_1842_3196.15958 # ::date 2015-05-11T01:33:03 # ::file bel_pmid_1842_3196_15958.txt # ::snt By contrast, LPS-induced IL-6 production in alveolar macrophages was dependent on TLR4, MyD88, and TRIF (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG2 (d / depend-01 :ARG0 (p / produce-01 :ARG1 (p2 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2-of (i / induce-01 :ARG0 (m / molecular-physical-entity :name (n2 / name :op1 "LPS") :xref (x4 / xref :value "PUBCHEM:53481794" :prob "9.905254"))) :location (m2 / macrophage :mod (a / alveolus))) :ARG1 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "TLR4") :xref (x2 / xref :value "UNIPROT:TLR4_HUMAN" :prob "1.004")) :op2 (p4 / protein :name (n4 / name :op1 "MyD88") :xref (x1 / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663")) :op3 (p5 / protein :name (n5 / name :op1 "TRIF") :xref (x3 / xref :value "UNIPROT:TCAM1_HUMAN" :prob "1.002")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id bel_pmid_1843_4325.28378 # ::date 2015-05-11T01:37:50 # ::file bel_pmid_1843_4325_28378.txt # ::snt IL-6 reduced the expression levels of Foxp3 at 48–72 h. This is probably a direct effect of IL-6 on the Foxp3 promoter because IL-6 suppressed TGF-?1-mediated Foxp3 promoter activity in primary T cells (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (r / reduce-01 :ARG0 (p / protein :name (n / name :op1 "IL-6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (l / level :degree-of (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Foxp3") :xref (x1 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")))) :time (b / between :op1 (t / temporal-quantity :quant "48" :unit (h / hour)) :op2 (t2 / temporal-quantity :quant "72" :unit h))) :snt2 (p8 / probable :domain (a / affect-01 :ARG0 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (m3 / molecular-physical-entity :ARG0-of (p9 / promote-01 :ARG1 (p5 / protein :name (n4 / name :op1 "Foxp3") :xref (x3 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")))) :ARG1-of (d / direct-02) :domain (t3 / this) :ARG1-of (c / cause-01 :ARG0 (s2 / suppress-01 :ARG0 p3 :ARG1 (a2 / activity-06 :ARG0 m3 :ARG1-of (m2 / mediate-01 :ARG0 (p6 / protein :name (n5 / name :op1 "TGF-beta1") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.693")))) :location (c2 / cell :name (n6 / name :op1 "T") :mod (p7 / primary)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s3 / show-01 :polarity "-")))))) # ::id bel_pmid_1843_4325.33034 # ::date 2015-05-11T01:47:28 # ::file bel_pmid_1843_4325_33034.txt # ::snt As shown in Fig. 4C, transient overexpression of WT Foxp3, but not {Delta}2 or {Delta}FKH, inhibited induction of IL-17A transcription (Fig. 4C). Taken together, these observations suggest that Foxp3 interacts with ROR{gamma}t in the exon 2 region and that the FKH domain plays a critical role in the suppression of ROR{gamma}t-mediated IL-17A transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "Foxp3") :mod (w / wild-type) :xref (x6 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :ARG1-of (t / transient-02)) :ARG1 (i2 / induce-01 :ARG2 (t2 / transcribe-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-17A") :xref (x1 / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003"))))) :ARG2 (i3 / inhibit-01 :polarity "-" :ARG0 (o2 / overexpress-01 :ARG1 (o3 / or :op1 (p3 / protein :name (n3 / name :op1 "Foxp3Δ2") :xref (x2 / xref :value "UNIPROT:FOXP2_HUMAN" :prob "0.242")) :op2 (p4 / protein :name (n4 / name :op1 "Foxp3ΔFNK") :xref (x4 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.222"))) :ARG2 t) :ARG1 i2) :ARG1-of (s / show-01 :medium (f / figure :mod "4C")) :ARG1-of (d / describe-01 :ARG0 f)) :snt2 (h / have-condition-91 :ARG1 (s2 / suggest-01 :ARG0 (t3 / thing :ARG1-of (o4 / observe-02) :mod (t4 / this)) :ARG1 (a / and :op1 (i4 / interact-01 :ARG0 (p7 / protein-segment :name (n7 / name :op1 "exon" :op2 "2") :part-of (p5 / protein :name (n5 / name :op1 "Foxp3") :xref (x5 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603"))) :ARG1 (p6 / protein :name (n6 / name :op1 "RORgammat") :xref (x3 / xref :value "UNIPROT:RORG_HUMAN" :prob "0.202"))) :op2 (p8 / play-08 :ARG0 (p9 / protein-segment :name (n8 / name :op1 "FKH") :part-of p5) :ARG1 (s3 / suppress-01 :ARG1 (t5 / transcribe-01 :ARG1 (p10 / protein :name (n9 / name :op1 "IL-17A") :xref (x / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003")) :ARG1-of (m2 / mediate-01 :ARG0 p6))) :ARG1-of (c2 / critical-02 :ARG2 s3)))))) # ::id bel_pmid_1843_4325.33936 # ::date 2015-05-11T05:13:56 # ::file bel_pmid_1843_4325_33936.txt # ::snt Then, IL-17A promoter activity was examined with or without an ROR{gamma}t expression vector in the HEK 293T cells in which ROR{gamma}t was not expressed. In the presence of ROR{gamma}t, the promoter activity was significantly increased (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / multi-sentence :snt1 (e / examine-01 :ARG1 (a / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n / name :op1 "IL-17A") :xref (x / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003"))))) :manner (o / or :op1 (v / vector :mod (e2 / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "RORgammat") :xref (x1 / xref :value "UNIPROT:RORG_HUMAN" :prob "0.202")))) :op2 (v2 / vector :polarity "-" :mod e2)) :location (c / cell-line :name (n3 / name :op1 "HEK" :op2 "293T") :ARG3-of (e3 / express-03 :polarity "-" :ARG2 p3)) :time (t / then)) :snt2 (i / increase-01 :ARG1 (a2 / activity-06 :ARG0 (m3 / molecular-physical-entity :ARG0-of (p4 / promote-01))) :ARG2 (s / significant-02) :condition (p6 / present-02 :ARG1 (p5 / protein :name (n4 / name :op1 "RORgammat") :xref (x2 / xref :value "UNIPROT:RORG_HUMAN" :prob "0.202"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A")))) # ::id bel_pmid_1848_3625.9006 # ::date 2015-05-11T05:24:02 # ::file bel_pmid_1848_3625_9006.txt # ::snt Germline expression of the endogenous H-RasG12V oncogene, even in homozygosis, resulted in hyperplasia of the mammary gland. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (e / express-03 :ARG1 (g3 / gene :name (n2 / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :value "G12V") :mod (e2 / endogenous) :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG3 (g2 / germline)) :ARG2 (h / hyperplasia :mod (g / gland :mod (m2 / mammary))) :location (h2 / homozygosis :mod (e3 / even))) # ::id bel_pmid_1855_5587.7928 # ::date 2015-05-11T05:34:36 # ::file bel_pmid_1855_5587_7928.txt # ::snt We investigated whether globular adiponectin (gAd) affects the expression of inflammation-related genes in murine macrophages (RAW264 cells). DNA microarray analysis indicated that granulocyte colony-stimulating factor (G-CSF) showed the largest increase in expression in gAd-stimulated RAW264 cells. The gAd-induced secretion of G-CSF increased in a time- and dose-dependent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m2 / multi-sentence :snt1 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :mode "interrogative" :ARG0 (p / protein :name (n / name :op1 "globular" :op2 "adiponectin")) :ARG1 (e / express-03 :ARG1 (g / gene :ARG1-of (r / relate-01 :ARG2 (i2 / inflame-01))) :ARG3 (m3 / macrophage :ARG1-of (m5 / mean-01 :ARG2 (c / cell :name (n3 / name :op1 "RAW264"))) :part-of (o / organism :name (n2 / name :op1 "Murinae")))))) :snt2 (i3 / indicate-01 :ARG0 (a3 / analyze-01 :instrument (m4 / microarray :mod (n6 / nucleic-acid :wiki "DNA" :name (n11 / name :op1 "DNA")))) :ARG1 (s / show-01 :ARG0 (p3 / protein :name (n5 / name :op1 "granulocyte" :op2 "colony-stimulating" :op3 "factor") :xref (x / xref :value "UNIPROT:CSF3_HUMAN" :prob "0.702")) :ARG1 (i4 / increase-01 :ARG1 (e2 / express-03 :ARG3 (c2 / cell :name (n7 / name :op1 "RAW264") :ARG1-of (s2 / stimulate-01 :ARG2 (p5 / protein :name (n8 / name :op1 "gAd") :xref (x2 / xref :value "UNIPROT:DCE1_HUMAN" :prob "0.602"))))) :ARG2 (l / large :degree (m / most))))) :snt3 (i5 / increase-01 :ARG1 (s3 / secrete-01 :ARG1 (p7 / protein :name (n10 / name :op1 "G-CSF") :xref (x1 / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.002")) :ARG2-of (i6 / induce-01 :ARG0 (p6 / protein :name (n9 / name :op1 "gAd") :xref (x3 / xref :value "UNIPROT:DCE1_HUMAN" :prob "0.602")))) :manner (d3 / depend-01 :ARG1 (a2 / and :op1 (t2 / time) :op2 (d4 / dose))))) # ::id bel_pmid_1855_5587.24926 # ::date 2015-05-11T05:50:36 # ::file bel_pmid_1855_5587_24926.txt # ::snt gAd induced the phosphorylation of MEK1/2 and ERK1/2 in RAW264 cells. In addition, the gAd-induced phosphorylation of MEK1/2 and ERK1/2 was dramatically reduced by PD98059 and U0126, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "gAd") :xref (x7 / xref :value "UNIPROT:DCE1_HUMAN" :prob "0.602")) :ARG2 (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x8 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2") :xref (x6 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n5 / name :op1 "ERK1") :xref (x5 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op4 (e4 / enzyme :name (n6 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :location (c / cell :name (n7 / name :op1 "RAW264"))) :snt2 (a2 / and :op2 (r / reduce-01 :ARG0 (a3 / and :op1 (s2 / small-molecule :name (n8 / name :op1 "PD98059") :xref (x10 / xref :value "PUBCHEM:4713" :prob "18.349844")) :op2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x11 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :manner (r2 / respective)) :ARG1 (p3 / phosphorylate-01 :ARG1 (a4 / and :op1 (e5 / enzyme :name (n9 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e6 / enzyme :name (n10 / name :op1 "MEK2") :xref (x4 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :op3 (e7 / enzyme :name (n11 / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op4 (e8 / enzyme :name (n12 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG2-of (i2 / induce-01 :ARG0 (p4 / protein :name (n13 / name :op1 "gAd") :xref (x9 / xref :value "UNIPROT:DCE1_HUMAN" :prob "0.602")))) :manner (d / dramatic)))) # ::id bel_pmid_1866_6314.27860 # ::date 2015-05-11T02:58:25 # ::file bel_pmid_1866_6314_27860.txt # ::snt from full text - An inactivation of IL-10 in mice results in an increased production of IL-12 and IFN-gamma [42,43]. Inflamed tissues and granulomas of CD show low IL-10[44]. Melgar et al[45] reported a highly significant increase in IL-10 mRNA levels in T lymphocytes and in IL-10-positive cells in the colons of UC patients. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (r / result-01 :ARG1 (a / activate-01 :polarity "-" :ARG1 (p14 / protein :name (n / name :op1 "IL-10") :xref (x4 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :location (m2 / mouse)) :ARG2 (p / produce-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n3 / name :op1 "IL-12") :xref (x2 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343")) :op2 (p3 / protein :name (n4 / name :op1 "IFN-gamma") :xref (x5 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "42" :op2 "43")))) :source (t2 / text :ARG1-of (f / full-09))) :snt2 (s / show-01 :ARG0 (a4 / and :op1 (t / tissue) :op2 (g2 / granuloma) :part-of (d2 / disease :name (n5 / name :op1 "CD")) :ARG1-of (i / inflame-01)) :ARG1 (p11 / protein :name (n6 / name :op1 "IL-10") :ARG1-of (l / low-04) :xref (x3 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "44")))) :snt3 (r2 / report-01 :ARG0 (a5 / and :op1 (p6 / person :name (n7 / name :op1 "Melgar")) :op2 (p7 / person :mod (o2 / other))) :ARG1 (i2 / increase-01 :ARG1 (l2 / level :quant-of (n8 / nucleic-acid :name (n9 / name :op1 "mRNA") :location (p13 / protein :name (n13 / name :op1 "IL-10") :xref (x / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")))) :ARG2 (s2 / significant-02 :ARG1-of (h / high-02)) :location (a6 / and :op1 (c3 / cell :name (n10 / name :op1 "T" :op2 "lymphocyte")) :op2 (c4 / cell :mod (p10 / positive :mod (p12 / protein :name (n12 / name :op1 "IL10") :xref (x1 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.004")))) :location (c5 / colon :part-of (p8 / patient :mod (d4 / disease :name (n11 / name :op1 "UC")))))) :ARG1-of (d5 / describe-01 :ARG0 (p9 / publication :ARG1-of (c6 / cite-01 :ARG2 "45"))))) # ::id bel_pmid_1866_6314.28188 # ::date 2015-05-11T03:12:06 # ::file bel_pmid_1866_6314_28188.txt # ::snt from full text - in a murine model of UC, Sugimoto et al demonstrated a novel protective role for IL-22, in which IL-22 attenuates in the intestine inflammation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / demonstrate-01 :ARG0 (a / and :op1 (p / person :name (n / name :op1 "Sugimoto")) :op2 (p2 / person :mod (o2 / other))) :ARG1 (p3 / protect-01 :ARG0 (p4 / protein :name (n6 / name :op1 "IL-22") :xref (x / xref :value "UNIPROT:IL22_HUMAN" :prob "1.002")) :ARG0-of (m2 / mean-01 :ARG2 (a3 / attenuate-01 :ARG0 p4 :location (i / inflame-01 :ARG1 (i2 / intestine)))) :mod (n3 / novel)) :medium (m / model :mod (o / organism :name (n4 / name :op1 "Muridae")) :mod (d2 / disease :name (n2 / name :op1 "ulcerative" :op2 "colitis"))) :source (t / text :ARG1-of (f / full-09))) # ::id bel_pmid_1866_6314.28300 # ::date 2015-05-11T03:12:39 # ::file bel_pmid_1866_6314_28300.txt # ::snt from full text - T-cell receptor alpha chain-deficient mice (TCR -/-) treated with anti-IL-4 monoclonal antibody showed a decrease in Th2-type mRNA cytokine production and an increase in expression of IFN-gamma, suggesting that IL-4 plays a major role in inducing Th2-type CD4+ cells in the gut to shift towards a Th1 response[51]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / and :op1 (s / show-01 :ARG0 (m5 / mouse :mod (d / deficient :mod (c / chain :mod (p / protein :name (n2 / name :op1 "T-cell" :op2 "receptor") :xref (x5 / xref :value "UNIPROT:CD3G_HUMAN" :prob "0.312")) :mod (a2 / alpha))) :ARG1-of (t / treat-04 :ARG2 (a4 / antibody :mod (m2 / monoclonal) :ARG0-of (c4 / counter-01 :ARG1 "p7"))) :ARG1-of (m4 / mean-01 :ARG2 (p2 / protein :name (n3 / name :op1 "TCR") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:A2NZL2_HUMAN" :prob "1.001")))) :ARG1 (a3 / and :op1 (d2 / decrease-01 :ARG1 (p4 / produce-01 :ARG1 (c5 / cytokine) :ARG2 (n11 / nucleic-acid :name (n10 / name :op1 "mRNA") :mod (p11 / protein :name (n6 / name :op1 "Th2"))))) :op2 (i / increase-01 :ARG1 (e / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "IFN-gamma") :xref (x3 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")))))) :op2 (s2 / suggest-01 :ARG1 (p6 / play-08 :ARG0 (p7 / protein :name (n7 / name :op1 "IL-4") :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :ARG1 (i2 / induce-01 :ARG2 (s3 / shift-01 :ARG1 (p9 / protein :name (n8 / name :op1 "Th2") :location (g / gut) :mod (p3 / protein :name (n4 / name :op1 "CD4+") :xref (x2 / xref :value "UNIPROT:CD4_HUMAN" :prob "0.652"))) :ARG2 (r / respond-01 :ARG0 (p8 / protein :name (n9 / name :op1 "Th1") :xref (x4 / xref :value "UNIPROT:NELFD_HUMAN" :prob "0.622"))))) :ARG1-of (m3 / major-02))) :ARG1-of (d3 / describe-01 :ARG0 (p10 / publication :ARG1-of (c2 / cite-01 :ARG2 "51"))) :source (t2 / text :ARG1-of (f / full-09))) # ::id bel_pmid_1866_6314.28380 # ::date 2015-05-11T03:12:55 # ::file bel_pmid_1866_6314_28380.txt # ::snt from full text - anti-IL-6 receptor monoclonal antibody to a murine colitis model and found that the treatment with this antibody reduced IFN-gamma, TNF-alpha, and IL-1beta mRNA, and suppressed expression of several intracellular adhesion molecules in the colonic vascular endothelium. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (i / introduce-02 :ARG0 (a5 / and :op1 (p2 / person :name (n5 / name :op1 "Yamamoto")) :op2 (p3 / person :mod (o / other)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (p5 / person :name (n9 / name :op1 "Kallen" :op2 "KJ")) :ARG1-of (c2 / cite-01 :ARG2 "25")))) :ARG1 (a6 / antibody :mod (m / monoclonal) :ARG0-of (c3 / counter-01 :ARG1 (r5 / receptor :name (n10 / name :op1 "IL-6")))) :ARG2 (m2 / model :topic (d / disease :name (n8 / name :op1 "colitis") :mod (o2 / organism :name (n7 / name :op1 "Muridae"))))) :op2 (f / find-01 :ARG1 (a3 / and :op1 (r / reduce-01 :ARG0 (t / treat-04 :ARG2 (a2 / antibody :mod (t2 / this))) :ARG1 (n / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (a7 / and :op1 (p6 / protein :name (n11 / name :op1 "IFN-gamma") :xref (x2 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")) :op2 (p7 / protein :name (n12 / name :op1 "TNF-alpha") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op3 (p8 / protein :name (n13 / name :op1 "IL-1beta") :xref (x3 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692"))))) :location "e2") :op2 (s / suppress-01 :ARG0 t :ARG1 (e / express-03 :ARG2 (p / protein :name (n4 / name :op1 "intracellular" :op2 "adhesion" :op3 "molecule") :quant (s2 / several) :xref (x / xref :value "UNIPROT:ICAM1_HUMAN" :prob "0.372"))) :location (e2 / endothelium :part-of (v / vesel :part-of (c / colon)))))) :source (t3 / text :ARG1-of (f2 / full-09))) # ::id bel_pmid_1866_6314.35398 # ::date 2015-05-11T03:15:41 # ::file bel_pmid_1866_6314_35398.txt # ::snt from full text - STAT-3 itself induces the anti-apoptotic factors Bcl-2 and Bcl-xL # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "STAT-3") :mod (i2 / it) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.683")) :ARG2 (f / factor :example (a / and :op1 (p2 / protein :name (n2 / name :op1 "Bcl-2") :xref (x / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.701")) :op2 (p3 / protein :name (n3 / name :op1 "Bcl-xL") :xref (x1 / xref :value "UNIPROT:BCL9_HUMAN" :prob "0.232"))) :ARG0-of (c / counter-01 :ARG1 (a2 / apoptosis))) :source (t / text :ARG1-of (f2 / full-09))) # ::id bel_pmid_1866_6314.35432 # ::date 2015-05-11T03:15:54 # ::file bel_pmid_1866_6314_35432.txt # ::snt from full text - Increased levels of IL-1 in IBD may be result of stimulation of colonic macrophages that can activate interleukin (IL)-1 converting enzyme (ICE) and hence release mature IL-1beta into the colonic mucosa[20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (r / result-01 :ARG1 (s / stimulate-01 :ARG1 (c / cell :name (n / name :op1 "macrophage") :mod (c2 / colon) :ARG0-of (a3 / activate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "interleukin-1" :op2 "converting" :op3 "enzyme") :xref (x1 / xref :value "UNIPROT:CASP1_HUMAN" :prob "0.382")) :ARG1-of (p3 / possible-01) :ARG0-of (r2 / release-01 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-1" :op2 "beta") :ARG1-of (m / mature-02) :xref (x2 / xref :value "UNIPROT:IL1B_HUMAN" :prob "1.002")) :destination (m2 / mucosa :mod (c4 / colon)))))) :ARG2 (l / level :quant-of (p2 / protein :name (n2 / name :op1 "IL-1") :xref (x / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382")) :ARG1-of (i / increase-01))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c5 / cite-01 :ARG2 "20"))) :topic (d / disease :name (n3 / name :op1 "inflammatory" :op2 "bowel" :op3 "disease")) :source (t / text :ARG1-of (f / full-09))) # ::id bel_pmid_1866_6314.36060 # ::date 2015-05-11T03:16:10 # ::file bel_pmid_1866_6314_36060.txt # ::snt from full text - Both cytokines (IL-12 and IL-23) activate TYK2 and JAK2 as well as STAT1, STAT3, STAT4, and STAT5 [60]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "cytokine") :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "IL-12") :xref (x3 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343")) :op2 (p3 / protein :name (n3 / name :op1 "IL-23") :xref (x4 / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.312")))) :mod (b / both) :xref (x / xref :value "UNIPROT:RED_HUMAN" :prob "0.342")) :ARG1 (a3 / and :op1 (e / enzyme :name (n4 / name :op1 "TYK2") :xref (x5 / xref :value "UNIPROT:TYK2_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "JAK2") :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :op3 (p5 / protein :name (n6 / name :op1 "STAT1") :xref (x7 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :op4 (p6 / protein :name (n7 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op5 (p7 / protein :name (n8 / name :op1 "STAT4") :xref (x6 / xref :value "UNIPROT:STAT4_HUMAN" :prob "1.004")) :op6 (p8 / protein :name (n9 / name :op1 "STAT5") :xref (x8 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003"))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "60"))) :source (t / text :ARG1-of (f / full-09))) # ::id bel_pmid_1866_6314.38544 # ::date 2015-05-11T03:17:04 # ::file bel_pmid_1866_6314_38544.txt # ::snt from full text - IL-6 signalling through signal transducer and activator of transcription- 3 (STAT3) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s / signal-07 :ARG0 (p / protein :name (n / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :path (p3 / protein :name (n3 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription-3") :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n2 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.693")) :source (t / text :ARG1-of (f / full-09))) # ::id bel_pmid_1866_6314.39148 # ::date 2015-05-11T03:17:25 # ::file bel_pmid_1866_6314_39148.txt # ::snt from full text - TNF-alpha exerts its pro-inflammatory effects through increased production of IL-1beta and IL-6, expression of adhesion molecules, proliferation of fibroblasts and procoagulant factors, as well as initiation of cytotoxic, apoptotic, acute-phase responses, and inhibition of apoptosis [8,9]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a9 / affect-01 :ARG0 (p / protein :name (n / name :op1 "TNF-alpha") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :ARG0-of (f2 / favor-01 :ARG1 (i / inflame-01)) :manner (a / and :op1 (p3 / produce-01 :ARG1 (a2 / and :op1 (p4 / protein :name (n2 / name :op1 "IL-1beta") :xref (x / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :op2 (p5 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (i2 / increase-01)) :op2 (e3 / express-03 :ARG2 (m / molecule :ARG0-of (a3 / adhere-01))) :op3 (p6 / proliferate-01 :ARG0 (a4 / and :op1 (f / fibroblast) :op2 (f4 / factor :ARG0-of (f3 / favor-01 :ARG1 (c / coagulate-01))))) :op4 (i3 / initiate-01 :ARG1 (a10 / and :op1 (r / respond-01 :mod (c2 / cytotoxic)) :op2 (r2 / respond-01 :mod (a5 / apoptosis)) :op3 (r3 / respond-01 :mod (p2 / phase :mod (a6 / acute))))) :op5 (i4 / inhibit-01 :ARG1 a5)) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 (a8 / and :op1 "8" :op2 "9")))) :source (t / text :ARG1-of (f5 / full-09))) # ::id bel_pmid_1866_6314.39746 # ::date 2015-05-11T03:18:26 # ::file bel_pmid_1866_6314_39746.txt # ::snt from full text - Defective transforming growth factor TGF-beta1 signaling due to high levels of Smad7 is a feature of IBD[55]. UC patients have exhibited increased production of TGF-beta1 by LPMC as compared with both CD patients and controls # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (f / feature :domain (s2 / signal-07 :ARG0 (p6 / protein :name (n2 / name :op1 "transforming" :op2 "growth" :op3 "factor" :op4 "beta1") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.693")) :mod (d / defective) :ARG1-of (c4 / cause-01 :ARG0 (l / level :ARG1-of (h / high-02) :quant-of (p5 / protein :name (n / name :op1 "Smad7") :xref (x2 / xref :value "UNIPROT:SMAD7_HUMAN" :prob "1.003"))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "55"))) :poss (d2 / disease :name (n3 / name :op1 "IBD"))) :snt2 (e / exhibit-01 :ARG0 (p2 / patient :mod (d5 / disease :name (n4 / name :op1 "ulcerative" :op2 "colitis"))) :ARG1 (i / increase-01 :ARG1 (p3 / produce-01 :ARG0 (c2 / cell :name (n5 / name :op1 "LPMC")) :ARG1 (p7 / protein :name (n6 / name :op1 "TGF-beta1") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.693"))) :compared-to (a / and :op1 (p4 / patient :mod (d4 / disease :name (n7 / name :op1 "coeliac" :op2 "disease"))) :op2 (c3 / control))))) # ::id bel_pmid_1876_9721.19816 # ::date 2015-05-11T03:19:41 # ::file bel_pmid_1876_9721_19816.txt # ::snt To determine if XIAP enhanced proinflammatory gene expression in vivo, we performed qRT-PCR analysis on splenic RNA from WT and XIAP knockout mice. RNA was isolated from splenocytes harvested from uninfected animals or animals infected with L. monocytogenes for 48 h (Figure 6) {to activate XIAP}. The expression of il6 and ifng mRNAs were significantly enhanced in the presence of XIAP during infection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt2 (i3 / isolate-01 :ARG1 (n4 / nucleic-acid :name (n10 / name :op1 "RNA")) :source (c / cell :name (n7 / name :op1 "splenocyte") :ARG1-of (h / harvest-01 :source (o3 / or :op1 (a3 / animal :ARG1-of (i4 / infect-01 :polarity "-")) :op2 (a4 / animal :ARG1-of (i5 / infect-01 :ARG2 (o / organism :name (n8 / name :op1 "L." :op2 "monocytogene")) :duration (t2 / temporal-quantity :quant "48" :unit (h2 / hour))))))) :purpose (a5 / activate-01 :ARG1 (p4 / protein :name (n9 / name :op1 "XIAP") :xref (x4 / xref :value "UNIPROT:XIAP_HUMAN" :prob "1.003"))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6"))) :snt3 (e3 / enhance-01 :ARG1 (e4 / express-03 :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e6 / encode-01 :ARG1 (a7 / and :op1 (p / protein :name (n6 / name :op1 "IL6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")) :op2 (p7 / protein :name (n13 / name :op1 "IFNG") :xref (x3 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.003")))))) :ARG3 (s2 / significant-02) :condition (p2 / present-02 :ARG1 (p5 / protein :name (n12 / name :op1 "XIAP") :xref (x5 / xref :value "UNIPROT:XIAP_HUMAN" :prob "1.003"))) :time (i6 / infect-01)) :snt1 (a / analyze-01 :ARG0 (w / we) :ARG1 (n11 / nucleic-acid :name (n14 / name :op1 "RNA") :mod (s / spleen) :source (a2 / and :op1 (m3 / mouse :mod (w2 / wild-type)) :op2 (m4 / mouse :ARG3-of (e5 / express-03 :ARG2 (p3 / protein :name (n5 / name :op1 "XIAP") :ARG1-of (k / knock-out-03) :xref (x2 / xref :value "UNIPROT:XIAP_HUMAN" :prob "1.003")))))) :purpose (d / determine-01 :ARG0 w :ARG1 (e / enhance-01 :ARG0 (p6 / protein :name (n / name :op1 "XIAP") :xref (x1 / xref :value "UNIPROT:XIAP_HUMAN" :prob "1.003")) :ARG1 (e2 / express-03 :ARG1 (g2 / gene) :manner (i2 / in-vivo) :ARG0-of (f / favor-01 :ARG1 (i / inflame-01))))) :instrument (t / thing :name (n15 / name :op1 "qRT-PCR")))) # ::id bel_pmid_1897_5310.25820 # ::date 2015-05-11T03:20:15 # ::file bel_pmid_1897_5310_25820.txt # ::snt Furthermore, the hydroxyproline content was significantly reduced in the anti-CD154 mAb–treated group compared with the control IgG– treated group (Figure 5c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a / and :op2 (r / reduce-01 :ARG1 (c / contain-01 :ARG1 (a2 / amino-acid :name (n / name :op1 "hydroxyproline") :xref (x2 / xref :value "PUBCHEM:825" :prob "14.410205"))) :ARG2 (s / significant-02) :location (g / group :ARG1-of (t / treat-03 :ARG3 (a3 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n2 / name :op1 "CD154") :xref (x1 / xref :value "UNIPROT:CD40L_HUMAN" :prob "1.002"))) :mod (m / monoclone)))) :compared-to (g2 / group :ARG1-of (t2 / treat-03 :ARG3 (p2 / protein :name (n3 / name :op1 "IgG") :xref (x / xref :value "UNIPROT:Q9Y298_HUMAN" :prob "0.211"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5c"))) # ::id bel_pmid_1897_5310.25824 # ::date 2015-05-11T03:21:00 # ::file bel_pmid_1897_5310_25824.txt # ::snt In contrast, the number of BrdU-positive proliferating dermal fibroblasts at 1 week was significantly reduced in the anti-CD154 mAb–treated group compared with the control IgG–treated group # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (r / reduce-01 :ARG1 (n / number :quant-of (f / fibroblast :mod (d / dermis) :ARG0-of (p / proliferate-01) :mod (p2 / positive :mod (s2 / small-molecule :name (n2 / name :op1 "BrdU") :xref (x2 / xref :value "PUBCHEM:6035" :prob "18.013371"))))) :ARG2 (s / significant-02) :location (g / group :ARG1-of (t2 / treat-03 :ARG3 (a / antibody :mod (m / monoclonal) :ARG0-of (c3 / counter-01 :ARG1 (p4 / protein :name (n3 / name :op1 "CD154") :xref (x / xref :value "UNIPROT:CD40L_HUMAN" :prob "1.002")))))) :compared-to (g2 / group :mod (c2 / control) :ARG1-of (t3 / treat-03 :ARG3 (p5 / protein :name (n4 / name :op1 "IgG") :xref (x1 / xref :value "UNIPROT:Q9Y298_HUMAN" :prob "0.211")))) :time (a2 / after :op1 (a3 / and :op1 t2 :op2 t3) :quant (t / temporal-quantity :quant "1" :unit (w / week))))) # ::id bel_pmid_1897_5310.25836 # ::date 2015-05-11T03:21:24 # ::file bel_pmid_1897_5310_25836.txt # ::snt In addition, the anti-CD154 mAb treatment suppressed the up-regulated expression of COL1A1, RANTES, and MCP-1 mRNA (Figure 5g). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (a / and :op2 (s / suppress-01 :ARG0 (t / treat-04 :ARG2 (a3 / antibody :mod (m / monoclonal) :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "CD154") :xref (x3 / xref :value "UNIPROT:CD40L_HUMAN" :prob "1.002"))))) :ARG1 (e / express-03 :ARG1 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (a5 / and :op1 (p2 / protein :name (n6 / name :op1 "COL1A1") :xref (x / xref :value "UNIPROT:CO1A1_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n7 / name :op1 "RANTES") :xref (x1 / xref :value "UNIPROT:CCR1_HUMAN" :prob "0.352")) :op3 (p4 / protein :name (n8 / name :op1 "MCP-1") :xref (x2 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002"))))) :ARG1-of (u / upregulate-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5g")))) # ::id bel_pmid_1897_5310.36028 # ::date 2015-05-11T03:21:37 # ::file bel_pmid_1897_5310_36028.txt # ::snt Upon stimulation with soluble CD154, cultured fibroblasts induced to express CD40 by adenoviral gene transfer proliferated and showed up-regulation of the genes for intercellular adhesion molecule 1, interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), and RANTES, as well as up-regulation of their proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (a / and :op1 (p / proliferate-01 :ARG0 (f / fibroblast :mod (c / cultured) :ARG1-of (i / induce-01 :ARG2 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "CD40") :xref (x2 / xref :value "UNIPROT:TNR5_HUMAN" :prob "1.002")) :ARG3 f :manner (t / transfer-01 :ARG1 (g / gene :mod (a2 / adenoviral))))))) :op2 (s3 / show-01 :ARG0 f :ARG1 (a3 / and :op1 (u / upregulate-01 :ARG1 (g2 / gene :ARG0-of (e2 / encode-01 :ARG1 (a4 / and :op1 (p4 / protein :name (n3 / name :op1 "intercellular" :op2 "adhesion" :op3 "molecule" :op4 "1") :xref (x4 / xref :value "UNIPROT:ICAM1_HUMAN" :prob "0.702")) :op2 (p5 / protein :name (n4 / name :op1 "interleukin-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703")) :op3 (p6 / protein :name (n5 / name :op1 "monocyte" :op2 "chemoattractant" :op3 "protein") :xref (x1 / xref :value "UNIPROT:CCL2_HUMAN" :prob "0.392")) :op4 (p7 / protein :name (n6 / name :op1 "RANTES") :xref (x / xref :value "UNIPROT:CCR1_HUMAN" :prob "0.352")))))) :op2 (u2 / upregulate-01 :ARG1 a4))) :condition (s / stimulate-01 :ARG1 f :ARG2 (p3 / protein :name (n2 / name :op1 "CD154") :mod (s2 / soluble) :xref (x3 / xref :value "UNIPROT:CD40L_HUMAN" :prob "1.002")))) # ::id bel_pmid_1903_3457.27030 # ::date 2015-05-11T03:22:00 # ::file bel_pmid_1903_3457_27030.txt # ::snt Consistent with diminished numbers of squamous type I cells in epFoxm1-/- lungs, mRNA levels of T1-alpha and aquaporin 5 were significantly decreased as demonstrated by quantitative real-time (RT-PCR) (qRT-PCR) analysis (Fig. 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (d / decrease-01 :ARG1 (l / level :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "T1-alpha") :xref (x1 / xref :value "UNIPROT:PDPN_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n3 / name :op1 "aquaporin" :op2 "5") :xref (x / xref :value "UNIPROT:AQP5_HUMAN" :prob "0.682")))))) :ARG2 (s / significant-02) :ARG1-of (d2 / demonstrate-01 :ARG0 (a2 / analyze-01 :mod (q / quantity) :mod (r2 / real-time) :ARG1-of (m / mean-01 :ARG2 (t / thing :name (n5 / name :op1 "RT-PCR"))))) :ARG1-of (c / consistent-01 :ARG2 (n7 / number :quant-of (c2 / cell :name (n6 / name :op1 "squamous" :op2 "type" :op3 "I" :op4 "cell") :location (l2 / lung :mod (p3 / protein :name (n8 / name :op1 "epFoxm1") :ARG2-of (m3 / mutate-01 :mod "−/−")))) :ARG1-of (d4 / diminish-01))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id bel_pmid_1903_3457.27038 # ::date 2015-05-11T03:22:28 # ::file bel_pmid_1903_3457_27038.txt # ::snt Significantly decreased mRNA levels of M-phase-promoting Cdc25B phosphatase (Fig. 3B), a known transcriptional target of Foxm1 (15), were observed in the lungs of epFoxm1-/- mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (o / observe-01 :ARG1 (d / decrease-01 :ARG1 (l / level :quant-of (n6 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Cdc25B" :op2 "phosphatase") :ARG1-of (t / target-01 :ARG0 (p2 / protein :name (n3 / name :op1 "Foxm1") :xref (x / xref :value "UNIPROT:FOXM1_HUMAN" :prob "0.603")) :ARG1-of (k / know-01) :purpose (t2 / transcribe-01) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "15")))) :ARG0-of (p4 / promote-01 :ARG1 (e3 / event :name (n7 / name :op1 "M-phase"))))))) :ARG2 (s / significant-02) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3B"))) :location (l2 / lung :part-of (m2 / mouse :mod (p3 / protein :name (n5 / name :op1 "Foxm1") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:FOXM1_HUMAN" :prob "0.603"))))) # ::id bel_pmid_1905_2556.19692 # ::date 2015-05-11T03:23:42 # ::file bel_pmid_1905_2556_19692.txt # ::snt The authors demonstrate that HMGB1 binds to TLR4 and that HMGB1, which is released by chemotherapy-induced cell death, can activate TLR4 and induce anti-tumour T-cell immunity79. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / demonstrate-01 :ARG0 (p5 / person :ARG0-of (a / author-01)) :ARG1 (a2 / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "HMGB1") :ARG1-of (r / release-01 :ARG0 (d2 / die-01 :ARG1 (c / cell) :ARG2-of (i2 / induce-01 :ARG0 (c2 / chemotherapy)))) :xref (x1 / xref :value "UNIPROT:HMGB1_HUMAN" :prob "1.004")) :ARG2 (p3 / protein :name (n2 / name :op1 "TLR4") :xref (x / xref :value "UNIPROT:TLR4_HUMAN" :prob "1.004"))) :op2 (p2 / possible-01 :ARG1 (a3 / and :op1 (a4 / activate-01 :ARG0 p :ARG1 p3) :op2 (i / induce-01 :ARG0 p :ARG2 (i3 / immune-02 :ARG1 (c3 / cell :name (n3 / name :op1 "T-cell")) :ARG0-of (c4 / counter-01 :ARG1 (t / tumor))))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "79")))) # ::id bel_pmid_1905_2556.29386 # ::date 2015-05-11T03:23:53 # ::file bel_pmid_1905_2556_29386.txt # ::snt In response to hepatocyte cell death, MyD88 signalling was responsible for the activation of NF-?B and for the production of factors such as IL-6 (ReF. 122). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 10, 2015 (r / responsible-01 :ARG0 (s / signal-07 :ARG0 (p / protein :name (n / name :op1 "MyD88") :xref (x2 / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663"))) :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "NF-kB") :xref (x / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272"))) :op2 (p3 / produce-01 :ARG1 (f / factor :example (p4 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :ARG2-of (r2 / respond-01 :ARG1 (d / die-01 :ARG1 (c / cell :name (n4 / name :op1 "hepatocyte")))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "122")))) # ::id bel_pmid_1905_2556.35940 # ::date 2015-05-11T03:24:04 # ::file bel_pmid_1905_2556_35940.txt # ::snt All TLRs (except for TLR3) and IL-1 receptor family members signal through MyD88. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s / signal-07 :ARG0 (a2 / and :op1 (p / protein :name (n5 / name :op1 "TLR") :mod (a / all) :ARG2-of (e / except-01 :ARG1 (p2 / protein :name (n2 / name :op1 "TLR3") :xref (x / xref :value "UNIPROT:TLR3_HUMAN" :prob "1.003"))) :xref (x2 / xref :value "UNIPROT:TLR4_HUMAN" :prob "0.263")) :op2 (m / member :ARG1-of (i2 / include-91 :ARG2 (p3 / protein-family :name (n3 / name :op1 "IL-1"))))) :manner (p4 / protein :name (n4 / name :op1 "MyD88") :xref (x1 / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663"))) # ::id bel_pmid_1905_3174.34990 # ::date 2015-05-11T01:45:29 # ::file bel_pmid_1905_3174_34990.txt # ::snt We veri?ed the secretion levels of several SASP proteins by ELISAs (Figure S1 and Text S1). Further, because secretion increased greater than 10-fold for some SASP factors, we could verify up-regulation by intracellular immunostaining. For example, IL-6 and IL-8 were barely visible in PRE cells but clearly detectable in SEN cells (Figure 1B, Figure S2, and Text S1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (v / verify-01 :ARG0 (w / we) :ARG1 (l / level :degree-of (s / secrete-01 :ARG1 (p / protein :quant (s2 / several) :mod (t5 / thing :name (n2 / name :op1 "SASP"))))) :instrument (t / thing :name (n / name :op1 "ELISA")) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "S1") :op2 (t2 / text :mod "S1")))) :snt2 (p2 / possible-01 :ARG1 (v2 / verify-01 :ARG0 (w2 / we) :ARG1 (u / upregulate-01) :ARG1-of (c / cause-01 :ARG0 (i / increase-01 :ARG1 (s3 / secrete-01 :ARG1 (f2 / factor :mod (t3 / thing :name (n3 / name :op1 "SASP")) :mod (s4 / some))) :ARG2 (m2 / more-than :mod (p4 / product-of :op1 "10")))) :manner (i2 / immunostain-01 :manner (i3 / intracellular))) :mod (f5 / further)) :snt3 (e / exemplify-01 :ARG0 (c2 / contrast-01 :ARG1 (p5 / possible-01 :ARG1 (s5 / see-01 :ARG1 (a2 / and :op1 (p6 / protein :name (n5 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p7 / protein :name (n6 / name :op1 "IL-8") :xref (x / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003"))) :degree (b / bare) :location (c3 / cell :mod (p8 / presenescent)))) :ARG2 (p9 / possible-01 :ARG1 (d2 / detect-01 :ARG1 a2 :ARG1-of (c4 / clear-06) :location (c5 / cell :mod (s6 / senescent))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f3 / figure :mod "1B") :op2 (f4 / figure :mod "S2") :op3 (t4 / text :mod "S1"))))) # ::id bel_pmid_1905_3174.35034 # ::date 2015-05-11T02:36:54 # ::file bel_pmid_1905_3174_35034.txt # ::snt SASP components included inflammatory and immune-modulatory cytokines and chemokines (e.g., IL-6, ?7, and ?8, MCP-2, and MIP-3a). They also included growth factors (e.g., GRO, HGF, and IGFBPs), shed cell surface molecules (e.g., ICAMs, uPAR, and TNF receptors), and survival factors (Figure 1A and Table S2) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (m / multi-sentence :snt1 (i / include-01 :ARG1 (a / and :op1 (c2 / cytokine) :op2 (c3 / chemokine) :ARG0-of (i4 / inflame-01) :ARG0-of (m2 / modulate-01 :ARG1-of (i2 / immune-02)) :example (a2 / and :op1 (c4 / cytokine :name (n2 / name :op1 "IL-6")) :op2 (c5 / cytokine :name (n3 / name :op1 "IL-7")) :op3 (c6 / chemokine :name (n4 / name :op1 "IL-8")) :op4 (c7 / chemokine :name (n5 / name :op1 "MCP-2")) :op5 (c8 / chemokine :name (n6 / name :op1 "MIP-3a")))) :ARG2 (c / component :mod (t / thing :name (n / name :op1 "SASP")))) :snt2 (i3 / include-01 :ARG1 (a3 / and :op1 (g / growth-factor :example (a4 / and :op1 (g2 / growth-factor :name (n7 / name :op1 "GRO")) :op2 (g3 / growth-factor :name (n8 / name :op1 "HGF")) :op3 (g4 / growth-factor :name (n9 / name :op1 "IGFBP")))) :op2 (m3 / molecule :mod (s / surface) :source (c9 / cell :ARG1-of (s2 / shed-01)) :example (a5 / and :op1 (p / protein :name (n10 / name :op1 "ICAM") :xref (x / xref :value "UNIPROT:ICAM1_HUMAN" :prob "0.312")) :op2 (p3 / protein :name (n11 / name :op1 "uPAR") :xref (x2 / xref :value "UNIPROT:UPAR_HUMAN" :prob "1.004")) :op3 (p2 / protein :name (n12 / name :op1 "TNF" :op2 "receptor") :xref (x1 / xref :value "UNIPROT:TRAF1_HUMAN" :prob "0.262")))) :op3 (f2 / factor :mod (s3 / survive-01))) :ARG2 (t2 / they) :mod (a6 / also)) :ARG1-of (d / describe-01 :ARG0 (a7 / and :op1 (f3 / figure :mod "1A") :op2 (t3 / table :mod "S2")))) # ::id bel_pmid_1917_3740.18146 # ::date 2015-05-11T04:14:08 # ::file bel_pmid_1917_3740_18146.txt # ::snt Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls ...In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (l / lead-03 :ARG0 (e / expose-01 :ARG1 (m2 / mouse :mod (p / protein :name (n / name :op1 "IL-6") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (h / hypoxia)) :ARG2 (i / increase-01 :ARG1 (a / and :op1 (l2 / level :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :op2 (l3 / level :quant-of p2)) :ARG1-of (m3 / mark-01) :time (w2 / week :ord (o / ordinal-entity :value "1"))) :accompanier (i2 / immunostain-01 :ARG1 (w3 / wall :mod (v / vessel :mod (p4 / pulmonary))) :ARG3 p2 :mod (p3 / positive))) :snt2 (r2 / reveal-01 :ARG0 (s / study-01 :ARG1 (a2 / and :op1 (c4 / cell :mod (m4 / mucle :ARG1-of (s4 / smooth-06)) :mod (a3 / artery :mod (l4 / lung)) :mod (h3 / human) :ARG1-of (c2 / culture-01)) :op2 (c5 / cell :mod (e3 / endothelium :mod (m5 / microvascular)))) :manner (i3 / in-vitro)) :ARG1 (s2 / synthesize-01 :ARG0 c4 :ARG1 (p5 / protein :name (n6 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (p6 / prominent) :ARG1-of (s3 / stimulate-01 :ARG0 (h2 / hypoxia) :mod (f / further))))) # ::id bel_pmid_1922_8664.9182 # ::date 2015-05-11T04:32:36 # ::file bel_pmid_1922_8664_9182.txt # ::snt In CIA synoviocytes, IL-17 increased the expression of TLR-2, 4, and 9, and this effect was significantly alleviated by neutralizing antibodies to IL-17, IL-1beta, and IL-6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "IL-17") :xref (x / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003")) :ARG1 (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "TLR-2") :xref (x1 / xref :value "UNIPROT:TLR2_HUMAN" :prob "0.672")) :op2 (p3 / protein :name (n3 / name :op1 "TLR-4") :xref (x2 / xref :value "UNIPROT:D0EWT7_HUMAN" :prob "1.001")) :op3 (p4 / protein :name (n4 / name :op1 "TLR-9") :xref (x3 / xref :value "UNIPROT:TLR9_HUMAN" :prob "0.672")))) :location (c5 / cell :name (n9 / name :op1 "synoviocyte") :mod (d / disease :name (n10 / name :op1 "collagen-induced" :op2 "arthritis")))) :op2 (a3 / alleviate-01 :ARG0 (n6 / neutralize-01 :ARG0 (a4 / and :op1 (a5 / antibody :ARG0-of (c2 / counter-01 :ARG1 p)) :op2 (a6 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p5 / protein :name (n7 / name :op1 "IL-1beta") :xref (x4 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")))) :op3 (a7 / antibody :ARG0-of (c4 / counter-01 :ARG1 (p6 / protein :name (n8 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))))) :ARG1 i :ARG1-of (s2 / significant-02))) # ::id bel_pmid_1923_8385.18998 # ::date 2015-05-11T04:45:30 # ::file bel_pmid_1923_8385_18998.txt # ::snt CX3CR1 may also be of importance as it confers a survival signal, which prevents cell death of monocytes and foam cells [52]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (p / possible-01 :ARG1 (i / important :domain (p2 / protein :name (n / name :op1 "CX3CR1") :xref (x / xref :value "UNIPROT:CX3C1_HUMAN" :prob "1.002")) :mod (a2 / also)) :ARG1-of (c / cause-01 :ARG0 (c2 / confer-02 :ARG0 p2 :ARG1 (s / signal :mod (s2 / survive-01) :ARG0-of (p3 / prevent-01 :ARG1 (d / die-01 :ARG1 (a / and :op1 (m / monocyte) :op2 (c3 / cell :mod (f / foam)))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "52")))) # ::id bel_pmid_1923_8385.27652 # ::date 2015-05-11T04:54:23 # ::file bel_pmid_1923_8385_27652.txt # ::snt The same group demonstrated just recently that mast cells actively participate in the formation of aortic aneurysms by release of IL-6 and IFN?, which induced apoptosis of smooth muscle cells and protease expression [111]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / demonstrate-01 :ARG0 (g / group :ARG1-of (s / same-01)) :ARG1 (p / participate-01 :ARG0 (c / cell :mod (m / mast)) :ARG1 (f / form-01 :ARG1 (a2 / aneurysm :mod (a3 / aorta))) :ARG1-of (a / activity-06 :ARG0 c) :manner (r / release-01 :ARG1 (a4 / and :op1 (p2 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n2 / name :op1 "IFN-γ") :xref (x2 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.232")) :ARG0-of (i / induce-01 :ARG2 (a6 / and :op1 (a5 / apoptosis :mod (c2 / cell :part-of (m2 / muscle :ARG1-of (s2 / smooth-06)))) :op2 (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "protease") :xref (x1 / xref :value "UNIPROT:VP113_HUMAN" :prob "0.702")))))))) :time (r2 / recent :mod (j / just)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "111")))) # ::id bel_pmid_1927_3391.16158 # ::date 2015-05-11T10:04:51 # ::file bel_pmid_1927_3391_16158.txt # ::snt Several receptor tyrosine kinases exhibit stimulated activity upon peroxynitrite exposure, triggering downstream phosphotyrosine-dependent signalling, as shown for the platelet-derived growth factor receptor (PDGFR) and the receptor for brain-derived neurotrophic factor (TrkB) in murine fibroblasts (24,25), as well as the Epidermal Growth Factor Receptor (EGFR) in rat lung myofibroblasts (26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e2 / exhibit-01 :ARG0 (p / protein :name (n3 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :quant (s2 / several) :ARG0-of (t / trigger-01 :ARG1 (s / signal-07 :location (d / downstream) :ARG0-of (d2 / depend-01 :ARG1 (a2 / amino-acid :name (n5 / name :op1 "tyrosine") :ARG3-of (p2 / phosphorylate-01) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :ARG1-of (s6 / show-01 :topic (a3 / and :op1 (p3 / protein :name (n6 / name :op1 "platelet-derived" :op2 "growth" :op3 "factor" :op4 "receptor") :xref (x1 / xref :value "UNIPROT:PGFRA_HUMAN" :prob "0.393")) :op2 (p4 / protein :name (n7 / name :op1 "brain-derived" :op2 "neutrophic" :op3 "factor" :op4 "receptor") :xref (x2 / xref :value "UNIPROT:BDNF_HUMAN" :prob "0.373"))) :location (f / fibroblast :part-of (o / organism :name (n8 / name :op1 "Muridae"))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a5 / and :op1 "24" :op2 "25"))))) :ARG1-of (s7 / show-01 :topic (e / enzyme :name (n9 / name :op1 "Epidermal" :op2 "Growth" :op3 "Factor" :op4 "Receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.703")) :location (m / myofibroblast :source (l / lung :part-of (r / rat))) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 "26"))))) :xref (x3 / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392")) :ARG1 (a / activity-06 :ARG1-of (s3 / stimulate-01)) :condition (e3 / expose-01 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "peroxynitrite") :xref (x4 / xref :value "PUBCHEM:104806" :prob "18.349844")))) # ::id bel_pmid_1927_3391.16160 # ::date 2015-05-11T10:38:07 # ::file bel_pmid_1927_3391_16160.txt # ::snt Peroxynitrite-mediated JNK activation has been associated with apoptotic cell death in murine alveolar C10 cells, in which JNK was activated upon the oxidation of the death receptor Fas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / associate-01 :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG1-of (m / mediate-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "peroxynitrite") :xref (x2 / xref :value "PUBCHEM:104806" :prob "18.349844")))) :ARG2 (d / die-01 :ARG1 (c / cell) :mod (a3 / apoptosis)) :location (c2 / cell-line :name (n3 / name :op1 "C10") :mod (a4 / alveolus) :part-of (o2 / organism :name (n4 / name :op1 "Muridae")) :location-of (a6 / activate-01 :ARG1 e :condition (o / oxidize-01 :ARG1 (p / protein :name (n6 / name :op1 "death" :op2 "receptor" :op3 "Fas") :xref (x1 / xref :value "UNIPROT:TNR25_HUMAN" :prob "0.372")))))) # ::id bel_pmid_1927_3391.16162 # ::date 2015-05-11T10:44:17 # ::file bel_pmid_1927_3391_16162.txt # ::snt Nomiyama et al, who reported that peroxynitrite inhibited insulin-stimulated glucose uptake in preadipocyte-derived 3T3-L1 cells by reducing insulin receptor substrate-1 (IRS-1) protein levels and associated PI3K activity, upstream of Akt/PKB (122). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (r / report-01 :ARG0 (a / and :op1 (p2 / person :name (n2 / name :op1 "Nomiyama")) :op2 (p / person :mod (o2 / other))) :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "peroxynitrite") :xref (x4 / xref :value "PUBCHEM:104806" :prob "18.349844")) :ARG1 (t / take-up-13 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "glucose") :xref (x3 / xref :value "PUBCHEM:206" :prob "11.89276")) :ARG1-of (s3 / stimulate-01 :ARG0 (p7 / protein :name (n5 / name :op1 "insulin") :xref (x2 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")))) :location (c / cell-line :name (n6 / name :op1 "3T3-L1") :ARG1-of (d / derive-01 :ARG2 (p3 / preadipocyte))) :manner (r2 / reduce-01 :ARG0 s :ARG1 (a2 / and :op1 (l / level :quant-of (p4 / protein :name (n7 / name :op1 "insulin" :op2 "receptor" :op3 "substrate-1") :xref (x / xref :value "UNIPROT:IRS1_HUMAN" :prob "0.693"))) :op2 (a3 / activity-06 :ARG0 (e / enzyme :name (n8 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :ARG1-of (a4 / associate-01))) :location (r3 / relative-position :op1 (p5 / pathway :name (n9 / name :op1 "Akt/PKB")) :direction (u2 / upstream)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "122")))) # ::id bel_pmid_1927_3391.30174 # ::date 2015-05-11T10:59:41 # ::file bel_pmid_1927_3391_30174.txt # ::snt Administration of PTEN-specific siRNA reversed PKB/Akt inhibition and mitigated apoptosis in diabetic mouse aortas. These findings therefore suggest that hyperglycaemia may promote apoptosis in endothelial cells through PKB/Akt downregulation, via a peroxynitrite-mediated, LKB1-dependent PTEN activation (46). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (m / multi-sentence :snt1 (a2 / and :op1 (r / reverse-01 :ARG0 (a3 / administer-01 :ARG1 (n8 / nucleic-acid :name (n / name :op1 "siRNA") :ARG1-of (s / specific-02 :ARG2 (p / protein :name (n2 / name :op1 "PTEN") :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))) :ARG1 (i / inhibit-01 :ARG1 (p2 / pathway :name (n3 / name :op1 "PKB/Akt")))) :op2 (m2 / mitigate-01 :ARG0 a3 :ARG1 (a4 / apoptosis)) :location (a5 / aorta :part-of (m3 / mouse :mod (d2 / diabetes)))) :snt2 (i2 / infer-01 :ARG1 (s2 / suggest-01 :ARG0 (t2 / thing :ARG1-of (f / find-01) :mod (t / this)) :ARG1 (p3 / possible-01 :ARG1 (p4 / promote-01 :ARG0 (h / hyperglycaemia) :ARG1 (a6 / apoptosis) :location (c / cell :mod (e / endothelium)) :manner (d3 / downregulate-01 :ARG1 (p5 / pathway :name (n4 / name :op1 "PKB/Akt")) :manner (a7 / activate-01 :ARG1 (p6 / protein :name (n5 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG1-of (m4 / mediate-01 :ARG0 (s3 / small-molecule :name (n7 / name :op1 "peroxynitrite") :xref (x3 / xref :value "PUBCHEM:104806" :prob "18.349844"))) :ARG0-of (d4 / depend-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "LKB1") :xref (x1 / xref :value "UNIPROT:STK11_HUMAN" :prob "1.002")))))))) :ARG1-of (d5 / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 "46"))))) # ::id bel_pmid_1927_3391.36758 # ::date 2015-05-11T11:14:45 # ::file bel_pmid_1927_3391_36758.txt # ::snt activation of ERK depended on EGFR, Src tyrosine kinase and calcium calmodulin in PC12 cells (31), while requiring ras/Raf-1/MEK activation in human neutrophils (58). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 11, 2015 (c / contrast-01 :ARG1 (d / depend-01 :ARG0 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (t / tyrosine-kinase :name (n3 / name :op1 "Src")) :op3 (p / protein :name (n4 / name :op1 "calcium" :op2 "calmodulin") :xref (x2 / xref :value "UNIPROT:CALM_HUMAN" :prob "0.303"))) :location (c2 / cell-line :name (n5 / name :op1 "PC12")) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "31")))) :ARG2 (r / require-01 :ARG0 a :ARG1 (a3 / activate-01 :ARG1 (p2 / pathway :name (n6 / name :op1 "ras/Raf-1/MEK"))) :location (n7 / neutrophil :mod (h / human)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "58"))))) # ::id bel_pmid_1927_3391.37186 # ::date 2015-05-11T12:31:33 # ::file bel_pmid_1927_3391_37186.txt # ::snt we reported in H9C2 cardiomyocytes that peroxynitritemediated activation of ERK, although dependent on Raf-1 and MEK, was not due to upstream activation of p21ras (63). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / report-01 :ARG0 (w / we) :ARG1 (c3 / cause-01 :polarity "-" :ARG0 (a3 / activate-01 :ARG1 (p2 / protein :name (n7 / name :op1 "p21ras") :xref (x2 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :location (u / upstream)) :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (m / mediate-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "peroxynitrite") :xref (x4 / xref :value "PUBCHEM:104806" :prob "18.349844"))) :location (c / cardiomyocyte :source (c2 / cell-line :name (n6 / name :op1 "H9C2")))) :concession (d / depend-01 :ARG0 a :ARG1 (a2 / and :op1 (e3 / enzyme :name (n5 / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "63")))) # ::id bel_pmid_1934_2884.19318 # ::date 2015-05-11T12:39:37 # ::file bel_pmid_1934_2884_19318.txt # ::snt we found that IL6 effectively inhibited LIF signalling, repressing transcription of the LIF receptor gp190, and strongly inducing axotrophin/MARCH-7, a novel E3 ubitquitin ligase that we discovered to be active in degradation of gp190 protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "IL6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.004")) :ARG1 (s / signal-07 :ARG0 (p2 / protein :name (n2 / name :op1 "LIF") :xref (x / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003"))) :manner (a2 / and :op1 (r / repress-01 :ARG1 (t / transcribe-01 :ARG1 (p3 / protein :name (n3 / name :op1 "gp190") :mod p2 :xref (x1 / xref :value "UNIPROT:IL6RB_HUMAN" :prob "0.283")))) :op2 (i2 / induce-01 :ARG2 (p4 / protein :name (n6 / name :op1 "axotrophin/MARCH-7") :ARG1-of (m / mean-01 :ARG2 (p5 / protein :name (n7 / name :op1 "E3" :op2 "ubiquitin" :op3 "ligase") :mod (n4 / novel) :xref (x2 / xref :value "UNIPROT:A0A024R711_HUMAN" :prob "0.381"))) :ARG0-of (a / activity-06 :ARG1 (d / degrade-01 :ARG1 p3) :ARG1-of (d2 / discover-01 :ARG0 (w2 / we)))) :ARG1-of (s2 / strong-02))) :ARG1-of (e / effective-04))) # ::id bel_pmid_1934_2884.27058 # ::date 2015-05-11T12:56:34 # ::file bel_pmid_1934_2884_27058.txt # ::snt Unlike IL6, LIF supported expression of Foxp3, the Treg lineage transcription factor, and LIF opposed IL6 by suppressing IL-6-induced IL-17A protein release. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (s / support-01 :ARG0 (p2 / protein :name (n3 / name :op1 "LIF") :xref (x / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Foxp3") :ARG1-of (m / mean-01 :ARG2 (f / factor :ARG0-of (t / transcribe-01 :ARG1 (l / lineage :mod (c / cell :name (n2 / name :op1 "Treg")))))) :xref (x3 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603"))) :ARG1-of (r / resemble-01 :polarity "-" :ARG2 "p3")) :op2 (o / oppose-01 :ARG0 p2 :ARG1 (p3 / protein :name (n4 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :manner (s2 / suppress-01 :ARG1 (r2 / release-01 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-17A") :xref (x2 / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003")) :ARG2-of (i / induce-01 :ARG0 p3))))) # ::id bel_pmid_1935_9600.29984 # ::date 2015-05-12T01:33:39 # ::file bel_pmid_1935_9600_29984.txt # ::snt Macrophages from PC Tg mice can express high level of human PON2 besides intrinsic mouse PON2 and PON3 ... PC Tg macrophages maintained significantly lower levels of ROS for at least 2 hours than macrophages from Wt mice ... Inflammatory factors such as TNF-alpha and IL-6 are expressed at lower levels in PC Tg MPMs compared with Wt MPMs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m2 / multi-sentence :snt1 (p / possible-01 :ARG1 (e / express-03 :ARG2 (a3 / and :op1 (l / level :quant-of (p2 / protein :wiki "PON2" :name (n2 / name :op1 "PON2") :mod (h3 / human) :xref (x1 / xref :value "UNIPROT:PON2_HUMAN" :prob "1.003")) :ARG1-of (h2 / high-02)) :op2 (p3 / protein :wiki "PON2" :name (n3 / name :op1 "PON2") :mod (i / intrinsic) :mod (m7 / mouse) :xref (x2 / xref :value "UNIPROT:PON2_HUMAN" :prob "1.003")) :op3 (p4 / protein :wiki "PON3" :name (n4 / name :op1 "PON3") :mod i :mod m7 :xref (x3 / xref :value "UNIPROT:PON3_HUMAN" :prob "1.003"))) :ARG3 (m3 / macrophage :source (m4 / mouse :mod (s3 / small-molecule :wiki "Phosphocholine" :name (n / name :op1 "phosphocholine") :mod (t2 / transgenic) :xref (x5 / xref :value "PUBCHEM:1014" :prob "11.703453")))))) :snt2 (m8 / maintain-01 :ARG0 (m9 / macrophage :mod (s4 / small-molecule :wiki "Phosphocholine" :name (n5 / name :op1 "phosphocholine") :mod (t3 / transgenic) :xref (x7 / xref :value "PUBCHEM:1014" :prob "11.703453"))) :ARG1 (l3 / level :quant-of (s / small-molecule :wiki "Reactive_oxygen_species" :name (n6 / name :op1 "ROS") :xref (x8 / xref :value "PUBCHEM:128351" :prob "11.468653")) :ARG1-of (l2 / low-04 :degree (m / more) :ARG1-of (s2 / significant-02) :compared-to (m5 / macrophage :source (m10 / mouse :mod (w / wild-type))))) :duration (a / at-least :op1 (t / temporal-quantity :quant "2" :unit (h / hour)))) :snt3 (e2 / express-03 :ARG2 (f / factor :ARG0-of (i2 / inflame-01) :example (a4 / and :op1 (p5 / protein :wiki "Tumor_necrosis_factor_alpha" :name (n7 / name :op1 "TNF-alpha") :xref (x4 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (p6 / protein :wiki "Interleukin_6" :name (n8 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG3 (m14 / medical-condition :wiki "-" :name (n12 / name :op1 "malignant" :op2 "pleural" :op3 "mesothelioma") :mod (s5 / small-molecule :wiki "Phosphocholine" :name (n10 / name :op1 "phosphocholine") :mod (t4 / transgenic) :xref (x6 / xref :value "PUBCHEM:1014" :prob "11.703453"))) :degree (l4 / level :ARG1-of (l5 / low-04 :degree (m11 / more) :compared-to (m15 / medical-condition :wiki "-" :name (n9 / name :op1 "malignant" :op2 "pleural" :op3 "mesothelioma") :mod (w2 / wild-type)))))) # ::id bel_pmid_1938_6603.36754 # ::date 2015-05-12T02:10:55 # ::file bel_pmid_1938_6603_36754.txt # ::snt ATP-mediated ADAM17 activation was also suppressed by the EGFR kinase inhibitor AG1478 and, to a lesser extent, by preincubation with ?-EGFR antibody (Fig. 6B), indicating a role for EGFR in ADAM17 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a6 / and :op1 (s / suppress-01 :ARG0 (s3 / small-molecule :name (n4 / name :op1 "AG1478") :ARG0-of (i3 / inhibit-01 :ARG1 (k / kinase :name (n5 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :xref (x2 / xref :value "PUBCHEM:2051" :prob "18.86067")) :ARG1 (a / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "ADAM17") :xref (x1 / xref :value "UNIPROT:ADA17_HUMAN" :prob "1.003")) :ARG1-of (m / mediate-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ATP") :xref (x3 / xref :value "PUBCHEM:5957" :prob "14.368295")))) :mod (a2 / also)) :op2 (s4 / suppress-01 :ARG0 (p2 / preincubate-01 :ARG2 (a4 / antibody :ARG0-of (c / counter-01 :ARG1 k)) :degree (l / less :mod (m2 / more))) :ARG1 a :degree (l2 / less :degree (m3 / more))) :ARG0-of (i5 / indicate-01 :ARG1 (r / role :mod k :prep-in (a5 / activate-01 :ARG1 p))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id bel_pmid_1938_6603.36760 # ::date 2015-05-12T02:23:28 # ::file bel_pmid_1938_6603_36760.txt # ::snt addition of AG1478 also suppressed ATP-mediated phosphorylation of ERK1/2 and I-?B? (Fig. 4A), indicating the involvement of EGFR activation in these signaling events. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 18, 2015 (s / suppress-01 :ARG0 (a / add-02 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "AG1478") :xref (x2 / xref :value "PUBCHEM:2051" :prob "18.86067"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a3 / and :op1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2")) :op2 (p4 / protein :name (n4 / name :op1 "I-κBα"))) :ARG1-of (m / mediate-01 :ARG0 (s3 / small-molecule :name (n5 / name :op1 "ATP") :xref (x1 / xref :value "PUBCHEM:5957" :prob "14.368295")))) :mod (a2 / also) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A")) :ARG0-of (i / indicate-01 :ARG1 (i2 / involve-01 :ARG1 (a4 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG2 (e2 / event :mod (t / this) :mod (s4 / signal-07))))) # ::id bel_pmid_1938_6603.38056 # ::date 2015-05-12T02:28:36 # ::file bel_pmid_1938_6603_38056.txt # ::snt As shown in Fig. 6A, both ATP and ?-ASGM1 indeed resulted in enhanced ADAM17 activity, measured by increased cleavage of a fluorogenic ADAM17 substrate, and this was attenuated after siRNA silencing of DUOX1 (Fig. 6A # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a / and :op1 (r / result-01 :ARG1 (a2 / and :op1 (s2 / small-molecule :name (n / name :op1 "ATP") :xref (x3 / xref :value "PUBCHEM:5957" :prob "14.368295")) :op2 (a3 / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n2 / name :op1 "ASGM1") :xref (x2 / xref :value "UNIPROT:ASGL1_HUMAN" :prob "0.282"))))) :ARG2 (a4 / activity-06 :ARG0 (p2 / protein :name (n3 / name :op1 "ADAM17") :xref (x1 / xref :value "UNIPROT:ADA17_HUMAN" :prob "1.003")) :ARG1-of (e / enhance-01) :ARG1-of (m / measure-01 :ARG2 (c2 / cleave-01 :ARG1 (s3 / substrate :mod p2 :mod (f2 / fluorogenic)) :ARG1-of (i / increase-01)))) :mod (i2 / indeed)) :op2 (a5 / attenuate-01 :ARG1 a4 :time (a6 / after :op1 (s4 / silence-01 :ARG0 (n6 / nucleic-acid :name (n5 / name :op1 "siRNA")) :ARG1 (e2 / enzyme :name (n4 / name :op1 "DUOX1") :xref (x / xref :value "UNIPROT:DUOX1_HUMAN" :prob "1.003"))))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "6A"))) # ::id bel_pmid_1938_6603.38058 # ::date 2015-05-12T02:36:20 # ::file bel_pmid_1938_6603_38058.txt # ::snt Silencing of DUOX1 attenuated the ATP- and ?-ASGM1-induced TGF-? production observed in the presence of EGFR mAb (Fig. 5B), indicating the involvement of DUOX1 activation in ATP-induced TGF-? production and EGFR activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / attenuate-01 :ARG0 (s / silence-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "DUOX1") :xref (x / xref :value "UNIPROT:DUOX1_HUMAN" :prob "1.003"))) :ARG1 (p2 / produce-01 :ARG1 (p3 / protein :name (n4 / name :op1 "TGF-α") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233")) :ARG1-of (i / induce-01 :ARG0 (a7 / and :op1 (s2 / small-molecule :name (n5 / name :op1 "ATP") :xref (x4 / xref :value "PUBCHEM:5957" :prob "14.368295")) :op2 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n3 / name :op1 "ASGM1") :xref (x3 / xref :value "UNIPROT:ASGL1_HUMAN" :prob "0.282")))))) :ARG1-of (o / observe-01 :condition (p4 / present-02 :ARG1 (a3 / antibody :mod (m / monoclonal) :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B")) :ARG0-of (i2 / indicate-01 :ARG1 (i3 / involve-01 :ARG1 (a4 / activate-01 :ARG1 e2) :ARG2 (a5 / and :op1 (p5 / produce-01 :ARG1 p3 :ARG2-of (i4 / induce-01 :ARG0 s2)) :op2 (a6 / activate-01 :ARG1 e))))) # ::id bel_pmid_1943_9223.25342 # ::date 2015-05-12T02:57:42 # ::file bel_pmid_1943_9223_25342.txt # ::snt As shown in Fig. 1A, the HO-1 level in Bach1-/- mouse lungs was significantly higher than that of WT mice even before hyperoxic exposure, and the time-dependent increase in HO-1 expression in Bach1-/- mouse lungs was much greater than that ofWT mice during hyperoxic exposure. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (f / figure :mod "1A") :ARG1 (a / and :op1 (h / high-02 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "HO-1") :xref (x1 / xref :value "UNIPROT:HMOX1_HUMAN" :prob "1.002")) :location (l2 / lung :part-of (m3 / mouse :ARG3-of (e / express-03 :ARG1 (g3 / gene :name (n2 / name :op1 "Bach1") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:BACH1_HUMAN" :prob "0.603")))))) :degree (m / more) :ARG1-of (s2 / significant-02) :time (b / before :op1 (e3 / expose-01 :ARG2 (h2 / hyperoxia)) :mod (e2 / even)) :compared-to (m5 / mouse :mod (w / wild-type))) :op2 (g / great :degree (m2 / more :degree (m6 / much)) :domain (i / increase-01 :ARG1 (e4 / express-03 :ARG1 p :ARG3 l2) :ARG0-of (d / depend-01 :ARG1 (t / time))) :compared-to (i2 / increase-01 :ARG1 (e5 / express-03 :ARG2 p :ARG3 m5) :time e3)))) # ::id bel_pmid_1943_9223.32684 # ::date 2015-05-12T03:54:10 # ::file bel_pmid_1943_9223_32684.txt # ::snt unexpectedly, however, the levels of IL-6 in bronchoalveolar lavage (BAL) fluid from Bach1(-/-) mice were significantly higher than those of WT mice. ..... In addition, a chromatin immunoprecipitation analysis revealed the binding of Bach1 to the IL-6 promoter and its detachment after oxidative stress. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m2 / multi-sentence :snt2 (a / and :op2 (r / reveal-01 :ARG0 (a2 / analyze-01 :manner (i / immunoprecipitate-01 :ARG3 (m8 / macro-molecular-complex :name (n7 / name :op1 "chromatin")))) :ARG1 (a3 / and :op1 (b / bind-01 :ARG1 (g2 / gene :name (n6 / name :op1 "Bach1") :xref (x / xref :value "UNIPROT:BACH1_HUMAN" :prob "0.603")) :ARG2 (m7 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :op2 (d / detach-01 :ARG1 g2 :ARG2 m7 :time (a4 / after :op1 (s2 / stress-02 :ARG3 (o / oxidize-01))))))) :snt1 (c / contrast-01 :ARG2 (h / high-02 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (f / fluid :source (m4 / mouse :ARG3-of (e / express-03 :ARG1 (g / gene :name (n3 / name :op1 "Bach1") :ARG2-of (m5 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:BACH1_HUMAN" :prob "0.603")))) :mod (l3 / lavage :mod (a5 / alveolus :mod (b2 / bronchus))))) :degree (m / more) :ARG1-of (s / significant-02) :ARG1-of (e2 / expect-01 :polarity "-") :compared-to (l2 / level :mod (m6 / mouse :mod (w / wild-type)) :quant-of p)))) # ::id bel_pmid_1958_0863.2728 # ::date 2015-05-12T04:05:31 # ::file bel_pmid_1958_0863_2728.txt # ::snt Inhibition of COX2 markedly reduced both IL-1 beta and IL-6 release. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (r / reduce-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "COX2") :xref (x1 / xref :value "UNIPROT:COX2_HUMAN" :prob "1.003"))) :ARG1 (r2 / release-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "IL-1" :op2 "beta") :xref (x2 / xref :value "UNIPROT:IL1B_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :manner (m / marked)) # ::id bel_pmid_1958_0863.38416 # ::date 2015-05-12T04:08:54 # ::file bel_pmid_1958_0863_38416.txt # ::snt The addition of IL-1b (100 pg/ml) alone significantly increased the levels of IL-6, and approximately to the same level as 160 lg/cm2 silica. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / increase-01 :ARG0 (a / add-02 :ARG1 (p / protein :name (n / name :op1 "IL-1b") :quant (c / concentration-quantity :quant "100" :unit (p2 / picogram-per-milliliter)) :mod (a2 / alone) :xref (x1 / xref :value "UNIPROT:O43645_HUMAN" :prob "0.671"))) :ARG1 (l / level :quant-of (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (s3 / same-01) :ARG0-of (a4 / approximate-01 :ARG1 (l2 / level :ARG4-of (i2 / increase-01 :ARG0 (a3 / add-02 :ARG1 (s2 / silica :quant (c2 / concentration-quantity :quant "160" :unit (m / microgram-per-square-centimeter)))))))) :ARG2 (s / significant-02)) # ::id bel_pmid_1969_3649.9324 # ::date 2015-05-12T04:20:15 # ::file bel_pmid_1969_3649_9324.txt # ::snt In TNBS colitis, no differences were found in interleukin (IL)-18 and tumor necrosis factor (TNF)-alpha expression between IRF4 knockout and wild-type mice. However, significant differences were detected in IL-6 and IL-17 production. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (m / multi-sentence :snt1 (f / find-01 :ARG1 (d5 / differ-02 :polarity "-" :ARG1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "interleukin" :op2 "18") :xref (x4 / xref :value "UNIPROT:IL18_HUMAN" :prob "0.693")) :op2 (p2 / protein :name (n2 / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.382"))) :ARG3 (m2 / mouse :ARG3-of (e2 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "IRF4") :ARG1-of (k / knock-out-03) :xref (x2 / xref :value "UNIPROT:IRF4_HUMAN" :prob "1.003"))))) :ARG2 (e3 / express-03 :ARG1 e :ARG3 (m4 / mouse :mod (w / wild-type))) :prep-in (d / disease :name (n4 / name :op1 "TNBS" :op2 "colitis")))) :snt2 (h / have-concession-91 :ARG2 (d3 / detect-01 :ARG1 (d4 / differ-02 :ARG1 (p3 / produce-01 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (p6 / produce-01 :ARG1 (p5 / protein :name (n6 / name :op1 "IL-17") :xref (x3 / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003"))) :ARG1-of (s / significant-02))))) # ::id bel_pmid_1970_6765.28338 # ::date 2015-05-11T01:53:07 # ::file bel_pmid_1970_6765_28338.txt # ::snt More importantly, persistent activation of IL-6 downstream Stat3 in AT II epithelial cellsdirec tly induced lung inflammation and bronchioalveolar adenocarcinoma (22). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / induce-01 :ARG0 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "IL-6") :location (r / relative-position :op1 (p2 / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :direction (d4 / downstream)) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (p3 / persist-01) :location (c / cell-line :name (n3 / name :op1 "AT" :op2 "II") :mod (e / epithelium))) :ARG2 (a2 / and :op1 (i2 / inflame-01 :ARG1 (l / lung)) :op2 (m2 / medical-condition :name (n4 / name :op1 "adenocarcinoma") :mod (b / bronchioalveolar))) :ARG1-of (d / direct-02) :mod (i3 / important :degree (m / more)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "22")))) # ::id bel_pmid_1970_6765.29240 # ::date 2015-05-11T03:33:44 # ::file bel_pmid_1970_6765_29240.txt # ::snt As shown in Fig. 3A, there was a steady increase of BrdUrd pulse-labeled AT II epithelial cells in the doxycycline-treated bitransgenic mice compared with untreated littermates. The increase of MMP12-induced cell proliferation wastime dependent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (i / increase-01 :ARG1 (c / cell-line :name (n2 / name :op1 "AT" :op2 "II") :mod (e / epithelium) :ARG1-of (l / label-01 :ARG0 (p / pulse-01 :ARG1 (s4 / small-molecule :name (n / name :op1 "BrdUrd") :xref (x2 / xref :value "PUBCHEM:6035" :prob "19.266134"))))) :ARG1-of (s / steady-01) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "3A")) :location (m3 / mouse :mod (b / bitransgenic) :ARG1-of (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "doxycycline") :xref (x1 / xref :value "PUBCHEM:54671203" :prob "15.91623")))) :compared-to (l2 / littermate :ARG1-of (t3 / treat-04 :polarity "-"))) :snt2 (d / depend-01 :ARG0 (i2 / increase-01 :ARG1 (p2 / proliferate-01 :ARG0 (c2 / cell) :ARG2-of (i3 / induce-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "MMP12") :xref (x / xref :value "UNIPROT:MMP12_HUMAN" :prob "1.003"))))) :ARG1 (t4 / time))) # ::id bel_pmid_1970_6765.29242 # ::date 2015-05-11T07:20:56 # ::file bel_pmid_1970_6765_29242.txt # ::snt MMP12 overexpression in lung epithelial cells, bitransgenic mice were treated with doxycycline for various time lengths. Histopathologic analyses revealed lung abnormalities in bitransgenic mice beginning at 6 weeks of doxycycline treatment. At this stage, marked inflammatory cell infiltration and emphysema were readily detectable (Fig. 2A, +Dox 6W). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (a / and :op1 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "MMP12") :xref (x / xref :value "UNIPROT:MMP12_HUMAN" :prob "1.003")) :location (c / cell :mod (e2 / epithelium) :mod (l / lung))) :op2 (t2 / treat-04 :ARG1 (m2 / mouse :mod (b / bitransgenic)) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "doxycycline") :xref (x1 / xref :value "PUBCHEM:54671203" :prob "15.91623")) :duration (t4 / temporal-quantity :mod (v / various)))) :snt2 (r / reveal-01 :ARG0 (a2 / analyze-01 :mod (h / histopahtology)) :ARG1 (a3 / abnormality :mod (l3 / lung) :location (m3 / mouse :mod (b2 / bitransgenic)) :ARG1-of (b3 / begin-01 :time (a4 / after :op1 (t5 / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "doxycycline") :xref (x2 / xref :value "PUBCHEM:54671203" :prob "15.91623"))) :quant (t / temporal-quantity :quant "6" :unit (w / week)))))) :snt3 (d / detect-01 :ARG1 (a5 / and :op1 (i / infiltrate-01 :ARG0 (c2 / cell :ARG0-of (i2 / inflame-01)) :ARG1-of (m4 / mark-01)) :op2 (e3 / emphysema)) :ARG1-of (p / possible-01) :manner (r2 / ready) :time (s / stage :mod (t7 / this)) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (f / figure :mod "2A") :op2 (t3 / thing :name (n4 / name :op1 "+Dox" :op2 "6W")))))) # ::id bel_pmid_1970_6765.29244 # ::date 2015-05-11T07:43:53 # ::file bel_pmid_1970_6765_29244.txt # ::snt FACS analysis showed a more than 5-fold decrease of Annexin V–labeled AT II epithelial cellsin 9-month doxycyclinetreated bitransgenic mice compared with untreated littermates (21.41% versus 4.91%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s2 / show-01 :ARG0 (a / analyze-01 :mod (t4 / thing :name (n3 / name :op1 "FACS"))) :ARG1 (d / decrease-01 :ARG1 (c / cell-line :name (n2 / name :op1 "AT" :op2 "II") :mod (e / epithelium) :ARG1-of (l / label-01 :ARG0 (p3 / protein :name (n / name :op1 "Annexin" :op2 "V") :xref (x / xref :value "UNIPROT:ANXA5_HUMAN" :prob "1.002")))) :ARG2 (m2 / more-than :op1 (p4 / product-of :value "5") :ARG1-of (m4 / mean-01 :ARG2 (p / percentage-entity :value "21.41"))) :location (m3 / mouse :mod (b / bitransgenic) :ARG1-of (t2 / treat-04 :ARG2 (s / small-molecule :name (n4 / name :op1 "doxycycline") :xref (x1 / xref :value "PUBCHEM:54671203" :prob "15.91623"))) :age (t / temporal-quantity :quant "9" :unit (m / month))) :compared-to (d3 / decrease-01 :ARG1 p3 :ARG2 (p2 / percentage-entity :value "4.91") :location (l2 / littermate :ARG1-of (t3 / treat-04 :polarity "-"))))) # ::id bel_pmid_1970_6765.29246 # ::date 2015-05-11T09:08:03 # ::file bel_pmid_1970_6765_29246.txt # ::snt Bronchioalveolar adenocarcinomas were observed in the lungs of bitransgenic mice after doxycycline treatment asearly as16 weeks (Fig. 2A, +Dox 16W). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (o / observe-01 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "adenocarcinoma") :mod (b / bronchioalveolar)) :location (l / lung :part-of (m / mouse :mod (b2 / bitransgenic))) :time (a2 / after :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "doxycycline") :xref (x / xref :value "PUBCHEM:54671203" :prob "15.91623")) :quant (t2 / temporal-quantity :quant "16" :unit (w / week) :mod (e / early)))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2A") :op2 (t3 / thing :name (n2 / name :op1 "+Dox" :op2 "16W"))))) # ::id bel_pmid_1970_6765.29248 # ::date 2015-05-11T09:18:54 # ::file bel_pmid_1970_6765_29248.txt # ::snt After 10 to 15 weeksof doxycycline treatment, the bitransgenic mice began to develop adenomatoid hyperplasia in both parenchyma and small conducting airways(F ig. 2A, +Dox 10W), which resembles to the histopathologic feature of dysplasia in clinical lesions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (b2 / begin-01 :ARG0 (m / mouse :mod (b3 / bitransgenic)) :ARG1 (d / develop-01 :ARG1 (a2 / and :op1 (p / parenchyma) :op2 (a3 / airway :mod (s / small) :ARG1-of (c / conduct-03)) :part-of m) :ARG2 (h / hyperplasia :mod (a / adenomatoid) :ARG1-of (r / resemble-01 :ARG2 (f2 / feature :poss (d5 / dysplasia) :mod (h2 / histopathologic) :location (l / lesion :mod (c2 / clinic)))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2A") :op2 (t3 / thing :name (n2 / name :op1 "+Dox" :op2 "10W")))) :time (a5 / after :op1 (t / treat-04 :ARG1 m :ARG2 (s2 / small-molecule :name (n / name :op1 "doxycycline") :xref (x / xref :value "PUBCHEM:54671203" :prob "15.91623")) :duration (b4 / between :op1 (t2 / temporal-quantity :quant "10" :unit (w2 / week)) :op2 (t4 / temporal-quantity :quant "15" :unit (w3 / week)))))) # ::id bel_pmid_1970_6765.29250 # ::date 2015-05-11T09:38:46 # ::file bel_pmid_1970_6765_29250.txt # ::snt In addition, Stat3-induced downstream developmental gene HNF4a wasup-regulated to 78.6-fold, Foxa3 to 9.3-fold, and SHH to 3.3-fold (Fig. 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op2 (a3 / and :op1 (u / upregulate-01 :ARG1 (g / gene :name (n2 / name :op1 "HNF4a") :mod (g2 / growth) :location (d / downstream) :ARG2-of (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "Stat3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :xref (x1 / xref :value "UNIPROT:HNF4A_HUMAN" :prob "0.663")) :degree (p2 / product-of :value "78.6")) :op2 (u2 / upregulate-01 :ARG1 (g3 / gene :name (n3 / name :op1 "Foxa3") :xref (x / xref :value "UNIPROT:FOXA3_HUMAN" :prob "0.603")) :degree (p4 / product-of :value "9.3")) :op3 (u3 / upregulate-01 :ARG1 (g4 / gene :name (n4 / name :op1 "SHH") :xref (x3 / xref :value "UNIPROT:SHH_HUMAN" :prob "1.003")) :degree (p6 / product-of :value "3.3")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4D")))) # ::id bel_pmid_1970_6765.29252 # ::date 2015-05-11T10:03:24 # ::file bel_pmid_1970_6765_29252.txt # ::snt As shown in Fig. 4A, IL-6 concentration in BALF of doxycycline-treated mice was steadily increased compared with those in untreated bitransgenic mice in a time-dependent fashion, # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i / increase-01 :ARG1 (c / concentrate-02 :ARG1 (p / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (f2 / fluid :mod (m / mouse :ARG1-of (t / treat-04 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "doxycycline") :xref (x1 / xref :value "PUBCHEM:54671203" :prob "15.91623")))) :mod (l / lavage :mod (a / alveolus :mod (b / bronchus))))) :manner (s / steady) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "4A")) :compared-to (c2 / concentrate-01 :ARG1 p :location (m3 / mouse :ARG1-of (t3 / treat-04 :polarity "-") :mod (b3 / bitransgenic))) :manner (d2 / depend-01 :ARG0 "i" :ARG1 (t4 / time))) # ::id bel_pmid_1970_6765.29260 # ::date 2015-05-11T11:56:23 # ::file bel_pmid_1970_6765_29260.txt # ::snt increased expression of several other MMPs was also observed in doxycycline-treated bitransgenic mice compared with untreated mice. (Fig 4D) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (o2 / observe-01 :ARG1 (i / increase-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MMP") :quant (s / several) :mod (o / other) :xref (x / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263"))) :compared-to (m2 / mouse :ARG1-of (t2 / treat-04 :polarity "-"))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4D")) :location (m / mouse :mod (b / bitransgenic) :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "doxycycline") :xref (x1 / xref :value "PUBCHEM:54671203" :prob "15.91623"))))) # ::id bel_pmid_1974_2316.9502 # ::date 2015-05-11T12:12:13 # ::file bel_pmid_1974_2316_9502.txt # ::snt In this study, we found disorganized actin in the form of membrane ruffling and enhanced cell migration in LRP1-deficient (LRP1-/-) SMCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (a / and :op1 (a2 / actin :ARG1-of (d / disorganize-01 :manner (f2 / form :mod (m / membrane :ARG1-of (r / ruffle-02) :xref (x1 / xref :value "GO:0016020" :prob "0.8"))))) :op2 (m2 / migrate-01 :ARG0 (c / cell) :ARG1 (c2 / cell :name (n / name :op1 "SMC") :mod (p / protein :name (n2 / name :op1 "LRP1") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:LRP1_HUMAN" :prob "1.003"))) :ARG1-of (e / enhance-01))) :medium (s / study-01 :mod (t / this))) # ::id bel_pmid_1974_2316.22040 # ::date 2015-05-11T12:21:29 # ::file bel_pmid_1974_2316_22040.txt # ::snt Because PDGFRb activation, through transphosphorylation of tyrosine residues in its cytoplasmic domain, triggers a cascade of phosphorylation events which eventually lead to the activation of extracellular regulated-protein kinases (Erks), phosphorylated- Erk1/2 was used as an indicator of PDGFRb activation [7]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / cause-01 :ARG0 (t2 / trigger-01 :ARG0 (a / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "PDGFRb") :xref (x / xref :value "UNIPROT:PGFRB_HUMAN" :prob "0.673")) :manner (t3 / transphosphorylate-01 :ARG1 (r / residue :mod (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (d / domain :mod (c2 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :part-of p2) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :ARG1 (c3 / cascade-01 :subevent (p / phosphorylate-01)) :ARG0-of (l / lead-03 :ARG2 (a3 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "extracellular" :op2 "regulated-protein" :op3 "kinase") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.323"))) :time (e / eventual))) :ARG1 (u / use-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Erk1/2") :ARG1-of (p3 / phosphorylate-01)) :ARG2 (t / thing :ARG0-of (i / indicate-01 :ARG1 a))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "7")))) # ::id bel_pmid_1974_2316.28806 # ::date 2015-05-12T03:23:02 # ::file bel_pmid_1974_2316_28806.txt # ::snt An approximately 2.5-fold increase of Smad2 phosphorylation at Ser 465/467 was also detected in LDLR expressing, LRP1-deficient SMCs (Figure 6B, C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 19, 2015 (d / detect-01 :ARG1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (a5 / and :op1 (a2 / amino-acid :mod "465" :name (n / name :op1 "serine") :part-of (p2 / protein :name (n2 / name :op1 "Smad2") :xref (x / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a6 / amino-acid :mod "467" :name (n6 / name :op1 "serine") :part-of p2 :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :ARG2 (a3 / approximately :op1 (p3 / product-of :value "2.5"))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "6B") :op2 (f2 / figure :mod "6C"))) :location (c / cell :name (n4 / name :op1 "SMC") :mod (p5 / protein :name (n5 / name :op1 "LRP1") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:LRP1_HUMAN" :prob "1.003")) :ARG3-of (e / express-03 :ARG2 (p4 / protein :name (n3 / name :op1 "LDLR") :xref (x1 / xref :value "UNIPROT:LDLR_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1974_2316.28914 # ::date 2015-05-12T04:34:20 # ::file bel_pmid_1974_2316_28914.txt # ::snt About a two-fold increase of PDGFRb expression was detected in smLRP1-/- mice regardless of LDLR genotype (Figure 2A, C). Increased Erk1/2 phosphorylation was also observed in these aortas (Figure 2A). These data suggest that the expression and activation of PDGFRb is only regulated by LRP1, not LDLR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (m / multi-sentence :snt1 (d / detect-01 :ARG1 (i / increase-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "PDGFRb") :xref (x2 / xref :value "UNIPROT:PGFRB_HUMAN" :prob "0.673"))) :ARG2 (a / about :op1 (p3 / product-of :value "2"))) :location (m2 / mouse :mod (p4 / protein :name (n2 / name :op1 "smLRP1") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:SMLR1_HUMAN" :prob "0.272"))) :ARG1-of (r3 / regardless-91 :ARG2 (g / genotype :mod (p5 / protein :name (n3 / name :op1 "LDLR") :xref (x4 / xref :value "UNIPROT:LDLR_HUMAN" :prob "1.003")))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2C")))) :snt2 (o / observe-01 :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Erk1/2")) :ARG1-of (i2 / increase-01) :location (a4 / aorta :mod (t / this))) :mod (a3 / also) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "2A"))) :snt3 (s / suggest-01 :ARG0 (d4 / data :mod (t2 / this)) :ARG1 (c / contrast-01 :ARG1 (r / regulate-01 :ARG0 (p6 / protein :name (n5 / name :op1 "LRP1") :xref (x1 / xref :value "UNIPROT:LRP1_HUMAN" :prob "1.003")) :ARG1 (a5 / and :op1 (e3 / express-03 :ARG2 (p7 / protein :name (n6 / name :op1 "PDGFRb") :xref (x / xref :value "UNIPROT:PGFRB_HUMAN" :prob "0.673"))) :op2 (a6 / activate-01 :ARG1 p7)) :mod (o2 / only)) :ARG2 (r2 / regulate-01 :polarity "-" :ARG0 (p8 / protein :name (n7 / name :op1 "LDLR") :xref (x5 / xref :value "UNIPROT:LDLR_HUMAN" :prob "1.003")) :ARG1 a5)))) # ::id bel_pmid_1974_2316.28918 # ::date 2015-05-12T05:00:16 # ::file bel_pmid_1974_2316_28918.txt # ::snt Studies from our laboratory have shown that LRP1 suppresses PDGF receptor b (PDGFRb) activation and protects against atherosclerosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (s / show-01 :ARG0 (s2 / study-01 :source (l / laboratory :poss-of (w / we))) :ARG1 (a / and :op1 (s3 / suppress-01 :ARG0 (p / protein :name (n / name :op1 "LRP1") :xref (x1 / xref :value "UNIPROT:LRP1_HUMAN" :prob "1.003")) :ARG1 (a2 / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "PDGF" :op2 "receptor" :op3 "b") :xref (x / xref :value "UNIPROT:PDGFC_HUMAN" :prob "0.273")))) :op2 (p3 / protect-01 :ARG0 p :ARG2 (a3 / atherosclerosis)))) # ::id bel_pmid_1980_5133.8276 # ::date 2015-05-12T05:06:15 # ::file bel_pmid_1980_5133_8276.txt # ::snt Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (c2 / cause-01 :ARG1 (r / require-01 :ARG0 (u / upregulate-01 :ARG1 (g2 / gene :ARG1-of (s / specific-02 :ARG2 (c / cell :name (n2 / name :op1 "M2"))))) :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "Cebpb") :xref (x / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.604"))) :purpose (i / infiltrate-01) :location (m / macrophage))) # ::id bel_pmid_1980_5133.25992 # ::date 2015-05-12T05:24:27 # ::file bel_pmid_1980_5133_25992.txt # ::snt deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1, Il10, II13ra, and Arg-1 genes, whereas the inflammatory (M1) genes Il1, Il6, Tnfa, and Il12 are not affected # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (a / abrogate-01 :ARG0 (d / delete-01 :ARG1 (p / protein-segment :quant "2" :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n / name :op1 "CREB") :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))) :part-of (m3 / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (p4 / protein :name (n2 / name :op1 "Cebpb") :xref (x7 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.604")))))) :ARG1 (i / induce-01 :ARG2 p4) :time (a2 / activate-01 :ARG1 (m2 / macrophage))) :snt2 (b2 / block-01 :ARG0 (t2 / this) :ARG1 (i2 / induce-01 :ARG2 (g / gene :ARG2-of (i3 / include-91 :ARG1 (a3 / and :op1 (g2 / gene :name (n5 / name :op1 "Msr1") :xref (x4 / xref :value "UNIPROT:MSRE_HUMAN" :prob "0.602")) :op2 (g3 / gene :name (n6 / name :op1 "Il10") :xref (x3 / xref :value "UNIPROT:IL10_HUMAN" :prob "0.654")) :op3 (g4 / gene :name (n7 / name :op1 "II13ra")) :op4 (g5 / gene :name (n8 / name :op1 "Arg-1") :xref (x2 / xref :value "UNIPROT:ARGI1_HUMAN" :prob "0.592")))) :ARG1-of (s / specific-02 :ARG2 (c2 / cell :name (n4 / name :op1 "M2")))) :mod (d2 / downstream)) :ARG1-of (c / contrast-01 :ARG2 (a4 / affect-01 :polarity "-" :ARG1 (g11 / gene :ARG2-of (i4 / include-91 :ARG1 (a5 / and :op1 (g7 / gene :name (n10 / name :op1 "Il1") :xref (x / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.282")) :op2 (g8 / gene :name (n11 / name :op1 "Il6") :xref (x6 / xref :value "UNIPROT:IL6_HUMAN" :prob "0.624")) :op3 (g9 / gene :name (n12 / name :op1 "Tnfa") :xref (x5 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.603")) :op4 (g10 / gene :name (n13 / name :op1 "Il12") :xref (x8 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.263")))) :ARG0-of (i5 / inflame-01)))))) # ::id bel_pmid_1984_2832.19720 # ::date 2015-05-12T06:34:03 # ::file bel_pmid_1984_2832_19720.txt # ::snt Studies using TLR-4 -/- mice have demonstrated that induction of MCP-1 in BAL fluid upon exposure of mice to subacute (exposed for a period of 5 weeks) levels of CS depends on the presence of wild-type TLR-4, whereas TLR-4 plays a minor role in MCP-1 induction in the presence of chronic smoke exposure (26 weeks) [45]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (d / demonstrate-01 :ARG0 (s / study-01 :ARG0-of (u / use-01 :ARG1 (m / mouse :mod (p / protein :name (n / name :op1 "TLR-4") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x3 / xref :value "UNIPROT:D0EWT7_HUMAN" :prob "1.001"))))) :ARG1 (d2 / depend-01 :ARG0 (i / induce-01 :ARG2 (p2 / protein :name (n2 / name :op1 "MCP-1") :xref (x1 / xref :value "UNIPROT:CCL2_HUMAN" :prob "1.002")) :location (f / fluid :mod (l2 / lavage :mod (a / alveolus :mod (b / bronchus)))) :time (e / expose-01 :ARG1 (m3 / mouse) :ARG2 (l / level :quant-of (p4 / protein :name (n4 / name :op1 "CS") :xref (x2 / xref :value "UNIPROT:CISY_HUMAN" :prob "1.002")) :mod (s2 / subacute)) :duration (t4 / temporal-quantity :quant "5" :unit (w / week)))) :ARG1 (p5 / present-02 :ARG1 (p6 / protein :name (n5 / name :op1 "TLR-4") :mod (w3 / wild-type) :xref (x / xref :value "UNIPROT:D0EWT7_HUMAN" :prob "1.001"))) :ARG1-of (c / contrast-01 :ARG2 (p7 / play-02 :ARG0 p6 :ARG1 (r / role :ARG1-of (m4 / minor-01) :domain (i2 / induce-01 :ARG2 p2 :condition (p8 / present-02 :ARG1 (e2 / expose-01 :ARG2 (s3 / smoke :mod (c2 / chronic)) :duration (t2 / temporal-quantity :quant "26" :unit (w2 / week))))))))) :ARG1-of (d3 / describe-01 :ARG0 (p10 / publication :ARG1-of (c3 / cite-01 :ARG2 "45")))) # ::id bel_pmid_1984_2832.26184 # ::date 2015-05-12T07:08:00 # ::file bel_pmid_1984_2832_26184.txt # ::snt LPS stimulated pulmonary neutrophil recruitment, NF-kB promoter activity, and TNF-a secretion are found to be severely impaired in GM-CSF-/- mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (f / find-01 :ARG1 (i / impair-01 :ARG1 (a / and :op1 (r / recruit-01 :ARG1 (c / cell :name (n2 / name :op1 "neutrophil") :mod (p / pulmonary)) :ARG1-of (s / stimulate-01 :ARG0 (m / molecular-physical-entity :name (n / name :op1 "LPS") :xref (x3 / xref :value "PUBCHEM:53481794" :prob "9.905254")))) :op2 (a2 / activity-06 :ARG0 (t / thing :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n3 / name :op1 "NF-kB") :xref (x / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272"))))) :op3 (s2 / secrete-01 :ARG1 (p4 / protein :name (n4 / name :op1 "TNF-a") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :manner (s3 / severe) :location (m2 / mouse :mod (p5 / protein :name (n5 / name :op1 "GM-CSF") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1984_2832.28124 # ::date 2015-05-12T07:25:09 # ::file bel_pmid_1984_2832_28124.txt # ::snt IL-1b increased the production of neutrophil chemoattractants such as Gro-alpha (CXCL1) and MIP-2 (CXCL2) in lungs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 19, 2015 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "IL-1b") :xref (x4 / xref :value "UNIPROT:O43645_HUMAN" :prob "0.671")) :ARG1 (p2 / produce-01 :ARG1 (c / chemoattractants :mod (n2 / neutrophil) :example (a / and :op1 (p3 / protein :name (n3 / name :op1 "Gro-alpha") :ARG1-of (m / mean-01 :ARG2 (p5 / protein :name (n5 / name :op1 "CXCL1") :xref (x3 / xref :value "UNIPROT:GROA_HUMAN" :prob "1.002"))) :xref (x2 / xref :value "UNIPROT:GROA_HUMAN" :prob "0.292")) :op2 (p4 / protein :name (n4 / name :op1 "MIP-2") :ARG1-of (m2 / mean-01 :ARG2 (p6 / protein :name (n6 / name :op1 "CXCL2") :xref (x / xref :value "UNIPROT:CXCL2_HUMAN" :prob "1.003"))) :xref (x1 / xref :value "UNIPROT:WDR26_HUMAN" :prob "0.672"))) :location (l / lung)))) # ::id bel_pmid_1984_2832.31640 # ::date 2015-05-12T07:34:40 # ::file bel_pmid_1984_2832_31640.txt # ::snt Tollip has been shown to associate directly with TLR-4 and inhibit TLR-4-mediated activation of NF- kB luciferase reporter vectors in a mouse macrophage cell line (RAW-264.7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG1 (a3 / and :op1 (a / associate-01 :ARG1 (p2 / protein :name (n / name :op1 "Tollip") :xref (x / xref :value "UNIPROT:TOLIP_HUMAN" :prob "0.602")) :ARG2 (p3 / protein :name (n2 / name :op1 "TLR-4") :xref (x1 / xref :value "UNIPROT:D0EWT7_HUMAN" :prob "1.001")) :ARG1-of (d / direct-02)) :op2 (i / inhibit-01 :ARG0 p2 :ARG1 (a2 / activate-01 :ARG1 (v / vector :mod (p / protein :name (n3 / name :op1 "NF-" :op2 "kB" :op3 "luciferase" :op4 "reporter"))) :ARG1-of (m / mediate-01 :ARG0 p3)) :location (c / cell-line :name (n4 / name :op1 "RAW-264.7") :mod (m2 / mouse) :mod (m3 / macrophage))))) # ::id bel_pmid_1984_2832.34344 # ::date 2015-05-12T08:00:54 # ::file bel_pmid_1984_2832_34344.txt # ::snt Treatment of sputum cells from COPD patients with acetylcholine produced increased amounts of LTB4, which was sensitive both to treatment with a muscarinic receptor antagonist and to the inhibition of ERK- 1/2 phosphorylation. This increased LTB4 synthesis also directly correlated with increased neutrophil chemotaxis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt1 (p2 / produce-01 :ARG0 (t / treat-04 :ARG1 (c / cell :mod (s / sputum) :source (p3 / patient :mod (d / disease :name (n2 / name :op1 "COPD")))) :ARG2 (s4 / small-molecule :name (n / name :op1 "acetylcholine") :xref (x3 / xref :value "PUBCHEM:187" :prob "16.403933"))) :ARG1 (a / amount :ARG1-of (i / increase-01) :quant-of (p4 / protein :name (n3 / name :op1 "LTB4") :ARG0-of (s2 / sensitive-03 :ARG1 (a3 / and :op1 (t2 / treat-04 :ARG2 (p5 / protein :name (n4 / name :op1 "muscarinic" :op2 "receptor" :op3 "antagonist") :xref (x2 / xref :value "UNIPROT:ACM1_HUMAN" :prob "0.272"))) :op2 (i2 / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "ERK-1/2")))))) :xref (x1 / xref :value "UNIPROT:CP4F3_HUMAN" :prob "0.312")))) :snt2 (c2 / correlate-01 :ARG1 (s3 / synthesize-01 :ARG1 (p6 / protein :name (n6 / name :op1 "LTB4") :xref (x / xref :value "UNIPROT:CP4F3_HUMAN" :prob "0.312")) :ARG1-of (i3 / increase-01) :mod (t3 / this)) :ARG2 (c3 / chemotaxis :mod (n7 / neutrophil) :ARG1-of (i4 / increase-01)) :mod (a4 / also) :ARG1-of (d2 / direct-02))) # ::id bel_pmid_1984_2832.36854 # ::date 2015-05-12T11:16:20 # ::file bel_pmid_1984_2832_36854.txt # ::snt IRAK-1 activation and recruitment is essential for activation of TRAF6 (TNF-associated factor 6), which is an essential adaptor for MyD88-dependent NF-kB activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (e / essential :domain (a / and :op1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "IRAK-1") :xref (x3 / xref :value "UNIPROT:IRAK1_HUMAN" :prob "1.002"))) :op2 (r / recruit-01 :ARG1 e2) :purpose (a3 / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "TRAF6") :ARG0-of (a4 / adapt-01 :ARG1 (a5 / activate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "NF-kB") :xref (x / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272")) :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n4 / name :op1 "MyD88") :xref (x1 / xref :value "UNIPROT:MYD88_HUMAN" :prob "0.663")))) :mod (e3 / essential)) :xref (x2 / xref :value "UNIPROT:TRAF6_HUMAN" :prob "1.003"))))) # ::id bel_pmid_1984_2832.38430 # ::date 2015-05-12T11:32:17 # ::file bel_pmid_1984_2832_38430.txt # ::snt It has also been shown that IL-1b stimulates the release and activity of MMP-9 (matrix metalloproteinase-9) from AM obtained from COPD smokers, which is significantly higher in comparison with those obtained from healthy smokers and non-smokers [155]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s2 / show-01 :ARG1 (s3 / stimulate-01 :ARG0 (p2 / protein :name (n / name :op1 "IL-1b") :xref (x / xref :value "UNIPROT:O43645_HUMAN" :prob "0.671")) :ARG1 (a2 / and :op1 (r / release-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MMP-9") :xref (x1 / xref :value "UNIPROT:MMP9_HUMAN" :prob "1.002"))) :op2 (a3 / activity-06 :ARG0 e) :source (s7 / small-molecule :name (n3 / name :op1 "AM") :ARG1-of (o / obtain-01 :ARG2 (p / person :ARG0-of (s / smoke-02) :mod (d / disease :name (n4 / name :op1 "COPD")))) :xref (x2 / xref :value "PUBCHEM:21810" :prob "11.082318")) :ARG1-of (h / high-02 :degree (m / more) :ARG1-of (s4 / significant-02) :compared-to (a5 / and :op1 (r2 / release-01 :ARG1 e) :op2 (a6 / activity-06 :ARG0 e) :ARG1-of (o2 / obtain-01 :ARG2 (a4 / and :op1 (p3 / person :ARG0-of (s5 / smoke-02) :mod (h2 / healthy)) :op2 (p4 / person :ARG0-of (s6 / smoke-02 :polarity "-") :mod h2))))))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "155")))) # ::id bel_pmid_1984_2832.38592 # ::date 2015-05-12T23:39:44 # ::file bel_pmid_1984_2832_38592.txt # ::snt Similarly, preincubation with F(ab')2 fragments of a monoclonal anti-human IL-8 antibody inhibited neutrophil chemotaxis to CB sputum supernatants by 75% [30]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i / inhibit-01 :ARG0 (p2 / preincubate-01 :ARG2 (f / fragment-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "F(ab')2") :part-of (a / antibody :name (n4 / name :op1 "monoclonal" :op2 "anti-human" :op3 "IL-8" :op4 "antibody") :ARG0-of (c2 / counter-01 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-8") :mod (h / human) :xref (x / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003"))) :mod (m / monoclone))))) :ARG1 (c / chemotaxis :mod (n2 / neutrophil)) :location (s / supernatant :mod (s2 / sputum :mod (d2 / disease :name (n / name :op1 "chronic" :op2 "bronchitis")))) :quant (p / percentage-entity :value "75") :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "30"))) :ARG1-of (r / resemble-01)) # ::id bel_pmid_1984_6878.15410 # ::date 2015-05-12T23:48:30 # ::file bel_pmid_1984_6878_15410.txt # ::snt Including adenosine with IFN-gamma treatment delayed any measureable increase in STAT1 activation by >60 min, and led to significantly reduced STAT1 activity at 60, 120, and 240 min post-stimulation compared with cells treated with IFN-gamma alone ( p < 0.05; Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (d / delay-01 :ARG0 (i / include-01 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "adenosine") :xref (x2 / xref :value "PUBCHEM:60961" :prob "11.072318")) :ARG2 (t / treat-04 :ARG2 (p / protein :name (n / name :op1 "IFN-gamma") :xref (x1 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")))) :ARG1 (i2 / increase-01 :ARG1 (a3 / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "STAT1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))) :ARG1-of (m / measure-01 :ARG1-of (p5 / possible-01))) :ARG2 (m2 / more-than :op1 (t2 / temporal-quantity :quant "60" :unit (m3 / minute)))) :op2 (l / lead-03 :ARG0 i :ARG2 (r / reduce-01 :ARG1 (a4 / activity-06 :ARG0 p2) :ARG2 (s / significant-02) :time (a2 / after :op1 (s2 / stimulate-01 :quant (a5 / and :op1 (t3 / temporal-quantity :quant "60" :unit m3) :op2 (t4 / temporal-quantity :quant "120" :unit m3) :op3 (t5 / temporal-quantity :quant "240" :unit m3)))) :compared-to (c / cell :ARG1-of (t6 / treat-04 :ARG2 p :manner (a6 / alone))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4")) :ARG1-of (s3 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.05"))) # ::id bel_pmid_1984_6878.18750 # ::date 2015-05-13T00:12:19 # ::file bel_pmid_1984_6878_18750.txt # ::snt Pretreatment with CCPA (A1 receptor agonist), NECA (non-specific A1 and A2 receptor agonist), and CGS21680 (A2A receptor agonist) all resulted in a 14- to 15-fold increase in STAT1 activity over control cells, levels comparable to what was observed in cells treated with IFN-gamma alone (Fig. 6, A?C) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (r / result-01 :ARG1 (p / pretreat-01 :ARG3 (a2 / and :op1 (a3 / agonist :name (n / name :op1 "CCPA") :ARG1-of (m / mean-01 :ARG2 (a12 / agonist :mod (r3 / receptor :name (n8 / name :op1 "A1"))))) :op2 (a4 / agonist :name (n2 / name :op1 "NECA") :ARG1-of (m2 / mean-01 :ARG2 (a10 / and :op1 (a13 / agonist :mod "r2") :op2 (a14 / agonist :mod "r2") :ARG1-of (s / specific-02 :polarity "-")))) :op3 (a5 / agonist :name (n3 / name :op1 "CGS21680") :ARG1-of (m3 / mean-01 :ARG2 (a9 / agonist :mod (r2 / receptor :name (n7 / name :op1 "A2A"))))))) :ARG2 (i / increase-01 :ARG1 (a6 / activity-06 :ARG0 (p2 / protein :name (n4 / name :op1 "STAT1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))) :ARG2 (b / between :op1 (p3 / product-of :value "14") :op2 (p4 / product-of :value "15") :ARG1-of (c3 / comparable-03 :ARG2 (l2 / level :ARG1-of (o / observe-01 :location (c4 / cell :ARG1-of (t2 / treat-04 :ARG2 (p5 / protein :name (n5 / name :op1 "IFN-gamma") :mod (a7 / alone) :xref (x1 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")))))))) :location (c / cell :mod (c2 / control-01)))) :ARG1-of (d / describe-01 :ARG0 (a8 / and :op1 (f / figure :mod "6A") :op2 (f2 / figure :mod "6C")))) # ::id bel_pmid_1984_6878.27666 # ::date 2015-05-13T00:22:13 # ::file bel_pmid_1984_6878_27666.txt # ::snt As expected, we found that IFN-gamma led to a rapid rise in both JAK1 and JAK2 phosphorylation band density above baseline levels, and this IFN-gamma-induced JAK activation was not altered by adenosine treatment at any time point (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (f / find-01 :ARG0 (w / we) :ARG1 (l / lead-03 :ARG1 (p2 / protein :name (n / name :op1 "IFN-gamma") :xref (x3 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")) :ARG2 (r / rise-01 :ARG1 (d / density :poss (b / band :mod (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e3 / enzyme :name (n2 / name :op1 "JAK1") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n3 / name :op1 "JAK2") :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")))))) :ARG4 (a7 / above :op1 (l2 / level :mod (b2 / baseline))) :mod (r2 / rapid)))) :op2 (a3 / alter-01 :polarity "-" :ARG0 (t / treat-04 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "adenosine") :xref (x4 / xref :value "PUBCHEM:60961" :prob "11.072318"))) :ARG1 (a4 / activate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "JAK") :xref (x / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")) :ARG2-of (i / induce-01 :ARG0 p2)) :time (p6 / point :mod (a6 / any))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s / show-01 :polarity "-"))) :ARG1-of (e / expect-01)) # ::id bel_pmid_1996_7723.42048 # ::date 2015-05-11T12:38:04 # ::file bel_pmid_1996_7723_42048.txt # ::snt Mechanistically, endothelial a6-integrin deficiency elevated significantly VEGF-mediated angiogenesis both in vivo and ex vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (e / elevate-01 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "a6-integrin") :mod (e2 / endothelium))) :ARG1 (a / angiogenesis :ARG1-of (m2 / mediate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")))) :ARG1-of (s / significant-02) :manner (m / mechanistic) :manner (a2 / and :op2 (i / in-vivo) :op2 (e3 / ex-vivo) :mod (b / both))) # ::id bel_pmid_1996_7723.42050 # ::date 2015-05-11T12:39:11 # ::file bel_pmid_1996_7723_42050.txt # ::snt In particular, a6-integrin-deficient endothelial cells displayed increased levels of VEGF-receptor 2 (VEGFR2) and VEGF-mediated downstream ERK1/2 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 19, 2015 (d / display-01 :ARG0 (c / cell :mod (e / endothelium) :ARG0-of (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "a6-integrin")))) :ARG1 (a / and :op1 (l2 / level :quant-of (p2 / protein :name (n2 / name :op1 "VEGF-receptor" :op2 "2") :xref (x / xref :value "UNIPROT:VGFR2_HUMAN" :prob "0.253")) :ARG1-of (i / increase-01)) :op2 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2")) :location (d2 / downstream) :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "VEGF") :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003"))))) :mod (p4 / particular)) # ::id bel_pmid_1996_7723.42052 # ::date 2015-05-11T14:07:22 # ::file bel_pmid_1996_7723_42052.txt # ::snt Blood vessels associated with IDC showed a significant reduction in mean a6-integrin pixel intensity when compared with blood vessels from normal breast tissue (**p < 0.0001, Figure 1b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (v / vessel :mod (b / blood) :ARG1-of (a / associate-01 :ARG2 (d / disease :name (n3 / name :op1 "IDC")))) :ARG1 (r / reduce-01 :ARG1 (i2 / intensify-01 :ARG1 (p / pixel :mod (p4 / protein :name (n / name :op1 "a6-integrin"))) :mod (m / mean)) :ARG2 (s2 / significant-02) :compared-to (v2 / vessel :mod (b2 / blood) :location (t / tissue :mod (b3 / breast) :ARG1-of (n2 / normal-02))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1b"))) # ::id bel_pmid_1996_7723.42058 # ::date 2015-05-11T15:11:06 # ::file bel_pmid_1996_7723_42058.txt # ::snt The results showed that there was a significant increase in tumour blood vessel density in a6fl/fl-Tie1Cre+ mice compared with a6fl/fl-Tie1Cre- controls (*p < 0.02, Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (t2 / thing :ARG2-of (r / result-01)) :ARG1 (i / increase-01 :ARG1 (d / density :poss (v / vessel :mod (b / blood) :mod (t / tumor))) :ARG2 (s2 / significant-02) :location (m / mouse :mod (g / gene :name (n / name :op1 "a6fl/fl-Tie1Cre") :mod (w / wild-type))) :ARG1-of (c / compare-01 :ARG2 (c2 / control :mod (g2 / gene :name (n2 / name :op1 "a6fl/fl-Tie1Cre") :ARG2-of (m2 / mutate-01 :mod "-/-")))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.02"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id bel_pmid_1996_7723.42064 # ::date 2015-05-11T15:38:52 # ::file bel_pmid_1996_7723_42064.txt # ::snt As predicted, the absence of a6-integrin reduced the ability of the a6-/— cells to adhere and migrate to Lm but did not affect the ability of these cells to adhere or migrate on Fn, Col or Vn (*p < 0.05, Figures 5c and 5d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / reduce-01 :ARG0 (a / absent-01 :ARG1 (p / protein :name (n / name :op1 "a6-integrin"))) :ARG1 (c / capable-01 :ARG1 (c2 / cell :mod (p2 / protein :name (n2 / name :op1 "a6-integrin") :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG2 (a2 / and :op1 (a3 / adhere-01 :ARG1 c2 :ARG2 (p3 / protein :name (n3 / name :op1 "laminin") :xref (x / xref :value "UNIPROT:LM-111_HUMAN_COMPLEX" :prob "0.33"))) :op2 (m2 / migrate-01 :ARG0 c2 :ARG2 p3))) :ARG1-of (c3 / contrast-01 :ARG2 (a4 / affect-01 :polarity "-" :ARG0 a :ARG1 (c4 / capable-01 :ARG1 c2 :ARG2 (a5 / and :op1 (a6 / adhere-01 :ARG1 c2 :ARG2 (o / or :op1 (p4 / protein :name (n4 / name :op1 "fibronectin") :xref (x2 / xref :value "UNIPROT:FINC_HUMAN" :prob "0.703")) :op2 (p5 / protein :name (n5 / name :op1 "collagen") :xref (x3 / xref :value "UNIPROT:COLLAGEN_I_HUMAN" :prob "1.002")) :op3 (p6 / protein :name (n6 / name :op1 "vitronectin") :xref (x1 / xref :value "UNIPROT:VTNC_HUMAN" :prob "0.703")))) :op2 (m3 / migrate-01 :ARG0 c2 :ARG1 (o2 / or :op1 p4 :op2 p5 :op2 p6)))))) :ARG1-of (d / describe-01 :ARG0 (a7 / and :op1 (f / figure :mod "5c") :op2 (f2 / figure :mod "5d"))) :ARG1-of (p9 / predict-01) :ARG1-of (s / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) # ::id bel_pmid_1996_7723.42068 # ::date 2015-05-12T10:25:19 # ::file bel_pmid_1996_7723_42068.txt # ::snt Western blot analysis revealed that VEGF stimulated the phosphorylation of ERK1/2 in both a6fl/fl-Tie1Cre-and a6fl/fl-Tie1Cre+ endothelial cells and that the levels of phosphorylated ERK1/2 (pERK1/2) detected in a6fl/fl-Cre+ endothelial cells after a VEGF stimulus were dramatically higher than those detected in a6fl/flTie1Cre- endothelial cells (Figure 6b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reveal-01 :ARG0 (a5 / analyze-01 :manner (i / immunoblot-01)) :ARG1 (a2 / and :op1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :ARG1 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2"))) :location (a3 / and :op1 (c / cell :mod (g2 / gene :name (n3 / name :op1 "a6fl/fl-Tie1Cre") :ARG2-of (m / mutate-01 :mod "-/-")) :mod (e2 / endothelium)) :op2 (c2 / cell :mod (g / gene :name (n4 / name :op1 "a6fl/fl-Tie1Cre") :mod (w2 / wild-type)) :mod e2))) :op2 (h / high-02 :ARG1 (l / level :quant-of (e3 / enzyme :name (n5 / name :op1 "ERK1/2") :ARG3-of (p5 / phosphorylate-01) :ARG1-of (d2 / detect-01 :location c))) :mod (d / dramatic) :time (a4 / after :op1 (s2 / stimulus :mod p)) :degree (m2 / more) :ARG1-of (c3 / compare-01 :ARG2 (l2 / level :ARG1-of (d3 / detect-01 :location c2))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "6b"))) # ::id bel_pmid_1996_7723.42070 # ::date 2015-05-12T12:35:38 # ::file bel_pmid_1996_7723_42070.txt # ::snt Furthermore, blockade of VEGFR2 using the function blocking monoclonal antibody to VEGFR2, DC101 [26], ablated these enhanced VEGF-mediated responses, demonstrating that the enhanced ERK1/2 phosphorylation was via VEGFR2 (Figure 6b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (a2 / ablate-01 :ARG1 (t / thing :ARG2-of (r / respond-01) :mod (t2 / this) :ARG1-of (e2 / enhance-01) :ARG1-of (m2 / mediate-01 :ARG0 (p / protein :name (n5 / name :op1 "VEGF") :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")))) :ARG3 (b / block-01 :ARG1 (p3 / protein :name (n / name :op1 "VEGFR2") :xref (x / xref :value "UNIPROT:VGFR2_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "26"))) :ARG0-of (u / use-01 :ARG1 (s / small-molecule :name (n7 / name :op1 "DC101") :ARG0-of (c3 / counter-01 :ARG1 p3) :ARG1-of (m / mean-01 :ARG2 (a3 / antibody :mod (m3 / monoclonal) :ARG0-of (b2 / block-01 :ARG1 (f2 / function-01))))))) :ARG0-of (d2 / demonstrate-01 :ARG1 (p4 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n6 / name :op1 "ERK1/2")) :ARG2 p3 :ARG1-of (e4 / enhance-01))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "6b")))) # ::id bel_pmid_2001_8915.2588 # ::date 2015-05-12T13:30:19 # ::file bel_pmid_2001_8915_2588.txt # ::snt The mouse tumors mimic molecular hallmarks of their human tumor counterparts, including elevated IL-6/Stat3/Bcl-X(L) signaling. The newly developed mouse strains may provide a good preclinical research tool for the design and testing of new approaches to target IL-6 in treatment and prevention of human PCNs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m / multi-sentence :snt1 (m2 / mimic-01 :ARG0 (t / tumor :mod (m3 / mouse)) :ARG1 (h / hallmark :mod (m4 / molecule) :poss (c / counterpart :mod (t2 / tumor :mod (h2 / human)) :poss m3) :ARG2-of (i / include-01 :ARG1 (s / signal-07 :ARG1 (p / pathway :name (n / name :op1 "IL-6/Stat3/Bcl-X(L)")) :ARG1-of (e / elevate-01))))) :snt2 (p2 / possible-01 :ARG1 (p3 / provide-01 :ARG0 (s2 / strain :mod (m5 / mouse) :ARG1-of (d / develop-02 :ARG1-of (n2 / new-01))) :ARG1 (t4 / tool :mod (p4 / preclinical) :mod (r / research-01) :purpose (a / and :op1 (d2 / design-01 :ARG1 (a2 / approach-02 :ARG1 (t6 / target-01 :ARG1 (p5 / protein :name (n4 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :purpose (a3 / and :op1 (t7 / treat-03 :ARG1 (d3 / disease :name (n5 / name :op1 "PCN") :mod (h3 / human))) :op2 (p6 / prevent-01 :ARG1 d3))) :ARG1-of (n3 / new-01))) :op2 (t5 / test-01 :ARG1 a2)) :ARG1-of (g / good-02))))) # ::id bel_pmid_2013_1264.5500 # ::date 2015-05-12T14:13:47 # ::file bel_pmid_2013_1264_5500.txt # ::snt In contrast to TGFbeta1/IL-6, IL-23 was critical for the induction of IL-22 in CD4+ T cells from both naive and CII-immunized DBA/1 mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / critical-02 :ARG1 (p / protein :name (n / name :op1 "IL-23") :ARG1-of (c3 / contrast-01 :ARG2 (m4 / macro-molecular-complex :part (p5 / protein :name (n8 / name :op1 "TGFbeta1") :xref (x5 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.673")) :part (p6 / protein :name (n9 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :xref (x / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.312")) :ARG3 (i / induce-01 :ARG2 (p2 / protein :name (n2 / name :op1 "IL-22") :xref (x1 / xref :value "UNIPROT:IL22_HUMAN" :prob "1.002")) :location (c2 / cell :name (n3 / name :op1 "T") :mod (p3 / protein :name (n4 / name :op1 "CD4") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:CD4_HUMAN" :prob "1.003")) :source (a / and :op1 (o / organism :name (n5 / name :op1 "DBA/1" :op2 "mouse") :mod (n7 / naive)) :op2 (o2 / organism :name (n6 / name :op1 "DBA/1" :op2 "mouse") :ARG1-of (i2 / immunize-01 :ARG0 (p4 / protein :name (n10 / name :op1 "collagen" :op2 "II") :xref (x4 / xref :value "UNIPROT:COLLAGEN_I_HUMAN" :prob "0.361")))) :mod (b / both))))) # ::id bel_pmid_2013_1264.5504 # ::date 2015-05-12T15:05:29 # ::file bel_pmid_2013_1264_5504.txt # ::snt : In CD4+ T cells from naive DBA/1 mice, IL-23 alone hardly induced retinoic acid-related orphan receptor gammat (RORgammat), Th17 polarization, and Th17 cytokines, but it inhibited T-bet expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "IL-23") :mod (a / alone) :xref (x3 / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.312")) :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "retinoic" :op2 "acid-related" :op3 "orphan" :op4 "receptor" :op5 "gammat") :xref (x / xref :value "UNIPROT:RORG_HUMAN" :prob "0.372")) :op2 (p3 / polarize-01 :ARG1 (c2 / cell :name (n3 / name :op1 "Th17"))) :op3 (c3 / cytokine :mod c2)) :manner (h / hardly)) :ARG2 (i2 / inhibit-01 :ARG0 p :ARG1 (e / express-03 :ARG1 (p4 / protein :name (n4 / name :op1 "T-bet") :xref (x1 / xref :value "UNIPROT:TBX21_HUMAN" :prob "0.592")))) :location (c4 / cell :name (n5 / name :op1 "T") :mod (p5 / protein :name (n6 / name :op1 "CD4") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:CD4_HUMAN" :prob "1.003")) :source (o / organism :name (n8 / name :op1 "DBA/1" :op2 "mouse")))) # ::id bel_pmid_2013_1264.20312 # ::date 2015-05-12T15:27:48 # ::file bel_pmid_2013_1264_20312.txt # ::snt However, in CD4+ T cells from naive mice, IL-23 significantly increased the TGFbeta1/IL-6-induced Th17 polarization, including elevated levels of IL-17A and IL-17F and decreased expression of T-bet and FoxP3. Of note, the IL-23-induced increase in IL-17A and IL-17F levels was prevented in T-bet-deficient mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (c / contrast-01 :ARG2 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "IL-23") :xref (x10 / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.312")) :ARG1 (p2 / polarize-01 :ARG1 (c2 / cell :name (n2 / name :op1 "Th17")) :ARG2-of (i2 / induce-01 :ARG0 (m2 / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "TGFbeta1") :xref (x4 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.673")) :part (p4 / protein :name (n4 / name :op1 "IL-6") :xref (x6 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :ARG2 (s / significant-02) :ARG2-of (i3 / include-01 :ARG1 (a / and :op1 (l / level :quant-of (p5 / protein :name (n5 / name :op1 "IL-17A") :xref (x7 / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003")) :ARG1-of (e / elevate-01)) :op2 (l2 / level :quant-of (p6 / protein :name (n6 / name :op1 "IL-17F") :xref (x3 / xref :value "UNIPROT:IL17F_HUMAN" :prob "1.003")) :ARG1-of e) :op3 (e2 / express-03 :ARG2 (a2 / and :op1 (p7 / protein :name (n7 / name :op1 "T-bet") :xref (x5 / xref :value "UNIPROT:TBX21_HUMAN" :prob "0.592")) :op2 (p8 / protein :name (n8 / name :op1 "FoxP3") :xref (x8 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.633"))) :ARG1-of (d / decrease-01))))) :location (c3 / cell :name (n9 / name :op1 "T") :mod (p9 / protein :name (n10 / name :op1 "CD4") :mod (w / wild-type) :xref (x9 / xref :value "UNIPROT:CD4_HUMAN" :prob "1.003")) :source (m4 / mouse :mod (n11 / naive)))) :snt2 (p10 / prevent-01 :ARG1 (i4 / increase-01 :ARG1 (a3 / and :op1 (l3 / level :quant-of (p12 / protein :name (n13 / name :op1 "IL-17A") :xref (x / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003"))) :op2 (l4 / level :quant-of (p13 / protein :name (n14 / name :op1 "IL-17F") :xref (x11 / xref :value "UNIPROT:IL17F_HUMAN" :prob "1.003")))) :ARG2-of (i5 / induce-01 :ARG0 (p11 / protein :name (n12 / name :op1 "IL-23") :xref (x1 / xref :value "UNIPROT:IL23R_HUMAN" :prob "0.312")))) :location (m5 / mouse :ARG0-of (l5 / lack-01 :ARG1 (p14 / protein :name (n15 / name :op1 "T-bet") :xref (x2 / xref :value "UNIPROT:TBX21_HUMAN" :prob "0.592")))) :ARG1-of (n16 / note-01))) # ::id bel_pmid_2017_6957.28510 # ::date 2015-05-12T15:52:31 # ::file bel_pmid_2017_6957_28510.txt # ::snt However, on stimulation with R848 or CpG DNA, B cells from both young and old Irf5 -/- mice produced lower levels of IL-6 than the B cells from C57BL/6 mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (p / produce-01 :ARG0 (c2 / cell :name (n6 / name :op1 "B") :source (a / and :op1 (m / mouse :mod (y / young) :mod (p3 / protein :name (n2 / name :op1 "Irf5") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:IRF5_HUMAN" :prob "0.603"))) :op2 (m3 / mouse :mod (o / old) :mod p3) :mod (b / both))) :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (l2 / low-04 :degree (m4 / more)) :compared-to (c3 / cell :name (n5 / name :op1 "B") :source (o3 / organism :name (n7 / name :op1 "C57BL/6" :op2 "mouse")))) :time (s / simulate-01 :ARG2 (o2 / or :op1 (s2 / small-molecule :name (n3 / name :op1 "R848") :xref (x2 / xref :value "PUBCHEM:159603" :prob "18.86067")) :op2 (n8 / nucleic-acid :name (n4 / name :op1 "CpG" :op2 "DNA")))))) # ::id bel_pmid_2017_6957.28512 # ::date 2015-05-12T16:19:42 # ::file bel_pmid_2017_6957_28512.txt # ::snt There was also a decrease in IRF-4 expression in Irf5 -/- B cells, seen both on RNA and protein levels (Fig. 4 A and B ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (d / decrease-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "IRF-4") :xref (x1 / xref :value "UNIPROT:IRF4_HUMAN" :prob "1.002")) :ARG3 (c2 / cell-line :name (n3 / name :op1 "B") :mod (p2 / protein :name (n2 / name :op1 "Irf5") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:IRF5_HUMAN" :prob "0.603")))) :mod (a / also) :ARG1-of (s / see-01 :location (a2 / and :op1 (l2 / level :quant-of (n4 / nucleic-acid :name (n5 / name :op1 "RNA"))) :op2 (l / level :quant-of (p3 / protein)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B")))) # ::id bel_pmid_2017_6957.28516 # ::date 2015-05-12T16:25:55 # ::file bel_pmid_2017_6957_28516.txt # ::snt Analysis of the expression of these factors by semiquantitative RT-PCR shows that purified B cells from both young and old Irf5 -/- mice exhibit significantly lower levels of Blimp-1 mRNA than B cells from the age-matched C57BL/6 mice (Fig. 4A ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (e / express-03 :ARG2 (f / factor :mod (t / this))) :manner (t2 / thing :name (n4 / name :op1 "RT-PCR") :mod (q / quantity :degree (s2 / semi)))) :ARG1 (e2 / exhibit-01 :ARG0 (c / cell :name (n6 / name :op1 "B") :ARG1-of (p / purify-01) :source (a2 / and :op1 (m / mouse :mod (y / young) :mod (p2 / protein :name (n / name :op1 "Irf5") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:IRF5_HUMAN" :prob "0.603"))) :op2 (m3 / mouse :mod (o / old) :mod p2) :mod (b / both))) :ARG1 (l / level :quant-of (n8 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Blimp-1") :xref (x1 / xref :value "UNIPROT:PRDM1_HUMAN" :prob "0.612")))) :ARG1-of (l2 / low-04 :degree (m5 / more) :compared-to (c2 / cell :name (n5 / name :op1 "B") :source (o2 / organism :name (n7 / name :op1 "C57BL/6" :op2 "mouse") :ARG1-of (m6 / match-01 :ARG2 (a3 / age)))) :ARG1-of (s3 / significant-02)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "A4"))) # ::id bel_pmid_2020_0353.35654 # ::date 2015-05-12T16:54:25 # ::file bel_pmid_2020_0353_35654.txt # ::snt we found that IL-33R signaling induced a time-dependent activation of Erk1/2, protein kinase B (PKB), JNK1/2, NF-kB, and p38, and degradation of IkB (supplemental Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (i2 / induce-01 :ARG0 (s / signal-07 :ARG0 (p / protein :name (n / name :op1 "IL-33R") :xref (x4 / xref :value "UNIPROT:IL3RA_HUMAN" :prob "0.333"))) :ARG2 (a3 / and :op1 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "Erk1/2")) :op2 (e2 / enzyme :name (n3 / name :op1 "protein" :op2 "kinase" :op3 "B") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.703")) :op3 (e3 / enzyme :name (n4 / name :op1 "JNK1/2")) :op4 (p2 / protein :name (n5 / name :op1 "NF-kB") :xref (x / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272")) :op5 (e4 / enzyme :name (n6 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))) :ARG0-of (d / depend-01 :ARG1 (t / time))) :op2 (d2 / degrade-01 :ARG1 (p4 / protein :name (n7 / name :op1 "IkB") :xref (x3 / xref :value "UNIPROT:IKKB_HUMAN" :prob "0.382"))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "1B" :mod (s2 / supplement)))) # ::id bel_pmid_2020_0353.38622 # ::date 2015-05-12T17:14:28 # ::file bel_pmid_2020_0353_38622.txt # ::snt Y721-c-Kit is autophosphorylated in response to stem cell factor (SCF). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "721" :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "c-Kit") :xref (x1 / xref :value "UNIPROT:SCF_HUMAN" :prob "0.233")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 a :ARG2-of (r / respond-01 :ARG1 (p3 / protein :name (n3 / name :op1 "stem" :op2 "cell" :op3 "factor") :xref (x / xref :value "UNIPROT:SCF_HUMAN" :prob "0.703")))) # ::id bel_pmid_2022_6760.28942 # ::date 2015-05-12T17:31:11 # ::file bel_pmid_2022_6760_28942.txt # ::snt The supernatants from cultured LN cells were also collected and the production of various cytokines (TNF-alpha, IFN-gamma, IL-6, and IL-17) was measured (Fig. 3B). The cytokine levels in BLT1-/- cells were significantly lower than those in BLT1+/+ cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (a / and :op1 (c / collect-01 :ARG1 (s / supernatant :source (c2 / cell :ARG1-of (c3 / culture-01) :mod (p8 / protein :name (n7 / name :op1 "laminin") :xref (x2 / xref :value "UNIPROT:LM-111_HUMAN_COMPLEX" :prob "0.33")))) :mod (a3 / also)) :op2 (m2 / measure-01 :ARG1 (p / produce-01 :ARG1 (c4 / cytokine :mod (v / various) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (c8 / cytokine :name (n / name :op1 "TNF-alpha")) :op2 (c9 / cytokine :name (n2 / name :op1 "IFN-gamma")) :op3 (c10 / cytokine :name (n3 / name :op1 "IL-6")) :op4 (c11 / cytokine :name (n4 / name :op1 "IL-17"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) :snt2 (l / low-04 :ARG1 (l3 / level :quant-of (c5 / cytokine) :location (c6 / cell :mod (p6 / protein :name (n5 / name :op1 "BLT1") :ARG2-of (m5 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:LT4R1_HUMAN" :prob "1.002")))) :degree (m4 / more) :ARG1-of (s2 / significant-02) :compared-to (l4 / level :location (c7 / cell :mod (p7 / protein :name (n6 / name :op1 "BLT1") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:LT4R1_HUMAN" :prob "1.002")))))) # ::id bel_pmid_2033_8026.31778 # ::date 2015-05-12T17:51:56 # ::file bel_pmid_2033_8026_31778.txt # ::snt Table 2 Comparison of expression ratios between microarray and RT-qPCR, lipid and mixed annotated genes ## WT vs Tyk2-/- peritoneal macrophages ## # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (c / compare-01 :ARG1 (r / ratio-of :op1 (e / express-03 :ARG1 (a / and :op1 (g / gene :mod (l / lipid)) :op2 (g2 / gene :mod (m3 / mixed)) :ARG1-of (a2 / annotate-01))) :mod (m2 / microarray)) :ARG2 (r2 / ratio-of :op1 e :mod (t / thing :name (n / name :op1 "RT-qPCR")))) :snt2 (c2 / contrast-01 :ARG1 (m4 / macrophage :mod (w / wild-type) :mod (p / peritoneum)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Tyk2") :ARG2-of (m5 / mutate-01 :mod "-/-") :mod p :xref (x / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603"))) :ARG1-of (d / describe-01 :ARG0 (t2 / table :mod "2"))) # ::id bel_pmid_2049_7020.1770 # ::date 2015-05-12T18:24:16 # ::file bel_pmid_2049_7020_1770.txt # ::snt Leptin-induced MUC5B expression was blocked by the ERK1/2 and p38 pathway inhibitors, but not by the JAK2/STAT3 pathway inhibitor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (b / block-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (a2 / and :op1 (p5 / pathway :name (n3 / name :op1 "ERK1/2")) :op2 (p3 / pathway :name (n4 / name :op1 "p38"))))) :ARG1 (e / express-03 :ARG1 (p / protein :name (n / name :op1 "MUC5B") :xref (x1 / xref :value "UNIPROT:MUC5B_HUMAN" :prob "1.003")) :ARG2-of (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "leptin") :xref (x / xref :value "UNIPROT:LEP_HUMAN" :prob "0.702")))) :ARG1-of (c / contrast-01 :ARG2 (b2 / block-01 :polarity "-" :ARG0 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p4 / pathway :name (n5 / name :op1 "JAK2/STAT3")))) :ARG1 e))) # ::id bel_pmid_2060_5485.40420 # ::date 2015-05-12T18:45:52 # ::file bel_pmid_2060_5485_40420.txt # ::snt Both IL-6 and G-CSF treatment did not markedly change surface IL-4Ra amounts on BM cells; moreover, IL-6 had a detrimental effect on cell viability, thereby preventing any further functional characterization. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (m / multi-sentence :snt1 (c / change-01 :polarity "-" :ARG0 (t / treat-04 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "G-CSF") :xref (x / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.002")) :mod (b2 / both))) :ARG1 (a2 / amount :quant-of (p3 / protein :name (n3 / name :op1 "IL-4Ra") :mod (s / surface) :xref (x1 / xref :value "UNIPROT:IL4RA_HUMAN" :prob "0.673"))) :manner (m2 / marked) :location (c2 / cell) :mod (m3 / marrow :mod (b / bone))) :snt2 (a3 / and :op2 (a4 / affect-01 :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (v / viability :mod (c3 / cell)) :mod (d / detrimental) :ARG0-of (p5 / prevent-01 :ARG1 (c4 / characterize-01 :ARG0-of (f / function-01) :mod (f2 / further) :mod (a5 / any)))))) # ::id bel_pmid_2060_5485.40422 # ::date 2015-05-12T19:08:06 # ::file bel_pmid_2060_5485_40422.txt # ::snt Despite the increased IL-4Ra expression following G-CSF treatment, this cytokine did not induce any appreciable imunosuppressive function in BM cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :polarity "-" :ARG0 (c / cytokine :mod (t / this)) :ARG2 (f / function :ARG1-of (a / appreciate-03 :ARG1-of (p / possible-01)) :mod (i2 / imunosuppressive) :mod (a2 / any)) :location (c2 / cell :mod (m / marrow :mod (b / bone))) :concession (i3 / increase-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "IL-4Ra") :xref (x / xref :value "UNIPROT:IL4RA_HUMAN" :prob "0.673")) :ARG1-of (f2 / follow-01 :ARG2 (t2 / treat-04 :ARG2 (p3 / protein :name (n2 / name :op1 "G-CSF") :xref (x1 / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.002"))))))) # ::id bel_pmid_2060_5485.40424 # ::date 2015-05-12T19:17:25 # ::file bel_pmid_2060_5485_40424.txt # ::snt GM-CSF induced a significant increase (p = 0.028 versus untreated BM) of IL-4Ra expression, and BM cells cultured with this cytokine inhibited CTL activity in a dose-dependent fashion (Figures 1A and 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "GM-CSF") :xref (x1 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.003")) :ARG2 (i2 / increase-01 :ARG1 (e2 / express-03 :ARG2 (p4 / protein :name (n2 / name :op1 "IL-4Ra") :xref (x / xref :value "UNIPROT:IL4RA_HUMAN" :prob "0.673"))) :ARG2 (s / significant-02) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.028" :ARG5 (c6 / cell-line :mod "m2" :ARG1-of (t / treat-04 :polarity "-"))))) :op2 (i3 / inhibit-01 :ARG0 (c3 / cell-line :mod (m2 / marrow :mod (b / bone)) :ARG1-of (c4 / culture-01 :instrument (c5 / cytokine :mod (t2 / this)))) :ARG1 (a2 / activity-06 :ARG0 (c2 / cell :name (n3 / name :op1 "CTL"))) :manner (d / depend-01 :ARG0 a2 :ARG1 (d2 / dose-01))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1A") :op2 (f2 / figure :mod "1B")))) # ::id bel_pmid_2060_5485.40432 # ::date 2015-05-12T19:51:54 # ::file bel_pmid_2060_5485_40432.txt # ::snt When we analyzed the percentage of the different subsets of CD11b+Gr-1+ cells, percentages of CD11bhiGr-1hi and CD11bhiGr-1- cells were decreased in both C/EBPp-deficient strains, but subsets characterized by low and intermediate expression of the Gr-1 marker were significantly decreased only in fully ablated mice (Figure 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / decrease-01 :ARG1 (a / and :op1 (p / percentage :quant-of (c / cell :name (n / name :op1 "CD11bhiGr-1hi"))) :op2 (p2 / percentage :quant-of (c2 / cell :name (n2 / name :op1 "CD11bhiGr-1-")))) :location (s / strain :ARG0-of (l / lack-01 :ARG1 (p3 / protein :name (n3 / name :op1 "C/EBPp"))) :mod (b / both)) :time (a2 / analyze-01 :ARG0 (w / we) :ARG1 (p4 / percentage :quant-of (s2 / subset :poss (c3 / cell :name (n4 / name :op1 "CD11b+Gr-1+")) :ARG1-of (d4 / differ-02)))) :ARG1-of (c4 / contrast-01 :ARG2 (d2 / decrease-01 :ARG1 (s3 / subset :ARG1-of (c5 / characterize-01 :ARG2 (a3 / and :op1 (e / express-03 :ARG2 (m / marker :mod (p5 / protein :name (n5 / name :op1 "Gr-1"))) :ARG1-of (l2 / low-04)) :op2 (e2 / express-03 :ARG2 m :mod (i / intermediate))))) :ARG2 (s4 / significant-02) :location (m2 / mouse :ARG1-of (a4 / ablate-01 :degree (f / full))) :mod (o / only))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "3D"))) # ::id bel_pmid_2060_5485.40442 # ::date 2015-05-12T20:17:25 # ::file bel_pmid_2060_5485_40442.txt # ::snt Following separation of CD11b+ cells from MCA203 tumor infiltrate, we found that loss of C/EBPp caused a significant reduction in both arginase 1 (Arg1) and nitric oxide synthase 2 (Nos2) proteins (Figure 6A), two enzymes that were described as crucial components of MDSC inhibitory machinery (Bronte and Zanovello, 2005; Gabrilovich and Nagaraj, 2009). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (c / cause-01 :ARG0 (l / lose-02 :ARG1 (p / protein :name (n / name :op1 "C/EBPp"))) :ARG1 (r / reduce-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "arginase" :op2 "1") :xref (x2 / xref :value "UNIPROT:ARGI1_HUMAN" :prob "0.672")) :op2 (e2 / enzyme :name (n3 / name :op1 "nitric" :op2 "oxide" :op3 "synthase" :op4 "2") :xref (x / xref :value "UNIPROT:A0A090N8H8_HUMAN" :prob "0.391")) :mod (b / both) :ARG1-of (d2 / describe-01 :ARG2 (c3 / component :mod (c4 / crucial) :part-of (m / machinery :ARG0-of (i2 / inhibit-01) :mod (c5 / cell :name (n6 / name :op1 "MDSC")))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n7 / name :op1 "Bronte")) :op2 (p5 / person :name (n8 / name :op1 "Zanovello"))) :time (d4 / date-entity :year "2015")) :op2 (p6 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :name (n9 / name :op1 "Gabrilovich")) :op2 (p8 / person :name (n10 / name :op1 "Nagaraj"))) :time (d5 / date-entity :year "2009")))))) :ARG2 (s2 / significant-02) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6A")))) :ARG1-of (f3 / follow-01 :ARG2 (s / separate-01 :ARG1 (c2 / cell :mod (p9 / protein :name (n4 / name :op1 "CD11b+") :xref (x3 / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682"))) :ARG2 (i / infiltrate-01 :ARG0 (p2 / protein :name (n5 / name :op1 "MCA203") :xref (x1 / xref :value "UNIPROT:MCA3_HUMAN" :prob "0.282")) :mod (t / tumor))))) # ::id bel_pmid_2060_5485.40446 # ::date 2015-05-12T20:46:58 # ::file bel_pmid_2060_5485_40446.txt # ::snt Cytokines were able to upregulate IL-4Ra expression, but a more pronounced effect was obtained by G-CSF+GM-CSF combination (Figure 7B and Figure S6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (u / upregulate-01 :ARG0 (c / cytokine) :ARG1 (e / express-03 :ARG1 (p2 / protein :name (n / name :op1 "IL-4Ra") :xref (x / xref :value "UNIPROT:IL4RA_HUMAN" :prob "0.673")))) :ARG1-of (c2 / contrast-01 :ARG2 (o / obtain-01 :ARG1 (a2 / affect-01 :ARG1-of (p5 / pronounced-02 :degree (m / more))) :ARG2 (c3 / combine-01 :ARG1 (p3 / protein :name (n2 / name :op1 "G-CSF") :xref (x1 / xref :value "UNIPROT:CSF3_HUMAN" :prob "1.002")) :ARG2 (p4 / protein :name (n3 / name :op1 "GM-CSF") :xref (x2 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.003"))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "7B") :op2 (f2 / figure :mod "S6B")))) # ::id bel_pmid_2069_3421.19238 # ::date 2015-05-12T05:50:33 # ::file bel_pmid_2069_3421_19238.txt # ::snt These results indicate that the endogenous IL-33/ST2 signaling pathway enhances the expression of CCR3 on eosinophils. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 19, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (e / enhance-01 :ARG0 (p / pathway :name (n / name :op1 "IL-33/ST2") :ARG0-of (s / signal-07) :mod (e2 / endogenous)) :ARG1 (e3 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "CCR3") :xref (x / xref :value "UNIPROT:CCR3_HUMAN" :prob "1.003")) :ARG3 (c / cell :name (n3 / name :op1 "eosinophil"))))) # ::id bel_pmid_2069_3421.19240 # ::date 2015-05-12T06:44:55 # ::file bel_pmid_2069_3421_19240.txt # ::snt IL-33 triggered the production of IL-13 and IL-6 and strongly increased the production of CCL17 and TGF-b from WT eosinophils, but not ST2-/- eosinophils, in a dosedependent manner (Fig. 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (t / trigger-01 :ARG0 (p3 / protein :name (n / name :op1 "IL-33") :xref (x1 / xref :value "UNIPROT:IL33_HUMAN" :prob "1.002")) :ARG1 (p4 / produce-01 :ARG1 (a2 / and :op1 (p5 / protein :name (n2 / name :op1 "IL-13") :xref (x4 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :op2 (c / contrast-01 :ARG1 (i / increase-01 :ARG0 p3 :ARG1 (p / produce-01 :ARG1 (a3 / and :op1 (p7 / protein :name (n4 / name :op1 "CCL17") :xref (x3 / xref :value "UNIPROT:CCL17_HUMAN" :prob "1.003")) :op2 (p8 / protein :name (n5 / name :op1 "TGF-b") :xref (x5 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.633")) :source (c2 / cell :name (n6 / name :op1 "eosinophil") :mod (w / wild-type)))) :ARG1-of (s / strong-02) :manner (d / depend-01 :ARG1 (d2 / dose-01))) :ARG2 (i2 / increase-01 :polarity "-" :ARG0 p3 :ARG1 (p2 / produce-01 :ARG1 (a4 / and :op1 p7 :op2 p8 :source (c3 / cell :name (n7 / name :op1 "eosinophil") :mod (g / gene :name (n8 / name :op1 "ST2") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:ILRL1_HUMAN" :prob "1.002"))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id bel_pmid_2092_1519.3016 # ::date 2015-05-12T07:12:05 # ::file bel_pmid_2092_1519_3016.txt # ::snt Pharmacological intervention with a VEGFR-2-neutralizing Ab (anti-Flk1 mAb) abolished the production of IL-6 (but not IL-12p70) and the subsequent development of allergen-specific Th17 cell response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c3 / contrast-01 :ARG1 (a / abolish-01 :ARG0 (i / intervene-01 :mod (p2 / pharmacology) :instrument (a3 / antibody :ARG0-of (n / neutralize-01 :ARG1 (p6 / protein :name (n2 / name :op1 "VEGFR-2") :xref (x1 / xref :value "UNIPROT:VGFR2_HUMAN" :prob "1.003"))))) :ARG1 (a2 / and :op2 (d / develop-01 :ARG1 (r / respond-01 :ARG0 (c2 / cell :name (n5 / name :op1 "Th17")) :ARG1-of (s2 / specific-02 :ARG2 (a5 / allergen))) :mod (s / subsequent)) :op2 (p / produce-01 :ARG1 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :ARG2 (a6 / abolish-01 :polarity "-" :ARG1 (p4 / produce-01 :ARG1 (p5 / protein :name (n4 / name :op1 "IL-12p70") :xref (x2 / xref :value "UNIPROT:IL12A_HUMAN" :prob "0.262"))))) # ::id bel_pmid_2092_1519.3466 # ::date 2015-05-12T07:27:41 # ::file bel_pmid_2092_1519_3466.txt # ::snt In vivo production of VEGF and Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) were upregulated by airway exposure to LPS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / upregulate-01 :ARG0 (e / expose-01 :ARG2 (m2 / molecular-physical-entity :name (n6 / name :op1 "LPS") :xref (x2 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :mod (a3 / airway)) :ARG1 (p / produce-01 :ARG1 (a / and :op1 (p3 / protein :name (n3 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :op2 (c / cytokine :name (n / name :op1 "IL-12p70") :ARG0-of (p2 / polarize-01 :ARG1 (p5 / protein :name (n4 / name :op1 "Th1") :xref (x1 / xref :value "UNIPROT:NELFD_HUMAN" :prob "0.622")))) :op3 (c2 / cytokine :name (n2 / name :op1 "IL-6") :ARG0-of (p4 / polarize-01 :ARG1 (c4 / cell :name (n5 / name :op1 "Th17"))))) :manner (i / in-vivo))) # ::id bel_pmid_2094_4008.19124 # ::date 2015-05-12T07:42:49 # ::file bel_pmid_2094_4008_19124.txt # ::snt Both Fyn and Hck phosphorylate the adaptor protein Gab2 to activate PI3K signaling and promote microtubule formation that is important for granule translocation to the plasma membrane (9, 11). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p4 / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Gab2") :mod (a3 / adaptor) :xref (x2 / xref :value "UNIPROT:GAB2_HUMAN" :prob "0.604")) :ARG2 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "Fyn") :xref (x1 / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604")) :op2 (e3 / enzyme :name (n2 / name :op1 "Hck") :xref (x / xref :value "UNIPROT:HCK_HUMAN" :prob "0.604")) :mod (b / both)) :purpose (a4 / and :op1 (a5 / activate-01 :ARG0 a2 :ARG1 (s / signal-07 :ARG0 (p6 / pathway :name (n4 / name :op1 "PI3K")))) :op2 (p2 / promote-01 :ARG0 a2 :ARG1 (f / form-01 :ARG1 (m / microtubule) :mod (i / important :purpose (t / translocate-01 :ARG2 (m2 / membrane :poss (p / plasma) :xref (x3 / xref :value "GO:0016020" :prob "0.8")) :path (g3 / granule)))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 "9" :op2 "11"))))) # ::id bel_pmid_2094_4008.19126 # ::date 2015-05-12T08:00:51 # ::file bel_pmid_2094_4008_19126.txt # ::snt PTP? is required for SCF-induced c-Kit and Fyn activation, and in this way regulates a Fyn-based c-Kit signaling axis (Fyn/Gab2/Shp2/Vav/PAK/Rac/JNK) that mediates mast cell migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a3 / and :op1 (r / require-01 :ARG1 (e / enzyme :name (n / name :op1 "PTPβ") :xref (x7 / xref :value "UNIPROT:MPCP_HUMAN" :prob "0.652")) :purpose (a / activate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "c-Kit") :xref (x5 / xref :value "UNIPROT:SCF_HUMAN" :prob "0.233")) :op2 (e3 / enzyme :name (n3 / name :op1 "Fyn") :xref (x4 / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604"))) :ARG2-of (i / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "SCF") :xref (x6 / xref :value "UNIPROT:SCF_HUMAN" :prob "1.004"))))) :op2 (r2 / regulate-01 :ARG0 e :ARG1 (a4 / axis :ARG0-of (s / signal-07 :ARG1 e2) :ARG1-of (b / base-02 :ARG2 e3) :ARG0-of (m / mediate-01 :ARG1 (m2 / migrate-01 :ARG0 (c / cell :mod (m3 / mast)))) :consist-of (a5 / and :op1 e2 :op2 (p / protein :name (n6 / name :op1 "Gab2") :xref (x8 / xref :value "UNIPROT:GAB2_HUMAN" :prob "0.604")) :op3 (e6 / enzyme :name (n7 / name :op1 "Shp2") :xref (x3 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :op4 (p2 / protein :name (n8 / name :op1 "Vav") :xref (x / xref :value "UNIPROT:VAV_HUMAN" :prob "0.604")) :op5 (e7 / enzyme :name (n9 / name :op1 "PAK") :xref (x2 / xref :value "UNIPROT:PAK1_HUMAN" :prob "0.263")) :op6 (e8 / enzyme :name (n10 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :op7 (e9 / enzyme :name (n11 / name :op1 "JNK") :xref (x9 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")))) :manner (w / way :mod (t / this)))) # ::id bel_pmid_2108_5614.26518 # ::date 2015-05-12T09:02:20 # ::file bel_pmid_2108_5614_26518.txt # ::snt Furthermore, we find that basal arginase 1 expression and associated arginase activity is markedly increased in MKP-2 deletion mice, a response which would also mediate a reduction in NO formation, this is again different to the findings in MKP-1?/? macrophages . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op2 (f / find-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG1 (a2 / and :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "arginase-1") :mod (b / basal) :xref (x3 / xref :value "UNIPROT:ARGI1_HUMAN" :prob "0.702"))) :op2 (a3 / activity-06 :ARG0 (e3 / enzyme :name (n2 / name :op1 "arginase") :xref (x2 / xref :value "UNIPROT:A0A024R6A0_HUMAN" :prob "0.701")) :ARG1-of (a4 / associate-01))) :ARG1-of (m / mark-01) :location (m2 / mouse :ARG2-of (d / delete-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "MKP-2") :xref (x1 / xref :value "UNIPROT:DUS4_HUMAN" :prob "1.002")))) :ARG2-of (r / respond-01 :ARG0-of (m3 / mediate-01 :ARG1 (r2 / reduce-01 :ARG1 (f2 / form-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "NO") :xref (x4 / xref :value "PUBCHEM:84878" :prob "11.070387")))) :mod (a5 / also))) :ARG0-of (d2 / differ-01 :ARG1 (t / thing :ARG1-of (f3 / find-01 :location (c / cell :name (n5 / name :op1 "macrophage") :part (g / gene :mode "interrogative" :name (n6 / name :op1 "MKP-1") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x / xref :value "UNIPROT:DUS1_HUMAN" :prob "1.002"))))) :mod (a6 / again))))) # ::id bel_pmid_2108_5614.26520 # ::date 2015-05-12T09:26:19 # ::file bel_pmid_2108_5614_26520.txt # ::snt MKP-2 negatively regulated IL-12, IL-6 and TNF-a expression and positively regulates IL-10 confirming this hypothesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jun 13, 2015 (a / and :op1 (d / downregulate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "MKP-2") :xref (x4 / xref :value "UNIPROT:DUS4_HUMAN" :prob "1.002")) :ARG1 (e / express-03 :ARG2 (a2 / and :op1 (p / protein :name (n2 / name :op1 "IL-12") :xref (x3 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343")) :op2 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n4 / name :op1 "TNF") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))))) :op2 (u / upregulate-01 :ARG0 e2 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-10") :xref (x2 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003"))) :ARG0-of (c / confirm-01 :ARG1 (t2 / thing :ARG1-of (h / hypothesize-01) :mod (t / this)))) # ::id bel_pmid_2111_5688.4192 # ::date 2015-05-12T09:35:06 # ::file bel_pmid_2111_5688_4192.txt # ::snt pDCs were found to rapidly infiltrate both murine and human skin wounds and to transiently produce type I IFNs via TLR7- and TLR9-dependent recognition of nucleic acids. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (i / infiltrate-01 :ARG0 (e / enzyme :name (n / name :op1 "pDC") :xref (x2 / xref :value "UNIPROT:PHOS_HUMAN" :prob "0.672")) :ARG1 (a2 / and :op1 (w / wound :mod (s / skin :mod (h / human))) :op2 (w2 / wound :location (s2 / skin :mod (m / murine)))) :manner (r / rapid)) :op2 (p / produce-01 :ARG0 e :ARG1 (p5 / protein :name (n6 / name :op1 "type" :op2 "I" :op3 "IFN") :xref (x3 / xref :value "UNIPROT:HCD2_HUMAN" :prob "0.252")) :ARG1-of (t / transient-02) :instrument (r2 / recognize-02 :ARG1 (n2 / nucleic-acid) :ARG0-of (d / depend-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "TLR-7") :xref (x1 / xref :value "UNIPROT:TLR7_HUMAN" :prob "0.672")) :op2 (p4 / protein :name (n4 / name :op1 "TLR-9") :xref (x / xref :value "UNIPROT:TLR9_HUMAN" :prob "0.672")))))) :ARG1-of (f / find-01)) # ::id bel_pmid_2111_5688.27614 # ::date 2015-05-12T09:50:30 # ::file bel_pmid_2111_5688_27614.txt # ::snt Like pDC-depleted mice, IFN-alpha/beta receptor-deficient mice showed a significant delay in wound reepithelization (Fig. 5 E) and displayed a profound deficiency in IL-6, IL-17, and IL-22 expression levels in injured skin, without affecting the expression of IFN-gamma (Fig. 5 F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 20, 2015 (a / and :op1 (s / show-01 :ARG0 (m2 / mouse :consist-of (d6 / deficit :consist-of (r2 / receptor :name (n2 / name :op1 "IFN-alpha/beta")))) :ARG1 (d3 / delay-01 :ARG1 (r3 / reepithelize-00 :ARG1 (w / wound)) :ARG1-of (s3 / significant-02)) :ARG1-of (r / resemble-01 :ARG2 (m / mouse :ARG2-of (d2 / deplete-01 :ARG1 (e / enzyme :name (n / name :op1 "pDC") :xref (x3 / xref :value "UNIPROT:PHOS_HUMAN" :prob "0.672"))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "5E"))) :op2 (d / display-01 :ARG0 m2 :ARG1 (l2 / lack-01 :ARG1 (l3 / level :degree-of (e2 / express-03 :ARG2 (a2 / and :op1 (p / protein :name (n3 / name :op1 "IL-6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n4 / name :op1 "IL-17") :xref (x1 / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n5 / name :op1 "IL-22") :xref (x2 / xref :value "UNIPROT:IL22_HUMAN" :prob "1.002")))) :location (s2 / skin :ARG1-of (i / injure-01))) :mod (p5 / profound)) :ARG0-of (a3 / affect-01 :polarity "-" :ARG1 (e3 / express-03 :ARG2 (p4 / protein :name (n6 / name :op1 "IFN-gamma") :xref (x / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")))) :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure :mod "5F")))) # ::id bel_pmid_2111_5688.31368 # ::date 2015-05-12T22:47:22 # ::file bel_pmid_2111_5688_31368.txt # ::snt Expression of both IFN-a2 and IFN-b mRNA was found to be profoundly abrogated in TLR7-deficient mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / abrogate-01 :ARG1 (e / express-03 :ARG2 (a3 / and :op1 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n / name :op1 "IFN-a2") :xref (x2 / xref :value "UNIPROT:IFNA2_HUMAN" :prob "0.652")))) :op2 (n7 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IFN-b") :xref (x / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.632")))))) :manner (p3 / profound) :location (m / mouse :ARG0-of (d / delete-01 :ARG1 (p4 / protein :name (n4 / name :op1 "TLR7") :xref (x1 / xref :value "UNIPROT:TLR7_HUMAN" :prob "1.003")))) :ARG1-of (f / find-01)) # ::id bel_pmid_2123_9520.35054 # ::date 2015-05-12T23:12:42 # ::file bel_pmid_2123_9520_35054.txt # ::snt In the present study, we found that when RSK4 is inhibited in vitro using short hairpin RNA technology, cells can bypass stress-induced senescence and oncogene-induced senescence: normal human fibroblasts grew following oxidative stress, induction of DNA damage and KRAS(V12) or BRAF(E600) overexpression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / possible-01 :ARG1 (b / bypass-01 :ARG0 (c / cell) :ARG1 (a / and :op1 (s / senescence :ARG2-of (i / induce-01 :ARG0 (s2 / stress-02))) :op2 (s3 / senescence :ARG2-of (i2 / induce-01 :ARG0 (o / oncogene)))) :manner (g / grow-01 :ARG1 (f2 / fibroblast :mod (h / human) :ARG1-of (n2 / normal-02)) :time (a2 / after :op1 (s4 / stress-02 :ARG3 (o2 / oxidize-01)) :op2 (i5 / induce-01 :ARG2 (d / damage-01 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA")))) :op3 (o3 / overexpress-01 :ARG1 (a3 / and :op1 (e2 / enzyme :name (n5 / name :op1 "KRAS") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n6 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "E600") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))) :time (i3 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "RSK4") :xref (x2 / xref :value "UNIPROT:KS6A6_HUMAN" :prob "1.002")) :instrument (t / technology :mod (n8 / nucleic-acid :name (n3 / name :op1 "short" :op2 "hairpin" :op3 "RNA"))) :manner (i4 / in-vitro)) :ARG1-of (f / find-01 :ARG0 (w / we) :medium (s5 / study-01 :time (p2 / present)))) # ::id bel_pmid_2123_9520.37214 # ::date 2015-05-12T23:35:57 # ::file bel_pmid_2123_9520_37214.txt # ::snt Two days after BRAFE600 selection, we seeded cells at low density and performed growth curves. RSK4 inhibition partially rescued BRAFE600-induced senescence in both TIG3 and TIG3 p16-null (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (m / multi-sentence :snt1 (a / and :op1 (s / seed-02 :ARG0 (w / we) :ARG2 (c / cell) :mod (d2 / dense :ARG1-of (l / low-04))) :op2 (p / perform-02 :ARG0 w :ARG1 (c2 / curve :topic (g / grow-01))) :time (a2 / after :op1 (s2 / select-01 :ARG1 (e2 / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "E600") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :quant (t2 / temporal-quantity :quant "2" :unit (d3 / day)))) :snt2 (r / rescue-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "RSK4") :xref (x3 / xref :value "UNIPROT:KS6A6_HUMAN" :prob "1.002")) :degree (p2 / part)) :ARG1 (s3 / senescence :ARG2-of (i2 / induce-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "E600") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :location (a3 / and :op1 (c3 / cell :mod (p3 / protein :name (n4 / name :op1 "TIG3") :xref (x2 / xref :value "UNIPROT:HRSL4_HUMAN" :prob "1.002"))) :op2 (c4 / cell :mod (p4 / protein :name (n5 / name :op1 "TIG3") :xref (x4 / xref :value "UNIPROT:HRSL4_HUMAN" :prob "1.002")) :mod (p5 / protein :name (n6 / name :op1 "p16") :mod (n7 / null) :xref (x5 / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262")))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "4A")))) # ::id bel_pmid_2123_9533.1678 # ::date 2015-05-12T23:49:08 # ::file bel_pmid_2123_9533_1678.txt # ::snt This IFNg-stimulated expression of T-bet is dependent on signaling through JAK2 and signal transducers and activators of transcription 1 (STAT1) and activates T-bet-dependent DNA binding activity # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a3 / and :op1 (d / depend-01 :ARG0 (e / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "T-bet") :xref (x / xref :value "UNIPROT:TBX21_HUMAN" :prob "0.592")) :ARG1-of (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "IFNg") :xref (x2 / xref :value "UNIPROT:IFNG_HUMAN" :prob "0.653"))) :mod (t4 / this)) :ARG1 (a2 / and :op1 (s2 / signal-07 :instrument (e2 / enzyme :name (n3 / name :op1 "JAK2") :xref (x3 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :op2 (p4 / protein :name (n5 / name :op1 "signal" :op2 "transducers" :op3 "and" :op4 "activators" :op5 "of" :op6 "transcription" :op7 "1") :xref (x1 / xref :value "UNIPROT:STAT2_HUMAN" :prob "0.383")))) :op2 (a4 / activate-01 :ARG0 e :ARG1 (a / activity-06 :ARG1 (b / bind-01 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))) :ARG0-of (d3 / depend-01 :ARG1 p3)))) # ::id bel_pmid_2137_8275.40580 # ::date 2015-05-13T00:04:57 # ::file bel_pmid_2137_8275_40580.txt # ::snt In the lung, the concentration of IL-6 was increased, which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / increase-01 :ARG1 (c / concentrate-02 :ARG1 (p / protein :name (n / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :location (l / lung) :ARG0-of (a / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Stat3") :ARG0-of (c3 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :manner (a2 / aberrant)) :ARG0-of (i2 / increase-01 :ARG1 (e / express-03 :ARG1 (g / gene :name (n3 / name :op1 "Stat3") :location (d / downstream) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :location (c2 / cell :ARG0-of (b / bear-02 :ARG1 (t / tumor :mod (e2 / epithelium)))))) # ::id bel_pmid_2137_8275.40582 # ::date 2015-05-13T00:20:13 # ::file bel_pmid_2137_8275_40582.txt # ::snt Spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 overexpression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / develop-01 :ARG2 (a / and :op1 (d2 / disease :name (n / name :op1 "emphysema") :mod (s2 / spontaneous)) :op2 (m / medical-condition :name (n2 / name :op1 "adenocarcinoma") :mod (l / lung))) :manner (s / sequential) :time (a2 / after :op1 (o / overexpress-01 :ARG1 (e / enzyme :name (n3 / name :op1 "MMP12") :xref (x / xref :value "UNIPROT:MMP12_HUMAN" :prob "1.003"))))) # ::id bel_pmid_2137_8275.40590 # ::date 2015-05-13T00:25:34 # ::file bel_pmid_2137_8275_40590.txt # ::snt MMP12 suppresses T-cell proliferation and function in vivo The CD4+ T-lymphocyte population was significantly decreased in the spleen of doxycycline-treated bitransgenic mice (5.58%) compared with that in untreated ones (21.14%), while the CD8+ T-lymphocyte population was less affected (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m2 / multi-sentence :snt1 (s / suppress-01 :ARG0 (e / enzyme :name (n / name :op1 "MMP12") :xref (x1 / xref :value "UNIPROT:MMP12_HUMAN" :prob "1.003")) :ARG1 (a / and :op1 (p3 / proliferate-01 :ARG0 (c / cell :name (n2 / name :op1 "T-cell"))) :op2 (f / function-01 :ARG0 c)) :manner (i / in-vivo)) :snt2 (d / decrease-01 :ARG1 (p4 / population :quant-of (c2 / cell :name (n3 / name :op1 "T-lymphocyte") :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n4 / name :op1 "CD4+") :xref (x / xref :value "UNIPROT:CD4_HUMAN" :prob "0.652"))))) :ARG2 (p5 / percentage-entity :value "5.58") :ARG1-of (s2 / significant-02) :location (s3 / spleen :part-of (m3 / mouse :ARG1-of (t / treat-03 :ARG3 (d2 / doxycycline)) :mod (b / bitransgenic))) :compared-to (d3 / decrease-01 :ARG1 (p6 / population :quant-of c2) :ARG2 (p7 / percentage-entity :value "21.14") :location (m4 / mouse :ARG1-of (t2 / treat-04 :polarity "-"))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "2A")) :ARG1-of (c5 / contrast-01 :ARG2 (a3 / affect-01 :ARG1 (p8 / population :quant-of (c4 / cell :name (n7 / name :op1 "T-lymphocyte") :ARG1-of (e6 / express-03 :ARG2 e3) :mod (p / protein :name (n6 / name :op1 "CD8+") :xref (x2 / xref :value "UNIPROT:C5AR1_HUMAN" :prob "0.292")))) :degree (l / less))))) # ::id bel_pmid_2137_8275.40594 # ::date 2015-05-13T01:00:47 # ::file bel_pmid_2137_8275_40594.txt # ::snt The culture medium showed decreased secretion of IL-2, IL-4, and IFN7 in the activated MMP12-treated samples (Figure 2F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG0 (m / medium :mod (c / culture)) :ARG1 (s2 / secrete-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "IL-2") :xref (x3 / xref :value "UNIPROT:IL2_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "IL-4") :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "IFN7") :xref (x2 / xref :value "UNIPROT:IFN17_HUMAN" :prob "0.312"))) :ARG1-of (d2 / decrease-01)) :location (t2 / thing :ARG1-of (t / treat-04 :ARG2 (e / enzyme :name (n4 / name :op1 "MMP12") :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "UNIPROT:MMP12_HUMAN" :prob "1.003"))) :ARG1-of (s3 / sample-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2F"))) # ::id bel_pmid_2137_8275.40598 # ::date 2015-05-13T01:09:14 # ::file bel_pmid_2137_8275_40598.txt # ::snt CD11b+/Gr-1+ cells from doxcycline-treated bitransgenic mice showed the strongest inhibition on proliferation of wild-type CD4+ T cells (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (c / cell :mod (s2 / slash :op1 (p2 / protein :name (n / name :op1 "CD11b+") :xref (x / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682")) :op2 (p3 / protein :name (n2 / name :op1 "Gr-1+"))) :source (m / mouse :mod (b / bitransgenic) :ARG1-of (t / treat-04 :ARG2 (s4 / small-molecule :name (n5 / name :op1 "doxycycline") :xref (x2 / xref :value "PUBCHEM:54671203" :prob "15.91623"))))) :ARG1 (i / inhibit-01 :ARG1 (p / proliferate-01 :ARG0 (c2 / cell :name (n3 / name :op1 "T-cell") :ARG3-of (e / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "CD4+") :xref (x1 / xref :value "UNIPROT:CD4_HUMAN" :prob "0.652"))) :mod (w / wild-type))) :ARG1-of (s3 / strong-02 :degree (m2 / most))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3C"))) # ::id bel_pmid_2137_8275.40600 # ::date 2015-05-13T01:15:58 # ::file bel_pmid_2137_8275_40600.txt # ::snt This inhibition was further confirmed by a significant reduction of IL-2 and IL-4 secretion, implicating a functional impairment of CD4+ T cells by CD11b+/Gr-1+ cells from doxcycline-treated bitransgenic mice (Figure 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / confirm-01 :ARG0 (r / reduce-01 :ARG1 (s / secrete-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "IL-2") :xref (x3 / xref :value "UNIPROT:IL2_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "IL-4") :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")))) :ARG2 (s3 / significant-02)) :ARG1 (i / inhibit-01 :mod (t / this)) :degree (f / further) :ARG0-of (i2 / implicate-01 :ARG1 (i3 / impair-01 :ARG0 (c3 / cell :part (s2 / slash :op1 (p3 / protein :name (n5 / name :op1 "CD11b+") :xref (x1 / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682")) :op2 (p4 / protein :name (n6 / name :op1 "Gr-1+"))) :source (m / mouse :mod (b / bitransgenic) :ARG1-of (t2 / treat-04 :ARG2 (s4 / small-molecule :name (n7 / name :op1 "doxycycline") :xref (x4 / xref :value "PUBCHEM:54671203" :prob "15.91623"))))) :ARG1 (f2 / function-01 :ARG0 (c2 / cell :name (n3 / name :op1 "T-cell") :ARG3-of (e / express-03 :ARG2 (p5 / protein :name (n4 / name :op1 "CD4+") :xref (x2 / xref :value "UNIPROT:CD4_HUMAN" :prob "0.652"))))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "3D"))) # ::id bel_pmid_2137_8275.40608 # ::date 2015-05-13T10:03:59 # ::file bel_pmid_2137_8275_40608.txt # ::snt Compared with doxycycline-untreated bitransgenic mice, the expression levels of IL-1p, IL-6, MIP-2, and TNF-a were abnormally increased in the plasma of doxycycline-treated bitransgenic mice (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / increase-01 :ARG1 (l / level :degree-of (e / express-03 :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "IL-1p") :xref (x3 / xref :value "UNIPROT:IL18R_HUMAN" :prob "0.292")) :op2 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "MIP-2") :xref (x1 / xref :value "UNIPROT:WDR26_HUMAN" :prob "0.672")) :op4 (p4 / protein :name (n4 / name :op1 "TNF-a") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))))) :ARG1-of (n5 / normal-02 :polarity "-") :location (p5 / plasma :part-of (m / mouse :mod (b / bitransgenic) :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :name (n6 / name :op1 "doxycycline") :xref (x4 / xref :value "PUBCHEM:54671203" :prob "15.91623"))))) :compared-to (m2 / mouse :mod (b2 / bitransgenic) :ARG1-of (t2 / treat-04 :polarity "-" :ARG2 s)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id bel_pmid_2145_4454.35882 # ::date 2015-05-13T10:13:00 # ::file bel_pmid_2145_4454_35882.txt # ::snt To determine if the ERK-MAPK pathway was also activated by TLR2 in megakaryocytes, lysates of Meg-01 cells were treated with 1 ?g/mL Pam3CSK4 for up to 1 hour and were immunoblotted for phosphorylated ERK1/2. As shown in Figure 1A, there was an increase in the phosphorylation of ERK beginning at 5 minutes that peaks at 30 minutes (105.8% ±3.9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m4 / multi-sentence :snt1 (a / and :op1 (t4 / treat-04 :ARG1 (l / lysate :source (c / cell-line :name (n2 / name :op1 "Meg-01"))) :ARG2 (p3 / protein :name (n3 / name :op1 "Pam3CSK4") :quant (c3 / concentration-quantity :quant "1" :unit (g / gram-per-milliliter))) :duration (u / up-to :op1 (t6 / temporal-quantity :quant "1" :unit (h2 / hour)))) :op2 (i / immunoblot-01 :ARG1 (s / slash :op1 (e2 / enzyme :name (n4 / name :op1 "ERK-1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK-2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1-of (p4 / phosphorylate-01)) :ARG2 l) :purpose (d / determine-01 :ARG1 (a2 / activate-01 :mode "interrogative" :ARG0 (p6 / protein :name (n7 / name :op1 "TLR2") :xref (x3 / xref :value "UNIPROT:TLR2_HUMAN" :prob "1.003")) :ARG1 (p5 / pathway :name (n6 / name :op1 "ERK-MAPK")) :location (c2 / cell :name (n8 / name :op1 "megakaryocyte")) :mod (a5 / also)))) :snt2 (i2 / increase-01 :ARG1 (p7 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n9 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG0-of (b / begin-01 :time (a6 / after :op1 (t3 / temporal-quantity :quant "5" :unit (m3 / minute)))) :ARG1-of (p8 / peak-01 :ARG2 (p9 / percentage-entity :value "105.8" :ARG2-of (a4 / add-02 :ARG1 (p / percentage-entity :value "3.9")) :ARG2-of (s3 / subtract-01 :ARG1 (p2 / percentage-entity :value "3.9"))) :time (a3 / after :op1 (t / temporal-quantity :quant "30" :unit (m2 / minute)))) :ARG1-of (s2 / show-01 :location (f2 / figure :mod "1A")))) # ::id bel_pmid_2145_4454.35884 # ::date 2015-05-13T10:52:59 # ::file bel_pmid_2145_4454_35884.txt # ::snt GP1b is part of the GPIb-IX-V complex that binds vWF and thrombin. Its expression level was significantly increased by 162% and cell surface expression, as determined by flow cytometry, was also increased by 114% with Pam3CSK4 treatment (Figure 5A and Supplemental Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (m / multi-sentence :snt2 (a / and :op1 (i / increase-01 :ARG1 (l / level :degree-of (e2 / express-03 :ARG2 (p6 / protein :name (n6 / name :op1 "GP1b") :xref (x1 / xref :value "UNIPROT:GP1BB_HUMAN" :prob "0.312")))) :ARG2 (p / percentage-entity :value "162") :ARG1-of (s / significant-02)) :op2 (i2 / increase-01 :ARG1 (e3 / express-03 :ARG2 p6 :location (s2 / surface :poss (c2 / cell)) :ARG1-of (d / determine-01 :ARG0 (c3 / cytometry :mod (f / flow)))) :ARG2 (p2 / percentage-entity :value "114") :mod (a2 / also) :instrument (t / treat-04 :ARG2 (p5 / protein :name (n5 / name :op1 "Pam3CSK4")))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "5A") :op2 (f3 / figure :mod "4C" :ARG2-of (s3 / supplement-01))))) :snt1 (h / have-part-91 :ARG1 (c / complex :name (n2 / name :op1 "GPIb-IX-V") :ARG1-of (b / bind-01 :ARG2 (a4 / and :op1 (p4 / protein :name (n3 / name :op1 "vWF") :xref (x2 / xref :value "UNIPROT:VWF_HUMAN" :prob "1.003")) :op2 (e / enzyme :name (n4 / name :op1 "thrombin") :xref (x3 / xref :value "UNIPROT:THRB_HUMAN" :prob "0.292"))))) :ARG2 (p3 / protein :name (n / name :op1 "GP1b") :xref (x / xref :value "UNIPROT:GP1BB_HUMAN" :prob "0.312")))) # ::id bel_pmid_2145_4454.35890 # ::date 2015-05-13T11:35:14 # ::file bel_pmid_2145_4454_35890.txt # ::snt CD41, also known as integrin ?IIb, part of the ?IIb?III receptor that binds fibrinogen, was also significantly increased in the presence of Pam3CSK4 by 123% (Figure 5B). Surface expression of CD41 was increased by 125% as shown by flow cytometry (Supplemental Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (m / multi-sentence :snt1 (i / increase-01 :ARG1 (p3 / protein :name (n / name :op1 "CD41") :ARG1-of (k / know-02 :ARG2 (p4 / protein :mode "interrogative" :name (n2 / name :op1 "integrin-IIb") :xref (x2 / xref :value "UNIPROT:ITA2B_HUMAN" :prob "0.343")) :mod (a / also)) :part-of (r / receptor :name (n3 / name :op1 "IIb/IIIa") :ARG0-of (b / bind-01 :ARG1 (p5 / protein :name (n4 / name :op1 "fibrinogen") :ARG1-of (i2 / increase-01 :ARG2 (p / percentage-entity :value "123") :ARG1-of (s2 / significant-02) :mod (a2 / also) :condition (p6 / present-02 :ARG1 (p7 / protein :name (n5 / name :op1 "Pam3CSK4")))) :xref (x3 / xref :value "UNIPROT:FIBRINOGEN_HUMAN_COMPLEX" :prob "1.001")))) :xref (x1 / xref :value "UNIPROT:ITA2B_HUMAN" :prob "1.003")) :ARG2 s2 :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B"))) :snt2 (i3 / increase-01 :ARG1 (e / express-03 :ARG2 (p8 / protein :name (n6 / name :op1 "CD41") :xref (x / xref :value "UNIPROT:ITA2B_HUMAN" :prob "1.003")) :location (s3 / surface)) :ARG2 (p2 / percentage-entity :value "125") :ARG1-of (s4 / show-01 :ARG0 (c / cytometry :mod (f2 / flow))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "4D" :ARG2-of (s5 / supplement-01))))) # ::id bel_pmid_2151_8970.1890 # ::date 2015-05-14T00:31:11 # ::file bel_pmid_2151_8970_1890.txt # ::snt Unexpectedly, TGF-beta treatment also induced increased IL-6 production by pDC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (t / treat-04 :ARG2 (p / protein :name (n / name :op1 "TGF-beta") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.373"))) :ARG2 (p2 / produce-01 :ARG0 (e / enzyme :name (n3 / name :op1 "pDC") :xref (x1 / xref :value "UNIPROT:PHOS_HUMAN" :prob "0.672")) :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (i2 / increase-01)) :ARG1-of (e2 / expect-01 :polarity "-") :mod (a / also)) # ::id bel_pmid_2169_7282.25874 # ::date 2015-05-14T00:37:49 # ::file bel_pmid_2169_7282_25874.txt # ::snt Api6 overexpression in lung epithelial cells only caused regional inflammation, not systemic inflammation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c3 / contrast-01 :ARG1 (c / cause-01 :ARG0 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "Api6") :xref (x / xref :value "UNIPROT:CD5L_HUMAN" :prob "0.602")) :location (c2 / cell :part-of (e / epithelium :mod (l / lung)))) :ARG1 (i / inflame-01 :mod (r / region)) :mod (o2 / only)) :ARG2 (c4 / cause-01 :polarity "-" :ARG0 o :ARG1 (i2 / inflame-01 :ARG1 (s / system)))) # ::id bel_pmid_2169_7282.25878 # ::date 2015-05-14T00:42:54 # ::file bel_pmid_2169_7282_25878.txt # ::snt At the gene transcriptional level, Api6 overexpression stimulated mRNA expression of Stat3 and its upstream stimuli IL-6 in whole lung cells, AT II epithelial cells, and alveolar macrophages (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (s / stimulate-01 :ARG0 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "Api6") :xref (x3 / xref :value "UNIPROT:CD5L_HUMAN" :prob "0.602"))) :ARG1 (a / and :op1 (e / express-03 :ARG1 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA")) :ARG2 (p2 / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :op2 (e2 / express-03 :ARG1 n7 :ARG2 (p3 / protein :name (n4 / name :op1 "IL-6") :ARG0-of (s2 / stimulate-01 :ARG1 p2) :location (u / upstream) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :location (l / level :mod (t / transcribe-01 :ARG1 (g / gene))) :location (a2 / and :op1 (c / cell :mod (l2 / lung) :mod (w / whole)) :op2 (c2 / cell :part-of (e3 / epithelium :part (p4 / protein :name (n5 / name :op1 "AT-II") :xref (x2 / xref :value "UNIPROT:ANT3_HUMAN" :prob "0.342")))) :op3 (c3 / cell :name (n6 / name :op1 "macrophage") :mod (a3 / alveolus))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id bel_pmid_2193_6896.27282 # ::date 2015-05-13T04:44:00 # ::file bel_pmid_2193_6896_27282.txt # ::snt Significant reductions in brain levels of early cytokines, including IL-1beta and IL-6 mRNA expression, and late cytokine high mobility group box-1 protein (HMGB1), were found in the gelsolin-treated group compared to the placebo group at all time points (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 25, 2015 (f / find-01 :ARG1 (r / reduce-01 :ARG1 (a / and :op1 (c / cytokine :ARG2-of (i / include-91 :ARG1 (e / express-03 :ARG2 (a2 / and :op1 (n7 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-1β") :xref (x3 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.332")))) :op2 (n8 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))))) :mod (e4 / early)) :op2 (c2 / cytokine :domain (p3 / protein :name (n5 / name :op1 "high" :op2 "mobility" :op3 "group" :op4 "box-1") :xref (x1 / xref :value "UNIPROT:HMGB1_HUMAN" :prob "0.353")) :mod (l / late))) :ARG2 (s / significant-02) :location (l2 / level :mod (b / brain)) :compared-to (g / group :mod (p4 / placebo))) :location (g2 / group :ARG1-of (t / treat-04 :ARG2 (p5 / protein :name (n6 / name :op1 "gelsolin") :xref (x2 / xref :value "UNIPROT:GELS_HUMAN" :prob "0.703")))) :time (p6 / point :mod (t2 / time :mod (a3 / all))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4"))) # ::id bel_pmid_2213_2131.40908 # ::date 2015-05-13T05:49:39 # ::file bel_pmid_2213_2131_40908.txt # ::snt Factors from murine pancreatic cancer cells cause the down-regulation of SHIP-1 expression, which may potentially contribute to MDSC expansion, and the suppression of CD8+ T cell immune responses. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (c / cause-01 :ARG0 (f / factor :source (c2 / cell :part-of (o / organism :name (n2 / name :op1 "Muridae")) :mod (d3 / disease :wiki "Pancreatic_cancer" :name (n7 / name :op1 "pancreatic" :op2 "cancer")))) :ARG1 (d2 / downregulate-01 :ARG0 f :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))) :ARG0-of (c3 / contribute-01 :ARG2 (a / and :op1 (e2 / expand-01 :ARG0 d2 :ARG1 (c4 / cell :name (n4 / name :op1 "MDSC"))) :op2 (s / suppress-01 :ARG0 d2 :ARG1 (t / thing :ARG2-of (r / respond-01 :ARG0 (c5 / cell :name (n5 / name :op1 "T") :mod (p3 / protein :name (n6 / name :op1 "CD8") :xref (x1 / xref :value "UNIPROT:C5AR1_HUMAN" :prob "0.342")))) :ARG1-of (i / immune-02)))) :mod (p4 / potential) :ARG1-of (p5 / possible-01)))) # ::id bel_pmid_2213_2131.40910 # ::date 2015-05-13T06:35:06 # ::file bel_pmid_2213_2131_40910.txt # ::snt qRT-PCR and Western blot analyses revealed the in vivo down-regulation of SHIP-1 expression in splenocytes from TB mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / reveal-01 :ARG0 (a / and :op1 (a2 / analyze-01 :instrument (t2 / thing :name (n / name :op1 "qRT-PCR"))) :op2 (a3 / analyze-01 :manner (i2 / immunoblot-01))) :ARG1 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n3 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))) :manner (i / in-vivo) :location (s / splenocyte :source (m / mouse :ARG0-of (b / bear-01 :ARG1 (t / tumor)))))) # ::id bel_pmid_2213_2131.40912 # ::date 2015-05-13T06:58:11 # ::file bel_pmid_2213_2131_40912.txt # ::snt Western blot analyses also detected reduced SHIP-1 activity, increased AKT-1 and BAD hyper-phosphorylation and up-regulation of BCL-2 expression in splenocytes from TB mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / detect-01 :ARG0 (a / analyze-01 :manner (i2 / immunoblot-01)) :ARG1 (a2 / and :op1 (a3 / activity-06 :ARG0 (p3 / protein :name (n2 / name :op1 "SHIP-1") :xref (x2 / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003")) :ARG1-of (r / reduce-01)) :op2 (a4 / and :op1 (h / hyperphosphorylate-01 :ARG1 (a5 / and :op1 (e2 / enzyme :name (n3 / name :op1 "AKT-1") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.673")) :op2 (p / protein :name (n4 / name :op1 "BAD") :xref (x3 / xref :value "UNIPROT:BAD_HUMAN" :prob "1.004"))) :ARG1-of (i / increase-01))) :op3 (u / upregulate-01 :ARG1 (e3 / express-03 :ARG2 (p2 / protein :name (n5 / name :op1 "BCL-2") :xref (x / xref :value "UNIPROT:BCL2_HUMAN" :prob "0.672"))))) :mod (a6 / also) :location (s / splenocyte :source (m / mouse :ARG0-of (b / bear-01 :ARG1 (t / tumor))))) # ::id bel_pmid_2213_2131.40914 # ::date 2015-05-13T07:37:55 # ::file bel_pmid_2213_2131_40914.txt # ::snt In vitro, qRT-PCR and Western blot analyses detected reduced SHIP-1 mRNA and protein expression in control splenocytes co-cultured with Panc 02.03 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / detect-01 :ARG0 (a / and :op1 (a2 / analyze-01 :instrument (t / thing :name (n / name :op1 "qRT-PCR"))) :op2 (a3 / analyze-01 :manner (i2 / immunoblot-01))) :ARG1 (a4 / and :op1 (e / express-03 :ARG1 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n4 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))))) :op2 (e3 / express-03 :ARG2 p) :ARG1-of (r2 / reduce-01)) :location (s / splenocyte :ARG2-of (c / control-01) :op1-of (a5 / and :op2 (c3 / cell :name (n5 / name :op1 "Panc" :op2 "02.03")) :ARG1-of (c2 / culture-01))) :manner (i / in-vitro)) # ::id bel_pmid_2213_2131.40918 # ::date 2015-05-13T08:19:13 # ::file bel_pmid_2213_2131_40918.txt # ::snt Results from the Inflammatory Cytometric Bead Analysis (CBA) Kit detected pro-inflammatory factors Interleukin-6 (IL-6), Interleukin-10 (IL-10) and Monocyte Chemoattractant Protein-1 (MCP-1) to a greater extent than Tumor Necrosis Factor (TNF), Interferon gamma (IFN-y and Interleukin-12p 70 (IL-12p70) in the supernatants of cultured murine Panc 02.03 cells (Figure 1a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / detect-01 :ARG0 (t / thing :ARG2-of (r / result-01) :source (k / kit :name (n / name :op1 "Inflammatory" :op2 "Cytometric" :op3 "Bead" :op4 "Analysis"))) :ARG1 (e / extent :mod (g / great :degree (m / more)) :domain (a / and :op1 (p / protein :name (n2 / name :op1 "Interleukin-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n3 / name :op1 "Interleukin-10") :xref (x / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n4 / name :op1 "Monocyte" :op2 "Chemoattractant" :op3 "Protein-1") :xref (x2 / xref :value "UNIPROT:CCL2_HUMAN" :prob "0.692")) :ARG0-of (f8 / favor-01 :ARG1 (i2 / inflame-01))) :compared-to (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "Tumor" :op2 "Necrosis" :op3 "Factor") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.702")) :op2 (p5 / protein :name (n6 / name :op1 "Interferon" :op2 "gamma") :xref (x4 / xref :value "UNIPROT:IFNG_HUMAN" :prob "1.002")) :op3 (p6 / protein :name (n7 / name :op1 "Interleukin-12p-70") :xref (x1 / xref :value "UNIPROT:IL10_HUMAN" :prob "0.383")))) :location (s / supernatant :part-of (c / cell :name (n8 / name :op1 "Panc" :op2 "02.03") :part-of (o / organism :name (n9 / name :op1 "Muridae")) :ARG1-of (c2 / culture-01))) :ARG1-of (d2 / describe-01 :ARG0 (f7 / figure :mod "1a"))) # ::id bel_pmid_2213_2131.40920 # ::date 2015-05-13T09:12:36 # ::file bel_pmid_2213_2131_40920.txt # ::snt TB splenocytes have a reduction in SHIP-1 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 22, 2015 (h / have-03 :ARG0 (s / splenocyte :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG1 (r / reduce-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))))) # ::id bel_pmid_2213_2131.40922 # ::date 2015-05-13T09:16:08 # ::file bel_pmid_2213_2131_40922.txt # ::snt Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) results detected a decrease in SHIP-1 mRNA expression in TB compared to control splenocytes (Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 22, 2015 (d / detect-01 :ARG0 (t / thing :ARG2-of (r / result-01) :source (t2 / thing :name (n / name :op1 "Quantitative" :op2 "Reverse" :op3 "Transcription" :op4 "Polymerase" :op5 "Chain" :op6 "Reaction"))) :ARG1 (d2 / decrease-01 :ARG1 (e / express-03 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))))) :location (s / splenocyte :ARG0-of (b / bear-01 :ARG1 (t3 / tumor))) :compared-to (s2 / splenocyte :ARG2-of (c / control-01))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id bel_pmid_2213_2131.40924 # ::date 2015-05-13T09:34:54 # ::file bel_pmid_2213_2131_40924.txt # ::snt TB splenocytes have reduced SHIP-1 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :ARG0 (s / splenocyte :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG1 (a / activity-06 :ARG1 (p / protein :name (n / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003")) :ARG1-of (r / reduce-01))) # ::id bel_pmid_2213_2131.40926 # ::date 2015-05-13T09:43:28 # ::file bel_pmid_2213_2131_40926.txt # ::snt Western blot analyses did not detect phosphorylation of tyrosine 1020 on SHIP-1, in splenocytes from TB compared to control mice (Figure 4a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (d / detect-01 :polarity "-" :ARG0 (a / analyze-01 :manner (i / immunoblot-01)) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "1020" :name (n2 / name :op1 "tyrosine") :part-of (p2 / protein :name (n3 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003")) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :location (s / splenocyte :source (m / mouse :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :compared-to (s2 / splenocyte :source (m2 / mouse :ARG2-of (c / control-01))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4a"))) # ::id bel_pmid_2213_2131.40928 # ::date 2015-05-13T11:01:25 # ::file bel_pmid_2213_2131_40928.txt # ::snt TB splenocytes have increased AKT activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (h / have-03 :ARG0 (s / splenocyte :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG1 (a / activity-06 :ARG1 (e / enzyme :name (n / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (i / increase-01))) # ::id bel_pmid_2213_2131.40930 # ::date 2015-05-13T11:07:01 # ::file bel_pmid_2213_2131_40930.txt # ::snt Western Blot results revealed hyper-phosphorylation of AKT-1 at Ser473 in whole splenocytes from TB compared to control mice (Figure 4b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (r / reveal-01 :ARG0 (t / thing :ARG2-of (r2 / result-01 :ARG1 (i / immunoblot-01))) :ARG1 (h / hyperphosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT-1") :part (a / amino-acid :mod "473" :name (n2 / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.673")) :location (s / splenocyte :mod (w / whole) :source (m / mouse :ARG0-of (b / bear-01 :ARG1 (t3 / tumor)))) :compared-to (s2 / splenocyte :source (m2 / mouse :ARG2-of (c / control-01)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4b"))) # ::id bel_pmid_2213_2131.40932 # ::date 2015-05-13T12:50:40 # ::file bel_pmid_2213_2131_40932.txt # ::snt TB splenocytes have increased BCL-2 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 22, 2015 (h / have-03 :ARG0 (s / splenocyte :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "BCL-2") :xref (x / xref :value "UNIPROT:BCL2_HUMAN" :prob "0.672")) :ARG1-of (i / increase-01))) # ::id bel_pmid_2213_2131.40934 # ::date 2015-05-13T12:59:13 # ::file bel_pmid_2213_2131_40934.txt # ::snt Western Blot results showed hyperphosphorylation of BAD at Ser112 in splenocytes from TB mice compared to control mice (Figure 4c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01 :ARG1 (i / immunoblot-01))) :ARG1 (h / hyperphosphorylate-01 :ARG1 (p / protein :name (n / name :op1 "BAD") :part (a / amino-acid :mod "112" :name (n2 / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :xref (x / xref :value "UNIPROT:BAD_HUMAN" :prob "1.004")) :location (s2 / splenocyte :source (m / mouse :ARG0-of (b / bear-01 :ARG1 (t3 / tumor)))) :compared-to (s3 / splenocyte :source (m2 / mouse :ARG2-of (c / control-01)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4c"))) # ::id bel_pmid_2213_2131.40936 # ::date 2015-05-13T14:10:14 # ::file bel_pmid_2213_2131_40936.txt # ::snt Western blot results revealed an up-regulation in BCL-2 expression in splenocytes from TB mice (Figure 4d) compared to control. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (r / reveal-01 :ARG0 (t / thing :ARG2-of (r2 / result-01 :ARG1 (i / immunoblot-01))) :ARG1 (u / upregulate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "BCL-2") :xref (x / xref :value "UNIPROT:BCL2_HUMAN" :prob "0.672"))) :location (s / splenocyte :source (m / mouse :ARG0-of (b / bear-01 :ARG1 (t3 / tumor))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4d"))) :compared-to (s2 / splenocyte :source (m2 / mouse :ARG2-of (c / control-01))))) # ::id bel_pmid_2213_2131.40938 # ::date 2015-05-13T14:25:37 # ::file bel_pmid_2213_2131_40938.txt # ::snt Murine Panc 02.03 cells down-regulate SHIP-1 expression in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed May 13, 2015 (d / downregulate-01 :ARG0 (c / cell :name (n / name :op1 "Panc" :op2 "02.03") :part-of (o / organism :name (n2 / name :op1 "Muridae"))) :ARG1 (e / express-03 :ARG2 (p / protein :name (n3 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))) :manner (i / in-vitro)) # ::id bel_pmid_2213_2131.40940 # ::date 2015-05-13T14:30:13 # ::file bel_pmid_2213_2131_40940.txt # ::snt qRT-PCR analysis revealed a significant decrease in SHIP-1 mRNA expression in control splenocytes co-cultured with Panc 02.03 cells compared to control splenocytes cultured alone (Figure 5a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / reveal-01 :ARG0 (a / analyze-01 :instrument (t / thing :name (n6 / name :op1 "qRT-PCR"))) :ARG1 (d / decrease-01 :ARG1 (e / express-03 :ARG1 (n5 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))))) :ARG2 (s / significant-02) :location (s2 / splenocyte :ARG2-of (c / control-01) :op1-of (a3 / and :op2 (c3 / cell :name (n4 / name :op1 "Panc" :op2 "02.03")) :ARG1-of (c2 / culture-01))) :compared-to (s3 / splenocyte :ARG2-of c :ARG1-of (c4 / culture-01 :manner (a2 / alone)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5a"))) # ::id bel_pmid_2213_2131.40942 # ::date 2015-05-13T14:48:28 # ::file bel_pmid_2213_2131_40942.txt # ::snt In addition, western blot results revealed greater than a a 2-fold reduction in SHIP-1 protein expression in control splenocytes cocultured with Panc 02.03 cells compared to control splenocytes cultured alone (Figure 5b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op2 (r / reveal-01 :ARG0 (t / thing :ARG2-of (r2 / result-01 :ARG1 (i / immunoblot-01))) :ARG1 (r3 / reduce-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))) :ARG2 (g / great :degree (m / more) :compared-to (p2 / product-of :op1 "2")) :location (s / splenocyte :ARG2-of (c / control-01) :compared-to (s2 / splenocyte :ARG1-of (c4 / culture-01 :manner (a2 / alone))) :op1-of (a3 / and :op2 (c3 / cell :name (n3 / name :op1 "Panc" :op2 "02.03")) :ARG1-of (c2 / culture-01))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5b"))) # ::id bel_pmid_2213_2131.40944 # ::date 2015-05-14T10:57:24 # ::file bel_pmid_2213_2131_40944.txt # ::snt These results correlate with our in vivo data and show that Panc 02.03 cells are able to suppress SHIP-1 mRNA and protein expression in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 22, 2015 (a / and :op1 (c / correlate-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (d / data :manner (i / in-vivo) :poss (w / we))) :op2 (s / show-01 :ARG0 t :ARG1 (p / possible-01 :ARG1 (s2 / suppress-01 :ARG0 (c2 / cell :name (n / name :op1 "Panc" :op2 "02.03")) :ARG1 (a2 / and :op1 (e / express-03 :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n3 / name :op1 "SHIP-1") :xref (x / xref :value "UNIPROT:SHIP1_HUMAN" :prob "1.003"))))) :op2 (e3 / express-03 :ARG2 p2)) :manner (i2 / in-vitro))))) # ::id bel_pmid_2219_4859.25580 # ::date 2015-05-14T11:06:14 # ::file bel_pmid_2219_4859_25580.txt # ::snt In WT mice CH induced an approximate 2-fold increase in IL-6 mRNA at three weeks that was abrogated in C3 -/- mice... We observed increases in lung intracellular adhesion molecule 1 (ICAM-1)...the increase in ICAM-1 was abrogated in C3 -/- mice (Fig. 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (i / induce-01 :ARG0 (m7 / medical-condition :name (n / name :op1 "chronic" :op2 "hypoxia")) :ARG2 (a / approximately :op1 (p / product-of :op1 "2") :op2 (i2 / increase-01 :ARG1 (n8 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG1-of (a2 / abrogate-01 :location (m2 / mouse :mod (p3 / protein :name (n4 / name :op1 "C3") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:CO3_HUMAN" :prob "1.002")))) :time (a4 / after :op1 (t / temporal-quantity :quant "3" :unit (w / week))))) :location (m4 / mouse :mod (w2 / wild-type))) :snt2 (o / observe-01 :ARG0 (w3 / we) :ARG1 (i3 / increase-01 :ARG1 (p4 / protein :name (n5 / name :op1 "intracellular" :op2 "adhesion" :op3 "molecule-1") :part-of (l / lung) :xref (x3 / xref :value "UNIPROT:ICAM1_HUMAN" :prob "0.382")))) :snt3 (a3 / abrogate-01 :ARG1 (i4 / increase-01 :ARG1 (p5 / protein :name (n6 / name :op1 "ICAM-1") :xref (x4 / xref :value "UNIPROT:ICAM1_HUMAN" :prob "1.002"))) :location (m5 / mouse :mod (p6 / protein :name (n7 / name :op1 "C3") :ARG2-of (m6 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:CO3_HUMAN" :prob "1.002")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7"))) # ::id bel_pmid_2220_9329.1840 # ::date 2015-05-14T12:41:37 # ::file bel_pmid_2220_9329_1840.txt # ::snt This Raf-1-mediated fine tuning of Rok-a signaling allows the activation of junctional myosin and the timely maturation of AJ essential for maintaining cell cohesion during sprouting angiogenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / allow-01 :ARG0 (f2 / finetune-01 :ARG1 (s / signal-07 :ARG0 (e / enzyme :name (n / name :op1 "Rok-α"))) :ARG1-of (m / mediate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :mod (t2 / this)) :ARG1 (a2 / and :op1 (a3 / activate-01 :ARG1 (p / protein :name (n3 / name :op1 "myosin") :mod (j / junctional) :xref (x1 / xref :value "UNIPROT:MYH1_HUMAN" :prob "0.322"))) :op2 (m2 / maturate-03 :ARG1 (p2 / protein :name (n4 / name :op1 "AJ")) :ARG1-of (t3 / timely-03)) :mod (e3 / essential :purpose (m3 / maintain-01 :ARG1 (c / cohere-01 :ARG1 (c2 / cell)) :time (a4 / angiogenesis :ARG1-of (s2 / sprout-01)))))) # ::id bel_pmid_2226_7479.1138 # ::date 2015-05-14T13:15:36 # ::file bel_pmid_2226_7479_1138.txt # ::snt In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-? (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (r / reduce-01 :ARG0 (s7 / small-molecule :name (n / name :op1 "NA") :xref (x3 / xref :value "PUBCHEM:923" :prob "12.914376")) :ARG1 (s / secrete-01 :ARG1 (p / protein :name (n2 / name :op1 "TNF-α") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642"))) :ARG2 (o / or :op1 (p4 / percentage-entity :value "48.6" :ARG2-of (a3 / add-02 :ARG1 (p5 / percentage-entity :value "7.1"))) :op2 (p6 / percentage-entity :value "48.6" :ARG2-of (s2 / subtract-01 :ARG1 p5)))) :op2 (r2 / reduce-01 :ARG0 s7 :ARG1 (s5 / secrete-01 :ARG1 (p2 / protein :name (n3 / name :op1 "interleukin-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))) :ARG2 (o3 / or :op1 (p7 / percentage-entity :value "60.9" :ARG2-of (a4 / add-02 :ARG1 (p8 / percentage-entity :value "1.6"))) :op2 (p9 / percentage-entity :value "60.9" :ARG2-of (s3 / subtract-01 :ARG1 p8)))) :op3 (r3 / reduce-01 :ARG0 s7 :ARG1 (s6 / secrete-01 :ARG1 (p3 / protein :name (n4 / name :op1 "monocyte" :op2 "chemoattractant" :op3 "protein-1") :xref (x1 / xref :value "UNIPROT:CCL2_HUMAN" :prob "0.692"))) :ARG2 (o4 / or :op1 (p10 / percentage-entity :value "59.3" :ARG2-of (a5 / add-02 :ARG1 (p11 / percentage-entity :value "5.3"))) :op2 (p12 / percentage-entity :value "59.3" :ARG2-of (s4 / subtract-01 :ARG1 p11)))) :location (a6 / agonist :name (n5 / name :op1 "TLR2") :mod (c / cell :name (n6 / name :op1 "monocyte") :part-of (h / human) :ARG1-of (a7 / activate-01 :ARG0 (o2 / organism :name (n7 / name :op1 "Listeria" :op2 "monocytogene") :ARG1-of (k / kill-01 :ARG0 (h2 / heat-01))))))) # ::id bel_pmid_2236_7719.24892 # ::date 2015-05-14T13:46:39 # ::file bel_pmid_2236_7719_24892.txt # ::snt Cytokine determination within BAL fluid revealed that LPS challenged Tie2-adam17 -/- mice showed reduced release of IL-6 (Fig 7A, 3.9-fold) and TNF-a (Fig 7B, 1.6-fold), whereas no effect was observed in PBS-challenged mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (r / reveal-01 :ARG0 (d / determine-01 :ARG1 (c / cytokine) :location (f / fluid :mod (l / lavage :mod (a3 / alveolus :mod (b / bronchus))))) :ARG1 (c2 / contrast-01 :ARG1 (s / show-01 :ARG0 (m / mouse :mod (e / enzyme :name (n2 / name :op1 "Tie2-adam17") :ARG2-of (m2 / mutate-01 :mod "-/-")) :ARG1-of (c3 / challenge-01 :ARG0 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS") :xref (x3 / xref :value "PUBCHEM:53481794" :prob "9.905254")))) :ARG1 (r2 / release-01 :ARG1 (a / and :op1 (p / protein :name (n4 / name :op1 "IL-6") :ARG1-of (r3 / reduce-01 :ARG2 (p2 / product-of :op1 "3.9")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "7A")) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n5 / name :op1 "TNF-α") :ARG1-of (r4 / reduce-01 :ARG2 (p4 / product-of :op1 "1.6")) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "7B")) :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.642"))))) :ARG2 (o / observe-01 :polarity "-" :ARG1 (a2 / affect-01) :location (m4 / mouse :ARG1-of (c4 / challenge-01 :ARG0 (s2 / small-molecule :name (n6 / name :op1 "PBS") :xref (x2 / xref :value "PUBCHEM:14819" :prob "11.035435"))))))) # ::id bel_pmid_2243_8032.25776 # ::date 2015-05-14T21:27:36 # ::file bel_pmid_2243_8032_25776.txt # ::snt . The concentration of IL-6, IL-13 and IL-17 was significantly higher in KO mice relative to wild-type mice, while that of IL-12 was significantly higher in wild-type mice relative to KO mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (h / high-02 :ARG1 (c2 / concentrate-02 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "IL-13") :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "IL-17") :xref (x1 / xref :value "UNIPROT:IL17_HUMAN" :prob "1.003")))) :degree (m / more) :location (m2 / mouse :location-of (k / knock-out-03)) :ARG2-of (r / relative-05 :ARG3 (m3 / mouse :mod (w / wild-type))) :ARG1-of (s / significant-02)) :ARG2 (h2 / high-02 :ARG1 (c3 / concentrate-02 :ARG1 (p4 / protein :name (n4 / name :op1 "IL-12") :xref (x2 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343"))) :degree m :location m3 :ARG2-of (r2 / relative-05 :ARG3 m2))) # ::id bel_pmid_2243_8032.25784 # ::date 2015-05-14T21:44:37 # ::file bel_pmid_2243_8032_25784.txt # ::snt the expression of tissue damage-related proteins, TGF-? and mesothelin was more markedly increased in the lungs of KO mice relative to wild-type mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / increase-01 :ARG1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "TGF-βl") :xref (x1 / xref :value "UNIPROT:TGR3L_HUMAN" :prob "0.222")) :op2 (p2 / protein :name (n2 / name :op1 "mesothelin") :xref (x / xref :value "UNIPROT:MSLN_HUMAN" :prob "0.702")) :ARG1-of (r / relate-01 :ARG2 (d / damage-01 :ARG1 (t / tissue))))) :ARG2 (m / marked :degree (m2 / more)) :location (l / lung :part-of (m3 / mouse :ARG1-of (k / knock-out-03))) :ARG2-of (r2 / relative-05 :ARG3 (m4 / mouse :mod (w / wild-type)))) # ::id bel_pmid_2254_4933.40994 # ::date 2015-05-12T11:37:40 # ::file bel_pmid_2254_4933_40994.txt # ::snt In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors, as an essential player in regulating the accumulation and activity of MDSCs by targeting of phosphatase and tensin homolog (PTEN) and activation of the Akt pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / identify-01 :ARG0 (w / we) :ARG1 (n4 / nucleic-acid :name (n / name :op1 "RNA-494") :mod (m / micro) :ARG2-of (e / express-03 :ARG2-of (i2 / induce-01 :ARG0 (f / factor :ARG1-of (d2 / derive-01 :ARG2 (t3 / tumor))) :manner (d / dramatic) :manner (p / play-08 :ARG0 e :ARG1 (r2 / regulate-01 :ARG1 (a / and :op1 (a2 / accumulate-01 :ARG1 (c / cell :name (n3 / name :op1 "MDSC"))) :op2 (a3 / activity-06 :ARG0 c)) :manner (a5 / and :op1 (t2 / target-01 :ARG0 e :ARG1 (p3 / protein :name (n2 / name :op1 "phosphatase" :op2 "and" :op3 "tensin" :op4 "homolog") :ARG1-of (m2 / mean-01 :ARG2 (p5 / protein :name (n7 / name :op1 "PTEN") :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "0.703"))) :op2 (a6 / activate-01 :ARG0 e :ARG1 (p2 / pathway :name (n6 / name :op1 "Akt"))))) :mod (e3 / essential))))) :medium (s / study-01 :mod (t / this))) # ::id bel_pmid_2254_4933.41002 # ::date 2015-05-13T11:51:56 # ::file bel_pmid_2254_4933_41002.txt # ::snt miR-494 is highly expressed in tumor-expanded MDSCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / express-03 :ARG2 (n3 / nucleic-acid :name (n / name :op1 "miR-494")) :ARG3 (c / cell :name (n2 / name :op1 "MDSC") :ARG1-of (e2 / expand-01 :ARG0 (t / tumor))) :ARG1-of (h / high-02)) # ::id bel_pmid_2254_4933.41006 # ::date 2015-05-13T11:57:58 # ::file bel_pmid_2254_4933_41006.txt # ::snt As shown in Fig. 1C, significantly increased expression of miR-494 was detected in both subpopulations compared with their counterpart from tumor-free mice (granulocytic MDSCs, p < 0.01; monocytic MDSCs, p < 0.001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a2 / and :op1 (d / detect-01 :ARG1 (e / express-03 :ARG2 (n4 / nucleic-acid :name (n / name :op1 "miR-494")) :ARG1-of (i / increase-01 :ARG2 (s2 / significant-02))) :location (c2 / cell :name (n2 / name :op1 "MDSC") :mod (g / granulocytic)) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.01"))) :op2 (d2 / detect-01 :ARG1 e :location (c3 / cell :name (n3 / name :op1 "MDSC") :mod (m3 / monocytic)) :ARG1-of (s5 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.001"))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "1C")) :compared-to (c / counterpart :location (m / mouse :ARG1-of (f2 / free-04 :ARG2 (t / tumor))) :poss (a / and :op1 c2 :op2 c3))) # ::id bel_pmid_2254_4933.41010 # ::date 2015-05-14T00:28:57 # ::file bel_pmid_2254_4933_41010.txt # ::snt Tumor-derived factors, especially TG'F-fH, markedly induce the upregulation of miR-494 in MDSCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (f / factor :example (p2 / protein :name (n2 / name :op1 "TG'F-fH") :manner (e / especially)) :ARG1-of (d / derive-01 :ARG2 (t / tumor))) :ARG2 (u / upregulate-01 :ARG1 (n / nucleic-acid :name (n3 / name :op1 "miR-494")) :location (c / cell :name (n4 / name :op1 "MDSC"))) :manner (m / marked)) # ::id bel_pmid_2254_4933.41012 # ::date 2015-05-14T00:36:33 # ::file bel_pmid_2254_4933_41012.txt # ::snt As expected, we found that miR-494 expression was significantly induced by TCCM in a dose-dependent manner (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG2 (e2 / express-03 :ARG1 (t / thing :name (n2 / name :op1 "TCCM")) :ARG2 (n3 / nucleic-acid :name (n / name :op1 "miR-494"))) :ARG0-of (d / depend-01 :ARG1 (d2 / dose-01)) :manner (s / significant-02)) :ARG1-of (e / expect-01) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2A"))) # ::id bel_pmid_2254_4933.41014 # ::date 2015-05-13T13:24:22 # ::file bel_pmid_2254_4933_41014.txt # ::snt As shown in Fig. 2B, we found that the expression of miR-494 in Gr-1+ CD11b+ cells was not affected by GM-CSF and IL-6, but interestingly, miR-494 expression was significantly induced by TGF-b1 treatment (p < 0.001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (a / affect-01 :polarity "-" :ARG0 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "GM-CSF") :xref (x1 / xref :value "UNIPROT:CSF2_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n5 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1 (e / express-03 :ARG2 (n7 / nucleic-acid :name (n / name :op1 "miR-494")) :ARG3 (c2 / cell :mod (p / protein :name (n2 / name :op1 "Gr-1+")) :mod (p2 / protein :name (n3 / name :op1 "CD11b+") :xref (x / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682")))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :ARG2 (i / induce-01 :ARG0 (t / treat-04 :ARG2 (p5 / protein :name (n6 / name :op1 "TGF-b1") :xref (x3 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.653"))) :ARG2 e :ARG2-of (i2 / interest-01) :ARG1-of (s2 / significant-02))) :ARG1-of (s / show-01 :ARG0 (f2 / figure :mod "2B"))) # ::id bel_pmid_2254_4933.41016 # ::date 2015-05-13T13:45:05 # ::file bel_pmid_2254_4933_41016.txt # ::snt Moreover, the induction of miR-494 was partially blocked by anti-TGF-p1 mAb in cells stimulated with 4T1 TCCM (Fig. 2C), and the upregulation of miR-494 was impaired in Smad 3-deficient Gr-1+ CD11b+ cells isolated from the spleen of Smad 3_/_ mice (Fig. 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op2 (a2 / and :op1 (b / block-01 :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-p1") :ARG1-of (c / counter-01 :ARG0 (a4 / antidoby)) :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.263")) :ARG1 (i2 / induct-02 :ARG1 (n9 / nucleic-acid :name (n / name :op1 "miR-494"))) :degree (p / part) :location (c2 / cell :ARG1-of (s / stimulate-01 :ARG2 (c5 / cell-line :name (n8 / name :op1 "4T1") :part-of (t / thing :name (n4 / name :op1 "TCCM"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2C"))) :op2 (i / impair-01 :ARG1 (u / upregulate-01 :ARG1 n9) :location (c3 / cell :ARG1-of (i3 / isolate-01 :ARG2 (s2 / spleen :part-of (m2 / mouse :mod (p6 / protein :name (n5 / name :op1 "Smad" :op2 "3") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:SMAD3_HUMAN" :prob "0.682")))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2D")) :location (a3 / and :op1 (c6 / cell :mod (p4 / protein :name (n6 / name :op1 "Gr-1+"))) :op2 (c7 / cell :mod (p3 / protein :name (n3 / name :op1 "CD11b+") :xref (x1 / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682"))) :ARG0-of (l / lack-01 :ARG1 p6))))) # ::id bel_pmid_2254_4933.41022 # ::date 2015-05-13T14:14:49 # ::file bel_pmid_2254_4933_41022.txt # ::snt As expected, the expression levels of ARG1, MMP2, MMP13, and MMP14 were significantly upregulated in lv-494-infected MDSCs compared with those in lv-ctrl-infected MDSCs (Fig. 4B); moreover, lv-sponge overtly blocked the induction in the expression of these molecules. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (u / upregulate-01 :ARG1 (l2 / level :degree-of (e3 / express-03 :ARG2 (a3 / and :op1 (e4 / enzyme :name (n / name :op1 "ARG1") :xref (x / xref :value "UNIPROT:ARGI1_HUMAN" :prob "1.002")) :op2 (e5 / enzyme :name (n2 / name :op1 "MMP2") :xref (x1 / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.003")) :op3 (e6 / enzyme :name (n3 / name :op1 "MMP13") :xref (x3 / xref :value "UNIPROT:MMP13_HUMAN" :prob "1.003")) :op4 (e7 / enzyme :name (n4 / name :op1 "MMP14") :xref (x2 / xref :value "UNIPROT:MMP14_HUMAN" :prob "1.003"))))) :ARG1-of (e2 / expect-01) :ARG1-of (s / significant-02) :location (c / cell :name (n5 / name :op1 "MDSC") :ARG1-of (i2 / infect-01 :ARG0 (s2 / small-molecule :name (n6 / name :op1 "lv-494")))) :compared-to (l4 / level :location (c2 / cell :name (n7 / name :op1 "MDSC") :ARG1-of (i3 / infect-01 :ARG0 (s4 / small-molecule :name (n8 / name :op1 "lv-ctrl")))) :degree-of e3) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4B"))) :op2 (a2 / and :op2 (b / block-01 :ARG0 (s3 / small-molecule :name (n9 / name :op1 "lv-sponge")) :ARG1 (i / induce-01 :ARG2 (e / express-03 :ARG1 a3)) :manner (o / overt)))) # ::id bel_pmid_2254_4933.41028 # ::date 2015-05-13T13:35:27 # ::file bel_pmid_2254_4933_41028.txt # ::snt As shown in Fig. 4G, OT-1 CD8+ T cell proliferation was significantly suppressed by lv-494-infected MDSCs in comparison with lv-ctrl-infected MDSCs, and this suppressive activity could be partially blocked by an ARG1 inhibitor nor-NOHA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (s / suppress-01 :ARG0 (c4 / cell :name (n6 / name :op1 "MDSC") :ARG1-of (i2 / infect-01 :ARG0 (s5 / small-molecule :name (n7 / name :op1 "lv-494")))) :ARG1 (p2 / proliferate-01 :ARG0 (c / cell :name (n3 / name :op1 "T" :op2 "cell") :source (o / organism :name (n4 / name :op1 "OT-1")) :mod (p4 / protein :name (n5 / name :op1 "CD8") :mod (p5 / positive) :xref (x1 / xref :value "UNIPROT:C5AR1_HUMAN" :prob "0.342")))) :ARG1-of (s2 / significant-02) :compared-to (c5 / cell :name (n8 / name :op1 "MDSC") :ARG1-of (i3 / infect-01 :ARG0 (s4 / small-molecule :name (n9 / name :op1 "lv-ctrl"))))) :op2 (p3 / possible-01 :ARG1 (b / block-01 :ARG0 (s6 / small-molecule :name (n / name :op1 "Nor-NOHA") :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ARG1") :xref (x / xref :value "UNIPROT:ARGI1_HUMAN" :prob "1.002"))) :xref (x2 / xref :value "PUBCHEM:3253680" :prob "19.115147")) :ARG1 s :degree (p / part))) :ARG1-of (s3 / show-01 :ARG0 (f / figure :mod "4G"))) # ::id bel_pmid_2254_4933.41038 # ::date 2015-05-13T14:41:06 # ::file bel_pmid_2254_4933_41038.txt # ::snt Notably, the PTEN protein level was significantly downregulated in tumor-expanded MDSCs compared with that in Gr-1+ CD11b+ cells from tumor-free mice, whereas PTEN mRNA expression showed no difference (Fig. 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (d2 / downregulate-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "PTEN") :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :ARG1-of (s / significant-02) :location (c2 / cell :name (n2 / name :op1 "MDSC") :ARG1-of (e / expand-01 :ARG0 (t / tumor))) :compared-to (l2 / level :location (c3 / cell :source (m / mouse :ARG1-of (f2 / free-04 :ARG2 t)) :ARG1-of (m2 / mutate-01 :ARG2 (a / and :op1 (p2 / protein :name (n3 / name :op1 "Gr-1+")) :op2 (p3 / protein :name (n4 / name :op1 "CD11b+") :xref (x / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682"))))) :degree-of p)) :ARG2 (s2 / show-01 :polarity "-" :ARG0 (e2 / express-03 :ARG2 (n7 / nucleic-acid :name (n5 / name :op1 "mRNA") :mod p)) :ARG1 (d3 / differ-02)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A")) :ARG1-of (n6 / notable-04)) # ::id bel_pmid_2254_4933.41040 # ::date 2015-05-14T00:09:54 # ::file bel_pmid_2254_4933_41040.txt # ::snt When the reporter plasmids with miR-494 mimics or the scrambled oligonucleotide were cotransfected to HEK-293 cells, we observed that the miR-494 mimics markedly decreased the luciferase activity (Fig. 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (d / decrease-01 :ARG0 (m2 / mimic-01 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "miR-494"))) :ARG1 (a / activity-06 :ARG0 (l / luciferase)) :manner (m / marked)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6B")) :time (c / cotransfect-01 :ARG1 (c2 / cell :name (n2 / name :op1 "HEK-293")) :ARG2 (o2 / or :op1 (p / plasmid :instrument m2 :ARG0-of (r2 / report-01)) :op2 (o3 / oligonucleotide :ARG1-of (s / scramble-02))))) # ::id bel_pmid_2254_4933.41042 # ::date 2015-05-14T00:16:11 # ::file bel_pmid_2254_4933_41042.txt # ::snt Furthermore, transfection of lv-494 significantly decreased PTEN expression in MDSCs, thus suggesting that endogenous PTEN is targeted and regulated by miR-494 (Fig. 6C).. To confirm whether miR-494-induced activation of MDSCs was mediated by targeting of PTEN expression, we designed a lentiviral vector encoding 39-UTR-depleted PTEN to enforce the expression of PTEN in MDSCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt1 (a / and :op2 (d2 / decrease-01 :ARG0 (t / transfect-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "lv-494"))) :ARG1 (e / express-03 :ARG2 "p2" :ARG3 (c / cell :name (n3 / name :op1 "MDSC"))) :ARG1-of (s / significant-02) :ARG0-of (s2 / suggest-01 :ARG1 (a2 / and :op1 (t2 / target-01 :ARG0 (n9 / nucleic-acid :name (n4 / name :op1 "miR-494")) :ARG1 (p2 / protein :name (n5 / name :op1 "PTEN") :mod (m2 / monocot) :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :op2 (r / regulate-01 :ARG0 n9 :ARG1 p2)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "6C"))) :snt2 (d / design-01 :ARG0 (w / we) :ARG1 (v / vector :mod (l2 / lentiviral) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "PTEN") :ARG1-of (d5 / deplete-01 :ARG2 (d3 / dna-sequence :name (n6 / name :op1 "39-UTR"))) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")))) :purpose (e4 / enforce-01 :ARG0 v :ARG1 (e5 / express-03 :ARG2 p :ARG3 (c2 / cell :name (n7 / name :op1 "MDSC")))) :purpose (c3 / confirm-01 :ARG0 w :ARG1 (m4 / mediate-01 :ARG0 (a3 / activate-01 :ARG1 c2 :ARG2-of (i / induce-01 :ARG0 (n10 / nucleic-acid :name (n8 / name :op1 "miR-494")))) :ARG1 (t3 / target-01 :ARG1 (e6 / express-03)))))) # ::id bel_pmid_2254_4933.41044 # ::date 2015-05-14T02:04:39 # ::file bel_pmid_2254_4933_41044.txt # ::snt Overexpression of PTEN in Gr-1+ CD11b+ cells did not affect the TDF-induced miR-494 up-regulation, whereas the increased expression of MMPs induced by TCCM were significantly blocked (Fig. 6D), and SDF-1/CXCL12-mediated MDSC migration was abrogated (Fig. 6E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (a / affect-01 :polarity "-" :ARG0 (o / overexpress-01 :ARG1 (p3 / protein :name (n3 / name :op1 "PTEN") :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :location (c2 / cell :ARG1-of (m / mutate-01 :ARG0 (a3 / and :op1 (p / protein :name (n / name :op1 "Gr-1+")) :op2 (p2 / protein :name (n2 / name :op1 "CD11b+") :xref (x / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682")))))) :ARG1 (u / upregulate-01 :ARG1 (n11 / nucleic-acid :name (n5 / name :op1 "miR-494")) :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "TDF") :xref (x1 / xref :value "UNIPROT:SRY_HUMAN" :prob "1.002"))))) :ARG2 (a4 / and :op1 (b / block-01 :ARG1 (e / express-03 :ARG2 (p5 / protein :name (n6 / name :op1 "MMP") :xref (x4 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263")) :ARG1-of (i2 / increase-01) :ARG2-of (i3 / induce-01 :ARG0 (t / thing :name (n7 / name :op1 "TCCM")))) :ARG1-of (s / significant-02) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6D"))) :op2 (a5 / abrogate-01 :ARG1 (m2 / migrate-01 :ARG0 (c3 / cell :name (n8 / name :op1 "MDSC")) :ARG1-of (m3 / mediate-01 :ARG0 (a6 / and :op1 (p7 / protein :name (n9 / name :op1 "SDF-1") :xref (x3 / xref :value "UNIPROT:SDF1_HUMAN" :prob "1.003")) :op2 (p8 / protein :name (n10 / name :op1 "CXCL12") :xref (x5 / xref :value "UNIPROT:SDF1_HUMAN" :prob "1.003"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6E"))) # ::id bel_pmid_2254_4933.41046 # ::date 2015-05-14T02:16:51 # ::file bel_pmid_2254_4933_41046.txt # ::snt Significantly reduced PTEN expression was also detected in Gr-1+ CD11b+ cells after TCCM stimulation (Fig. 6G); this was inversely correlated with the phosphorylation levels of mTOR and NF-kB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (m / multi-sentence :snt1 (d / detect-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "PTEN") :xref (x3 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG1-of (r / reduce-01 :ARG2 (s / significant-02))) :mod (a / also) :location (c / cell :ARG1-of (m2 / mutate-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Gr-1+")) :op2 (p3 / protein :name (n3 / name :op1 "CD11b+") :xref (x1 / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682"))))) :time (a3 / after :op1 (s2 / stimulate-01 :ARG0 (t2 / thing :name (n4 / name :op1 "TCCM")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6G"))) :snt2 (c2 / correlate-01 :ARG1 (t / this) :ARG2 (l2 / level :degree-of (p5 / phosphorylate-01 :ARG1 (l / level :quant-of (a4 / and :op1 (p6 / protein :name (n5 / name :op1 "mTOR") :xref (x2 / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")) :op2 (p7 / protein :name (n6 / name :op1 "NF-kB") :xref (x / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272")))))) :manner (i / inverse))) # ::id bel_pmid_2254_4933.41048 # ::date 2015-05-14T01:42:51 # ::file bel_pmid_2254_4933_41048.txt # ::snt As shown in Fig. 6H, the increased levels of MMPs induced by TCCM were completely abolished by LY294002, suggesting that the Akt activity is indispensable for the activation of MDSCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / abolish-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (l / level :ARG1-of (i / increase-01) :quant-of (e / enzyme :name (n2 / name :op1 "MMP") :xref (x / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263")) :ARG2-of (i2 / induce-01 :ARG0 (t / thing :name (n3 / name :op1 "TCCM")))) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "6H")) :ARG1-of (c / complete-02) :ARG0-of (s / suggest-01 :ARG1 (p2 / possible-01 :ARG1 (i3 / indispensable-01 :ARG1 (a2 / activity-06 :ARG0 (p3 / pathway :name (n5 / name :op1 "Akt"))) :ARG2 (a3 / activate-01 :ARG1 (c2 / cell :name (n6 / name :op1 "MDSC"))))))) # ::id bel_pmid_2254_4933.41050 # ::date 2015-05-14T01:55:00 # ::file bel_pmid_2254_4933_41050.txt # ::snt BAY-117802 significantly blocked MMP13 expression but had a limited effect on the upregulation of MMP2 and MMP14, whereas rapamycin eliminated the expression of all MMPs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / contrast-01 :ARG1 (c2 / contrast-01 :ARG1 (b / block-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "BAY-117802")) :ARG1 (e4 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MMP13") :xref (x2 / xref :value "UNIPROT:MMP13_HUMAN" :prob "1.003"))) :ARG1-of (s / significant-02)) :ARG2 (a3 / affect-01 :ARG0 s2 :ARG1 (u / upregulate-01 :ARG1 (a2 / and :op1 (e5 / enzyme :name (n4 / name :op1 "MMP2") :xref (x / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.003")) :op2 (e6 / enzyme :name (n5 / name :op1 "MMP14") :xref (x1 / xref :value "UNIPROT:MMP14_HUMAN" :prob "1.003")))) :ARG1-of (l / limit-01))) :ARG2 (e / eliminate-01 :ARG0 (r / rapamycin) :ARG1 (e2 / express-03 :ARG2 (p / protein-family :name (n / name :op1 "MMP") :mod (a / all))))) # ::id bel_pmid_2254_4933.41052 # ::date 2015-05-14T01:05:48 # ::file bel_pmid_2254_4933_41052.txt # ::snt TGF-p1-induced miR-494 was involved in the negative regulation of PTEN expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / involve-01 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "miR-494") :ARG2-of (i2 / induce-01 :ARG0 (p / protein :name (n2 / name :op1 "TGF-p1") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.263")))) :ARG2 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))) # ::id bel_pmid_2295_2847.42202 # ::date 2015-05-14T01:08:22 # ::file bel_pmid_2295_2847_42202.txt # ::snt Transcriptional reprogramming of tumors via DmiR-580, 588 or 190 over-expression resulted in downregulation of pro-angiogenic factors such as TIMP-3, bFGF and TGFalpha. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (r / result-01 :ARG1 (r2 / reprogram-00 :ARG1 (t2 / tumor) :mod (t / transcribe-01) :path (o / overexpress-01 :ARG1 (o2 / or :op1 (n7 / nucleic-acid :name (n4 / name :op1 "DmiR-580")) :op2 (n8 / nucleic-acid :name (n5 / name :op1 "DmiR-588")) :op3 (n9 / nucleic-acid :name (n6 / name :op1 "DmiR-190"))))) :ARG2 (d / downregulate-01 :ARG1 (f / factor :ARG0-of (f2 / favor-01 :ARG1 (a3 / angiogenesis)) :example (a / and :op1 (p / protein :name (n / name :op1 "TIMP-3") :xref (x2 / xref :value "UNIPROT:TIMP3_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n2 / name :op1 "bFGF") :xref (x1 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n3 / name :op1 "TGFalpha") :xref (x / xref :value "UNIPROT:TGFA_HUMAN" :prob "0.692")))))) # ::id bel_pmid_2295_2847.42206 # ::date 2015-05-14T01:18:50 # ::file bel_pmid_2295_2847_42206.txt # ::snt Figure 2D shows the high rate of proliferative Ki67+ cells in a representative dormant miR-588 expressing A-GBM tumor at day 113 post injection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s / show-01 :ARG0 (f / figure :mod "2D") :ARG1 (r / rate :ARG1-of (h / high-02) :degree-of (c / cell :name (n / name :op1 "Ki67+") :ARG0-of (p / proliferate-01))) :location (n4 / nucleic-acid :name (n3 / name :op1 "miR-588") :ARG1-of (e / express-03 :ARG2 (t / tumor :mod (c2 / cell :name (n2 / name :op1 "A-GBM"))) :time (a / after :op1 (i / inject-01) :quant (t2 / temporal-quantity :quant "113" :unit (d2 / day)))) :mod (d / dormant) :ARG0-of (r3 / represent-01))) # ::id bel_pmid_2295_2847.42214 # ::date 2015-05-13T11:58:43 # ::file bel_pmid_2295_2847_42214.txt # ::snt We found that antiangiogenic and dormancy promoting genes, Angiomotin (AMOT-1) and Eph receptor A5 (EphA5), were both upregulated in all DmiR expressing A-GBM tumors as compared to the GFP-vector- control A-GBM cells (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (u / upregulate-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "Angiomotin") :xref (x1 / xref :value "UNIPROT:AMOT_HUMAN" :prob "1.002")) :op2 (g3 / gene :name (n3 / name :op1 "Eph" :op2 "receptor" :op3 "A5") :xref (x / xref :value "UNIPROT:EPHAA_HUMAN" :prob "0.213")) :ARG0-of (p2 / promote-02 :ARG1 (d3 / dormancy)) :ARG0-of (c3 / counter-01 :ARG1 (a2 / angiogenesis))) :compared-to (c / cell :name (n6 / name :op1 "GFP-vector-control" :op2 "A-GBM")) :location (t / tumor :mod (c2 / cell :name (n4 / name :op1 "A-GBM") :ARG3-of (e / express-03 :ARG1 (n2 / nucleic-acid :name (n5 / name :op1 "Dmir")))) :mod (a3 / all))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4"))) # ::id bel_pmid_2295_2847.42216 # ::date 2015-05-14T01:42:09 # ::file bel_pmid_2295_2847_42216.txt # ::snt In contrast, genes involved in pro-angiogenic signaling, including tissue inhibitor of metalloprotei-nases 3 (TIMP-3), hypoxia-induced factor 1 alpha (HIF-1-alpha), basic fibroblast growth factor (bFGF, FGF2), and the K-ras tumor oncogene, were consistently downregulated in DmiR expressing A-GBM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (c / contrast-01 :ARG2 (d / downregulate-01 :ARG1 (g2 / gene :ARG1-of (i / involve-01 :ARG2 (s / signal-07 :ARG0-of (f / favor-01 :ARG1 (a2 / angiogenesis)))) :ARG2-of (i2 / include-91 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "tissue" :op2 "inhibitor" :op3 "of" :op4 "metalloprotei-nase" :op5 "3") :xref (x3 / xref :value "UNIPROT:TIMP1_HUMAN" :prob "0.392")) :op2 (p3 / protein :name (n2 / name :op1 "hypoxia-induced" :op2 "factor" :op3 "1") :xref (x / xref :value "UNIPROT:ARNT_HUMAN" :prob "0.342")) :op3 (p4 / protein :name (n5 / name :op1 "basic" :op2 "fibroblast" :op3 "growth" :op4 "factor") :xref (x2 / xref :value "UNIPROT:FGF2_HUMAN" :prob "0.703")) :op4 (o / oncogene :mod (e / enzyme :name (n6 / name :op1 "K-ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "1.001")) :mod (t / tumor))))) :ARG2 (c3 / cell :name (n3 / name :op1 "A-GBM") :ARG3-of (e2 / express-03 :ARG1 (n7 / nucleic-acid :name (n4 / name :op1 "DmiR")))) :manner (c2 / consistent-02))) # ::id bel_pmid_2295_2847.42218 # ::date 2015-05-13T13:12:09 # ::file bel_pmid_2295_2847_42218.txt # ::snt Importantly, we found Bv8 also known as prokineticin 2 (Prok2) to be markedly downregulated in all three DmiR expressing A-GBM (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (d2 / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "Bv8") :ARG1-of (k / know-02 :ARG2 (p2 / protein :name (n5 / name :op1 "prokineticin" :op2 "2") :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n2 / name :op1 "Prok2") :xref (x1 / xref :value "UNIPROT:PROK2_HUMAN" :prob "0.603"))) :xref (x / xref :value "UNIPROT:PROK2_HUMAN" :prob "0.692")) :mod (a2 / also)) :xref (x2 / xref :value "UNIPROT:PROK2_HUMAN" :prob "0.622")) :manner (m2 / marked) :location (n6 / nucleic-acid :quant "3" :name (n3 / name :op1 "DmiR") :mod (a / all) :ARG1-of (e / express-03 :ARG2 (c / cell :name (n4 / name :op1 "A-GBM"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5A")) :manner (i / important)) # ::id bel_pmid_2295_2847.42226 # ::date 2015-05-13T11:58:53 # ::file bel_pmid_2295_2847_42226.txt # ::snt Over-expression of miR-580, miR-588 and miR-190 in fast-growing angiogenic glioblastoma. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (o / overexpress-01 :ARG1 (a / and :op1 (n4 / nucleic-acid :name (n / name :op1 "miR-580")) :op2 (n5 / nucleic-acid :name (n2 / name :op1 "miR-588")) :op3 (n6 / nucleic-acid :name (n3 / name :op1 "miR-190"))) :location (g / glioblastoma :mod (a2 / angiogenic) :ARG1-of (g2 / grow-01 :ARG1-of (f / fast-02)))) # ::id bel_pmid_2313_1846.42236 # ::date 2015-05-13T12:08:45 # ::file bel_pmid_2313_1846_42236.txt # ::snt In contrast, VEGF plugs in Pld1~-~ mice exhibited almost no vascularization (Fig. 2, A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / contrast-01 :ARG2 (e / exhibit-01 :ARG0 (p / plug :poss (p2 / protein :name (n / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :location (m / mouse :mod (g / gene :name (n2 / name :op1 "Pld1") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:PLD1_HUMAN" :prob "0.604")))) :ARG1 (v / vascularize-01 :ARG1 p :mod (a2 / almost :polarity "-"))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B")))) # ::id bel_pmid_2313_1846.42240 # ::date 2015-05-13T12:23:58 # ::file bel_pmid_2313_1846_42240.txt # ::snt PLD1 deficiency reduced basal phosphorylation of Ser473 in Akt and prevented VEGF-induced phosphorylation of Akt at Ser473 (Fig. 3, C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (r / reduce-01 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "PLD1") :xref (x1 / xref :value "UNIPROT:PLD1_HUMAN" :prob "1.004"))) :ARG1 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n2 / name :op1 "Ser473") :part-of (e / enzyme :name (n4 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :mod (b / basal))) :op2 (p2 / prevent-01 :ARG0 l :ARG1 (p5 / phosphorylate-01 :ARG1 e :ARG2-of (i / induce-01 :ARG0 (p6 / protein :name (n3 / name :op1 "VEGF") :xref (x2 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003"))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3C") :op2 (f2 / figure :mod "3D")))) # ::id bel_pmid_2313_1846.42242 # ::date 2015-05-14T01:33:18 # ::file bel_pmid_2313_1846_42242.txt # ::snt Pldl-- endothelial cells similarly exhibited a 50% reduction in basal phosphorylation of ERK1/2 but otherwise exhibited similar kinetics to wild-type cells for VEGF-induced phosphorylation of ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (e / exhibit-01 :ARG0 (c2 / cell :mod (e2 / endothelium) :mod (p3 / protein :name (n / name :op1 "Pldl") :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1 (r2 / reduce-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK1/2")) :mod (b / basal)) :ARG2 (p / percentage-entity :value "50")) :manner (r / resemble-01)) :ARG2 (e3 / exhibit-01 :ARG1 (a / and :op1 (k / kinetics :mod (r3 / resemble-01)) :op2 (c3 / cell :mod (w / wild-type)) :purpose (p5 / phosphorylate-01 :ARG1 e4 :ARG2-of (i / induce-01 :ARG0 (p6 / protein :name (n3 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003"))))))) # ::id bel_pmid_2313_1846.42248 # ::date 2015-05-14T02:36:10 # ::file bel_pmid_2313_1846_42248.txt # ::snt Histological and quantitative analyses of the tumors revealed a 79% decrease in microvessels in the tumors that formed in FIPI-treated mice (Fig. 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (r / reveal-01 :ARG0 (a / and :op1 (a2 / analyze-01 :ARG1 (t / tumor) :mod (h / histology)) :op2 (a3 / analyze-01 :ARG1 t :mod (q / quantitative))) :ARG1 (d2 / decrease-01 :ARG1 (m / microvessel :part-of (t2 / tumor :ARG0-of (f2 / form-01 :location (m2 / mouse :ARG1-of (t3 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "FIPI") :xref (x / xref :value "PUBCHEM:16739265" :prob "18.86067"))))))) :ARG2 (p / percentage-entity :value "79")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id bel_pmid_2334_3326.26540 # ::date 2015-05-14T08:28:31 # ::file bel_pmid_2334_3326_26540.txt # ::snt Engagement of Gi- and Gq-protein-coupled ETB receptors by ET-1 led to phosphorylation of ERK1/2, p38 MAPK, and JNK1/2 and then activated transcription factor NF-?B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (a4 / and :op1 (l / lead-03 :ARG0 (e / engage-01 :ARG0 (p / protein :name (n / name :op1 "ET-1") :xref (x / xref :value "UNIPROT:EDN1_HUMAN" :prob "1.003")) :ARG1 (r / receptor :name (n2 / name :op1 "ETB") :ARG1-of (c / couple-01 :ARG2 (a / and :op1 (p2 / protein :name (n3 / name :op1 "Gi")) :op2 (p3 / protein :name (n4 / name :op1 "Gq")))))) :ARG2 (p4 / phosphorylate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1") :xref (x5 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n6 / name :op1 "ERK2") :xref (x4 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :op3 (e4 / enzyme :name (n8 / name :op1 "p38" :op2 "MAPK") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203")) :op4 (e6 / enzyme :name (n9 / name :op1 "JNK1") :xref (x3 / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003")) :op5 (e7 / enzyme :name (n10 / name :op1 "JNK2") :xref (x2 / xref :value "UNIPROT:MK09_HUMAN" :prob "1.003"))))) :op2 (a3 / activate-01 :ARG0 e :ARG1 (m / macro-molecular-complex :name (n11 / name :op1 "NF-kappaB") :mod (f / factor :ARG0-of (t2 / transcribe-01))) :time (t / then))) # ::id bel_pmid_2334_3326.38068 # ::date 2015-05-14T08:40:42 # ::file bel_pmid_2334_3326_38068.txt # ::snt Engagement of Gi- and Gq-protein-coupled ETB receptors by ET-1 led to phosphorylation of ERK1/2, p38 MAPK, and JNK1/2 and then activated transcription factor NF-?B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (a4 / and :op1 (l / lead-03 :ARG0 (e / engage-01 :ARG0 (p / protein :name (n / name :op1 "ET-1") :xref (x5 / xref :value "UNIPROT:EDN1_HUMAN" :prob "1.003")) :ARG1 (r / receptor :name (n2 / name :op1 "ETB")) :ARG1-of (c / couple-01 :ARG2 (a / and :op1 (p2 / protein :name (n3 / name :op1 "Gi")) :op2 (p3 / protein :name (n4 / name :op1 "Gq"))))) :ARG2 (p4 / phosphorylate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1") :xref (x4 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n6 / name :op1 "ERK2") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :op3 (e4 / enzyme :name (n7 / name :op1 "p38" :op2 "MAPK") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203")) :op4 (e5 / enzyme :name (n8 / name :op1 "JNK1") :xref (x / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003")) :op5 (e6 / enzyme :name (n9 / name :op1 "JNK2") :xref (x2 / xref :value "UNIPROT:MK09_HUMAN" :prob "1.003"))))) :op2 (a3 / activate-01 :ARG0 e :ARG1 (m / macro-molecular-complex :name (n10 / name :op1 "NF-kappaB") :mod (f / factor :ARG0-of (t2 / transcribe-01))) :time (t / then))) # ::id bel_pmid_2364_0055.42272 # ::date 2015-05-14T08:41:05 # ::file bel_pmid_2364_0055_42272.txt # ::snt Against this background, we conducted in vitro phosphorylation studies of the phosphorylation of in-tegrin avp3 dimer with activated ERK1 and found phosphorylation of the dimer (Fig. 3A) that was inhibited by the ERK inhibitor, FR180204. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c2 / contrast-01 :ARG1 (b / background :mod (t / this)) :ARG2 (a / and :op1 (c / conduct-01 :ARG0 (w / we) :ARG1 (s / study-01 :ARG1 (p / phosphorylate-01 :ARG1 (d / dimer :name (n / name :op1 "integrin" :op2 "αVβ3")) :ARG2 (e / enzyme :name (n3 / name :op1 "ERK1") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")))) :manner (i / in-vitro)) :op2 (f / find-01 :ARG0 w :ARG1 (i2 / inhibit-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "FR180204") :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "ERK")))) :ARG1 p) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3A"))))) # ::id bel_pmid_2364_0055.42278 # ::date 2015-05-14T08:53:20 # ::file bel_pmid_2364_0055_42278.txt # ::snt Integrin av bound to the COX-2 promoter in both OVCAR-3 and H522 cells in response to T4 (Fig. 4A) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "integrin" :op2 "av") :xref (x1 / xref :value "UNIPROT:ITAV_HUMAN" :prob "0.343")) :ARG2 (m / molecular-physical-entity :ARG0-of (p2 / promote-02 :ARG1 (e / enzyme :name (n2 / name :op1 "COX-2") :xref (x / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")))) :location (a / and :op1 (c / cell-line :name (n3 / name :op1 "OVCAR-3")) :op2 (c2 / cell-line :name (n4 / name :op1 "H522"))) :ARG2-of (r / respond-01 :ARG1 (s / small-molecule :name (n5 / name :op1 "T4") :xref (x2 / xref :value "PUBCHEM:5819" :prob "14.48701"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id bel_pmid_2364_0055.42282 # ::date 2015-05-14T09:03:34 # ::file bel_pmid_2364_0055_42282.txt # ::snt These results suggest that although T4 increased complex formation between integrin av and NCoR/SMRT, the association between NCoR/SMRT and DNA was unchanged. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (h / have-concession-91 :ARG1 (c / change-01 :polarity "-" :ARG1 (a / associate-01 :ARG1 "m" :ARG2 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")))) :ARG2 (i / increase-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "T4") :xref (x1 / xref :value "PUBCHEM:5819" :prob "14.48701")) :ARG1 (f / form-01 :ARG1 (m2 / macro-molecular-complex :part (p / protein :name (n2 / name :op1 "integrin" :op2 "av") :xref (x / xref :value "UNIPROT:ITAV_HUMAN" :prob "0.343")) :part (m / macro-molecular-complex :name (n3 / name :op1 "NCoR/SMRT"))))))) # ::id bel_pmid_2364_0055.42284 # ::date 2015-05-14T09:10:31 # ::file bel_pmid_2364_0055_42284.txt # ::snt The transcription of COX-2, ERa, HIF-la, and TR$1 was increased in thyroid hormone-treated cells (Fig. 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (i / increase-01 :ARG1 (t / transcribe-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "COX-2") :xref (x1 / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")) :op2 (p / protein :name (n2 / name :op1 "ERalpha") :xref (x3 / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.693")) :op3 (p2 / protein :name (n3 / name :op1 "HIF-1alpha") :xref (x / xref :value "UNIPROT:HIF1A_HUMAN" :prob "0.692")) :op4 (p3 / protein :name (n4 / name :op1 "TRbeta1") :xref (x2 / xref :value "UNIPROT:TRXR2_HUMAN" :prob "0.322")))) :location (c / cell :ARG1-of (t2 / treat-04 :ARG2 (h / hormone :source (t3 / thyroid)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id bel_pmid_2382_4538.18804 # ::date 2015-05-14T09:18:36 # ::file bel_pmid_2382_4538_18804.txt # ::snt Abundant autophagosomes in K-rasG12D/+;atg7+/+ but not in K-rasG12D/+;atg7 -/- tumors were confirmed by electron microscopy (Fig. 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 23, 2015 (c3 / contrast-01 :ARG1 (c / confirm-01 :ARG0 (m4 / microscopy :mod (e2 / electron)) :ARG1 (s / small-molecule :name (n / name :op1 "autophagosome") :mod (a / abundant)) :location (t / tumor :mod (s2 / slash :op1 (e / enzyme :name (n2 / name :op1 "K-ras") :ARG2-of (m / mutate-01 :value "G12D") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "1.001")) :op2 (p2 / protein :name (n3 / name :op1 "atg7") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:ATG7_HUMAN" :prob "0.603"))))) :ARG2 (c4 / confirm-01 :polarity "-" :ARG0 m4 :ARG1 s :location (t2 / tumor :mod (s3 / slash :op1 e :op2 (p3 / protein :name (n4 / name :op1 "atg7") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:ATG7_HUMAN" :prob "0.603"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id bel_pmid_2382_4538.18808 # ::date 2015-05-14T23:57:27 # ::file bel_pmid_2382_4538_18808.txt # ::snt Reduction of atg7-deficient tumor burden was coincident with reduced proliferation (Ki67) and decreased levels of phospho-MEK1/2 (P-MEK1/2) and P-ERK1/2 and p53 and p21 induction, compared with wild-type tumors (Fig. 1I; Supplemental Figs. S4A–C, S5A–C), suggesting that inhibition of tumor cell proliferation upon atg7 deletion is the main cause of reduced tumor burden. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (c / coincide-01 :ARG1 (r / reduce-01 :ARG1 (b / burden-01 :ARG2 (t / tumor :mod (p / protein :name (n / name :op1 "atg7") :ARG1-of (d4 / delete-01) :xref (x7 / xref :value "UNIPROT:ATG7_HUMAN" :prob "0.603"))))) :ARG2 (a / and :op1 (p2 / proliferate-01 :ARG1-of (r2 / reduce-01) :ARG1-of (m2 / measure-01 :ARG2 (p3 / protein :name (n2 / name :op1 "Ki67") :xref (x3 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653")))) :op2 (l2 / level :ARG1-of (d / decrease-01) :quant-of (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x4 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n5 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op4 (e4 / enzyme :name (n6 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1-of (p4 / phosphorylate-01))) :op3 (i / induce-01 :ARG2 (a3 / and :op1 (p5 / protein :name (n7 / name :op1 "p53") :xref (x5 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :op2 (p6 / protein :name (n8 / name :op1 "p21") :xref (x6 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")))) :compared-to (t2 / tumor :mod (w / wild-type))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "1I") :op2 (a5 / and :op1 (f4 / figure :mod "S4A") :op2 (f5 / figure :mod "S4B") :op3 (f6 / figure :mod "S4C") :ARG2-of (s / supplement-01)) :op3 (a6 / and :op1 (f2 / figure :mod "S5A") :op2 (f7 / figure :mod "S5B") :op3 (f8 / figure :mod "S5C") :ARG2-of s))) :ARG0-of (s2 / suggest-01 :ARG1 (c2 / cause-01 :ARG0 (i2 / inhibit-01 :ARG0 (d3 / delete-01 :ARG1 p) :ARG1 (p7 / proliferate-01 :ARG0 (c3 / cell :mod "t3"))) :ARG1 (b2 / burden-01 :ARG2 (t3 / tumor) :ARG1-of (r3 / reduce-01)) :mod (m / main)))) # ::id bel_pmid_2382_4538.18812 # ::date 2015-05-15T00:26:52 # ::file bel_pmid_2382_4538_18812.txt # ::snt atg7 deficiency in tumors prevented LC3-I processing to LC3-II and caused accumulation of LC3-I and autophagy substrate p62 in large aggregates apparent at 6 wk that increased throughout tumorigenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (p2 / prevent-01 :ARG0 (d / delete-01 :ARG1 (p / protein :name (n / name :op1 "atg7") :xref (x1 / xref :value "UNIPROT:ATG7_HUMAN" :prob "0.603")) :ARG2 (t / tumor)) :ARG1 (p3 / process-01 :ARG1 (p4 / protein :name (n2 / name :op1 "LC3-I")) :ARG2 (p5 / protein :name (n3 / name :op1 "LC3-II")))) :op2 (c / cause-01 :ARG0 d :ARG1 (a3 / accumulate-01 :ARG1 (a2 / and :op1 p4 :op2 (s / substrate :consist-of (p6 / protein :name (n4 / name :op1 "p62") :xref (x / xref :value "UNIPROT:MCAF1_HUMAN" :prob "0.222")) :mod (a4 / autophagy))) :ARG1-of (a5 / aggregate-01 :mod (l2 / large) :ARG1-of (a6 / appear-01 :time (a7 / after :op1 a3 :quant (t2 / temporal-quantity :quant "6" :unit (w / week)))) :ARG1-of (i / increase-01 :time (t3 / throughout :op1 (c2 / create-01 :ARG1 t))))))) # ::id bel_pmid_2465_2403.41226 # ::date 2015-05-15T00:41:37 # ::file bel_pmid_2465_2403_41226.txt # ::snt e ALDH1 activity in human PC (N = 11); representative flow cytometry plot of human PC tumor gated on live EpCAM+ cells using Aldefluor assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 11, 2016 (m / multi-sentence :snt1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ALDH1") :xref (x1 / xref :value "UNIPROT:AL1A1_HUMAN" :prob "1.002")) :ARG1 (d2 / disease :wiki "Pancreatic_cancer" :name (n3 / name :op1 "pancreatic" :op2 "cancer") :mod "h2" :ARG1-of (s / sample-01 :ARG2 (t2 / thing :quant "11")))) :snt2 (p2 / plot :mod (c2 / cytometry :mod (f / flow) :ARG0-of (r / represent-01)) :mod (t3 / tumor :mod (d4 / disease :wiki "Pancreatic_cancer" :name (n6 / name :op1 "pancreatic" :op2 "cancer") :mod (h2 / human) :ARG1-of (g / gate-01 :ARG0 (u / use-01 :ARG1 (a2 / assay-01 :instrument (t / thing :name (n5 / name :op1 "Aldefluor")))) :location (c / cell :mod (p3 / protein :name (n4 / name :op1 "EpCAM+") :xref (x / xref :value "UNIPROT:EPCAM_HUMAN" :prob "0.642")) :ARG0-of (l / live-01)))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "E"))) # ::id bel_pmid_2465_2403.41228 # ::date 2015-05-15T00:53:15 # ::file bel_pmid_2465_2403_41228.txt # ::snt Furthermore, GCSFR-/- mice exhibit a shift in the immune profile of PC tumors from a TH-2 to TH-1 immune response, characterized by increased expression of IFN-y, TNF-a and IL-12 with decreased expression of arginase-1, IL-6, TGF-P, IL-10 compared to WT mice (Fig. 2d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op2 (e / exhibit-01 :ARG0 (m / mouse :mod (p / protein :name (n / name :op1 "GCSFR") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x7 / xref :value "UNIPROT:CSF3R_HUMAN" :prob "1.002"))) :ARG1 (s / shift-01 :ARG1 (p2 / profile :ARG1-of (i / immune-02) :ARG1-of (c3 / characterize-01 :ARG2 (a2 / and :op1 (e2 / express-03 :ARG2 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "IFN-y") :xref (x1 / xref :value "UNIPROT:INAR1_HUMAN" :prob "0.223")) :op2 (p4 / protein :name (n5 / name :op1 "TNF-a") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op3 (p5 / protein :name (n6 / name :op1 "IL-12") :xref (x4 / xref :value "UNIPROT:I12R2_HUMAN" :prob "0.343"))) :ARG1-of (i2 / increase-01)) :op2 (e3 / express-03 :ARG2 (a4 / and :op1 (e4 / enzyme :name (n7 / name :op1 "arginase-1") :xref (x / xref :value "UNIPROT:ARGI1_HUMAN" :prob "0.702")) :op2 (p6 / protein :name (n8 / name :op1 "IL-6") :xref (x5 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p7 / protein :name (n9 / name :op1 "TGF-P") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.213")) :op4 (p8 / protein :name (n10 / name :op1 "IL-10") :xref (x6 / xref :value "UNIPROT:IL10_HUMAN" :prob "1.003"))) :ARG1-of (d / decrease-01 :compared-to (e5 / express-03 :ARG2 a4 :ARG3 (m3 / mouse :mod (w / wild-type))))))) :mod (t / tumor :mod (d4 / disease :wiki "Pancreatic_cancer" :name (n12 / name :op1 "pancreatic" :op2 "cancer")))) :ARG2 (r2 / respond-01 :ARG2 (i4 / immune-02 :ARG1 (c2 / cell :name (n3 / name :op1 "TH-1")))) :ARG3 (r / respond-01 :ARG2 (i3 / immune-02 :ARG1 (c / cell :name (n2 / name :op1 "TH-2")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2d"))) # ::id bel_pmid_2465_2403.41236 # ::date 2015-05-15T01:15:47 # ::file bel_pmid_2465_2403_41236.txt # ::snt These monocytes acquired a Mo-MDSC phenotype characterized by a significantly decreased expression of HLA-DR and increased expression of arginase-1 as well as the ability to suppress CD8+ T cell proliferation in vitro [29-32] (Fig. 4a-c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a / acquire-01 :ARG0 (c / cell :name (n / name :op1 "monocyte") :mod (t / this)) :ARG1 (p / phenotype :mod (c2 / cell :name (n2 / name :op1 "Mo-MDSC")) :ARG1-of (c3 / characterize-01 :ARG0 (a2 / and :op1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "HLA-DR") :xref (x1 / xref :value "UNIPROT:E1ACV6_HUMAN" :prob "1.001")) :ARG1-of (d / decrease-01 :ARG2 (s / significant-02))) :op2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n4 / name :op1 "arginase-1") :xref (x / xref :value "UNIPROT:ARGI1_HUMAN" :prob "0.702")) :ARG1-of (i / increase-01)) :op3 (c4 / capable-01 :ARG1 c :ARG2 (s2 / suppress-01 :ARG0 c :ARG1 (p3 / proliferate-01 :ARG0 (c5 / cell :name (n5 / name :op1 "CD8+" :op2 "T"))) :manner (i2 / in-vitro)))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 (v2 / value-interval :op1 "29" :op2 "32"))) :op2 (a4 / and :op1 (f / figure :mod "1a") :op2 (f2 / figure :mod "1b") :op3 (f3 / figure :mod "1c"))))) # ::id bel_pmid_2465_2403.41248 # ::date 2015-05-15T01:29:17 # ::file bel_pmid_2465_2403_41248.txt # ::snt While we found that IL-6 mRNA gene expression was significantly downregulated by STAT3 inhibition (Supplementary figure 11), IL-6 blockade using anti-IL-6 antibodies decreased but did not fully reverse the effect of Mo-MDSC on increasing the prevalence of ALDH1Bright CSCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (f / find-01 :ARG0 (w / we) :ARG1 (d / downregulate-01 :ARG1 (e / express-03 :ARG1 (g / gene) :ARG2 (n6 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :ARG2 (i / inhibit-01 :ARG1 (p2 / protein :name (n3 / name :op1 "STAT-3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.683"))) :ARG1-of (s / significant-02)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "11" :ARG2-of (s2 / supplement-01)))) :ARG2 (c2 / contrast-01 :ARG1 (d3 / decrease-01 :ARG0 (b / block-01 :ARG1 p :ARG3 (a / antibody :ARG0-of (c3 / counter-01 :ARG1 p))) :ARG1 (a2 / affect-01 :ARG0 (c4 / cell :name (n4 / name :op1 "Mo-MDSC")) :ARG1 (i2 / increase-01 :ARG1 (p4 / prevail-01 :ARG0 (c5 / cell :name (n5 / name :op1 "ALDH1" :op2 "Bright" :op3 "CSC")))))) :ARG2 (r2 / reverse-01 :polarity "-" :ARG0 b :ARG1 a2 :degree (f3 / full)))) # ::id bel_pmid_247_2096.38400 # ::date 2015-05-15T01:43:28 # ::file bel_pmid_247_2096_38400.txt # ::snt the 2 cytokines most intensively involved in eliciting the acute phase response are IL6 and IL1 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (c4 / cytokine :quant "2" :domain (a3 / and :op1 (c / cytokine :name (n / name :op1 "IL-6")) :op2 (c2 / cytokine :name (n2 / name :op1 "IL-1"))) :ARG1-of (i2 / involve-01 :ARG2 (e / elicit-01 :ARG1 (t / thing :ARG2-of (r / respond-01 :ARG1 (p / phase :mod (a2 / acute))))) :manner (i / intensive :degree (m / most)))) # ::id bel_pmid_248_3767.28356 # ::date 2015-05-15T01:52:57 # ::file bel_pmid_248_3767_28356.txt # ::snt alpha 2-macroglobulin, alpha 1-antichymotrypsin ( = contrapsin), cysteine protease inhibitor ( = thiostatin), alpha 1-antitrypsin, ceruloplasmin and fibrinogens are predominantly regulated by the keratinocyte-derived HSF-III/-II or IL-6 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 17, 2015 (r / regulate-01 :ARG0 (o / or :op1 (s / slash :op1 (p3 / protein :name (n2 / name :op1 "HSF-III") :xref (x5 / xref :value "UNIPROT:SFI1_HUMAN" :prob "0.202")) :op2 (p4 / protein :name (n3 / name :op1 "HSF-II") :xref (x7 / xref :value "UNIPROT:CXCL2_HUMAN" :prob "0.212"))) :op2 (p2 / protein :name (n / name :op1 "IL-6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (d / derive-01 :ARG2 (c / cell :name (n4 / name :op1 "keratinocyte")))) :ARG1 (a / and :op1 (p5 / protein :name (n5 / name :op1 "alpha-2-macroglobulin") :xref (x8 / xref :value "UNIPROT:A2MG_HUMAN" :prob "0.702")) :op2 (p6 / protein :name (n6 / name :op1 "alpha" :op2 "1-antichymotrypsin") :ARG1-of (m2 / mean-01 :ARG2 (p9 / protein :name (n11 / name :op1 "contrapsin") :xref (x10 / xref :value "UNIPROT:YBOX2_HUMAN" :prob "0.312"))) :xref (x6 / xref :value "UNIPROT:AACT_HUMAN" :prob "0.692")) :op3 (p10 / protein :name (n12 / name :op1 "thiostatin") :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n7 / name :op1 "cysteine" :op2 "protease") :xref (x2 / xref :value "UNIPROT:ATG4A_HUMAN" :prob "0.362"))) :xref (x1 / xref :value "UNIPROT:THIO_HUMAN" :prob "0.223")) :op4 (p7 / protein :name (n8 / name :op1 "alpha" :op2 "1-antitrypsin") :xref (x3 / xref :value "UNIPROT:A1AT_HUMAN" :prob "0.692")) :op5 (e2 / enzyme :name (n9 / name :op1 "ceruloplasmin") :xref (x / xref :value "UNIPROT:CERU_HUMAN" :prob "0.702")) :op6 (p8 / protein :name (n10 / name :op1 "fibrinogen") :xref (x9 / xref :value "UNIPROT:FIBRINOGEN_HUMAN_COMPLEX" :prob "1.001"))) :manner (p / predominant)) # ::id bel_pmid_2494_9077.41642 # ::date 2015-05-15T02:04:03 # ::file bel_pmid_2494_9077_41642.txt # ::snt The mRNA expression of Foxp3 and RORyt in the spleen was very low in the normal control group but significantly higher in the model control group (P < 0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (l / low-04 :ARG1 (e / express-03 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "Foxp3") :xref (x1 / xref :value "UNIPROT:FOXP3_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n3 / name :op1 "RORyt") :xref (x / xref :value "UNIPROT:TRI38_HUMAN" :prob "0.242"))))) :ARG3 (s / spleen)) :degree (v / very) :location (g / group :mod (c2 / control-01 :ARG1-of (n4 / normal-02)))) :ARG2 (h / high-02 :ARG1 e :degree (m / more) :ARG1-of (s2 / significant-02) :location (g2 / group :mod (c3 / control-01 :mod (m2 / model)))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.05"))) # ::id bel_pmid_2494_9077.41646 # ::date 2015-05-15T02:10:38 # ::file bel_pmid_2494_9077_41646.txt # ::snt SOCS3 protein expression was significantly downregulated in all groups except for the normal control group (P < 0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "SOCS3") :xref (x / xref :value "UNIPROT:SOCS3_HUMAN" :prob "1.004"))) :ARG1-of (s / significant-02) :location (g / group :mod (a / all) :ARG2-of (e2 / except-01 :ARG1 (g2 / group :mod (c / control-01 :ARG1-of (n2 / normal-02))))) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) # ::id bel_pmid_2494_9077.41648 # ::date 2015-05-15T02:14:26 # ::file bel_pmid_2494_9077_41648.txt # ::snt Jak2 and STAT3 protein expression was significantly higher in the model control group than in all other groups (P < 0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (h2 / high-02 :ARG1 (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Jak2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n2 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :degree (m / more) :ARG1-of (s / significant-02) :location (g / group :mod (c / control-01 :mod (m3 / model))) :compared-to (g2 / group :mod (a2 / all) :mod (o / other)) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) # ::id bel_pmid_2506_3873.41328 # ::date 2015-05-15T02:18:13 # ::file bel_pmid_2506_3873_41328.txt # ::snt Blocking STAT3 activation with the small molecule inhibitor JSI-124 significantly inhibited the accumulation of NIK and IDO expression in MDSCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (i2 / inhibit-01 :ARG0 (b / block-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :ARG3 (s / small-molecule :name (n2 / name :op1 "JSI-124") :ARG0-of (i / inhibit-01) :xref (x3 / xref :value "PUBCHEM:5281321" :prob "18.112881"))) :ARG1 (a2 / and :op1 (a3 / accumulate-01 :ARG0 "c" :ARG1 (e / enzyme :name (n3 / name :op1 "NIK") :xref (x / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002"))) :op2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n4 / name :op1 "IDO") :xref (x2 / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002")) :ARG3 (c / cell :name (n5 / name :op1 "MDSC")))) :ARG1-of (s2 / significant-02)) # ::id bel_pmid_2506_3873.41330 # ::date 2015-05-15T02:23:49 # ::file bel_pmid_2506_3873_41330.txt # ::snt Knockdown of NIK in MDSCs suppressed IDO expression but not STAT3 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (c / contrast-01 :ARG1 (s / suppress-01 :ARG0 (k / knock-down-02 :ARG1 (e / enzyme :name (n / name :op1 "NIK") :xref (x / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")) :location (c2 / cell :name (n2 / name :op1 "MDSC"))) :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "IDO") :xref (x2 / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002")))) :ARG2 (s2 / suppress-01 :polarity "-" :ARG0 k :ARG1 (a / activate-01 :ARG1 (p / protein :name (n4 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))))) # ::id bel_pmid_2506_3873.41332 # ::date 2015-05-15T02:26:54 # ::file bel_pmid_2506_3873_41332.txt # ::snt RelB-p52 dimers were found to directly bind to the IDO promoter, leading to IDO expression in MDSCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (f / find-01 :ARG1 (b / bind-01 :ARG1 (d2 / dimer :part (p3 / protein :name (n / name :op1 "p52") :xref (x / xref :value "UNIPROT:MPPB_HUMAN" :prob "0.652")) :part (p / protein :name (n2 / name :op1 "RelB") :xref (x2 / xref :value "UNIPROT:RELB_HUMAN" :prob "0.603"))) :ARG2 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n3 / name :op1 "IDO") :xref (x1 / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002")))) :ARG1-of (d / direct-02) :ARG0-of (l / lead-03 :ARG2 (e2 / express-03 :ARG2 e :ARG3 (c / cell :name (n4 / name :op1 "MDSC")))))) # ::id bel_pmid_2506_3873.41334 # ::date 2015-05-15T02:32:18 # ::file bel_pmid_2506_3873_41334.txt # ::snt STAT3 activation-induced IDO expression is independent of direct binding of STAT3 to the promoter region of IDO gene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / depend-01 :polarity "-" :ARG0 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "IDO") :xref (x1 / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002")) :ARG2-of (i / induce-01 :ARG0 (a / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))))) :ARG1 (b / bind-01 :ARG1 p :ARG2 (r / region :ARG0-of (p2 / promote-01) :part-of (g / gene :ARG0-of (e3 / encode-01 :ARG1 e2))) :ARG1-of (d2 / direct-02))) # ::id bel_pmid_2506_3873.41344 # ::date 2015-05-15T02:36:40 # ::file bel_pmid_2506_3873_41344.txt # ::snt Blocking STAT3 activation by JSI-124 dramatically decreased the levels of p52 and RelB in nuclei (Fig. 2C, p < 0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / decrease-01 :ARG0 (b / block-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :ARG3 (s / small-molecule :name (n2 / name :op1 "JSI-124") :xref (x4 / xref :value "PUBCHEM:5281321" :prob "18.112881"))) :ARG1 (l / level :quant-of (a2 / and :op1 (p2 / protein :name (n3 / name :op1 "p52") :xref (x / xref :value "UNIPROT:MPPB_HUMAN" :prob "0.652")) :op2 (p3 / protein :name (n4 / name :op1 "RelB") :xref (x1 / xref :value "UNIPROT:RELB_HUMAN" :prob "0.603")))) :degree (d2 / dramatic) :location (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2C")) :ARG1-of (s2 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.05"))) # ::id bel_pmid_2506_3873.41346 # ::date 2015-05-15T02:41:17 # ::file bel_pmid_2506_3873_41346.txt # ::snt The level of STAT3 phosphorylation in MDSCs was reduced at 30 min and completely suppressed at 4 h after treatment with JSI-124. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / and :op1 (r / reduce-01 :ARG1 (l / level :degree-of (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :location (c / cell :name (n2 / name :op1 "MDSC"))) :time (a2 / after :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "JSI-124") :xref (x1 / xref :value "PUBCHEM:5281321" :prob "18.112881"))) :quant (t2 / temporal-quantity :quant "30" :unit (m / minute)))) :op2 (s2 / suppress-01 :ARG1 l :ARG1-of (c2 / complete-02) :time (a3 / after :op1 t :quant (t3 / temporal-quantity :quant "4" :unit (h / hour))))) # ::id bel_pmid_2506_3873.41348 # ::date 2015-05-15T02:46:15 # ::file bel_pmid_2506_3873_41348.txt # ::snt Consistently, the level of NIK in MDSCs started to decline at 1 h and was completely blocked at 8 h after JSI-124 treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (a / and :op1 (s / start-01 :ARG0 (l / level :quant-of (e / enzyme :name (n / name :op1 "NIK") :xref (x / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")) :location (c / cell :name (n2 / name :op1 "MDSC"))) :ARG1 (d / decline-01 :ARG1 l) :time (a2 / after :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "JSI-124") :xref (x1 / xref :value "PUBCHEM:5281321" :prob "18.112881"))) :quant (t2 / temporal-quantity :quant "1" :unit (h / hour)))) :op2 (b / block-01 :ARG1 l :ARG1-of (c2 / complete-02) :time (a3 / after :op1 t :quant (t3 / temporal-quantity :quant "8" :unit h))) :manner (c3 / consistent-02)) # ::id bel_pmid_2506_3873.41350 # ::date 2015-05-15T02:51:11 # ::file bel_pmid_2506_3873_41350.txt # ::snt The level of IDO significantly decreased at 4 h after JSI-124 treatment (Fig. 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / decrease-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "IDO") :xref (x / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002"))) :ARG2 (s / significant-02) :time (a / after :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "JSI-124") :xref (x1 / xref :value "PUBCHEM:5281321" :prob "18.112881"))) :quant (t2 / temporal-quantity :quant "4" :unit (h / hour))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id bel_pmid_2506_3873.41352 # ::date 2015-05-15T02:53:36 # ::file bel_pmid_2506_3873_41352.txt # ::snt In NIK knockdown MDSCs, the level of IDO protein was reduced significantly, but the level of pSTAT3 protein was not affected (Fig. 3B, 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (r / reduce-01 :ARG1 (l / level :quant-of (e2 / enzyme :name (n3 / name :op1 "IDO") :xref (x2 / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002"))) :ARG2 (s / significant-02)) :ARG2 (a / affect-01 :polarity "-" :ARG1 (l2 / level :quant-of (p2 / protein :name (n4 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :location (c2 / cell :name (n / name :op1 "MDSC") :mod (k / knock-down-02 :ARG1 (e / enzyme :name (n2 / name :op1 "NIK") :xref (x1 / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3B") :op2 (f2 / figure :mod "3C")))) # ::id bel_pmid_2506_3873.41354 # ::date 2015-05-15T02:57:03 # ::file bel_pmid_2506_3873_41354.txt # ::snt In contrast, both IDO and NIK expression were reduced by JSI-124 treatment in MDSCs (Fig. 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (c / contrast-01 :ARG2 (r / reduce-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "JSI-124") :xref (x2 / xref :value "PUBCHEM:5281321" :prob "18.112881"))) :ARG1 (a / and :op1 (e / express-03 :ARG2 (e4 / enzyme :name (n / name :op1 "IDO") :xref (x / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002")) :ARG3 (c2 / cell :name (n4 / name :op1 "MDSC"))) :op2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "NIK") :xref (x1 / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")) :ARG3 c2))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id bel_pmid_2506_3873.41356 # ::date 2015-05-15T03:00:28 # ::file bel_pmid_2506_3873_41356.txt # ::snt RelB/p52 dimers directly bind to the IDO promoter to regulate IDO expression in MDSCs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (b / bind-01 :ARG1 (d3 / dimer :part (p4 / protein :name (n / name :op1 "p52") :xref (x / xref :value "UNIPROT:MPPB_HUMAN" :prob "0.652")) :part (p / protein :name (n2 / name :op1 "RelB") :xref (x1 / xref :value "UNIPROT:RELB_HUMAN" :prob "0.603"))) :ARG2 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "IDO") :xref (x2 / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002")))) :ARG1-of (d / direct-02) :purpose (r / regulate-01 :ARG0 d3 :ARG1 (e / express-03 :ARG2 e2 :ARG3 (c / cell :name (n4 / name :op1 "MDSC"))))) # ::id bel_pmid_2506_3873.41366 # ::date 2015-05-15T03:02:40 # ::file bel_pmid_2506_3873_41366.txt # ::snt We isolated CD11b+ MDSCs from the spleen of JSI-124-treated mice and found decreased expression of p-STAT3, NIK, and IDO protein in CD11b+ MDSCs compared with those isolated from the controls (Fig. 6D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (i / isolate-01 :ARG0 (w / we) :ARG1 (c / cell :name (n / name :op1 "MDSC") :mod (p / protein :name (n2 / name :op1 "CD11b+") :xref (x3 / xref :value "UNIPROT:ITAM_HUMAN" :prob "0.682"))) :ARG2 (s / spleen :poss (m / mouse :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "JSI-124") :xref (x4 / xref :value "PUBCHEM:5281321" :prob "18.112881")))))) :op2 (f / find-01 :ARG0 w :ARG1 (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n4 / name :op1 "STAT3") :ARG3-of (p3 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n5 / name :op1 "NIK") :xref (x1 / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")) :op3 (e4 / enzyme :name (n6 / name :op1 "IDO") :xref (x / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002"))) :ARG3 c :ARG1-of (d / decrease-01) :compared-to (e2 / express-03 :ARG2 a2 :ARG3 (c2 / cell :name (n7 / name :op1 "MDSC") :mod p :ARG1-of (i2 / isolate-01 :ARG2 (c3 / control)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6D"))) # ::id bel_pmid_2506_3873.41374 # ::date 2015-05-15T03:12:17 # ::file bel_pmid_2506_3873_41374.txt # ::snt Furthermore, a specific IL-6-neutralizing Ab significantly decreased the levels of p-STAT3, NIK, and IDO in MDSCs (Fig. 7E, p < 0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op2 (d / decrease-01 :ARG0 (a2 / antibody :ARG0-of (n / neutralize-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (s2 / specific-02)) :ARG1 (l / level :quant-of (a3 / and :op1 (p2 / protein :name (n3 / name :op1 "STAT-3") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.683")) :op2 (e / enzyme :name (n4 / name :op1 "NIK") :xref (x2 / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")) :op3 (e2 / enzyme :name (n5 / name :op1 "IDO") :xref (x / xref :value "UNIPROT:I23O1_HUMAN" :prob "1.002")))) :ARG2 (s / significant-02) :location (c / cell :name (n6 / name :op1 "MDSC")) :ARG1-of (s3 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.05"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7E"))) # ::id bel_pmid_778_0739.6222 # ::date 2015-03-31T11:22:41 # ::file bel_pmid_778_0739_6222.txt # ::snt Mitogen-activated protein (MAP) kinase is central to a signal transduction pathway that triggers cell proliferation or differentiation. Activation of the p42mapk isoform requires its phosphorylation at two residues, Thr 183 and Tyr 185, and this phosphorylation is catalysed by MAP kinase kinase (MAPKK). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (c / central :purpose (p2 / pathway :ARG0-of (t2 / trigger-01 :ARG1 (o / or :op1 (p / proliferate-01 :ARG0 (c2 / cell)) :op2 (d / differentiate-01 :ARG1 c2))) :ARG2-of (t / transduce-01 :ARG1 (s / signal-07))) :domain (e4 / enzyme :name (n / name :op1 "Mitogen-activated" :op2 "protein" :op3 "kinase") :xref (x / xref :value "UNIPROT:A0A024QZ12_HUMAN" :prob "1.001"))) :snt2 (r / require-01 :ARG0 (a2 / activate-01 :ARG0 (e3 / enzyme :name (n7 / name :op1 "p42" :op2 "MAPK") :mod (i2 / isoform) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.683"))) :ARG1 (p4 / phosphorylate-01 :ARG1 (r2 / residue :quant "2" :part-of (i / isoform) :mod (a4 / amino-acid :mod "183" :name (n4 / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :mod (a5 / amino-acid :mod "185" :name (n5 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (c3 / catalyze-01 :ARG0 (e / enzyme :name (n2 / name :op1 "MAP" :op2 "kinase" :op3 "kinase") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.393")))))) # ::id bel_pmid_812_5955.5778 # ::date 2015-04-01T22:26:06 # ::file bel_pmid_812_5955_5778.txt # ::snt Stable transfection of activated Ha-ras into a number of murine cells correlated with a down-regulation of the expression of the NF1 genes NF1/CTF and NF1/X. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / correlate-01 :ARG1 (t / transfect-01 :ARG1 (c2 / cell :quant (n4 / number) :mod (m / murine)) :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ha-ras") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "0.673")) :ARG1-of (s / stable-03)) :ARG2 (d / downregulate-01 :ARG1 (e / express-03 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "NF1/CTF")) :op2 (g2 / gene :name (n2 / name :op1 "NF1/X")))))) # ::id bel_pmid_812_5955.9008 # ::date 2015-04-02T03:35:27 # ::file bel_pmid_812_5955_9008.txt # ::snt The level of the DNA binding activity of the NF1 proteins was also reduced in Ha-v-ras-transformed cells, and the expression of a gene that depends on this family of transcription factors was specifically repressed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (r / reduce-01 :ARG1 (l / level :degree-of (a3 / activity-06 :ARG0 (p / protein :name (n / name :op1 "NF1") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "1.004")) :ARG1 (b / bind-01 :ARG0 p :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))))) :location (c / cell :ARG2-of (t / transform-01 :ARG0 (g / gene :name (n2 / name :op1 "Ha-v-ras")))) :mod (a2 / also)) :op2 (r2 / repress-01 :ARG1 (e / express-03 :ARG1 (g2 / gene :ARG0-of (d2 / depend-01 :ARG1 (f / family :consist-of (f2 / factor :ARG0-of (t3 / transcribe-01)) :mod p)))) :ARG1-of (s / specific-02))) # ::id bel_pmid_822_6933.9532 # ::date 2015-04-03T09:17:44 # ::file bel_pmid_822_6933_9532.txt # ::snt MEK1 and MEK2 can also be activated by autophosphorylation. Autophosphorylation of MEKs correlates with their ability to phosphorylate and activate ERKs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / multi-sentence :snt1 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (p2 / phosphorylate-01 :ARG1 "a2" :ARG2 "a2") :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (a5 / also))) :snt2 (c / correlate-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG2 e3) :ARG2 (c2 / capable-01 :ARG1 e3 :ARG2 (a3 / and :op1 (p4 / phosphorylate-01 :ARG2 (p5 / protein-family :name (n4 / name :op1 "ERK"))) :op2 (a4 / activate-01 :ARG1 p5))))) # ::id bel_pmid_854_8291.16558 # ::date 2015-04-03T10:20:36 # ::file bel_pmid_854_8291_16558.txt # ::snt The two SAPK isoforms are 46 and 54 kDa. A 46 kDa kinase activity was induced in response to anisomycin but not in response to TPA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (a / and :op1 (i4 / isoform :mod (e3 / enzyme :name (n5 / name :op1 "SAPK") :xref (x / xref :value "UNIPROT:MK08_HUMAN" :prob "0.313")) :quant (m2 / mass-quantity :quant "46" :unit (k / kilodalton))) :op2 (i5 / isoform :mod e3 :quant (m3 / mass-quantity :quant "54" :unit (k3 / kilodalton))) :domain (i3 / isoform :quant "2" :mod e3)) :snt2 (i / induce-01 :ARG2 (a2 / activity-06 :ARG0 (k2 / kinase :quant (m4 / mass-quantity :quant "46" :unit (k4 / kilodalton)))) :ARG2-of (r / respond-01 :ARG1 (s / small-molecule :name (n6 / name :op1 "anisomycin") :xref (x2 / xref :value "PUBCHEM:31549" :prob "17.186693"))) :ARG1-of (c / contrast-01 :ARG2 (i2 / induce-01 :polarity "-" :ARG2 a2 :ARG2-of (r2 / respond-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082"))))))) # ::id bel_pmid_854_8291.16560 # ::date 2015-04-12T13:47:52 # ::file bel_pmid_854_8291_16560.txt # ::snt In NIH3T3 cells, co-transfection of an expression vector for Gal-Elk mediates expression from a transfected GAL-CAT reporter gene, which, as shown in Figure 6a,b, is potentiated upon treatment of serum-starved cells with anisomycin. Replacement of the major SAPK phosphorylation site in Gal-Elk, Ser383, with alanine (Gal-Elks 383 A) abrogates induction of reporter gene expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m2 / multi-sentence :snt1 (m / mediate-01 :ARG0 (c2 / cotransfect-01 :ARG2 (v / vector :ARG1-of (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "Gal-Elk") :xref (x3 / xref :value "UNIPROT:LEG1_HUMAN" :prob "0.213"))))) :ARG1 (e2 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "GAL-CAT") :ARG0-of (r / report-01) :ARG2-of (t / transfect-01) :xref (x2 / xref :value "UNIPROT:B4GN1_HUMAN" :prob "0.252")) :ARG1-of (p2 / potentiate-01 :ARG2 (t2 / treat-04 :ARG1 (c3 / cell :ARG1-of (s / starve-01 :ARG2 (s2 / serum))) :ARG2 (s4 / small-molecule :name (n7 / name :op1 "anisomycin") :xref (x4 / xref :value "PUBCHEM:31549" :prob "17.186693"))) :ARG1-of (s3 / show-01 :ARG0 (a2 / and :op1 (f / figure :mod "6a") :op2 (f2 / figure :mod "6b"))))) :location (c / cell-line :name (n / name :op1 "NIH3T3"))) :snt2 (a3 / abrogate-01 :ARG0 (r2 / replace-01 :ARG1 (p5 / protein-segment :mod (a / amino-acid :mod "383" :name (n5 / name :op1 "serine") :part-of (p4 / protein :name (n6 / name :op1 "Gal-Elk") :xref (x1 / xref :value "UNIPROT:LEG1_HUMAN" :prob "0.213")) :ARG1-of (p3 / phosphorylate-01 :ARG2 (e4 / enzyme :name (n8 / name :op1 "SAPK") :xref (x / xref :value "UNIPROT:MK08_HUMAN" :prob "0.313"))) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (m3 / major-02)) :ARG2 (a5 / amino-acid :mod "383" :name (n4 / name :op1 "alanine") :part-of p4 :xref (x6 / xref :value "PUBCHEM:602" :prob "10.089661"))) :ARG1 (i / induce-01 :ARG0 r2 :ARG2 (e3 / express-03 :ARG1 (g2 / gene :ARG0-of (r3 / report-01)))))) # ::id bel_pmid_854_8291.18250 # ::date 2015-04-04T01:28:36 # ::file bel_pmid_854_8291_18250.txt # ::snt Elk-1 is phosphorylated by both kinases (MAPK8 and MAPK9) , each of which is strongly stimulated by pre-treatment of cells with ultraviolet light. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "Elk-1") :xref (x / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :ARG2 (a / and :op1 (k / kinase :name (n2 / name :op1 "MAPK8") :xref (x1 / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003")) :op2 (k2 / kinase :name (n3 / name :op1 "MAPK9") :xref (x2 / xref :value "UNIPROT:MK09_HUMAN" :prob "1.003")) :ARG1-of (s / stimulate-01 :ARG0 (t / treat-04 :ARG1 (c / cell) :ARG2 (l / light :mod (u / ultraviolet)) :time (b / before)) :ARG1-of (s2 / strong-02)) :mod (b2 / both))) # ::id bel_pmid_854_8291.21982 # ::date 2015-04-04T02:11:20 # ::file bel_pmid_854_8291_21982.txt # ::snt Figure 3b shows that activated SAPKs isolated from cells stimulate the formation of a ternary complex by Elk-1 (Fig. 3b, lanes 8 and 10). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Apr 6, 2015 (s / show-01 :ARG0 (f / figure :mod "3b") :ARG1 (e / enzyme :name (n / name :op1 "SAPK") :ARG1-of (a / activate-01) :ARG1-of (i / isolate-01 :ARG2 (c / cell)) :ARG0-of (s2 / stimulate-01 :ARG1 (f2 / form-01 :ARG0 (p / protein :name (n2 / name :op1 "Elk-1") :xref (x1 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :ARG1 (c2 / complex :mod (t / ternary)))) :xref (x / xref :value "UNIPROT:MK08_HUMAN" :prob "0.313")) :ARG1-of (d / describe-01 :ARG0 (l / lane :ARG1-of (l2 / label-01 :ARG2 (a2 / and :op1 "8" :op2 "10")) :part-of f))) # ::id bel_pmid_854_8291.22000 # ::date 2015-04-06T00:43:58 # ::file bel_pmid_854_8291_22000.txt # ::snt As shown in Figure 6e, expression of MEKK1 fails to activate either ERK1 or ERK2, whereas both p46 SAPK and p54SAPK are activated at expression levels that result in reporter gene expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 24, 2015 (f2 / fail-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEKK1") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003"))) :ARG2 (a / activate-01 :ARG0 e :ARG1 (o / or :op1 (e3 / enzyme :name (n2 / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n3 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :ARG1-of (c / contrast-01 :ARG2 (a2 / activate-01 :ARG0 (l / level :ARG1-of (r / result-01 :ARG2 (e8 / express-03 :ARG1 (g / gene :ARG0-of (r2 / report-01)))) :degree-of e) :ARG1 (a3 / and :op1 (e5 / enzyme :name (n4 / name :op1 "p46" :op2 "SAPK") :xref (x / xref :value "UNIPROT:PDIP3_HUMAN" :prob "0.202")) :op2 (e6 / enzyme :name (n5 / name :op1 "p54" :op2 "SAPK") :xref (x2 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.202")) :mod (b / both)))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "6e"))) # ::id bel_pmid_854_8291.29024 # ::date 2015-04-07T22:51:45 # ::file bel_pmid_854_8291_29024.txt # ::snt Co-transfection of 1.25 ug MEKK1 expression vector elicited a 24-fold activation of Gal-Elk-dependent reporter expression in serum-starved NIH3T3 cells (Fig. 6c,d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / elicit-01 :ARG0 (c / cotransfect-01 :ARG2 (v / vector :ARG1-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n / name :op1 "MEKK1") :quant (m / mass-quantity :quant "1.25" :unit (m2 / microgram)) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003"))))) :ARG1 (a / activate-01 :ARG0 c :ARG1 (e4 / express-03 :ARG1 (g / gene :ARG0-of (r / report-01) :ARG0-of (d / depend-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Gal-Elk") :xref (x / xref :value "UNIPROT:LEG1_HUMAN" :prob "0.213")))) :ARG3 (c2 / cell-line :name (n3 / name :op1 "NIH3T3") :ARG1-of (s / starve-01 :ARG2 (s2 / serum)))) :quant (p / product-of :op1 "24")) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "6c") :op2 (f2 / figure :mod "6d")))) # ::id bel_pmid_854_8291.32900 # ::date 2015-04-06T09:17:27 # ::file bel_pmid_854_8291_32900.txt # ::snt The observation that Elk-1 is phosphorylated directly and activated by p46SAPK and p54SAPK further implicates it in the stress-response induction of the c-fos gene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / implicate-01 :ARG0 (o / observe-01 :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "Elk-1") :xref (x / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :ARG2 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "p46SAPK") :xref (x1 / xref :value "UNIPROT:PDIP3_HUMAN" :prob "0.202")) :op2 (e2 / enzyme :name (n3 / name :op1 "p54SAPK") :xref (x2 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.202"))) :ARG1-of (d / direct-02)) :op2 (a2 / activate-01 :ARG0 a3 :ARG1 p2))) :ARG1 p2 :ARG2 (i2 / induce-01 :ARG2 (g / gene :name (n4 / name :op1 "c-fos")) :ARG2-of (r / respond-01 :ARG1 (s / stress-02))) :degree (f / further)) # ::id bel_pmid_854_8291.36930 # ::date 2015-04-07T00:33:38 # ::file bel_pmid_854_8291_36930.txt # ::snt For comparison, ElkC was also phosphorylated using recombinant ERK1 that had been activated by phosphorylation with a constitutively active mutant of the MAPK/ERK kinase MKK1 [23]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "ElkC") :xref (x / xref :value "UNIPROT:EPHB1_HUMAN" :prob "0.203")) :ARG2 (u / use-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1") :ARG0-of (r / recombine-01) :ARG1-of (a2 / activate-01 :ARG0 (p3 / phosphorylate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n3 / name :op1 "MKK1") :ARG0-of (a3 / activity-06 :mod (c2 / constitutive)) :ARG1-of (i / include-91 :ARG2 (p5 / protein-family :name (n5 / name :op1 "MAPK/ERK"))) :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")))) :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))) :purpose (c / compare-01) :mod (a / also) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 "23")))) # ::id bel_pmid_859_8496.27892 # ::date 2015-04-09T21:25:46 # ::file bel_pmid_859_8496_27892.txt # ::snt In the case of Th2-type cytokines, enhanced production of IL-4 and IL-6 was reduced by treatment with anti-TGF-/3 or anti-IL- IO (Fig. 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / reduce-01 :ARG0 (t / treat-04 :ARG1 (c4 / cytokine :name (n4 / name :op1 "Th2") :ARG1-of (t2 / type-03)) :ARG2 (o / or :op1 (a2 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p4 / protein :name (n3 / name :op1 "TGF-/3")))) :op2 (a3 / antibody :ARG0-of (c / counter-01 :ARG1 (p7 / protein :name (n5 / name :op1 "IL-IO")))))) :ARG1 (p / produce-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "IL-4") :xref (x / xref :value "UNIPROT:IL4_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (e / enhance-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id bel_pmid_859_8496.31126 # ::date 2015-04-15T21:52:07 # ::file bel_pmid_859_8496_31126.txt # ::snt As shown in Figure 5A, reduced production of Th I -type cytokines (IFN-y, not detected; IL-2, 38.0 -t 10.0%) by EL4-T was significantly rcstored by treatmcnt with anti-TGF-P (IFN-y, 191.0 i 21.9%; IL-2, 8 I . 1 i 17.5%), while anti-IL- IO treatment had little etfect # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / restore-01 :ARG1 (p / produce-01 :ARG1 (c3 / cytokine :name (n8 / name :op1 "Th1") :ARG1-of (t3 / type-03) :example (a / and :op1 (p2 / protein :name (n2 / name :op1 "IFN-y") :ARG1-of (d / detect-01 :polarity "-") :xref (x1 / xref :value "UNIPROT:INAR1_HUMAN" :prob "0.223")) :op2 (p6 / protein :name (n5 / name :op1 "IL-2," :op2 "38.0" :op3 "-t") :quant (p7 / percentage-entity :value "10.0") :xref (x2 / xref :value "UNIPROT:IL23A_HUMAN" :prob "0.213")))) :ARG1-of (r2 / reduce-01 :ARG0 (c2 / cell :name (n / name :op1 "EL4-T")))) :ARG1-of (s2 / significant-02) :manner (t / treat-04 :ARG1 c2 :ARG2 (a4 / antibody :ARG0-of (c6 / counter-01 :ARG1 (p5 / protein :name (n4 / name :op1 "TGF-P") :example (a3 / and :op1 (p8 / protein :name (n6 / name :op1 "IFN-y," :op2 "191.0" :op3 "i") :quant (p9 / percentage-entity :value "21.9")) :op2 (p10 / protein :name (n7 / name :op1 "IL-2," :op2 "8" :op3 "I" :op4 "." :op5 "1" :op6 "i") :quant (p11 / percentage-entity :value "17.5") :xref (x / xref :value "UNIPROT:IFNL2_HUMAN" :prob "0.212"))) :xref (x3 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.213"))))) :ARG1-of (c4 / contrast-01 :ARG2 (a2 / affect-01 :ARG0 (t2 / treat-04 :ARG1 c2 :ARG2 (a5 / antibody :ARG0-of (c5 / counter-01 :ARG1 (p4 / protein :name (n3 / name :op1 "IL-IO"))))) :ARG1 c2 :degree (l / little))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "5A"))) # ::id bel_pmid_862_1729.21570 # ::date 2015-04-07T04:29:41 # ::file bel_pmid_862_1729_21570.txt # ::snt Similar observation that immunoprecipitated B-Raf from EGF-stimulated Swiss3T3 cells could activate both MEK1 and MEK2 was also obtained (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (o / obtain-01 :ARG1 (o2 / observe-01 :ARG1 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :ARG1-of (i / immunoprecipitate-01 :ARG2 (c / cell-line :name (n2 / name :op1 "Swiss3T3") :ARG1-of (s / stimulate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (a2 / and :op1 (e2 / enzyme :name (n4 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n5 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :mod (b / both)))) :ARG1-of (r / resemble-01)) :mod (a3 / also) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity "-")))) # ::id bel_pmid_862_1729.36932 # ::date 2015-04-15T08:57:17 # ::file bel_pmid_862_1729_36932.txt # ::snt The activated GST-MEK1 was then used to activate the purified recombinant extracellular signal-regulated kinase 1, whose activity was measured by the [32P-g]ATP incorporation into MBP, an extracellular signal-regulated kinase 1 substrate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / use-01 :ARG1 (e / enzyme :name (n / name :op1 "GST-MEK1") :ARG1-of (a / activate-01) :xref (x2 / xref :value "UNIPROT:GSTM1_HUMAN" :prob "0.252")) :ARG2 (a2 / activate-01 :ARG0 e :ARG1 (e2 / enzyme :name (n2 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase" :op4 "1") :ARG0-of (r / recombine-01) :ARG1-of (p / purify-01) :ARG0-of (a3 / activity-06 :ARG1-of (m / measure-01 :manner (i / incorporate-02 :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP") :part (p3 / phosphate :quant (m2 / molecular-mass :value "32") :mod (g / gamma)) :xref (x3 / xref :value "PUBCHEM:5957" :prob "14.368295")) :ARG2 (p2 / protein :name (n4 / name :op1 "MBP") :ARG1-of (m4 / mean-01 :ARG2 (s2 / substrate :poss e2)) :xref (x / xref :value "UNIPROT:MBP_HUMAN" :prob "1.003"))))) :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.703"))) :time (t / then)) # ::id bel_pmid_862_1729.37176 # ::date 2015-04-04T03:10:14 # ::file bel_pmid_862_1729_37176.txt # ::snt c-Raf activates MEK1 by phosphorylating at serine residues 218 and 222 (30–32). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "c-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :ARG1 "e3" :manner (p / phosphorylate-01 :ARG1 (r / residue :mod "218" :mod "222" :mod (a2 / amino-acid :name (n3 / name :op1 "serine") :part-of (e3 / enzyme :name (n4 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :mod (b / between :op1 (a3 / amino-acid :mod "30") :op2 (a4 / amino-acid :mod "32")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))))) # ::id bel_pmid_862_2669.21840 # ::date 2015-04-04T13:31:38 # ::file bel_pmid_862_2669_21840.txt # ::snt activated MEK1 increased Elk-1- and c-Jun-dependent gene expression but not ATF2-dependent gene expression (Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 22, 2015 (i / increase-01 :ARG0 (e / enzyme :name (n / name :op1 "MEK1") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :ARG1 (e2 / express-03 :ARG1 (g / gene :ARG0-of (d / depend-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "Elk-1") :xref (x2 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :op2 (p2 / protein :name (n3 / name :op1 "c-Jun")))))) :ARG1-of (c / contrast-01 :ARG2 (i2 / increase-01 :polarity "-" :ARG0 e :ARG1 (e3 / express-03 :ARG1 (g2 / gene :ARG0-of (d2 / depend-01 :ARG1 (p3 / protein :name (n4 / name :op1 "ATF2") :xref (x1 / xref :value "UNIPROT:ATF2_HUMAN" :prob "1.003"))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4"))) # ::id bel_pmid_862_2669.21852 # ::date 2015-04-05T22:27:26 # ::file bel_pmid_862_2669_21852.txt # ::snt MKK3(Glu) increased ATF2- and Elk-1-dependent reporter gene expression but caused only a small increase in Jun-dependent gene expression (Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 22, 2015 (c / contrast-01 :ARG1 (i / increase-01 :ARG0 (e / enzyme :name (n / name :op1 "MKK3(Glu)")) :ARG1 (e2 / express-03 :ARG1 (g / gene :ARG0-of (r / report-01) :ARG0-of (d / depend-01 :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "ATF2") :xref (x / xref :value "UNIPROT:ATF2_HUMAN" :prob "1.003")) :op2 (p / protein :name (n3 / name :op1 "Elk-1") :xref (x2 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592"))))))) :ARG2 (c2 / cause-01 :ARG0 e :ARG1 (i2 / increase-01 :ARG1 (e4 / express-03 :ARG1 (g2 / gene :ARG0-of (d2 / depend-01 :ARG1 (p3 / protein :name (n4 / name :op1 "Jun") :xref (x1 / xref :value "UNIPROT:JUN_HUMAN" :prob "0.603"))))) :degree (s / small :mod (o / only)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4"))) # ::id bel_pmid_862_2669.21858 # ::date 2015-04-05T23:27:41 # ::file bel_pmid_862_2669_21858.txt # ::snt In contrast, the effect of MKK6(Glu) was markedly reduced in experiments using phosphorylation-defective (Ala-69, Ala-71) ATF2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (c / contrast-01 :ARG2 (r / reduce-01 :ARG1 (a / affect-01 :ARG0 (e2 / enzyme :name (n / name :op1 "MKK6(Glu)"))) :manner (m / marked) :topic (e3 / experiment-01 :ARG2 (u / use-01 :ARG1 (p2 / protein :name (n2 / name :op1 "ATF2") :ARG2-of (p / phosphorylate-01 :mod (d / defective)) :part (a4 / amino-acid :mod "69" :mod "71" :name (n5 / name :op1 "alanine") :xref (x1 / xref :value "PUBCHEM:602" :prob "10.089661")) :xref (x / xref :value "UNIPROT:ATF2_HUMAN" :prob "1.003")))))) # ::id bel_pmid_862_2669.21860 # ::date 2015-04-14T04:16:44 # ::file bel_pmid_862_2669_21860.txt # ::snt Increased ATF2-dependent gene expression was observed in cells transfected with MKK6(Glu). In contrast, MKK3(Glu) did not increase ATF2-dependent gene expression in the absence of overexpression of p38 MAP kinase (Fig. 8A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (m / multi-sentence :snt1 (o / observe-01 :ARG1 (e / express-03 :ARG1 (g / gene :ARG0-of (d / depend-01 :ARG1 (p / protein :name (n / name :op1 "ATF2") :xref (x1 / xref :value "UNIPROT:ATF2_HUMAN" :prob "1.003")))) :ARG3 (c / cell :ARG1-of (t / transfect-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MKK6(Glu)")))) :ARG1-of (i / increase-01))) :snt2 (i2 / increase-01 :polarity "-" :ARG0 (e4 / enzyme :name (n3 / name :op1 "MKK3(Glu)")) :ARG1 (e5 / express-03 :ARG1 (g2 / gene :ARG0-of (d2 / depend-01 :ARG1 (p2 / protein :name (n4 / name :op1 "ATF2") :xref (x / xref :value "UNIPROT:ATF2_HUMAN" :prob "1.003"))))) :ARG2-of (c2 / contrast-01) :condition (a / absent-01 :ARG1 (o2 / overexpress-01 :ARG1 (k / kinase :name (n5 / name :op1 "p38" :op2 "MAP" :op3 "kinase")))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "8A")))) # ::id bel_pmid_872_5172.30236 # ::date 2015-04-09T09:13:49 # ::file bel_pmid_872_5172_30236.txt # ::snt Specifically, PTH and PTHrP rapidly and transiently induce expression of the mRNAs encoding IL-6 and LIF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / induce-01 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "PTH") :xref (x1 / xref :value "UNIPROT:PTH_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "PTHrP") :xref (x3 / xref :value "UNIPROT:PTHR_HUMAN" :prob "1.002"))) :ARG2 (e3 / express-03 :ARG1 (n5 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (a2 / and :op1 (p / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n4 / name :op1 "LIF") :xref (x / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")))))) :ARG1-of (s / specific-02) :manner (r / rapid) :ARG1-of (t / transient-02)) # ::id bel_pmid_879_8479.3974 # ::date 2015-04-11T22:16:31 # ::file bel_pmid_879_8479_3974.txt # ::snt endogenous GMF is rapidly phosphorylated upon stimulation of astrocytes by phorbol 12-myristate 13-acetate We further observed that protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor (IC50 = 3 nM) of the ERK1/ERK2 (p44/p42) subfamily of mitogen-activated protein (MAP) kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "GMF") :mod (e / endogenous) :xref (x4 / xref :value "UNIPROT:GMFB_HUMAN" :prob "0.262")) :ARG2 (e3 / enzyme :name (n6 / name :op1 "PKA") :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :manner (r / rapid) :condition (s / stimulate-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "phorbol" :op2 "12-myristate" :op3 "13-acetate") :xref (x6 / xref :value "PUBCHEM:4792" :prob "12.67005")) :ARG1 (a / astrocyte))) :snt2 (o / observe-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG0 (p3 / protein :name (n3 / name :op1 "GMF") :ARG1-of (p4 / phosphorylate-01 :ARG2 (e2 / enzyme :name (n10 / name :op1 "protein" :op2 "kinase" :op3 "A") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393"))) :xref (x5 / xref :value "UNIPROT:GMFB_HUMAN" :prob "0.262")) :ARG1 (s2 / slash :op1 (e6 / enzyme :name (n4 / name :op1 "p44" :op2 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.683")) :op2 (e7 / enzyme :name (n11 / name :op1 "p42" :op2 "ERK2") :xref (x / xref :value "UNIPROT:NUP43_HUMAN" :prob "0.262")) :ARG1-of (i2 / include-91 :ARG2 (p5 / protein-family :name (n9 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase")))) :mod (p6 / potent) :ARG3-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c / concentration-quantity :quant "3" :unit (n5 / nanomolar)))) :degree (f / further))) # ::id bel_pmid_879_8479.8862 # ::date 2015-04-08T00:14:46 # ::file bel_pmid_879_8479_8862.txt # ::snt PKA-phosphorylated GMF strongly enhances the activity of a related but distinct subfamily of MAP kinase, the p38 MAP kinase, showing an increase of 60-fold over baseline and an EC50 of 7 nM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (e / enhance-01 :ARG0 (p / protein :name (n / name :op1 "GMF") :ARG1-of (p2 / phosphorylate-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "PKA") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :xref (x2 / xref :value "UNIPROT:GMFB_HUMAN" :prob "0.262")) :ARG1 (a2 / activity-06 :ARG0 (k / kinase :name (n4 / name :op1 "p38" :op2 "MAP") :ARG1-of (r / relate-01 :ARG2 "p5" :concession-of (d / distinct :compared-to "p5")) :ARG1-of (i2 / include-91 :ARG2 (p5 / protein-family :name (n6 / name :op1 "MAP" :op2 "kinase"))) :xref (x1 / xref :value "UNIPROT:SP20H_HUMAN" :prob "0.252"))) :ARG1-of (s2 / strong-02)) :op2 (s / show-01 :ARG0 p :ARG1 (a3 / and :op1 (i / increase-01 :ARG1 k :ARG2 (p3 / product-of :op1 "60") :manner (o / over :op1 (b / baseline))) :op2 (h / have-percentage-maximal-effective-concentration-01 :ARG1 p :ARG2 "50" :ARG4 (c3 / concentration-quantity :quant "7" :unit (n5 / nanomolar)))))) # ::id bel_pmid_879_8479.16716 # ::date 2015-04-09T09:12:44 # ::file bel_pmid_879_8479_16716.txt # ::snt intracellular interaction of PKA, GMF, and p38 is supported by the phosphorylation of GMF upon cellular stimulation by forskolin (blocked by PKA inhibitor) and by the co-immunoprecipitation of p38 with GMF from cell lysates. Withdrawal of nerve growth factor from PC12 leads to increased GMF phosphorylation with a time course similar to that reported for p38 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (m / multi-sentence :snt1 (s / support-01 :ARG0 (a2 / and :op1 (p / phosphorylate-01 :ARG1 "p5" :ARG2 (s2 / stimulate-01 :ARG0 (s3 / small-molecule :name (n8 / name :op1 "forskolin") :ARG1-of (b / block-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 (e4 / enzyme :name (n9 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))))) :xref (x5 / xref :value "PUBCHEM:47936" :prob "16.627077")) :ARG1 (c / cell))) :op2 (c2 / coimmunoprecipitate-01 :ARG1 (e / enzyme :name (n / name :op1 "p38") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG2 (p5 / protein :name (n3 / name :op1 "GMF") :source (l / lysate :part-of (c3 / cell :ARG0-of (c4 / contain-01 :ARG1 (p3 / protein)))) :xref (x4 / xref :value "UNIPROT:GMFB_HUMAN" :prob "0.262")))) :ARG1 (i / interact-01 :ARG0 (a / and :op1 (e3 / enzyme) :op2 p3) :ARG1 e)) :snt2 (l2 / lead-03 :ARG1 (w / withdraw-01 :ARG1 (g / growth-factor :mod (n2 / nerve)) :ARG2 (c5 / cell-line :name (n4 / name :op1 "PC12"))) :ARG2 (p2 / phosphorylate-01 :ARG1 (p4 / protein :name (n6 / name :op1 "GMF") :ARG1-of (i3 / increase-01) :xref (x3 / xref :value "UNIPROT:GMFB_HUMAN" :prob "0.262")) :ARG0-of (h / have-03 :ARG1 (c6 / course :mod (t / time) :ARG1-of (r / resemble-01 :ARG2 (c7 / course :mod (t2 / time) :ARG1-of (r2 / report-01 :topic (a3 / activate-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))))))))))) # ::id bel_pmid_894_3354.24786 # ::date 2015-04-01T06:03:05 # ::file bel_pmid_894_3354_24786.txt # ::snt In addition, SHP-1 and its mutants showed similar association and dephosphorylation of the other Jak family members (JAK1, Tyk2, and JAK3) but not c-fes when coexpressed in Cos-7 cells (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op2 (s / show-01 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "SHP-1") :xref (x4 / xref :value "UNIPROT:SHPS1_HUMAN" :prob "0.312")) :op2 (e2 / enzyme :name (n8 / name :op1 "SHP-1") :ARG2-of (m / mutate-01) :xref (x3 / xref :value "UNIPROT:SHPS1_HUMAN" :prob "0.312"))) :ARG1 (a3 / and :op1 (a4 / associate-01 :ARG1 a2 :ARG2 (m2 / member :mod (o / other) :ARG1-of (m3 / mean-01 :ARG2 (a5 / and :op1 (e3 / enzyme :name (n3 / name :op1 "JAK1") :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n4 / name :op1 "Tyk2") :xref (x1 / xref :value "UNIPROT:TYK2_HUMAN" :prob "0.603")) :op3 (e5 / enzyme :name (n5 / name :op1 "JAK3") :xref (x / xref :value "UNIPROT:JAK3_HUMAN" :prob "1.004")))) :ARG1-of (c / contrast-01 :ARG2 (e8 / enzyme :name (n2 / name :op1 "c-fes"))) :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n6 / name :op1 "Jak"))))) :op2 (d / dephosphorylate-01 :ARG1 m2 :ARG2 a2) :ARG1-of (r / resemble-01)) :time (c2 / coexpress-01 :ARG2 a2 :ARG3 (c3 / cell-line :name (n7 / name :op1 "Cos-7")))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s2 / show-01 :polarity "-")))) # ::id bel_pmid_902_3347.41730 # ::date 2015-04-01T06:22:17 # ::file bel_pmid_902_3347_41730.txt # ::snt Hypoxia was capable of inducing VEGF mRNA in both immortalized and transformed endothelial cells (4.5-fold in cells expressing SV40 large T antigen alone or in combination with H-ras), but both baseline and induced VEGF mRNA expression was increased in cells containing activated ras (Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (c8 / contrast-01 :ARG1 (c / capable-01 :ARG1 (h / hypoxia) :ARG2 (i2 / induce-01 :ARG2 (n3 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p / protein :name (n4 / name :op1 "VEGF") :xref (x2 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")))) :location (a / and :op1 (c2 / cell :ARG1-of (i / immortalize-03)) :op2 (c3 / cell :ARG1-of (t / transform-01)) :part-of (e4 / endothelium) :mod (b3 / both)) :ARG1-of (m2 / mean-01 :ARG2 (p2 / product-of :op1 "4.5") :location (c6 / cell :ARG3-of (e7 / express-03 :ARG1 (o / or :op1 (p3 / protein :name (n5 / name :op1 "SV40" :op2 "large" :op3 "T" :op4 "antigen") :mod (a4 / alone)) :op2 (c7 / combine-01 :ARG1 p3 :ARG2 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))))))) :ARG2 (i4 / increase-01 :ARG1 (a3 / and :op1 (e5 / express-03 :ARG2 n3 :mod (b / baseline)) :op2 (e6 / express-03 :ARG2 n3 :ARG1-of i2) :mod (b2 / both)) :location (c4 / cell :ARG0-of (c5 / contain-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4"))) # ::id bel_pmid_902_3347.41732 # ::date 2015-04-01T06:49:52 # ::file bel_pmid_902_3347_41732.txt # ::snt Treatment of cells with wortmannin, a steroidal inhibitor of phosphatidylinositol-3-kinase (15), resulted in a decreased level of VEGF under hypoxic conditions but the fold stimulation of VEGF mRNA was not changed (Fig. 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 8, 2015 (c3 / contrast-01 :ARG1 (r / result-01 :ARG1 (t / treat-04 :ARG1 (c / cell) :ARG2 (s3 / small-molecule :name (n / name :op1 "wortmannin") :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "phosphatidylinositol-3-kinase") :xref (x1 / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.691"))) :mod (s / steroid) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "15"))) :xref (x2 / xref :value "PUBCHEM:312145" :prob "18.013371"))) :ARG2 (l / level :quant-of (p2 / protein :name (n3 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :ARG1-of (d2 / decrease-01)) :condition (h / hypoxia)) :ARG2 (c4 / change-01 :polarity "-" :ARG1 (s2 / stimulate-01 :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 p2)) :extent (f / fold))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "5"))) # ::id bel_pmid_902_3347.41734 # ::date 2015-04-01T07:04:28 # ::file bel_pmid_902_3347_41734.txt # ::snt Cells with activated ras demonstrated high level of expression of 72-kDa metalloproteinase (MMP-2, gelatinase A), and 92-kDa metalloproteinase (MMP-9, gelatinase B) compared with cells containing SV40 large T antigen alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / demonstrate-01 :ARG0 (c / cell :ARG0-of (c2 / contain-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (a / activate-01) :xref (x5 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1 (l / level :ARG1-of (h / high-02 :compared-to (c3 / cell :ARG0-of (c4 / contain-01 :ARG1 (p / protein :name (n8 / name :op1 "SV40" :op2 "large" :op3 "T" :op4 "antigen") :mod (a5 / alone))))) :degree-of (e2 / express-03 :ARG2 (a2 / and :op1 (e3 / enzyme :name (n2 / name :op1 "metalloproteinase") :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (e5 / enzyme :name (n4 / name :op1 "MMP-2") :xref (x1 / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.002")) :op2 (e6 / enzyme :name (n5 / name :op1 "gelatinase" :op2 "A") :xref (x3 / xref :value "UNIPROT:MMP2_HUMAN" :prob "0.702")))) :quant (m3 / mass-quantity :quant "72" :unit (k / kilodalton)) :xref (x4 / xref :value "UNIPROT:PREP_HUMAN" :prob "0.352")) :op2 (e4 / enzyme :name (n3 / name :op1 "metalloproteinase") :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 (e7 / enzyme :name (n6 / name :op1 "MMP-9") :xref (x2 / xref :value "UNIPROT:MMP9_HUMAN" :prob "1.002")) :op2 (e8 / enzyme :name (n7 / name :op1 "gelatinase" :op2 "B") :xref (x6 / xref :value "UNIPROT:MMP9_HUMAN" :prob "0.702")))) :quant (m4 / mass-quantity :quant "92" :unit (k2 / kilodalton)) :xref (x / xref :value "UNIPROT:PREP_HUMAN" :prob "0.352")))))) # ::id bel_pmid_902_3347.41736 # ::date 2015-04-01T07:16:48 # ::file bel_pmid_902_3347_41736.txt # ::snt Treatment of ras-containing cells with wortmannin resulted in a decrease in MMP expression (Fig. 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 8, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG1 (c / cell :ARG0-of (c2 / contain-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (s / small-molecule :name (n2 / name :op1 "wortmannin") :xref (x2 / xref :value "PUBCHEM:312145" :prob "18.013371"))) :ARG2 (d / decrease-01 :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "MMP") :xref (x1 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6"))) # ::id bel_pmid_902_3347.41744 # ::date 2015-04-01T07:21:26 # ::file bel_pmid_902_3347_41744.txt # ::snt Since wortmannin inhibits VEGF and MMP activity, but does not restore TIMP activity, tumor-igenesis is not expected to be fully suppressed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (e / expect-01 :polarity "-" :ARG1 (s / suppress-01 :ARG1 (c3 / create-01 :ARG1 (t / tumor)) :degree (f / full)) :ARG1-of (c / cause-01 :ARG0 (c2 / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "wortmannin") :xref (x3 / xref :value "PUBCHEM:312145" :prob "18.013371")) :ARG1 (a / activity-06 :ARG0 (a2 / and :op1 (p / protein :name (n2 / name :op1 "VEGF") :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "MMP") :xref (x2 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263"))))) :ARG2 (r / restore-01 :polarity "-" :ARG0 s2 :ARG1 (a3 / activity-06 :ARG0 (p2 / protein :name (n4 / name :op1 "TIMP") :xref (x / xref :value "UNIPROT:TIMP1_HUMAN" :prob "1.002"))))))) # ::id bel_pmid_902_3347.41748 # ::date 2015-04-01T07:30:11 # ::file bel_pmid_902_3347_41748.txt # ::snt Wortmannin could inhibit ras-mediated induction of VEGF, but it did not inhibit the hypoxic regulation of VEGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "wortmannin") :xref (x2 / xref :value "PUBCHEM:312145" :prob "18.013371")) :ARG1 (i2 / induce-01 :ARG2 (p2 / protein :name (n2 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :ARG1-of (m2 / mediate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :ARG2 (i3 / inhibit-01 :polarity "-" :ARG0 s :ARG1 (r / regulate-01 :ARG1 p2 :mod (h / hypoxia)))) # ::id bel_pmid_902_3347.41750 # ::date 2015-04-01T07:33:57 # ::file bel_pmid_902_3347_41750.txt # ::snt This suggests that the hypoxic regulation of VEGF is independent of phosphatidylinositol-3-kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 8, 2015 (s / suggest-01 :ARG0 (t / this) :ARG1 (d / depend-01 :polarity "-" :ARG0 (r / regulate-01 :ARG1 (p / protein :name (n / name :op1 "VEGF") :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :mod (h / hypoxia)) :ARG1 (e / enzyme :name (n2 / name :op1 "phosphatidylinositol-3-kinase") :xref (x / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.691")))) # ::id bel_pmid_911_5219.31418 # ::date 2015-04-01T07:36:46 # ::file bel_pmid_911_5219_31418.txt # ::snt PITSLRE kinases are a superfamily of Cdc2-like kinases that have been implicated in apoptotic signaling and tumorigenesis. In this paper we report that tumor necrosis factor (TNF)-mediated apoptosis is associated with a CrmA- and Bcl-2-inhibitable cleavage of PITSLRE kinases, indicating a role for CASPs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (s / superfamily :domain (k2 / kinase :name (n / name :op1 "PITSLRE") :xref (x1 / xref :value "UNIPROT:CD11B_HUMAN" :prob "0.372")) :ARG1-of (i / implicate-01 :ARG2 (a / and :op1 (s2 / signal-07 :ARG1 (a2 / apoptosis)) :op2 (c2 / create-01 :ARG1 (t / tumor)))) :ARG2-of (i4 / include-91 :ARG1 (k / kinase :ARG1-of (r / resemble-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Cdc2") :xref (x2 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")))))) :snt2 (r2 / report-01 :ARG0 (w / we) :ARG1 (a3 / associate-01 :ARG1 (a4 / apoptosis :ARG1-of (m2 / mediate-01 :ARG0 (p4 / protein :name (n3 / name :op1 "TNF") :xref (x4 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :ARG2 (c / cleave-01 :ARG1 (k3 / kinase :name (n6 / name :op1 "PITSLRE") :xref (x / xref :value "UNIPROT:CD11B_HUMAN" :prob "0.372")) :ARG1-of (i2 / inhibit-01 :ARG0 (a5 / and :op1 (p6 / protein :name (n4 / name :op1 "CrmA")) :op1 (p7 / protein :name (n5 / name :op1 "Bcl-2") :xref (x3 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.701"))) :ARG1-of (p5 / possible-01)))) :medium (p3 / paper :mod (t2 / this)) :ARG0-of (i3 / indicate-01 :ARG1 (r3 / role :poss (e / enzyme :name (n7 / name :op1 "CASP") :xref (x5 / xref :value "UNIPROT:CASP_HUMAN" :prob "1.003")))))) # ::id bel_pmid_930_0710.10502 # ::date 2015-04-01T07:39:08 # ::file bel_pmid_930_0710_10502.txt # ::snt Elevated levels of human TNF-alpha were accompanied by increases in synovial cell expression of murine IL-1beta and IL-6 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 1, 2015 (a / accompany-01 :ARG0 (i / increase-01 :ARG1 (e2 / express-03 :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "IL-1beta") :xref (x2 / xref :value "UNIPROT:IL1B_HUMAN" :prob "0.692")) :op2 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (m / murine)) :ARG3 (c / cell :mod (s / synovial)))) :ARG1 (l / level :mod (e / elevated) :quant-of (p2 / protein :name (n2 / name :op1 "TNF-alpha") :mod (h / human) :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) # ::id bel_pmid_930_5854.5780 # ::date 2015-04-01T07:43:56 # ::file bel_pmid_930_5854_5780.txt # ::snt e show here that oncogenic forms of Ha-Ras activate NF-kappaB, not through induced nuclear translocation, but rather through the activation of the transcriptional function of the NF-kappaB RelA/p65 subunit. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "Ha-Ras") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG1 (p / protein :name (n2 / name :op1 "NF-kB") :xref (x1 / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.272")) :manner (i / instead-of-91 :ARG1 (a2 / activate-01 :ARG1 (f2 / function-01 :ARG0 (p2 / protein :name (n5 / name :op1 "RelA/p65" :op2 "subunit") :part-of p) :ARG1 (t2 / transcribe-01)) :mod (r / rather)) :ARG2 (t / translocate-01 :ARG2 (n3 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :ARG2-of (i2 / induce-01)))) :medium (h / here)) # ::id bel_pmid_930_5939.36880 # ::date 2015-04-01T07:56:08 # ::file bel_pmid_930_5939_36880.txt # ::snt 1) STAT proteins play an essential role in angiotensin II-induced vascular smooth muscle cell proliferation, 2) JAK2 plays an essential role in the tyrosine phosphorylation of Raf-1, and 3) convergent mitogenic signaling cascades involving the cytosolic kinases JAK2, MEK1, and ERK1 mediate vascular smooth muscle cell proliferation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (p2 / play-08 :li "1" :ARG0 (p3 / protein :name (n / name :op1 "STAT") :xref (x4 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")) :ARG1 (p4 / proliferate-01 :ARG0 (c / cell :part-of (m / muscle :ARG1-of (s / smooth-06) :mod (v / vascular))) :ARG2-of (i / induce-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "angiotensin" :op2 "II") :xref (x6 / xref :value "PUBCHEM:172198" :prob "11.266794")))) :mod (e / essential)) :op2 (p5 / play-08 :li "2" :ARG0 (e2 / enzyme :name (n3 / name :op1 "JAK2") :xref (x3 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (e4 / enzyme :name (n5 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :xref (x7 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :mod e) :op3 (m2 / mediate-01 :li "3" :ARG0 (c2 / cascade :mod (m3 / mitogenic) :ARG0-of (c3 / converge-01) :ARG0-of (s3 / signal-07) :ARG2-of (i2 / involve-01 :ARG1 (k / kinase :part-of (c4 / cytosol :xref (x5 / xref :value "GO:0005829" :prob "0.8")) :ARG1-of (m4 / mean-01 :ARG2 (a3 / and :op1 e2 :op2 (e3 / enzyme :name (n6 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op3 (e5 / enzyme :name (n7 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))))))) :ARG1 p4)) # ::id bel_pmid_934_4843.8622 # ::date 2015-04-02T00:56:22 # ::file bel_pmid_934_4843_8622.txt # ::snt The present study demonstrates that erythropoietin (Epo) and IL-3 induce tyrosine phosphorylation of the SH2/SH3-containing adapter protein CrkL and its transient association with tyrosine-phosphorylated SHP-2, Shc, and Cbl in a murine IL-3-dependent cell line, 32D, expressing the Epo receptor (EpoR). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / demonstrate-01 :ARG0 (s / study-01 :time (p3 / present)) :ARG1 (i / induce-01 :ARG0 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "erythropoietin") :ARG1-of (d2 / describe-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "Epo") :xref (x8 / xref :value "PUBCHEM:5288169" :prob "16.321695"))) :xref (x9 / xref :value "PUBCHEM:6257657" :prob "9.006685")) :op2 (p4 / protein :name (n4 / name :op1 "IL-3") :xref (x3 / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003"))) :ARG2 (a5 / and :op1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n / name :op1 "tyrosine") :part-of (p / protein :name (n5 / name :op1 "CrkL") :ARG0-of (a3 / adapt-01) :ARG0-of (c / contain-01 :ARG1 (a4 / and :op1 (p5 / protein-segment :name (n6 / name :op1 "SH2")) :op2 (p6 / protein-segment :name (n7 / name :op1 "SH3")))) :xref (x6 / xref :value "UNIPROT:CRKL_HUMAN" :prob "0.604")) :xref (x11 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :op2 (a6 / associate-01 :ARG1 p :ARG2 (a7 / and :op1 (a8 / amino-acid :name (n14 / name :op1 "tyrosine") :part-of (p11 / protein :name (n8 / name :op1 "SHP-2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :ARG1-of (p8 / phosphorylate-01) :xref (x7 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a9 / amino-acid :name (n15 / name :op1 "tyrosine") :part-of (p10 / protein :name (n9 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG1-of p8 :xref (x12 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op3 (a10 / amino-acid :name (n16 / name :op1 "tyrosine") :part-of (p12 / protein :name (n10 / name :op1 "Cbl") :xref (x5 / xref :value "UNIPROT:CBL_HUMAN" :prob "0.604")) :ARG1-of p8 :xref (x10 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (t / transient-02))) :location (c3 / cell-line :name (n12 / name :op1 "32D") :mod (m / murine) :ARG0-of (d3 / depend-01 :ARG1 p4) :ARG3-of (e2 / express-03 :ARG2 (p7 / protein :name (n11 / name :op1 "Epo" :op2 "receptor") :ARG1-of (d4 / describe-01 :ARG2 (p9 / protein :name (n13 / name :op1 "EpoR") :xref (x4 / xref :value "UNIPROT:EPOR_HUMAN" :prob "0.604"))) :xref (x2 / xref :value "UNIPROT:EPOR_HUMAN" :prob "0.223")))))) # ::id bel_pmid_946_1509.18046 # ::date 2015-04-02T01:18:51 # ::file bel_pmid_946_1509_18046.txt # ::snt The hsp90beta gene promoter contains binding sites for the transcription factors nuclear factor IL-6 (\"NF-IL6\") and signal transducer and activator of transcription 3 (STAT-3), which are activated respectively by the mitogen-activated-protein-kinase and Jak-kinase pathways following IL-6 treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contain-01 :ARG0 (p8 / protein :name (n / name :op1 "hsp90beta") :ARG0-of (p / promote-01 :ARG1 (g / gene)) :xref (x4 / xref :value "UNIPROT:Q58FF5_HUMAN" :prob "0.261")) :ARG1 (p2 / protein-segment :ARG2-of (b / bind-01 :ARG1 (f4 / factor :ARG0-of (t2 / transcribe-01) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (p5 / protein :name (n2 / name :op1 "nuclear" :op2 "factor" :op3 "IL-6") :ARG1-of (d / describe-01 :ARG2 (p9 / protein :name (n7 / name :op1 "NF-IL6") :xref (x5 / xref :value "UNIPROT:CEBPD_HUMAN" :prob "0.282"))) :xref (x3 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.383")) :op2 (p6 / protein :name (n3 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "3") :ARG1-of (d2 / describe-01 :ARG2 (p10 / protein :name (n8 / name :op1 "STAT-3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.683"))) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.703")))) :ARG1-of (a3 / activate-01 :ARG0 (a4 / and :op1 (p3 / pathway :name (n4 / name :op1 "mitogen-activated-protein-kinase")) :op2 (p4 / pathway :name (n5 / name :op1 "Jak-kinase"))) :manner (r / respective) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG2 (p7 / protein :name (n6 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))))))) # ::id bel_pmid_946_1509.22508 # ::date 2015-04-02T01:29:36 # ::file bel_pmid_946_1509_22508.txt # ::snt In contrast, IL-1, which activates only the \"NF-IL6\" pathway, synergizes with heat shock to produce strong activation of hsp90. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / contrast-01 :ARG2 (s / synergize-01 :ARG0 (p / protein :name (n / name :op1 "IL-1") :ARG0-of (a / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "NF-IL6")) :mod (o / only)) :xref (x1 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382")) :ARG1 (s2 / shock :mod (h / heat)) :ARG2 (p3 / produce-01 :ARG0 p :ARG1 (a2 / activate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "hsp90") :xref (x / xref :value "UNIPROT:HS90B_HUMAN" :prob "0.622")) :mod (s3 / strong))))) # ::id bel_pmid_982_0826.5420 # ::date 2015-04-02T01:46:19 # ::file bel_pmid_982_0826_5420.txt # ::snt formation of the hCAF-1/BTG1 complex is driven by phosphorylation at BTG1 (Ser-159) and implicates this complex in the signalling events of cell division that lead to changes in cellular proliferation associated with cell-cell contact. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 22, 2015 (a2 / and :op1 (d / drive-02 :ARG0 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "159" :name (n3 / name :op1 "serine") :part-of "p3" :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (f / form-01 :ARG1 (m / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "hCAF-1") :xref (x / xref :value "UNIPROT:ACO12_HUMAN" :prob "0.272")) :part (p3 / protein :name (n2 / name :op1 "BTG1") :xref (x1 / xref :value "UNIPROT:BTG1_HUMAN" :prob "1.003"))))) :op2 (i / implicate-01 :ARG0 f :ARG1 m :ARG2 (e / event :ARG0-of (s / signal-07) :subevent-of (d2 / divide-02 :ARG1 (c / cell)) :ARG0-of (l / lead-03 :ARG2 (c2 / change-01 :ARG1 (p4 / proliferate-01 :ARG0 c :ARG1-of (a3 / associate-01 :ARG2 (c3 / contact-01 :ARG0 (c4 / cell) :ARG1 c)))))))) # ::id bel_pmid_982_0826.5840 # ::date 2015-04-02T02:00:34 # ::file bel_pmid_982_0826_5840.txt # ::snt in vitro the hCAF-1/BTG1 complex formation was dependent on the phosphorylation of a putative p34cdc2 kinase site on BTG1 (Ser-159). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Apr 21, 2015 (d / depend-01 :ARG0 (f / form-01 :ARG1 (m / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "hCAF-1") :xref (x / xref :value "UNIPROT:ACO12_HUMAN" :prob "0.272")) :part (p3 / protein :name (n2 / name :op1 "BTG1") :xref (x1 / xref :value "UNIPROT:BTG1_HUMAN" :prob "1.003")))) :ARG1 (p / phosphorylate-01 :ARG1 (p4 / protein-segment :ARG1-of (t / think-01) :part-of p3 :mod (k / kinase :name (n5 / name :op1 "p34cdc2") :xref (x2 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.612")) :ARG1-of (m2 / mean-01 :ARG2 (a / amino-acid :mod "159" :name (n4 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))))) :manner (i / in-vitro)) # ::id bel_pmid_982_0826.8154 # ::date 2015-04-02T02:08:54 # ::file bel_pmid_982_0826_8154.txt # ::snt The human BTG1 protein is thought to be a potential tumour suppressor because its overexpression inhibits NIH 3T3 cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (t / think-01 :ARG1 (s / suppress-01 :ARG0 (p / protein :name (n / name :op1 "BTG1") :mod (h / human) :xref (x / xref :value "UNIPROT:BTG1_HUMAN" :prob "1.003")) :ARG1 (t2 / tumor) :mod (p2 / potential)) :ARG1-of (c / cause-01 :ARG0 (i / inhibit-01 :ARG0 (o / overexpress-01 :ARG1 p) :ARG1 (p3 / proliferate-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "NIH" :op2 "3T3")))))) # ::id bel_pmid_982_3899.2738 # ::date 2015-04-02T02:13:22 # ::file bel_pmid_982_3899_2738.txt # ::snt Pak3 phosphorylates Raf-1 on serine 338 in vitro and in vivo. The p21-activated protein kinases are regulated by the Rho-family GTPases Rac and Cdc42. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Raf-1") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG2 (e / enzyme :name (n2 / name :op1 "Pak3") :xref (x3 / xref :value "UNIPROT:PAK3_HUMAN" :prob "0.603")) :location (a / amino-acid :mod "338" :name (n / name :op1 "serine") :part-of e2 :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :manner (a2 / and :op1 (i / in-vitro) :op2 (i2 / in-vivo))) :snt2 (r / regulate-01 :ARG0 (a4 / and :op1 (e5 / enzyme :name (n7 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :op2 (p5 / protein :name (n8 / name :op1 "Cdc42") :xref (x4 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family :name (n4 / name :op1 "Rho" :op2 "GTPase")))) :ARG1 (k / kinase :ARG1-of (a3 / activate-01 :ARG0 (p2 / protein :name (n5 / name :op1 "p21") :xref (x / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002"))) :mod (p3 / protein)))) # ::id bio.chicago_2015.9828 # ::date 2015-10-22T07:21:22 # ::file bio_chicago_2015_9828.txt # ::snt The amino acids altered in mutation DECM2 (YEG G), which have a strong effect on DEC binding to beta-cateninArm in our assays, are bold and underlined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (b / bold-03 :ARG1 (a6 / amino-acid :ARG1-of (a3 / alter-01 :time (m / mutate-01 :ARG2 (p3 / protein :name (n2 / name :op1 "DECM2") :xref (x1 / xref :value "UNIPROT:BHE41_HUMAN" :prob "0.312")))) :ARG0-of (a4 / affect-01 :ARG1 (b2 / bind-01 :ARG1 (p / protein :name (n3 / name :op1 "DEC") :xref (x2 / xref :value "UNIPROT:BHE40_HUMAN" :prob "0.262")) :ARG2 (p2 / protein :name (n4 / name :op1 "beta-cateninArm") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.363")) :location (a5 / assay-01 :ARG0 (w / we))) :ARG1-of (s / strong-02)) :ARG1-of (l / label-01 :ARG2 (s2 / string-entity :value "YEG-G")))) :op2 (u / underline-01 :ARG1 a6)) # ::id bio.chicago_2015.19528 # ::date 2015-10-21T18:07:43 # ::file bio_chicago_2015_19528.txt # ::snt The less efficient phosphorylation of MLC by Rho-kinase may become sufficient when the myosin phosphatase activity is inhibited by Rho-kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (p / possible-01 :ARG1 (s / suffice-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "MLC") :xref (x / xref :value "UNIPROT:MYL9_HUMAN" :prob "0.302")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Rho-kinase") :xref (x1 / xref :value "UNIPROT:ROCK2_HUMAN" :prob "0.353")) :ARG1-of (e / efficient-01 :degree (l / less)))) :condition (i / inhibit-01 :ARG0 e2 :ARG1 (a / activity-06 :ARG0 (p4 / phosphatase :name (n3 / name :op1 "myosin"))))) # ::id bio.chicago_2015.19534 # ::date 2015-10-21T18:29:58 # ::file bio_chicago_2015_19534.txt # ::snt In support of these findings, it has also been found that displacement of Rb-E2F complexes from promoters with a dominant-negative E2F (DN-E2F) containing a DNA binding domain but lacking an Rb binding site, or titration of Rb-E2F complexes away from promoters by transfection of a plasmid containing multiple E2F binding site repeats, prevents Rb-mediated repression of cyclin E and A expression and growth arrest by p16 (Zhang et al., 1999 ; # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (f / find-01 :ARG1 (p7 / prevent-01 :ARG0 (o / or :op1 (d / displace-01 :ARG1 (m5 / macro-molecular-complex :part "p3" :part "p6") :ARG2 (m / molecular-physical-entity :ARG0-of (p / promote-02) :ARG0-of (h / have-03 :ARG1 (p14 / protein :name (n2 / name :op1 "E2F") :ARG0-of (c2 / contain-01 :ARG1 (d3 / domain :ARG1-of (b / bind-01 :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "DNA")))) :ARG1-of (c3 / contrast-01 :ARG2 (l / lack-01 :ARG0 p14 :ARG1 (s / site :ARG2-of (b2 / bind-01 :ARG1 (p3 / protein :name (n5 / name :op1 "Rb") :xref (x2 / xref :value "UNIPROT:RB_HUMAN" :prob "1.003"))))))) :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of (d2 / dominate-01) :xref (x1 / xref :value "UNIPROT:E2F1_HUMAN" :prob "0.262"))))) :op2 (t / titrate-01 :ARG1 m5 :location (a2 / away :op1 (m3 / molecular-physical-entity :ARG0-of (p2 / promote-02))) :manner (t2 / transfect-01 :ARG1 (p5 / plasmid :ARG0-of (c4 / contain-01 :ARG1 (r / repeat-01 :ARG1 (s2 / site :ARG2-of (b3 / bind-01 :ARG1 (p6 / protein :name (n6 / name :op1 "E2F") :xref (x3 / xref :value "UNIPROT:E2F1_HUMAN" :prob "0.262")))))))))) :ARG1 (a4 / and :op1 (r2 / repress-01 :ARG1 (e / express-03 :ARG2 (a3 / and :op1 (p8 / protein :name (n7 / name :op1 "cyclin" :op2 "E") :xref (x4 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")) :op2 (p9 / protein :name (n8 / name :op1 "cyclin" :op2 "A") :xref (x5 / xref :value "UNIPROT:CCNA2_HUMAN" :prob "0.662")))) :ARG1-of (m4 / mediate-01 :ARG0 p3)) :op2 (a5 / arrest-02 :ARG0 (p10 / protein :name (n9 / name :op1 "p16") :xref (x / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262")) :ARG1 (g3 / grow-01)))) :mod (a / also) :ARG0-of (s3 / support-01 :ARG1 (t3 / thing :ARG1-of (f2 / find-01) :mod (t4 / this))) :ARG1-of (d5 / describe-01 :ARG0 (p11 / publication-91 :ARG0 (a6 / and :op1 (p12 / person :name (n10 / name :op1 "Zhang")) :op2 (p13 / person :mod (o2 / other))) :time (d6 / date-entity :year "1999")))) # ::id bio.chicago_2015.19551 # ::date 2015-10-21T19:15:29 # ::file bio_chicago_2015_19551.txt # ::snt More recently, PSQ was found to colocalize and coimmunoprecipitate with TRL/ GAF, an interaction that was shown to depend on the BTB/ POZ domains of the two proteins ( 64). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (f / find-01 :ARG1 (a / and :op1 (c / colocalize-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "PSQ")) :op2 (s / slash :op1 (p2 / protein :name (n2 / name :op1 "TRL")) :op2 (p3 / protein :name (n3 / name :op1 "GAF") :xref (x / xref :value "UNIPROT:FGF9_HUMAN" :prob "1.003"))))) :op2 (c2 / coimmunoprecipitate-01 :ARG1 p :ARG2 s) :ARG1-of (m2 / mean-01 :ARG2 (i / interact-01 :ARG0-of (d / depend-01 :ARG1 (s2 / slash :op1 (p5 / protein-segment :name (n4 / name :op1 "BTB")) :op2 (p6 / protein-segment :name (n5 / name :op1 "POZ")) :part-of s) :ARG1-of (s3 / show-01))))) :time (r / recent :degree (m / more)) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "64")))) # ::id bio.chicago_2015.19555 # ::date 2015-10-21T19:59:16 # ::file bio_chicago_2015_19555.txt # ::snt The PI3K inhibitory domain inhibits p110 , but not p110 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (d / domain :ARG0-of (i2 / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :ARG1 (p / protein :name (n / name :op1 "p110") :xref (x1 / xref :value "UNIPROT:EXOS6_HUMAN" :prob "0.262"))) :ARG2 (i3 / inhibit-01 :polarity "-" :ARG0 d :ARG1 p)) # ::id bio.chicago_2015.19589 # ::date 2015-10-21T20:06:47 # ::file bio_chicago_2015_19589.txt # ::snt The spatial expression and sequence of ppa suggest that Ppa might negatively regulate Prd, either by transcriptional co-repression or degradation of the Prd protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / suggest-01 :ARG0 (a / and :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "ppa") :xref (x1 / xref :value "UNIPROT:PPARA_HUMAN" :prob "0.233")) :mod (s2 / space)) :op2 (s3 / sequence :poss p :mod s2)) :ARG1 (p2 / possible-01 :ARG1 (d2 / downregulate-01 :ARG0 p :ARG1 (p3 / protein :name (n3 / name :op1 "Prd") :xref (x / xref :value "UNIPROT:PEPD_HUMAN" :prob "0.602")) :manner (o / or :op1 (c / corepress-00 :ARG1 (t / transcribe-01)) :op2 (d / degrade-01 :ARG1 p3))))) # ::id bio.chicago_2015.19651 # ::date 2015-10-21T20:15:42 # ::file bio_chicago_2015_19651.txt # ::snt Within this complex, NDPK interacts with dynamin I through a proline-rich domain, whereas its interaction with phocein is ill defined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (c / contrast-01 :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "NDPK") :xref (x1 / xref :value "UNIPROT:NDKA_HUMAN" :prob "0.313")) :ARG1 (p / protein :name (n2 / name :op1 "dynamin" :op2 "I") :xref (x2 / xref :value "UNIPROT:DYN2_HUMAN" :prob "0.313")) :ARG2 (d / domain :mod (r / rich :mod (a / amino-acid :name (n3 / name :op1 "proline") :xref (x3 / xref :value "PUBCHEM:614" :prob "10.45396"))))) :ARG2 (i2 / interact-01 :ARG0 e :ARG1 (p2 / protein :name (n4 / name :op1 "phocein") :xref (x / xref :value "UNIPROT:PTPR2_HUMAN" :prob "0.242")) :ARG1-of (d2 / define-01 :ARG1-of (i3 / ill-02))) :location (c2 / complex :mod (t / this))) # ::id bio.chicago_2015.19673 # ::date 2015-10-21T20:23:04 # ::file bio_chicago_2015_19673.txt # ::snt However, although Rb has been shown to bind at least 10 distinct proteins including the transcription factors ATF-2 ( 44) and E2F ( 45), direct interaction of Rb with Sp proteins has not been reported. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (c3 / contrast-01 :ARG2 (h / have-concession-91 :ARG1 (r / report-01 :polarity "-" :ARG1 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "Rb") :xref (x3 / xref :value "UNIPROT:RB_HUMAN" :prob "1.003")) :ARG1 (p2 / protein :name (n2 / name :op1 "Sp") :xref (x / xref :value "UNIPROT:TFF2_HUMAN" :prob "0.602")) :ARG1-of (d / direct-02))) :ARG2 (s / show-01 :ARG1 (b / bind-01 :ARG1 p :ARG2 (p3 / protein :mod (d2 / distinct) :ARG2-of (i2 / include-01 :ARG1 (a2 / and :op1 (p4 / protein :name (n3 / name :op1 "ATF-2") :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 "44"))) :xref (x1 / xref :value "UNIPROT:ATF2_HUMAN" :prob "0.672")) :op2 (p5 / protein :name (n4 / name :op1 "E2F") :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 "45"))) :xref (x2 / xref :value "UNIPROT:E2F1_HUMAN" :prob "0.262")) :mod (f / factor :ARG0-of (t / transcribe-01)))) :quant (a / at-least :op1 "10")))))) # ::id bio.chicago_2015.19721 # ::date 2015-10-21T20:41:15 # ::file bio_chicago_2015_19721.txt # ::snt In addition, the amino-terminal PTB domain can directly interact with EGFR and Syk/Zap-70 ( Lupher and Thien). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (a / and :op2 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (p2 / protein-segment :wiki "N-terminus" :name (n7 / name :op1 "amino-terminus") :part-of (p8 / protein :wiki "Polypyrimidine_tract-binding_protein" :name (n8 / name :op1 "PTB") :xref (x3 / xref :value "UNIPROT:PTBP1_HUMAN" :prob "1.002"))) :ARG1 (a3 / and :op1 (e / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n2 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (s / slash :op1 (e2 / enzyme :wiki "Syk" :name (n3 / name :op1 "Syk") :xref (x / xref :value "UNIPROT:KSYK_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :wiki "ZAP70" :name (n4 / name :op1 "Zap-70") :xref (x1 / xref :value "UNIPROT:ZAP70_HUMAN" :prob "0.623")))) :ARG1-of (d / direct-02)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :wiki "-" :name (n5 / name :op1 "Lupher")) :op2 (p7 / person :wiki "-" :name (n6 / name :op1 "Thien"))))))) # ::id bio.chicago_2015.19785 # ::date 2015-10-21T20:49:13 # ::file bio_chicago_2015_19785.txt # ::snt Here, we demonstrate that V-ATPase binds directly to actin filaments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "V-ATPase") :xref (x / xref :value "UNIPROT:VATA_HUMAN" :prob "0.272")) :ARG2 (f / filament :part-of (p / protein :name (n2 / name :op1 "actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :ARG1-of (d2 / direct-02)) :medium (h / here)) # ::id bio.chicago_2015.19847 # ::date 2015-10-21T20:55:30 # ::file bio_chicago_2015_19847.txt # ::snt Rho-kinase phosphorylates MBS and consequently inactivates myosin phosphatase ( 12). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (c / cause-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :name (n2 / name :op1 "MBS")) :ARG2 (e2 / enzyme :name (n / name :op1 "Rho-kinase") :xref (x / xref :value "UNIPROT:ROCK2_HUMAN" :prob "0.353"))) :ARG1 (a / activate-01 :polarity "-" :ARG0 e2 :ARG1 (p3 / phosphatase :name (n3 / name :op1 "myosin"))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "12")))) # ::id bio.chicago_2015.19850 # ::date 2015-10-21T21:06:52 # ::file bio_chicago_2015_19850.txt # ::snt Some E2F may remain bound to a partially phosphorylated Rb throughout the normal cell cycle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p / possible-01 :ARG1 (r / remain-01 :ARG1 (p2 / protein :name (n / name :op1 "E2F") :quant (s / some) :xref (x / xref :value "UNIPROT:E2F1_HUMAN" :prob "0.262")) :ARG3 (b / bind-01 :ARG1 p2 :ARG2 (p3 / protein :name (n2 / name :op1 "Rb") :ARG2-of (p4 / phosphorylate-01 :degree (p5 / part)) :xref (x1 / xref :value "UNIPROT:RB_HUMAN" :prob "1.003"))) :duration (c / cycle-02 :ARG1 (c2 / cell) :ARG1-of (n3 / normal-02)))) # ::id bio.chicago_2015.19878 # ::date 2015-10-20T14:31:08 # ::file bio_chicago_2015_19878.txt # ::snt ( B) A model on how the proneural complex encompassing Pnr, Chip, and the (Ac/Sc)- Da heterodimer is regulated by Osa. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (m5 / model-01 :li "b" :ARG1 (t / thing :manner-of (r / regulate-01 :ARG0 (p2 / protein :name (n5 / name :op1 "Osa") :xref (x / xref :value "UNIPROT:ARI1A_HUMAN" :prob "0.202")) :ARG1 (c / complex :mod (p / proneuron) :ARG0-of (e / encompass-01 :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "pnr") :xref (x2 / xref :value "UNIPROT:NR2E3_HUMAN" :prob "0.602")) :op2 (p4 / protein :name (n3 / name :op1 "chip") :xref (x1 / xref :value "UNIPROT:CHIP_HUMAN" :prob "0.603")) :op3 (h / heterodimer :part (p5 / protein :name (n / name :op1 "Ac/Sc")) :part (p6 / protein :name (n6 / name :op1 "Da"))))))))) # ::id bio.chicago_2015.19893 # ::date 2015-10-20T14:46:56 # ::file bio_chicago_2015_19893.txt # ::snt This possibility is supported by the demonstration that phosphorylation of Thr-654 in the proximal membrane domain of the EGF receptor by protein kinase C decreases EGF-dependent activation of the EGF receptor [ 6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / support-01 :li "6" :ARG0 (d / demonstrate-01 :ARG1 (d2 / decrease-01 :ARG0 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "654" :name (n4 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "protein" :op2 "kinase" :op3 "C") :xref (x1 / xref :value "UNIPROT:A0A087X0I9_HUMAN" :prob "0.701")) :location (d3 / domain :mod (p4 / proximal :mod (m / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :part-of (e / enzyme :name (n / name :op1 "EGF" :op2 "receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.213")))) :ARG1 (a / activate-01 :ARG1 e :ARG0-of (d4 / depend-01 :ARG1 e)))) :ARG1 (p2 / possible-01 :ARG1 (t / this))) # ::id bio.chicago_2015.19949 # ::date 2015-10-20T14:48:42 # ::file bio_chicago_2015_19949.txt # ::snt In contrast, EGF failed to promote the spreading of MDCK cells and Paxillin displayed a diffuse distribution within the cytoplasm ( Figure 1A), similar to unstimulated MDCK cells ( Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (a2 / and :op1 (f / fail-01 :ARG1 (p3 / protein :name (n / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG2 (p / promote-01 :ARG0 p3 :ARG1 (s2 / spread-03 :ARG1 (c2 / cell :name (n2 / name :op1 "MDCK"))))) :op2 (d / display-01 :ARG0 (p2 / protein :name (n3 / name :op1 "Paxillin") :xref (x / xref :value "UNIPROT:PAXI_HUMAN" :prob "1.003")) :ARG1 (d2 / distribute-01 :ARG1-of (d3 / diffuse-01) :location (c3 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (r / resemble-01 :ARG2 (c5 / cell :name (n4 / name :op1 "MDCK") :ARG1-of (s3 / stimulate-01 :polarity "-")) :ARG1-of "d4")) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "1A"))))) # ::id bio.chicago_2015.19979 # ::date 2015-10-20T21:01:08 # ::file bio_chicago_2015_19979.txt # ::snt The lack of PKA activity in the purified I B/PKAc fractions ( Figure 1A and data not shown) and in purified NF- B - I B - PKAc complexes ( Figure 1D) suggested that the binding of I B to PKAc inhibits the enzymatic activity of PKA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (s / suggest-01 :ARG0 (l / lack-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1 (a2 / and :op1 (f / fraction-01 :ARG1 (s3 / slash :op1 (e2 / enzyme :name (n2 / name :op1 "IB")) :op2 e) :ARG1-of (p / purify-01) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "1A") :op2 (d2 / data :ARG1-of (s2 / show-01 :polarity "-"))))) :op2 (m3 / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "NF-B") :xref (x / xref :value "UNIPROT:RRP5_HUMAN" :prob "0.202")) :part e2 :part e :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "1D")) :ARG1-of p)))) :ARG1 (i / inhibit-01 :ARG0 (b / bind-01 :ARG1 e2 :ARG2 e) :ARG1 (a4 / activity-06 :ARG0 e :mod (e4 / enzyme)))) # ::id bio.chicago_2015.20002 # ::date 2015-10-20T21:10:55 # ::file bio_chicago_2015_20002.txt # ::snt E, concentration-dependent inhibitory effect of AG1478 on EGF-induced phosphorylation of the EGF-R at Tyr1173. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (a / affect-01 :li "e" :ARG0 (s / small-molecule :name (n5 / name :op1 "AG1478") :xref (x2 / xref :value "PUBCHEM:2051" :prob "18.86067")) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "1173" :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n2 / name :op1 "EGF-R") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.673")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG2 (i / inhibit-01) :ARG0-of (d / depend-01 :ARG1 (c / concentrate-02))) # ::id bio.chicago_2015.20021 # ::date 2015-10-20T21:19:57 # ::file bio_chicago_2015_20021.txt # ::snt Importantly, this peptide also blocked EGF activation of endogenous Ral. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 20, 2015 (b / block-01 :ARG0 (p / peptide :mod (t / this)) :ARG1 (a2 / activate-01 :ARG0 (p2 / protein :name (n / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p3 / protein :name (n2 / name :op1 "Ral") :mod (e / endogenous) :xref (x1 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.603"))) :mod (a / also) :mod (i / important)) # ::id bio.chicago_2015.20023 # ::date 2015-10-20T21:26:03 # ::file bio_chicago_2015_20023.txt # ::snt Kek1 inhibits ligand binding To examine the mechanistic details underlying Kek1 suppression of EGFR activity, we used the baculovirus/ Sf9 insect cell expression system. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (m / multi-sentence :snt1 (i / inhibit-01 :ARG0 (p2 / protein :name (n / name :op1 "Kek1")) :ARG1 (b / bind-01 :ARG1 (l / ligand))) :snt2 (u2 / use-01 :ARG0 (w / we) :ARG1 (s2 / system :mod (e3 / express-03 :ARG2 (o / organism :name (n4 / name :op1 "baculovirus")) :ARG3 (c2 / cell-line :name (n5 / name :op1 "Sf9") :mod (i2 / insect)))) :ARG2 (e2 / examine-01 :ARG0 w :ARG1 (d / detail :mod (m2 / mechanistic) :ARG0-of (u / underlie-01 :ARG1 (s / suppress-01 :ARG0 (p / protein :name (n2 / name :op1 "Kek1")) :ARG1 (a / activity-06 :ARG0 (e4 / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))))))) # ::id bio.chicago_2015.20029 # ::date 2015-10-20T21:41:14 # ::file bio_chicago_2015_20029.txt # ::snt To test whether the extracellular domain of Kek1, which contains five LRR and one Ig motif (Musacchio and Perrimon, 1996 ), is required for the inhibition of the EGFR activity by Kek1, we generated transgenic lines that contain either UAS-kek1extra or UAS-kek1intra. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (g / generate-01 :ARG0 (w / we) :ARG1 (l / line :mod (t / transgenic) :ARG0-of (c / contain-01 :ARG1 (o / or :op1 (s / small-molecule :name (n2 / name :op1 "UAS-kek1") :mod (e2 / extra)) :op2 (s2 / small-molecule :name (n3 / name :op1 "UAS-kek1") :mod (i / intra))))) :purpose (t2 / test-01 :ARG0 w :ARG1 (r / require-01 :mode "interrogative" :ARG0 (i2 / inhibit-01 :ARG0 "p5" :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG1 (d2 / domain :mod (e4 / extracellular) :mod (p5 / protein :name (n4 / name :op1 "Kek1")) :ARG0-of (c2 / contain-01 :ARG1 (a2 / and :op1 (s3 / small-molecule :quant "5" :name (n5 / name :op1 "LRR") :xref (x2 / xref :value "PUBCHEM:25108557" :prob "8.881028")) :op2 (m4 / motif :quant "1" :mod (p3 / protein :name (n8 / name :op1 "immunoglobulin") :xref (x / xref :value "UNIPROT:IGJ_HUMAN" :prob "0.372")))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p / person :name (n6 / name :op1 "Musacchio")) :op2 (p2 / person :name (n7 / name :op1 "Perrimon"))) :time (d / date-entity :year "1996")))))))) # ::id bio.chicago_2015.20072 # ::date 2015-10-20T21:41:26 # ::file bio_chicago_2015_20072.txt # ::snt Pharmacological disruption of actin affects MT organization, and vice versa ( Lin and Forscher, 1993 ; Rochlin et al., 1999 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (a / and :op1 (a2 / affect-01 :ARG0 (d3 / disrupt-01 :ARG1 (p5 / protein :name (n4 / name :op1 "actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :mod (p / pharmacology)) :ARG1 (o / organize-01 :ARG1 (p6 / protein :name (n5 / name :op1 "MT") :xref (x / xref :value "UNIPROT:FABD_HUMAN" :prob "1.002")))) :op2 (a3 / affect-01 :ARG0 o :ARG1 d3) :ARG1-of (d4 / describe-01 :ARG0 (a8 / and :op1 (p7 / publication-91 :ARG0 (a5 / and :op1 (p2 / person :name (n / name :op1 "Lin")) :op2 (p3 / person :name (n2 / name :op1 "Forscher"))) :time (d / date-entity :year "1993")) :op2 (p8 / publication-91 :ARG0 (a6 / and :op1 (p4 / person :name (n3 / name :op1 "Rochlin")) :op2 (p9 / person :mod (o2 / other))) :time (d2 / date-entity :year "1999"))))) # ::id bio.chicago_2015.20206 # ::date 2015-10-20T21:46:28 # ::file bio_chicago_2015_20206.txt # ::snt An N-terminal peptide of Ral-GDS prevents EGF-induced complex formation between PDK1 and Ral-GDS and suppresses EGF-induced activation of Ral If this hypothesis is correct, then expression of just the N-terminus of Ral-GDS (N-Ral-GDS) should bind to PDK1 in cells, block binding of PDK1 to Ral-GDS and interfere with Ral activation by EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (a / and :op1 (p2 / prevent-01 :ARG0 (p13 / peptide :part-of (p9 / protein-segment :name (n9 / name :op1 "N-terminus") :part-of (p10 / protein :name (n10 / name :op1 "Ral-GDS") :xref (x1 / xref :value "UNIPROT:GNDS_HUMAN" :prob "0.693")))) :ARG1 (f / form-02 :ARG1 (m4 / macro-molecular-complex :part (e3 / enzyme :name (n11 / name :op1 "PDK1") :xref (x2 / xref :value "UNIPROT:PDK1_HUMAN" :prob "1.003")) :part p10))) :op2 (s / suppress-01 :ARG0 p9 :ARG1 (a3 / activate-01 :ARG1 (p5 / protein :name (n4 / name :op1 "Ral") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.603")) :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n3 / name :op1 "EGF") :xref (x4 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))))) :snt2 (h2 / have-condition-91 :ARG1 (r / recommend-01 :ARG1 (a4 / and :op1 (b / bind-01 :ARG1 (e / express-03 :ARG2 (p / protein-segment :name (n / name :op1 "N-terminus") :mod (j / just) :part-of p10) :ARG3 (c3 / cell)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "PDK1") :xref (x3 / xref :value "UNIPROT:PDK1_HUMAN" :prob "1.003"))) :op2 (b2 / block-01 :ARG0 e :ARG1 (b3 / bind-01 :ARG1 e2 :ARG2 (p6 / peptide))) :op3 (i3 / interfere-01 :ARG0 e :ARG1 (a5 / activate-01 :ARG0 (p8 / protein :name (n8 / name :op1 "EGF") :xref (x6 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p7 / protein :name (n7 / name :op1 "Ral") :xref (x5 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.603")))))) :ARG2 (c2 / correct-02 :ARG1 (t / thing :ARG1-of (h / hypothesize-01) :mod (t3 / this))))) # ::id bio.chicago_2015.20220 # ::date 2015-10-20T21:46:41 # ::file bio_chicago_2015_20220.txt # ::snt Surprisingly, we observed that KSR specifically blocks EGF and Ras-induced phosphorylation and activation of ternary complex factors (TCF), physiological substrates of MAP kinases, without affecting the activation of MAP kinase itself. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (b / block-01 :ARG0 (e2 / enzyme :name (n / name :op1 "KSR") :xref (x1 / xref :value "UNIPROT:KSR1_HUMAN" :prob "1.003")) :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (a5 / and :op1 (p / phosphorylate-01 :ARG1 "p5") :op2 (a2 / activate-01 :ARG1 (p5 / protein :name (n5 / name :op1 "ternary" :op2 "complex" :op3 "factor"))) :ARG2-of (i / induce-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op4 (s2 / substrate :mod (p3 / physiologic) :poss (p6 / protein-family :name (n6 / name :op1 "MAP" :op2 "kinase")))) :ARG1-of (s / specific-02) :manner (a3 / affect-01 :polarity "-" :ARG1 (a4 / activate-01 :ARG1 (k / kinase)))) :ARG0-of (s3 / surprise-01)) # ::id bio.chicago_2015.20225 # ::date 2015-10-20T21:56:14 # ::file bio_chicago_2015_20225.txt # ::snt The activation of DER by EGF leads to the stimulation of the Ras/mitogen-activated protein (MAP) kinase pathway ( 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (l / lead-03 :ARG0 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (e / enzyme :name (n2 / name :op1 "DER") :xref (x / xref :value "UNIPROT:DERL1_HUMAN" :prob "0.262"))) :ARG2 (s / stimulate-01 :ARG1 (p3 / pathway :name (n5 / name :op1 "Ras/MAPK"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "7")))) # ::id bio.chicago_2015.20250 # ::date 2015-10-20T22:04:21 # ::file bio_chicago_2015_20250.txt # ::snt Ser1 expression is regulated positively by Notch activity; Dl1 and Ser2 are regulated negatively ( 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (a5 / and :op1 (r / regulate-01 :ARG0 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "Notch") :xref (x / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.323"))) :ARG1 (e / express-03 :ARG2 (a2 / amino-acid :mod "1" :name (n2 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :manner (p2 / positive)) :op2 (d2 / downregulate-01 :ARG1 (a3 / and :op1 (a4 / amino-acid :mod "11" :name (n3 / name :op1 "aspartate") :xref (x1 / xref :value "PUBCHEM:5960" :prob "13.722911")) :op2 (a6 / amino-acid :mod "2" :name (n5 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "7")))) # ::id bio.chicago_2015.20268 # ::date 2015-10-21T11:18:09 # ::file bio_chicago_2015_20268.txt # ::snt However, in cell lines expressing the dominant negative mutants S222A and K97A, which showed inhibition of RSK activation by EGF, the decrease in GSK-3beta activity was partially blocked. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c2 / contrast-01 :ARG2 (b / block-01 :ARG1 (d / decrease-01 :ARG1 (a / activity-06 :ARG0 (e4 / enzyme :name (n2 / name :op1 "GSK-3beta") :xref (x2 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")))) :degree (p / part) :location (c / cell-line :ARG3-of (e2 / express-03 :ARG2 (a2 / and :op1 (m2 / mutate-01 :value "S222A") :op2 (m3 / mutate-01 :value "K97A") :ARG0-of (d2 / dominate-01 :mod (n / negative)) :ARG0-of (s / show-01 :ARG1 (i / inhibit-01 :ARG0 (p2 / protein :name (n6 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (a3 / activate-01 :ARG0 (e3 / enzyme :name (n5 / name :op1 "RSK") :xref (x1 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262")))))))))) # ::id bio.chicago_2015.20273 # ::date 2015-10-21T12:46:30 # ::file bio_chicago_2015_20273.txt # ::snt The antibody binds equally well to both the wt EGFR and deltaEGFR and does not affect the binding of EGF to the wt EGFR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (a / and :op1 (b / bind-01 :ARG1 (a2 / antibody) :ARG2 (a3 / and :op1 (e / enzyme :name (n / name :op1 "EGFR") :mod (w2 / wild-type) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e5 / enzyme :name (n4 / name :op1 "delta-EGFR") :xref (x2 / xref :value "UNIPROT:SCNND_HUMAN" :prob "0.262"))) :ARG1-of (w / well-09 :ARG1-of (e2 / equal-01))) :op2 (a4 / affect-01 :polarity "-" :ARG0 a2 :ARG1 (b3 / bind-01 :ARG1 (p / protein :name (n3 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG2 e))) # ::id bio.chicago_2015.20290 # ::date 2015-10-21T12:52:32 # ::file bio_chicago_2015_20290.txt # ::snt Instead, PtdIns(4,5)- P2 binding was found to inhibit alpha-actinin binding to actin filaments and did not appear to be required for localization to focal adhesions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / and :op1 (f / find-01 :ARG1 (b / bind-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "PtdIns(4,5)-" :op2 "P2")) :ARG0-of (i / inhibit-01 :ARG1 (b2 / bind-01 :ARG1 (p / protein :name (n / name :op1 "alpha-actinin") :xref (x1 / xref :value "UNIPROT:ACTN2_HUMAN" :prob "0.383")) :ARG2 (f2 / filament :mod (p2 / protein :name (n3 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))))))) :op2 (a2 / appear-02 :polarity "-" :ARG1 (r / require-01 :ARG0 (l / localize-01 :location (a3 / adhere-01 :mod (f3 / focal))) :ARG1 b)) :ARG1-of (i2 / instead-of-91)) # ::id bio.chicago_2015.20303 # ::date 2015-10-21T13:02:48 # ::file bio_chicago_2015_20303.txt # ::snt Our study establishes Rac/ Cdc42/Pak as an upstream module for Raf-1 activation in association with the integrity of microtubules, but not for EGF activation of Raf. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / establish-01 :ARG0 (s / study-01 :ARG0 (w / we)) :ARG1 (p3 / pathway :name (n3 / name :op1 "Rac/Cdc42/Pak")) :ARG2 (m / module :direction (u / upstream) :beneficiary (a / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1-of (a3 / associate-01 :ARG2 (i / integrity :poss (m2 / microtubule)) :ARG1-of (c / contrast-01 :ARG2 (a4 / activate-01 :polarity "-" :ARG0 (p / protein :name (n / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (e2 / enzyme :name (n4 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))))))) # ::id bio.chicago_2015.20312 # ::date 2015-10-21T13:11:19 # ::file bio_chicago_2015_20312.txt # ::snt Enhancement of EGF-induced EGF receptor autophosphorylation and MAPK phosphorylation by GD1a. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (e / enhance-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "EGF" :op2 "receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.213")) :ARG2 e3 :ARG2-of (i / induce-01 :ARG0 e3))) :op2 (p4 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2 (s / small-molecule :name (n3 / name :op1 "GD1a") :xref (x2 / xref :value "PUBCHEM:25229561" :prob "10.138507")))) # ::id bio.chicago_2015.20319 # ::date 2015-10-21T13:16:56 # ::file bio_chicago_2015_20319.txt # ::snt EGF receptor levels were significantly decreased following EGF stimulation of cells co-expressing ACK2 and SH3PX1, thus highlighting a novel role for ACK2, working together with SH3PX1 to promote the degradation of the EGF receptor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c2 / cause-01 :ARG0 (d / decrease-01 :ARG1 (l / level :quant-of (e2 / enzyme :name (n3 / name :op1 "EGF" :op2 "receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.213"))) :ARG1-of (s / significant-02) :ARG1-of (f / follow-01 :ARG2 (s2 / stimulate-01 :ARG0 e2 :ARG1 (c / cell :ARG3-of (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "ACK2") :xref (x2 / xref :value "UNIPROT:ACKR2_HUMAN" :prob "0.312")) :op2 (p3 / protein :name (n5 / name :op1 "SH3PX1") :xref (x1 / xref :value "UNIPROT:SNX9_HUMAN" :prob "1.002"))) :mod (t2 / together)))))) :ARG1 (a4 / and :op1 (h / highlight-01 :ARG0 l :ARG1 (r2 / role :mod (n4 / novel) :beneficiary p)) :op2 (w / work-01 :ARG0 l :ARG1 (p2 / promote-01 :ARG0 (a2 / and :op1 l :op2 p3) :ARG1 (d2 / degrade-01 :ARG1 e2)) :ARG3 p3))) # ::id bio.chicago_2015.20334 # ::date 2015-10-21T13:29:58 # ::file bio_chicago_2015_20334.txt # ::snt At the Z line, titin may determine the minimum extent and tropomyosin the maximum extent of thin filament overlap by regulating alpha-actinin binding to actin, while a unique Z filament may bind to capZ and regulate barbed end capping. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / possible-01 :ARG1 (a / and :op1 (d2 / determine-01 :ARG0 (p3 / protein :name (n2 / name :op1 "titin") :xref (x1 / xref :value "UNIPROT:TITIN_HUMAN" :prob "0.704")) :ARG1 (e / extent :degree (m / minimum) :poss (f / filament :mod (t / thin) :ARG1-of (o / overlap-01 :ARG0 (b / bind-01 :ARG1 (p4 / protein :name (n3 / name :op1 "alpha-actinin") :ARG0-of (r / regulate-01) :xref (x3 / xref :value "UNIPROT:ACTN2_HUMAN" :prob "0.383")) :ARG2 (p5 / protein :name (n4 / name :op1 "actin") :xref (x4 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))))))) :op2 (d3 / determine-01 :ARG0 (p2 / protein :name (n / name :op1 "tropomyosin") :xref (x / xref :value "UNIPROT:TPM1_HUMAN" :prob "0.382")) :ARG1 (e2 / extent :degree (m2 / maximum) :poss f))) :time (p6 / possible-01 :ARG1 (a2 / and :op1 (b2 / bind-01 :ARG1 (f2 / filament :name (n7 / name :op1 "Z") :mod (u / unique)) :ARG2 (p7 / protein :name (n5 / name :op1 "capZ") :xref (x2 / xref :value "UNIPROT:CAPZB_HUMAN" :prob "0.232"))) :op2 (r2 / regulate-01 :ARG0 f2 :ARG1 (e3 / end :ARG1-of (b3 / barb-01) :ARG0-of (c / cap-02))))) :location (l / line :mod "Z")) # ::id bio.chicago_2015.20374 # ::date 2015-10-21T13:48:45 # ::file bio_chicago_2015_20374.txt # ::snt Binding of Tubulin to Synaptotagmin I-- To identify soluble proteins that specifically interact with synaptotagmin I, the soluble fraction from the rat brain was incubated with GST fusion protein of the cytoplasmic portion of synaptotagmin I immobilized on glutathione-Sepharose. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "tubulin") :xref (x4 / xref :value "UNIPROT:TBB4A_HUMAN" :prob "0.282")) :ARG2 (p5 / protein :name (n2 / name :op1 "Synaptotagmin" :op2 "I-") :xref (x3 / xref :value "UNIPROT:SYT1_HUMAN" :prob "0.692"))) :snt2 (i / incubate-01 :ARG1 (f / fraction :mod (s / soluble) :part-of (b2 / brain :part-of (r / rat))) :ARG2 (e / enzyme :name (n3 / name :op1 "GST") :ARG1-of (f2 / fuse-01) :source (p3 / portion-01 :ARG1 (p6 / protein :name (n4 / name :op1 "synaptotagmin" :op2 "I") :ARG1-of (i2 / immobilize-01 :location (s4 / small-molecule :name (n5 / name :op1 "glutathione-Sepharose"))) :xref (x / xref :value "UNIPROT:SYT1_HUMAN" :prob "0.702")) :mod (c / cytoplasm :xref (x5 / xref :value "GO:0005737" :prob "0.8"))) :xref (x1 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :purpose (i3 / identify-01 :ARG1 (p4 / protein :mod (s2 / soluble) :ARG0-of (i4 / interact-01 :ARG1 (p7 / protein :name (n6 / name :op1 "Synaptotagmin" :op2 "I") :xref (x2 / xref :value "UNIPROT:SYT1_HUMAN" :prob "1.002")) :ARG1-of (s3 / specific-02)))))) # ::id bio.chicago_2015.20674 # ::date 2015-10-21T13:48:56 # ::file bio_chicago_2015_20674.txt # ::snt As previously reported, CSP also binds to Hsc70 (right diagram, col. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "CSP") :xref (x1 / xref :value "UNIPROT:DNJC5_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n2 / name :op1 "Hsc70") :xref (x / xref :value "UNIPROT:HSP7C_HUMAN" :prob "0.633")) :ARG1-of (r / report-01 :time (p3 / previous)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (d2 / diagram :ARG1-of (r2 / right-04)) :op2 (c / col))) :mod (a2 / also)) # ::id bio.chicago_2015.20679 # ::date 2015-10-21T14:00:25 # ::file bio_chicago_2015_20679.txt # ::snt Furthermore, we provide the first evidence of interaction of NK-4 with the p300 coactivator and the Groucho corepressor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (p / provide-01 :ARG0 (w / we) :ARG1 (e / evidence-01 :ARG1 (i / interact-01 :ARG0 (p3 / protein :name (n4 / name :op1 "NK-4") :xref (x1 / xref :value "UNIPROT:IL32_HUMAN" :prob "0.652")) :ARG1 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "p300") :ARG0-of (a2 / activate-01 :mod "t") :xref (x / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")) :op2 (p4 / protein :name (n / name :op1 "Groucho") :xref (x2 / xref :value "UNIPROT:TLE4_HUMAN" :prob "0.212")) :ARG0-of (r / repress-01 :mod (t / together)))) :mod (o / ordinal-entity :value "1")))) # ::id bio.chicago_2015.20700 # ::date 2015-10-21T14:07:32 # ::file bio_chicago_2015_20700.txt # ::snt Note that despite the extensive cell-cell rearrangements occurring after Raf activation, E-cadherin still colocalizes with cortical actin at areas of cell-cell contact (in yellow-orange). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (n2 / note-01 :ARG0 (y / you) :ARG1 (h / have-concession-91 :ARG1 (c / colocalize-01 :ARG1 (a5 / and :op1 (p2 / protein :name (n3 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p / protein :name (n / name :op1 "actin") :mod (c4 / cortical) :xref (x2 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :ARG2 (a2 / area :mod (c5 / contact-01 :ARG0 "c3" :ARG1 "c3")) :mod (s / still)) :ARG2 (r / rearrange-01 :ARG0 "c3" :ARG1 (c3 / cell) :ARG1-of (e / extensive-03) :time (a4 / after :op1 (a / activate-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (y2 / yellow) :op2 (o / orange)))) # ::id bio.chicago_2015.20701 # ::date 2015-10-21T20:31:36 # ::file bio_chicago_2015_20701.txt # ::snt In fact, an earlier report ( 31) suggests that Src, which can up-regulate NMDA receptor activity, binds to the NMDA receptor complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (s / suggest-01 :ARG0 (r / report-01 :mod (e2 / early :degree (m2 / more)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "31")))) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "Src") :ARG0-of (u2 / upregulate-01 :ARG1 (a / activity-06 :ARG0 "r3") :ARG1-of (p3 / possible-01)) :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :ARG2 (c2 / complex :mod (r3 / receptor :name (n2 / name :op1 "NMDA")))) :mod (i / in-fact)) # ::id bio.chicago_2015.20736 # ::date 2015-10-21T20:53:26 # ::file bio_chicago_2015_20736.txt # ::snt In SW 48 the beta-catenin protein coprecipitated with E-cadherin and APC but not with alpha-catenin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c3 / contrast-01 :ARG1 (c / coprecipitate-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "beta-catenin") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :op2 (a / and :op1 (p2 / protein :name (n3 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n5 / name :op1 "APC") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")))) :location (c2 / cell-line :name (n / name :op1 "SW48"))) :ARG2 (c4 / coprecipitate-01 :polarity "-" :ARG1 (a3 / and :op1 p :op2 (p3 / protein :name (n4 / name :op1 "alpha-catenin") :xref (x2 / xref :value "UNIPROT:CTNA3_HUMAN" :prob "0.392"))) :location c2)) # ::id bio.chicago_2015.20797 # ::date 2015-10-21T21:01:42 # ::file bio_chicago_2015_20797.txt # ::snt To study the significance of TFIID interactions with the Inr and downstream regions in greater detail, we performed DNase I footprinting, EMSA, and in vitro transcription experiments with the natural AdML promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / perform-01 :ARG0 (w / we) :ARG1 (a / and :op1 (f / footprint :mod (e3 / enzyme :name (n6 / name :op1 "DNase" :op2 "I") :xref (x / xref :value "UNIPROT:DNAS1_HUMAN" :prob "1.002"))) :op2 (t / thing :name (n / name :op1 "EMSA")) :op3 (e / experiment-01 :ARG1 (t3 / transcribe-01) :ARG2 (m3 / molecular-physical-entity :ARG1-of (n3 / natural-03) :ARG0-of (p2 / promote-01) :mod (l / late :mod (m4 / major)) :mod (a3 / adenovirus)) :manner (i / in-vitro))) :purpose (s / study-01 :ARG0 (w2 / we) :ARG1 (s2 / signify-01 :ARG0 (i2 / interact-01 :ARG0 (p3 / protein :name (n4 / name :op1 "TFIID") :xref (x1 / xref :value "UNIPROT:TBP_HUMAN" :prob "1.002")) :ARG1 (a2 / and :op1 (m / molecular-physical-entity :ARG0-of (i3 / initiate-01)) :op2 (r / region :direction (d / downstream)))) :manner (d2 / detail-01 :mod (g / great :degree (m2 / most)))))) # ::id bio.chicago_2015.20835 # ::date 2015-10-21T21:09:04 # ::file bio_chicago_2015_20835.txt # ::snt In addition, overexpression of a FAK mutant that is incapable of binding to Src fails to induce paxillin phosphorylation, and expression of the COOH-terminal domain of FAK inhibits both FAK activation and paxillin tyrosine phosphorylation (Schaller and Parsons, 1995 ; Richardson and Parsons, 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (a2 / and :op1 (f / fail-01 :ARG1 (o / overexpress-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "FAK") :ARG2-of (m2 / mutate-01) :ARG1-of (c / capable-01 :polarity "-" :ARG2 (b / bind-01 :ARG1 e2 :ARG2 (p2 / protein :name (n2 / name :op1 "Src") :xref (x2 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")))) :xref (x1 / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003"))) :ARG2 (i / induce-01 :ARG0 e2 :ARG2 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "paxillin") :xref (x3 / xref :value "UNIPROT:PAXI_HUMAN" :prob "0.703"))))) :op2 (i2 / inhibit-01 :ARG0 (e / express-03 :ARG3 (p5 / protein-segment :name (n / name :op1 "COOH-terminus") :part-of (p12 / protein :name (n6 / name :op1 "FAK") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")))) :ARG1 (a3 / and :op1 (a4 / activate-01 :ARG1 p12) :op2 (p / phosphorylate-01 :ARG1 (a8 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of p4 :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")))))) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and :op1 (p6 / publication-91 :ARG0 (a6 / and :op1 (p8 / person :name (n7 / name :op1 "Schaller")) :op2 (p9 / person :name (n8 / name :op1 "Parsons"))) :time (d / date-entity :year "1995")) :op2 (p7 / publication-91 :ARG0 (a7 / and :op1 (p10 / person :name (n9 / name :op1 "Richardson")) :op2 p9) :time (d2 / date-entity :year "1996"))))) # ::id bio.chicago_2015.20957 # ::date 2015-10-21T21:21:30 # ::file bio_chicago_2015_20957.txt # ::snt SRC can be activated by EGFR engagement in various cell types ( 51-53) and potentiates the ability of the EGFR to transform murine fibroblasts ( 54). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (a / and :op1 (p / possible-01 :ARG1 (a2 / activate-01 :ARG0 (e2 / engage-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG2 (t / type :mod (v / various) :mod (c / cell))) :ARG1 (p2 / protein :name (n2 / name :op1 "SRC") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "1.004"))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 (v2 / value-interval :op1 "51" :op2 "53"))))) :op2 (p4 / potentiate-01 :ARG0 p2 :ARG1 (c2 / capable-01 :ARG1 e3 :ARG2 (t2 / transform-01 :ARG0 e3 :ARG1 (f / fibroblast :mod (m / murine))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "54")))) # ::id bio.chicago_2015.20967 # ::date 2015-10-21T21:27:26 # ::file bio_chicago_2015_20967.txt # ::snt Anterior cells that receive high doses of Hh (the AP wing organiser) activate Col, which, in turn, upregulates expression of BS, vn, emc and mtv, and represses expression of EGFR (aMohler et al., 2000 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / activate-01 :ARG0 (c / cell :mod (a2 / anterior) :ARG0-of (r / receive-01 :ARG1 (d2 / dose-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Hh") :ARG0-of (o2 / organize-01 :ARG1 (w / wing :mod (a5 / anterior) :mod (p9 / posterior)))) :ARG1-of (h / high-02)))) :ARG1 (e2 / enzyme :name (n / name :op1 "Col") :ARG0-of (u / upregulate-01 :ARG1 (e3 / express-03 :ARG2 (a3 / and :op1 (p4 / protein :name (n4 / name :op1 "BS")) :op2 (p5 / protein :name (n5 / name :op1 "vn") :xref (x3 / xref :value "UNIPROT:VTNC_HUMAN" :prob "0.603")) :op3 (p6 / protein :name (n6 / name :op1 "emc") :xref (x2 / xref :value "UNIPROT:EMC1_HUMAN" :prob "0.202")) :op4 (p7 / protein :name (n7 / name :op1 "mtv")))) :mod (i / in-turn)) :ARG0-of (r3 / repress-01 :ARG1 (e4 / express-03 :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :xref (x1 / xref :value "UNIPROT:COL_HUMAN" :prob "0.603")) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and :op1 (p / person :name (n8 / name :op1 "Mohler")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "2000")))) # ::id bio.chicago_2015.21011 # ::date 2015-10-21T21:40:26 # ::file bio_chicago_2015_21011.txt # ::snt If this was the case, we would predict that increased levels of Dl expression would enhance the spl mutant phenotype. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (h / have-condition-91 :ARG1 (p / predict-01 :ARG0 (w / we) :ARG1 (e2 / enhance-01 :ARG0 (l / level :ARG1-of (i / increase-01) :degree-of (e / express-03 :ARG1 (g / gene :name (n / name :op1 "D1")))) :ARG1 (p2 / phenotype :mod (g2 / gene :name (n2 / name :op1 "sp1") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "0.671"))))) :ARG2 (c / case-04 :ARG1 (t / this))) # ::id bio.chicago_2015.21196 # ::date 2015-10-21T21:45:37 # ::file bio_chicago_2015_21196.txt # ::snt Myosin phosphatase interacts with both ERM family proteins and adducin through MBS, and dephosphorylates the phosphorylated ERM family proteins and adducin ( Fukata et al. 1998 ; Kimura et al. 1998 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op1 (i / interact-01 :ARG0 (e2 / enzyme :name (n7 / name :op1 "Myosin" :op2 "phosphatase") :xref (x / xref :value "UNIPROT:MYPT1_HUMAN" :prob "0.312")) :ARG1 (a2 / and :op1 (p3 / protein-family :name (n2 / name :op1 "ERM")) :op2 (p4 / protein-family :name (n3 / name :op1 "adducin"))) :manner (p / protein-segment :name (n4 / name :op1 "MBS"))) :op2 (d2 / dephosphorylate-01 :ARG1 (a3 / and :op1 p3 :op2 p4 :ARG3-of (p2 / phosphorylate-01)) :ARG2 e2) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p7 / publication-91 :ARG0 (a5 / and :op1 (p5 / person :name (n5 / name :op1 "Fukata")) :op2 (p9 / person :mod (o / other))) :time (d / date-entity :year "1998")) :op2 (p8 / publication-91 :ARG0 (a7 / and :op1 (p6 / person :name (n6 / name :op1 "Kimura")) :op2 p9) :time d)))) # ::id bio.chicago_2015.22716 # ::date 2015-10-21T21:56:34 # ::file bio_chicago_2015_22716.txt # ::snt In Drosophila, it was reported that ceramide functions downstream of caspases during Rpr-induced apoptosis on the basis of the effects of the tripeptide caspase inhibitor N-benzyloxycarbonyl-VAD-fluoromethylketone (zVAD. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (r / report-01 :ARG1 (f / function-01 :ARG0 (s / small-molecule :name (n / name :op1 "ceramide") :xref (x2 / xref :value "PUBCHEM:2498" :prob "8.570734")) :location (r2 / relative-position :op1 (p / protein :name (n6 / name :op1 "caspase") :xref (x1 / xref :value "UNIPROT:A0A024R3C0_HUMAN" :prob "0.701")) :direction (d / downstream)) :time (a / apostosis :ARG2-of (i3 / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Rpr") :xref (x / xref :value "UNIPROT:RPRM_HUMAN" :prob "0.202")))) :ARG1-of (b / base-02 :ARG2 (a2 / affect-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "N-benzyloxycarbonyl-VAD-fluoromethylketone") :mod (t / tripeptide) :ARG0-of (i / inhibit-01 :ARG1 p))))) :location (o / organism :name (n5 / name :op1 "Drosophila"))) # ::id bio.chicago_2015.22780 # ::date 2015-10-21T02:55:53 # ::file bio_chicago_2015_22780.txt # ::snt After 5 min of incubation, the reaction was stopped by the addition of 5 mul of 5xLaemmli's SDS-sample buffer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / stop-01 :ARG0 (a / add-02 :ARG1 (p / product :name (n / name :op1 "5x" :op2 "Laemmli" :op3 "SDS" :op4 "sample" :op5 "buffer") :quant (v / volume-quantity :quant "5" :unit (m2 / milliliter)))) :ARG1 (r / react-01) :time (a2 / after :op1 (i / incubate-01 :duration (t / temporal-quantity :quant "5" :unit (m4 / minute))))) # ::id bio.chicago_2015.22788 # ::date 2015-10-21T03:08:24 # ::file bio_chicago_2015_22788.txt # ::snt We show that E2F1 has a clear role in the induction of p53-dependent apoptosis and, surprisingly, is also required for the tumor cell division cycle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (a / and :op1 (h / have-03 :ARG0 (p / protein :name (n / name :op1 "E2F1") :xref (x1 / xref :value "UNIPROT:E2F1_HUMAN" :prob "1.003")) :ARG1 (r / role :ARG1-of (c / clear-06) :prep-in (i / induce-01 :ARG1 (a2 / apoptosis :ARG0-of (d / depend-01 :ARG1 (p2 / protein :name (n2 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))))))) :op1 (r2 / require-01 :ARG0 (c2 / cycle-02 :ARG1 (d2 / divide-02 :ARG1 (c3 / cell :mod (t / tumor)))) :ARG1 p :ARG0-of (s2 / surprise-01) :mod (a3 / also)))) # ::id bio.chicago_2015.22808 # ::date 2015-10-21T03:18:23 # ::file bio_chicago_2015_22808.txt # ::snt SV-SOD1 wt, but not SV-SOD1 M or SV-SOD1 R, potentiates SV-induced apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / contrast-01 :ARG1 (p / potentiate-01 :ARG0 (v / virus :name (n / name :op1 "sindbis") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "superoxide" :op2 "dismutase") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:A0A0C4DFU1_HUMAN" :prob "0.701")))) :ARG1 (a / apoptosis :ARG1-of (i / induce-01 :ARG0 v))) :ARG2 (p2 / potentiate-01 :polarity "-" :ARG0 (o / or :op1 (v3 / virus :name (n3 / name :op1 "sindbis") :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n4 / name :op1 "superoxide" :op2 "dismutase") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:A0A0C4DFU1_HUMAN" :prob "0.701")))) :op2 (v2 / virus :name (n5 / name :op1 "sindbis") :ARG3-of (e5 / express-03 :ARG2 (e6 / enzyme :name (n6 / name :op1 "superoxide" :op2 "dismutase") :ARG1-of (r / reverse-01) :xref (x1 / xref :value "UNIPROT:A0A0C4DFU1_HUMAN" :prob "0.701"))))) :ARG1 a)) # ::id bio.chicago_2015.22836 # ::date 2015-10-21T03:43:58 # ::file bio_chicago_2015_22836.txt # ::snt Together, these studies provide substantial evidence that E2F1 has a key role in p53-dependent apoptosis associated with aberrant cell cycle activity in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (p / provide-01 :ARG0 (s / study-01 :mod (t2 / this)) :ARG1 (e / evidence-01 :ARG1 (h / have-03 :ARG0 (p2 / protein :name (n / name :op1 "E2F1") :xref (x / xref :value "UNIPROT:E2F1_HUMAN" :prob "1.003")) :ARG1 (r / role :ARG1-of (k / key-02 :ARG2 (a / apoptosis :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n2 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG1-of (a2 / associate-01 :ARG2 (a3 / activity-06 :ARG0 (c / cell) :ARG1 (c2 / cycle-02 :ARG1 c) :mod (a4 / aberrant)) :manner (i / in-vivo)))))) :mod (s2 / substantial)) :manner (t / together)) # ::id bio.chicago_2015.22874 # ::date 2015-10-21T03:53:36 # ::file bio_chicago_2015_22874.txt # ::snt PAK is involved in Agrin-induced AChR clustering. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (i / involve-01 :ARG1 (e / enzyme :name (n / name :op1 "PAK") :xref (x1 / xref :value "UNIPROT:PAK1_HUMAN" :prob "0.263")) :ARG2 (c / cluster-01 :ARG1 (p2 / protein :name (n2 / name :op1 "AChR") :xref (x / xref :value "UNIPROT:ACHA_HUMAN" :prob "0.232")) :ARG2-of (i2 / induce-01 :ARG0 (p / protein :name (n3 / name :op1 "Agrin") :xref (x2 / xref :value "UNIPROT:AGRIN_HUMAN" :prob "1.003"))))) # ::id bio.chicago_2015.22906 # ::date 2015-10-21T04:33:11 # ::file bio_chicago_2015_22906.txt # ::snt However, Sina has also been implicated in ubiquitin-dependent proteolysis ( 21, 29, 46). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 21, 2015 (c / contrast-01 :ARG2 (i / implicate-01 :ARG1 (p / protein :name (n / name :op1 "Sina") :xref (x1 / xref :value "UNIPROT:SIN3A_HUMAN" :prob "0.232")) :ARG2 (p2 / proteolysis :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n2 / name :op1 "ubiquitin") :xref (x / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")))) :mod (a / also)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "21" :op2 "29" :op3 "46"))))) # ::id bio.chicago_2015.22931 # ::date 2015-10-21T06:59:12 # ::file bio_chicago_2015_22931.txt # ::snt Induction of apoptosis by p53 is critical for the tumor suppressor function of p53. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (c / critical-02 :ARG1 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG2 (a / apoptosis)) :ARG2 (f / function-01 :ARG0 p :ARG1 (s / suppress-01 :ARG0 p :ARG1 (t / tumor)))) # ::id bio.chicago_2015.23115 # ::date 2015-10-21T07:01:58 # ::file bio_chicago_2015_23115.txt # ::snt We conclude that TFIIE contamination is not responsible for the enhanced CTD phosphorylation by TFIIH relative to free CAK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / conclude-01 :ARG0 (w / we) :ARG1 (r / responsible-01 :polarity "-" :ARG0 (c2 / contaminate-01 :ARG2 (p2 / protein :name (n / name :op1 "TFIIE") :xref (x / xref :value "UNIPROT:TF2B_HUMAN" :prob "0.282"))) :ARG1 (p / phosphorylate-01 :ARG1 (p4 / protein-segment :name (n3 / name :op1 "C-terminus")) :ARG2 (p5 / protein :name (n4 / name :op1 "TFIIH") :xref (x1 / xref :value "UNIPROT:TCEA3_HUMAN" :prob "0.332")) :ARG1-of (e / enhance-01) :ARG1-of (r2 / relative-05 :ARG2 (e2 / enzyme :name (n2 / name :op1 "CAK") :ARG1-of (f / free-04) :xref (x2 / xref :value "UNIPROT:CDK7_HUMAN" :prob "1.002")))))) # ::id bio.chicago_2015.23123 # ::date 2015-10-21T07:13:50 # ::file bio_chicago_2015_23123.txt # ::snt U1 snRNP bound to the 5' splice site, U2AF65 bound to the Py tract, and bridging activities, for which members of the SR family of factors are strong candidates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (b / bind-01 :ARG1 (p3 / protein :name (n / name :op1 "U1" :op2 "snRNP") :xref (x / xref :value "UNIPROT:SNRPA_HUMAN" :prob "0.372")) :ARG2 (d2 / dna-sequence :name (n5 / name :op1 "5'" :op2 "site") :ARG1-of (s2 / splice-01))) :op2 (b2 / bind-01 :ARG1 (p / protein :name (n2 / name :op1 "U2AF65") :xref (x1 / xref :value "UNIPROT:U2AF2_HUMAN" :prob "1.002")) :ARG2 (d / dna-sequence :name (n3 / name :op1 "Py" :op2 "tract"))) :op3 (c / candidate :purpose (a2 / activity-06 :ARG1 (b3 / bridge-01)) :domain (m / member :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n4 / name :op1 "SR") :mod (f2 / factor)))) :ARG1-of (s3 / strong-02))) # ::id bio.chicago_2015.23189 # ::date 2015-10-21T07:14:40 # ::file bio_chicago_2015_23189.txt # ::snt The observation that BDNF does not elicit calcium transients, but induces CREB phosphorylation also in acute slices of visual cortex strengthens the transferability in vivo of these results. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (s / strengthen-01 :ARG0 (o / observe-01 :ARG1 (c / contrast-01 :ARG1 (e / elicit-01 :polarity "-" :ARG0 (p2 / protein :name (n / name :op1 "BDNF") :xref (x / xref :value "UNIPROT:BDNF_HUMAN" :prob "1.004")) :ARG1 (e2 / event :name (n2 / name :op1 "calcium" :op2 "transient"))) :ARG2 (i / induce-01 :ARG0 p2 :ARG2 (p / phosphorylate-01 :ARG2 (p3 / protein :name (n3 / name :op1 "CREB") :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :location (s2 / slice :mod (a / acute) :part-of (c2 / cortex :mod (v / visual)) :mod (a2 / also)))))) :ARG1 (p4 / possible-01 :ARG1 (t / transfer-01 :ARG1 (t3 / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (i2 / in-vivo)))) # ::id bio.chicago_2015.23275 # ::date 2015-10-21T07:22:58 # ::file bio_chicago_2015_23275.txt # ::snt It has been proposed that enhancers function by promoting binding of U2AF65 to weak Py tracts (Wang et al. 1995 ; Zuo and Maniatis 1996 ; Bouck et al. 1998 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / propose-01 :ARG1 (f / function-01 :ARG0 (m / molecular-physical-entity :ARG0-of (e / enhance-01)) :manner (p2 / promote-01 :ARG0 m :ARG1 (b / bind-01 :ARG1 (p3 / protein :name (n / name :op1 "U2AF65") :xref (x / xref :value "UNIPROT:U2AF2_HUMAN" :prob "1.002")) :ARG2 (d4 / dna-sequence :name (n2 / name :op1 "Py" :op2 "tract") :ARG1-of (w / weak-02))))) :ARG1-of (d5 / describe-01 :ARG0 (a / and :op1 (p4 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n3 / name :op1 "Wang")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "1995")) :op2 (p7 / publication-91 :ARG0 (a3 / and :op1 (p8 / person :name (n4 / name :op1 "Zuo")) :op2 (p9 / person :name (n5 / name :op1 "Maniatis"))) :time (d2 / date-entity :year "1996")) :op3 (p10 / publication-91 :ARG0 (a4 / and :op1 (p11 / person :name (n6 / name :op1 "Bouck")) :op2 p6) :time (d3 / date-entity :year "1998"))))) # ::id bio.chicago_2015.23324 # ::date 2015-10-21T07:31:09 # ::file bio_chicago_2015_23324.txt # ::snt Because the GTP-bound form of Ras is a key transducer in the mitogen signaling pathway ( 18), we decided to examine Ras GTP loading in anchored or suspended 3T3 cells treated with either PDGF or EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (d / decide-01 :ARG0 (w / we) :ARG1 (e / examine-01 :ARG0 w :ARG1 (l / load-01 :ARG1 (o / or :op1 (c / cell-line :name (n3 / name :op1 "3T3") :ARG1-of (a / anchor-01)) :op2 (c2 / cell-line :name (n4 / name :op1 "3T3") :ARG1-of (s2 / suspend-01)) :ARG1-of (t / treat-04 :ARG2 (o2 / or :op1 (p2 / protein :name (n5 / name :op1 "PDGF") :xref (x / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :op2 (p3 / protein :name (n6 / name :op1 "EGF") :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG3 (e2 / enzyme :name (n / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1-of (c3 / cause-01 :ARG0 (m / molecular-physical-entity :ARG2-of (t2 / transduce-01) :ARG1-of (k / key-02) :prep-in (p5 / pathway :name (n8 / name :op1 "mitogen" :op2 "signaling" :op3 "pathway")) :domain (e3 / enzyme :name (n7 / name :op1 "Ras") :ARG1-of (b / bind-01 :ARG2 s) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 "18"))))) # ::id bio.chicago_2015.23329 # ::date 2015-10-22T10:11:53 # ::file bio_chicago_2015_23329.txt # ::snt We also found that the CaMK antagonist KN93, but not the inactive congener KN92, blocked BDNF-induced CREB phosphorylation, further suggesting that KN62 is acting specifically (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (b / block-01 :ARG0 (s / small-molecule :name (n / name :op1 "KN93") :ARG0-of (a2 / antagonize-01 :ARG1 (e / enzyme :name (n2 / name :op1 "CaMK") :xref (x2 / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.653"))) :xref (x5 / xref :value "PUBCHEM:5312122" :prob "18.572987")) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "CREB") :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :ARG2-of (i / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "BDNF") :xref (x1 / xref :value "UNIPROT:BDNF_HUMAN" :prob "1.004"))))) :ARG2 (b2 / block-01 :polarity "-" :ARG0 (s2 / small-molecule :name (n5 / name :op1 "KN92") :mod (c2 / congener :ARG0-of (a3 / act-02 :polarity "-")) :xref (x3 / xref :value "PUBCHEM:5353702" :prob "18.349844")) :ARG1 p) :ARG0-of (s3 / suggest-01 :ARG1 (a4 / act-02 :ARG0 (s4 / small-molecule :name (n6 / name :op1 "KN62") :xref (x4 / xref :value "PUBCHEM:5312126" :prob "18.86067")) :ARG1-of (s5 / specific-02)) :degree (f2 / further))) :mod (a / also) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s6 / show-01 :polarity "-")))) # ::id bio.chicago_2015.23353 # ::date 2015-10-22T10:40:16 # ::file bio_chicago_2015_23353.txt # ::snt However, the mechanism by which c- myc induces apoptosis is unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (c / contrast-01 :ARG2 (k / know-01 :polarity "-" :ARG1 (m / mechanism :manner-of (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "c-myc") :xref (x / xref :value "UNIPROT:Q16158_HUMAN" :prob "1.001")) :ARG2 (a / apoptosis))))) # ::id bio.chicago_2015.23361 # ::date 2015-10-22T10:41:55 # ::file bio_chicago_2015_23361.txt # ::snt These data show that activation of PKA by addition of cAMP or by depletion of the Bcy1p subunit stimulates phosphorylation of pyruvate kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 22, 2015 (s / show-01 :ARG0 (d / data :mod (t / this)) :ARG1 (s2 / stimulate-01 :ARG0 (a / activate-01 :ARG0 (o / or :op1 (a2 / add-02 :ARG1 (s3 / small-molecule :name (n / name :op1 "cAMP") :xref (x2 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :op2 (d2 / deplete-01 :ARG1 (s4 / subunit :mod (g / gene :name (n2 / name :op1 "Bcy1p"))))) :ARG1 (e / enzyme :name (n3 / name :op1 "PKA") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "pyruvate" :op2 "kinase") :xref (x1 / xref :value "UNIPROT:A0A024R5Z9_HUMAN" :prob "0.701"))))) # ::id bio.chicago_2015.23365 # ::date 2015-10-22T10:48:47 # ::file bio_chicago_2015_23365.txt # ::snt Ub exists in a dynamic equilibrium between free and conjugated forms that is determined by the relative rates of conjugation, deubiquitinylation by Ub-specific isopeptidases and Ub-dependent proteolysis, which releases free Ub. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (e / exist-01 :ARG1 (p / protein :name (n / name :op1 "ubiquitin") :xref (x2 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :ARG2 (e2 / equilibrate-01 :ARG1 (a / and :op1 (f / form :ARG1-of (f2 / free-04)) :op2 (f3 / form :ARG1-of (c / conjugate-02))) :mod (d / dynamic) :ARG1-of (d2 / determine-01 :ARG0 (a2 / and :op1 (r / rate :ARG1-of (r2 / relative-05) :mod c) :op2 (d3 / deubiquitinylate-00 :ARG0 (e3 / enzyme :name (n2 / name :op1 "isopeptidase") :ARG1-of (s / specific-02 :ARG2 p) :xref (x / xref :value "UNIPROT:UBP5_HUMAN" :prob "0.382"))) :op3 (p2 / proteolysis :ARG0-of (d4 / depend-01 :ARG1 p) :ARG0-of (r3 / release-01 :ARG1 (p3 / protein :name (n3 / name :op1 "ubiquitin") :ARG1-of f2 :xref (x1 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")))))))) # ::id bio.chicago_2015.23430 # ::date 2015-10-22T10:56:01 # ::file bio_chicago_2015_23430.txt # ::snt In order to determine which sugars on Notch are required for Notch signaling and/or for fringe to function, Jagged1-induced Notch signaling was measured in a series of CHO glycosylation mutants [ 2 and 50]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / measure-01 :ARG1 (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Notch")) :ARG1-of (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Jagged1") :xref (x / xref :value "UNIPROT:JAG1_HUMAN" :prob "1.003")))) :location (c / cell-line :name (n3 / name :op1 "CHO") :quant (s4 / series) :ARG2-of (m2 / mutate-01 :ARG0 (g / glycosylate-01))) :purpose (d / determine-01 :ARG1 (a / amr-unknown :mod (s2 / sugar) :ARG1-of (r / require-01 :ARG0 (a4 / and-or :op1 (s3 / signal-07 :ARG0 p) :op2 (f / function-01 :ARG0 (f2 / fringe)))) :part-of p)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "2" :op2 "50"))))) # ::id bio.chicago_2015.23434 # ::date 2015-10-22T11:05:05 # ::file bio_chicago_2015_23434.txt # ::snt Unlike Mad2 or Mad2B, Emi1 can inhibit APC already activated by Cdc20 or Cdh1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (r / resemble-01 :polarity "-" :ARG1 (p / possible-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "Emi1")) :ARG1 (p2 / protein :name (n2 / name :op1 "APC") :ARG1-of (a / activate-01 :ARG0 (o / or :op1 (p3 / protein :name (n3 / name :op1 "Cdc20") :xref (x3 / xref :value "UNIPROT:CDC20_HUMAN" :prob "0.633")) :op2 (p4 / protein :name (n4 / name :op1 "Cdh1") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "0.603"))) :time (a2 / already)) :xref (x / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")))) :ARG2 (o2 / or :op1 (p5 / protein :name (n5 / name :op1 "Mad2") :xref (x4 / xref :value "UNIPROT:MD2L1_HUMAN" :prob "0.602")) :op2 (p6 / protein :name (n6 / name :op1 "Mad2B") :xref (x1 / xref :value "UNIPROT:MD2L2_HUMAN" :prob "0.632")))) # ::id bio.chicago_2015.23439 # ::date 2015-10-23T01:33:06 # ::file bio_chicago_2015_23439.txt # ::snt Upregulation of the p53 protein, mediated either by irradiation [ 81] or by a temperature-sensitive p53 transgene [ 80], together with E2F1 overexpression induced apoptosis even in the presence of serum growth factors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (i / induce-01 :ARG0 (a2 / and :op1 (u / upregulate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1-of (m / mediate-01 :ARG0 (o / or :op1 (i2 / irradiate-01 :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "81")))) :op2 (t / transgene :mod p2 :ARG0-of (s2 / sensitive-03 :ARG1 (t2 / temperature)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "80"))))))) :op2 (o2 / overexpress-01 :ARG1 (p3 / protein :name (n3 / name :op1 "E2F1") :xref (x1 / xref :value "UNIPROT:E2F1_HUMAN" :prob "1.003")))) :ARG2 (a / apoptosis) :concession (p / present-02 :ARG1 (s / small-molecule :name (n / name :op1 "serum" :op2 "growth" :op3 "factor") :xref (x2 / xref :value "PUBCHEM:3085284" :prob "5.548434")))) # ::id bio.chicago_2015.23524 # ::date 2015-10-23T01:39:36 # ::file bio_chicago_2015_23524.txt # ::snt (B) TRAF6 failed to activate IKK in Uev1A-depleted extracts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (f / fail-01 :ARG1 (p / protein :name (n / name :op1 "TRAF6") :xref (x2 / xref :value "UNIPROT:TRAF6_HUMAN" :prob "1.003")) :ARG2 (a / activate-01 :ARG0 p :ARG1 (e / enzyme :name (n2 / name :op1 "IKK") :xref (x1 / xref :value "UNIPROT:IKKA_HUMAN" :prob "0.262")) :location (e2 / extract :ARG1-of (d / deplete-01 :ARG2 (p2 / protein :name (n3 / name :op1 "Uev1A") :xref (x / xref :value "UNIPROT:UB2V1_HUMAN" :prob "0.232"))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "B"))) # ::id bio.chicago_2015.23580 # ::date 2015-10-23T01:44:02 # ::file bio_chicago_2015_23580.txt # ::snt Thus, Ptc inhibits the activity of Smo and HH binding to Ptc releases Smo from this inhibitory process. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (i / infer-01 :ARG1 (a / and :op1 (i2 / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "Ptc") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "0.603")) :ARG1 (a2 / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "Smo") :xref (x / xref :value "UNIPROT:SMO_HUMAN" :prob "0.604")))) :op2 (r / release-01 :ARG0 (b / bind-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "HH")) :ARG2 p) :ARG1 p2 :ARG2 (p4 / process-02 :ARG1 (i3 / inhibit-01 :ARG0 p2))))) # ::id bio.chicago_2015.23632 # ::date 2015-10-23T01:49:13 # ::file bio_chicago_2015_23632.txt # ::snt These data demonstrated that Tyr phosphorylation was not required for JNK activation by MKK7. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (d / demonstrate-01 :ARG0 (d2 / data :mod (t / this)) :ARG1 (r / require-01 :polarity "-" :ARG0 (a / activate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "MKK7") :xref (x1 / xref :value "UNIPROT:MP2K7_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) # ::id bio.chicago_2015.23691 # ::date 2015-10-23T02:08:43 # ::file bio_chicago_2015_23691.txt # ::snt Whereas the highly conserved cysteine-rich domain is able to inhibit EGF-induced MAP kinase activation, the amino-terminal domain potentiates EGF-induced MAP kinase activation by interfering with EGFR ubiquitination and down-regulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (c / contrast-01 :ARG1 (p2 / potentiate-01 :ARG0 (p3 / protein-segment :name (n2 / name :op1 "amino-terminal" :op2 "domain")) :ARG1 (a / activate-01 :ARG1 (k / kinase :name (n3 / name :op1 "MAP") :xref (x2 / xref :value "UNIPROT:MOTI_HUMAN" :prob "1.002")) :ARG2-of (i / induce-01 :ARG0 (p4 / protein :name (n4 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :manner (i2 / interfere-01 :ARG0 p3 :ARG1 (a2 / and :op1 (u / ubiquitinate-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op2 (d / downregulate-01 :ARG1 e)))) :ARG2 (c3 / capable-01 :ARG1 "p5" :ARG2 (i3 / inhibit-01 :ARG0 (p5 / protein-segment :name (n5 / name :op1 "cysteine-rich" :op2 "domain") :ARG1-of (c2 / conserve-01 :degree (h / high-02))) :ARG1 a))) # ::id bio.chicago_2015.23692 # ::date 2015-10-23T02:19:19 # ::file bio_chicago_2015_23692.txt # ::snt Reduction of profilin suppresses the disorganized actin phenotype caused by reduction of capping protein function, suggesting that profilin promotes actin assembly in the elongating bristle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (s / suggest-01 :ARG0 (s2 / suppress-01 :ARG0 (r / reduce-01 :ARG1 (p / protein :name (n / name :op1 "profilin") :xref (x1 / xref :value "UNIPROT:B4DNH1_HUMAN" :prob "0.701"))) :ARG1 (p2 / phenotype :mod (p3 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG1-of (d / disorganize-01) :ARG1-of (c / cause-01 :ARG0 (r2 / reduce-01 :ARG1 (f / function-01 :ARG0 (p4 / protein :name (n3 / name :op1 "capping" :op2 "protein") :xref (x2 / xref :value "UNIPROT:CPZIP_HUMAN" :prob "0.232"))))))) :ARG1 (p5 / promote-01 :ARG0 p :ARG1 (a / assemble-01 :ARG1 p3 :location (b / bristle :ARG0-of (e / elongate-01))))) # ::id bio.chicago_2015.23746 # ::date 2015-10-23T02:25:10 # ::file bio_chicago_2015_23746.txt # ::snt Significantly, it is shown that Zap-70 plays an adaptor role in Cbl-induced Ub conjugation to TCRzeta chain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / show-01 :ARG1 (p / play-02 :ARG0 (e / enzyme :name (n / name :op1 "Zap-70") :xref (x1 / xref :value "UNIPROT:ZAP70_HUMAN" :prob "0.623")) :ARG1 (c / conjugate-02 :ARG1 (p3 / protein :name (n3 / name :op1 "ubiquitin") :xref (x / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :ARG2 (p4 / protein :name (n4 / name :op1 "TCRzeta" :op2 "chain")) :mod (m / molecular-physical-entity :ARG0-of (a / adapt-01)) :ARG2-of (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Cbl") :xref (x2 / xref :value "UNIPROT:CBL_HUMAN" :prob "0.604"))))) :ARG1-of (s2 / significant-02)) # ::id bio.chicago_2015.23757 # ::date 2015-10-23T02:38:58 # ::file bio_chicago_2015_23757.txt # ::snt Thus, Eya-induced apoptosis involves both caspase-dependent and caspase-independent pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (i2 / involve-01 :ARG1 (a2 / and :op1 (p2 / pathway :ARG0-of (d / depend-01 :ARG1 (p4 / protein :name (n2 / name :op1 "caspase") :xref (x / xref :value "UNIPROT:A0A024R3C0_HUMAN" :prob "0.701")))) :op2 (p3 / pathway :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 p4))) :ARG2 (a / apoptosis :ARG2-of (i3 / induce-01 :ARG0 (p / protein :name (n / name :op1 "Eya") :xref (x1 / xref :value "UNIPROT:EYA1_HUMAN" :prob "0.202")))))) # ::id bio.chicago_2015.23765 # ::date 2015-10-23T04:31:30 # ::file bio_chicago_2015_23765.txt # ::snt A number of proteins have recently been identified that specifically interact with the GTP-bound form of Rho (reviewed in [30] ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / identify-01 :ARG1 (p / protein :quant (n / number) :ARG0-of (i2 / interact-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Rho") :ARG1-of (b / bind-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")) :ARG1-of (s / specific-02)) :ARG1-of (r2 / review-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "30")))) :time (r / recent)) # ::id bio.chicago_2015.23795 # ::date 2015-10-23T04:37:52 # ::file bio_chicago_2015_23795.txt # ::snt However, this reduction in tension could contribute to checkpoint activation by other mechanisms, such as those that regulate BubR1 inhibition of Cdc20 activation of the APC/C ( Skoufias et al., 2001; Sudakin et al., 2001; Tang et al., 2001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (c / contrast-01 :ARG2 (p2 / possible-01 :ARG1 (c2 / contribute-01 :ARG0 (r / reduce-01 :ARG1 (t / tension) :mod (t2 / this)) :ARG2 (a / activate-01 :ARG0 (m / mechanism :mod (o / other) :example (m2 / mechanism :ARG0-of (r2 / regulate-01 :ARG1 (i / inhibit-01 :ARG0 (e / enzyme :name (n / name :op1 "BubR1") :xref (x1 / xref :value "UNIPROT:BUB1B_HUMAN" :prob "0.632")) :ARG1 (a2 / activate-01 :ARG0 (p3 / protein :name (n2 / name :op1 "Cdc20") :xref (x / xref :value "UNIPROT:CDC20_HUMAN" :prob "0.633")) :ARG1 (p4 / protein :name (n3 / name :op1 "APC/C"))))))) :ARG1 (c3 / checkpoint)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p5 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n4 / name :op1 "Skoufias")) :op2 (p9 / person :mod (o2 / other))) :time (d / date-entity :year "2001")) :op2 (p6 / publication-91 :ARG0 (a5 / and :op1 (p10 / person :name (n5 / name :op1 "Sudakin")) :op2 p9) :time d) :op3 (p7 / publication-91 :ARG0 (a6 / and :op1 (p12 / person :name (n6 / name :op1 "Tang")) :op2 p9) :time d)))) # ::id bio.chicago_2015.23851 # ::date 2015-10-23T04:47:16 # ::file bio_chicago_2015_23851.txt # ::snt Axin binds directly to GSK-3beta, beta-catenin, and APC, whereas APC also directly binds to GSK-3beta and beta-catenin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (c / contrast-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "axin") :xref (x3 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG2 (a / and :op1 (e / enzyme :name (n2 / name :op1 "GSK-3beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :op2 (p2 / protein :name (n3 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :op3 (p3 / protein :name (n4 / name :op1 "APC") :xref (x2 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004"))) :ARG1-of (d / direct-02)) :ARG2 (b2 / bind-01 :ARG1 p3 :ARG2 (a3 / and :op1 e :op2 p2) :ARG1-of d :mod (a2 / also))) # ::id bio.chicago_2015.23862 # ::date 2015-10-23T05:18:06 # ::file bio_chicago_2015_23862.txt # ::snt Thus, prolonged or transient activation of ERK induced by nerve growth factor or EGF stimulation of PC12 cells, respectively( 28 ) , may involve different VH-1-like PTPases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / cause-01 :ARG1 (p2 / possible-01 :ARG1 (i2 / involve-01 :ARG1 (e / enzyme :name (n5 / name :op1 "PTPase") :ARG1-of (d2 / differ-02) :ARG1-of (r / resemble-01 :ARG2 (e2 / enzyme :name (n6 / name :op1 "VH-1") :xref (x1 / xref :value "UNIPROT:DUS1_HUMAN" :prob "0.652"))) :xref (x2 / xref :value "UNIPROT:PTPRO_HUMAN" :prob "0.322")) :ARG2 (o / or :op1 (a / activate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (p3 / prolong-01) :ARG2-of (i3 / induce-01 :ARG0 (s2 / stimulate-01 :ARG0 (p / protein :name (n2 / name :op1 "nerve" :op2 "growth" :op3 "factor") :xref (x4 / xref :value "UNIPROT:NTF3_HUMAN" :prob "0.393")) :ARG1 (c / cell-line :name (n3 / name :op1 "PC12"))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "28"))))) :op2 (a2 / activate-01 :ARG1 e3 :ARG1-of (t / transient-02) :ARG2-of (i4 / induce-01 :ARG0 (s3 / stimulate-01 :ARG0 (p4 / protein :name (n4 / name :op1 "EGF") :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 c) :ARG1-of d3)))))) # ::id bio.chicago_2015.23867 # ::date 2015-10-23T05:28:12 # ::file bio_chicago_2015_23867.txt # ::snt Conversely, Ubc4/5 cannot substitute for Ubc13/Uev1A in the activation of IKK by TRAF6 ( Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (p / possible-01 :polarity "-" :ARG1 (s / substitute-01 :ARG1 (e / enzyme :name (n / name :op1 "Ubc4/5")) :ARG2 (p2 / protein :name (n2 / name :op1 "Ubc13/Uev1A")) :ARG3 (a / activate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "TRAF6") :xref (x / xref :value "UNIPROT:TRAF6_HUMAN" :prob "1.003")) :ARG1 (e3 / enzyme :name (n4 / name :op1 "IKK") :xref (x1 / xref :value "UNIPROT:IKKA_HUMAN" :prob "0.262"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4D"))) # ::id bio.chicago_2015.23926 # ::date 2015-10-23T05:34:53 # ::file bio_chicago_2015_23926.txt # ::snt A, lysates of biosynthetically labeled MOLT16 cells were first cleared with protein A-Sepharose ( lane 1) or with GST coupled to glutathione-Sepharose 4B beads ( lane 6) and then precipitated ( PP) with mAb 6G4 coupled to protein A-Sepharose ( lane 2) or GST-DI ( lane 3), GST-DII ( lane 4), or GST-DIII ( lane 5) coupled to glutathione-Sepharose 4B beads, as described under # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (c / clear-01 :ARG0 (o2 / or :op1 (p3 / protein :name (n2 / name :op1 "A-sepharose") :ARG1-of (d / describe-01 :ARG0 (l3 / lane :mod "1")) :xref (x3 / xref :value "UNIPROT:ARSE_HUMAN" :prob "0.202")) :op2 (e / enzyme :name (n3 / name :op1 "GST") :ARG1-of (c3 / couple-01 :ARG2 (b2 / bead :consist-of (s / small-molecule :name (n4 / name :op1 "gluthatione-Sepharose" :op2 "4b") :xref (x5 / xref :value "PUBCHEM:13816" :prob "0.856216")))) :ARG1-of (d2 / describe-01 :ARG0 (l4 / lane :mod "6")) :xref (x4 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002"))) :ARG1 (c2 / cell-line :name (n / name :op1 "MOLT16") :ARG1-of (l / lysate-00) :ARG1-of (l2 / label-01 :ARG2 (b / biosynthetic))) :time (f / first)) :op2 (p / precipitate-00 :ARG1 c2 :instrument (o3 / or :op1 (a2 / antibody :ARG1-of (c4 / couple-01 :ARG2 p3) :ARG1-of (d5 / describe-01 :ARG0 (l5 / lane :mod "2")) :ARG0-of (c7 / counter-01 :ARG1 (p2 / protein :name (n5 / name :op1 "6G5"))) :mod (m3 / monoclone)) :op2 (a3 / antibody :ARG1-of (c5 / couple-01 :ARG2 (e2 / enzyme :name (n7 / name :op1 "GST-DI") :xref (x1 / xref :value "UNIPROT:CHST3_HUMAN" :prob "0.232"))) :ARG1-of (d6 / describe-01 :ARG0 (l6 / lane :mod "3")) :ARG0-of c7 :mod m3) :op3 (e3 / enzyme :name (n9 / name :op1 "GST-DII") :ARG1-of (d7 / describe-01 :ARG0 (l7 / lane :mod "4")) :xref (x / xref :value "UNIPROT:CHST3_HUMAN" :prob "0.212")) :op4 (e4 / enzyme :name (n8 / name :op1 "GST-DIII") :ARG1-of (c6 / couple-01 :ARG2 s) :ARG1-of (d8 / describe-01 :ARG0 (l8 / lane :mod "5")) :xref (x2 / xref :value "UNIPROT:CHST3_HUMAN" :prob "0.202"))) :time (t / then)) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "A"))) # ::id bio.chicago_2015.23937 # ::date 2015-10-23T05:52:03 # ::file bio_chicago_2015_23937.txt # ::snt Several proteins have been isolated as putative Rho effectors on the basis of their selective interaction with the GTP-bound form of Rho. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (i / isolate-01 :ARG1 (p / protein :mod (e / effector :mod (p2 / protein :name (n / name :op1 "Rho") :xref (x / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")) :ARG1-of (t / think-01)) :quant (s / several)) :ARG1-of (b2 / base-02 :ARG2 (i2 / interact-01 :ARG0 p :ARG1 (p3 / protein :name (n3 / name :op1 "Rho") :ARG1-of (b / bind-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x1 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")) :manner (s2 / selective)))) # ::id bio.chicago_2015.23977 # ::date 2015-10-23T06:02:06 # ::file bio_chicago_2015_23977.txt # ::snt These results demonstrate that Sp1 and Sp3 can both bind to the Sp1 consensus sequence in the IGF-II promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (d / demonstrate-01 :ARG0 (t2 / thing :mod (t / this) :ARG2-of (r / result-01)) :ARG1 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "Sp1") :xref (x / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001")) :op2 (p3 / protein :name (n2 / name :op1 "Sp3") :xref (x1 / xref :value "UNIPROT:SP3_HUMAN" :prob "0.623"))) :ARG2 (s / sequence :mod (c / consensus) :part-of (m / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (p5 / protein :name (n3 / name :op1 "IGF-II") :xref (x2 / xref :value "UNIPROT:IGF2_HUMAN" :prob "1.003")))) :mod p2)))) # ::id bio.chicago_2015.24061 # ::date 2015-10-23T06:08:52 # ::file bio_chicago_2015_24061.txt # ::snt Alternatively, the absence of an Xbra band in the ActRIIBdn cells would suggest that activin induces Xbra directly. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (s / suggest-01 :ARG0 (a2 / absent-01 :ARG1 (b / band :mod (g / gene :name (n / name :op1 "Xbra") :xref (x / xref :value "UNIPROT:REST_HUMAN" :prob "0.202"))) :ARG2 (c / cell-line :name (n2 / name :op1 "ActRIIBdn"))) :ARG1 (i / induce-01 :ARG0 (p / protein :name (n3 / name :op1 "activin") :xref (x1 / xref :value "UNIPROT:INHBA_HUMAN" :prob "0.273")) :ARG1 g :ARG1-of (d / direct-02)) :manner (a / alternative)) # ::id bio.chicago_2015.24105 # ::date 2015-10-23T06:12:52 # ::file bio_chicago_2015_24105.txt # ::snt In contrast, as previously described ( 13), co-expression of kinase-inactive MEKK1 markedly reduced NIK activation of JNK (Fig. 7 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / contrast-01 :ARG2 (r / reduce-01 :ARG0 (c2 / coexpress-01 :ARG2 (e / enzyme :name (n / name :op1 "MEKK1") :ARG0-of (a / activity-06 :polarity "-" :mod (k / kinase)) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003"))) :ARG1 (a2 / activate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "NIK") :xref (x2 / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")) :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :manner (m / marked) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7B"))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 "13")) :time (p2 / previous))) # ::id bio.chicago_2015.24115 # ::date 2015-10-23T06:17:39 # ::file bio_chicago_2015_24115.txt # ::snt Additionally, we recently showed that kinase subdomain VIII of PAK1 could be phosphorylated in vitro by PDK1, suggesting phosphorylation events within the catalytic domain may regulate PAK1 activity ( 26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op2 (s / show-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein-segment :mod "8" :part-of (e / enzyme :name (n2 / name :op1 "PAK1") :xref (x1 / xref :value "UNIPROT:PAK1_HUMAN" :prob "1.004"))) :ARG2 (e2 / enzyme :name (n3 / name :op1 "PDK1") :xref (x / xref :value "UNIPROT:PDK1_HUMAN" :prob "1.003")) :manner (i / in-vitro)) :ARG0-of (s2 / suggest-01 :ARG1 (p4 / possible-01 :ARG1 (r2 / regulate-01 :ARG0 (p5 / phosphorylate-01 :location (d2 / domain :mod (c / catalytic))) :ARG1 (a2 / activity-06 :ARG0 e))))) :time (r / recent) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "26"))))) # ::id bio.chicago_2015.24118 # ::date 2015-10-23T06:26:09 # ::file bio_chicago_2015_24118.txt # ::snt Direct Phosphorylation and Inhibition of Cdc25 by Cds1 and Chk1 In Vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (a / and :op1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "Cdc25") :xref (x / xref :value "UNIPROT:RGRF1_HUMAN" :prob "0.633")) :ARG2 (a2 / and :op1 (e3 / enzyme :name (n2 / name :op1 "Cds1") :xref (x1 / xref :value "UNIPROT:CDS1_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n3 / name :op1 "Chk1") :xref (x2 / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604")))) :op2 (i / inhibit-01 :ARG0 a2 :ARG1 e) :ARG1-of (d / direct-02) :manner (i2 / in-vitro)) # ::id bio.chicago_2015.24126 # ::date 2015-10-23T06:29:37 # ::file bio_chicago_2015_24126.txt # ::snt It is unclear why activation of endogenous PKC by TPA, which strongly inhibits the DNA-binding activity of endogenous HES-1 protein, does not also induce neurite outgrowth although it greatly potentiates the response to NGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / clear-06 :polarity "-" :ARG1 (c2 / cause-01 :ARG0 (a / amr-unknown) :ARG1 (i / induce-01 :polarity "-" :ARG0 (a3 / activate-01 :ARG0 (s / small-molecule :name (n / name :op1 "TPA") :ARG0-of (i2 / inhibit-01 :ARG1 (a4 / activity-06 :ARG0 (p / protein :name (n3 / name :op1 "HES-1") :xref (x2 / xref :value "UNIPROT:ES1_HUMAN" :prob "0.672")) :ARG1 (b / bind-01 :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "DNA")))) :ARG1-of (s2 / strong-02)) :xref (x3 / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1 (e / enzyme :name (n2 / name :op1 "PKC") :mod (e2 / endogenous) :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :ARG1-of (c3 / contrast-01 :ARG2 (p2 / potentiate-01 :ARG1 (r / respond-01 :ARG1 (p3 / protein :name (n5 / name :op1 "NGF") :xref (x / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004"))) :manner (g2 / great)))) :ARG2 (o / outgrow-01 :ARG0 (n4 / neurite)) :mod (a2 / also)))) # ::id bio.chicago_2015.24129 # ::date 2015-10-23T06:35:12 # ::file bio_chicago_2015_24129.txt # ::snt C-Daam1 activation of RhoA is not affected by deltaPDZ-Dvl (Figure 3A), which inhibits RhoA activation by Fz or Dvl (Figure 1F), further demonstrating that Daam1 functions downstream of Dvl in Rho activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (a / affect-01 :polarity "-" :ARG0 (p / protein-segment :name (n / name :op1 "deltaPDZ-Dvl") :ARG0-of (i / inhibit-01 :ARG1 (a3 / activate-01 :ARG0 (o / or :op1 (p4 / protein :name (n4 / name :op1 "Fz")) :op2 (p5 / protein :name (n5 / name :op1 "Dvl") :xref (x3 / xref :value "UNIPROT:DVLP1_HUMAN" :prob "0.602"))) :ARG1 "p3") :ARG0-of (d2 / demonstrate-01 :ARG1 (f3 / function-01 :ARG0 (p6 / protein :name (n6 / name :op1 "Daam1") :xref (x1 / xref :value "UNIPROT:DAAM1_HUMAN" :prob "0.604")) :ARG1 (a4 / activate-01 :ARG1 (p7 / protein :name (n7 / name :op1 "Rho") :xref (x2 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602"))) :location (r / relative-position :op1 p5 :direction (d3 / downstream))) :manner (f2 / further)) :ARG1-of (d4 / describe-01 :ARG0 (f4 / figure :mod "1F")))) :ARG1 (a2 / activate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "C-Daam1")) :ARG1 (p3 / protein :name (n3 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id bio.chicago_2015.24156 # ::date 2015-10-31T09:54:47 # ::file bio_chicago_2015_24156.txt # ::snt Furthermore, manipulation of other wingless signaling molecules downstream from shaggy demonstrated that components of the Wnt signaling pathway modulate neurodegeneration induced by tau pathology in vivo but suggested that tau phosphorylation by GSK-3 differs from canonical Wnt effects on - catenin stability and TCF activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op2 (c / contrast-01 :ARG1 (d / demonstrate-01 :ARG0 (m2 / manipulate-01 :ARG1 (m3 / molecule :ARG0-of (s3 / signal-07 :ARG1 (g / gene :name (n4 / name :op1 "wingless"))) :mod (o / other) :location (r / relative-position :op1 (e / enzyme :name (n5 / name :op1 "shaggy") :xref (x3 / xref :value "UNIPROT:CANT1_HUMAN" :prob "0.202")) :direction (d3 / downstream)))) :ARG1 (m / modulate-01 :ARG0 (c2 / component :ARG1-of (i / include-91 :ARG2 (p2 / pathway :name (n / name :op1 "Wnt") :ARG0-of (s2 / signal-07)))) :ARG1 (n2 / neurodegeneration :ARG2-of (i2 / induce-01 :ARG0 (p3 / pathology :mod (p4 / protein :name (n3 / name :op1 "tau") :xref (x1 / xref :value "UNIPROT:TAU_HUMAN" :prob "0.603")))) :manner (i3 / in-vivo)))) :ARG2 (s / suggest-01 :ARG0 m2 :ARG1 (d2 / differ-02 :ARG1 (p / phosphorylate-01 :ARG1 p4 :ARG2 (e2 / enzyme :name (n7 / name :op1 "GSK-3") :xref (x2 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.262"))) :ARG2 (a2 / affect-01 :ARG0 (p6 / pathway :name (n8 / name :op1 "Wnt")) :ARG1 (a3 / and :op1 (s4 / stability :mod (p7 / protein :name (n10 / name :op1 "β-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :op2 (a4 / activity-06 :ARG0 (p5 / protein :name (n9 / name :op1 "TCF") :xref (x4 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.263")))) :mod (c3 / canon)))))) # ::id bio.chicago_2015.24160 # ::date 2015-10-31T10:32:26 # ::file bio_chicago_2015_24160.txt # ::snt The cell surface expression of glypican-1 in these cells was analyzed by quantitative immunofluorescence flow cytometry (data not shown), and the effects of cells expressing one-chain ( SAA), two-chain ( SSA), or wild-type ( SSS) forms of glypican-1 on FGF2-induced FGFR1 autophosphorylation were compared. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (a2 / analyze-01 :ARG1 (e / express-03 :ARG2 (p2 / protein) :ARG3 (c / cell :ARG1-of (s / surface-02)) :location (c2 / cell :mod (t / this))) :manner (c3 / cytometry :mod (i / immunofluoresce-01 :mod (q / quantitative)) :mod (f / flow)) :ARG1-of (d2 / describe-01 :ARG0 (d / data :ARG1-of (s2 / show-01 :polarity "-")))) :op2 (c4 / compare-01 :ARG1 (a3 / affect-01 :ARG0 (c5 / cell :ARG2-of (e2 / express-03 :ARG1 (o / or :op1 (p / protein :name (n7 / name :op1 "glypican-1") :mod (f3 / form) :mod (c11 / chain :quant "1") :ARG1-of (m / mean-01 :ARG2 (n / name :op1 "SAA")) :xref (x4 / xref :value "UNIPROT:GPC1_HUMAN" :prob "0.703")) :op2 (p6 / protein :name (n8 / name :op1 "glypican-1") :mod (f4 / form) :mod (c12 / chain :quant "2") :ARG1-of (m2 / mean-01 :ARG2 (n5 / name :op1 "SSA")) :xref (x3 / xref :value "UNIPROT:GPC1_HUMAN" :prob "0.703")) :op3 (p7 / protein :name (n9 / name :op1 "glypican-1") :mod (w2 / wild-type) :ARG1-of (m3 / mean-01 :ARG2 (n6 / name :op1 "SSS")) :xref (x / xref :value "UNIPROT:GPC1_HUMAN" :prob "0.703"))))) :ARG1 (p3 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "FGFR1") :xref (x1 / xref :value "UNIPROT:FGFR1_HUMAN" :prob "1.004")) :ARG2 e4 :ARG2-of (i2 / induce-01 :ARG0 (p4 / protein :name (n4 / name :op1 "FGF2") :xref (x2 / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.004"))))))) # ::id bio.chicago_2015.24247 # ::date 2015-10-31T11:01:24 # ::file bio_chicago_2015_24247.txt # ::snt Moreover, the Raf-1 bound to Ras membranes undergoes activation, whereas Raf-1 bound to control membranes does not (Fig. 5A and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (a / and :op2 (c / contrast-01 :ARG1 (u / undergo-28 :ARG1 (a2 / activate-01 :ARG1 "e") :ARG2 (e / enzyme :name (n2 / name :op1 "Raf-1") :ARG1-of (b / bind-01 :ARG2 (m / membrane :mod (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :xref (x4 / xref :value "GO:0016020" :prob "0.8"))) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :ARG2 (u2 / undergo-28 :polarity "-" :ARG1 (a3 / activate-01 :ARG1 "e3") :ARG2 (e3 / enzyme :name (n / name :op1 "Raf-1") :ARG1-of (b2 / bind-01 :ARG2 (m2 / membrane :ARG0-of (c2 / control-01) :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "5A") :op2 (f2 / figure :mod "5C")))) # ::id bio.chicago_2015.24257 # ::date 2015-10-31T11:15:07 # ::file bio_chicago_2015_24257.txt # ::snt DAG activates PKC directly. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (a / activate-01 :ARG0 (s / small-molecule :name (n / name :op1 "DAG") :xref (x1 / xref :value "PUBCHEM:2784000" :prob "12.363392")) :ARG1 (e / enzyme :name (n2 / name :op1 "PKC") :xref (x / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :ARG1-of (d / direct-02)) # ::id bio.chicago_2015.24353 # ::date 2015-10-31T11:19:00 # ::file bio_chicago_2015_24353.txt # ::snt On the other hand, PD98059 (50 muM) reduced Cr(VI)-activated ERK to endogenous levels and decreased Cr(VI)-activated p38 by ~60%, but did not significantly alter Cr(VI)-activated JNK (Figure 9 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (c2 / contrast-01 :ARG1 (a / and :op1 (r / reduce-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "PD98059") :mod (c3 / concentration-quantity :quant "50" :unit (m / micromolar)) :xref (x3 / xref :value "PUBCHEM:4713" :prob "18.349844")) :ARG1 (e / enzyme :name (n3 / name :op1 "ERK") :ARG1-of (a3 / activate-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "Cr(VI)"))) :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG4 (l / level :mod (e2 / endogene))) :op2 (d / decrease-01 :ARG0 s3 :ARG1 (e4 / enzyme :name (n5 / name :op1 "p38") :ARG1-of a3 :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG2 (a6 / about :op1 (p / percentage-entity :value "60")))) :ARG2 (a2 / alter-01 :polarity "-" :ARG0 s3 :ARG1 (e3 / enzyme :name (n / name :op1 "JNK") :ARG1-of (a5 / activate-01 :ARG0 s) :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG1-of (s2 / significant-02))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "9"))) # ::id bio.chicago_2015.24368 # ::date 2015-10-31T11:38:15 # ::file bio_chicago_2015_24368.txt # ::snt However, we do not believe that our findings exclude the possibility that MDM2 may also inhibit p53-dependent transcription by masking its activation domain from important basal factor contacts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (c / contrast-01 :ARG2 (b / believe-01 :polarity "-" :ARG0 (w / we) :ARG1 (e / exclude-01 :ARG0 (t2 / thing :ARG1-of (f / find-01 :ARG0 w)) :ARG1 (p / possible-01 :ARG1 (i / inhibit-01 :ARG0 (p3 / protein :name (n / name :op1 "MDM2") :xref (x / xref :value "UNIPROT:MDM2_HUMAN" :prob "1.003")) :ARG1 (t / transcribe-01 :ARG0-of (d2 / depend-01 :ARG1 (p4 / protein :name (n2 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :mod (a / also) :ARG1-of (p2 / possible-01) :manner (m / mask-01 :ARG0 p3 :ARG1 (d3 / domain :location-of (a2 / activate-01) :poss p3 :source (c3 / contact :mod (f3 / factor) :mod (b3 / basal) :mod (i2 / important))))))))) # ::id bio.chicago_2015.24456 # ::date 2015-11-01T01:06:38 # ::file bio_chicago_2015_24456.txt # ::snt Stoichiometry of Binding of eIF4A with eIF4G(613-1560)-- The forgoing result indicated that one molecule of eIF4A could bind to either the central or COOH-terminal sites of eIF4G. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (m / multi-sentence :snt1 (s / stoichiometry :mod (b2 / bind-01 :ARG1 (p / protein :name (n / name :op1 "eIF4A") :xref (x3 / xref :value "UNIPROT:IF4A1_HUMAN" :prob "0.702")) :ARG3 (p3 / protein :name (n2 / name :op1 "eIF4G") :mod (v / value-interval :op1 "613" :op2 "1560") :xref (x / xref :value "UNIPROT:IF4G1_HUMAN" :prob "0.702")))) :snt2 (i / indicate-01 :ARG0 (t / thing :ARG1-of (r / result-01) :ARG1-of (f / forgo-02)) :ARG1 (p2 / possible-01 :ARG1 (b4 / bind-01 :ARG1 (m4 / molecule :quant "1" :mod (p5 / protein :name (n3 / name :op1 "eIF4A") :xref (x2 / xref :value "UNIPROT:IF4A1_HUMAN" :prob "0.702"))) :ARG2 (o2 / or :op1 (s4 / site :mod (c2 / central)) :op2 (p4 / protein-segment :name (n4 / name :op1 "COOH-terminus")) :part-of (p6 / protein :name (n5 / name :op1 "eIF4G") :xref (x1 / xref :value "UNIPROT:IF4G1_HUMAN" :prob "0.702"))))))) # ::id bio.chicago_2015.24491 # ::date 2015-11-01T01:28:47 # ::file bio_chicago_2015_24491.txt # ::snt (B) Rho-N19, but neither Rac-N17 nor Cdc42-N17, blocks RhoA activation by Wnt, Fz, Dvl, or C-Daam1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :li "B" :ARG1 (b / block-01 :ARG0 (p5 / protein :name (n / name :op1 "Rho-N19")) :ARG1 (a / activate-01 :ARG0 (o / or :op1 (p / protein :name (n3 / name :op1 "Wnt") :xref (x4 / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")) :op2 (p2 / protein :name (n4 / name :op1 "Fz")) :op3 (p3 / protein :name (n5 / name :op1 "Dvl") :xref (x2 / xref :value "UNIPROT:DVLP1_HUMAN" :prob "0.602")) :op4 (p4 / protein :name (n6 / name :op1 "C-Daam1"))) :ARG1 (p6 / protein :name (n2 / name :op1 "RhoA") :xref (x3 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")))) :ARG2 (b2 / block-01 :polarity "-" :ARG0 (a2 / and :op1 (e3 / enzyme :name (n7 / name :op1 "Rac-N17") :xref (x1 / xref :value "UNIPROT:PKCB1_HUMAN" :prob "0.252")) :op2 (e4 / enzyme :name (n8 / name :op1 "Cdc42-N17") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.223"))) :ARG1 o)) # ::id bio.chicago_2015.24497 # ::date 2015-11-01T01:36:16 # ::file bio_chicago_2015_24497.txt # ::snt Although we could not evaluate the effect of PI3K inhibition on mutant huntingtin-induced cell death due to the high toxicity of the PI3K inhibitor LY in striatal neurons, we found an increase in the percentage of striatal neurons containing intranuclear inclusions when treated with subtoxic doses of LY (100 nM; data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (i2 / increase-01 :ARG1 (p2 / percentage :quant-of (n / neuron :mod (s / striatum) :ARG0-of (c / contain-01 :ARG1 (t / thing :ARG1-of (i3 / include-01 :location (i4 / intranuclear)))))) :time (t2 / treat-04 :ARG1 n :ARG2 (d / dose-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "LY") :quant (c2 / concentration-quantity :quant "100" :unit (n3 / nanomolar)) :xref (x2 / xref :value "PUBCHEM:16196600" :prob "11.455812")) :mod (s2 / subtoxic)))) :concession (p3 / possible-01 :polarity "-" :ARG1 (e / evaluate-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1 (d3 / die-01 :ARG1 (c3 / cell) :ARG1-of (c4 / cause-01 :ARG0 (t3 / toxicity :ARG1-of (h / high-02) :location n :poss (s5 / small-molecule :name (n7 / name :op1 "LY") :ARG0-of (i5 / inhibit-01 :ARG1 e2) :xref (x3 / xref :value "PUBCHEM:16196600" :prob "11.455812")))) :ARG2-of (i6 / induce-01 :ARG0 (p5 / protein :name (n5 / name :op1 "huntingtin") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:HD_HUMAN" :prob "0.702"))))))) :ARG2-of (d4 / describe-01 :ARG0 (d5 / data :ARG1-of (s7 / show-01 :polarity "-")))) # ::id bio.chicago_2015.24503 # ::date 2015-11-01T01:04:26 # ::file bio_chicago_2015_24503.txt # ::snt The morphologic features of apoptosis induced by Diva, including rounding and membrane blebbing (Fig. 5 B) as well as nuclear fragmentation (Fig. 5 C) were inhibited by vBcl-2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "vBcl-2")) :ARG1 (f / feature-01 :ARG1 (a / apoptosis :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Diva")))) :mod (m / morphology) :ARG2-of (i3 / include-91 :ARG1 (a2 / and :op1 (r / round-04) :op2 (b / bleb-00 :ARG1 (m3 / membrane :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5B"))) :op3 (f5 / fragment-01 :ARG1 (n3 / nucleus :xref (x / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "5C"))))))) # ::id bio.chicago_2015.24508 # ::date 2015-11-01T01:13:31 # ::file bio_chicago_2015_24508.txt # ::snt Mist1 efficiently inhibits MyoD from activating the TnI-Luc gene whereas Mist1mutbasic has no effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "Mist1") :xref (x1 / xref :value "UNIPROT:BHA15_HUMAN" :prob "0.602")) :ARG1 (p2 / protein :name (n2 / name :op1 "MyoD") :ARG0-of (a / activate-01 :ARG1 (g / gene :name (n3 / name :op1 "TnI-Luc"))) :xref (x / xref :value "UNIPROT:MYOD1_HUMAN" :prob "0.602")) :ARG2-of (e / efficient-01)) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 (p3 / protein :name (n4 / name :op1 "Mist1mutbasic")))) # ::id bio.chicago_2015.24550 # ::date 2015-11-01T01:18:29 # ::file bio_chicago_2015_24550.txt # ::snt It is also well established that JNK and IKK are activated by LPS or the proinflammatory cytokines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (e / establish-01 :ARG1 (a / activate-01 :ARG0 (o / or :op1 (m / molecular-physical-entity :name (n3 / name :op1 "LPS") :xref (x2 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :op2 (c / cytokine :ARG0-of (f / favor-01 :ARG1 (i / inflame-01)))) :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op2 (e3 / enzyme :name (n2 / name :op1 "IKK") :xref (x / xref :value "UNIPROT:IKKA_HUMAN" :prob "0.262")))) :mod (a3 / also) :mod (w / well)) # ::id bio.chicago_2015.24562 # ::date 2015-11-01T01:23:04 # ::file bio_chicago_2015_24562.txt # ::snt The formation of a functional signaling complex of active ligand dimer and type I and II receptor dimer heterotetramer, results in the phosphorylation of type I receptor by the constitutively active type II receptor (for review, see Massague 1998). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a3 / and :op1 (r / result-01 :ARG1 (f / form-01 :ARG1 (m / macro-molecular-complex :ARG0-of (s / signal-07 :ARG1-of (f2 / function-01)) :part (d / dimer :mod (l / ligand :ARG0-of (a2 / activity-06))) :part (h / heterotetramer :part (d3 / dimer :name (n4 / name :op1 "type" :op2 "II" :op3 "receptor")) :part (d2 / dimer :name (n3 / name :op1 "type" :op2 "I" :op3 "receptor"))))) :ARG2 (p2 / phosphorylate-01 :ARG1 d2 :ARG3 (d5 / dimer :name (n / name :op1 "type" :op2 "I" :op3 "receptor") :ARG1-of (a / activate-01 :mod (c / constitutive))))) :op2 (s2 / see-01 :mode "imperative" :ARG0 (y / you) :ARG1 (p / publication-91 :ARG0 (p5 / person :wiki "-" :name (n5 / name :op1 "Massague")) :time (d4 / date-entity :year "1998")) :purpose (r2 / review-01))) # ::id bio.chicago_2015.24596 # ::date 2015-11-01T01:38:40 # ::file bio_chicago_2015_24596.txt # ::snt Moreover, association is accompanied by reciprocal phosphorylation of Dlar and Ena by Abl and dephosphorylation of phosphorylated Abl and Ena by Dlar. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (a / and :op2 (a2 / accompany-01 :ARG0 (a3 / associate-01) :ARG1 (a4 / and :op1 (p2 / phosphorylate-01 :ARG1 (a5 / and :op1 (p3 / protein :name (n / name :op1 "Dlar")) :op2 (p4 / protein :name (n2 / name :op1 "Ena") :xref (x / xref :value "UNIPROT:SCNNA_HUMAN" :prob "0.232"))) :ARG2 (p5 / protein :name (n3 / name :op1 "Abl") :xref (x1 / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603")) :manner (r / reciprocal)) :op2 (d / dephosphorylate-01 :ARG1 (a6 / and :op1 p5 :op2 p4 :ARG3-of (p / phosphorylate-01)) :ARG2 p3)))) # ::id bio.chicago_2015.24600 # ::date 2015-11-01T01:45:02 # ::file bio_chicago_2015_24600.txt # ::snt Mad2 binds Cdc20 to inhibit APC activity (Alexandru et al., 1999 ; Fang et al., 1998b ; Hwang et al., 1998 ; Kallio et al., 1998 ; Kim et al., 1998 ; Li et al., 1997 ; Wassmann and Benezra, 1998 ), although how Mad2 inhibits APCCdc20 is not clear. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (b / bind-01 :ARG0 (p2 / protein :name (n / name :op1 "Mad2") :xref (x1 / xref :value "UNIPROT:MD2L1_HUMAN" :prob "0.602")) :ARG1 (p3 / protein :name (n2 / name :op1 "Cdc20") :xref (x2 / xref :value "UNIPROT:CDC20_HUMAN" :prob "0.633")) :purpose (i / inhibit-01 :ARG0 p2 :ARG1 (a2 / activity-06 :ARG0 (p25 / protein :name (n3 / name :op1 "APC") :xref (x / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (p / publication-91 :ARG0 (a4 / and :op1 (p5 / person :wiki "-" :name (n5 / name :op1 "Alexandru")) :op2 (p6 / person :mod (o / other))) :time (d2 / date-entity :year "1999")) :op2 (p7 / publication-91 :ARG0 (a5 / and :op1 (p8 / person :wiki "-" :name (n6 / name :op1 "Fang")) :op2 (p9 / person :mod (o2 / other))) :time (d3 / date-entity :year "1998" :li "b")) :op3 (p10 / publication-91 :ARG0 (a6 / and :op1 (p11 / person :wiki "-" :name (n7 / name :op1 "Hwang")) :op2 (p12 / person :mod (o3 / other))) :time (d4 / date-entity :year "1998")) :op4 (p13 / publication-91 :ARG0 (a7 / and :op1 (p14 / person :wiki "-" :name (n8 / name :op1 "Kallio")) :op2 (p15 / person :mod (o4 / other))) :time (d5 / date-entity :year "1998")) :op5 (p16 / publication-91 :ARG0 (a8 / and :op1 (p17 / person :wiki "-" :name (n9 / name :op1 "Kim")) :op2 (p18 / person :mod (o5 / other))) :time (d6 / date-entity :year "1998")) :op6 (p19 / publication-91 :ARG0 (a9 / and :op1 (p20 / person :wiki "-" :name (n10 / name :op1 "Li")) :op2 (p21 / person :mod (o6 / other))) :time (d7 / date-entity :year "1997")) :op7 (p22 / publication-91 :ARG0 (a10 / and :op1 (p23 / person :wiki "-" :name (n11 / name :op1 "Wassmann")) :op2 (p24 / person :wiki "-" :name (n12 / name :op1 "Benezra"))) :time (d8 / date-entity :year "1998")))) :concession (c / clear-06 :polarity "-" :ARG1 (t / thing :manner-of (i3 / inhibit-01 :ARG0 p2 :ARG1 (p4 / protein :name (n4 / name :op1 "APCCdc20")))))) # ::id bio.chicago_2015.24623 # ::date 2015-11-01T03:38:35 # ::file bio_chicago_2015_24623.txt # ::snt Aliquots of filtrate (10 mul) were separated by SDS-PAGE and processed for Western blotting using an anti-cytochrome c monoclonal antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (a / and :op1 (s / separate-01 :ARG1 (a2 / aliquot :mod (f / filtrate :quant (c / concentration-quantity :quant "10" :unit (m / micromolar)))) :manner (a3 / analyze-01 :mod (t / thing :name (n2 / name :op1 "SDS-PAGE")))) :op2 (p / process-01 :ARG1 a2 :purpose (i / immunoblot-01 :ARG3 (a5 / antibody :mod (m2 / monoclone) :ARG0-of (c2 / counter-01 :ARG1 (p3 / protein :name (n4 / name :op1 "cytochrome" :op2 "c"))))))) # ::id bio.chicago_2015.24629 # ::date 2015-11-01T04:06:56 # ::file bio_chicago_2015_24629.txt # ::snt The early, broad snail pattern might create a broad domain of potential Notch signaling by repressing components of the Notch pathway, such as Delta and T3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (p2 / possible-01 :ARG1 (c2 / create-01 :ARG0 (p3 / pattern-01 :ARG1 (p7 / protein :name (n4 / name :op1 "snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (b / broad-02) :time (e / early)) :ARG1 (d / domain :ARG1-of (b2 / broad-02) :mod (p / potential) :poss (s2 / signal-07 :ARG0 (p4 / pathway :name (n / name :op1 "Notch")))) :manner (r / repress-01 :ARG1 (c3 / component :ARG1-of (i / include-91 :ARG2 p4) :example (a / and :op1 (p5 / protein :name (n2 / name :op1 "Delta") :xref (x1 / xref :value "UNIPROT:DLL3_HUMAN" :prob "0.333")) :op2 (p6 / protein :name (n3 / name :op1 "T3"))))))) # ::id bio.chicago_2015.24662 # ::date 2015-11-01T04:20:12 # ::file bio_chicago_2015_24662.txt # ::snt The simplest mechanism by which Mck1p might inhibit PKA activity is by phosphorylating PKA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (m2 / mechanism :ARG1-of (s / simple-02 :degree (m / most)) :instrument-of (i / inhibit-01 :ARG0 (p3 / protein :name (n / name :op1 "Mck1p") :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.212")) :ARG1 (a / activity-06 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG1-of (p2 / possible-01)) :domain (p / phosphorylate-01 :ARG1 e2)) # ::id bio.chicago_2015.24678 # ::date 2015-11-01T04:28:01 # ::file bio_chicago_2015_24678.txt # ::snt PTEN controls p53 transcriptional activity # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c / control-01 :ARG0 (p2 / protein :name (n / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG1 (a / activity-06 :ARG0 (t / transcribe-01 :ARG0 (p / protein :name (n2 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))))) # ::id bio.chicago_2015.24683 # ::date 2015-11-01T04:30:10 # ::file bio_chicago_2015_24683.txt # ::snt (A) Histone H1 inhibits ERalpha-mediated transcription in the presence of added p300. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (i / inhibit-01 :li "A" :ARG0 (p / protein :name (n / name :op1 "Histone" :op2 "H1") :xref (x2 / xref :value "UNIPROT:H10_HUMAN" :prob "0.692")) :ARG1 (t / transcribe-01 :ARG1-of (m / mediate-01 :ARG0 (p4 / protein :name (n2 / name :op1 "ERalpha") :xref (x1 / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.693")))) :condition (p2 / present-02 :ARG1 (p3 / protein :name (n3 / name :op1 "p300") :ARG1-of (a / add-02) :xref (x / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")))) # ::id bio.chicago_2015.24739 # ::date 2015-11-01T04:33:27 # ::file bio_chicago_2015_24739.txt # ::snt At higher concentrations, inhibition of certain JNK isoforms may occur; however, these kinases are not activated by LPS in the neutrophil under our experimental conditions ( 13). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (i / inhibit-01 :ARG1 (i2 / isoform :mod (e2 / enzyme :name (n / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :mod (c2 / certain))) :condition (c3 / concentrate-02 :ARG1-of (h2 / high-02 :degree (m3 / more)))) :ARG2 (a / activate-01 :polarity "-" :ARG0 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS") :xref (x1 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :ARG1 i2 :condition (e / experiment-01 :ARG0 (w / we)) :location (c4 / cell :name (n4 / name :op1 "neutrophil"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "13")))) # ::id bio.chicago_2015.24746 # ::date 2015-11-01T04:41:47 # ::file bio_chicago_2015_24746.txt # ::snt In addition, the back-phosphorylation experiments demonstrated an increase in a PKC-specific phosphorylation of AC7 within HEK 293 cells after exposure of the intact cells to ethanol. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (a / and :op2 (d / demonstrate-01 :ARG0 (e / experiment-01 :ARG2 (p2 / phosphorylate-01 :ARG1-of (b / back-02))) :ARG1 (i / increase-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (p / protein :name (n2 / name :op1 "AC7")) :ARG2 (e2 / enzyme :name (n3 / name :op1 "PKC") :xref (x / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :ARG1-of (s / specific-02) :location (c / cell :name (n / name :op1 "HEK" :op2 "293"))) :time (a2 / after :op1 (e3 / expose-01 :ARG1 (c2 / cell :mod (i2 / intact)) :ARG2 (e4 / ethanol)))))) # ::id bio.chicago_2015.24858 # ::date 2015-11-01T04:48:48 # ::file bio_chicago_2015_24858.txt # ::snt More recent study demonstrated Akt also phosphorylates FKHRL1, one of the Forkhead transcription factor family members, and transcriptionally regulates Fas-dependent apoptosis in cerebellar granule neurons. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (d / demonstrate-01 :ARG0 (s / study-01 :time (r2 / recent :degree (m / more))) :ARG1 (a2 / and :op1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "FKHRL1") :ARG1-of (i / include-91 :ARG2 (p5 / protein-family :name (n6 / name :op1 "Forkhead") :ARG0-of (t / transcribe-01))) :xref (x2 / xref :value "UNIPROT:FOXO3_HUMAN" :prob "1.002")) :ARG2 (e / enzyme :name (n / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :mod (a / also)) :op2 (r / regulate-01 :ARG0 e :ARG1 (a3 / apoptosis :ARG0-of (d2 / depend-01 :ARG1 (p3 / protein :name (n4 / name :op1 "Fas") :xref (x / xref :value "UNIPROT:FAS_HUMAN" :prob "0.603")))) :manner t) :location (n5 / neuron :mod (g / granule) :mod (c / cerebellar)))) # ::id bio.chicago_2015.24920 # ::date 2015-11-01T05:05:07 # ::file bio_chicago_2015_24920.txt # ::snt These results suggest that p38 and JNK activation by Cr(VI) is mediated differently through oxidative stress in CL3 cells, while ERK is less sensitive. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t / thing :ARG1-of (r / result-01) :mod (t2 / this)) :ARG1 (c / contrast-01 :ARG1 (m / mediate-01 :ARG1 (a / activate-01 :ARG0 (s4 / small-molecule :name (n3 / name :op1 "Cr(VI)")) :ARG1 (a2 / and :op1 (e3 / enzyme :name (n4 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op2 (e / enzyme :name (n5 / name :op1 "JNK") :xref (x2 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")))) :ARG1-of (d / differ-02 :manner (s2 / stress-02 :mod (o / oxidize-01) :location (c2 / cell-line :name (n2 / name :op1 "CL3"))))) :ARG2 (s3 / sensitive-03 :ARG0 (e2 / enzyme :name (n6 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :degree (l / less)))) # ::id bio.chicago_2015.24932 # ::date 2015-11-01T05:13:29 # ::file bio_chicago_2015_24932.txt # ::snt We have identified a new SH3-containing Rac target, POSH, which activates JNK when transfected into Cos-1 cells and induces nuclear translocation of NF-kappaB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (i / identify-01 :ARG0 (w2 / we) :ARG1 (p / protein :name (n7 / name :op1 "POSH") :ARG0-of (t4 / target-01 :ARG1 (e / enzyme :name (n / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG0-of (a / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :condition (t2 / transfect-01 :ARG1 (c2 / cell-line :name (n4 / name :op1 "Cos-1")))) :ARG0-of (i2 / induce-01 :ARG2-of (t3 / translocate-01 :ARG1 (p2 / protein :name (n6 / name :op1 "NF-kappaB") :xref (x / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.382")) :ARG3 (n5 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8"))))) :ARG0-of (c / contain-01 :ARG1 (p4 / protein-segment :name (n2 / name :op1 "SH3"))) :ARG1-of (n8 / new-02) :xref (x3 / xref :value "UNIPROT:SH3R1_HUMAN" :prob "1.002"))) # ::id bio.chicago_2015.24982 # ::date 2015-11-01T05:26:59 # ::file bio_chicago_2015_24982.txt # ::snt Recent reports on Cdc42 and Rac1 activation of JNK also failed to establish a clear hierarchal action of these Rho-related GTPases( 38, 39) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (f / fail-01 :ARG1 (r / report-01 :ARG1 (a2 / activate-01 :ARG0 (a3 / and :op1 (p / protein :name (n / name :op1 "Cdc42") :xref (x3 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :op2 (p2 / protein :name (n2 / name :op1 "Rac1") :xref (x2 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :time (r3 / recent)) :ARG2 (e / establish-01 :ARG0 r :ARG1 (a4 / act-02 :ARG0 (e2 / enzyme :name (n4 / name :op1 "GTPase") :ARG1-of (r2 / relate-01 :ARG2 (p4 / protein-family :name (n5 / name :op1 "Rho"))) :xref (x1 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :mod (h / hierarchy :ARG1-of (c / clear-06)))) :mod (a / also) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a6 / and :op1 "38" :op2 "39"))))) # ::id bio.chicago_2015.25001 # ::date 2015-11-01T05:32:38 # ::file bio_chicago_2015_25001.txt # ::snt A dominant negative form of RHAMMv4 inhibits mutant active Ras activation of ERK and coimmunoprecipitates with both mitogen-activated protein kinase kinase and ERK, suggesting that the intracellular RHAMMv4 acts downstream of Ras, possibly at the level of mitogen-activated protein kinase kinase-ERK interactions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a5 / and :op1 (i / inhibit-01 :ARG0 (p2 / protein :name (n3 / name :op1 "RHAMMv4") :mod (f / form :ARG0-of (d / dominate-01) :ARG2-of (m / mutate-01 :mod "-/-")) :xref (x3 / xref :value "UNIPROT:HMMR_HUMAN" :prob "0.312")) :ARG1 (a2 / activate-01 :ARG0 (e / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m2 / mutate-01) :ARG1-of (a / activate-01) :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (e3 / enzyme :name (n6 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :op2 (c / coimmunoprecipitate-01 :ARG1 p2 :ARG2 (a3 / and :op1 (e4 / enzyme :name (n7 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase") :xref (x / xref :value "UNIPROT:A0A024QZ12_HUMAN" :prob "0.701")) :op2 e3)) :ARG0-of (s2 / suggest-01 :ARG1 (a4 / act-02 :ARG0 (p / protein :name (n / name :op1 "RHAMMv4") :mod (i4 / intracellular) :xref (x5 / xref :value "UNIPROT:HMMR_HUMAN" :prob "0.312")) :location (r / relative-position :op1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :direction (d2 / downstream)) :condition (l2 / level :location-of (i3 / interact-01 :ARG0 e4 :ARG1 e3) :ARG1-of (p3 / possible-01))))) # ::id bio.chicago_2015.25013 # ::date 2015-11-01T05:49:30 # ::file bio_chicago_2015_25013.txt # ::snt Dishevelled decreases GSK-3beta phosphorylation of tau. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (d / decrease-01 :ARG0 (p2 / protein :name (n / name :op1 "Dishevelled") :xref (x / xref :value "UNIPROT:DVL1_HUMAN" :prob "0.393")) :ARG1 (p3 / phosphorylate-01 :ARG1 (p / protein :name (n2 / name :op1 "tau") :xref (x1 / xref :value "UNIPROT:TAU_HUMAN" :prob "0.603")) :ARG2 (e2 / enzyme :name (n3 / name :op1 "GSK-3beta") :xref (x2 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")))) # ::id bio.chicago_2015.25044 # ::date 2015-11-01T05:52:00 # ::file bio_chicago_2015_25044.txt # ::snt Isolated S.cerevisiae mitochondria released cytochrome c, but did not induce apoptosis when incubated in Xenopus extracts (R.M.Kluck, D.R.Green, M.Yaffe, E.Margoliash and D.D.Newmeyer, in preparation). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c / contrast-01 :ARG1 (r / release-01 :ARG0 (m / mitochondria :part-of (o2 / organism :name (n8 / name :op1 "S.cerevisiae") :ARG1-of (i3 / isolate-01)) :xref (x / xref :value "GO:0005739" :prob "0.8")) :ARG1 (p8 / protein :name (n7 / name :op1 "cytochrome" :op2 "c"))) :ARG2 (i / induce-01 :polarity "-" :ARG0 m :ARG2 (a2 / apoptosis)) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n2 / name :op1 "R.M.Kluck")) :op2 (p2 / person :name (n / name :op1 "D.R.Green")) :op3 (p4 / person :name (n3 / name :op1 "M.Yaffe")) :op4 (p5 / person :name (n4 / name :op1 "E.Margoliash")) :op5 (p6 / person :name (n5 / name :op1 "D.D.Newmeyer"))) :ARG1-of (p7 / prepare-01))) :condition (i2 / incubate-01 :ARG1 m :location (e / extract-01 :mod (o / organism :name (n6 / name :op1 "Xenopus"))))) # ::id bio.chicago_2015.25064 # ::date 2015-11-01T06:01:32 # ::file bio_chicago_2015_25064.txt # ::snt ( A) Functional Rho is required for efficient VASP-induced SRF activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (r / require-01 :li "A" :ARG0 (a / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "SRF") :xref (x / xref :value "UNIPROT:SRF_HUMAN" :prob "1.003")) :ARG1-of (e2 / efficient-01) :ARG2-of (i / induce-01 :ARG0 (p / protein :name (n3 / name :op1 "VASP") :xref (x2 / xref :value "UNIPROT:VASP_HUMAN" :prob "1.003")))) :ARG1 (e / enzyme :name (n / name :op1 "Rho") :ARG0-of (f / function-01) :xref (x1 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602"))) # ::id bio.chicago_2015.25079 # ::date 2015-11-01T06:05:02 # ::file bio_chicago_2015_25079.txt # ::snt Phosphorylation of AC7 by PKC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "AC7")) :ARG2 (e / enzyme :name (n / name :op1 "PKC") :xref (x / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))) # ::id bio.chicago_2015.25123 # ::date 2015-11-01T06:42:14 # ::file bio_chicago_2015_25123.txt # ::snt PDK1 phosphorylation of PAK1 was not blocked by pretreatment with wortmannin or when PDK1 was mutated to prevent phosphatidylinositol binding, indicating this process is independent of phosphatidylinositol 3-kinase activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (b / block-01 :polarity "-" :ARG1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "PAK1") :xref (x / xref :value "UNIPROT:PAK1_HUMAN" :prob "1.004")) :ARG2 (e / enzyme :name (n / name :op1 "PDK1") :xref (x2 / xref :value "UNIPROT:PDK1_HUMAN" :prob "1.003"))) :ARG3 (o / or :op1 (p3 / pretreat-01 :ARG3 (s / small-molecule :name (n3 / name :op1 "wortmannin") :xref (x4 / xref :value "PUBCHEM:312145" :prob "18.013371"))) :op1 (m / mutate-01 :ARG1 e :purpose (p / prevent-01 :ARG1 (b2 / bind-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "phosphatidylinositol") :xref (x3 / xref :value "PUBCHEM:53477912" :prob "13.111277")))))) :ARG0-of (i / indicate-01 :ARG1 (d / depend-01 :polarity "-" :ARG0 (p5 / process-02 :mod (t / this)) :ARG1 (a / activity-06 :ARG0 (e2 / enzyme :name (n5 / name :op1 "phosphatidylinositol" :op2 "3-kinase") :xref (x1 / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.701")))))) # ::id bio.chicago_2015.25144 # ::date 2015-11-01T07:53:24 # ::file bio_chicago_2015_25144.txt # ::snt Requirements for Presenilin-Dependent Cleavage of Notch and Other Transmembrane Proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (r / require-01 :ARG0 (c / cleave-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "Notch") :xref (x1 / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.323")) :op2 (p2 / protein :mod (t / transmembrane) :mod (o / other))) :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n / name :op1 "Presenilin") :xref (x / xref :value "UNIPROT:A0A024R6A3_HUMAN" :prob "1.001"))))) # ::id bio.chicago_2015.25172 # ::date 2015-11-01T08:04:51 # ::file bio_chicago_2015_25172.txt # ::snt In contrast, intersectin activated Elk-1 to levels 2- to 3-fold higher than the level obtained with maximal EGF stimulation (see Fig. 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (a / activate-01 :ARG0 (p4 / protein :name (n / name :op1 "intersectin") :xref (x / xref :value "UNIPROT:ITSN1_HUMAN" :prob "0.383")) :ARG1 (p / protein :name (n2 / name :op1 "Elk-1") :xref (x2 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :degree (l / level :quant-of p :degree (p2 / product-of :op1 (b / between :op1 "2" :op2 "3")) :ARG1-of (h2 / high-02 :compared-to (l2 / level :ARG1-of (o / obtain-01 :condition (s2 / stimulate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :degree (m2 / maximum)))) :degree (m3 / more)))) :ARG1-of (s3 / see-01 :mode "imperative" :ARG0 (y / you) :medium (f / figure :mod "2"))) # ::id bio.chicago_2015.25207 # ::date 2015-11-01T08:18:44 # ::file bio_chicago_2015_25207.txt # ::snt In contrast, MEFs deficient in downstream Apaf-1 once again displayed only early protection from BIM- or BAD-induced death (Figures 3B and 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c / contrast-01 :ARG2 (d / display-01 :ARG0 (c2 / cell :name (n / name :op1 "MEF") :ARG0-of (l / lack-01 :ARG1 (p / protein :name (n2 / name :op1 "Apaf-1") :location (d3 / downstream) :xref (x2 / xref :value "UNIPROT:APAF_HUMAN" :prob "0.622")))) :ARG1 (p2 / protect-01 :ARG2 (d4 / die-01 :ARG2-of (i / induce-01 :ARG0 (o3 / or :op1 (p3 / protein :name (n3 / name :op1 "BIM") :xref (x / xref :value "UNIPROT:B2L11_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n4 / name :op1 "BAD") :xref (x1 / xref :value "UNIPROT:BAD_HUMAN" :prob "1.004"))))) :time (e / early)) :mod (o4 / only) :mod (a3 / again :mod (o2 / once))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3B") :op2 (f2 / figure :mod "3C")))) # ::id bio.chicago_2015.25236 # ::date 2015-11-01T08:31:20 # ::file bio_chicago_2015_25236.txt # ::snt Taken together, the data indicate that PTEN can control p53 stability by both phosphatase and MDM2-dependent and -independent mechanisms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (i / indicate-01 :ARG0 (d / data) :ARG1 (p / possible-01 :ARG1 (c / control-01 :ARG0 (p2 / protein :name (n / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG1 (s / stability :poss (p3 / protein :name (n2 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :instrument (a / and :op1 (m / mechanism :mod (p4 / phosphatase)) :op2 (m2 / mechanism :ARG0-of (d2 / depend-01 :ARG1 (p5 / protein :name (n3 / name :op1 "MDM2") :xref (x2 / xref :value "UNIPROT:MDM2_HUMAN" :prob "1.003"))) :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 p5))))) :condition (t / take-01 :ARG1 d :mod (t2 / together))) # ::id bio.chicago_2015.25358 # ::date 2015-11-01T08:39:25 # ::file bio_chicago_2015_25358.txt # ::snt p300 acetylates histones H3 and H4 within nucleosomes located in the promoter and 5' proximal regions of the template. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / acetylate-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "histone" :op2 "H3") :xref (x / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "0.701")) :op2 (p3 / protein :name (n3 / name :op1 "histone" :op2 "H4") :xref (x1 / xref :value "UNIPROT:H4_HUMAN" :prob "0.702")) :location (n4 / nucleosome :location (a3 / and :op1 (r2 / region :mod (m / molecular-physical-entity :ARG0-of (p4 / promote-01))) :op2 (r3 / region :mod (p5 / proximal :mod "5")) :part-of (t / template)))) :ARG2 (p / protein :name (n / name :op1 "p300") :xref (x2 / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702"))) # ::id bio.chicago_2015.25362 # ::date 2015-11-01T08:44:02 # ::file bio_chicago_2015_25362.txt # ::snt The proposed cooperativity between sites may also explain why eIF4F complexes purified from plant ( 31, 47, 48), yeast ( 33), and Drosophila ( 35) do not contain eIF4A, despite the fact that direct binding of eIF4A to eIF4G can be demonstrated in wheat germ ( 49, 50) and yeast ( 51, 52) and that the affinity of yeast eIF4G for eIF4A ( K d 30 nM; Ref. 52) is comparable with that of the central site of human eIF4G ( K d = 17 nM; Fig. 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (p / possible-01 :ARG1 (e / explain-01 :ARG0 (c / cooperate-01 :ARG0 (s / site) :ARG1-of (p2 / propose-01)) :ARG1 (t / thing :ARG0-of (c2 / cause-01 :ARG1 (c3 / contain-01 :polarity "-" :ARG0 (m / macro-molecular-complex :ARG1-of (p3 / purify-01 :ARG2 (a2 / and :op1 (p4 / plant :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c8 / cite-01 :ARG2 (a10 / and :op1 "31" :op2 "47" :op3 "48"))))) :op2 (y / yeast :ARG1-of (d6 / describe-01 :ARG0 (p8 / publication :ARG1-of (c9 / cite-01 :ARG2 "33")))) :op3 (o / organism :name (n2 / name :op1 "Drosophila") :ARG1-of (d8 / describe-01 :ARG0 (p9 / publication :ARG1-of (c10 / cite-01 :ARG2 "35")))))) :mod (p12 / protein :name (n / name :op1 "eIF4F") :xref (x2 / xref :value "UNIPROT:IF4A2_HUMAN" :prob "0.702"))) :ARG1 (p6 / protein :name (n3 / name :op1 "eIF4A") :xref (x1 / xref :value "UNIPROT:IF4A1_HUMAN" :prob "0.702"))))) :concession (p5 / possible-01 :ARG1 (d10 / demonstrate-01 :ARG1 (a7 / and :op1 (b / bind-01 :ARG1 p6 :ARG2 p12 :ARG1-of (d / direct-02) :location (a4 / and :op1 (g / germ :mod (w / wheat) :ARG1-of (d12 / describe-01 :ARG0 (p10 / publication :ARG1-of (c11 / cite-01 :ARG2 (a3 / and :op1 "49" :op2 "50"))))) :op2 (y2 / yeast :ARG1-of (d15 / describe-01 :ARG0 (p11 / publication :ARG1-of (c12 / cite-01 :ARG2 (a5 / and :op1 "51" :op2 "52"))))))) :op2 (c4 / comparable-03 :ARG1 (a8 / affinity :poss (y3 / yeast :mod (p13 / protein :name (n4 / name :op1 "eIF4G") :quant (c5 / concentration-quantity :quant "30" :unit (n6 / nanomolar)) :xref (x / xref :value "UNIPROT:IF4G1_HUMAN" :prob "0.702"))) :ARG1-of (d18 / describe-01 :ARG0 (r / reference :mod "52")) :topic p6) :ARG2 (a9 / affinity :poss (s2 / site :mod (c6 / central) :mod (h / human) :part-of p13) :quant (c7 / concentration-quantity :quant "17" :unit (n5 / nanomolar)) :ARG1-of (d19 / describe-01 :ARG0 (f / figure :mod "6"))))))) :mod (a6 / also))) # ::id bio.chicago_2015.25364 # ::date 2015-11-01T08:44:36 # ::file bio_chicago_2015_25364.txt # ::snt In somatic cells, Cdc20 and Cdh1 binding to the APC is differentially regulated, resulting in a peak of APCCdc20 activity in mitosis and APCCdh1 activity in G1 (Kramer et al., 2000 ; Shirayama et al., 1998 ; Zachariae et al., 1998 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (r3 / regulate-01 :ARG1 (b / bind-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n / name :op1 "Cdc20") :xref (x / xref :value "UNIPROT:CDC20_HUMAN" :prob "0.633")) :op2 (p3 / protein :name (n2 / name :op1 "Cdh1") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "0.603"))) :ARG2 (p4 / protein :name (n3 / name :op1 "APC") :xref (x2 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004"))) :ARG1-of (r4 / result-01 :ARG2 (p5 / peak-01 :ARG1 (a3 / and :op1 (a4 / activity-06 :ARG0 (p14 / protein :name (n4 / name :op1 "APCCdc20")) :ARG1 (m / mitosis)) :op2 (a5 / activity-06 :ARG0 (p15 / protein :name (n5 / name :op1 "APCCdh1") :xref (x3 / xref :value "UNIPROT:APCD1_HUMAN" :prob "0.262")) :ARG1 (e / event :name (n6 / name :op1 "G1"))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (p6 / publication-91 :ARG0 (a6 / and :op1 (p7 / person :wiki "-" :name (n7 / name :op1 "Kramer")) :op2 (p / person :mod (o / other))) :time (d2 / date-entity :year "2000")) :op2 (p8 / publication-91 :ARG0 (a7 / and :op1 (p9 / person :wiki "-" :name (n8 / name :op1 "Shirayama")) :op2 (p10 / person :mod (o2 / other))) :time (d4 / date-entity :year "1998")) :op3 (p11 / publication-91 :ARG0 (a8 / and :op1 (p12 / person :wiki "-" :name (n9 / name :op1 "Zachariae")) :op2 (p13 / person :mod (o3 / other))) :time d4))) :location (c / cell :mod (s / somatic))) :ARG1-of (d3 / differ-02)) # ::id bio.chicago_2015.25419 # ::date 2015-11-01T08:57:55 # ::file bio_chicago_2015_25419.txt # ::snt Inhibition of NESK-induced JNK Activation by the Dominant Negative Mutants of MKK4 and MEKK1-- MKK4 is an upstream activator of JNK, which phosphorylates and activates JNK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m / multi-sentence :snt1 (i / inhibit-01 :ARG0 (a3 / and :op1 (e / enzyme :name (n4 / name :op1 "MKK4") :xref (x5 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "MEKK1") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of (d / dominate-01)) :ARG1 (a2 / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "JNK") :xref (x3 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG2-of (i2 / induce-01 :ARG0 (e4 / enzyme :name (n / name :op1 "NESK") :xref (x1 / xref :value "UNIPROT:NEST_HUMAN" :prob "0.262"))))) :snt2 (a4 / and :op1 (a6 / activate-01 :ARG0 (e7 / enzyme :name (n8 / name :op1 "MKK4") :xref (x2 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003")) :ARG1 (e8 / enzyme :name (n9 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :location (u2 / upstream)) :op2 (p / phosphorylate-01 :ARG1 e8 :ARG2 e7) :op3 (a5 / activate-01 :ARG0 e7 :ARG1 e8))) # ::id bio.chicago_2015.25430 # ::date 2015-11-01T09:06:15 # ::file bio_chicago_2015_25430.txt # ::snt The convex shape of the Scatchard plot indicated that Arg binds to F-actin with positive cooperativity (Fig. 1 G; ref. 19). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (i / indicate-01 :ARG0 (s / shape-01 :ARG1 (t / thing :name (n / name :op1 "Scatchard" :op2 "plot")) :ARG2 (c / convex)) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n2 / name :op1 "Arg") :xref (x1 / xref :value "UNIPROT:ABL2_HUMAN" :prob "0.603")) :ARG2 (p2 / protein :name (n3 / name :op1 "F-actin") :xref (x / xref :value "UNIPROT:NEXN_HUMAN" :prob "0.252")) :manner (c2 / cooperate-01 :ARG0 p :ARG1 p2 :mod (p3 / positive))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1G") :op2 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "19"))))) # ::id bio.chicago_2015.25436 # ::date 2015-11-01T09:13:24 # ::file bio_chicago_2015_25436.txt # ::snt Related chromosome binding sites for zeste, suppressors of zeste and Polycomb group proteins in Drosophila and their dependence on Enhancer of zeste function. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (a / and :op1 (a2 / and :op1 (s3 / site :ARG2-of (b2 / bind-01 :ARG0 (c / chromosome :ARG1-of (r / relate-01) :xref (x / xref :value "GO:0005694" :prob "0.8")) :ARG1 (p2 / protein :name (n3 / name :op1 "zeste")))) :op2 (m / molecular-physical-entity :ARG0-of (s4 / suppress-01 :ARG1 (a3 / and :op1 p2 :op2 (p3 / protein-family :name (n4 / name :op1 "Polycomb")))) :location (o / organism :name (n5 / name :op1 "Drosophila")))) :op2 (d / depend-01 :ARG0 a2 :ARG1 (m2 / molecular-physical-entity :ARG0-of (e2 / enhance-01 :ARG1 (f2 / function-01 :ARG1 p2))))) # ::id bio.chicago_2015.25466 # ::date 2015-11-01T09:38:28 # ::file bio_chicago_2015_25466.txt # ::snt The reason for the difference between this result in COS-7 cells and that in the yeast assay (Fig. 1 B) is not known, but the difference in mammalian cells and in yeast was also observed in the interaction of FKBP12 with TbetaR-I ( 11). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c / contrast-01 :ARG1 (k2 / know-01 :polarity "-" :ARG1 (t3 / thing :ARG0-of (c5 / cause-01 :ARG1 (d / differ-02 :ARG1 (t / thing :ARG1-of (r / result-01 :mod (t4 / this)) :location (c3 / cell-line :name (n / name :op1 "COS-7"))) :ARG2 (t2 / thing :ARG1-of (r2 / result-01) :time (a / assay-01 :instrument (y / yeast)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1B"))) :ARG2 (o / observe-01 :ARG1 (d3 / differ-02 :location (a2 / and :op1 (c4 / cell :mod (m / mammalian)) :op2 (y2 / yeast))) :time (i / interact-01 :ARG0 (p2 / protein :name (n3 / name :op1 "FKBP12") :xref (x / xref :value "UNIPROT:FKB1A_HUMAN" :prob "1.003")) :ARG1 (p / protein :name (n2 / name :op1 "TbetaR-I") :xref (x1 / xref :value "UNIPROT:TGFR1_HUMAN" :prob "1.003"))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "11"))) :mod (a3 / also))) # ::id bio.chicago_2015.25467 # ::date 2015-11-01T09:46:31 # ::file bio_chicago_2015_25467.txt # ::snt (C) A TSC syndrome-related GAP mutant of TSC2 fails to inhibit Rheb-induced S6K1 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / fail-01 :li "C" :ARG1 (m / mutate-01 :ARG1 (p / protein :name (n3 / name :op1 "GAP") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :ARG3 (p5 / protein :name (n4 / name :op1 "TSC2") :xref (x2 / xref :value "UNIPROT:TSC2_HUMAN" :prob "1.003")) :ARG1-of (r / relate-01 :ARG2 (s / syndrome :name (n5 / name :op1 "TSC")))) :ARG2 (i / inhibit-01 :ARG0 m :ARG1 (p2 / phosphorylate-01 :ARG3 (e / enzyme :name (n / name :op1 "S6K1") :xref (x / xref :value "UNIPROT:KS6B1_HUMAN" :prob "1.003")) :ARG2-of (i2 / induce-01 :ARG0 (p4 / protein :name (n2 / name :op1 "Rheb") :xref (x1 / xref :value "UNIPROT:RHEB_HUMAN" :prob "0.603")))))) # ::id bio.chicago_2015.25525 # ::date 2015-11-01T09:51:36 # ::file bio_chicago_2015_25525.txt # ::snt Tyr phosphorylation of PLSCR1 was detected by Western blotting with anti-Tyr(P) mAb PY99 ( upper panel, A) and abundance of immunoprecipitated PLSCR1 protein was detected with anti-PLSCR1 mAb 4D2 ( lower panel, A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op1 (d / detect-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n2 / name :op1 "Tyrosine") :part-of (p4 / protein :name (n3 / name :op1 "PLSCR1") :xref (x1 / xref :value "UNIPROT:PLS1_HUMAN" :prob "1.002")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG2 (i2 / immunoblot-01 :ARG3 (a4 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p3 / protein :name (n8 / name :op1 "PY99"))))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / panel :mod (u / upper) :mod (s2 / string-entity :value "A")))) :op2 (d2 / detect-01 :ARG1 (a2 / abound-01 :ARG2 (p7 / protein :name (n6 / name :op1 "PLSCR1") :ARG1-of (i / immunoprecipitate-01) :xref (x / xref :value "UNIPROT:PLS1_HUMAN" :prob "1.002"))) :ARG2 (a5 / antibody :ARG0-of (c / counter-01 :ARG1 (p8 / protein :name (n7 / name :op1 "PLSCR1") :xref (x2 / xref :value "UNIPROT:PLS1_HUMAN" :prob "1.002"))) :ARG1-of (l2 / label-01 :ARG2 (s / string-entity :value "4D2")) :mod (m / monoclone)) :ARG1-of (d4 / describe-01 :ARG0 (p9 / panel :ARG1-of (l / low-04 :degree (m3 / more)) :mod s2)))) # ::id bio.chicago_2015.25541 # ::date 2015-11-01T13:13:33 # ::file bio_chicago_2015_25541.txt # ::snt In transient transfection assays, we demonstrate that TLD cleaves SOG and that cleavage is stimulated by DPP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (a / and :op1 (c / cleave-01 :ARG0 (p / protein :name (n / name :op1 "TLD") :xref (x2 / xref :value "UNIPROT:TLDC1_HUMAN" :prob "0.232")) :ARG1 (p2 / protein :name (n2 / name :op1 "SOG") :xref (x / xref :value "UNIPROT:SOGA1_HUMAN" :prob "0.262"))) :op2 (s / stimulate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "DPP") :xref (x1 / xref :value "UNIPROT:DSPP_HUMAN" :prob "1.002")) :ARG1 c)) :time (a2 / assay-01 :ARG1 (t4 / transfect-01 :ARG1-of (t5 / transient-02)))) # ::id bio.chicago_2015.25564 # ::date 2015-11-01T13:17:50 # ::file bio_chicago_2015_25564.txt # ::snt In vitro transcription and translation of full-length wild-type Sgk (Wt Sgk), kinase dead Sgk (K127 M Sgk), N- and C -terminal deleted Sgk (deltaN Sgk, deltaC Sgk), catalytic domain of Sgk (Cat 60-355 Sgk), and truncated fragments of the Sgk central catalytic domain (60-157 Sgk) and (66-122 Sgk) subcloned into pCDNA3 vectors or pCite vectors were performed using the TNT coupled rabbit reticulocyte kit (Promega Corporation) according to manufacturer's instructions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / perform-01 :ARG1 (a2 / and :op1 (t2 / transcribe-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "Sgk") :mod (w / wild-type) :ARG1-of (l / long-03 :ARG2 (f / full)) :xref (x6 / xref :value "UNIPROT:SGK1_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n4 / name :op1 "Sgk") :xref (x5 / xref :value "UNIPROT:SGK1_HUMAN" :prob "0.603")) :op3 (e3 / enzyme :name (n9 / name :op1 "Sgk") :ARG1-of (m6 / mean-01 :ARG2 (a5 / and :op1 (e4 / enzyme :name (n10 / name :op1 "deltaN" :op2 "Sgk") :xref (x1 / xref :value "UNIPROT:DLL3_HUMAN" :prob "0.233")) :op2 (e5 / enzyme :name (n11 / name :op1 "deltaC" :op2 "Sgk") :xref (x / xref :value "UNIPROT:DLL3_HUMAN" :prob "0.233")))) :ARG0-of (h / have-03 :ARG1 (a4 / and :op1 (p5 / protein-segment :name (n12 / name :op1 "N-terminus")) :op2 (p6 / protein-segment :name (n13 / name :op1 "C-terminus")) :ARG1-of (d2 / delete-01))) :ARG1-of (d / die-01) :xref (x4 / xref :value "UNIPROT:SGK1_HUMAN" :prob "0.603")) :op4 (d3 / domain :mod (c4 / catalytic) :mod (e6 / enzyme :name (n14 / name :op1 "Sgk") :xref (x3 / xref :value "UNIPROT:SGK1_HUMAN" :prob "0.603")) :ARG1-of (m11 / mean-01 :ARG2 (e7 / enzyme :name (n15 / name :op1 "Cat" :op2 "Sgk") :extent (v / value :quant (b4 / between :op1 "60" :op2 "355")) :xref (x2 / xref :value "UNIPROT:CATS_HUMAN" :prob "0.212")))) :op5 (f2 / fragment-01 :ARG1 d3 :ARG1-of (t5 / truncate-01 :ARG4 (a6 / and :op1 (e8 / enzyme :name (n18 / name :op1 "Sgk") :value (b5 / between :op1 "60" :op2 "157") :xref (x8 / xref :value "UNIPROT:SGK1_HUMAN" :prob "0.603")) :op2 (e9 / enzyme :name (n19 / name :op1 "Sgk") :value (b6 / between :op1 "66" :op2 "122") :xref (x7 / xref :value "UNIPROT:SGK1_HUMAN" :prob "0.603")))) :ARG1-of (s / subclone-01 :ARG3 (o2 / or :op1 (v3 / vector :name (n17 / name :op1 "pCDNA3")) :op2 (v2 / vector :name (n16 / name :op1 "pCite"))))))) :op2 (t / translate-02 :ARG1 a3) :manner (i2 / in-vitro)) :ARG2 (u / use-01 :ARG1 (k / kit :consist-of (r / reticulocyte :part-of (r2 / rabbit) :mod (s2 / small-molecule :name (n / name :op1 "TNT") :ARG1-of (c2 / couple-01) :xref (x9 / xref :value "PUBCHEM:8376" :prob "17.126066"))) :mod (o / organization :wiki "-" :name (n2 / name :op1 "Promega" :op2 "Corporation"))) :ARG3-of (i / instruct-01 :ARG0 o))) # ::id bio.chicago_2015.25584 # ::date 2015-10-23T08:37:21 # ::file bio_chicago_2015_25584.txt # ::snt These results suggest that multiple positive-feedback loops exist among these genes during normal eye development and raised the possibility that ey may be required for ectopic retinal induction by eya and dac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op1 (s / suggest-01 :ARG0 (t / thing :ARG1-of (r / result-01) :mod (t2 / this)) :ARG1 (e / exist-01 :ARG1 (l / loop :mod (f / feedback) :mod (p / positive) :quant (m / multiple)) :location (g / gene :ARG1-of (i / include-91 :ARG2 (g2 / gene :mod (t3 / this)))) :time (d2 / develop-02 :ARG1 (e2 / eye) :ARG1-of (n / normal-02)))) :op1 (r2 / raise-01 :ARG0 t :ARG1 (p2 / possible-01 :ARG1 (p3 / possible-01 :ARG1 (r3 / require-01 :ARG0 (i2 / induce-01 :ARG0 (a2 / and :op1 (g5 / gene :name (n3 / name :op1 "eya") :xref (x / xref :value "UNIPROT:EYA1_HUMAN" :prob "0.202")) :op2 (g4 / gene :name (n4 / name :op1 "dac") :xref (x1 / xref :value "UNIPROT:AAAD_HUMAN" :prob "0.602"))) :ARG2 (r4 / retinal :mod (e3 / ectopic))) :ARG1 (p4 / protein :name (n2 / name :op1 "ey"))))))) # ::id bio.chicago_2015.25656 # ::date 2015-10-23T08:54:22 # ::file bio_chicago_2015_25656.txt # ::snt PKG phosphorylation of SF1 blocked its ability to bind to U2AF65 and inhibited pre-spliceosome assembly. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (b / block-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "SF1") :xref (x / xref :value "UNIPROT:SF01_HUMAN" :prob "1.002")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKG"))) :ARG1 (c / capable-01 :ARG1 e :ARG2 (b2 / bind-01 :ARG1 e :ARG2 (p3 / protein :name (n3 / name :op1 "U2AF65") :xref (x1 / xref :value "UNIPROT:U2AF2_HUMAN" :prob "1.002"))))) :op2 (i / inhibit-01 :ARG0 p :ARG1 (a2 / assemble-01 :time (b3 / before :op1 (s / small-molecule :name (n4 / name :op1 "spliceosome")))))) # ::id bio.chicago_2015.25659 # ::date 2015-10-23T09:53:45 # ::file bio_chicago_2015_25659.txt # ::snt The possibility that caffeine inhibits ATM directly was therefore tested. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (t / test-01 :ARG1 (p2 / possible-01 :ARG1 (i / inhibit-01 :ARG0 (c / caffeine) :ARG1 (e / enzyme :name (n / name :op1 "ATM") :xref (x / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")) :ARG1-of (d / direct-02)) :ARG0-of (c2 / cause-01))) # ::id bio.chicago_2015.25663 # ::date 2015-10-23T09:59:58 # ::file bio_chicago_2015_25663.txt # ::snt In quiescent Swiss 3T3 fibroblasts, the activation of Rho induces the assembly of actin into bundles and stress fibers, while the activation of Rac and Cdc42 induces actin polymerization leading to ruffles and filopodia, respectively (reviewed by Hall and Nobes, 2000 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (c2 / contrast-01 :ARG1 (i / induce-01 :ARG0 (a / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "Rho") :xref (x3 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602"))) :ARG2 (a2 / assemble-01 :ARG1 (f / fiber :ARG1-of (s / stress-02) :ARG1-of (b / bundle-01)) :ARG2 (p2 / protein :name (n3 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :ARG2 (i2 / induce-01 :ARG0 (a3 / activate-01 :ARG1 (a4 / and :op1 (e / enzyme :name (n4 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :op2 (p3 / protein :name (n5 / name :op1 "Cdc-42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.623")))) :ARG2 (p4 / polymerize-01 :ARG1 p2) :ARG0-of (l / lead-03 :ARG2 (a5 / and :op1 (t / thing :ARG1-of (r / ruffle-02)) :op2 (f2 / filopodia) :mod (r2 / respective)))) :location (f3 / fibroblast :mod (q / quiescent) :mod (c4 / cell-line :name (n9 / name :op1 "Swiss" :op2 "3T3"))) :ARG1-of (r3 / review-01 :ARG0 (a6 / and :op1 (p5 / person :name (n7 / name :op1 "Hall")) :op2 (p6 / person :name (n8 / name :op1 "Nobes"))) :time (d / date-entity :year "2000"))) # ::id bio.chicago_2015.25683 # ::date 2015-10-23T10:14:51 # ::file bio_chicago_2015_25683.txt # ::snt firstly, the isolated SH3 domain binds tightly to dynamin in vitro; and secondly, coexpression of both dynamin and the amphiphysin SH3 domain rescues the transferrin uptake. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (b / bind-01 :ARG1 (p / protein-segment :name (n / name :op1 "SH3" :op2 "domain") :ARG1-of (i / isolate-01)) :ARG2 (p5 / protein :name (n2 / name :op1 "dynamin") :xref (x2 / xref :value "UNIPROT:DYN2_HUMAN" :prob "0.343")) :ARG1-of (t / tight-05) :manner (i2 / in-vitro) :ord (o / ordinal-entity :value "1")) :op2 (r / rescue-01 :ARG0 (c / coexpress-01 :ARG2 (a2 / and :op1 p5 :op2 (p2 / protein-segment :name n :part-of (p3 / protein :name (n4 / name :op1 "amphiphysin") :xref (x / xref :value "UNIPROT:AMPH_HUMAN" :prob "0.702"))))) :ARG1 (t2 / take-up-13 :ARG2 (p4 / protein :name (n5 / name :op1 "transferrin") :xref (x1 / xref :value "UNIPROT:TRFE_HUMAN" :prob "0.702"))) :ord (o2 / ordinal-entity :value "2"))) # ::id bio.chicago_2015.25696 # ::date 2015-10-23T10:28:29 # ::file bio_chicago_2015_25696.txt # ::snt RACK1 also interacted with the IGF-1R in fibroblasts and MCF-7 cells and with endogenous insulin receptor in COS cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (a / and :op1 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "RACK1") :xref (x1 / xref :value "UNIPROT:GBLP_HUMAN" :prob "1.003")) :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1R") :xref (x / xref :value "UNIPROT:IGF1R_HUMAN" :prob "0.683")) :mod (a2 / also) :location (a3 / and :op1 (f / fibroblast) :op2 (c / cell-line :name (n3 / name :op1 "MCF-7")))) :op2 (i2 / interact-01 :ARG0 p :ARG1 (r2 / receptor :mod (i3 / insulin) :mod (e / endogenous)) :location (c2 / cell-line :name (n5 / name :op1 "COS")))) # ::id bio.chicago_2015.25712 # ::date 2015-10-23T10:39:05 # ::file bio_chicago_2015_25712.txt # ::snt Given that DLAK has the most extensive sequence similarity with IKK and that DLAK exists in the form of a complex with Cactus and LPS-induced Cactus degradation is specifically blocked by dominant-negative DLAK, we could speculate that the dominant-negative form of DLAK fails to transmit the Cactus degradation signal, essential for Rel/ NF-kappaB activation and subsequently prevents LPS inducibility of at least certain kappaB-dependent antimicrobial peptide genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (a2 / and :op1 (h / have-03 :ARG0 (e / enzyme :name (n / name :op1 "DLAK") :xref (x4 / xref :value "UNIPROT:DNS2B_HUMAN" :prob "0.222")) :ARG1 (r / resemble-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "IKK") :xref (x1 / xref :value "UNIPROT:IKKA_HUMAN" :prob "0.262")) :mod (s / sequence) :ARG1-of (e3 / extensive-03 :ARG2 (m / most)))) :op2 (e4 / exist-01 :ARG1 e :ARG2 (f / form-02 :ARG0 (a5 / and :op1 e :op2 (p2 / protein :name (n3 / name :op1 "Cactus") :xref (x2 / xref :value "UNIPROT:CATIN_HUMAN" :prob "0.242"))) :ARG1 (c2 / complex))) :op3 (b / block-01 :ARG0 (e5 / enzyme :name (n6 / name :op1 "DLAK") :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of (d2 / dominate-01) :xref (x / xref :value "UNIPROT:DNS2B_HUMAN" :prob "0.222")) :ARG1 (d / degrade-01 :ARG1 p2 :ARG2-of (i / induce-01 :ARG0 (m3 / molecular-physical-entity :name (n5 / name :op1 "LPS") :xref (x7 / xref :value "PUBCHEM:53481794" :prob "9.905254")))) :ARG1-of (s3 / specific-02))) :ARG1 (p / possible-01 :ARG1 (s4 / speculate-01 :ARG0 (w / we) :ARG1 (a4 / and :op1 (f2 / fail-01 :ARG0 e5 :ARG1 (t / transmit-01 :ARG0 (f3 / form-02) :ARG1 (s5 / signal-07 :ARG1 d :mod (e6 / essential) :condition-of (a3 / activate-01 :ARG1 (s7 / slash :op1 (p4 / protein :name (n7 / name :op1 "Rel") :xref (x5 / xref :value "UNIPROT:REL_HUMAN" :prob "0.603")) :op2 (p3 / protein :name (n10 / name :op1 "NF-kappaB") :xref (x3 / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.382"))))))) :op2 (p6 / prevent-01 :ARG0 f3 :ARG1 (i2 / induce-01 :ARG0 m3 :ARG1 (g / gene :mod (p8 / peptide) :ARG0-of (o / oppose-01 :ARG1 (m4 / microbe)) :ARG0-of (d3 / depend-01 :ARG1 (p5 / protein :name (n8 / name :op1 "kappaB") :xref (x6 / xref :value "UNIPROT:KBRS1_HUMAN" :prob "0.272"))) :mod (a / at-least) :mod (c3 / certain)) :ARG1-of (p7 / possible-01)) :time (s6 / subsequent)))))) # ::id bio.chicago_2015.25761 # ::date 2015-10-23T12:05:09 # ::file bio_chicago_2015_25761.txt # ::snt However, only the JNK cascade can activate c-Jun ( 16, 65, 66, 67). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (h / have-concession-91 :ARG1 (p4 / possible-01 :ARG1 (a / activate-01 :ARG0 (p / pathway :name (n3 / name :op1 "JNK")) :ARG1 (p2 / protein :name (n2 / name :op1 "c-Jun")) :mod (o / only))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 "16" :op2 "65" :op3 "66" :op4 "67"))))) # ::id bio.chicago_2015.25828 # ::date 2015-10-23T12:12:43 # ::file bio_chicago_2015_25828.txt # ::snt Under conditions where Rac induced strong actin polymerization and lamellipodia, POSH induced no detectable assembly of actin filaments (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (c / condition-01 :ARG1 (i2 / induce-01 :ARG0 (p5 / protein :name (n4 / name :op1 "POSH") :xref (x1 / xref :value "UNIPROT:SH3R1_HUMAN" :prob "1.002")) :ARG2 (a2 / assemble-02 :ARG2 (f / filament :mod "p2") :ARG1-of (d / detect-01 :ARG1-of (p4 / possible-01 :polarity "-")))) :ARG2 (i / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG2 (a / and :op1 (p / polymerize-01 :ARG1 (p2 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG1-of (s / strong-02)) :op2 (p3 / protein :name (n3 / name :op1 "lamellipodia") :xref (x3 / xref :value "UNIPROT:RAPH1_HUMAN" :prob "0.372")))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s2 / show-01 :polarity "-")))) # ::id bio.chicago_2015.25847 # ::date 2015-10-23T13:06:00 # ::file bio_chicago_2015_25847.txt # ::snt Dvl2 Activation of JNK Does Not Require MEKK1 and Binding of Dvl2 to Axin Is Independent of the Axin-MEKK1 Interaction-- We have previously demonstrated that MEKK1 binds Axin and is critical for Axin activation of JNK ( 22). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (m / multi-sentence :snt1 (a / and :op1 (r / require-01 :polarity "-" :ARG0 (a2 / activate-01 :ARG0 (p / protein :name (n / name :op1 "Dvl2") :xref (x6 / xref :value "UNIPROT:DVL2_HUMAN" :prob "0.604")) :ARG1 (e / enzyme :name (n2 / name :op1 "JNK") :xref (x5 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEKK1") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003"))) :op2 (d / depend-01 :polarity "-" :ARG0 (b / bind-01 :ARG1 p :ARG2 (p2 / protein :name (n4 / name :op1 "Axin") :xref (x / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602"))) :ARG1 (i / interact-01 :ARG0 p2 :ARG1 e2))) :snt2 (d2 / demonstrate-01 :ARG0 (w2 / we) :ARG1 (b2 / bind-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "MEKK1") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :ARG2 (p3 / protein :name (n6 / name :op1 "Axin") :xref (x4 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1-of (c / critical-02 :ARG2 (a3 / activate-01 :ARG0 p3 :ARG1 (e4 / enzyme :name (n7 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))))) :time (p4 / previous) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "22"))))) # ::id bio.chicago_2015.25875 # ::date 2015-10-23T13:15:12 # ::file bio_chicago_2015_25875.txt # ::snt We show that the Tuberin-Hamartin heterodimer inhibits Rheb-induced S6K1 activation during conditions of amino acid withdrawal (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG0 (h / heterodimer :part (p / protein :name (n / name :op1 "Tuberin") :xref (x3 / xref :value "UNIPROT:TSC2_HUMAN" :prob "1.002")) :part (p2 / protein :name (n2 / name :op1 "Hamartin") :xref (x / xref :value "UNIPROT:TSC1_HUMAN" :prob "1.002"))) :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "S6K1") :xref (x1 / xref :value "UNIPROT:KS6B1_HUMAN" :prob "1.003")) :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "Rheb") :xref (x2 / xref :value "UNIPROT:RHEB_HUMAN" :prob "0.603")))) :ARG1-of (c / condition-01 :ARG2 (w2 / withdraw-01 :ARG1 (a2 / amino-acid)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id bio.chicago_2015.25880 # ::date 2015-10-23T13:27:32 # ::file bio_chicago_2015_25880.txt # ::snt Therefore, downregulation of Rho activity by Cdc42 may either involve activation of Rac or occur independently of Rac, possibly by a downstream signaling pathway shared by Cdc42 and Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (c / cause-01 :ARG1 (p3 / possible-01 :ARG1 (o / or :op1 (i / involve-01 :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG2 (d / downregulate-01 :ARG1 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "Rho") :xref (x2 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602"))) :ARG2 (p2 / protein :name (n2 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")))) :op2 (d3 / depend-01 :polarity "-" :ARG0 d :ARG1 e :ARG1-of (c2 / cause-01 :ARG0 (s / share-01 :ARG0 (a3 / and :op1 p2 :op2 e) :ARG1 (p5 / pathway :ARG0-of (s2 / signal-07 :direction (d4 / downstream)))) :ARG1-of (p4 / possible-01)))))) # ::id bio.chicago_2015.25882 # ::date 2015-10-23T13:55:36 # ::file bio_chicago_2015_25882.txt # ::snt Ethanol-induced Cbl tyrosine phosphorylation in rat cerebellum # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (p3 / protein :name (n2 / name :op1 "Cbl") :xref (x / xref :value "UNIPROT:CBL_HUMAN" :prob "0.604")) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2-of (i / induce-01 :ARG0 (e / ethanol)) :location (c / cerebellum :mod (r / rat))) # ::id bio.chicago_2015.25952 # ::date 2015-10-23T13:59:03 # ::file bio_chicago_2015_25952.txt # ::snt Importantly, the RNAi oligo inhibits RhoA activation by Wnt-1, Fz, or Dvl, but not by Ephexin (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (n / nucleic-acid :name (n8 / name :op1 "RNAi" :op2 "oligo")) :ARG1 (a / activate-01 :ARG0 (o / or :op1 (p2 / protein :name (n3 / name :op1 "Wnt-1") :xref (x1 / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.592")) :op2 (p3 / protein :name (n4 / name :op1 "Fz")) :op3 (p4 / protein :name (n5 / name :op1 "Dvl") :xref (x2 / xref :value "UNIPROT:DVLP1_HUMAN" :prob "0.602"))) :ARG1 (p / protein :name (n6 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")))) :ARG2 (i3 / inhibit-01 :polarity "-" :ARG0 (n2 / nucleic-acid :name (n9 / name :op1 "RNA")) :ARG1 (a2 / activate-01 :ARG0 (p5 / protein :name (n7 / name :op1 "Ephexin") :xref (x3 / xref :value "UNIPROT:NGEF_HUMAN" :prob "0.363")) :ARG1 p)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3C")) :mod (i2 / important)) # ::id bio.chicago_2015.26022 # ::date 2015-10-23T14:09:48 # ::file bio_chicago_2015_26022.txt # ::snt Regulation of GSK-3beta by PKA and PP1 in the AKAP220 Complex-- Finally we examined the physiological significance of the binding of GSK-3beta to AKAP220. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (m / multi-sentence :snt1 (r / regulate-01 :ARG0 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "PKA") :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :op2 (p / protein :name (n3 / name :op1 "PP1") :xref (x5 / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002"))) :ARG1 (e / enzyme :name (n / name :op1 "GSK-3beta") :xref (x3 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :location (c / complex :mod (p2 / protein :name (n4 / name :op1 "AKAP220") :xref (x / xref :value "UNIPROT:AKA11_HUMAN" :prob "1.002")))) :snt2 (e3 / examine-01 :ARG0 (w / we) :ARG1 (s / signify-01 :ARG0 (b / bind-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "GSK-3beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :ARG2 (p4 / protein :name (n6 / name :op1 "AKAP220") :xref (x4 / xref :value "UNIPROT:AKA11_HUMAN" :prob "1.002"))) :mod (p3 / physiology) :time (f / final)))) # ::id bio.chicago_2015.26080 # ::date 2015-10-23T14:14:08 # ::file bio_chicago_2015_26080.txt # ::snt In accordance with our previous results in 32D/EpoR-Wt cells ( 4), Epo stimulation induced activation of ERK1 and ERK2, which was detected by their phosphorylation on tyrosines, in 32DE/Tet- CrkL cells (Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / induce-01 :ARG0 (s / stimulate-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "Epo") :xref (x3 / xref :value "PUBCHEM:5288169" :prob "16.321695"))) :ARG2 (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1-of (d / detect-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (a4 / amino-acid :name (n5 / name :op1 "tyrosine") :part-of a3 :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :location (c / cell-line :name (n6 / name :op1 "32DE") :mod (p / protein :name (n / name :op1 "Tet-CrkL")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3")) :ARG1-of (a / accord-02 :ARG2 (t / thing :ARG2-of (r / result-01 :ARG1 (c2 / cell-line :name (n7 / name :op1 "32D") :mod (p6 / protein :name (n8 / name :op1 "EpoR") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:EPOR_HUMAN" :prob "0.604"))) :time (p4 / previous)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "4")))))) # ::id bio.chicago_2015.26085 # ::date 2015-10-23T14:23:59 # ::file bio_chicago_2015_26085.txt # ::snt Cross Talk between ERK and PKA Is Required for Ca2+ Stimulation of CREB-Dependent Transcription and ERK Nuclear Translocation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / require-01 :ARG0 (a / and :op1 (s / stimulate-01 :ARG0 (c2 / calcium :ARG1-of (i / ionize-01 :value "2+")) :ARG1 (t2 / transcribe-01 :ARG0-of (d / depend-01 :ARG1 (p2 / protein :name (n3 / name :op1 "CREB") :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))))) :op2 (t3 / translocate-01 :ARG1 "e2" :mod (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")))) :ARG1 (t / talk-01 :ARG0 (e2 / enzyme :name (n / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1-of (c / cross-01))) # ::id bio.chicago_2015.26119 # ::date 2015-10-23T14:31:59 # ::file bio_chicago_2015_26119.txt # ::snt Acetylation of MyoD Directed by PCAF Is Necessary for the Execution of the Muscle Program. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (n2 / need-01 :ARG0 (e / execute-02 :ARG1 (p2 / program :mod (m / muscle))) :ARG1 (a / acetylate-01 :ARG1 (p / protein :name (n3 / name :op1 "MyoD") :xref (x1 / xref :value "UNIPROT:MYOD1_HUMAN" :prob "0.602")) :ARG1-of (d / direct-01 :ARG0 (p3 / protein :name (n4 / name :op1 "PCAF") :xref (x / xref :value "UNIPROT:KAT2B_HUMAN" :prob "1.002"))))) # ::id bio.chicago_2015.26145 # ::date 2015-10-23T14:34:15 # ::file bio_chicago_2015_26145.txt # ::snt Binding of Cdc20 and Cdh1 to the APC is differentially regulated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (r / regulate-01 :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "Cdc20") :xref (x2 / xref :value "UNIPROT:CDC20_HUMAN" :prob "0.633")) :op2 (p2 / protein :name (n2 / name :op1 "Cdh1") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "0.603"))) :ARG2 (p3 / protein :name (n3 / name :op1 "APC") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004"))) :manner (d / differential)) # ::id bio.chicago_2015.26161 # ::date 2015-10-23T14:38:04 # ::file bio_chicago_2015_26161.txt # ::snt As shown in Figure 3, neither of these fractions alone supported dATP-dependent activation of CPP32 (lanes 3 - 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (s / support-01 :polarity "-" :ARG0 (f / fraction-01 :mod (t / this) :mod (a / alone)) :ARG1 (a2 / activate-01 :ARG1 (p / protein :wiki "Caspase_3" :name (n / name :op1 "CPP32") :xref (x / xref :value "UNIPROT:CASP3_HUMAN" :prob "1.002")) :ARG0-of (d / depend-01 :ARG1 (s3 / small-molecule :wiki "Deoxyadenosine_triphosphate" :name (n2 / name :op1 "dATP") :xref (x1 / xref :value "PUBCHEM:15993" :prob "16.321695")))) :ARG1-of (s2 / show-01 :ARG0 (f2 / figure :mod "3")) :ARG1-of (d2 / describe-01 :ARG0 (v / value-interval :op1 (l / lane :mod "3") :op2 (l2 / lane :mod "6")))) # ::id bio.chicago_2015.26163 # ::date 2015-10-25T06:06:51 # ::file bio_chicago_2015_26163.txt # ::snt We do not know at present how Bni1p and Bnr1p are involved in this profilin-actin interaction, but the genetic results that the phenotypes of the bni1 bnr1 mutant are similar to those of the pfy1 mutant indicate that the interactions of Bni1p and Bnr1p with profilin are important for the proper functions of profilin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (c / contrast-01 :ARG1 (k / know-01 :polarity "-" :ARG0 (w / we) :ARG1 (t2 / thing :manner-of (i / involve-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "Bni1p")) :op2 (p3 / protein :name (n2 / name :op1 "Bnr1p"))) :ARG2 (i2 / interact-01 :ARG0 (p4 / protein :name (n3 / name :op1 "profilin") :xref (x / xref :value "UNIPROT:B4DNH1_HUMAN" :prob "0.701")) :ARG1 (p5 / protein :name (n4 / name :op1 "actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :mod (t / this)))) :time (p / present)) :ARG2 (i3 / indicate-01 :ARG0 (r2 / result-01 :ARG2 (r / resemble-01 :ARG1 (a2 / and :op1 (p6 / phenotype :mod (p8 / protein :name (n5 / name :op1 "bni1") :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:SEC20_HUMAN" :prob "0.232"))) :op2 (p7 / phenotype :mod (p9 / protein :name (n6 / name :op1 "bnr1") :ARG2-of m))) :ARG2 (p10 / phenotype :mod (p11 / protein :name (n7 / name :op1 "pfy1") :ARG2-of m))) :mod (g / genetic)) :ARG1 (i4 / important :domain (i5 / interact-01 :ARG0 (a3 / and :op1 p2 :op2 p3) :ARG1 p4) :purpose (f / function-01 :ARG0 p4 :mod (p12 / proper))))) # ::id bio.chicago_2015.26193 # ::date 2015-10-25T06:25:50 # ::file bio_chicago_2015_26193.txt # ::snt Moreover, CBP/ p300 directly acetylates transcription factors such as GATA-1 ( 6) and p53 ( 21). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Oct 25, 2015 (a / and :op2 (a2 / acetylate-01 :ARG0 (s / slash :op1 (p / protein :name (n / name :op1 "CBP") :xref (x3 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "p300") :xref (x / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702"))) :ARG1 (f / factor :ARG0-of (t / transcribe-01) :example (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "GATA-1") :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "6"))) :xref (x1 / xref :value "UNIPROT:GATA1_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "p53") :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "21"))) :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :ARG1-of (d / direct-02))) # ::id bio.chicago_2015.26198 # ::date 2015-10-25T09:04:24 # ::file bio_chicago_2015_26198.txt # ::snt To identify a direct target molecule of Ras, we have established a cell-free assay system using Xenopus oocyte extract in which Ras activates ERK through MEK( 39 ) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / establish-01 :ARG0 (w2 / we) :ARG1 (s / system :mod (a / assay-01 :ARG1-of (f / free-04 :ARG2 (c / cell)))) :instrument (e2 / extract-01 :ARG1 (c2 / cell :name (n3 / name :op1 "Xenopus" :op2 "oocyte") :location-of (a2 / activate-01 :ARG0 (e3 / enzyme :name (n / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :path (e5 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :purpose (i / identify-01 :ARG0 w2 :ARG1 (m / molecule :ARG1-of (t / target-01 :ARG0 e3) :ARG1-of (d / direct-02))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "39")))) # ::id bio.chicago_2015.26222 # ::date 2015-10-25T09:13:50 # ::file bio_chicago_2015_26222.txt # ::snt Chain Valence Mutants of Glypican-1 in FGF2-induced FGFR1 Phosphorylation-- All syndecans and glypicans carry multiple HS chains, which are clustered in one small domain of the protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt1 (m2 / mutate-01 :ARG2 (p / protein :name (n / name :op1 "Glypican-1") :xref (x4 / xref :value "UNIPROT:GPC1_HUMAN" :prob "1.003")) :mod (v / valence) :mod (c / chain) :location (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "FGFR1") :xref (x2 / xref :value "UNIPROT:FGFR1_HUMAN" :prob "1.004")) :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "FGF2") :xref (x / xref :value "UNIPROT:FGF2_HUMAN" :prob "1.004"))))) :snt2 (c2 / carry-01 :ARG0 (a / and :op1 (p3 / protein :name (n4 / name :op1 "syndecan") :xref (x1 / xref :value "UNIPROT:A0A024R9D1_HUMAN" :prob "0.701")) :op2 (p4 / protein :name (n5 / name :op1 "glypican") :xref (x3 / xref :value "UNIPROT:GPC1_HUMAN" :prob "0.353")) :mod (a2 / all)) :ARG1 (c3 / chain :mod (s2 / small-molecule :name (n6 / name :op1 "HS") :xref (x5 / xref :value "PUBCHEM:24842" :prob "14.387128")) :ARG1-of (c4 / cluster-01 :ARG2 (p5 / protein-segment :quant "1" :mod (s / small) :part-of (p6 / protein))) :quant (m4 / multiple)))) # ::id bio.chicago_2015.26233 # ::date 2015-10-25T09:26:19 # ::file bio_chicago_2015_26233.txt # ::snt For the case of PKC activation by PMA, we also tested the possibility of an increased Ca2+ sensitivity of the vesicle supply process without a change of the maximal activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (t / test-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (i / increase-01 :ARG1 (s / sensitive-03 :ARG0 (p2 / process-02 :ARG1 (s2 / supply-01 :ARG1 (v / vesicle))) :ARG1 (c3 / calcium :ARG1-of (i2 / ionize-01 :value "2+"))) :manner (c / change-01 :polarity "-" :ARG1 (a2 / activity-06 :mod (m2 / maximal))))) :mod (a / also) :purpose (c2 / case-04 :ARG1 (a3 / activate-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "PMA") :xref (x1 / xref :value "PUBCHEM:4792" :prob "16.591986")) :ARG1 (e / enzyme :name (n2 / name :op1 "PKC") :xref (x / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))))) # ::id bio.chicago_2015.26279 # ::date 2015-10-25T09:33:38 # ::file bio_chicago_2015_26279.txt # ::snt Using co-immunoprecipitation approaches, we showed that dSlo binds only to free PKAc but not to the PKA holoenzyme, and that both PKA regulatory subunit and PKI inhibit the association between dSlo and PKAc. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (a / and :op1 (c / contrast-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "dSlo")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKAc") :ARG1-of (f / free-04) :xref (x3 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.272")) :mod (o / only)) :ARG2 (b2 / bind-01 :polarity "-" :ARG1 p :ARG2 (e2 / enzyme :name (n3 / name :op1 "PKA") :mod (h / holoenzyme) :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")))) :op2 (i / inhibit-01 :ARG0 (a2 / and :op1 (s2 / subunit :ARG0-of (r / regulate-01) :mod e2) :op2 (e3 / enzyme :name (n4 / name :op1 "PKI") :xref (x1 / xref :value "UNIPROT:IPKA_HUMAN" :prob "0.262"))) :ARG1 (a3 / associate-01 :ARG1 p :ARG2 (e4 / enzyme :name n2 :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.272"))))) :manner (u / use-01 :ARG0 w :ARG1 (a4 / approach-02 :mod (c2 / coimmunoprecipitate-01)))) # ::id bio.chicago_2015.26283 # ::date 2015-10-25T09:44:24 # ::file bio_chicago_2015_26283.txt # ::snt Therefore, RBP interaction with TFIID and TFIIA alters optimal interaction between these two coactivators, not to dislodge them from the promoter, but instead to subvert activated transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / cause-01 :ARG1 (a / alter-01 :ARG0 (i / interact-01 :ARG0 (p / protein-family :name (n / name :op1 "RBP")) :ARG1 (a4 / and :op1 (p2 / protein :name (n2 / name :op1 "TFIID") :xref (x / xref :value "UNIPROT:TBP_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n3 / name :op1 "TFIIA") :xref (x1 / xref :value "UNIPROT:TF3A_HUMAN" :prob "0.392")) :ARG0-of (c2 / coactivate-01))) :ARG1 (i2 / interact-01 :ARG0 p2 :ARG1 p3 :mod (o / optimal)) :purpose (i3 / instead-of-91 :ARG1 (s / subvert-01 :ARG0 i :ARG1 (t2 / transcribe-01 :ARG1-of (a3 / activate-01))) :ARG2 (d / dislodge-01 :polarity "-" :ARG0 i :ARG1 a4 :ARG2 (t / thing :ARG1-of (p4 / promote-02)))))) # ::id bio.chicago_2015.26335 # ::date 2015-10-25T09:50:57 # ::file bio_chicago_2015_26335.txt # ::snt Currently it is unclear whether within the centromere chromatin CENP-A replaces all histone H3 subunits (Choo, 2000 ; Lo et al., 2001a ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (c / clear-06 :polarity "-" :ARG1 (r / replace-01 :mode "interrogative" :ARG0 (p / protein :name (n / name :op1 "CENP-A") :xref (x1 / xref :value "UNIPROT:CENPA_HUMAN" :prob "1.002")) :ARG1 (s / subunit :part-of (p2 / protein :name (n2 / name :op1 "histone" :op2 "H3") :xref (x / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "0.701")) :mod (a / all)) :location (c2 / chromatin :mod (c3 / centromere) :xref (x2 / xref :value "GO:0000785" :prob "0.8"))) :time (c4 / current) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication-91 :ARG0 (p4 / person :name (n3 / name :op1 "Choo")) :time (d / date-entity :year "2000")) :op2 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n4 / name :op1 "Lo")) :op2 (p7 / person :mod (o / other))) :time (d2 / date-entity :year "2001"))))) # ::id bio.chicago_2015.26340 # ::date 2015-10-25T09:57:55 # ::file bio_chicago_2015_26340.txt # ::snt d, in vitro reconstitution of SUMO-1 modification of the indicated HDAC1 mutants with (+) or without ( ) addition of the assay mix (as in Fig. 1 b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / reconstitute-01 :li "d" :ARG2 (m / modify-01 :ARG0 (p / protein :name (n / name :op1 "SUMO-1") :xref (x1 / xref :value "UNIPROT:SUMO1_HUMAN" :prob "1.002")) :ARG1 (m2 / mutate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "HDAC1") :xref (x / xref :value "UNIPROT:HDAC1_HUMAN" :prob "1.003")) :ARG1-of (i2 / indicate-01)) :manner (o2 / or :op1 (a / add-02 :ARG1 (m3 / mix-01 :ARG1 (a2 / assay-01)) :mod (p2 / positive)) :op2 (a3 / add-02 :polarity "-" :ARG1 m3 :ARG2-of (n3 / negative-01)))) :manner (i / in-vitro) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1b"))) # ::id bio.chicago_2015.26346 # ::date 2015-10-25T12:35:46 # ::file bio_chicago_2015_26346.txt # ::snt We therefore examined whether GSK-3beta, PKA, and PP1 bind simultaneously to AKAP220. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Oct 25, 2015 (c / cause-01 :ARG1 (e / examine-01 :ARG0 (w / we) :ARG1 (b / bind-01 :mode "interrogative" :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "GSK-3beta") :xref (x3 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :op2 (e3 / enzyme :name (n2 / name :op1 "PKA") :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :op3 (p / protein :name (n3 / name :op1 "PP1") :xref (x1 / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002"))) :ARG2 (p2 / protein :name (n4 / name :op1 "AKAP220") :xref (x / xref :value "UNIPROT:AKA11_HUMAN" :prob "1.002")) :manner (s / simultaneous)))) # ::id bio.chicago_2015.26365 # ::date 2015-10-25T12:37:53 # ::file bio_chicago_2015_26365.txt # ::snt Activin and TGFbeta also lead to the specific association of Smad2 and Smad4 as assessed by co-immunoprecipitation from cultured cells following ligand binding ( 9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Oct 25, 2015 (l / lead-03 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "activin") :xref (x3 / xref :value "UNIPROT:INHBA_HUMAN" :prob "0.273")) :op2 (p2 / protein :name (n2 / name :op1 "TGFbeta") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.333"))) :ARG1 (a3 / associate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Smad2") :xref (x1 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :ARG2 (p4 / protein :name (n4 / name :op1 "Smad4") :xref (x2 / xref :value "UNIPROT:SMAD4_HUMAN" :prob "1.003")) :ARG1-of (s / specific-02)) :mod (a2 / also) :ARG1-of (a4 / assess-01 :ARG0 (c / coimmunoprecipitate-01 :ARG4 (c2 / cell :ARG1-of (c3 / culture-01))) :ARG1-of (f / follow-01 :ARG2 (b / bind-01 :ARG1 (l2 / ligand)))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 "9")))) # ::id bio.chicago_2015.26400 # ::date 2015-10-25T12:44:46 # ::file bio_chicago_2015_26400.txt # ::snt PTB is known to bind to the CU elements within the 3 splice site upstream of N1 ( Chan and Black 1995 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (k / know-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "PTB") :xref (x / xref :value "UNIPROT:PTBP1_HUMAN" :prob "1.002")) :ARG2 (e / element :mod (p2 / protein-family :name (n2 / name :op1 "CU"))) :location (s / site :mod (d2 / distance-quantity :quant "3" :unit (s2 / splice)) :location (r / relative-position :op1 (e2 / enzyme :name (n3 / name :op1 "N1")) :direction (u / upstream)))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and :op1 (p4 / person :name (n4 / name :op1 "Chan")) :op2 (p5 / person :name (n5 / name :op1 "Black"))) :time (d / date-entity :year "1995")))) # ::id bio.chicago_2015.26414 # ::date 2015-10-25T12:50:25 # ::file bio_chicago_2015_26414.txt # ::snt However, PKA-induced PKB translocation is abolished after pretreatment of the cells with high concentrations (300 nM) of wortmannin, implying that translocation to the cell surface may require the generation of phospholipids. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (h / have-concession-91 :ARG1 (a / abolish-01 :ARG1 (t / translocate-01 :ARG1 (e / enzyme :name (n / name :op1 "PKB") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003")) :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")))) :time (a2 / after :op1 (p / pretreat-01 :ARG1 (c / cell) :ARG3 (c2 / concentrate-02 :ARG1 (s / small-molecule :name (n3 / name :op1 "wortmannin") :xref (x2 / xref :value "PUBCHEM:312145" :prob "18.013371")) :quant (c3 / concentration-quantity :quant "300" :unit (n4 / nanomolar)) :ARG1-of (h2 / high-02)))) :ARG0-of (i2 / imply-01 :ARG1 (p2 / possible-01 :ARG1 (r / require-01 :ARG0 (t2 / translocate-01 :ARG2 (s2 / surface :mod (c4 / cell))) :ARG1 (g / generate-01 :ARG1 (p3 / phospholipid))))))) # ::id bio.chicago_2015.26430 # ::date 2015-10-25T12:56:35 # ::file bio_chicago_2015_26430.txt # ::snt We have thus examined whether actin binding of fascin can be regulated in a calcium-dependent way by controlling actin binding of caldesmon with Ca2+/calmodulin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (c / cause-01 :ARG1 (e / examine-01 :ARG0 (w2 / we) :ARG1 (p / possible-01 :ARG1 (r / regulate-01 :mode "interrogative" :ARG0 (c3 / control-01 :ARG1 (b2 / bind-01 :ARG1 "p2" :ARG2 (p4 / protein :name (n3 / name :op1 "caldesmon") :xref (x2 / xref :value "UNIPROT:CALD1_HUMAN" :prob "0.702")) :ARG3 (s / slash :op1 (c4 / calcium :ARG1-of (i / ionize-01 :value "2+")) :op2 (p5 / protein :name (n4 / name :op1 "calmodulin") :xref (x3 / xref :value "UNIPROT:CALM_HUMAN" :prob "0.703"))))) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG2 (p3 / protein :name (n2 / name :op1 "fascin") :xref (x1 / xref :value "UNIPROT:FSCN1_HUMAN" :prob "0.702"))) :manner (w3 / way :ARG0-of (d / depend-01 :ARG1 (c2 / calcium))))))) # ::id bio.chicago_2015.26440 # ::date 2015-10-25T13:07:12 # ::file bio_chicago_2015_26440.txt # ::snt Affinity chromatography demonstrates a direct binding between cytoplasmic dynein and the dynactin complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Oct 25, 2015 (d / demonstrate-01 :ARG0 (c / chromatography :mod (a / affinity)) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "dynein") :mod (c2 / cytoplasmic) :xref (x1 / xref :value "UNIPROT:DYHC2_HUMAN" :prob "0.202")) :ARG2 (c3 / complex :mod (p2 / protein :name (n2 / name :op1 "dynactin") :xref (x / xref :value "UNIPROT:DCTN1_HUMAN" :prob "0.272"))) :ARG1-of (d2 / direct-02))) # ::id bio.chicago_2015.26449 # ::date 2015-10-25T13:09:55 # ::file bio_chicago_2015_26449.txt # ::snt In mink lung epithelial (Mv1Lu) cells, TNF-alpha-induced JNK activation and apoptosis were dependent on another upstream kinase, ASK1, which displayed sequence similarities to upstream kinases in the S. cerevisiae HOG pathway ( 230). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Oct 25, 2015 (d / depend-01 :ARG0 (a / and :op1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG2-of (i / induce-01 :ARG0 (p / protein :name (n2 / name :op1 "TNF-alpha-") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.692")))) :op2 (a3 / apoptosis)) :ARG1 (e2 / enzyme :name (n3 / name :op1 "ASK1") :mod (k / kinase :mod (a4 / another) :direction (u / upstream)) :xref (x / xref :value "UNIPROT:M3K5_HUMAN" :prob "1.003")) :ARG0-of (d2 / display-01 :ARG1 (r / resemble-01 :ARG1 (s / sequence) :ARG2 (k2 / kinase :direction u)) :ARG2 (p2 / pathway :name (n4 / name :op1 "S." :op2 "cerevisiae" :op3 "HOG"))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "230"))) :location (c2 / cell :mod (e3 / epithelium) :mod (l / lung) :mod (m / mink))) # ::id bio.chicago_2015.26503 # ::date 2015-10-25T13:42:56 # ::file bio_chicago_2015_26503.txt # ::snt However, the kinetics of their activation were different, i.e. Cr(VI) activated p38 faster than JNK (Figure 3 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (h / have-concession-91 :ARG1 (d / differ-02 :ARG1 (k / kinetic :topic (a / activate-01 :ARG1 (t / they))) :ARG3 (a2 / activate-01 :ARG0 (s / small-molecule :name (n / name :op1 "Cr(VI)")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG1-of (f / fast-02 :degree (m / more)) :compared-to (a3 / activate-01 :ARG0 s :ARG1 (e / enzyme :name (n3 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "3"))) # ::id bio.chicago_2015.26513 # ::date 2015-10-25T14:04:17 # ::file bio_chicago_2015_26513.txt # ::snt Taken together with the finding that mutation of CREB Ser133 to alanine blocks PKA stimulation of CREB-dependent transcription, it demonstrates that PKA phosphorylation is required for CREB activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 26, 2015 (d / demonstrate-01 :ARG0 (f / find-01 :ARG1 (b / block-01 :ARG0 (a4 / and :op1 (m / mutate-01 :ARG1 (a / amino-acid :mod "133" :name (n4 / name :op1 "serine") :part-of "p2" :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (a5 / amino-acid :name (n5 / name :op1 "alanine") :xref (x2 / xref :value "PUBCHEM:602" :prob "10.089661")))) :ARG1 (s / stimulate-01 :ARG0 "e" :ARG1 (t2 / transcribe-01 :ARG0-of (d2 / depend-01 :ARG1 "p2")))) :ARG1-of (t / take-01 :manner (t3 / together))) :ARG1 (r / require-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :purpose (a2 / activity-06 :ARG0 (p2 / protein :name (n3 / name :op1 "CREB") :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))))) # ::id bio.chicago_2015.26539 # ::date 2015-10-25T14:11:35 # ::file bio_chicago_2015_26539.txt # ::snt Activation of JNK, p38 and ERK by Cr(VI) CL3 cells were treated with 10 - 80 muM Cr(VI) in serum-free medium for 3 h and a whole cell extract prepared to examine activation of JNK, p38 and ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (t / treat-04 :ARG1 (a2 / activate-01 :ARG0 (c / cell-line :name (n5 / name :op1 "CL3") :mod (s / small-molecule :name (n6 / name :op1 "Cr(VI)"))) :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "JNK") :xref (x2 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op2 (e5 / enzyme :name (n3 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op3 (e2 / enzyme :name (n4 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG2 (s2 / small-molecule :name n6 :quant (c2 / concentration-quantity :quant (v / value-interval :op1 "10" :op2 "80") :unit (m / millimolar))) :location (m2 / medium :ARG1-of (f / free-04 :ARG2 (s3 / serum))) :duration (t2 / temporal-quantity :quant "3" :unit (h / hour))) :op2 (p3 / prepare-02 :ARG1 (e3 / extract-01 :ARG1 (c3 / cell) :mod (w / whole)) :ARG2 (e4 / examine-01 :ARG1 (a4 / activate-01 :ARG1 a3)))) # ::id bio.chicago_2015.26566 # ::date 2015-10-25T14:22:34 # ::file bio_chicago_2015_26566.txt # ::snt Nor is it known whether the amyloid-induced tau hyperphosphorylation and NFT formation observed recently in mutant tau transgenic mice (Gotz et al., 2001 ; Lewis et al., 2001 ) occurs via tau phosphorylation by GSK-3 or an alternate pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (k / know-01 :polarity "-" :ARG1 (a / and :op1 (h / hyperphosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "tau") :xref (x / xref :value "UNIPROT:TAU_HUMAN" :prob "0.603")) :ARG2-of (i / induce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "amyloid") :xref (x3 / xref :value "PUBCHEM:71312114" :prob "10.08165")))) :op2 (f / form-01 :ARG1 (p10 / protein :name (n3 / name :op1 "NFT"))) :ARG1-of (o / observe-01 :time (r / recent) :location (m3 / mouse :mod (t / transgenic) :mod (p3 / protein :name n :ARG2-of (m4 / mutate-01) :xref (x1 / xref :value "UNIPROT:TAU_HUMAN" :prob "0.603")))) :manner (o2 / or :op1 (p / phosphorylate-01 :ARG1 p2 :ARG2 (e / enzyme :name (n5 / name :op1 "GSK-3") :xref (x2 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.262"))) :op2 (p4 / pathway :ARG1-of (a2 / alternate-01))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n6 / name :op1 "Gotz")) :op2 (p7 / person :mod (o3 / other))) :time (d / date-entity :year "2001")) :op2 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n7 / name :op1 "Lewis")) :op2 p7) :time d))))) # ::id bio.chicago_2015.34132 # ::date 2015-10-25T14:56:00 # ::file bio_chicago_2015_34132.txt # ::snt Without Ca2+, Rho-kinase but not MLCK can phosphorylate MLC, and this phosphorylation was completely inhibited by 10 mug/ml HA1077 (lane 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (p2 / possible-01 :ARG1 (c / contrast-01 :ARG1 (p / phosphorylate-01 :ARG0 (e / enzyme :name (n / name :op1 "Rho-kinase") :xref (x1 / xref :value "UNIPROT:ROCK2_HUMAN" :prob "0.353")) :ARG1 (p3 / protein :name (n2 / name :op1 "MLC") :xref (x / xref :value "UNIPROT:MYL9_HUMAN" :prob "0.302")) :manner (c4 / calcium :polarity "-" :ARG1-of (i2 / ionize-01 :value "2+")) :ARG1-of (i / inhibit-01 :ARG0 (s / small-molecule :name (n5 / name :op1 "HA1077") :quant (c3 / concentration-quantity :quant "10" :unit (m / microgram-per-milliliter)) :xref (x3 / xref :value "PUBCHEM:3547" :prob "19.266134")) :ARG1-of (c2 / complete-02))) :ARG2 (p4 / phosphorylate-01 :polarity "-" :ARG0 (e2 / enzyme :name (n3 / name :op1 "MLCK") :xref (x2 / xref :value "UNIPROT:MYLK3_HUMAN" :prob "1.002")) :ARG1 p3)) :ARG1-of (d / describe-01 :ARG0 (l / lane :mod "3"))) # ::id bio.chicago_2015.34134 # ::date 2015-10-25T23:54:27 # ::file bio_chicago_2015_34134.txt # ::snt The fact that Rb preferentially associates with specific E2F target promoters during senescence suggests that it may play a particularly important role in SAHF formation and the silencing of E2F target promoters. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / suggest-01 :ARG0 (f / fact :domain (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "Rb") :xref (x1 / xref :value "UNIPROT:RB_HUMAN" :prob "1.003")) :ARG2 (m2 / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (t2 / target-01 :ARG1 (p7 / protein :name (n2 / name :op1 "E2F") :xref (x / xref :value "UNIPROT:E2F1_HUMAN" :prob "0.262")))) :ARG1-of (s4 / specific-02)) :ARG1-of (p2 / prefer-01) :time (s2 / senescence))) :ARG1 (p4 / possible-01 :ARG1 (p5 / play-01 :ARG0 f :ARG1 (r / role :mod (i / important :mod (p6 / particular)) :topic (a2 / and :op1 (f2 / form-01 :ARG1 (f3 / focus :mod (h / heterochromatin) :ARG1-of (a3 / associate-01 :ARG2 (s5 / senescence)))) :op2 (s3 / silence-01 :ARG1 m2)))))) # ::id bio.chicago_2015.34138 # ::date 2015-10-26T00:09:50 # ::file bio_chicago_2015_34138.txt # ::snt We report that arsenite induces rapid phosphorylation and acetylation of histone H3, events that precede the induction of both c- fos and c- jun in normal human diploid fibroblasts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / report-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "arsenite") :xref (x1 / xref :value "PUBCHEM:544" :prob "15.354111")) :ARG2 (a / and :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "histone" :op2 "H3") :xref (x / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "0.701")) :mod (r2 / rapid)) :op2 (a2 / acetylate-01 :ARG1 p2) :ARG1-of (p3 / precede-01 :ARG2 (i2 / induce-01 :ARG1 (a3 / and :op1 (p5 / protein :name (n3 / name :op1 "c-fos")) :op2 (p4 / protein :name (n4 / name :op1 "c-jun"))) :location (f / fibroblast :mod (d2 / diploid) :ARG1-of (n5 / normal-02))))))) # ::id bio.chicago_2015.34199 # ::date 2015-10-27T04:33:35 # ::file bio_chicago_2015_34199.txt # ::snt EGF stimulated the phosphorylation of Ser369 and Ser386 in the linker of RSK2, apparently via activation of ERK and the CTK, respectively, and both sites contributed to the activation of RSK2 by EGF, as evidenced by mutational analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a5 / and :op1 (s / stimulate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "369" :name (n3 / name :op1 "serine") :part-of (p / protein-segment :part-of (e / enzyme :name (n5 / name :op1 "RSK2") :xref (x3 / xref :value "UNIPROT:KS6A3_HUMAN" :prob "1.002")) :ARG0-of (l / link-01)) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :manner (a2 / activate-01 :ARG0 p2 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :op2 (s3 / stimulate-01 :ARG0 p2 :ARG1 (p4 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "386" :name (n4 / name :op1 "serine") :part-of p :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :manner (a6 / activate-01 :ARG0 p2 :ARG1 (e3 / enzyme :name (n6 / name :op1 "CTK") :xref (x / xref :value "UNIPROT:MATK_HUMAN" :prob "1.002")))) :ARG1-of (a7 / appear-02) :manner (r / respective)) :op2 (c / contribute-01 :ARG0 (a8 / and :op1 a3 :op2 a4) :ARG2 (a9 / activate-01 :ARG0 p2 :ARG1 e) :ARG1-of (e4 / evidence-01 :ARG0 (a10 / analyze-01 :mod (m / mutate-01))))) # ::id bio.chicago_2015.34201 # ::date 2015-10-27T04:54:30 # ::file bio_chicago_2015_34201.txt # ::snt There appear to be multiple mechanisms through which p53 promotes apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 30, 2015 (a / appear-02 :ARG1 (m / mechanism :quant (m2 / multiple) :manner-of (p / promote-02 :ARG0 (p2 / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1 (a2 / apoptosis)))) # ::id bio.chicago_2015.34258 # ::date 2015-10-27T04:57:08 # ::file bio_chicago_2015_34258.txt # ::snt Moreover, we found that paxillin alpha associates with both the kinase-inactive and the Cdc42-activated forms of PAK3 in vivo; and that the paxillin alpha binding to PAK3 could be competitive with the betaPIX binding to PAK3 in vivo and in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (f / find-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (a3 / associate-01 :ARG1 (p2 / protein :name (n / name :op1 "paxillin" :op2 "alpha") :xref (x2 / xref :value "UNIPROT:PAXI_HUMAN" :prob "0.303")) :ARG2 (a4 / and :op1 (e / enzyme :name (n2 / name :op1 "PAK3") :ARG1-of (a5 / activate-01 :polarity "-" :mod (k / kinase)) :xref (x4 / xref :value "UNIPROT:PAK3_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "PAK3") :ARG1-of (a6 / activate-01 :ARG0 (p4 / protein :name (n4 / name :op1 "Cdc42") :xref (x5 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634"))) :xref (x1 / xref :value "UNIPROT:PAK3_HUMAN" :prob "1.003"))) :manner (i / in-vivo)) :op2 (p / possible-01 :ARG1 (c / compete-01 :ARG0 (b / bind-01 :ARG1 p2 :ARG2 (e4 / enzyme :name (n6 / name :op1 "PAK3") :xref (x / xref :value "UNIPROT:PAK3_HUMAN" :prob "1.003"))) :ARG1 (b2 / bind-01 :ARG1 (p3 / protein :name (n5 / name :op1 "betaPIX") :xref (x3 / xref :value "UNIPROT:ARHG7_HUMAN" :prob "0.603")) :ARG2 e4)) :manner (a7 / and :op1 i :op2 (i2 / in-vitro)))))) # ::id bio.chicago_2015.34262 # ::date 2015-10-27T05:08:30 # ::file bio_chicago_2015_34262.txt # ::snt However, our preliminary results indicate that when paxillin alpha was highly phosphorylated by PAK3 in vitro, these two phosphorylated proteins could no longer stay bound to each other. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 30, 2015 (c / contrast-01 :ARG2 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we) :mod (p2 / preliminary)) :ARG1 (p / possible-01 :ARG1 (s / stay-01 :ARG1 (b / bind-01 :ARG1 (p5 / protein :quant "2" :ARG1-of (p6 / phosphorylate-01) :mod (t2 / this)) :ARG2 p5) :time (n / no-longer)) :time (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "paxillin" :op2 "alpha") :xref (x / xref :value "UNIPROT:PAXI_HUMAN" :prob "0.303")) :ARG2 (e / enzyme :name (n3 / name :op1 "PAK3") :xref (x1 / xref :value "UNIPROT:PAK3_HUMAN" :prob "1.003")) :ARG1-of (h / high-02) :manner (i2 / in-vitro))))) # ::id bio.chicago_2015.34268 # ::date 2015-10-27T05:15:43 # ::file bio_chicago_2015_34268.txt # ::snt While it is still unclear how Rac downregulates Rho and to what extent the influence of oncogenic Ras on the relative activities of Rac and Rho is common to epithelial cells other than MDCK cells, it is reasonable to assume that cross-talk between Ras, Rac, and Rho contributes to the morphologic phenotype of Ras-transformed cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c4 / contrast-01 :ARG1 (c5 / clear-06 :polarity "-" :ARG1 (a3 / and :op1 (t2 / thing :manner-of (d / downregulate-01 :ARG1 "p2" :ARG2 "e2")) :op2 (t3 / thing :extent-of (c6 / common :domain (i / influence-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras") :ARG0-of (c7 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (a5 / and :op1 (a6 / act-02 :ARG0 e) :op2 (a7 / act-02 :ARG0 "p2") :ARG1-of (r2 / relative-05))) :prep-to (c9 / cell :part-of (e3 / epithelium) :ARG2-of (e4 / except-01 :ARG1 (c10 / cell :name (n / name :op1 "MDCK"))))))) :mod (s / still)) :ARG2 (r / reasonable-02 :ARG1 (a / assume-02 :ARG1 (c / contribute-01 :ARG0 (c2 / crosstalk-00 :ARG0 (a2 / and :op1 (e5 / enzyme :name (n5 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n3 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :op3 (p2 / protein :name (n4 / name :op1 "Rho") :xref (x / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")))) :ARG2 (p3 / phenotype :mod (m / morphology) :poss (c3 / cell :ARG1-of (t / transform-01 :ARG0 e5))))))) # ::id bio.chicago_2015.34272 # ::date 2015-10-27T05:34:03 # ::file bio_chicago_2015_34272.txt # ::snt Recently, using GST-binding assays, we demonstrated that Sox10 can directly interact with Sp1 and Sp3 in vitro ( Melnikova et al., 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 30, 2015 (d2 / demonstrate-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "Sox10") :xref (x / xref :value "UNIPROT:SOX10_HUMAN" :prob "0.633")) :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "Sp1") :xref (x1 / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001")) :op2 (p4 / protein :name (n3 / name :op1 "Sp3") :xref (x3 / xref :value "UNIPROT:SP3_HUMAN" :prob "0.623"))) :ARG1-of (d3 / direct-02) :manner (i2 / in-vitro))) :time (r / recent) :manner (u / use-01 :ARG0 w :ARG1 (a2 / assay-01 :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n4 / name :op1 "GST") :xref (x2 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002"))))) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n5 / name :op1 "Melnikova")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "2000")))) # ::id bio.chicago_2015.34275 # ::date 2015-10-27T05:43:22 # ::file bio_chicago_2015_34275.txt # ::snt duplicate Shc IPs were resolved by 15% SDS-PAGE and Grb2 associated with Shc was visualized by anti-Grb2 blotting (lanes 5-8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (a / and :op1 (r / resolve-01 :ARG0 (t / thing :name (n2 / name :op1 "SDS-PAGE") :mod (p / percentage-entity :value "15")) :ARG1 (i / immunoprecipitate-01 :ARG1 (p2 / protein :name (n / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG1-of (d / duplicate-01))) :op2 (v / visualize-01 :ARG1 (a2 / associate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2 p2) :manner (i2 / immunoblot-01 :ARG0-of (c / counter-01 :ARG1 p3))) :ARG1-of (d2 / describe-01 :ARG0 (l / lane :mod (v2 / value-interval :op1 "5" :op2 "8")))) # ::id bio.chicago_2015.34279 # ::date 2015-10-27T05:51:56 # ::file bio_chicago_2015_34279.txt # ::snt Moreover, c-Src inhibition of hSlo is enhanced by its beta1 subunit and switched on by micromolar Ca2+ (>1.5 muM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op2 (a2 / and :op1 (e / enhance-01 :ARG0 (p3 / protein-segment :name (n3 / name :op1 "beta1") :part-of "e2") :ARG1 (i / inhibit-01 :ARG0 (e2 / enzyme :name (n / name :op1 "c-Src") :xref (x1 / xref :value "UNIPROT:CSK_HUMAN" :prob "0.212")) :ARG1 (p2 / protein :name (n2 / name :op1 "hSlo") :xref (x / xref :value "UNIPROT:KCMA1_HUMAN" :prob "1.002")))) :op2 (s / switch-01 :ARG0 (c2 / calcium :quant (m2 / more-than :op1 (c / concentration-quantity :quant "1.5" :unit (m / micromolar))) :mod m :ARG1-of (i2 / ionize-01 :value "2+")) :ARG1 i :ARG2 (o / on)))) # ::id bio.chicago_2015.34309 # ::date 2015-10-27T06:01:57 # ::file bio_chicago_2015_34309.txt # ::snt Treatment of cells with IL-1 activates endogenous TAK1 activity and consequently stimulates the MAPK cascade and IKK, leading to the activation of JNK/ p38 MAPKs and NF-kappaB, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (a / and :op1 (a2 / activate-01 :ARG0 (t / treat-04 :ARG1 (c / cell) :ARG2 (p2 / protein :name (n2 / name :op1 "IL-1") :xref (x1 / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382"))) :ARG1 (a3 / act-02 :ARG0 (e / enzyme :name (n3 / name :op1 "TAK1") :mod (e2 / endogenous) :xref (x2 / xref :value "UNIPROT:M3K7_HUMAN" :prob "1.002")))) :op2 (s / stimulate-01 :ARG0 t :ARG1 (a4 / and :op1 (c2 / cascade :mod (p / pathway :name (n / name :op1 "MAPK"))) :op2 (e5 / enzyme :name (n4 / name :op1 "IKK") :xref (x / xref :value "UNIPROT:IKKA_HUMAN" :prob "0.262"))) :ARG1-of (c3 / cause-01 :ARG0 a2)) :ARG0-of (l / lead-03 :ARG2 (a5 / activate-01 :ARG1 (a6 / and :op1 (p3 / pathway :name (n5 / name :op1 "JNK/" :op2 "p38" :op3 "MAPK")) :op2 (m / macro-molecular-complex :name (n7 / name :op1 "NF-kappaB")) :manner (r / respective))))) # ::id bio.chicago_2015.34324 # ::date 2015-10-27T06:14:03 # ::file bio_chicago_2015_34324.txt # ::snt Using P19 cells, we show that BMP7 and activin bind to the common type II receptors, ActRII and IIB, but recruit different type I receptors into the ligand-receptor complex and activate distinct Smad signaling pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (c2 / contrast-01 :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "BMP7") :xref (x1 / xref :value "UNIPROT:BMP7_HUMAN" :prob "1.004")) :op2 (p2 / protein :name (n3 / name :op1 "activin") :xref (x / xref :value "UNIPROT:INHBA_HUMAN" :prob "0.273"))) :ARG2 (r / receptor :mod (t / type :ord (o / ordinal-entity :value "2")) :mod (c3 / common) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (r2 / receptor :name (n4 / name :op1 "ActRII")) :op2 (r3 / receptor :name (n5 / name :op1 "IIB")))))) :ARG2 (a3 / and :op1 (r4 / recruit-01 :ARG0 a :ARG1 (r5 / receptor :mod (t2 / type :ord (o2 / ordinal-entity :value "1")) :ARG1-of (d / differ-02)) :ARG2 (c4 / complex :part (l2 / ligand) :part (r6 / receptor))) :op2 (a4 / activate-01 :ARG0 a :ARG1 (p3 / pathway :name (n6 / name :op1 "Smad") :ARG0-of (s2 / signal-07) :mod (d2 / distinct))))) :manner (u / use-01 :ARG0 w :ARG1 (c / cell :name (n / name :op1 "P19")))) # ::id bio.chicago_2015.34338 # ::date 2015-10-27T06:26:33 # ::file bio_chicago_2015_34338.txt # ::snt Using COS cells we demonstrate that, in the absence of ectopically overexpressed proteins, endogenous PKB can be activated by cAMP-elevating drugs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (d2 / drug :ARG0-of (e3 / elevate-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "cAMP") :xref (x1 / xref :value "PUBCHEM:6076" :prob "15.374314")))) :ARG1 (e / enzyme :name (n2 / name :op1 "PKB") :mod (e2 / endogenous) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003"))) :condition (a2 / absent-01 :ARG1 (p2 / protein :ARG1-of (o / overexpress-01 :manner (e4 / ectopic))))) :manner (u / use-01 :ARG0 w :ARG1 (c / cell-line :name (n / name :op1 "COS")))) # ::id bio.chicago_2015.34339 # ::date 2015-10-27T06:32:51 # ::file bio_chicago_2015_34339.txt # ::snt In contrast to a preferential binding to GTP S-bound Rac, PlexB binds to the GTP S and GDP-bound forms of RhoA equally well ( Figure 3B, lanes 3 and 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (c / contrast-01 :ARG1 (b2 / bind-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Rac") :ARG1-of (b3 / bind-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "GTP" :op2 "S") :xref (x5 / xref :value "PUBCHEM:1764" :prob "10.762665"))) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1-of (p / prefer-01)) :ARG2 (b / bind-01 :ARG1 (p2 / protein :name (n4 / name :op1 "PlexB") :xref (x / xref :value "UNIPROT:PLXA3_HUMAN" :prob "0.242")) :ARG2 (a / and :op1 (p3 / protein :name (n5 / name :op1 "RhoA") :ARG1-of b3 :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :op2 (p4 / protein :name (n6 / name :op1 "RhoA") :ARG1-of (b4 / bind-01 :ARG2 (s3 / small-molecule :name (n7 / name :op1 "GDP") :xref (x4 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :xref (x3 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))) :ARG1-of (w / well-09 :ARG1-of (e2 / equal-01))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (l / lane :mod "3") :op2 (l2 / lane :mod "4") :part-of (f / figure :mod "3B")))) # ::id bio.chicago_2015.34385 # ::date 2015-10-27T06:34:53 # ::file bio_chicago_2015_34385.txt # ::snt ( B) Heat shock induction of one GAL4 - HP1 transgene results in variegation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 30, 2015 (r / result-01 :li "B" :ARG1 (i / induce-01 :ARG0 (s / shock-01 :ARG0 (h / heat)) :ARG2 (t / transgene :quant "1" :name (n / name :op1 "GAL4-HP1"))) :ARG2 (v / variegation)) # ::id bio.chicago_2015.34424 # ::date 2015-10-27T06:57:22 # ::file bio_chicago_2015_34424.txt # ::snt The binding sites on EVL for profilin, WW domains, and SH3 domains overlap, and several of these interactions are selectively modulated by PKA phosphorylation of EVL. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (a / and :op1 (o / overlap-01 :ARG0 (a2 / and :op1 (s / site :location-of (b / bind-01 :ARG2 (p2 / protein :name (n / name :op1 "profilin") :xref (x / xref :value "UNIPROT:B4DNH1_HUMAN" :prob "0.701")))) :op2 (s2 / site :location-of (b2 / bind-01 :ARG2 (p4 / protein-segment :name (n3 / name :op1 "WW")))) :op3 (s3 / site :location-of (b3 / bind-01 :ARG2 (p5 / protein-segment :name (n4 / name :op1 "SH3")))) :part-of (p3 / protein :name (n2 / name :op1 "EVL") :xref (x1 / xref :value "UNIPROT:EVL_HUMAN" :prob "1.003")))) :op2 (m / modulate-01 :ARG0 (p / phosphorylate-01 :ARG1 p3 :ARG2 (e / enzyme :name (n5 / name :op1 "PKA") :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG1 (i / interact-01 :quant (s5 / several) :mod (t / this)) :manner (s4 / selective))) # ::id bio.chicago_2015.34435 # ::date 2015-10-27T07:08:06 # ::file bio_chicago_2015_34435.txt # ::snt Those studies also suggested that we could create competition between the binding of HSF and a histone H2A-H2B dimer by rotating the HSF binding determinants so that they face into the histone octamer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 30, 2015 (s / suggest-01 :ARG0 (s2 / study-01 :mod (t / that)) :ARG1 (p2 / possible-01 :ARG1 (c / create-01 :ARG0 (w / we) :ARG1 (c2 / compete-01 :ARG0 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "HSF") :xref (x2 / xref :value "UNIPROT:CXCL2_HUMAN" :prob "1.002"))) :ARG1 (d2 / dimer :part (p3 / protein :name (n2 / name :op1 "histone" :op2 "H2A") :xref (x / xref :value "UNIPROT:A0A024R017_HUMAN" :prob "0.701")) :part (p4 / protein :name (n3 / name :op1 "histone" :op2 "H2B") :xref (x1 / xref :value "UNIPROT:A0A024QZZ7_HUMAN" :prob "0.701")))) :manner (r / rotate-01 :ARG0 w :ARG1 (m3 / molecular-physical-entity :ARG0-of (d / determine-01 :ARG1 (b2 / bind-01 :ARG1 p))) :purpose (f / face-01 :ARG0 m3 :ARG1 (m2 / macro-molecular-complex :name (n4 / name :op1 "histone" :op2 "octamer")))))) :mod (a / also)) # ::id bio.chicago_2015.34462 # ::date 2015-10-27T07:18:44 # ::file bio_chicago_2015_34462.txt # ::snt Inhibition of calcineurin activity by CsA suppresses biochemical markers of differentiation, as well as p21 WAF1/CIP1 and p27KIP1 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (s / suppress-01 :ARG0 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "CsA") :xref (x2 / xref :value "PUBCHEM:5284373" :prob "15.696602")) :ARG1 (a / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "calcineurin") :xref (x1 / xref :value "UNIPROT:CANB2_HUMAN" :prob "0.352")))) :ARG1 (a2 / and :op1 (m / marker :mod (b / biochemistry) :mod (d / differentiate-01)) :op2 (e / express-03 :ARG2 (a3 / and :op1 (p2 / protein :name (n3 / name :op1 "p21" :op2 "WAF1/CIP1")) :op2 (p3 / protein :name (n4 / name :op1 "p27KIP1") :xref (x / xref :value "UNIPROT:CDN1B_HUMAN" :prob "0.663")))))) # ::id bio.chicago_2015.34464 # ::date 2015-10-27T07:24:53 # ::file bio_chicago_2015_34464.txt # ::snt Our finding that arsenite induces histone H3 phosphorylation-acetylation may provide additional insight into the mechanisms for both the carcinogenic properties and the therapeutic effects of arsenite. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (p / possible-01 :ARG1 (p2 / provide-01 :ARG0 (t / thing :poss (w / we) :ARG1-of (f / find-01) :topic (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "arsenite") :xref (x1 / xref :value "PUBCHEM:544" :prob "15.354111")) :ARG2 (a / and :op1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "histone" :op2 "H3") :xref (x / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "0.701"))) :op2 (a2 / acetylate-01 :ARG1 p4)))) :ARG1 (i2 / insight :mod (a3 / additional) :topic (a4 / and :op1 (m2 / mechanism :mod (p5 / property :ARG0-of (c / cause-01 :ARG1 (c2 / carcinoma)) :poss s)) :op2 (m3 / mechanism :mod (a5 / affect-01 :ARG0 s :mod (t2 / therapy))))))) # ::id bio.chicago_2015.34540 # ::date 2015-10-27T07:31:44 # ::file bio_chicago_2015_34540.txt # ::snt However, it should be noted that the amounts of vinculin as well as talin that bound to paxillin were quite low, compared with Fak binding to paxillin (see Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (r / recommend-01 :ARG1 (n / note-01 :ARG1 (l / low-04 :ARG1 (a / and :op1 (a2 / amount :quant-of (p / protein :name (n2 / name :op1 "vinculin") :xref (x3 / xref :value "UNIPROT:VINC_HUMAN" :prob "0.703"))) :op2 (a3 / amount :quant-of (p2 / protein :name (n3 / name :op1 "talin") :xref (x / xref :value "UNIPROT:TLN1_HUMAN" :prob "0.293"))) :ARG1-of (b / bind-01 :ARG2 (p3 / protein :name (n4 / name :op1 "paxillin") :xref (x1 / xref :value "UNIPROT:PAXI_HUMAN" :prob "0.703")))) :mod (q / quite) :compared-to (b2 / bind-01 :ARG1 (e / enzyme :name (n5 / name :op1 "Fak") :xref (x2 / xref :value "UNIPROT:FAK1_HUMAN" :prob "0.603")) :ARG2 p3)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3" :ARG1-of (s / see-01 :mode "imperative" :ARG0 (y / you))))) # ::id bio.chicago_2015.34551 # ::date 2015-10-27T07:37:18 # ::file bio_chicago_2015_34551.txt # ::snt Mitochondrially targeted expression of ActA largely simulates the initial phase of actin recruitment, namely the formation of actin clouds, which normally occurs around intracytoplasmic Listeria. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 30, 2015 (s / simulate-01 :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "ActA") :xref (x1 / xref :value "UNIPROT:ACTA_HUMAN" :prob "0.603")) :ARG3 (m / mitochondrion :xref (x2 / xref :value "GO:0005739" :prob "0.8")) :ARG1-of (t / target-01)) :ARG1 (p2 / phase :mod (i / initial) :subevent-of (r / recruit-01 :ARG1 (p3 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :ARG1-of (m2 / mean-01 :ARG2 (f / form-01 :ARG1 (c / cloud :consist-of p3) :location (a / around :op1 (o2 / organism :name (n4 / name :op1 "Listeria") :mod (i2 / intracytoplasmic)) :ARG1-of (n3 / normal-02))))) :degree (l / large)) # ::id bio.chicago_2015.34559 # ::date 2015-10-27T07:44:33 # ::file bio_chicago_2015_34559.txt # ::snt We also analyzed functions of the specific phosphorylation of GFAP by Rho-kinase during cytokinesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (f / function-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "GFAP") :xref (x / xref :value "UNIPROT:GFAP_HUMAN" :prob "1.003")) :ARG2 (e / enzyme :name (n2 / name :op1 "Rho-kinase") :xref (x1 / xref :value "UNIPROT:ROCK2_HUMAN" :prob "0.353")) :ARG1-of (s / specific-02)) :time (c / cytokinesis)) :mod (a2 / also)) # ::id bio.chicago_2015.34560 # ::date 2015-10-27T07:47:04 # ::file bio_chicago_2015_34560.txt # ::snt Thus, the association of TFIIA with TBP is an excellent candidate for regulation by posttranslational modification. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 3, 2016 (i / infer-01 :ARG1 (c / candidate :ARG0-of (e / excel-01 :ARG1 (r / regulate-01 :ARG0 (m / modify-01 :time (a2 / after :op1 (t / translate-02))))) :domain (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "TFIIA") :xref (x1 / xref :value "UNIPROT:TF3A_HUMAN" :prob "0.392")) :ARG2 (p2 / protein :name (n2 / name :op1 "TBP") :xref (x / xref :value "UNIPROT:TBP_HUMAN" :prob "1.003"))))) # ::id bio.chicago_2015.34581 # ::date 2015-10-27T07:50:31 # ::file bio_chicago_2015_34581.txt # ::snt Snail represses sim in the mesoderm, and thereby restricts expression to lateral regions that form the mesectoderm (Kasai et al., 1992 ; Kasai et al., 1998 ; Nibu et al., 1998 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (a / and :op1 (r / repress-01 :ARG0 (p7 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1 (g / gene :name (n2 / name :op1 "sim") :xref (x1 / xref :value "UNIPROT:SIM1_HUMAN" :prob "0.202")) :location (m / mesoderm)) :op2 (r2 / restrict-01 :ARG0 p7 :ARG1 (e2 / express-03 :ARG1 g) :ARG2 (r3 / region :mod (l / lateral) :ARG0-of (f / form-01 :ARG1 (m2 / mesectoderm))) :manner (t / thereby)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n3 / name :op1 "Kasai")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "1992")) :op2 (p4 / publication-91 :ARG0 a3 :time (d2 / date-entity :year "1998")) :op3 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n4 / name :op1 "Nibu")) :op2 p3) :time d2)))) # ::id bio.chicago_2015.34679 # ::date 2015-10-27T07:57:53 # ::file bio_chicago_2015_34679.txt # ::snt GRB2 Becomes Associated with RasGAP and Shc, in Lateral Amygdala, following Fear Conditioning # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (b / become-01 :ARG1 (p / protein :name (n / name :op1 "GRB2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "1.004")) :ARG2 (a / associate-01 :ARG1 p :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "RasGAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n3 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))) :location (a3 / amygdala :mod (l / lateral)) :ARG1-of (f / follow-01 :ARG2 (c / condition-01 :ARG0 (f2 / fear)))) # ::id bio.chicago_2015.34680 # ::date 2015-10-27T08:01:42 # ::file bio_chicago_2015_34680.txt # ::snt We use signal transduction inhibitors and ES cells lacking p90RSK activity and ES cells deficient in MSK1 to demonstrate that phosphorylation of LKB1 induced by EGF and TPA is likely to be mediated by p90RSK rather than by MSK1 or S6K1 and that phosphorylation of LKB1 induced by forskolin is mediated by PKA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (a / and :op1 (s / small-molecule :name (n / name :op1 "signal" :op2 "transduction" :op3 "inhibitor") :xref (x8 / xref :value "PUBCHEM:23690499" :prob "2.131669")) :op2 (c / cell :name (n2 / name :op1 "ES") :ARG0-of (l / lack-01 :ARG1 (a2 / act-02 :ARG0 (e / enzyme :name (n3 / name :op1 "p90RSK") :xref (x5 / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.362"))))) :op3 (c2 / cell :name (n4 / name :op1 "ES") :ARG0-of (l2 / lack-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "MSK1") :xref (x3 / xref :value "UNIPROT:KS6A5_HUMAN" :prob "1.002"))))) :ARG2 (d2 / demonstrate-01 :ARG0 w :ARG1 (a4 / and :op1 (l3 / likely-01 :ARG1 (m / mediate-01 :ARG0 e :ARG1 (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n6 / name :op1 "LKB1") :xref (x2 / xref :value "UNIPROT:STK11_HUMAN" :prob "1.002")) :ARG2-of (i2 / induce-01 :ARG0 (a3 / and :op1 (p3 / protein :name (n7 / name :op1 "EGF") :xref (x4 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (s3 / small-molecule :name (n8 / name :op1 "TPA") :xref (x6 / xref :value "PUBCHEM:27924" :prob "16.198082"))))) :ARG1-of (i3 / instead-of-91 :ARG2 (m2 / mediate-01 :ARG0 (o / or :op1 e2 :op2 (e4 / enzyme :name (n9 / name :op1 "S6K1") :xref (x / xref :value "UNIPROT:KS6B1_HUMAN" :prob "1.003"))) :ARG1 p)))) :op2 (m3 / mediate-01 :ARG0 (e5 / enzyme :name (n11 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1 (p2 / phosphorylate-01 :ARG1 e3 :ARG2-of (i4 / induce-01 :ARG0 (s4 / small-molecule :name (n10 / name :op1 "forskolin") :xref (x7 / xref :value "PUBCHEM:47936" :prob "16.627077")))))))) # ::id bio.chicago_2015.34743 # ::date 2015-10-27T08:13:58 # ::file bio_chicago_2015_34743.txt # ::snt (C) EMSAs of the SMA promoter show that CRP2 and GATA4 recruited by SRF vastly increased cooperative SRF DNA binding affinity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (s / show-01 :li "C" :ARG0 (t / thing :name (n / name :op1 "EMSA") :mod (p / protein :name (n2 / name :op1 "SMA") :ARG0-of (p2 / promote-01) :xref (x3 / xref :value "UNIPROT:SMAKA_HUMAN" :prob "0.332"))) :ARG1 (i / increase-01 :ARG0 (a / and :op1 (p3 / protein :name (n3 / name :op1 "CRP2") :xref (x1 / xref :value "UNIPROT:CRIP2_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n4 / name :op1 "GATA4") :xref (x / xref :value "UNIPROT:GATA4_HUMAN" :prob "1.003")) :ARG1-of (r / recruit-01 :ARG0 (p5 / protein :name (n5 / name :op1 "SRF") :xref (x2 / xref :value "UNIPROT:SRF_HUMAN" :prob "1.003")))) :ARG1 (a2 / affinity :mod (b / bind-01 :ARG1 p5 :ARG2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA")) :mod (c / cooperate-01))) :ARG2 (v / vast))) # ::id bio.chicago_2015.34745 # ::date 2015-10-27T08:24:22 # ::file bio_chicago_2015_34745.txt # ::snt Because CsA inhibits calcineurin, this finding implicated the calcium-calmodulin dependent phosphatase as an essential regulator of chondrogenesis, even in the absence of the calcium ionophore. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (i / implicate-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (e / enzyme :name (n / name :op1 "calcium-calmodulin" :op2 "dependent" :op3 "phosphatase") :xref (x / xref :value "UNIPROT:CSKP_HUMAN" :prob "0.312")) :ARG2 (r2 / regulate-01 :ARG0 e :ARG1 (c / chondrogenesis) :mod (e2 / essential)) :concession (a / absent-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "calcium" :op2 "ionophore") :xref (x3 / xref :value "PUBCHEM:1959" :prob "9.247584"))) :ARG1-of (c2 / cause-01 :ARG0 (i2 / inhibit-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "CsA") :xref (x2 / xref :value "PUBCHEM:5284373" :prob "15.696602")) :ARG1 (e3 / enzyme :name (n4 / name :op1 "calcineurin") :xref (x1 / xref :value "UNIPROT:CANB2_HUMAN" :prob "0.352"))))) # ::id bio.chicago_2015.34748 # ::date 2015-10-27T08:34:15 # ::file bio_chicago_2015_34748.txt # ::snt In the absence of stimulation, basal Tyr phosphorylation of Fus3 is governed by the balance between autophosphorylation by the kinase and dephosphorylation by Ptp3 phosphatase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 30, 2015 (g / govern-01 :ARG0 (b2 / balance-01 :ARG1 (p3 / phosphorylate-01 :ARG1 "k" :ARG2 (k / kinase)) :ARG2 (d / dephosphorylate-01 :ARG2 (e / enzyme :name (n3 / name :op1 "Ptp3" :op2 "phosphatase")))) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "Fus3") :xref (x / xref :value "UNIPROT:CXCR4_HUMAN" :prob "0.203")) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :mod (b / basal)) :condition (a3 / absent-01 :ARG1 (s / stimulate-01))) # ::id bio.chicago_2015.34764 # ::date 2015-10-27T08:42:08 # ::file bio_chicago_2015_34764.txt # ::snt R62C Defines a Novel Rab Mutation utations that have previously been studied for rab6 are those engineered based on the GTP- and GDP-bound forms of ras-like molecules. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (m / multi-sentence :snt1 (d / define-01 :ARG0 (m6 / mutate-01 :ARG1 (a2 / amino-acid :mod "62" :name (n7 / name :op1 "arginine") :xref (x5 / xref :value "PUBCHEM:232" :prob "11.348415")) :ARG2 (a3 / amino-acid :name (n8 / name :op1 "cysteine") :xref (x4 / xref :value "PUBCHEM:594" :prob "11.272514"))) :ARG1 (m2 / mutate-01 :ARG1 (p / protein :name (n2 / name :op1 "Rab") :xref (x2 / xref :value "UNIPROT:AGFG1_HUMAN" :prob "0.602")) :mod (n3 / novel))) :snt2 (m3 / mutate-01 :ARG1 (p4 / protein :name (n6 / name :op1 "Rab6") :xref (x1 / xref :value "UNIPROT:RAB6A_HUMAN" :prob "0.672")) :ARG1-of (s2 / study-01 :time (p2 / previous)) :domain (m7 / mutate-01 :ARG1-of (e / engineer-01 :ARG1-of (b / base-02 :ARG2 (a / and :op1 (m4 / molecule :ARG1-of (r2 / resemble-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (b2 / bind-01 :ARG2 (s / small-molecule :name (n / name :op1 "GTP") :xref (x6 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :op2 (m5 / molecule :ARG1-of r2 :ARG1-of (b3 / bind-01 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257")))))))))) # ::id bio.chicago_2015.34874 # ::date 2015-10-27T10:01:42 # ::file bio_chicago_2015_34874.txt # ::snt Indeed, our results demonstrate that YY1 was acetylated by both p300 and PCAF and was deacetylated by HDAC1 and HDAC2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (d / demonstrate-01 :ARG0 (t / thing :poss (w / we) :ARG2-of (r / result-01)) :ARG1 (a / and :op1 (a2 / acetylate-01 :ARG1 (p / protein :name (n / name :op1 "YY1") :xref (x3 / xref :value "UNIPROT:TYY1_HUMAN" :prob "1.002")) :ARG2 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "p300") :xref (x / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")) :op2 (p3 / protein :name (n3 / name :op1 "PCAF") :xref (x2 / xref :value "UNIPROT:KAT2B_HUMAN" :prob "1.002")))) :op2 (d2 / deacetylate-01 :ARG1 p :ARG2 (a4 / and :op1 (e / enzyme :name (n4 / name :op1 "HDAC1") :xref (x1 / xref :value "UNIPROT:HDAC1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "HDAC2") :xref (x4 / xref :value "UNIPROT:HDAC2_HUMAN" :prob "1.003"))))) :mod (i / indeed)) # ::id bio.chicago_2015.34888 # ::date 2015-10-27T10:05:39 # ::file bio_chicago_2015_34888.txt # ::snt Oxidative stress differentially modulates phosphorylation of ERK, p38 and CREB induced by NGF or EGF in PC12 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / modulate-01 :ARG0 (s / stress-02 :ARG0 (o / oxidize-01)) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op2 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))) :op3 (p3 / phosphorylate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "CREB") :xref (x4 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))) :ARG2-of (i / induce-01 :ARG0 (o2 / or :op1 (p6 / protein :name (n4 / name :op1 "NGF") :xref (x / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :op2 (p4 / protein :name (n5 / name :op1 "EGF") :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :manner (d / differential) :location (c / cell-line :name (n6 / name :op1 "PC12"))) # ::id bio.chicago_2015.34920 # ::date 2015-10-27T10:10:51 # ::file bio_chicago_2015_34920.txt # ::snt Cross Talk between ERK and PKA Is Required for Ca2+ Stimulation of CREB-Dependent Transcription and ERK Nuclear Translocation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / require-01 :ARG0 (s / stimulate-01 :ARG0 (c2 / calcium :ARG1-of (i / ionize-01 :value "2+")) :ARG1 (a3 / and :op1 (t / transcribe-01 :ARG0-of (d / depend-01 :ARG1 (p / protein :name (n5 / name :op1 "CREB") :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")))) :op2 (t2 / translocate-01 :ARG1 "e" :ARG2 (n6 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8"))))) :ARG1 (c / crosstalk-00 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "PKA") :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))))) # ::id bio.chicago_2015.34944 # ::date 2015-10-27T10:15:31 # ::file bio_chicago_2015_34944.txt # ::snt It is conceivable that alpha-adducin phosphorylated by PKC dissociates from a spectrin-F-actin meshwork during membrane ruffling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (p / possible-01 :ARG1 (c / conceive-01 :ARG1 (d / dissociate-01 :ARG1 (p2 / protein :name (n / name :op1 "alpha-adducin") :ARG1-of (p3 / phosphorylate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))) :xref (x / xref :value "UNIPROT:ADDA_HUMAN" :prob "0.702")) :ARG2 (m / meshwork :consist-of (a / and :op1 (p4 / protein :name (n3 / name :op1 "spectrin") :xref (x2 / xref :value "UNIPROT:SPERI_HUMAN" :prob "0.242")) :op2 (p5 / protein :name (n4 / name :op1 "F-actin") :xref (x3 / xref :value "UNIPROT:NEXN_HUMAN" :prob "0.252")))) :time (r / ruffle-02 :ARG1 (m2 / membrane :xref (x4 / xref :value "GO:0016020" :prob "0.8")))))) # ::id bio.chicago_2015.34963 # ::date 2015-10-27T10:21:01 # ::file bio_chicago_2015_34963.txt # ::snt Since many of the inflammatory cytokines are produced by macrophages upon activation by LPS, a potent activator of the p38 MAPK pathway, LPS-activated p38 MAPK activity in MKK3-deficient macrophages was studied. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / study-01 :ARG1 (a2 / act-02 :ARG0 (p2 / pathway :name (n2 / name :op1 "p38" :op2 "MAPK")) :ARG1-of (a3 / activate-01 :ARG0 "m4") :location (m / macrophage :ARG0-of (l / lack-01 :ARG1 (e / enzyme :name (n4 / name :op1 "MKK3") :xref (x / xref :value "UNIPROT:MP2K3_HUMAN" :prob "1.003"))))) :ARG1-of (c / cause-01 :ARG0 (p3 / produce-01 :ARG0 (m3 / macrophage) :ARG1 (p4 / protein :name (n5 / name :op1 "cytokines") :quant (m2 / many) :ARG0-of (i / inflame-01) :xref (x1 / xref :value "UNIPROT:RED_HUMAN" :prob "0.322")) :time (a4 / activate-01 :ARG0 (m4 / molecular-physical-entity :name (n3 / name :op1 "LPS") :mod (p5 / potent) :ARG0-of (a5 / activate-01 :ARG1 p2) :xref (x2 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :ARG1 m3)))) # ::id bio.chicago_2015.34991 # ::date 2015-10-27T10:31:37 # ::file bio_chicago_2015_34991.txt # ::snt Stimulation of PKC by phorbol esters or Gq-coupled receptors results in activation of Pyk2 ( 35, 38, 39, 46). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (s / stimulate-01 :ARG0 (o / or :op1 (e3 / ester :mod (s3 / small-molecule :name (n5 / name :op1 "phorbol") :xref (x3 / xref :value "PUBCHEM:290670" :prob "14.445852"))) :op2 (p2 / protein :name (n3 / name :op1 "Gq-coupled" :op2 "receptor") :xref (x1 / xref :value "UNIPROT:GP139_HUMAN" :prob "0.292"))) :ARG1 (e / enzyme :name (n / name :op1 "PKC") :xref (x2 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))) :ARG2 (a / activate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Pyk2") :xref (x / xref :value "UNIPROT:FAK2_HUMAN" :prob "0.603"))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "35")) :op2 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "38")) :op3 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "39")) :op4 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 "46"))))) # ::id bio.chicago_2015.34994 # ::date 2015-10-27T10:36:43 # ::file bio_chicago_2015_34994.txt # ::snt These data indicate that the interactions of Gab1 with SHP-2 and PI-3 kinase are not simply mediated by interactions between phosphotyrosines and SH2 domains. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (i / indicate-01 :ARG0 (d / data :mod (t / this)) :ARG1 (m / mediate-01 :polarity "-" :ARG0 (i3 / interact-01 :ARG0 (a2 / amino-acid :name (n4 / name :op1 "tyrosine") :ARG1-of (p2 / phosphorylate-01) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1 (p5 / protein-segment :name (n7 / name :op1 "SH2" :op2 "domain"))) :ARG1 (i2 / interact-01 :ARG0 (p / protein :name (n / name :op1 "Gab1") :xref (x / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.604")) :ARG1 (a / and :op1 (k / kinase :name (n2 / name :op1 "SHP-2") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :op2 (k2 / kinase :name (n3 / name :op1 "PI-3") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "1.002")))) :ARG1-of (s / simple-02))) # ::id bio.chicago_2015.34997 # ::date 2015-10-27T10:40:48 # ::file bio_chicago_2015_34997.txt # ::snt First, Rabaptin-5 binds directly to the GTP-bound form of Rab5 and is recruited to early endosomes by Rab5 in a GTP-dependent manner (Stenmark et al., 1995b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op1 (b / bind-01 :ARG1 (p4 / protein :name (n / name :op1 "Rabaptin-5") :xref (x / xref :value "UNIPROT:RABE1_HUMAN" :prob "1.002")) :ARG2 (p5 / protein :name (n2 / name :op1 "Rab5") :ARG1-of (b2 / bind-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x1 / xref :value "UNIPROT:RAB5A_HUMAN" :prob "0.603")) :ARG1-of (d2 / direct-02)) :op2 (r / recruit-01 :ARG0 p5 :ARG1 p4 :ARG2 (e3 / endosome :mod (e4 / early)) :manner (d3 / depend-01 :ARG0 r :ARG1 s)) :time (f / first) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n4 / name :op1 "Stenmark")) :op2 (p3 / person :mod (o2 / other))) :time (d / date-entity :year "1995")))) # ::id bio.chicago_2015.35041 # ::date 2015-10-27T10:47:30 # ::file bio_chicago_2015_35041.txt # ::snt Since alpha-catenin binds to actin, ARM (or beta-catenin) establishes a bridge between cadherins and the actin cytoskeleton, a bridge that is needed for proper cell adhesion ( K EMLER 1993 ; C OX et al. 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / establish-01 :ARG0 (o / or :op1 (p / protein-segment :name (n / name :op1 "ARM")) :op2 (p2 / protein :name (n2 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))) :ARG1 (b / bridge :location (b2 / between :op1 (p3 / protein-family :name (n3 / name :op1 "cadherin")) :op2 (c / cytoskeleton :mod (p4 / protein :name (n4 / name :op1 "actin") :xref (x2 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :xref (x3 / xref :value "GO:0005856" :prob "0.8"))) :ARG1-of (n5 / need-01 :ARG0 (a / adhere-01 :ARG1 (c2 / cell) :mod (p5 / proper)))) :ARG1-of (c3 / cause-01 :ARG0 (b3 / bind-01 :ARG1 (p6 / protein :name (n6 / name :op1 "alpha-catenin") :xref (x1 / xref :value "UNIPROT:CTNA3_HUMAN" :prob "0.392")) :ARG2 p4)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p7 / publication-91 :ARG0 (p8 / person :name (n7 / name :op1 "Kemler")) :time (d / date-entity :year "1993")) :op2 (p9 / publication-91 :ARG0 (a3 / and :op1 (p10 / person :name (n8 / name :op1 "Cox")) :op2 (p11 / person :mod (o2 / other))) :time (d2 / date-entity :year "1996"))))) # ::id bio.chicago_2015.35048 # ::date 2015-10-27T11:07:57 # ::file bio_chicago_2015_35048.txt # ::snt It previously has been shown that GSK3beta can phosphorylate APC in vitro (Rubinfeld et al., 1996 ), that Axin promotes this event (Hart et al., 1998 ), and that this phosphorylation enhances the ability of APC to bind to beta-catenin (Rubinfeld et al., 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (s / show-01 :ARG1 (a / and :op1 (p3 / possible-01 :ARG1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "APC") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")) :ARG2 (e / enzyme :name (n / name :op1 "GSK3" :op2 "beta") :xref (x / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :manner (i / in-vitro)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and :op1 (p6 / person :name (n3 / name :op1 "Rubinfeld")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "1996")))) :op2 (p8 / promote-02 :ARG0 (p9 / protein :name (n4 / name :op1 "Axin") :xref (x2 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG1 p :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a3 / and :op1 (p11 / person :name (n5 / name :op1 "Hart")) :op2 p7) :time (d2 / date-entity :year "1998")))) :op3 (e3 / enhance-01 :ARG0 p :ARG1 (c / capable-01 :ARG1 p4 :ARG2 (b / bind-01 :ARG1 p4 :ARG2 (p13 / protein :name (n6 / name :op1 "beta-catenin") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")))) :ARG1-of d3)) :time (p2 / previous)) # ::id bio.chicago_2015.35049 # ::date 2015-10-27T02:43:41 # ::file bio_chicago_2015_35049.txt # ::snt Activation of N-WASP by Cdc42 is required for initiating actin-based motility of intracellular Shigella In vitro studies have indicated that activation of N-WASP in cells requires Cdc42 bound to the GBD of N-WASP ( 47, 62, 66, 67). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (m2 / multi-sentence :snt1 (r / require-01 :ARG0 (i / initiate-01 :ARG1 (m / motility :ARG1-of (b / base-02 :ARG2 (p2 / protein :name (n3 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :poss (o / organism :name (n4 / name :op1 "Shigella") :mod (i2 / intracellular)))) :ARG1 (a / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "Cdc42") :xref (x4 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG1 (p4 / protein :name (n / name :op1 "N-WASP") :xref (x2 / xref :value "UNIPROT:WASL_HUMAN" :prob "1.003")))) :snt2 (i3 / indicate-01 :ARG0 (s / study-01 :manner (i4 / in-vitro)) :ARG1 (r2 / require-01 :ARG0 (a2 / activate-01 :ARG1 (p5 / protein :name (n6 / name :op1 "N-WASP") :xref (x3 / xref :value "UNIPROT:WASL_HUMAN" :prob "1.003")) :location (c / cell)) :ARG1 (b2 / bind-01 :ARG1 (p6 / protein :name (n7 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :ARG2 (p7 / protein-segment :name (n5 / name :op1 "GBD") :part-of p5))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "47" :op2 "62" :op3 "66" :op4 "67")))))) # ::id bio.chicago_2015.35062 # ::date 2015-10-27T02:56:42 # ::file bio_chicago_2015_35062.txt # ::snt In oocytes from one-third of Xenopus donors, the activation of CFTR by cGMP averaged 87 % of the level achieved by cAMP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / average-01 :ARG1 (a2 / activate-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cGMP") :xref (x1 / xref :value "PUBCHEM:24316" :prob "16.008038")) :ARG1 (p3 / protein :name (n / name :op1 "CFTR") :xref (x / xref :value "UNIPROT:CFTR_HUMAN" :prob "1.003"))) :ARG2 (p4 / percentage-entity :value "87" :ARG3-of (i / include-91 :ARG2 (l / level :ARG1-of (a3 / achieve-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "cAMP") :xref (x2 / xref :value "PUBCHEM:6076" :prob "15.374314")))))) :location (c / cell :name (n4 / name :op1 "oocyte") :source (o / organism :quant "1/3" :name (n5 / name :op1 "Xenopus") :ARG0-of (d2 / donate-01)))) # ::id bio.chicago_2015.35082 # ::date 2015-10-27T03:22:45 # ::file bio_chicago_2015_35082.txt # ::snt After washing with GST binding buffer, proteins associated with GST-agarose beads were analyzed with 4% - 20% SDS-PAGE and visualized by autoradiography. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a3 / and :op1 (a / analyze-01 :ARG1 (p3 / protein :ARG1-of (a2 / associate-01 :ARG2 (b2 / bead :consist-of (a6 / and :op1 "e" :op2 (a7 / agarose))))) :instrument (t / thing :name (n2 / name :op1 "SDS-PAGE") :quant (v / value-interval :op1 (p / percentage-entity :value "4") :op2 (p2 / percentage-entity :value "20")))) :op2 (v2 / visualize-01 :ARG1 p3 :instrument (a4 / autoradiography)) :time (a5 / after :op1 (w / wash-01 :ARG1 p3 :ARG2 (b3 / buffer :ARG1-of (b4 / bind-01 :ARG2 (e / enzyme :name (n3 / name :op1 "GST") :xref (x / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002"))))))) # ::id bio.chicago_2015.35109 # ::date 2015-10-27T03:30:02 # ::file bio_chicago_2015_35109.txt # ::snt As shown in Fig. 5 E, both the GTP- and the GDP-bound forms of RhoA are able to bind p116Rip. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (c / capable-01 :ARG1 (a / and :op1 (f / form :mod (p2 / protein :name (n2 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG1-of (b2 / bind-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :op2 (f2 / form :mod p2 :ARG1-of (b / bind-01 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257"))))) :ARG2 (b3 / bind-01 :ARG1 a :ARG2 (p3 / protein :name (n5 / name :op1 "p116Rip") :xref (x1 / xref :value "UNIPROT:MPRIP_HUMAN" :prob "1.002"))) :ARG1-of (s / show-01 :ARG0 (f3 / figure :mod "5E"))) # ::id bio.chicago_2015.35124 # ::date 2015-10-27T03:38:27 # ::file bio_chicago_2015_35124.txt # ::snt beta-Adrenergic receptor-induced apoptosis requires tyrosine kinase Lck. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (r / require-01 :ARG0 (a / apoptosis :ARG2-of (i / induce-01 :ARG0 (r2 / receptor :name (n3 / name :op1 "beta-Adrenergic")))) :ARG1 (t / tyrosine-kinase :name (n2 / name :op1 "Lck"))) # ::id bio.chicago_2015.35127 # ::date 2015-10-27T03:42:04 # ::file bio_chicago_2015_35127.txt # ::snt Like PKB, PKBR-1 kinase activity is stimulated in response to cAMP; however, unlike the activation of PKB the activation of PKBR-1 is not inhibited by the PI3K inhibitor LY294002 ( Meili et al. 2000 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / stimulate-01 :ARG1 (a / activity-06 :ARG0 (k / kinase :name (n / name :op1 "PKBR-1") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.213"))) :ARG2-of (r2 / respond-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "cAMP") :xref (x3 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :concession-of (i2 / inhibit-01 :polarity "-" :ARG0 (s2 / small-molecule :name (n4 / name :op1 "LY294002") :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :xref (x4 / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (a2 / activate-01 :ARG1 k) :ARG1-of (r4 / resemble-01 :polarity "-" :ARG2 (a3 / activate-01 :ARG1 "e"))) :ARG1-of (r3 / resemble-01 :ARG2 (e / enzyme :name (n3 / name :op1 "PKB") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003"))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a4 / and :op1 (p2 / person :name (n6 / name :op1 "Meili")) :op2 (p3 / person :mod (o / other))) :time (d3 / date-entity :year "2000")))) # ::id bio.chicago_2015.35185 # ::date 2015-10-27T03:53:11 # ::file bio_chicago_2015_35185.txt # ::snt Rb association with E2F not only blocks transcriptional activation by E2F but also forms an active transcriptional repressor complex at promoters that can block transcription by recruiting histone deacetylase (HDAC) and remodeling chromatin [ 98, 99, 100 and 101]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a3 / and :op1 (b / block-01 :ARG0 (a / associate-01 :ARG1 (p2 / protein :name (n / name :op1 "Rb") :xref (x / xref :value "UNIPROT:RB_HUMAN" :prob "1.003")) :ARG2 (p / protein :name (n2 / name :op1 "E2F") :xref (x2 / xref :value "UNIPROT:E2F1_HUMAN" :prob "0.262"))) :ARG1 (a2 / activate-01 :ARG0 p :ARG1 (t / transcribe-01))) :op2 (f / form-01 :ARG0 a :ARG1 (m / macro-molecular-complex :ARG0-of (r2 / repress-01 :ARG1 t) :ARG0-of (a5 / activity-06) :ARG0-of (b2 / block-01 :ARG1 t :ARG3 (a7 / and :op1 (r3 / recruit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "histone" :op2 "deacetylase") :xref (x1 / xref :value "UNIPROT:B3KUJ5_HUMAN" :prob "0.701"))) :op2 (r4 / remodel-01 :ARG1 (m3 / macro-molecular-complex :name (n5 / name :op1 "chromatin")))) :ARG1-of (p4 / possible-01))) :mod (a4 / also) :location (m2 / molecular-physical-entity :ARG0-of (p3 / promote-02))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a6 / and :op1 "98" :op2 "99" :op3 "100" :op4 "101"))))) # ::id bio.chicago_2015.35239 # ::date 2015-10-27T05:08:56 # ::file bio_chicago_2015_35239.txt # ::snt Reactions were allowed to elongate for the indicated amounts of time at room temperature and were stopped by the addition of 200 mul of Sarkosyl Stop Solution (100 mM Tris, 100 mM NaCl, 10 mM EDTA, 1% Sarkosyl, 200 mug/ml tRNA). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a3 / and :op1 (a / allow-01 :ARG1 (e / elongate-01 :ARG0 (t / thing :ARG2-of (r / react-01)) :duration (a2 / amount :quant-of (t2 / time) :ARG1-of (i / indicate-01)) :condition (t3 / temperature :mod (r2 / room)))) :op2 (s / stop-01 :ARG1 t :ARG2 (a4 / add-02 :ARG1 (p2 / product :name (n / name :op1 "Sarkosyl" :op2 "Stop" :op3 "Solution") :quant (v / volume-quantity :quant "200" :unit (m / microlitre)) :ARG1-of (e2 / equal-01 :ARG2 (a5 / and :op1 (s2 / small-molecule :name (n2 / name :op1 "Tris") :quant (c2 / concentration-quantity :quant "100" :unit (m3 / millimolar)) :xref (x1 / xref :value "PUBCHEM:6503" :prob "8.699933")) :op2 (s3 / small-molecule :name (n3 / name :op1 "NaCl") :quant (c3 / concentration-quantity :quant "100" :unit (m4 / millimolar)) :xref (x / xref :value "PUBCHEM:5234" :prob "16.963549")) :op3 (s4 / small-molecule :name (n4 / name :op1 "EDTA") :quant (c4 / concentration-quantity :quant "10" :unit (m5 / millimolar)) :xref (x3 / xref :value "PUBCHEM:6049" :prob "14.194091")) :op4 (s5 / small-molecule :name (n5 / name :op1 "Sarkosyl") :quant (p / percentage-entity :value "1") :xref (x2 / xref :value "PUBCHEM:7348" :prob "17.394333")) :op5 (n7 / nucleic-acid :name (n6 / name :op1 "tRNA") :quant (c5 / concentration-quantity :quant "200" :unit (m7 / microgram-per-milliliter))))))))) # ::id bio.chicago_2015.35250 # ::date 2015-10-27T05:22:23 # ::file bio_chicago_2015_35250.txt # ::snt Binding to the membrane is mediated by its PH domain, which binds PI(4,5) P2 ( 14, 15), and by a region upstream of this domain that can directly penetrate into the lipid bilayer ( 16). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m2 / mediate-01 :ARG0 (a4 / and :op1 (p7 / protein-segment :name (n / name :op1 "PH") :poss "m" :ARG2-of (b2 / bind-01 :ARG1 (a / and :op1 (s / small-molecule :name (n2 / name :op1 "PI(4,5)P2") :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "14" :op2 "15")))))))) :op2 (r / region :part-of p7 :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 "16"))) :location (r3 / relative-position :op1 p7 :direction (u / upstream)) :ARG1-of (c3 / capable-01 :ARG2 (p5 / penetrate-01 :ARG0 p7 :ARG1 (b3 / bilayer :mod (l / lipid)) :ARG1-of (d / direct-02))))) :ARG1 (b / bind-01 :ARG2 (m / membrane :xref (x / xref :value "GO:0016020" :prob "0.8")))) # ::id bio.chicago_2015.35259 # ::date 2015-10-27T05:29:32 # ::file bio_chicago_2015_35259.txt # ::snt PKA phosphorylation of adducin reduced activity of adducin in association with spectrin-actin complexes and in promoting binding of spectrin to F-actin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (r / reduce-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "adducin") :xref (x / xref :value "UNIPROT:ADDG_HUMAN" :prob "0.222")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG1-of (a2 / associate-01 :ARG2 (m / macro-molecular-complex :part (p4 / protein :name (n4 / name :op1 "spectrin") :xref (x2 / xref :value "UNIPROT:SPERI_HUMAN" :prob "0.242")) :part (p5 / protein :name (n5 / name :op1 "actin") :xref (x3 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :purpose (p3 / promote-02 :ARG1 (b / bind-01 :ARG1 p4 :ARG2 (p6 / protein :name (n3 / name :op1 "F-actin") :xref (x4 / xref :value "UNIPROT:NEXN_HUMAN" :prob "0.252"))))) :ARG1 (a / activity-06 :ARG0 p2)) # ::id bio.chicago_2015.35282 # ::date 2015-10-27T05:36:28 # ::file bio_chicago_2015_35282.txt # ::snt This domain mediates the association of NIK with MEKK1 and is critical for NIK activation of the SAPK pathway, suggesting that the C-terminal domain of these proteins encodes a new protein domain family that couples these kinases to the SAPK pathway, possibly by interacting with MEKK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a2 / and :op1 (m / mediate-01 :ARG0 (d / domain :mod (t / this)) :ARG1 (a / associate-01 :ARG1 (e / enzyme :name (n / name :op1 "NIK") :xref (x1 / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "MEKK1") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")))) :op2 (c / critical-02 :ARG1 d :ARG3 (a3 / activate-01 :ARG0 e :ARG1 (p / pathway :name (n3 / name :op1 "SAPK")))) :ARG0-of (s / suggest-01 :ARG1 (e3 / encode-01 :ARG0 (p4 / protein-segment :name (n4 / name :op1 "C-terminus") :part-of (a4 / and :op1 e :op2 e2)) :ARG1 (p2 / protein-family :mod (d3 / domain) :ARG0-of (c2 / couple-01 :ARG1 (a5 / and :op1 e :op2 e2) :ARG2 p :manner (i / interact-01 :ARG1 e2 :ARG1-of (p3 / possible-01))) :ARG1-of (n5 / new-02))))) # ::id bio.chicago_2015.35301 # ::date 2015-10-27T22:08:34 # ::file bio_chicago_2015_35301.txt # ::snt We conclude that ind represses msh and achaete gene expression directly or indirectly, and that ind is necessary for establishing proper intermediate-column identity within the neuroectoderm. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c / conclude-01 :ARG0 (w / we) :ARG1 (a / and :op1 (r / repress-01 :ARG0 (p2 / protein :name (n2 / name :op1 "ind") :xref (x / xref :value "UNIPROT:I23O1_HUMAN" :prob "0.202")) :ARG1 (e2 / express-03 :ARG1 (a2 / and :op1 (g / gene :name (n3 / name :op1 "msh") :xref (x2 / xref :value "UNIPROT:MSH2_HUMAN" :prob "0.202")) :op2 (g2 / gene :name (n4 / name :op1 "achaete") :xref (x1 / xref :value "UNIPROT:ASCL1_HUMAN" :prob "0.222")))) :manner (o / or :op1 (d / direct-02) :op2 (d2 / direct-02 :polarity "-"))) :op2 (n / need-01 :ARG0 (e3 / establish-01 :ARG1 (i / identity :mod (c2 / column :mod (i2 / intermediate)) :mod (p / proper)) :location (n5 / neuroectoderm)) :ARG1 p2))) # ::id bio.chicago_2015.35359 # ::date 2015-10-27T22:18:18 # ::file bio_chicago_2015_35359.txt # ::snt In vivo analysis of the association of PML and Sp1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (a / analyze-01 :ARG1 (a2 / associate-01 :ARG1 (p2 / protein :name (n / name :op1 "PML") :xref (x / xref :value "UNIPROT:PML_HUMAN" :prob "1.003")) :ARG2 (p / protein :name (n2 / name :op1 "Sp1") :xref (x1 / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001"))) :manner (i / in-vivo)) # ::id bio.chicago_2015.35392 # ::date 2015-10-27T22:23:23 # ::file bio_chicago_2015_35392.txt # ::snt A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / activate-01 :ARG0 (m / mutate-01 :ARG1 (k / kinase :name (n / name :op1 "MAP") :part-of (o / organism :name (n2 / name :op1 "Drosophila")) :xref (x1 / xref :value "UNIPROT:MOTI_HUMAN" :prob "1.002")) :mod (g2 / gain-02 :mod (f / function-01))) :ARG1 (p / pathway :ARG0-of (s / signal-07 :ARG1 (e / enzyme :name (n3 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :mod (m2 / multiple) :xref (x / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392"))))) # ::id bio.chicago_2015.35414 # ::date 2015-10-27T22:27:28 # ::file bio_chicago_2015_35414.txt # ::snt Since DEDD was found to associate with FADD and caspase-8 in vitro, we tested whether under conditions with significant amounts of DEDD in the cytoplasm an association with endogenous FADD and/or caspase-8 could be found in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (p / possible-01 :mode "interrogative" :ARG1 (f / find-01 :ARG1 (a / associate-01 :ARG1 (p4 / protein :name (n / name :op1 "DEDD") :xref (x2 / xref :value "UNIPROT:DEDD_HUMAN" :prob "1.003")) :ARG2 (a2 / and-or :op1 (p2 / protein :name (n2 / name :op1 "FADD") :mod (e / endogenous) :xref (x / xref :value "UNIPROT:FADD_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n3 / name :op1 "caspase-8") :xref (x1 / xref :value "UNIPROT:CASP8_HUMAN" :prob "0.702")))) :manner (i / in-vivo) :condition (a4 / amount :ARG1-of (s / significant-02) :quant-of p4 :location (c2 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8"))))) :ARG1-of (c / cause-01 :ARG0 (f2 / find-01 :ARG0 w :ARG1 (a5 / associate-01 :ARG1 p4 :ARG2 (a6 / and :op1 p2 :op2 p3) :manner (i2 / in-vitro))))) # ::id bio.chicago_2015.35423 # ::date 2015-10-27T22:37:22 # ::file bio_chicago_2015_35423.txt # ::snt Further, we also demonstrated that Dermo-1 represses the transactivation of MyoD and MEF2 through different mechanisms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (r / repress-01 :ARG0 (p / protein :name (n / name :op1 "Dermo-1") :xref (x2 / xref :value "UNIPROT:TWST2_HUMAN" :prob "1.002")) :ARG1 (t / transactivate-01 :ARG1 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "MyoD") :xref (x / xref :value "UNIPROT:MYOD1_HUMAN" :prob "0.602")) :op2 (p3 / protein :name (n3 / name :op1 "MEF2") :xref (x1 / xref :value "UNIPROT:MEF2A_HUMAN" :prob "1.002")))) :instrument (m / mechanism :ARG1-of (d2 / differ-02))) :mod (a / also) :mod (f / further)) # ::id bio.chicago_2015.35431 # ::date 2015-10-27T23:58:06 # ::file bio_chicago_2015_35431.txt # ::snt A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (a / affect-01 :ARG0 (g2 / group :mod (n3 / novel) :consist-of (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "pumilio") :xref (x / xref :value "UNIPROT:PUM1_HUMAN" :prob "0.342")))) :ARG1 (d / divide-02 :ARG1 (c / cell :mod (s / stem) :mod (g3 / germline)) :mod (s2 / symmetric :polarity "-") :location (o / ovary :part-of (o2 / organism :name (n2 / name :op1 "Drosophila"))))) # ::id bio.chicago_2015.35452 # ::date 2015-10-28T00:09:03 # ::file bio_chicago_2015_35452.txt # ::snt Moreover, PAK activation by Agrin is dependent on Cdc42 and Rac, suggesting that PAK may be downstream of the small GTPases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a3 / and :op2 (d2 / depend-01 :ARG0 (a / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "Agrin") :xref (x2 / xref :value "UNIPROT:AGRIN_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n / name :op1 "PAK") :xref (x1 / xref :value "UNIPROT:PAK1_HUMAN" :prob "0.263"))) :ARG1 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :op2 (e3 / enzyme :name (n4 / name :op1 "Rac") :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG0-of (s / suggest-01 :ARG1 (p2 / possible-01 :ARG1 (b / be-located-at-91 :ARG1 e :ARG2 (r / relative-position :op1 (e4 / enzyme :name (n5 / name :op1 "GTPase") :mod (s2 / small) :xref (x3 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :direction (d / downstream))))))) # ::id bio.chicago_2015.35459 # ::date 2015-10-28T00:15:01 # ::file bio_chicago_2015_35459.txt # ::snt B, IKAP significantly potentiates MEKK1-induced JNK activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (p / potentiate-01 :li "b" :ARG0 (p3 / protein :name (n2 / name :op1 "IKAP") :xref (x / xref :value "UNIPROT:ELP1_HUMAN" :prob "1.002")) :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEKK1") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")))) :ARG1-of (s / significant-02)) # ::id bio.chicago_2015.35483 # ::date 2015-10-28T00:19:51 # ::file bio_chicago_2015_35483.txt # ::snt It has been found that KSR is bound directly to MEK in the cytoplasm of quiescent cells; upon activation of the MAPK pathway by growth factors or activated RAS, KSR is relocalized to the plasma membrane in a complex containing RAF, MEK, and MAPK ( M ICHAUD et al. 1997 ; D ENOUEL-GALY et al. 1998 ; # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a / and :op1 (f / find-01 :ARG1 (b / bind-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "KSR") :xref (x1 / xref :value "UNIPROT:KSR1_HUMAN" :prob "1.003")) :ARG2 (e / enzyme :name (n / name :op1 "MEK") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (d3 / direct-02) :location (c / cytoplasm :part-of (c2 / cell :mod (q / quiescent)) :xref (x5 / xref :value "GO:0005737" :prob "0.8")))) :op2 (r / relocalize-00 :ARG1 e5 :destination (m / membrane :mod (p6 / plasma) :location (m2 / macro-molecular-complex :ARG0-of (c4 / contain-01 :ARG1 (a3 / and :op1 (e3 / enzyme :name (n4 / name :op1 "Raf") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op2 e :op3 (e4 / enzyme :name (n2 / name :op1 "MAPK") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))))) :xref (x6 / xref :value "GO:0016020" :prob "0.8")) :condition (a4 / activate-01 :ARG0 (o / or :op1 (g / growth-factor) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (p / pathway :name (n9 / name :op1 "MAPK")))) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and :op1 (p7 / publication-91 :ARG0 (a6 / and :op1 (p8 / person :name (n6 / name :op1 "Michaud")) :op2 (p9 / person :mod (o2 / other))) :time (d / date-entity :year "1997")) :op2 (p10 / publication-91 :ARG0 (a7 / and :op1 (p11 / person :name (n7 / name :op1 "Denouel-Galy")) :op2 (p12 / person :mod (o3 / other))) :time (d2 / date-entity :year "1998"))))) # ::id bio.chicago_2015.35489 # ::date 2015-10-28T00:50:05 # ::file bio_chicago_2015_35489.txt # ::snt SXL associates with the U1 snRNP particle in embryonic extracts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (a / associate-01 :ARG1 (p3 / protein :name (n / name :op1 "SXL")) :ARG2 (p / particle :name (n2 / name :op1 "U1") :part-of (p2 / protein :name (n3 / name :op1 "snRNP") :xref (x / xref :value "UNIPROT:Q15520_HUMAN" :prob "1.001"))) :location (m / molecular-physical-entity :ARG1-of (e / extract-01 :ARG2 (e2 / embryo)))) # ::id bio.chicago_2015.35547 # ::date 2015-10-28T00:54:01 # ::file bio_chicago_2015_35547.txt # ::snt Ubc9 Binding to Mdm2 Is Decreased after UV Irradiation-- Since UV irradiation has been shown to reduce the degree of Mdm2 sumoylation, we have monitored possible changes in the association of Ubc9 with Mdm2 in UV-treated cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (m / multi-sentence :snt1 (d / decrease-01 :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "Ubc9") :xref (x3 / xref :value "UNIPROT:UBC9_HUMAN" :prob "0.603")) :ARG2 (p2 / protein :name (n2 / name :op1 "Mdm2") :xref (x1 / xref :value "UNIPROT:A7UKX7_HUMAN" :prob "0.701"))) :time (a / after :op1 (i / irradiate-01 :ARG2 (u / ultraviolet)))) :snt2 (m2 / monitor-01 :ARG0 (w2 / we) :ARG1 (c / change-01 :ARG1 (a2 / associate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ubc9") :xref (x / xref :value "UNIPROT:UBC9_HUMAN" :prob "0.603")) :ARG2 (p3 / protein :name (n4 / name :op1 "Mdm2") :xref (x2 / xref :value "UNIPROT:A7UKX7_HUMAN" :prob "0.701")) :location (c2 / cell :ARG1-of (t / treat-04 :ARG2 "u2"))) :ARG1-of (p / possible-01)) :ARG1-of (c3 / cause-01 :ARG0 (s / show-01 :ARG1 (r / reduce-01 :ARG0 (i2 / irradiate-01 :ARG2 (u2 / ultraviolet)) :ARG1 (d2 / degree :degree-of (s2 / sumoylate-00 :ARG0 p2))))))) # ::id bio.chicago_2015.35599 # ::date 2015-10-28T01:09:32 # ::file bio_chicago_2015_35599.txt # ::snt From previous experiments it is known that a single application of 5HT induces STF, which declines to baseline levels within ~15 min, whereas five applications of 5HT induce LTF that lasts at least up to 24 hr after its induction (Walters et al., 1983 ; Emptage and Carew, 1993 ; # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (k / know-01 :ARG1 (c / contrast-01 :ARG1 (i / induce-01 :ARG0 (a2 / apply-03 :ARG1 (e / enzyme :name (n / name :op1 "5HT") :xref (x / xref :value "UNIPROT:SC6A4_HUMAN" :prob "0.342")) :ARG1-of (s / single-02)) :ARG2 (f / facilitate-01 :ARG1-of (d3 / decline-01 :ARG4 (l3 / level :mod (b / baseline)) :time (u / up-to :op1 (t2 / temporal-quantity :quant "15" :unit (m / minute)))) :ARG1-of (s2 / short-07))) :ARG2 (i2 / induce-01 :ARG0 (a3 / apply-03 :ARG1 e :mod (p / product-of :op1 "5")) :ARG2 (f2 / facilitate-01 :ARG1-of (l / last-01 :ARG2 (a4 / after :op1 i2) :quant (a8 / at-least :op1 (u2 / up-to :op1 (t4 / temporal-quantity :quant "24" :unit (h / hour))))) :ARG1-of (l2 / long-03)))) :source (e2 / experiment-01 :time (p2 / previous)) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and :op1 (p3 / publication-91 :ARG0 (a6 / and :op1 (p4 / person :name (n4 / name :op1 "Walters")) :op1 (p5 / person :mod (o / other))) :time (d / date-entity :year "1983")) :op2 (p6 / publication-91 :ARG0 (a7 / and :op1 (p7 / person :name (n5 / name :op1 "Emptage")) :op2 (p8 / person :name (n6 / name :op1 "Carew"))) :time (d2 / date-entity :year "1993"))))) # ::id bio.chicago_2015.35619 # ::date 2015-10-28T01:24:06 # ::file bio_chicago_2015_35619.txt # ::snt To examine whether AES interacts with p65 in cultured cells, we performed the co-immunoprecipitation experiment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (p / perform-02 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG2 (c / coimmunoprecipitate-01)) :purpose (e2 / examine-01 :ARG0 w :ARG1 (i / interact-01 :mode "interrogative" :ARG0 (p3 / protein :name (n / name :op1 "AES") :xref (x1 / xref :value "UNIPROT:AES_HUMAN" :prob "1.003")) :ARG1 (p2 / protein :name (n2 / name :op1 "p65") :xref (x / xref :value "UNIPROT:SYT1_HUMAN" :prob "1.002")) :location (c2 / cell :ARG1-of (c3 / culture-01))))) # ::id bio.chicago_2015.35635 # ::date 2015-10-28T01:28:05 # ::file bio_chicago_2015_35635.txt # ::snt Our results show that the C-terminal domains of the xCRYs are necessary for nuclear localization, but it is still unclear if this is achieved via importin binding to an authentic NLS within the C-terminal domain or via a more indirect mechanism. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (n / need-01 :ARG0 (l / localize-01 :ARG1 (n4 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8"))) :ARG1 (p2 / protein-segment :name (n2 / name :op1 "C-terminus") :part-of (p3 / protein :name (n3 / name :op1 "xCRY"))))) :ARG2 (c2 / clear-06 :polarity "-" :ARG1 (a / achieve-01 :mode "interrogative" :ARG1 n :instrument (o / or :op1 (b / bind-01 :ARG1 (p / protein :name (n5 / name :op1 "importin") :xref (x / xref :value "UNIPROT:IPO4_HUMAN" :prob "0.352")) :ARG2 (p4 / protein-segment :name (n6 / name :op1 "NLS") :ARG1-of (a3 / authentic-02)) :location p2) :op2 (m / mechanism :ARG1-of (d2 / direct-02 :polarity "-" :degree (m2 / more))))) :time (s2 / still))) # ::id bio.chicago_2015.35638 # ::date 2015-10-28T04:31:56 # ::file bio_chicago_2015_35638.txt # ::snt The Drosophila melanogaster suppressor of Hairy-wing protein binds to specific sequences of the gypsy retrotransposon. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (b / bind-01 :ARG1 (m / molecular-physical-entity :ARG0-of (s / suppress-01 :ARG1 (p2 / protein :name (n5 / name :op1 "Harry-wing"))) :mod (o / organism :name (n / name :op1 "Drosophila" :op2 "melanogaster"))) :ARG2 (s2 / sequence :ARG1-of (s3 / specific-02) :part-of (d / dna-sequence :name (n4 / name :op1 "retrotransposon") :mod (g / gypsy)))) # ::id bio.chicago_2015.35639 # ::date 2015-10-28T04:37:44 # ::file bio_chicago_2015_35639.txt # ::snt The fat facets gene is required for Drosophila eye and embryo development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (r / require-01 :ARG0 (d / develop-01 :ARG2 (a / and :op1 (e / eye) :op2 (e2 / embryo) :part-of (o / organism :name (n / name :op1 "Drosophila")))) :ARG1 (g / gene :name (n2 / name :op1 "fat" :op2 "facet") :xref (x / xref :value "UNIPROT:USP9X_HUMAN" :prob "0.252"))) # ::id bio.chicago_2015.35656 # ::date 2015-10-28T04:50:06 # ::file bio_chicago_2015_35656.txt # ::snt Our data showing that full-length TAF130p tightly binds TBP and prevents subsequent TBP-TATA DNA interactions, as well as the published work of others (see above), illustrates an intriguing conundrum. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (i / illustrate-01 :ARG0 (a2 / and :op1 (d / data :poss (w / we) :ARG0-of (s / show-01 :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p6 / protein-segment :name (n / name :op1 "TAF130p") :ARG1-of (l / long-03 :mod (f / full))) :ARG2 (p2 / protein :name (n2 / name :op1 "TBP") :xref (x / xref :value "UNIPROT:TBP_HUMAN" :prob "1.003")) :ARG1-of (t2 / tight-05)) :op2 (p / prevent-01 :ARG0 p2 :ARG1 (i2 / interact-01 :ARG0 p2 :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "DNA") :part-of (d2 / dna-sequence :name (n5 / name :op1 "TATA"))) :time (s3 / subsequent)))))) :op2 (w2 / work-01 :ARG0 (p5 / person :mod (o / other)) :ARG1-of (p4 / publish-01) :ARG1-of (s2 / see-01 :mode "imperative" :ARG0 (y / you) :location (a3 / above)))) :ARG1 (c / conundrum :ARG0-of (i3 / intrigue-01))) # ::id bio.chicago_2015.35670 # ::date 2015-10-28T04:58:51 # ::file bio_chicago_2015_35670.txt # ::snt Furthermore, we show that high Dpp signalling antagonizes Wg-mediated repression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (s / show-01 :ARG0 (w / we) :ARG1 (a2 / antagonize-02 :ARG1 (s2 / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Dpp")) :ARG1-of (h / high-02)) :ARG2 (r / repress-01 :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Wg"))))))) # ::id bio.chicago_2015.35685 # ::date 2015-10-28T05:02:54 # ::file bio_chicago_2015_35685.txt # ::snt The interaction of rAxin with beta-catenin was confirmed by the yeast two-hybrid method # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (c / confirm-01 :ARG0 (m / method :name (n3 / name :op1 "yeast" :op2 "two-hybrid")) :ARG1 (i / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "rAxin")) :ARG1 (p / protein :name (n2 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")))) # ::id bio.chicago_2015.35692 # ::date 2015-10-28T05:05:47 # ::file bio_chicago_2015_35692.txt # ::snt Consistent with data shown in Fig. 1, tyrosine phosphorylation of either cortactin or EC MLCK 1 by p60src resulted in enhanced affinity with measured Kd's of 0.2 M ( Fig. 2B) and 0.1 M ( Fig. 2C), respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (r / result-01 :ARG1 (p / phosphorylate-01 :ARG1 (o / or :op1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "cortactin") :xref (x / xref :value "UNIPROT:CORT_HUMAN" :prob "0.292")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a4 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (p3 / protein :name (n3 / name :op1 "EC" :op2 "MLCK" :op3 "1")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG2 (e5 / enzyme :name (n5 / name :op1 "p60" :op2 "src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.653"))) :ARG2 (a2 / affinity :ARG1-of (e / enhance-01) :ARG0-of (h / have-03 :ARG1 (a3 / and :op1 (d6 / dissociate-01 :ARG1 (e3 / equilibrium :quant (d / distance-quantity :quant "0.2" :unit (m / molar))) :ARG1-of (m3 / measure-01) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2B"))) :op2 (d2 / dissociate-01 :ARG1 (e4 / equilibrium :quant (c2 / concentration-quantity :quant "0.1" :unit m)) :ARG1-of m3 :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "2C")))))) :ARG1-of (c / consistent-01 :ARG2 (d5 / data :ARG1-of (s2 / show-01 :medium (f3 / figure :mod "1"))))) # ::id bio.chicago_2015.35756 # ::date 2015-10-28T05:13:05 # ::file bio_chicago_2015_35756.txt # ::snt Comparable to the interactions of GATA4 and FOG-2, Pnr and Ush heterodimerize through the amino-terminal zinc finger of Pnr ( 24), and genetic studies have shown that Ush antagonizes the function of Pnr in the establishment of the thoracic bristle pattern in the adult ( 24, 25). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a2 / and :op1 (h / heterodimerize-01 :ARG0 (p9 / protein-segment :name (n5 / name :op1 "amino-terminal" :op2 "zinc" :op3 "finger")) :ARG1 (p7 / protein :name (n / name :op1 "Pnr") :xref (x1 / xref :value "UNIPROT:NR2E3_HUMAN" :prob "0.602")) :ARG2 (p8 / protein :name (n2 / name :op1 "Ush") :xref (x3 / xref :value "UNIPROT:USH2A_HUMAN" :prob "0.202")) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "24"))) :ARG1-of (c2 / comparable-03 :ARG2 (i / interact-01 :ARG0 (p5 / protein :name (n3 / name :op1 "GATA4") :xref (x2 / xref :value "UNIPROT:GATA4_HUMAN" :prob "1.003")) :ARG1 (p6 / protein :name (n4 / name :op1 "FOG-2") :xref (x / xref :value "UNIPROT:FOG2_HUMAN" :prob "1.002"))))) :op2 (s / show-01 :ARG0 (s2 / study-01 :mod (g / genetics)) :ARG1 (a3 / antagonize-02 :ARG1 p8 :ARG2 (f2 / function-01 :ARG0 p7 :ARG1 (e3 / establish-01 :ARG0 p7 :ARG1 (p2 / pattern :mod (b / bristle) :mod (t3 / thoracic)) :location (a / adult)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a5 / and :op1 "24" :op2 "25")))))) # ::id bio.chicago_2015.35779 # ::date 2015-10-28T05:20:59 # ::file bio_chicago_2015_35779.txt # ::snt To test for functional association of DEDD with FADD or caspase-8, suboptimal non-cytotoxic concentrations of FADD or caspase-8 were co-transfected with suboptimal concentrations of the DEDD deletion mutants (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (c / cotransfect-01 :ARG1 (o / or :op1 (c2 / concentrate-02 :ARG1 (p2 / protein :wiki "FADD" :name (n / name :op1 "FADD") :xref (x / xref :value "UNIPROT:FADD_HUMAN" :prob "1.003"))) :op2 (c3 / concentrate-02 :ARG1 (p / protein :wiki "Caspase_8" :name (n2 / name :op1 "caspase-8") :xref (x2 / xref :value "UNIPROT:CASP8_HUMAN" :prob "0.702"))) :mod (s / suboptimal) :mod (c4 / cytotoxic :polarity "-")) :instrument (c5 / concentrate-02 :ARG1 (m / mutate-01 :ARG1-of (c6 / cause-01 :ARG0 (d / delete-01 :ARG1 (p3 / protein :wiki "DEDD" :name (n3 / name :op1 "DEDD") :xref (x1 / xref :value "UNIPROT:DEDD_HUMAN" :prob "1.003"))))) :mod s) :purpose (t3 / test-01 :ARG2 (a / associate-01 :ARG0 p3 :ARG1 (o2 / or :op1 p2 :op2 p) :ARG0-of (f / function-01))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4C"))) # ::id bio.chicago_2015.35797 # ::date 2015-10-28T05:27:34 # ::file bio_chicago_2015_35797.txt # ::snt However, Dox-induced expression of Axin during the first 4 days (aggregation), followed by withdrawal of Dox for the next 6 days (differentiation), had no effect on betaIII-tubulin expression (Fig. 6, compare lanes 2 and 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (h / have-concession-91 :ARG1 (a / affect-01 :polarity "-" :ARG0 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Axin") :xref (x / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG2-of (i / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "Dox") :xref (x2 / xref :value "PUBCHEM:32874" :prob "16.963549"))) :duration (t / temporal-quantity :quant "4" :unit (d / day) :ord (o2 / ordinal-entity :value "1")) :ARG1-of (m / mean-01 :ARG2 (a2 / aggregate-01)) :ARG2-of (f / follow-01 :ARG1 (w / withdraw-01 :ARG1 s :duration (t2 / temporal-quantity :quant "6" :unit (d2 / day) :mod (n4 / next)) :ARG1-of (m2 / mean-01 :ARG2 (d3 / differentiate-01))))) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "betaIII-tubulin") :xref (x1 / xref :value "UNIPROT:BTC_HUMAN" :prob "0.243")))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "6" :location-of (c / compare-01 :mode "imperative" :ARG0 (y / you) :ARG1 (l / lane :mod "2") :ARG2 (l2 / lane :mod "6"))))) # ::id bio.chicago_2015.35826 # ::date 2015-10-28T05:37:55 # ::file bio_chicago_2015_35826.txt # ::snt Thus, Robo2 does not control midline crossing of retinal axons, but rather shapes their pathway, by both preventing and correcting pathfinding errors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (c6 / cause-01 :ARG1 (c4 / contrast-01 :ARG1 (c2 / control-01 :polarity "-" :ARG0 (p4 / protein :name (n / name :op1 "Robo2") :xref (x / xref :value "UNIPROT:ROBO2_HUMAN" :prob "0.603")) :ARG1 (c3 / cross-01 :ARG1 (a2 / axon :mod (r / retina)) :mod (m / midline))) :ARG2 (s / shape-01 :ARG0 p4 :ARG1 (p / pathway :poss a2) :mod (r2 / rather) :manner (a3 / and :op1 (p2 / prevent-01 :ARG0 p4 :ARG1 (t / thing :ARG1-of (e / err-01) :ARG0-of (f / find-01 :ARG1 (p3 / path)))) :op2 (c5 / correct-01 :ARG0 p4 :ARG1 t))))) # ::id bio.chicago_2015.35827 # ::date 2015-10-27T02:07:41 # ::file bio_chicago_2015_35827.txt # ::snt ( A) PIASy represses LEF1 activity from a multimerized LEF1 reporter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (r2 / repress-01 :li "A" :ARG0 (e / enzyme :name (n / name :op1 "PIASy") :xref (x1 / xref :value "UNIPROT:PIAS4_HUMAN" :prob "1.002")) :ARG1 (a / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "LEF1") :xref (x / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.003"))) :ARG2 (m / molecular-physical-entity :ARG0-of (r / report-01 :ARG1 p2) :ARG1-of (m2 / multimerize-00))) # ::id bio.chicago_2015.35949 # ::date 2015-10-27T06:40:33 # ::file bio_chicago_2015_35949.txt # ::snt Furthermore, gamma-tubulin can interact with beta-tubulin (Leguy et al., 2000 ), the subunit exposed at the plus ends of microtubules (Nogales et al., 1999 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / and :op2 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (p7 / protein-family :name (n / name :op1 "gamma-tubulin")) :ARG1 (p8 / protein-family :name (n2 / name :op1 "beta-tubulin") :ARG1-of (d3 / describe-01 :ARG0 (p9 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n3 / name :op1 "Leguy")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2000")))) :manner (e / expose-01 :ARG1 (s / subunit) :location (e2 / end-02 :ARG1 (m4 / microtubule) :mod (p2 / plus)) :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n4 / name :op1 "Nogales")) :op2 (p4 / person :mod (o2 / other)) :time (d2 / date-entity :year "1999")))))))) # ::id bio.chicago_2015.35955 # ::date 2015-10-27T06:40:39 # ::file bio_chicago_2015_35955.txt # ::snt Interestingly, PDK1 phosphorylates and activates another pleckstrin homology domain containing protein kinase, Akt, as well ( 16, 17). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / and :op1 (p / phosphorylate-01 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "pleckstrin" :op2 "homology") :ARG0-of (c2 / contain-01 :ARG1 (e / enzyme :name (n3 / name :op1 "protein" :op2 "kinase" :op3 "Akt") :xref (x / xref :value "UNIPROT:AKT2_HUMAN" :prob "0.393")) :mod (a4 / as-well)) :mod (a5 / another)) :ARG2 (e2 / enzyme :name (n / name :op1 "PDK1") :xref (x1 / xref :value "UNIPROT:PDK1_HUMAN" :prob "1.003"))) :op2 (a2 / activate-01 :ARG0 e2 :ARG1 p3) :ARG2-of (i / interest-01) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "16" :op2 "17"))))) # ::id bio.chicago_2015.36045 # ::date 2015-10-27T06:40:49 # ::file bio_chicago_2015_36045.txt # ::snt The Torso receptor tyrosine kinase can activate Raf in a Ras-independent pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Torso" :op2 "receptor" :op3 "tyrosine" :op4 "kinase")) :ARG1 (e / enzyme :name (n / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :location (p2 / pathway :ARG0-of (d / depend-01 :polarity "-" :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) # ::id bio.chicago_2015.36075 # ::date 2015-10-27T06:52:10 # ::file bio_chicago_2015_36075.txt # ::snt Arabidopsis SGS2 and SGS3 Genes Are Required for Posttranscriptional Gene Silencing and Natural Virus Resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (r / require-01 :ARG0 (a2 / and :op1 (s / silence-01 :ARG1 (g3 / gene) :time (a3 / after :op1 (t / transcribe-01))) :op1 (r2 / resist-01 :ARG1 (v / virus) :ARG1-of (n4 / natural-03))) :ARG1 (a / and :op1 (g / gene :name (n2 / name :op1 "SGS2") :xref (x / xref :value "UNIPROT:SGSM2_HUMAN" :prob "0.312")) :op2 (g2 / gene :name (n3 / name :op1 "SGS3") :xref (x1 / xref :value "UNIPROT:SGSM3_HUMAN" :prob "0.312")) :source (o / organism :name (n / name :op1 "Arabidopsis")))) # ::id bio.chicago_2015.36082 # ::date 2015-10-27T07:29:32 # ::file bio_chicago_2015_36082.txt # ::snt Spatially Restricted Activation of the SAX Receptor by SCW Modulates DPP/ TKV Signaling in Drosophila Dorsal - Ventral Patterning. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (m / modulate-01 :ARG0 (a / activate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "SCW")) :ARG1 (p / protein :name (n / name :op1 "SAX" :op2 "Receptor")) :ARG1-of (r / restrict-01 :manner (s / space))) :ARG1 (s4 / signal-07 :ARG0 (p3 / pathway :name (n3 / name :op1 "DPP/TKV")) :time (p4 / pattern-01 :ARG1 (o / organism :name (n5 / name :op1 "Drosophila")) :mod (d / dorsal) :mod (v / ventral)))) # ::id bio.chicago_2015.36092 # ::date 2015-10-27T10:55:27 # ::file bio_chicago_2015_36092.txt # ::snt Supernatants were diluted in 40 mM Tris-HCl (pH 8), 0.1 M NaCl, 0.4 mg/ml bovine serum albumin, 1 mM dithiothreitol, 0.45 mM okadaic acid (Buffer 1) and incubated at 30 degrees C for 1 min in buffer 1 containing 1 mM of the peptide [ 32]- RII subunit of cyclic AMP-dependent protein kinase (PKA) and either 0.1 mM calmodulin (Sigma) and 0.66 mM Ca2+ or 0.33 mM EGTA (pH 7.5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (d / dilute-01 :ARG1 (s / supernatant) :ARG3 (a2 / and :op1 (m12 / macro-molecular-complex :name (n / name :op1 "Tris-HCl") :quant (c / concentration-quantity :quant "40" :unit (m / micromolar))) :op2 (s6 / small-molecule :name (n2 / name :op1 "NaCl") :quant (c2 / concentration-quantity :quant "0.1" :unit (m2 / molar)) :xref (x5 / xref :value "PUBCHEM:5234" :prob "16.963549")) :op3 (p4 / protein :name (n9 / name :op1 "albumin") :mod (s2 / serum :source (b / bovine)) :quant (c3 / concentration-quantity :quant "0.4" :unit (m3 / milligram-per-milliliter)) :xref (x2 / xref :value "UNIPROT:ALBU_HUMAN" :prob "0.212")) :op4 (s7 / small-molecule :name (n3 / name :op1 "dithiothreitol") :quant (c5 / concentration-quantity :quant "1" :unit (m4 / micromolar)) :xref (x4 / xref :value "PUBCHEM:19001" :prob "16.740406")) :op5 (s3 / small-molecule :name (n4 / name :op1 "okadaic" :op2 "acid") :quant (c4 / concentration-quantity :quant "0.45" :unit (m5 / micromolar)) :xref (x3 / xref :value "PUBCHEM:4584" :prob "10.68039")))) :op2 (i / incubate-01 :ARG1 s :ARG2 (b2 / buffer :mod "1" :ARG0-of (c6 / contain-01 :ARG1 (a5 / and :op1 (p5 / peptide :name (n10 / name :op1 "[32]-RII" :op2 "subunit") :quant (c7 / concentration-quantity :quant "1" :unit (m7 / micromolar)) :poss (e / enzyme :name (n5 / name :op1 "AMP-dependent" :op2 "protein" :op3 "kinase") :mod (c8 / cyclic) :xref (x1 / xref :value "UNIPROT:NUAK1_HUMAN" :prob "0.262"))) :op2 (o2 / or :op1 (p3 / protein :name (n6 / name :op1 "calmodulin") :quant (c9 / concentration-quantity :quant "0.1" :unit (m8 / micromolar)) :xref (x / xref :value "UNIPROT:CALM_HUMAN" :prob "0.703")) :op2 (s4 / small-molecule :name (n8 / name :op1 "calcium") :quant (c11 / concentration-quantity :quant "0.66" :unit (m11 / micromolar)) :ARG1-of (i2 / ionize-01 :value "2+") :xref (x7 / xref :value "PUBCHEM:5460341" :prob "10.601383"))) :op3 (s5 / small-molecule :name (n7 / name :op1 "EGTA") :quant (c10 / concentration-quantity :quant "0.33" :unit (m9 / micromolar)) :xref (x6 / xref :value "PUBCHEM:6207" :prob "17.186693"))))) :mod (t4 / temperature-quantity :quant "30" :scale (c12 / celsius)) :duration (t5 / temporal-quantity :quant "1" :unit (m6 / minute)))) # ::id bio.chicago_2015.36117 # ::date 2015-10-27T07:30:25 # ::file bio_chicago_2015_36117.txt # ::snt These results indicate that the inhibition of EGF-induced Erk2 activation by Abi-1 is specific to the Erk pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (s / specific-02 :ARG1 (i2 / inhibit-01 :ARG1 (a / activate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Abi-1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n3 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")) :ARG2-of (i3 / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :ARG2 (p / pathway :name (n / name :op1 "Erk")))) # ::id bio.chicago_2015.36125 # ::date 2015-10-27T07:37:09 # ::file bio_chicago_2015_36125.txt # ::snt The 60 kDa subunit of importin, importin , recognizes and directly binds the NLS (reviewed in Gorlich and Mattaj, 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op1 (r / recognize-02 :ARG0 (p / protein-family :name (n / name :op1 "subunit" :op2 "of" :op3 "importin") :quant (m / mass-quantity :quant "60" :unit (k / kilodalton))) :ARG1 "p5") :op2 (b / bind-01 :ARG0 p :ARG1 (p5 / protein-segment :name (n2 / name :op1 "NLS")) :ARG1-of (d2 / direct-02)) :ARG1-of (r2 / review-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n3 / name :op1 "Gorlich")) :op2 (p3 / person :name (n4 / name :op1 "Mattaj"))) :time (d / date-entity :year "1996")))) # ::id bio.chicago_2015.36130 # ::date 2015-10-27T10:13:22 # ::file bio_chicago_2015_36130.txt # ::snt Previous studies showed that both Smad6 and Smurf1 inhibit BMP signals in vivo (Tsuneizumi et al., 1997 ; Hata et al., 1998 ; Nakayama et al., 1998 ; Zhang et al., 2001 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (s / show-01 :ARG0 (s2 / study-01 :time (p / previous)) :ARG1 (i / inhibit-01 :ARG0 (a / and :op1 (p11 / protein :name (n / name :op1 "Smad6") :xref (x1 / xref :value "UNIPROT:SMAD6_HUMAN" :prob "1.003")) :op2 (p12 / protein :name (n2 / name :op1 "Smurf1") :xref (x2 / xref :value "UNIPROT:SMUF1_HUMAN" :prob "0.602"))) :ARG1 (s3 / signal-07 :ARG0 (p2 / protein :name (n3 / name :op1 "BMP") :xref (x / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263"))) :manner (i2 / in-vivo)) :ARG1-of (d6 / describe-01 :ARG0 (a6 / and :op1 (p16 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n4 / name :op1 "Tsuneizumi")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "1997")) :op2 (p13 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n5 / name :op1 "Hata")) :op2 (p6 / person :mod o)) :time (d2 / date-entity :year "1998")) :op3 (p14 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n6 / name :op1 "Nakayama")) :op2 (p7 / person :mod o)) :time d2) :op4 (p15 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n7 / name :op1 "Zhang")) :op2 (p10 / person :mod o)) :time (d4 / date-entity :year "2001"))))) # ::id bio.chicago_2015.36162 # ::date 2015-10-27T10:22:50 # ::file bio_chicago_2015_36162.txt # ::snt One prediction of these studies is that an overlap in MLL-and CREB-dependent target genes exists such that the cooperative interaction of MLL and CREB with CBP would play a role in regulating these genes (Fig. 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (p / predict-01 :quant "1" :ARG0 (s / study-01 :mod (t / this)) :ARG1 (e / exist-01 :ARG1 (o / overlap-01 :ARG0 (a2 / and :op1 (g / gene :ARG1-of (t2 / target-01 :ARG0 "p3")) :op2 (g2 / gene :ARG1-of (t3 / target-01 :ARG0 "p5")))) :purpose (p2 / play-02 :ARG0 (i / interact-01 :ARG0 (a / and :op1 (p3 / protein :name (n / name :op1 "MLL") :xref (x / xref :value "UNIPROT:KMT2A_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n2 / name :op1 "CREB") :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))) :ARG1 (p5 / protein :name (n3 / name :op1 "CBP") :xref (x2 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :ARG2-of (c / cooperate-01)) :ARG1 (r / regulate-01 :ARG0 i :ARG1 a2))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7"))) # ::id bio.chicago_2015.36163 # ::date 2015-10-27T08:31:09 # ::file bio_chicago_2015_36163.txt # ::snt Together, these results showed that the coiled-coil domain of PML was required for the association of PML with Sp1 in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (s / show-01 :ARG0 (t2 / thing :mod (t3 / this) :ARG2-of (r / result-01)) :ARG1 (r2 / require-01 :ARG0 (a / associate-01 :ARG1 "p" :ARG2 (p2 / protein :name (n2 / name :op1 "Sp1") :xref (x / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001")) :manner (i / in-vitro)) :ARG1 (p3 / protein-segment :name (n3 / name :op1 "coiled-coil") :part-of (p / protein :name (n / name :op1 "PML") :xref (x1 / xref :value "UNIPROT:PML_HUMAN" :prob "1.003")))) :mod (t / together)) # ::id bio.chicago_2015.36212 # ::date 2015-10-27T08:39:36 # ::file bio_chicago_2015_36212.txt # ::snt Receptor serine/ threonine kinase implicated in the control of Drosophila body pattern by decapentaplegic.. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (e / enzyme :name (n / name :op1 "receptor" :op2 "serine/threonine" :op3 "kinase") :ARG1-of (i / implicate-01 :ARG2 (c / control-01 :ARG0 (p2 / protein :name (n4 / name :op1 "decapentaplegic")) :ARG1 (p / pattern-01 :ARG2 (b / body :mod (o / organism :name (n3 / name :op1 "Drosophila"))))))) # ::id bio.chicago_2015.36218 # ::date 2015-10-27T09:42:36 # ::file bio_chicago_2015_36218.txt # ::snt In contrast to many soluble cytokines, UPD is associated with ECM (extracellular matrix), which may help it bind to the receptor and limit the range of activity of the ligand. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / contrast-01 :ARG1 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "UPD") :xref (x / xref :value "UNIPROT:DCUP_HUMAN" :prob "1.002")) :ARG2 (m2 / matrix :ARG0-of (h / help-01 :ARG1 p :ARG2 (a2 / and :op1 (b / bind-01 :ARG1 p :ARG2 (r / receptor)) :op2 (l / limit-01 :ARG1 (r2 / range-01 :ARG1 (a3 / activity-06 :ARG0 (l2 / ligand))))) :ARG1-of (p2 / possible-01)) :mod (e / extracellular))) :ARG2 (c2 / cytokine :mod (s / soluble) :quant (m / many))) # ::id bio.chicago_2015.36244 # ::date 2015-10-27T08:20:02 # ::file bio_chicago_2015_36244.txt # ::snt Overexpression of ARC Inhibits Apoptosis Induced by Caspases in 293T Cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (i / inhibit-01 :ARG0 (o / overexpress-01 :ARG1 (p / protein :name (n2 / name :op1 "ARC") :xref (x / xref :value "UNIPROT:ARC_HUMAN" :prob "1.003"))) :ARG1 (a / apoptosis :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein-family :name (n3 / name :op1 "caspase")) :location (c / cell-line :name (n / name :op1 "293T"))))) # ::id bio.chicago_2015.36265 # ::date 2015-10-27T08:23:31 # ::file bio_chicago_2015_36265.txt # ::snt activator interaction (through Ada2, Gcn5, and Ada3), histone acetylation (by Gcn5), and TBP interaction (through Spt8 and Spt3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a2 / and :op1 (i / interact-01 :ARG1 (m / molecular-physical-entity :ARG0-of (a3 / activate-01)) :instrument (a5 / and :op1 (p3 / protein :name (n6 / name :op1 "Ada2") :xref (x1 / xref :value "UNIPROT:CECR1_HUMAN" :prob "0.602")) :op2 "p5" :op3 (p4 / protein :name (n7 / name :op1 "Ada3") :xref (x4 / xref :value "UNIPROT:TADA3_HUMAN" :prob "0.602")))) :op2 (a / acetylate-01 :ARG1 (p / protein :name (n / name :op1 "histone") :xref (x6 / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332")) :ARG2 (p5 / protein :name (n5 / name :op1 "Gcn5") :xref (x5 / xref :value "UNIPROT:KAT2A_HUMAN" :prob "0.602"))) :op3 (i2 / interact-01 :ARG1 (p2 / protein :name (n2 / name :op1 "TBP") :xref (x / xref :value "UNIPROT:TBP_HUMAN" :prob "1.003")) :instrument (a4 / and :op1 (p7 / protein :name (n3 / name :op1 "Spt8") :xref (x3 / xref :value "UNIPROT:SPYA_HUMAN" :prob "0.202")) :op2 (p6 / protein :name (n4 / name :op1 "Spt3") :xref (x2 / xref :value "UNIPROT:SUPT3_HUMAN" :prob "0.602"))))) # ::id bio.chicago_2015.36278 # ::date 2015-10-27T06:52:46 # ::file bio_chicago_2015_36278.txt # ::snt The molecular mechanisms of tinman induction by Dpp have largely been clarified. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (c / clarify-10 :ARG1 (m / mechanism :mod (m2 / molecule) :instrument-of (i / induce-01 :ARG0 (p / protein :name (n2 / name :op1 "Dpp") :xref (x / xref :value "UNIPROT:DSPP_HUMAN" :prob "0.602")) :ARG2 (p2 / protein :name (n / name :op1 "tinman")))) :degree (l / large)) # ::id bio.chicago_2015.36299 # ::date 2015-10-27T06:56:59 # ::file bio_chicago_2015_36299.txt # ::snt The interaction of p110C with PAK1 occurred within the residues 210 - 332 of PAK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "p110C") :xref (x / xref :value "UNIPROT:EXOS6_HUMAN" :prob "0.232")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "PAK1") :xref (x1 / xref :value "UNIPROT:PAK1_HUMAN" :prob "1.004")) :location (b / between :op1 (r / residue :mod "210") :op2 (r2 / residue :mod "332") :part-of e2)) # ::id bio.chicago_2015.36305 # ::date 2015-10-27T07:04:05 # ::file bio_chicago_2015_36305.txt # ::snt The protein phosphatase activity is involved in PTEN downregulation of IGF-II signaling # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (i / involve-01 :ARG1 (a / activity-06 :ARG1 (e / enzyme :name (n / name :op1 "protein" :op2 "phosphatase") :xref (x1 / xref :value "UNIPROT:PPM1A_HUMAN" :prob "0.392"))) :ARG2 (d / downregulate-01 :ARG1 (s / signal-07 :ARG0 (p2 / protein :name (n3 / name :op1 "IGF-II") :xref (x / xref :value "UNIPROT:IGF2_HUMAN" :prob "1.003"))) :ARG2 (p / protein :name (n2 / name :op1 "PTEN") :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")))) # ::id bio.chicago_2015.36312 # ::date 2015-10-27T07:21:08 # ::file bio_chicago_2015_36312.txt # ::snt ( D) Direct interaction of rAxin with beta-catenin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (i / interact-01 :li "D" :ARG0 (p / protein :name (n2 / name :op1 "rAxin")) :ARG1 (p2 / protein :name (n / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG1-of (d / direct-02)) # ::id bio.chicago_2015.36320 # ::date 2015-10-27T07:24:35 # ::file bio_chicago_2015_36320.txt # ::snt JIP1 and JIP2 selectively bind components of the JNK signaling cascade such as JNK (MAP kinase), MKK7 (MAP kinase kinase), and mixed lineage kinase family proteins (MAP kinase kinase kinase) ( 23, 24). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (b / bind-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n / name :op1 "JIP1") :xref (x2 / xref :value "UNIPROT:JIP1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n2 / name :op1 "JIP2") :xref (x3 / xref :value "UNIPROT:JIP2_HUMAN" :prob "1.003"))) :ARG2 (c2 / component :part-of (p4 / pathway :name (n3 / name :op1 "JNK") :ARG0-of (s2 / signal-07)) :example (a3 / and :op1 (e / enzyme :name (n4 / name :op1 "JNK") :xref (x4 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op2 (e3 / enzyme :name (n6 / name :op1 "MKK7") :xref (x1 / xref :value "UNIPROT:MP2K7_HUMAN" :prob "1.003")) :op3 (e4 / enzyme :name (n5 / name :op1 "MAP" :op2 "kinase" :op3 "kinase" :op4 "kinase") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.313")))) :manner (s / selective) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 "23" :op2 "24"))))) # ::id bio.chicago_2015.36321 # ::date 2015-10-27T08:56:44 # ::file bio_chicago_2015_36321.txt # ::snt Similarly, treatment of cells with okadaic acid inhibited DLK association with JIP and resulted in DLK dimerization in the presence of JIP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / and :op1 (i / inhibit-01 :ARG0 (t / treat-04 :ARG1 (c / cell) :ARG2 (s / small-molecule :name (n3 / name :op1 "okadaic" :op2 "acid") :xref (x2 / xref :value "PUBCHEM:4584" :prob "10.68039"))) :ARG1 (a3 / associate-01 :ARG1 (p / protein :name (n / name :op1 "DLK") :xref (x1 / xref :value "UNIPROT:DLK1_HUMAN" :prob "1.003")) :ARG2 (p2 / protein :name (n2 / name :op1 "JIP") :xref (x / xref :value "UNIPROT:JIP1_HUMAN" :prob "0.262")))) :op2 (r / result-01 :ARG1 t :ARG2 (d / dimerize-01 :ARG1 p :condition (p3 / present-02 :ARG1 p2))) :ARG1-of (r2 / resemble-01)) # ::id bio.chicago_2015.36328 # ::date 2015-10-27T09:00:44 # ::file bio_chicago_2015_36328.txt # ::snt Concomitant with the insulin-stimulated decrease in association between Rap1 and Raf1, there was a reciprocal increase in the amount of Raf1 that was associated with Ras (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / increase-01 :ARG1 (a / amount :quant-of (e / enzyme :name (n / name :op1 "Raf1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.674")) :ARG1-of (a2 / associate-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :time (d / decrease-01 :ARG1 (a3 / associate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Rap1") :xref (x2 / xref :value "UNIPROT:RABX5_HUMAN" :prob "0.603")) :ARG2 e) :ARG1-of (s / stimulate-01 :ARG0 (p / protein :name (n4 / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")))) :mod (r / reciprocal) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id bio.chicago_2015.36331 # ::date 2015-10-27T09:02:44 # ::file bio_chicago_2015_36331.txt # ::snt Colocalization of ASIP with aPKC and ZO-1 at cell junctions in rat intestinal epithelium and hepatic bile capillaries. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / colocalize-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "ASIP") :xref (x1 / xref :value "UNIPROT:ASIP_HUMAN" :prob "1.003")) :op2 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "aPKC")) :op2 (p2 / protein :name (n2 / name :op1 "ZO-1") :xref (x / xref :value "UNIPROT:ZO1_HUMAN" :prob "0.652")))) :ARG2 (j / junction :mod (c2 / cell) :location (a / and :op1 (e / epithelium :source (i / intestine :mod (r / rat))) :op2 (c3 / capillary :source (b / bile :mod (h / hepatic)))))) # ::id bio.chicago_2015.36349 # ::date 2015-10-27T08:40:17 # ::file bio_chicago_2015_36349.txt # ::snt Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / and :op1 (b / boundary :mod (c2 / compartment)) :op2 (c / control-01 :ARG0 (p / protein-family :name (n / name :op1 "hedgehog" :op2 "protein")) :ARG1 (p2 / pattern-01 :ARG2 (l / limb :mod (o / organism :name (n2 / name :op1 "Drosophila")))))) # ::id bio.chicago_2015.36384 # ::date 2015-10-27T07:39:02 # ::file bio_chicago_2015_36384.txt # ::snt To address the issue, we determined the molecular interaction of QRS with ASK1 in 293 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (d / determine-01 :ARG0 "w" :ARG1 (i2 / interact-01 :ARG0 (m2 / macro-molecular-complex :name (n / name :op1 "QRS")) :ARG1 (e / enzyme :name (n2 / name :op1 "ASK1") :xref (x / xref :value "UNIPROT:M3K5_HUMAN" :prob "1.003")) :ARG2 (m / molecule) :location (c / cell :quant "293")) :purpose (a / address-02 :ARG0 (w / we) :ARG1 (i / issue-02))) # ::id bio.chicago_2015.36390 # ::date 2015-10-27T07:43:18 # ::file bio_chicago_2015_36390.txt # ::snt Figure 7C shows that in contrast to Irak, Irak D358N did not activate p38 in COS-1 cells, although both proteins were expressed at a comparable level. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (h / have-concession-91 :ARG1 (c / contrast-01 :ARG1 (p / protein :name (n / name :op1 "Irak") :xref (x / xref :value "UNIPROT:IRAK1_HUMAN" :prob "0.602")) :ARG2 (a / activate-01 :polarity "-" :ARG0 (p2 / protein :name (n2 / name :op1 "Irak" :op2 "D358N")) :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :location (c2 / cell-line :name (n3 / name :op1 "COS-1")))) :ARG2 (e / express-03 :ARG2 (a2 / and :op1 p :op2 p2) :mod (l / level :ARG1-of (c3 / comparable-03))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "7C"))) # ::id bio.chicago_2015.36404 # ::date 2015-10-27T06:33:44 # ::file bio_chicago_2015_36404.txt # ::snt The fat facets gene is required for Drosophila eye and embryo development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (r / require-01 :ARG0 (d / develop-01 :ARG1 (o / organism :name (n / name :op1 "Drosophila")) :ARG2 (a / and :op1 (e / eye) :op2 (e2 / embryo))) :ARG1 (g / gene :name (n2 / name :op1 "fat" :op2 "facets") :xref (x / xref :value "UNIPROT:USP9X_HUMAN" :prob "0.302"))) # ::id bio.chicago_2015.36407 # ::date 2015-10-27T06:43:47 # ::file bio_chicago_2015_36407.txt # ::snt B, HEL cells were exposed to increasing concentrations of chelerythrine for 30 min prior to the potentiation of PGE1-stimulated AC activity by the addition of ethanol (200 mM EtOH) or PDBu (100 nM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (e / expose-01 :li "B" :ARG1 (c2 / cell :name (n2 / name :op1 "HEL")) :ARG2 (c3 / concentrate-02 :ARG1 (s3 / small-molecule :name (n / name :op1 "chelerythrine") :xref (x1 / xref :value "PUBCHEM:2703" :prob "16.627077")) :ARG1-of (i / increase-01)) :duration (t / temporal-quantity :quant "30" :unit (m2 / minute)) :time (p / prior :op1 (p2 / potentiate-01 :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n3 / name :op1 "AC") :xref (x / xref :value "UNIPROT:ASAH1_HUMAN" :prob "1.002")) :ARG1-of (s / stimulate-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "PGE1") :xref (x2 / xref :value "PUBCHEM:5280723" :prob "15.415987")) :ARG2 (a3 / add-02 :ARG1 (o / or :op1 (e4 / ethanol :quant (c6 / concentration-quantity :quant "200" :unit (m / micromolar))) :op2 (s4 / small-molecule :name (n5 / name :op1 "PDBu") :quant (c5 / concentration-quantity :quant "100" :unit (n6 / nanomolar)) :xref (x3 / xref :value "PUBCHEM:37783" :prob "18.572987"))))))))) # ::id bio.chicago_2015.36416 # ::date 2015-10-27T10:34:16 # ::file bio_chicago_2015_36416.txt # ::snt The results showed that the 306-amino acid region between amino acids 827 and 1132 in the C-terminal half of GLI3 bound to CBP with almost the same efficiency as full-length GLI3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01)) :ARG1 (b / bind-01 :ARG1 (r2 / region :quant "306" :mod (a2 / amino-acid) :location (b2 / between :op1 (a3 / amino-acid :mod "827") :op2 (a4 / amino-acid :mod "1132") :location (h / half :part-of (p2 / protein-segment :name (n3 / name :op1 "C-terminus") :part-of "p3")))) :ARG2 (p / protein :name (n / name :op1 "CBP") :xref (x1 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :manner (e / efficient-01 :ARG1 p :ARG1-of (s2 / same-01 :ARG2 (p3 / protein :name (n2 / name :op1 "GLI3") :ARG1-of (l / long-03 :mod (f / full)) :xref (x / xref :value "UNIPROT:GLI3_HUMAN" :prob "1.003"))) :degree (a / almost)))) # ::id bio.chicago_2015.36428 # ::date 2015-10-27T10:24:58 # ::file bio_chicago_2015_36428.txt # ::snt It appears that Su(fu) binds directly to Fu and Ci, but not to Cos2, and that the bulk of these interactions are stable in both the presence and absence of Hh. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / appear-01 :ARG1 (a2 / and :op1 (c / contrast-01 :ARG1 (b2 / bind-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Su(fu)")) :ARG2 (a4 / and :op1 (p4 / protein :name (n3 / name :op1 "Fu")) :op2 (p5 / protein :name (n4 / name :op1 "Ci"))) :ARG1-of (d / direct-02)) :ARG2 (b3 / bind-01 :polarity "-" :ARG1 p3 :ARG2 (p6 / protein :name (n5 / name :op1 "Cos2")))) :op2 (s / stable-03 :ARG1 (b / bulk-01 :ARG1 (i / interact-01 :mod (t / this))) :condition (a5 / and :op1 (p / present-02 :ARG2 (p2 / protein :name (n / name :op1 "Hh"))) :op3 (a3 / absent-01 :ARG1 p2))))) # ::id bio.chicago_2015.36448 # ::date 2015-10-27T10:32:51 # ::file bio_chicago_2015_36448.txt # ::snt Phosphorylation of the alpha-subunit of eIF2, catalysed by any of several eIF2 kinases, leads to inhibition of eIF2B since eIF2(alphaP) is a potent competitive inhibitor of eIF2B (reviewed in Clemens, 1996; Hinnebusch, 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (l / lead-03 :ARG0 (p2 / phosphorylate-01 :ARG1 (p / protein-segment :name (n3 / name :op1 "alpha-subunit") :ARG1-of (c3 / catalyze-01 :ARG0 (k / kinase :ARG1-of (i4 / include-91 :ARG2 (k2 / kinase :name (n6 / name :op1 "eIF2") :quant (s / several) :xref (x / xref :value "UNIPROT:AGO2_HUMAN" :prob "0.332"))) :mod (a / any))) :part-of "p3")) :ARG2 (i2 / inhibit-01 :ARG1 "p4") :ARG1-of (c / cause-01 :ARG0 (p3 / protein :name (n / name :op1 "eIF2(alphaP)") :ARG0-of (i3 / inhibit-01 :ARG1 (p4 / protein :name (n2 / name :op1 "eIF2B") :xref (x1 / xref :value "UNIPROT:IF2B_HUMAN" :prob "0.702")) :ARG0-of (c2 / compete-01)) :mod (p5 / potent))) :ARG1-of (r / review-01 :ARG0 (a3 / and :op1 (p8 / publication-91 :ARG0 (p6 / person :name (n4 / name :op1 "Clemens")) :time (d / date-entity :year "1996")) :op2 (p9 / publication-91 :ARG0 (p7 / person :name (n5 / name :op1 "Hinnebusch")) :time (d2 / date-entity :year "2000"))))) # ::id bio.chicago_2015.36507 # ::date 2015-10-27T09:51:43 # ::file bio_chicago_2015_36507.txt # ::snt Overexpression of CrkL did not significantly change the time course of Epo-induced JNK activation, although the activation level at the peak was moderately enhanced (Fig. 5 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (c / change-01 :polarity "-" :ARG0 (o / overexpress-01 :ARG2 (p2 / protein :name (n / name :op1 "CrkL") :xref (x / xref :value "UNIPROT:CRKL_HUMAN" :prob "0.604"))) :ARG1 (c2 / course-01 :ARG0 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG2-of (i / induce-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "Epo") :xref (x2 / xref :value "PUBCHEM:5288169" :prob "16.321695")))) :mod (t / time)) :ARG1-of (s / significant-02)) :ARG2 (e / enhance-01 :ARG1 (l / level :degree-of (a / activate-01) :location (p / peak)) :ARG1-of (m / moderate-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id bio.chicago_2015.36510 # ::date 2015-10-27T09:15:12 # ::file bio_chicago_2015_36510.txt # ::snt APP and FE65 colocalize with actin and Mena, an Abl-associated signaling protein thought to regulate actin dynamics, in lamellipodia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / colocalize-01 :ARG1 (a4 / and :op1 (a / and :op1 (p / protein :name (n / name :op1 "APP") :xref (x5 / xref :value "UNIPROT:A4_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "FE65") :xref (x / xref :value "UNIPROT:APBB1_HUMAN" :prob "1.002"))) :op2 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :op2 (p4 / protein :name (n4 / name :op1 "Mena") :ARG1-of (m / mean-01 :ARG2 (p5 / protein :ARG0-of (s / signal-07) :ARG1-of (a3 / associate-01 :ARG2 (p7 / protein :name (n5 / name :op1 "Abl") :xref (x3 / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603"))) :ARG1-of (t / think-01 :ARG2 (r / regulate-01 :ARG0 p4 :ARG1 (d / dynamic :mod p3) :location (p6 / protein :name (n6 / name :op1 "lamellipodia") :xref (x2 / xref :value "UNIPROT:RAPH1_HUMAN" :prob "0.372")))))) :xref (x4 / xref :value "UNIPROT:ENAH_HUMAN" :prob "0.602"))))) # ::id bio.chicago_2015.36540 # ::date 2015-10-27T09:03:33 # ::file bio_chicago_2015_36540.txt # ::snt CRIPT, a Novel Postsynaptic Protein that Binds to the Third PDZ Domain of PSD-95/SAP90. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (p / protein :name (n / name :op1 "CRIPT") :ARG1-of (m / mean-01 :ARG2 (p2 / protein :mod (p3 / postsynaptic) :mod (n2 / novel) :ARG1-of (b / bind-01 :ARG2 (p4 / protein-segment :name (n3 / name :op1 "PDZ") :part-of (p5 / protein-family :name (n4 / name :op1 "PSD-95/SAP90")) :ord (o / ordinal-entity :value "3"))))) :xref (x / xref :value "UNIPROT:CRIPT_HUMAN" :prob "1.003")) # ::id bio.chicago_2015.36582 # ::date 2015-10-27T09:11:31 # ::file bio_chicago_2015_36582.txt # ::snt We previously demonstrated that Wnt-11 and Wnt-1 activate RhoA via Fz/Dvl signaling, and we identified Daam1, a Formin-homology protein, as being required for Wnt/ Fz/Dvl activation of RhoA, Wnt-induced Dvl-RhoA complex formation, and CE movements during Xenopus gastrulation (Habas et al. 2001 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / and :op1 (d3 / demonstrate-01 :ARG0 (w / we) :ARG1 (a3 / activate-01 :ARG0 (a4 / and :op1 (p11 / protein :name (n2 / name :op1 "Wnt-11") :xref (x / xref :value "UNIPROT:WNT11_HUMAN" :prob "0.622")) :op2 (p12 / protein :name (n3 / name :op1 "Wnt-1") :xref (x1 / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.592"))) :ARG1 (p4 / protein :name (n4 / name :op1 "RhoA") :xref (x4 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :manner (s / signal-07 :ARG0 (s2 / slash :op1 (p5 / protein :name (n5 / name :op1 "Fz")) :op2 (p6 / protein :name (n6 / name :op1 "Dvl") :xref (x2 / xref :value "UNIPROT:DVLP1_HUMAN" :prob "0.602"))))) :time (p3 / previous)) :op2 (i / identify-01 :ARG0 w :ARG1 (r / require-01 :ARG0 (a6 / and :op1 (a5 / activate-01 :ARG0 (s3 / slash :op1 (p9 / protein :name (n9 / name :op1 "Wnt") :xref (x6 / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")) :op2 p5 :op3 p6) :ARG1 p4) :op2 (f / form-01 :ARG1 (m2 / macro-molecular-complex :part p6 :part p4) :ARG2-of (i2 / induce-01 :ARG0 p9)) :op3 (m3 / move-01 :time (g3 / gastrulate-00 :ARG0 (o2 / organism :name (n11 / name :op1 "Xenopus"))) :mod (e / extension :mod (c / convergent)))) :ARG1 (p7 / protein :name (n7 / name :op1 "Daam1") :ARG1-of (m / mean-01 :ARG2 (p8 / protein :name (n8 / name :op1 "Formin-homology") :xref (x5 / xref :value "UNIPROT:FMN1_HUMAN" :prob "0.252"))) :xref (x3 / xref :value "UNIPROT:DAAM1_HUMAN" :prob "0.604")))) :ARG1-of (d2 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a2 / and :op1 (p / person :name (n / name :op1 "Habas")) :op2 (p2 / person :mod (o / other))) :time (d / date-entity :year "2001")))) # ::id bio.chicago_2015.36590 # ::date 2015-10-27T11:06:21 # ::file bio_chicago_2015_36590.txt # ::snt To verify that both the AHR and ARNT interact with TFIIB, similar coaffinity precipitation experiments were performed, except that we used either immobilized AHR or ARNT and 35S-TFIIB (Fig. 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (p / perform-02 :ARG0 "w" :ARG1 (e / experiment-01 :ARG1 (p2 / precipitate-01 :ARG1 (c / coaffinity)) :ARG1-of (r / resemble-01)) :purpose (v / verify-01 :ARG0 "w" :ARG1 (i / interact-01 :ARG0 (a / and :op1 (p3 / protein :name (n / name :op1 "AHR") :xref (x / xref :value "UNIPROT:AHR_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n2 / name :op1 "ARNT") :xref (x1 / xref :value "UNIPROT:ARNT_HUMAN" :prob "1.003"))) :ARG1 (p5 / protein :name (n3 / name :op1 "TFIIB") :xref (x2 / xref :value "UNIPROT:TF2B_HUMAN" :prob "1.002")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B")) :ARG2-of (e2 / except-01 :ARG1 (u / use-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (o / or :op1 p3 :op2 p4 :ARG1-of (i2 / immobilize-01)) :op2 (p6 / protein :name (n4 / name :op1 "35S-TFIIB")))))) # ::id bio.chicago_2015.36667 # ::date 2015-10-27T08:13:57 # ::file bio_chicago_2015_36667.txt # ::snt E1A, an adenoviral oncoprotein, interacts with p300 or CBP and directly inhibits the histone acetyltransferase activity ( 29). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / and :op1 (i / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "E1A") :ARG0-of (c2 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :mod (a3 / adenoviral) :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.262")) :ARG1 (o / or :op1 (p3 / protein :name (n2 / name :op1 "p300") :xref (x1 / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")) :op2 (p4 / protein :name (n3 / name :op1 "CBP") :xref (x3 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")))) :op2 (i2 / inhibit-01 :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n4 / name :op1 "histone" :op2 "acetyltransferase") :xref (x2 / xref :value "UNIPROT:A0A024R597_HUMAN" :prob "0.701"))) :ARG1-of (d2 / direct-02)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "29")))) # ::id bio.chicago_2015.36670 # ::date 2015-10-27T07:54:38 # ::file bio_chicago_2015_36670.txt # ::snt Binding of the 4E-BPs to eIF4E is regulated by phosphorylation ( Lin et al. 1994 ; Pause et al. 1994 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (r / regulate-01 :ARG0 (p / phosphorylate-01) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "4E-BP") :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "0.312")) :ARG2 (p3 / protein :name (n2 / name :op1 "eIF4E") :xref (x1 / xref :value "UNIPROT:IF4E_HUMAN" :prob "1.002"))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (p8 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n3 / name :op1 "Lin")) :op2 (p5 / person :mod (o / other))) :time (d2 / date-entity :year "1994")) :op2 (p9 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n4 / name :op1 "Pause")) :op2 (p6 / person :mod (o2 / other))) :time d2)))) # ::id bio.chicago_2015.36675 # ::date 2015-10-27T10:45:31 # ::file bio_chicago_2015_36675.txt # ::snt To test if oxidative stress modulates the activation of ERK1/2, p38 or CREB induced by NGF and EGF, PC12 cells were briefly (10 min) exposed to 200 M H2O2 before treatment with NGF or EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / expose-01 :ARG1 (c / cell-line :name (n / name :op1 "PC12")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "H2O2") :mod (c2 / concentration-quantity :quant "200" :unit (m4 / molar)) :xref (x4 / xref :value "PUBCHEM:784" :prob "17.186693")) :duration (t / temporal-quantity :quant "10" :unit (m2 / minute)) :manner (b / brief) :time (b2 / before :op1 (t2 / treat-04 :ARG1 c :ARG2 (o / or :op1 (p3 / protein :name (n3 / name :op1 "NGF") :xref (x2 / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :op2 (p2 / protein :name (n4 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :purpose (t3 / test-01 :ARG2 (m / modulate-01 :mode "interrogative" :ARG0 (s3 / stress-02 :ARG0 (o4 / oxidize-01)) :ARG1 (a / activate-01 :ARG1 (o3 / or :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1/2")) :op2 (e3 / enzyme :name (n6 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op3 (p / protein :name (n7 / name :op1 "CREB") :xref (x3 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))) :ARG2-of (i / induce-01 :ARG0 (a2 / and :op1 p3 :op2 p2)))))) # ::id bio.chicago_2015.36678 # ::date 2015-10-27T11:05:28 # ::file bio_chicago_2015_36678.txt # ::snt Together with cell culture experiments showing binding and phosphorylation of mPER1 and mPER2 by CKI and research in Drosophila showing the importance of the CKI homolog DOUBLE-TIME for destabilizing dPER, the genetic data in both rodents and humans strongly suggest that CKI -dependent phosphorylation of PER proteins is an essential and ancient part of the circadian clock mechanism (references in Toh et al., 2001 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (s / suggest-01 :ARG0 (d2 / data :topic (g / gene) :source (a / and :op1 (r / rodent) :op2 (h / human))) :ARG1 (p2 / part :mod (e / essential) :mod (a2 / ancient) :domain (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "PER") :xref (x1 / xref :value "UNIPROT:PER1_HUMAN" :prob "1.002")) :ARG0-of (d3 / depend-01 :ARG1 (e2 / enzyme :name (n / name :op1 "CKI") :xref (x / xref :value "UNIPROT:CHKA_HUMAN" :prob "1.002")))) :part-of (m / mechanism :mod (c / clock :mod (c2 / circadian)))) :ARG1-of (s2 / strong-02) :accompanier (a3 / and :op1 (e3 / experiment-01 :ARG1 (c3 / culture :mod (c4 / cell)) :ARG0-of (s3 / show-01 :ARG1 (a4 / and :op1 (b / bind-01 :ARG0 e2 :ARG1 (a5 / and :op1 (p8 / protein :name (n3 / name :op1 "mPER1") :xref (x2 / xref :value "UNIPROT:MPEG1_HUMAN" :prob "0.242")) :op2 (p9 / protein :name (n4 / name :op1 "mPER2")))) :op2 (p / phosphorylate-01 :ARG1 a5 :ARG2 e2)))) :op2 (r2 / research-01 :ARG1 (o / organism :name (n5 / name :op1 "Drosophila")) :ARG0-of (s4 / show-01 :ARG1 (i / importance :purpose (d4 / destabilize-01 :ARG1 (p11 / protein :name (n7 / name :op1 "dPER"))) :mod (p10 / protein :name (n9 / name :op1 "CKI" :op2 "homolog" :op3 "DOUBLE-TIME")))))) :ARG1-of (r3 / reference-04 :location (p5 / publication-91 :ARG0 (a6 / and :op1 (p6 / person :name (n8 / name :op1 "Toh")) :op2 (p7 / person :mod (o2 / other))) :time (d / date-entity :year "2001")))) # ::id bio.chicago_2015.36682 # ::date 2015-10-28T09:06:49 # ::file bio_chicago_2015_36682.txt # ::snt In response to cAMP, CREB bound to the CRE enhancer is phosphorylated, which results in recruitment of CBP/ p300 and eventually transcriptional activation of cAMP-responsive genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / phosphorylate-01 :ARG1 (p2 / protein :wiki "CREB" :name (n / name :op1 "CREB") :ARG1-of (b / bind-01 :ARG2 (e3 / enzyme :wiki "Cre_recombinase" :name (n2 / name :op1 "CRE") :mod (e / enhancer) :xref (x / xref :value "UNIPROT:CREG1_HUMAN" :prob "0.262"))) :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :ARG2-of (r / respond-01 :ARG1 (s / small-molecule :wiki "Cyclic_adenosine_monophosphate" :name (n3 / name :op1 "cAMP") :xref (x4 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :ARG1-of (r2 / result-01 :ARG2 (a / and :op1 (r3 / recruit-01 :ARG1 (o / or :op1 (p3 / protein :wiki "CREB-binding_protein" :name (n4 / name :op1 "CBP") :xref (x2 / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :op2 (p4 / protein :wiki "EP300" :name (n5 / name :op1 "p300") :xref (x3 / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")))) :op2 (a2 / activate-01 :ARG1 (g / gene :ARG0-of (r4 / respond-01 :ARG1 s)) :mod (t / transcribe-01) :time (e2 / eventual))))) # ::id bio.chicago_2015.36695 # ::date 2015-10-28T09:19:24 # ::file bio_chicago_2015_36695.txt # ::snt Association of DLC with nNOS in differentiated PC12 cells reduced nNOS activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (r / reduce-01 :ARG0 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "DLC") :xref (x1 / xref :value "UNIPROT:DLEC1_HUMAN" :prob "0.262")) :ARG2 (e / enzyme :name (n2 / name :op1 "nNOS") :xref (x / xref :value "UNIPROT:NOS1_HUMAN" :prob "1.002")) :location (c / cell-line :name (n3 / name :op1 "PC12") :ARG1-of (d / differentiate-01))) :ARG1 (a2 / activity-06 :ARG0 e)) # ::id bio.chicago_2015.36696 # ::date 2015-10-28T09:24:48 # ::file bio_chicago_2015_36696.txt # ::snt The time courses of p38, ERK1/2 and CREB phosphorylation induced by NGF and EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / induce-01 :ARG0 (a2 / and :op1 (p4 / protein :name (n4 / name :op1 "NGF") :xref (x / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :op2 (p / protein :name (n5 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG2 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "p38") :xref (x3 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op2 (e / enzyme :name (n2 / name :op1 "ERK1/2")) :op3 (p3 / protein :name (n3 / name :op1 "CREB") :xref (x1 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))) :duration (c / course :mod (t / time)))) # ::id bio.chicago_2015.36704 # ::date 2015-10-28T09:28:27 # ::file bio_chicago_2015_36704.txt # ::snt Regulation of Armadillo by a Drosophila APC Inhibits Neuronal Apoptosis during Retinal Development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (i / inhibit-01 :ARG0 (r / regulate-01 :ARG0 (p / protein :name (n / name :op1 "APC") :source (o / organism :name (n2 / name :op1 "Drosophila")) :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")) :ARG1 (p2 / protein :name (n3 / name :op1 "Armadillo") :xref (x / xref :value "UNIPROT:ARMC1_HUMAN" :prob "0.212"))) :ARG1 (a / apoptosis :mod (n4 / neuronal)) :time (d2 / develop-01 :ARG2 (r2 / retina))) # ::id bio.chicago_2015.36735 # ::date 2015-10-28T09:33:10 # ::file bio_chicago_2015_36735.txt # ::snt NGF induced co-association of IRAK with TRAF6 and atypical PKC binding protein/ p62. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / induce-01 :ARG0 (p3 / protein :name (n / name :op1 "NGF") :xref (x / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :ARG2 (a3 / associate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "IRAK") :xref (x4 / xref :value "UNIPROT:IRAK1_HUMAN" :prob "1.002")) :ARG2 (a / and :op1 (p / protein :name (n3 / name :op1 "TRAF6") :xref (x2 / xref :value "UNIPROT:TRAF6_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n4 / name :op1 "p62") :mod (a2 / atypical) :ARG0-of (b / bind-01 :ARG1 (e / enzyme :name (n5 / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))) :xref (x3 / xref :value "UNIPROT:MCAF1_HUMAN" :prob "0.222"))))) # ::id bio.chicago_2015.36749 # ::date 2015-10-28T09:39:15 # ::file bio_chicago_2015_36749.txt # ::snt PI3K induction of cyclin D1 was inhibited by a dominant negative Tcf, and a single Tcf site in the cyclin D1 promoter was required for its induction by IKKalpha and PI3K. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / and :op1 (i / inhibit-01 :ARG0 (p2 / protein :name (n3 / name :op1 "Tcf") :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of (d / dominate-01) :xref (x / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.203")) :ARG1 (i2 / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :ARG1 (p / protein :name (n2 / name :op1 "cyclin" :op2 "D1") :xref (x2 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")))) :op2 (r / require-01 :ARG0 (i3 / induce-01 :ARG0 (a2 / and :op1 (e2 / enzyme :name (n5 / name :op1 "IKKalpha") :xref (x3 / xref :value "UNIPROT:IKKA_HUMAN" :prob "0.692")) :op2 e) :ARG1 p) :ARG1 (s / site :mod p2 :ARG1-of (s2 / single-02) :location (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 p))))) # ::id bio.chicago_2015.36758 # ::date 2015-10-28T09:50:52 # ::file bio_chicago_2015_36758.txt # ::snt However, Zw5 does not bind to scs``; instead, scs`` has multiple target sites for the BEAF ( boundary element associated factor) proteins, BEAF 32A and BEAF 32B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (c / contrast-01 :ARG1 (b / bind-01 :polarity "-" :ARG1 (p / protein :name (n / name :op1 "Zw5")) :ARG2 (p5 / protein :name (n2 / name :op1 "scs``"))) :ARG2-of (i / instead-of-91 :ARG1 (h / have-03 :ARG0 p5 :ARG1 (s / site :mod (t2 / target) :quant (m / multiple) :beneficiary (a / and :op1 (p2 / protein :name (n3 / name :op1 "BEAF" :op2 "32A")) :op2 (p3 / protein :name (n4 / name :op1 "BEAF" :op2 "32B")) :ARG1-of (i2 / include-01 :ARG2 (p4 / protein-family :name (n6 / name :op1 "boundary" :op2 "element" :op3 "associated" :op4 "factor")))))))) # ::id bio.chicago_2015.36797 # ::date 2015-10-28T10:03:01 # ::file bio_chicago_2015_36797.txt # ::snt More specifically, cortactin binds and activates the Arp2/3 complex of actin polymerizing proteins at sites of peripheral cytoskeletal rearrangement while cross-linking and stabilizing actin filaments against depolymerization [ 23, 24 and 25]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (a / and :op1 (b / bind-01 :ARG0 (p / protein :name (n / name :op1 "cortactin") :xref (x1 / xref :value "UNIPROT:CORT_HUMAN" :prob "0.292")) :ARG1 (m / macro-molecular-complex :name (n2 / name :op1 "Arp2/3") :part (p2 / protein :ARG0-of (p3 / polymerize-01 :ARG1 (p4 / protein :name (n3 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))))) :location (s2 / site :mod (r / rearrange-01 :mod (c2 / cytoskeletal) :mod (p5 / peripheral)))) :op2 (a2 / activate-01 :ARG0 p :ARG1 m) :ARG1-of (s3 / specific-02 :degree (m2 / more)) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 "23" :op2 "24" :op3 "25")))) :time (a4 / and :op1 (l / link-01 :ARG0 p :ARG1 "f" :manner (c / cross)) :op2 (s / stabilize-01 :ARG0 p :ARG1 (f / filament :mod p4) :prep-against (d / depolymerize-00)))) # ::id bio.chicago_2015.36801 # ::date 2015-10-28T10:15:21 # ::file bio_chicago_2015_36801.txt # ::snt TGIF Recruits CtBP To Activated Smad Complexes-- To investigate the possibility that TGIF can recruit CtBP to a TGF-beta-activated Smad complex, COS-1 cells were transfected with FLAG-tagged CtBP, HA-tagged TGIF, and Smad2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (m / multi-sentence :snt1 (r / recruit-01 :ARG0 (p8 / protein :name (n / name :op1 "TGIF") :xref (x6 / xref :value "UNIPROT:TGIF1_HUMAN" :prob "1.002")) :ARG1 (p / protein :name (n2 / name :op1 "CtBP") :xref (x8 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652")) :ARG2 (c / complex :mod (p2 / protein :name (n3 / name :op1 "Smad") :xref (x1 / xref :value "UNIPROT:SMAD1_HUMAN" :prob "0.312")) :ARG1-of (a / activate-01))) :snt2 (t / transfect-01 :ARG1 (c2 / cell-line :name (n4 / name :op1 "COS-1")) :ARG2 (a2 / and :op1 (p3 / protein :name (n5 / name :op1 "CtBP") :ARG1-of (t2 / tag-01 :ARG2 (p4 / protein :name (n6 / name :op1 "FLAG") :xref (x4 / xref :value "UNIPROT:AL5AP_HUMAN" :prob "0.222"))) :xref (x2 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652")) :op2 (p10 / protein :name (n7 / name :op1 "TGIF") :ARG1-of (t3 / tag-01 :ARG2 (p5 / protein :name (n8 / name :op1 "HA") :xref (x5 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :xref (x / xref :value "UNIPROT:TGIF1_HUMAN" :prob "1.002")) :op3 (p6 / protein :name (n9 / name :op1 "Smad2") :xref (x3 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003"))) :purpose (i / investigate-01 :ARG1 (p7 / possible-01 :ARG1 (r2 / recruit-01 :ARG0 p10 :ARG1 p3 :ARG2 (c3 / complex :mod p6 :ARG1-of (a3 / activate-01 :ARG0 (p9 / protein :name (n10 / name :op1 "TGF" :op2 "beta") :xref (x7 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.323"))))))))) # ::id bio.chicago_2015.36813 # ::date 2015-10-28T12:13:02 # ::file bio_chicago_2015_36813.txt # ::snt Expression of the RasN17 dominant-negative mutant (deVries-Smits et al., 1992; Wood et al., 1992) blocked EGF-induced Elk-1 phosphorylation (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (b / block-01 :ARG0 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "N17" :mod "-/-") :ARG0-of (d2 / dominate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (p / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n5 / name :op1 "deVries-Smits")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "1992")) :op2 (p7 / publication-91 :ARG0 (a / and :op1 (p8 / person :name (n6 / name :op1 "Wood")) :op2 p6) :time d)))) :ARG1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "Elk-1") :xref (x2 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :ARG2-of (i / induce-01 :ARG0 (p2 / protein :name (n4 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id bio.chicago_2015.36817 # ::date 2015-10-28T12:24:53 # ::file bio_chicago_2015_36817.txt # ::snt Rb Interacts with Histone Deacetylase to Repress Transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "Rb") :xref (x1 / xref :value "UNIPROT:RB_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n2 / name :op1 "Histone" :op2 "Deacetylase") :xref (x / xref :value "UNIPROT:B3KUJ5_HUMAN" :prob "0.701")) :ARG2 (r / repress-01 :ARG0 (a / and :op1 p :op2 e) :ARG1 (t / transcribe-01))) # ::id bio.chicago_2015.36902 # ::date 2015-10-28T12:27:04 # ::file bio_chicago_2015_36902.txt # ::snt However, inhibition of PKA by H89 did not inhibit process formation (Figure 7e), contrary to inhibition of MARK by HD and did not inhibit the phosphorylation of KXGS motifs (Figure 8b, lane 2, staining with 12E8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (c / contrast-01 :ARG2 (a / and :op1 (i / inhibit-01 :polarity "-" :ARG0 (i2 / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "H89")) :ARG1 (e / enzyme :name (n2 / name :op1 "PKA") :xref (x2 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG1 (f / form-01 :ARG1 (p2 / process-02)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "7e")) :ARG1-of (c2 / contrary-01 :ARG2 (i3 / inhibit-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "HD") :xref (x3 / xref :value "PUBCHEM:10461" :prob "14.935401")) :ARG1 (e2 / enzyme :name (n3 / name :op1 "MARK") :xref (x / xref :value "UNIPROT:MARK1_HUMAN" :prob "1.002"))))) :op2 (i4 / inhibit-01 :polarity "-" :ARG1 (p / phosphorylate-01 :ARG1 (p4 / protein-segment :name (n5 / name :op1 "KXGS" :op2 "motif"))) :ARG1-of (d2 / describe-01 :ARG0 (s3 / stain-01 :ARG2 (p3 / protein :name (n6 / name :op1 "12E8") :xref (x1 / xref :value "UNIPROT:CD99_HUMAN" :prob "0.222")) :location (l / lane :mod "2" :part-of (f3 / figure :mod "8b"))))))) # ::id bio.chicago_2015.36940 # ::date 2015-10-28T12:49:41 # ::file bio_chicago_2015_36940.txt # ::snt Induction of LTP by tetanic stimulation (at Time = 0; see Experimental Procedures) is observed in hippocampal slices from wt ( n = 5) and - Syn / (n = 5) mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (o / observe-01 :ARG1 (i / induce-01 :ARG0 (s / simulate-01 :mod (t2 / tetanic) :time (t3 / time :ARG1-of (e2 / equal-01 :ARG2 "0")) :mod (s2 / see-01 :ARG1 (p / procedure :mod (e / experiment-01)))) :ARG2 (p2 / potentiate-01 :ARG1-of (l / long-03))) :location (s3 / slice :mod (h / hippocampus) :source (a2 / and :op1 (m / mouse :quant "5" :mod (w / wild-type)) :op2 (m2 / mouse :quant "5" :mod (e3 / enzyme :name (n2 / name :op1 "Syn") :ARG2-of (m3 / mutate-01 :mod "-/+") :xref (x / xref :value "UNIPROT:SYNEM_HUMAN" :prob "0.602")))))) # ::id bio.chicago_2015.36945 # ::date 2015-10-28T12:59:53 # ::file bio_chicago_2015_36945.txt # ::snt About 10 min after synthesis, a maximal amount of gp160 was bound to calnexin and calreticulin and about half remained bound after 25-35 min. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a2 / and :op1 (b2 / bind-01 :ARG1 (a3 / amount :quant-of (p / protein :name (n / name :op1 "gp160") :xref (x2 / xref :value "UNIPROT:GP160_HUMAN" :prob "0.663")) :quant (m / maximum)) :ARG2 (a4 / and :op1 (p2 / protein :name (n2 / name :op1 "calnexin") :xref (x / xref :value "UNIPROT:CALX_HUMAN" :prob "0.702")) :op2 (p3 / protein :name (n3 / name :op1 "calreticulin") :xref (x1 / xref :value "UNIPROT:CALR_HUMAN" :prob "0.702"))) :time (a7 / after :op1 "s" :duration (a / about :op1 (t2 / temporal-quantity :quant "10" :unit (m3 / minute))))) :op2 (r / remain-01 :ARG1 (a5 / amount :quant (h / half) :quant-of p) :ARG3 (b3 / bind-01 :ARG1 a5 :ARG2 a4) :time (a6 / after :op1 (s / synthesize-01) :duration (t / temporal-quantity :quant (v / value-interval :op1 "25" :op2 "35") :unit (m2 / minute))))) # ::id bio.chicago_2015.36967 # ::date 2015-10-28T13:12:00 # ::file bio_chicago_2015_36967.txt # ::snt Phosphorylation of GST-FKBP46 and FKBP46 by endogenous Sf9 CKII and human recombinant casein kinase II. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "GST-FKBP46")) :op2 (p3 / protein :name (n2 / name :op1 "FKBP46") :xref (x / xref :value "UNIPROT:FKBP4_HUMAN" :prob "0.332"))) :ARG2 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "CKII") :xref (x1 / xref :value "UNIPROT:CHKA_HUMAN" :prob "0.342")) :op2 (e2 / enzyme :name (n5 / name :op1 "human" :op2 "recombinant" :op3 "casein" :op4 "kinase" :op5 "II")) :mod (e3 / endogenous) :source (c / cell-line :name (n4 / name :op1 "Sf9")))) # ::id bio.chicago_2015.37004 # ::date 2015-10-28T13:24:01 # ::file bio_chicago_2015_37004.txt # ::snt Furthermore, LTP induced by either theta burst or tetanic stimulation is blocked by pretreating slices with the TrkB-IgG fusion protein, a protein that removes BDNF from extracellular fluids (Figurov et al. 1996 ; Kang et al. 1997 ), suggesting that endogenous BDNF is involved in the induction of LTP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / and :op2 (b / block-01 :ARG0 (p10 / pretreat-01 :ARG1 (s2 / slice) :ARG3 (p / protein :name (n2 / name :op1 "TrkB-IgG") :mod (f / fuse-01) :ARG0-of (r / remove-01 :ARG1 (p2 / protein :name (n3 / name :op1 "BDNF") :xref (x / xref :value "UNIPROT:BDNF_HUMAN" :prob "1.004")) :ARG2 (f2 / fluid :mod (e / extracellular)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n5 / name :op1 "Figurov")) :op2 (p6 / person :mod (o2 / other))) :time (d / date-entity :year "1996")) :op2 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n6 / name :op1 "Kang")) :op2 p6) :time (d2 / date-entity :year "1997"))))) :xref (x2 / xref :value "UNIPROT:NTRK2_HUMAN" :prob "0.223"))) :ARG1 (p11 / potentiate-01 :ARG1-of (l / long-03) :ARG2-of (i / induce-01 :ARG0 (o / or :op1 (t / theta-burst) :op2 (s / stimulate-01 :mod (t3 / tetanic))))) :ARG0-of (s3 / suggest-01 :ARG1 (i2 / involve-01 :ARG1 (p3 / protein :name (n4 / name :op1 "BDNF") :mod (e2 / endogenous) :xref (x1 / xref :value "UNIPROT:BDNF_HUMAN" :prob "1.004")) :ARG2 (i3 / induce-01 :ARG2 (p9 / protein)))))) # ::id bio.chicago_2015.37047 # ::date 2015-10-28T13:39:32 # ::file bio_chicago_2015_37047.txt # ::snt TFIIA interaction with TBP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "TFIIA") :xref (x1 / xref :value "UNIPROT:TF3A_HUMAN" :prob "0.392")) :ARG1 (p2 / protein :name (n2 / name :op1 "TBP") :xref (x / xref :value "UNIPROT:TBP_HUMAN" :prob "1.003"))) # ::id bio.chicago_2015.37055 # ::date 2015-10-28T13:40:33 # ::file bio_chicago_2015_37055.txt # ::snt Second, misexpression of ey can strongly induce dac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (p4 / possible-01 :ARG1 (i / induce-01 :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "ey")) :ARG1-of (w / wrong-04)) :ARG1 (p2 / protein :name (n2 / name :op1 "dac") :xref (x / xref :value "UNIPROT:AAAD_HUMAN" :prob "0.602")) :ARG1-of (s / strong-02)) :mod (o / ordinal-entity :value "2")) # ::id bio.chicago_2015.37068 # ::date 2015-10-28T13:44:45 # ::file bio_chicago_2015_37068.txt # ::snt The PTB domains of scaffolding proteins such as Shc, FRS2 or IRS-1 bind autophosphorylated receptors, positioning these proteins for multisite phosphorylation and subsequent binding of SH2 domain targets such as Grb2 (for Shc and FRS2) or PI 3''-kinase (for IRS-1) [ 98, 99 and 100]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (a / and :op1 (b / bind-01 :ARG0 (p12 / protein-segment :name (n8 / name :op1 "PTB" :op2 "domain") :part-of (p3 / protein :mod (s / scaffold) :example (a2 / and :op1 (p4 / protein :name (n2 / name :op1 "Shc") :xref (x3 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :op2 (p5 / protein :name (n3 / name :op1 "FRS2") :xref (x4 / xref :value "UNIPROT:FRS2_HUMAN" :prob "1.004")) :op3 (p6 / protein :name (n4 / name :op1 "IRS-1") :xref (x2 / xref :value "UNIPROT:IRS1_HUMAN" :prob "1.003"))))) :ARG1 (r / receptor :ARG1-of (p2 / phosphorylate-01 :ARG2 r))) :op2 (p7 / position-01 :ARG0 p12 :ARG1 (p8 / protein :mod (t / this)) :ARG2 (a4 / and :op1 (p9 / phosphorylate-01 :mod (m / multisite)) :op2 (b2 / bind-01 :ARG1 (m2 / molecular-physical-entity :ARG1-of (t2 / target-01 :ARG0 (p10 / protein-segment :name (n5 / name :op1 "SH2" :op2 "domain"))) :example (o / or :op1 (p11 / protein :name (n6 / name :op1 "Grb2") :prep-for (a5 / and :op1 p4 :op2 p5) :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (e / enzyme :name (n7 / name :op1 "PI" :op2 "3``-kinase") :prep-for p6 :xref (x1 / xref :value "UNIPROT:PK3C3_HUMAN" :prob "0.293")))) :time (s2 / subsequent)))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a6 / and :op1 "98" :op2 "99" :op3 "100"))))) # ::id bio.chicago_2015.37115 # ::date 2015-10-29T04:35:51 # ::file bio_chicago_2015_37115.txt # ::snt Like TAK1, two other MAP kinase kinase kinases, MEKK1 and MLK3, act downstream of HPK1 and upstream of MAPK kinase 4/SEK. However, we found that the dominant-negative mutants of MEKK1 and MLK3 did not inhibit TAK1-induced JNK activity, indicating that the activation of JNK1 by TAK1 is independent of MEKK1 and MLK3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (h / have-concession-91 :ARG1 (f / find-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :polarity "-" :ARG0 (a4 / and :op1 "e9" :op2 "e8" :ARG0-of (d2 / dominate-01) :ARG2-of (m2 / mutate-01 :mod "-/-")) :ARG1 (a5 / activity-06 :ARG0 (e4 / enzyme :wiki "C-Jun_N-terminal_kinases" :name (n9 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG2-of (i2 / induce-01 :ARG0 "e5")) :ARG0-of (i3 / indicate-01 :ARG1 (d3 / depend-01 :polarity "-" :ARG0 (a6 / activate-01 :ARG0 "e5" :ARG1 (e3 / enzyme :wiki "C-Jun_N-terminal_kinases" :name (n10 / name :op1 "JNK1") :xref (x3 / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003"))) :ARG1 (a7 / and :op1 "e9" :op2 "e8"))))) :ARG2 (a / act-02 :ARG0 (k / kinase :quant "2" :wiki "MAP_kinase_kinase_kinase" :name (n2 / name :op1 "MAP" :op2 "kinase" :op3 "kinase") :mod (o / other) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (e9 / enzyme :wiki "MAP3K1" :name (n3 / name :op1 "MEKK1") :xref (x5 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :op2 (e8 / enzyme :wiki "MAP3K11" :name (n4 / name :op1 "MLK3") :xref (x6 / xref :value "UNIPROT:M3K11_HUMAN" :prob "1.002")))) :xref (x4 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.393")) :location (a3 / and :op1 (r / relative-position :op1 (e7 / enzyme :wiki "MAP4K1" :name (n5 / name :op1 "HPK1") :xref (x2 / xref :value "UNIPROT:M4K1_HUMAN" :prob "1.002")) :direction (d / downstream)) :op2 (r2 / relative-position :op1 (p / pathway :wiki "-" :name (n / name :op1 "MAPK" :op2 "kinase" :op3 "4/SEK")) :direction (u / upstream))) :ARG1-of (s / same-01 :ARG2 (e5 / enzyme :wiki "MAP3K7" :name (n7 / name :op1 "TAK1") :xref (x / xref :value "UNIPROT:M3K7_HUMAN" :prob "1.002"))))) # ::id bio.chicago_2015.37124 # ::date 2015-10-29T05:05:14 # ::file bio_chicago_2015_37124.txt # ::snt Together, the modest activation of JNK exerted by Rac1 and Cdc42, and the observation that the Rac1L61C40 mutant still inhibits differentiation, raise questions about the involvement of the JNK pathway with respect to the block of differentiation by expression of these proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (r / raise-01 :ARG0 (a / and :op1 (a2 / activate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG1-of (e / exert-01 :ARG0 (a3 / and :op1 (p / protein :name (n2 / name :op1 "Rac1") :xref (x2 / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n3 / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")))) :mod (m2 / modest)) :op2 (o / observe-01 :ARG1 (i / inhibit-01 :ARG0 (p3 / protein :name (n4 / name :op1 "Rac1L61C40") :ARG2-of (m / mutate-01)) :ARG1 (d / differentiate-01) :mod (s / still))) :mod (t / together)) :ARG1 (q / question-01 :ARG1 (i2 / involve-01 :ARG1 (p4 / pathway :name (n5 / name :op1 "JNK")) :topic (b / block-01 :ARG0 (e2 / express-03 :ARG2 (p5 / protein :mod (t2 / this))) :ARG1 d)))) # ::id bio.chicago_2015.37139 # ::date 2015-10-29T05:15:24 # ::file bio_chicago_2015_37139.txt # ::snt Recently, controversial results have been reported by our group indicating that cellular Cdc42 is certainly required for the actin-based motility of Shigella in infected cells ( 83). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (r / report-01 :ARG0 (g / group :poss (w / we)) :ARG1 (t / thing :ARG2-of (r2 / result-01) :mod (c / controversy) :ARG0-of (i / indicate-01 :ARG1 (r4 / require-01 :ARG0 (m / motility :ARG1-of (b / base-02 :ARG2 (p2 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :mod (o / organism :name (n3 / name :op1 "Shigella")) :location (c4 / cell :ARG1-of (i2 / infect-01))) :ARG1 (p / protein :name (n / name :op1 "Cdc42") :mod (c2 / cellular) :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :manner (c3 / certain)))) :time (r3 / recent) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "83")))) # ::id bio.chicago_2015.37195 # ::date 2015-10-29T05:21:27 # ::file bio_chicago_2015_37195.txt # ::snt On the other hand, ADP significantly inhibited the actin-activated ATPase activity of myosin VIIA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (c / contrast-01 :ARG2 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "ADP") :xref (x3 / xref :value "PUBCHEM:6022" :prob "14.621743")) :ARG1 (a / activity-06 :ARG0 (p / protein :name (n2 / name :op1 "myosin" :op2 "VIIA") :xref (x2 / xref :value "UNIPROT:MYO3A_HUMAN" :prob "0.312")) :ARG1 (e / enzyme :name (n3 / name :op1 "ATPase") :ARG1-of (a2 / activate-01 :ARG0 (p2 / protein :name (n4 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :xref (x1 / xref :value "UNIPROT:Q0ZFE3_HUMAN" :prob "0.361"))) :ARG1-of (s2 / significant-02))) # ::id bio.chicago_2015.37242 # ::date 2015-10-29T05:26:45 # ::file bio_chicago_2015_37242.txt # ::snt Ethanol inhibited D2L receptor coupling to adenylyl cyclase as a function of increasing ethanol concentration (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (i / inhibit-01 :ARG0 (e / ethanol) :ARG1 (c / couple-01 :ARG1 (r / receptor :name (n / name :op1 "D2L")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "adenylyl" :op2 "cyclase") :xref (x / xref :value "UNIPROT:ADCY1_HUMAN" :prob "0.392"))) :ARG1-of (f / function-01 :ARG0 (i2 / increase-01 :ARG1 (c2 / concentrate-02 :ARG1 e))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2A"))) # ::id bio.chicago_2015.37257 # ::date 2015-10-29T05:32:06 # ::file bio_chicago_2015_37257.txt # ::snt In the Clk loop, CLK-CYC heterodimers activate vri transcription via E boxes in the vri promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / activate-01 :ARG0 (h / heterodimer :part (p / protein :name (n / name :op1 "CLK") :xref (x1 / xref :value "UNIPROT:CLK1_HUMAN" :prob "1.002")) :part (p2 / protein :name (n2 / name :op1 "CYC") :xref (x / xref :value "UNIPROT:CYC_HUMAN" :prob "1.003"))) :ARG1 (t / transcribe-01 :ARG1 (g / gene :name (n3 / name :op1 "vri")) :instrument (d / dna-sequence :name (n4 / name :op1 "E" :op2 "box") :location (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 g)))) :location (l / loop :mod p)) # ::id bio.chicago_2015.37286 # ::date 2015-10-29T05:43:23 # ::file bio_chicago_2015_37286.txt # ::snt The Caenorhabditis elegans unc-64 locus encodes a syntaxin that interacts genetically with synaptobrevin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (e / encode-01 :ARG0 (g / gene :name (n / name :op1 "unc-64" :op2 "locus") :source (o / organism :name (n2 / name :op1 "Caenorhabditis" :op2 "elegans"))) :ARG1 (p / protein :name (n3 / name :op1 "syntaxin") :ARG0-of (i / interact-01 :ARG1 (p2 / protein :name (n4 / name :op1 "synaptobrevin") :xref (x / xref :value "UNIPROT:VAMP1_HUMAN" :prob "0.392")) :manner (g2 / genetic)) :xref (x1 / xref :value "UNIPROT:STX2_HUMAN" :prob "0.352"))) # ::id bio.chicago_2015.37333 # ::date 2015-10-29T05:49:00 # ::file bio_chicago_2015_37333.txt # ::snt One of the modes by which interaction of E1A with p300 modulates transcription appears to involve disruption of a complex of p300 with a cellular acetyl transferase, P/CAF, which regulates transcription by chromatin remodeling ( 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (a / appear-02 :ARG1 (m / mode :ARG1-of (i / include-91 :ARG2 (m2 / mode :instrument-of (m3 / modulate-01 :ARG0 (i2 / interact-01 :ARG0 (p / protein :name (n / name :op1 "E1A") :xref (x2 / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.262")) :ARG1 (p2 / protein :name (n2 / name :op1 "p300") :xref (x1 / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702"))) :ARG1 (t / transcribe-01)))) :ARG2-of (i3 / involve-01 :ARG1 (d / disrupt-01 :ARG1 (c / complex :mod p2) :instrument (e / enzyme :name (n3 / name :op1 "P/CAF") :ARG1-of (m4 / mean-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "acetyltransferase") :mod (c2 / cell) :xref (x / xref :value "UNIPROT:NAT8B_HUMAN" :prob "0.392"))) :ARG0-of (r / regulate-01 :ARG1 (t3 / transcribe-01) :instrument (r2 / remodel-01 :ARG1 (c3 / chromatin :xref (x3 / xref :value "GO:0000785" :prob "0.8")))))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "4")))) # ::id bio.chicago_2015.37349 # ::date 2015-10-29T06:19:38 # ::file bio_chicago_2015_37349.txt # ::snt Alternative splicing removes repeat six ( cortactin B) or repeats 5 and 6 (cortactin C); all of these isoforms bind F-actin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (r / remove-01 :ARG0 (s / splice-01 :mod (a / alternative)) :ARG1 (o / or :op1 (d4 / dna-sequence :name (n7 / name :op1 "repeat" :op2 "6") :part-of (p / protein :name (n / name :op1 "cortactin" :op2 "B") :xref (x2 / xref :value "UNIPROT:SHAN2_HUMAN" :prob "0.242"))) :op2 (a2 / and :op1 (d / dna-sequence :name (n4 / name :op1 "repeat" :op2 "5") :part-of (p2 / protein :name (n2 / name :op1 "cortactin" :op2 "C") :xref (x / xref :value "UNIPROT:SHAN2_HUMAN" :prob "0.232"))) :op2 (d5 / dna-sequence :name (n8 / name :op1 "repeat" :op2 "6") :part-of p2)) :ARG0-of (b / bind-01 :ARG1 (p3 / protein :name (n3 / name :op1 "F-actin") :xref (x1 / xref :value "UNIPROT:NEXN_HUMAN" :prob "0.252"))) :mod (a3 / all)))) # ::id bio.chicago_2015.37392 # ::date 2015-10-29T06:23:47 # ::file bio_chicago_2015_37392.txt # ::snt ( iv) Upon amino acid starvation, uncharged tRNA binds to the HisRS domain of Gcn2 and induces a conformational change that results in the release of Hsp90. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (a / and :li "iv" :op1 (b / bind-01 :ARG0 (n5 / nucleic-acid :name (n / name :op1 "tRNA") :ARG1-of (c / charge-03 :polarity "-")) :ARG2 (p / protein-segment :name (n2 / name :op1 "HisRS" :op2 "domain") :part-of (e / enzyme :name (n3 / name :op1 "Gcn2") :xref (x1 / xref :value "UNIPROT:E2AK4_HUMAN" :prob "0.602")))) :op2 (i / induce-01 :ARG0 n5 :ARG2 (c2 / change-01 :mod (c3 / conformational) :ARG1-of (r2 / result-01 :ARG2 (r3 / release-01 :ARG1 (p2 / protein :name (n4 / name :op1 "Hsp90") :xref (x / xref :value "UNIPROT:HS90B_HUMAN" :prob "0.622")))))) :condition (s / starve-01 :ARG1 n5 :ARG2 (a2 / amino-acid))) # ::id bio.chicago_2015.37393 # ::date 2015-10-29T06:31:07 # ::file bio_chicago_2015_37393.txt # ::snt All four TnI-derived sequences bound TnC, with hcTnI, dTnIA, and dTnIV exhibiting the most robust binding signals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (a / and :op1 (b / bind-01 :ARG0 (s / sequence :quant "4" :mod (a2 / all) :ARG1-of (d / derive-01 :ARG2 (p / protein :name (n / name :op1 "TnI") :xref (x1 / xref :value "UNIPROT:TNIK_HUMAN" :prob "0.202")))) :ARG1 (p2 / protein :name (n2 / name :op1 "TnC") :xref (x / xref :value "UNIPROT:TENA_HUMAN" :prob "0.623"))) :op2 (e / exhibit-01 :ARG0 (a3 / and :op1 (p3 / protein-segment :name (n3 / name :op1 "hcTnI")) :op2 (p4 / protein-segment :name (n4 / name :op1 "dTnIA")) :op3 (p5 / protein-segment :name (n5 / name :op1 "dTnIV"))) :ARG1 (s2 / signal-07 :ARG3 (b2 / bind-01) :mod (r / robust :degree (m / most))))) # ::id bio.chicago_2015.37409 # ::date 2015-10-29T11:47:14 # ::file bio_chicago_2015_37409.txt # ::snt N-Wasp and cortactin can bind simultaneously to the Arp2/3 complex and activate actin assembly ( Weaver et al., 2002). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 29, 2015 (a / and :op1 (p7 / possible-01 :ARG1 (b / bind-01 :ARG0 (a2 / and :op1 (p / protein :name (n / name :op1 "N-Wasp") :xref (x2 / xref :value "UNIPROT:WASL_HUMAN" :prob "0.623")) :op2 (p2 / protein :name (n2 / name :op1 "cortactin") :xref (x / xref :value "UNIPROT:CORT_HUMAN" :prob "0.292"))) :ARG2 (m / macro-molecular-complex :name (n3 / name :op1 "Arp2/3")) :manner (s / simultaneous))) :op2 (a3 / activate-01 :ARG0 a2 :ARG1 (a4 / assemble-01 :ARG2 (p3 / protein :name (n4 / name :op1 "actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a5 / and :op1 (p5 / person :name (n5 / name :op1 "Weaver")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "2002")))) # ::id bio.chicago_2015.37426 # ::date 2015-10-29T11:51:56 # ::file bio_chicago_2015_37426.txt # ::snt Rb interacts with histone deacetylase to repress transcription. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "Rb") :xref (x1 / xref :value "UNIPROT:RB_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n2 / name :op1 "histone" :op2 "deacetylase") :xref (x / xref :value "UNIPROT:B3KUJ5_HUMAN" :prob "0.701")) :ARG2 (r / repress-01 :ARG0 (a / and :op1 p :op2 e) :ARG1 (t / transcribe-01))) # ::id bio.chicago_2015.37451 # ::date 2015-10-27T08:53:32 # ::file bio_chicago_2015_37451.txt # ::snt Although TIM can interact with dCLOCK in the absence of PER ( Figure 4), dCLOCK appears to have a higher affinity for the PER-TIM complex compared to a version of TIM that does not associate with PER ( Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (h3 / have-concession-91 :ARG1 (a2 / appear-02 :ARG1 (h / have-03 :ARG0 "p3" :ARG1 (a3 / affinity :ARG1-of (h2 / high-02 :degree (m / more)) :topic (m2 / macro-molecular-complex :part "p4" :part "p2") :compared-to (v / version :poss "p2" :ARG1-of (a4 / associate-01 :polarity "-" :ARG2 "p4")))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5"))) :ARG2 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "TIM") :xref (x / xref :value "UNIPROT:TIM_HUMAN" :prob "1.004")) :ARG2 (p3 / protein :name (n2 / name :op1 "dCLOCK")) :condition (a / absent-01 :ARG1 (p4 / protein :name (n3 / name :op1 "PER") :xref (x1 / xref :value "UNIPROT:PER1_HUMAN" :prob "1.002"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4"))))) # ::id bio.chicago_2015.37483 # ::date 2015-10-27T09:36:25 # ::file bio_chicago_2015_37483.txt # ::snt In an ATP-consuming reaction, the C terminus of ubiquitin is first activated by an enzyme called E1, to which it becomes attached by a thiolester bond. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "E1") :xref (x1 / xref :value "UNIPROT:Q8V9K6_HUMAN" :prob "1.001")) :ARG1 (p / protein-segment :name (n2 / name :op1 "C" :op2 "terminus") :part-of (p2 / protein :name (n3 / name :op1 "ubiquitin") :xref (x / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :ARG1-of (a2 / attach-01 :ARG2 e :ARG3 (s2 / small-molecule :name (n6 / name :op1 "thiolester") :ARG3-of (b2 / bond-01)) :ARG1-of (b / become-01))) :time (f / first) :condition (r / react-01 :ARG0-of (c / consume-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "ATP") :xref (x2 / xref :value "PUBCHEM:5957" :prob "14.368295"))))) # ::id bio.chicago_2015.37518 # ::date 2015-10-27T09:55:50 # ::file bio_chicago_2015_37518.txt # ::snt Moreover, HGF also increases the amount of newly synthesized E-cadherin molecules found in beta-catenin complexes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (a3 / and :op2 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "HGF") :xref (x2 / xref :value "UNIPROT:HGF_HUMAN" :prob "1.004")) :ARG1 (a2 / amount :quant-of (m / molecule :mod (p2 / protein :name (n2 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG1-of (s / synthesize-01 :ARG1-of (n3 / new-01)) :ARG1-of (f / find-01 :location (m2 / macro-molecular-complex :part (p3 / protein :name (n4 / name :op1 "beta-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")))))) :mod (a / also))) # ::id bio.chicago_2015.37572 # ::date 2015-10-27T10:10:10 # ::file bio_chicago_2015_37572.txt # ::snt Evidence suggests that DREF is required for DNA replication in both the endo and mitotic cell cycles. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (s / suggest-01 :ARG0 (e / evidence-01) :ARG1 (r / require-01 :ARG0 (r2 / replicate-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")) :time (a / and :op1 (c / cycle :mod (c2 / cell :mod (e2 / endo))) :op2 (c3 / cycle :mod (c4 / cell :mod (m / mitosis))))) :ARG1 (p / protein :name (n / name :op1 "DREF") :xref (x / xref :value "UNIPROT:ZBED1_HUMAN" :prob "1.002")))) # ::id bio.chicago_2015.37588 # ::date 2015-10-27T10:21:16 # ::file bio_chicago_2015_37588.txt # ::snt Induction of p21 by p16. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "p16") :xref (x1 / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262")) :ARG1 (p2 / protein :name (n2 / name :op1 "p21") :xref (x / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002"))) # ::id bio.chicago_2015.37589 # ::date 2015-10-27T10:22:18 # ::file bio_chicago_2015_37589.txt # ::snt In vitro, OTK associates with Plexins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "OTK") :xref (x1 / xref :value "UNIPROT:FKB1B_HUMAN" :prob "0.262")) :ARG2 (p2 / protein :name (n2 / name :op1 "Plexin") :xref (x / xref :value "UNIPROT:PLXA3_HUMAN" :prob "0.352")) :manner (i / in-vitro)) # ::id bio.chicago_2015.37606 # ::date 2015-10-27T10:56:02 # ::file bio_chicago_2015_37606.txt # ::snt It remains to be determined how the interaction of either the AHR or ARNT with TFIIB may influence the ability of either of these proteins to activate genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (r / remain-01 :ARG1 (d / determine-01 :ARG1 (t / thing :manner-of (i / influence-01 :ARG0 (i2 / interact-01 :ARG0 (o / or :op1 (p / protein :name (n / name :op1 "AHR") :xref (x2 / xref :value "UNIPROT:AHR_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "ARNT") :xref (x / xref :value "UNIPROT:ARNT_HUMAN" :prob "1.003"))) :ARG1 (p3 / protein :name (n3 / name :op1 "TFIIB") :xref (x1 / xref :value "UNIPROT:TF2B_HUMAN" :prob "1.002"))) :ARG1 (c / capable-01 :ARG1 o :ARG2 (a / activate-01 :ARG0 o :ARG1 (g / gene))) :ARG1-of (p4 / possible-01))))) # ::id bio.chicago_2015.37655 # ::date 2015-10-27T11:08:58 # ::file bio_chicago_2015_37655.txt # ::snt Hypoxia also induces VEGF ( 76-84), and there are also several cellular conditions or factors that down-regulate expression of this gene product, including the tumor suppressor gene p53 and the von Hippel-Lindau tumor suppressor gene product ( 85-89). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (a / and :op1 (i / induce-01 :ARG0 (h / hypoxia) :ARG1 (p / protein :name (n / name :op1 "VEGF") :ARG1-of (p2 / produce-01 :ARG0 (g / gene)) :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 (b / between :op1 "76" :op2 "84")))) :mod "a3") :op2 (d / downregulate-01 :ARG0 (o / or :op1 (c / condition :mod (c2 / cell) :quant (s / several)) :op2 (f / factor :mod c2 :quant s) :ARG2-of (i2 / include-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "p53") :ARG1-of (p4 / produce-01 :ARG0 (g2 / gene :ARG0-of (s3 / suppress-01 :ARG1 (t / tumor)))) :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :op2 (p5 / product :poss (g3 / gene :ARG0-of (s4 / suppress-01 :ARG1 (d2 / disease :name (n3 / name :op1 "Hippel-Lindau")))))))) :ARG1 (e / express-03 :ARG2 p) :mod (a3 / also) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c5 / cite-01 :ARG2 (b2 / between :op1 "85" :op2 "89")))))) # ::id bio.chicago_2015.37678 # ::date 2015-10-27T11:58:37 # ::file bio_chicago_2015_37678.txt # ::snt Extracellular death pathway Experiments using the egfrts1a allele confirmed that EGFR was required for survival of pupal retinal cells, as suggested by prior misexpression experiments (Miller and Cagan, 1998 ; Sawamoto et al., 1998 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (c / confirm-01 :ARG0 (e / experiment-01 :ARG1 (p / pathway :name (n / name :op1 "Extracellular" :op2 "death" :op3 "pathway")) :ARG2 (a / allele :name (n2 / name :op1 "egfrts1a"))) :ARG1 (r / require-01 :ARG0 (s / survive-01 :ARG0 (c2 / cell :source (r2 / retina) :mod (p2 / pupa))) :ARG1 (e2 / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (s2 / suggest-01 :ARG0 (e3 / experiment-01 :ARG1 (e4 / express-03 :ARG1-of (w / wrong-04)) :time (p3 / prior)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (p4 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n4 / name :op1 "Miller")) :op2 (p6 / person :name (n5 / name :op1 "Cagan"))) :time (d2 / date-entity :year "1998")) :op2 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n6 / name :op1 "Sawamoto")) :op2 (p9 / person :mod (o / other))) :time d2)))) # ::id bio.chicago_2015.37682 # ::date 2015-10-27T12:46:09 # ::file bio_chicago_2015_37682.txt # ::snt Using Biacore and yeast two-hybrid analyses, they found that Hrs interacts with Tsg101, although the PSAP-containing peptide from Hrs bound with lower affinity than that from HIV p6 to the UEV domain of Tsg101 ( Pornillos et al., 2003). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (f / find-01 :ARG0 (t / they) :ARG1 (h2 / have-concession-91 :ARG1 (i / interact-01 :ARG0 (p9 / protein :name (n2 / name :op1 "Hrs") :xref (x2 / xref :value "UNIPROT:HGS_HUMAN" :prob "1.002")) :ARG1 (p10 / protein :name (n4 / name :op1 "Tsg101") :xref (x / xref :value "UNIPROT:TS101_HUMAN" :prob "0.652"))) :ARG2 (b / bind-01 :ARG1 (p / peptide :ARG0-of (c3 / contain-01 :ARG1 (p2 / protein :name (n3 / name :op1 "PSAP") :xref (x1 / xref :value "UNIPROT:MTCH1_HUMAN" :prob "1.002"))) :source p9) :manner (a4 / affinity :ARG1-of (l / low-04 :degree (m / more) :compared-to (p3 / peptide :source (p11 / protein :name (n9 / name :op1 "HIV" :op2 "p6") :ARG1-of (b2 / bind-01 :ARG2 (p5 / protein-segment :name (n6 / name :op1 "UEV") :part-of p10)))))))) :instrument (a / and :op1 (a2 / analyze-01 :mod (c / company :name (n / name :op1 "Biacore"))) :op2 (a3 / analyze-01 :name (n5 / name :op1 "yeast" :op2 "two-hybrid"))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a5 / and :op1 (p7 / person :name (n7 / name :op1 "Pornillos")) :op2 (p8 / person :mod (o / other))) :time (d3 / date-entity :year "2003")))) # ::id bio.chicago_2015.37689 # ::date 2015-10-27T14:05:17 # ::file bio_chicago_2015_37689.txt # ::snt Parallel experiments in which the effects of PD098059 on IL-2 activation of E2F were monitored ( Figure 4C) showed that IL-2 can potently induce E2F activity in the presence of levels of PD098059 that completely block IL-2 activation of Elk-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Oct 27, 2015 (s / show-01 :ARG0 (e / experiment-01 :ARG1 (m / monitor-01 :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "PD098059")) :ARG1 (a2 / activate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "IL-2") :xref (x2 / xref :value "UNIPROT:IL2_HUMAN" :prob "1.003")) :ARG1 (p2 / protein :name (n2 / name :op1 "E2F") :xref (x / xref :value "UNIPROT:E2F1_HUMAN" :prob "0.262")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) :ARG0-of (p / parallel-01)) :ARG1 (p4 / possible-01 :ARG1 (i / induce-01 :ARG0 p3 :ARG2 (a3 / activity-06 :ARG0 p2) :manner (p5 / potent) :condition (p6 / present-02 :ARG1 (l / level :quant-of s2 :ARG0-of (b / block-01 :ARG1 (a4 / activate-01 :ARG0 p3 :ARG1 (p7 / protein :name (n4 / name :op1 "Elk-1") :xref (x1 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592"))) :ARG1-of (c / complete-02))))))) # ::id bio.chicago_2015.37690 # ::date 2015-10-27T15:10:55 # ::file bio_chicago_2015_37690.txt # ::snt Phosphorylation of rAxin by GSK-3beta. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "rAxin")) :ARG2 (e / enzyme :name (n / name :op1 "GSK-3beta") :xref (x / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692"))) # ::id bio.chicago_2015.37704 # ::date 2015-10-28T02:01:04 # ::file bio_chicago_2015_37704.txt # ::snt Phosphorylation of Munc-18 by PKC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Munc-18") :xref (x / xref :value "UNIPROT:UN13A_HUMAN" :prob "0.272")) :ARG2 (e / enzyme :name (n / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))) # ::id bio.chicago_2015.37713 # ::date 2015-10-28T02:02:36 # ::file bio_chicago_2015_37713.txt # ::snt The GCKH domain of NIK interacted with MEKK1, and the dominant negative mutant of MEKK1 inhibited NIK-induced JNK activation ( 12). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i / interact-01 :ARG0 (p / protein-segment :name (n / name :op1 "GCKH") :part-of (e4 / enzyme :name (n2 / name :op1 "NIK") :xref (x1 / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002"))) :ARG1 (e / enzyme :name (n3 / name :op1 "MEKK1") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003"))) :op2 (i2 / inhibit-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEKK1") :ARG2-of (m / mutate-01 :mod "-/-") :ARG0-of (d / dominate-01) :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :ARG1 (a2 / activate-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "JNK") :xref (x2 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG2-of (i3 / induce-01 :ARG0 e4))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "12")))) # ::id bio.chicago_2015.37728 # ::date 2015-10-28T02:28:45 # ::file bio_chicago_2015_37728.txt # ::snt Interestingly, CKI binds to mPER1 in a region that has no obvious sequence similarity to the suggested DBT-binding region of dPER ( 27). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "CKI") :xref (x1 / xref :value "UNIPROT:CHKA_HUMAN" :prob "1.002")) :ARG2 (p3 / protein :name (n2 / name :op1 "mPER1") :xref (x / xref :value "UNIPROT:MPEG1_HUMAN" :prob "0.242")) :location (r / region :ARG0-of (h / have-03 :ARG1 (r2 / resemble-01 :ARG1 (s / sequence) :ARG2 (r3 / region :ARG1-of (s2 / suggest-01) :ARG1-of (b2 / bind-01 :ARG2 (p / protein :name (n3 / name :op1 "DBT") :xref (x2 / xref :value "UNIPROT:ODB2_HUMAN" :prob "1.002"))) :part-of (p2 / protein :name (n4 / name :op1 "dPER"))) :ARG1-of (o / obvious-01 :polarity "-")))) :ARG2-of (i / interest-01) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "27")))) # ::id bio.chicago_2015.37742 # ::date 2015-10-28T02:50:42 # ::file bio_chicago_2015_37742.txt # ::snt The binding of Sp1 to the EBS and to the downstream canonical Sp1 site occurred with comparable affinities. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (a / affinity :ARG1-of (c / comparable-03) :topic (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Sp1") :xref (x2 / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001")) :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "EBS") :xref (x / xref :value "UNIPROT:NAT9_HUMAN" :prob "1.002")) :op2 (s / site :mod (p3 / protein :name (n3 / name :op1 "Sp1") :mod (c2 / canonical) :mod (d / downstream) :xref (x1 / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001")))))) # ::id bio.chicago_2015.37761 # ::date 2015-10-28T03:12:29 # ::file bio_chicago_2015_37761.txt # ::snt Perhaps intersectin plays a role in EGF-stimulated Ras activation specifically at clathrin-coated pits. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (p / possible-01 :ARG1 (p2 / play-02 :ARG0 (p3 / protein :name (n / name :op1 "intersectin") :xref (x / xref :value "UNIPROT:ITSN1_HUMAN" :prob "0.383")) :ARG1 (r / role) :topic (a / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (s / stimulate-01 :ARG0 (p4 / protein :name (n3 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :location (p5 / pit :ARG1-of (c / coat-01 :ARG2 (p6 / protein :name (n4 / name :op1 "clathrin") :xref (x3 / xref :value "UNIPROT:A0A087WVQ6_HUMAN" :prob "0.291"))) :ARG1-of (s2 / specific-02)))) # ::id bio.chicago_2015.37797 # ::date 2015-10-28T04:19:15 # ::file bio_chicago_2015_37797.txt # ::snt The substance has been shown previously not only to prevent phosphorylation-dependent activation of MEK by Raf-1 but also to interfere with signaling from activated MEK1 ( 1, 22). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (s / show-01 :ARG1 (a / and :op1 (p / prevent-01 :ARG0 (s2 / substance) :ARG1 (a2 / activate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG0-of (d / depend-01 :ARG1 (p3 / phosphorylate-01)))) :op2 (i / interfere-01 :ARG0 s2 :ARG1 (s3 / signal-07 :ARG0 (e3 / enzyme :name (n3 / name :op1 "MEK1") :ARG1-of (a3 / activate-01) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :mod (a5 / also))) :time (p2 / previous) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 "1" :op2 "22"))))) # ::id bio.chicago_2015.37803 # ::date 2015-10-28T04:34:50 # ::file bio_chicago_2015_37803.txt # ::snt Repression of hsp70 heat shock gene transcription by the suppressor of Hairy-wing protein of Drosophila melanogaster.. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (r / repress-01 :ARG0 (m / molecular-physical-entity :ARG0-of (s / suppress-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Hairy-wing") :source (o / organism :name (n3 / name :op1 "Drosophila" :op2 "melanogaster")) :xref (x / xref :value "UNIPROT:HES1_HUMAN" :prob "0.232")))) :ARG1 (t / transcribe-01 :ARG1 (g / gene :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n / name :op1 "hsp70" :op2 "heat" :op3 "shock")))))) # ::id bio.chicago_2015.37835 # ::date 2015-10-28T05:11:17 # ::file bio_chicago_2015_37835.txt # ::snt To investigate whether the binding of E1A to p300 correlates with a loss of p300 transcriptional activity, we examined the binding of full-length E1A to the series of mutant p300 proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "E1A") :ARG1-of (l2 / long-03 :ARG1-of (f / full-09)) :xref (x2 / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.262")) :ARG2 (s / series :consist-of (p3 / protein :name (n2 / name :op1 "p300") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")))) :purpose (i / investigate-01 :ARG0 w :ARG1 (c / correlate-01 :mode "interrogative" :ARG1 (b2 / bind-01 :ARG1 p :ARG2 (p2 / protein :name (n3 / name :op1 "p300") :xref (x / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702"))) :ARG2 (l / lose-02 :ARG1 (a / activity-06 :ARG0 p2 :ARG1 (t / transcribe-01 :ARG0 p2)))))) # ::id bio.chicago_2015.37883 # ::date 2015-10-28T05:25:30 # ::file bio_chicago_2015_37883.txt # ::snt We recently presented evidence that the rate of dephosphorylation of Cdc2 on tyrosine-15 is decreased in cells arrested in early S with HU, which indicates that Cdc25 might be inhibited by the S-M replication checkpoint (Rhind and Russell, 1998a ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 4, 2016 (p / present-01 :ARG0 (w / we) :ARG1 (e / evidence-01 :ARG1 (d / decrease-01 :ARG1 (r / rate :degree-of (d2 / dephosphorylate-01 :ARG1 (a / amino-acid :mod "15" :name (n2 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n / name :op1 "Cdc2") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :location (c / cell :ARG1-of (a2 / arrest-02 :instrument (s / small-molecule :name (n8 / name :op1 "HU") :xref (x3 / xref :value "PUBCHEM:3657" :prob "16.088081")) :time (e3 / early :op1 (p2 / phase :name (n3 / name :op1 "S"))))) :ARG0-of (i / indicate-01 :ARG1 (p3 / possible-01 :ARG1 (i2 / inhibit-01 :ARG0 (c2 / checkpoint :mod (r2 / replicate-01 :ARG1 (p4 / phase :name (n5 / name :op1 "S-M")))) :ARG1 (e4 / enzyme :name (n4 / name :op1 "Cdc25") :xref (x / xref :value "UNIPROT:RGRF1_HUMAN" :prob "0.633")))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n6 / name :op1 "Rhind")) :op2 (p7 / person :name (n7 / name :op1 "Russell"))) :time (d4 / date-entity :year "1998")))))) :time (r3 / recent)) # ::id bio.chicago_2015.37893 # ::date 2015-10-28T06:00:01 # ::file bio_chicago_2015_37893.txt # ::snt MSL2 and MSL3 interact with MSL1 in a yeast two-hybrid system (Copps et al., 1998) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (i / interact-01 :ARG0 (a / and :op1 (p4 / protein :name (n / name :op1 "MSL2") :xref (x1 / xref :value "UNIPROT:MSL2_HUMAN" :prob "1.003")) :op2 (p5 / protein :name (n2 / name :op1 "MSL3") :xref (x2 / xref :value "UNIPROT:MS3L1_HUMAN" :prob "1.002"))) :ARG1 (p6 / protein :name (n3 / name :op1 "MSL1") :xref (x / xref :value "UNIPROT:MSL1_HUMAN" :prob "1.003")) :condition (s / system :name (n4 / name :op1 "yeast" :op2 "two-hybrid")) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n5 / name :op1 "Copps")) :op2 (p3 / person :mod (o / other))) :time (d2 / date-entity :year "1998")))) # ::id bio.chicago_2015.37903 # ::date 2015-10-28T06:11:28 # ::file bio_chicago_2015_37903.txt # ::snt Phosphorylation of eIF2alpha by Hri1p and Hri2p is induced by heat shock or arsenic. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (i / induce-01 :ARG0 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "heat" :op2 "shock") :xref (x1 / xref :value "UNIPROT:HS90A_HUMAN" :prob "0.313")) :op2 (a3 / arsenic)) :ARG2 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "eIF2alpha") :xref (x / xref :value "UNIPROT:IF2A_HUMAN" :prob "0.692")) :ARG2 (a / and :op1 (e / enzyme :name (n2 / name :op1 "Hri1p") :xref (x2 / xref :value "UNIPROT:RIP_HUMAN" :prob "0.232")) :op2 (e2 / enzyme :name (n3 / name :op1 "Hri2p") :xref (x3 / xref :value "UNIPROT:RIP_HUMAN" :prob "0.232"))))) # ::id bio.chicago_2015.37947 # ::date 2015-10-28T06:20:33 # ::file bio_chicago_2015_37947.txt # ::snt Polyglutamine-Expanded Human Huntingtin Transgenes Induce Degeneration of Drosophila Photoreceptor Neurons. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (i / induce-01 :ARG0 (t / transgene :name (n / name :op1 "Polyglutamine-Expanded" :op2 "Human" :op3 "Huntingtin")) :ARG2 (d / degenerate-01 :ARG1 (n2 / neuron :mod (p2 / photoreceptor) :source (o / organism :name (n3 / name :op1 "Drosophila"))))) # ::id bio.chicago_2015.37956 # ::date 2015-10-28T06:30:50 # ::file bio_chicago_2015_37956.txt # ::snt Scattering measurements have suggested that the rate of activation of transducin by photoexcited rhodopsin could proceed as rapidly as 700 - 1000 s-1 ( Vuong et al 1984, Kahlert & Hofmann 1991, Bruckert et al 1992) under conditions of saturating guanosine triphosphate (GTP). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (s / suggest-01 :ARG0 (m / measure-01 :ARG0-of (s2 / scatter-01)) :ARG1 (p / possible-01 :ARG1 (p2 / proceed-01 :ARG1 (r / rate-entity-91 :ARG1 (b / between :op1 "700" :op2 "1000" :mod (r2 / rapid)) :ARG2 (t / temporal-quantity :quant "-1" :unit (s3 / second)) :degree-of (a / activate-01 :ARG0 (p4 / protein :name (n2 / name :op1 "rhodopsin") :ARG1-of (p5 / photoexcite-00) :xref (x1 / xref :value "UNIPROT:Q16415_HUMAN" :prob "1.001")) :ARG1 (p3 / protein :name (n / name :op1 "transducin") :xref (x / xref :value "UNIPROT:GBG1_HUMAN" :prob "0.312")))) :condition (s5 / small-molecule :name (n3 / name :op1 "guanosine" :op2 "triphosphate") :ARG2-of (s4 / saturate-01) :xref (x2 / xref :value "PUBCHEM:6830" :prob "10.866265")) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p6 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n4 / name :op1 "Vuong")) :op2 (p8 / person :mod (o / other))) :time (d2 / date-entity :year "1984")) :op2 (p9 / publication-91 :ARG0 (a4 / and :op1 (p10 / person :name (n5 / name :op1 "Kahlert")) :op2 (p11 / person :name (n6 / name :op1 "Hofmann"))) :time (d3 / date-entity :year "1991")) :op3 (p12 / publication-91 :ARG0 (a5 / and :op1 (p13 / person :name (n7 / name :op1 "Bruckert")) :op2 p8) :time (d4 / date-entity :year "1992"))))))) # ::id bio.chicago_2015.38037 # ::date 2015-10-28T07:41:26 # ::file bio_chicago_2015_38037.txt # ::snt It was also shown that the GST-A box of HMG-1 was able to pull down TFIID in crude HeLa extract, suggesting that HMG-1 binds to TBP and/or other TFIID components ( 41). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG1 (c / capable-01 :ARG1 (d / dna-sequence :name (n / name :op1 "GST-A" :op2 "box") :part-of (g / gene :name (n2 / name :op1 "HMG-1") :xref (x2 / xref :value "UNIPROT:HMGB1_HUMAN" :prob "1.003"))) :ARG2 (p / pull-down-08 :ARG1 (p2 / protein :name (n3 / name :op1 "TFIID") :xref (x / xref :value "UNIPROT:TBP_HUMAN" :prob "1.002")) :ARG2 (e / extract-01 :ARG2 (c2 / cell-line :name (n4 / name :op1 "HeLa")) :mod (c3 / crude)) :ARG3 d) :ARG0-of (s2 / suggest-01 :ARG1 (b / bind-01 :ARG1 g :ARG2 (a3 / and-or :op1 (a2 / and :op1 (p3 / protein :name (n5 / name :op1 "TBP") :xref (x1 / xref :value "UNIPROT:TBP_HUMAN" :prob "1.003")) :op2 (c4 / component :part-of p2 :mod (o / other))) :op2 (o2 / or :op1 p3 :op2 c4))))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "41")))) # ::id bio.chicago_2015.38040 # ::date 2015-10-28T08:02:07 # ::file bio_chicago_2015_38040.txt # ::snt If a similar structure mediates the formation of the MSL1-MSL2 heterodimer, then part of the region of MSL2 that interacts with MSL1 should form a coiled-coil structure. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (h / have-condition-91 :ARG1 (r2 / recommend-01 :ARG1 (f2 / form-01 :ARG0 (p3 / part :part-of (r3 / region :part-of (p4 / protein :name (n3 / name :op1 "MSL2") :ARG0-of (i / interact-01 :ARG1 "p") :xref (x2 / xref :value "UNIPROT:MSL2_HUMAN" :prob "1.003")))) :ARG1 (s3 / structure :mod (c / coil :ARG1-of (c2 / coil-01))))) :ARG2 (m / mediate-01 :ARG0 (s / structure :ARG1-of (r / resemble-01)) :ARG1 (f / form-01 :ARG1 (h2 / heterodimer :part (p / protein :name (n / name :op1 "MSL1") :xref (x1 / xref :value "UNIPROT:MSL1_HUMAN" :prob "1.003")) :part (p2 / protein :name (n2 / name :op1 "MSL2") :xref (x / xref :value "UNIPROT:MSL2_HUMAN" :prob "1.003")))))) # ::id bio.chicago_2015.38085 # ::date 2015-10-28T08:26:49 # ::file bio_chicago_2015_38085.txt # ::snt Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / control-01 :ARG1 (i / initiate-01 :ARG1 (a / anaphase) :location (o / organism :name (n / name :op1 "Saccharomyces" :op2 "cerevisiae"))) :ARG2 (d / degrade-01 :ARG1 (p / protein :name (n2 / name :op1 "Pds1p") :ARG0-of (i2 / inhibit-01 :ARG1 a)) :ARG0-of (d2 / depend-01 :ARG1 (p2 / protein :name (n3 / name :op1 "APC") :xref (x / xref :value "UNIPROT:APC_HUMAN" :prob "1.004"))))) # ::id bio.chicago_2015.38107 # ::date 2015-10-28T08:43:29 # ::file bio_chicago_2015_38107.txt # ::snt The role of these virus-like particles, if any, in neuronal cell death induced by huntingtin transgenes requires further analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (r / role :poss (p / particle :ARG1-of (r2 / resemble-01 :ARG2 (v / virus)) :mod (t2 / this)) :condition (a / any) :ARG0-of (r3 / require-01 :ARG1 (a2 / analyze-01 :mod (f / further))) :topic (d / die-01 :ARG1 (c / cell :mod (n / neuron)) :ARG2-of (i / induce-01 :ARG0 (t / transgene :name (n2 / name :op1 "huntingtin"))))) # ::id bio.chicago_2015.38113 # ::date 2015-10-28T09:22:03 # ::file bio_chicago_2015_38113.txt # ::snt These date indicate that MEK plays a crucial role in Epo-induced activation of Elk-1 and is also involved in CrkL-enhanced activation of Elk-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (d / data :mod (t / this)) :ARG1 (a / and :op1 (p / play-02 :ARG0 (e / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1 (r / role :mod (c / crucial) :topic (a2 / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Elk-1") :xref (x / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :ARG2-of (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "Epo") :xref (x3 / xref :value "PUBCHEM:5288169" :prob "16.321695")))))) :op2 (i3 / involve-01 :ARG1 e :ARG2 (a3 / activate-01 :ARG1 p2 :ARG1-of (e2 / enhance-01 :ARG0 (p3 / protein :name (n4 / name :op1 "CrkL") :xref (x2 / xref :value "UNIPROT:CRKL_HUMAN" :prob "0.604")))) :mod (a4 / also)))) # ::id bio.chicago_2015.38119 # ::date 2015-10-28T12:07:07 # ::file bio_chicago_2015_38119.txt # ::snt Because APC inhibition by Mad2 or proteasome inhibition by addition of MG132 (J.D.R.R. and P.J., unpublished data), rescued mitosis in Emi1-depleted extracts, Emi1 most likely affects cyclin B ubiquitylation and destruction, rather than, for example, its translation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (r / rescue-01 :ARG0 (o / or :op1 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "Mad2") :xref (x2 / xref :value "UNIPROT:MD2L1_HUMAN" :prob "0.602")) :ARG1 (p9 / protein :name (n2 / name :op1 "APC") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004"))) :op2 (i2 / inhibit-01 :ARG0 (a / add-02 :ARG1 (s / small-molecule :name (n4 / name :op1 "MG132") :xref (x3 / xref :value "PUBCHEM:462382" :prob "18.349844"))) :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "proteasome"))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n6 / name :op1 "J.D.R.R.")) :op2 (p6 / person :name (n7 / name :op1 "P.J.")))) :op2 (d3 / data :ARG1-of (p7 / publish-01 :polarity "-"))))) :ARG1 (m3 / mitosis) :condition (e / extract-01 :ARG1-of (d / deplete-01 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "Emi1"))))) :ARG1 (a4 / affect-01 :ARG0 s2 :ARG1 (a5 / and :op1 (u / ubiquitylate-00 :ARG1 (p8 / protein :name (n8 / name :op1 "cyclin" :op2 "B") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322"))) :op2 (d4 / destroy-01 :ARG1 p8) :ARG1-of (i3 / instead-of-91 :ARG2 (t / translate-02 :ARG1 p8 :ARG0-of (e2 / exemplify-01)))) :ARG1-of (l / likely-01 :degree (m4 / most)))) # ::id bio.chicago_2015.38154 # ::date 2015-10-28T12:47:17 # ::file bio_chicago_2015_38154.txt # ::snt In vivo, we observed that overexpression of the cytoplasmic domain of plexin-B1 inhibited the activation of PAK by Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (i2 / inhibit-01 :ARG0 (o2 / overexpress-01 :ARG1 (d / domain :mod (c / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :part-of (p / protein :name (n / name :op1 "plexin-B1") :xref (x1 / xref :value "UNIPROT:PLXB1_HUMAN" :prob "0.702")))) :ARG1 (a / activate-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1 (e / enzyme :name (n2 / name :op1 "PAK") :xref (x / xref :value "UNIPROT:PAK1_HUMAN" :prob "0.263")))) :manner (i / in-vivo)) # ::id bio.chicago_2015.38179 # ::date 2015-10-28T12:54:02 # ::file bio_chicago_2015_38179.txt # ::snt The transcriptional and genetic relationships we have identified between sens and ro imply that the process of R8 differentiation involves a hierarchical interaction where sens normally represses ro to prevent both ro repression of R8 and ro induction of R2/R5. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (i / imply-01 :ARG0 (a / and :op1 (r / relation-03 :ARG0 (p / protein :name (n / name :op1 "sens")) :ARG1 (t / transcribe-01) :ARG2 (p2 / protein :name (n2 / name :op1 "ro"))) :op2 (r2 / relation-03 :ARG0 p :ARG1 (g / genetic) :ARG2 p2) :ARG1-of (i2 / identify-01 :ARG0 (w / we))) :ARG1 (i3 / involve-01 :ARG0 (p3 / process-02 :ARG1 (d / differentiate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "R8")))) :ARG1 (i4 / interact-01 :ARG2 (h / hierarchy) :time (r3 / repress-01 :ARG0 p :ARG1 p2 :ARG1-of (n4 / normal-02) :purpose (p5 / prevent-01 :ARG0 p :ARG1 (a2 / and :op1 (r4 / repress-01 :ARG0 p2 :ARG1 p4) :op2 (i5 / induce-01 :ARG0 p2 :ARG1 (s / slash :op1 (p6 / protein :name (n5 / name :op1 "R2")) :op2 (p7 / protein :name (n6 / name :op1 "R5")))))))))) # ::id bio.chicago_2015.38213 # ::date 2015-10-28T13:26:23 # ::file bio_chicago_2015_38213.txt # ::snt Detection of bound probe employed anti-digoxigenin Fab conjugated to alkaline phosphatase, which catalyzed the degradation of the chemiluminescent substrate CDP-Star (Tropix, Bedford, MA), following the protocol of Engler-Blum et al. ( 26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (e / employ-02 :ARG0 (d / detect-01 :ARG1 (p / probe :ARG1-of (b / bind-01))) :ARG1 (p2 / protein :name (n / name :op1 "anti-digoxigenin" :op2 "Fab") :ARG1-of (c / conjugate-02 :ARG2 (e2 / enzyme :name (n2 / name :op1 "alkaline" :op2 "phosphatase") :xref (x / xref :value "UNIPROT:A0A024R4A2_HUMAN" :prob "0.701"))) :xref (x1 / xref :value "UNIPROT:UAP1_HUMAN" :prob "0.212")) :ARG0-of (c2 / catalyze-01 :ARG1 (d2 / degrade-01 :ARG1 (s / substrate :name (n3 / name :op1 "CDP-Star") :mod (c3 / chemiluminescent) :source (c4 / company :name (n4 / name :op1 "Tropix") :location (s2 / street-address-91 :ARG2 (s3 / state :name (n6 / name :op1 "MA")) :ARG4 (c5 / city :name (n5 / name :op1 "Bedford"))))))) :ARG0-of (f / follow-02 :ARG1 (p8 / protocol :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication-91 :ARG0 (a / and :op1 (p4 / person :name (n7 / name :op1 "Engler")) :op2 (p5 / person :name (n8 / name :op1 "Blum")) :op3 (p6 / person :mod (o / other)))) :op2 (p7 / publication :ARG1-of (c6 / cite-01 :ARG2 "26"))))))) # ::id bio.chicago_2015.38247 # ::date 2015-10-28T13:51:21 # ::file bio_chicago_2015_38247.txt # ::snt The Ou group showed that Nedd8 acts genetically downstream of Hh signaling components Smoothened ( Smo) and PKA to regulate Ci processing in cells anterior to the MF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (s / show-01 :ARG0 (g / group :name (n / name :op1 "Ou")) :ARG1 (a / act-02 :ARG0 (p / protein :name (n2 / name :op1 "Nedd8") :xref (x2 / xref :value "UNIPROT:NEDD8_HUMAN" :prob "0.603")) :location (r / relative-position :op1 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "Smoothened") :xref (x / xref :value "UNIPROT:SMO_HUMAN" :prob "0.313")) :op2 (p4 / protein :name (n5 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :ARG0-of (s2 / signal-07 :ARG1 (p2 / protein :name (n3 / name :op1 "Hh")))) :direction (d / downstream)) :mod (g2 / genetic) :purpose (r2 / regulate-01 :ARG0 p :ARG1 (p5 / process-01 :ARG1 (p6 / protein :name (n6 / name :op1 "Ci")) :location (c / cell) :time (a3 / anterior :op1 (p7 / protein :name (n7 / name :op1 "MF"))))))) # ::id bio.chicago_2015.38248 # ::date 2015-10-28T14:21:52 # ::file bio_chicago_2015_38248.txt # ::snt Association of CIZ with Cas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "CIZ") :xref (x1 / xref :value "UNIPROT:ZN384_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n2 / name :op1 "Cas") :xref (x / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.603"))) # ::id bio.chicago_2015.38266 # ::date 2015-10-28T14:23:36 # ::file bio_chicago_2015_38266.txt # ::snt Repression activity of MM-1 toward c-Myc was sensitive to TSA, a specific inhibitor of HDAC, indicating that HDAC is involved in the N-terminal transrepression pathway of c-Myc. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (s / sensitive-03 :ARG0 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "MM-1") :xref (x2 / xref :value "UNIPROT:PFD5_HUMAN" :prob "0.652")) :ARG1 (r / repress-01) :direction (p2 / protein :name (n2 / name :op1 "c-Myc") :xref (x / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.661"))) :ARG1 (s2 / small-molecule :name (n3 / name :op1 "TSA") :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "HDAC") :xref (x1 / xref :value "UNIPROT:HDAC1_HUMAN" :prob "0.312"))) :ARG1-of (s3 / specific-02) :xref (x3 / xref :value "PUBCHEM:444732" :prob "17.186693")) :ARG0-of (i2 / indicate-01 :ARG1 (i3 / involve-01 :ARG1 e :ARG2 (p3 / pathway :ARG0-of (t / transrepress-00 :ARG1 (p4 / protein-segment :name (n5 / name :op1 "N-terminus"))) :poss p2)))) # ::id bio.chicago_2015.38278 # ::date 2015-10-28T14:44:55 # ::file bio_chicago_2015_38278.txt # ::snt Cells were washed with phosphate-buffered saline and fed with 3 ml of either phosphate-free or methionine-free Dulbecco's modified Eagle's medium containing 10% dialyzed fetal bovine serum. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / and :op1 (w / wash-01 :ARG1 (c / cell) :ARG2 (s2 / small-molecule :wiki "Phosphate-buffered_saline" :name (n3 / name :op1 "phosphate-buffered" :op2 "saline") :xref (x / xref :value "PUBCHEM:24978514" :prob "15.955084"))) :op2 (f / feed-01 :ARG1 (o / or :op1 (t / thing :wiki "Eagle's_minimal_essential_medium" :name (n / name :op1 "Dulbecco's" :op2 "Modified" :op3 "Eagle's" :op4 "Medium") :quant (c2 / concentration-quantity :quant "3" :unit (m / milliliter)) :ARG1-of (f2 / free-04 :ARG2 (p2 / phosphate)) :ARG0-of (c3 / contain-01 :ARG1 (s / serum :source (f4 / fetus :mod (b / bovine)) :ARG1-of (d2 / dialyze-00) :quant (p3 / percentage-entity :value "10")))) :op2 (t2 / thing :wiki "Eagle's_minimal_essential_medium" :name (n2 / name :op1 "Dulbecco's" :op2 "Modified" :op3 "Eagle's" :op4 "Medium") :quant c2 :ARG1-of (f3 / free-04 :ARG2 (a2 / amino-acid :wiki "Methionine" :name (n4 / name :op1 "methionine") :xref (x1 / xref :value "PUBCHEM:876" :prob "11.787682"))) :ARG0-of c3)) :ARG2 c)) # ::id bio.chicago_2015.38344 # ::date 2015-10-28T15:03:11 # ::file bio_chicago_2015_38344.txt # ::snt (a) Plexin-B1 interacts with Rac in a GTP-dependent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "Plexin-B1") :xref (x1 / xref :value "UNIPROT:PLXB1_HUMAN" :prob "1.002")) :ARG1 (e / enzyme :name (n2 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :manner (d / depend-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "A"))) # ::id bio.chicago_2015.38348 # ::date 2015-10-28T15:11:49 # ::file bio_chicago_2015_38348.txt # ::snt Recovery of IKK was determined by immunoblotting ( IB). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (d / determine-01 :ARG0 (i / immunoblot-01) :ARG1 (r / recover-02 :ARG1 (e / enzyme :name (n / name :op1 "IKK") :xref (x / xref :value "UNIPROT:IKKA_HUMAN" :prob "0.262")))) # ::id bio.chicago_2015.38364 # ::date 2015-10-28T15:14:14 # ::file bio_chicago_2015_38364.txt # ::snt Sprouty, an intracellular inhibitor of Ras signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "Sprouty") :mod (i2 / intracellular)) :ARG1 (s / signal-07 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) # ::id bio.chicago_2015.38368 # ::date 2015-10-28T15:17:52 # ::file bio_chicago_2015_38368.txt # ::snt Interaction of RGL with Ras Effector Loop Mutants # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "RGL") :xref (x / xref :value "UNIPROT:RGL1_HUMAN" :prob "1.003")) :ARG1 (l / loop :ARG2-of (m / mutate-01) :mod (e / effector) :mod (p2 / protein-family :name (n2 / name :op1 "Ras")))) # ::id bio.chicago_2015.38377 # ::date 2015-10-28T15:25:37 # ::file bio_chicago_2015_38377.txt # ::snt Actin Binding Assay-- Actin binding of cultured cell TMs, caldesmon, and human fascin was assayed in the following four conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (a2 / assay-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Actin") :xref (x2 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.332")) :ARG2 (a / and :op1 (c2 / cell :name (n2 / name :op1 "TMs") :ARG1-of (c3 / culture-01)) :op2 (p2 / protein :name (n3 / name :op1 "caldesmon") :xref (x / xref :value "UNIPROT:CALD1_HUMAN" :prob "0.702")) :op3 (p3 / protein :name (n4 / name :op1 "fascin") :mod (h / human) :xref (x1 / xref :value "UNIPROT:FSCN1_HUMAN" :prob "0.702")))) :manner (c / condition :quant "4" :ARG1-of (f / follow-04))) # ::id bio.chicago_2015.38397 # ::date 2015-10-28T15:58:05 # ::file bio_chicago_2015_38397.txt # ::snt These results suggest that CIZ binds Cas at focal adhesions, at least when they are formed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (s / suggest-01 :ARG0 (t2 / thing :mod (t / this) :ARG2-of (r2 / result-01)) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "CIZ") :xref (x1 / xref :value "UNIPROT:ZN384_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n2 / name :op1 "Cas") :xref (x / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.603")) :location (a2 / adhere-01 :mod (f2 / focal)) :time (f / form-01 :ARG1 a2 :mod (a / at-least)))) # ::id bio.chicago_2015.38411 # ::date 2015-10-28T16:05:55 # ::file bio_chicago_2015_38411.txt # ::snt However, when the full-length Dlx3 protein was phosphorylated by PKC, a decreased DNA binding activity was observed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (h / have-concession-91 :ARG2 (o / observe-01 :ARG1 (a / activity-06 :ARG1 (b / bind-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"))) :ARG1-of (d / decrease-01)) :time (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Dlx3") :ARG1-of (l / long-03 :ARG1-of (f / full-09)) :xref (x / xref :value "UNIPROT:DLX3_HUMAN" :prob "0.603")) :ARG2 (e / enzyme :name (n4 / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))))) # ::id bio.chicago_2015.38447 # ::date 2015-10-28T16:13:29 # ::file bio_chicago_2015_38447.txt # ::snt Regardless of the extent of TRP binding to INAD in the InaD P215 mutant, however, the results of this study suggest that the presence of TRPL stabilizes the TRP channel and allows the latter to contribute to the photoreceptor response in InaD P215, implying physical interactions between these two proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (c / contrast-01 :ARG2 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r3 / result-01 :ARG1 (s2 / study :mod (t2 / this)))) :ARG1 (a / and :op1 (s3 / stabilize-01 :ARG0 (p / present-02 :ARG1 (p2 / protein :name (n / name :op1 "TRPL") :xref (x / xref :value "UNIPROT:TBPL1_HUMAN" :prob "0.262"))) :ARG1 (p8 / protein :name (n5 / name :op1 "TRP" :op2 "channel") :xref (x3 / xref :value "UNIPROT:TCAF1_HUMAN" :prob "0.252"))) :op2 (a2 / allow-01 :ARG0 p2 :ARG1 (c2 / contribute-01 :ARG0 (p5 / protein) :ARG2 (r2 / respond-01 :ARG0 (p3 / photoreceptor) :location (p4 / protein :name (n3 / name :op1 "INAD") :ARG2-of (m / mutate-01 :value "P215") :xref (x2 / xref :value "UNIPROT:INADL_HUMAN" :prob "0.312"))))) :ARG0-of (i / imply-01 :ARG1 (i2 / interact-01 :ARG1 p2 :ARG2 p5 :manner (p6 / physical)))) :ARG1-of (r / regardless-91 :ARG2 (e / extent :degree-of (b / bind-01 :ARG1 p5 :ARG2 (p7 / protein :name (n4 / name :op1 "INAD") :xref (x1 / xref :value "UNIPROT:INADL_HUMAN" :prob "0.312")) :location p4))))) # ::id bio.chicago_2015.38490 # ::date 2015-10-28T16:46:32 # ::file bio_chicago_2015_38490.txt # ::snt We investigated the association of CIZ with Cas by overexpressing CIZ-FLAG and Cas in COS-7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "CIZ") :xref (x2 / xref :value "UNIPROT:ZN384_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n2 / name :op1 "Cas") :xref (x / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.603"))) :manner (o / overexpress-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "CIZ-FLAG") :xref (x1 / xref :value "UNIPROT:ZN384_HUMAN" :prob "0.202")) :op2 p2) :location (c / cell-line :name (n4 / name :op1 "COS-7")))) # ::id bio.chicago_2015.38505 # ::date 2015-10-27T12:11:08 # ::file bio_chicago_2015_38505.txt # ::snt Sexual orientation in Drosophila is altered by the satori mutation in the sex-determination gene fruitless that encodes a zinc finger protein with a BTB domain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 7, 2015 (a / alter-01 :ARG0 (m / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "fruitless") :ARG0-of (d / determine-01 :ARG1 (s4 / sex)) :ARG0-of (e / encode-01 :ARG1 (p3 / protein :name (n4 / name :op1 "zinc" :op2 "finger") :part (p4 / protein-segment :name (n5 / name :op1 "BTB" :op2 "domain")) :xref (x / xref :value "UNIPROT:CHD3_HUMAN" :prob "0.302")))) :ARG2 (s3 / satori)) :ARG1 (o / orient-01 :ARG1 (o2 / organism :name (n / name :op1 "Drosophila")) :ARG3 (s / sex))) # ::id bio.chicago_2015.38519 # ::date 2015-10-27T12:51:00 # ::file bio_chicago_2015_38519.txt # ::snt Treatment of HeLa cells with leptomycin B ( LMB), a specific inhibitor of the NES-dependent transport, resulted in nuclear accumulation of cyclin B1 in G2 phase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (r / result-01 :ARG1 (t2 / treat-04 :ARG1 (c / cell-line :name (n / name :op1 "hela")) :ARG2 (s2 / small-molecule :name (n6 / name :op1 "leptomicin" :op2 "B") :ARG0-of (i / inhibit-01 :ARG1 (t3 / transport-01 :ARG0-of (d / depend-01 :ARG1 (p4 / protein-segment :name (n2 / name :op1 "NES")))) :ARG1-of (s / specific-02)) :xref (x2 / xref :value "PUBCHEM:6328187" :prob "0.784642"))) :ARG2 (a / accumulate-01 :ARG1 (p / protein :name (n4 / name :op1 "cyclin" :op2 "B1") :mod (e / event :name (n7 / name :op1 "phase" :op2 "G2")) :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361")) :mod (n3 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")))) # ::id bio.chicago_2015.38552 # ::date 2015-10-27T13:02:10 # ::file bio_chicago_2015_38552.txt # ::snt The Raf/ MEK/ ERK Signaling Pathway Is Involved in the CrkL-enhanced Activation of Elk-1-- To define the downstream signal transduction pathway leading to the Elk-1 activation, we next examined the possible involvement of the Raf/ MEK/ ERK cascade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (i / involve-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "Raf/MEK/ERK") :ARG0-of (s / signal-07)) :ARG2 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "Elk-1") :xref (x2 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :ARG1-of (e / enhance-01 :ARG0 (p3 / protein :name (n3 / name :op1 "CrkL") :xref (x1 / xref :value "UNIPROT:CRKL_HUMAN" :prob "0.604"))))) :snt2 (e2 / examine-01 :ARG0 (w / we) :ARG1 (i2 / involve-01 :ARG1 (c / cascade-01 :ARG1 (p4 / pathway :name (n4 / name :op1 "Raf/MEK/ERK"))) :ARG1-of (p5 / possible-01)) :time (n5 / next) :purpose (d / define-01 :ARG0 w :ARG1 (p9 / pathway :ARG0-of (l / lead-01 :ARG4 (a2 / activate-01 :ARG1 (p10 / protein :name (n9 / name :op1 "Elk-1") :xref (x / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")))) :ARG2-of (t / transduce-01 :ARG1 (s3 / signal-07 :direction (d2 / downstream))))))) # ::id bio.chicago_2015.38555 # ::date 2015-10-27T13:18:23 # ::file bio_chicago_2015_38555.txt # ::snt We show that precocious induction of Hoxb1 and Hoxb2 by RA is operational at E6.0 already, before primitive streak formation and long before the gene is transcriptionally initiated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (p4 / possible-01 :ARG1 (o2 / operate-01 :ARG0 (i / induce-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "RA") :xref (x2 / xref :value "PUBCHEM:1533" :prob "9.432343")) :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "Hoxb1") :xref (x / xref :value "UNIPROT:HXB1_HUMAN" :prob "0.602")) :op2 (p3 / protein :name (n2 / name :op1 "Hoxb2") :xref (x1 / xref :value "UNIPROT:HXB2_HUMAN" :prob "0.602"))) :mod (p / precocious)) :time (a3 / and :op1 (b / before :op1 (f / form-01 :ARG1 (s2 / streak :mod (p5 / primitive)))) :op2 (b2 / before :op1 (i2 / initiate-01 :ARG1 (g / gene) :manner (t / transcribe-01)) :ARG1-of (l / long-03))) :time (a2 / already) :time (a4 / age-01 :ARG1 (e / embryo) :ARG2 (t2 / temporal-quantity :quant "6" :unit (d / day)))))) # ::id bio.chicago_2015.38557 # ::date 2015-10-27T20:42:40 # ::file bio_chicago_2015_38557.txt # ::snt Because half-maximal binding of syntaxin 1A to the C2A domain of synaptotagmin 1 occurs at calcium levels required for vesicle fusion ( 200 muM calcium) (Heidelberger et al., 1994 ), this interaction may be particularly important for regulating neurotransmitter release by providing a direct means for calcium to regulate vesicle-plasma membrane fusion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c4 / cause-01 :ARG0 (b / bind-01 :ARG1 (p9 / protein :name (n6 / name :op1 "syntaxin" :op2 "A1") :xref (x1 / xref :value "UNIPROT:STX11_HUMAN" :prob "0.342")) :ARG2 (p5 / protein-segment :name (n4 / name :op1 "C2A") :part-of (p7 / protein :name (n2 / name :op1 "synaptotagmin" :op2 "1") :xref (x / xref :value "UNIPROT:SYT1_HUMAN" :prob "0.692"))) :mod (m2 / maximal :degree (h2 / half)) :condition (l / level :ARG1-of (r4 / require-01 :ARG0 (f2 / fuse-01 :ARG1 "v")) :quant-of "c" :ARG1-of (m3 / mean-01 :ARG2 (c3 / calcium :quant "200" :unit (m6 / millimolar)))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (p6 / person :name (n3 / name :op1 "Heidelberger")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "1994"))) :ARG1 (p / possible-01 :ARG1 (i / important :domain (i2 / interact-01 :mod (t / this)) :manner (p2 / particular) :topic (r / regulate-01 :ARG0 i2 :ARG1 (r2 / release-01 :ARG1 (n / neurotransmitter)) :manner (p3 / provide-01 :ARG0 i2 :ARG1 (m / mean :ARG1-of (d3 / direct-01)) :ARG2 (c / calcium) :purpose (r3 / regulate-01 :ARG0 c :ARG1 (f / fuse-01 :ARG1 (v / vesicle) :ARG2 (m5 / membrane :mod (p4 / plasma) :xref (x2 / xref :value "GO:0016020" :prob "0.8"))))))))) # ::id bio.chicago_2015.38559 # ::date 2015-10-27T21:08:06 # ::file bio_chicago_2015_38559.txt # ::snt Second, DRB potently inhibits phosphorylation of the CTD by P-TEFb, and DRB inhibition of P-TEFb kinase correlates well with DRB-induced inhibition of elongation by RNA polymerase II. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "DRB") :xref (x2 / xref :value "PUBCHEM:3165" :prob "17.561386")) :ARG1 (p3 / phosphorylate-01 :ARG1 (p / protein-segment :name (n2 / name :op1 "C-terminus")) :ARG2 (k / kinase :name (n3 / name :op1 "P-TEFb") :xref (x1 / xref :value "UNIPROT:ACOT4_HUMAN" :prob "0.232"))) :manner (p2 / potent)) :op2 (c / correlate-01 :ARG1 (i2 / inhibit-01 :ARG0 s :ARG1 k) :ARG2 (i3 / inhibit-01 :ARG1 (e2 / elongate-01 :ARG0 (n4 / nucleic-acid :name (n6 / name :op1 "RNA") :ARG0-of (e3 / encode-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "polymerase" :op2 "II") :xref (x / xref :value "UNIPROT:TMPS9_HUMAN" :prob "0.302"))))) :ARG2-of (i4 / induce-01 :ARG0 s)) :ARG1-of (w / well-09)) :mod (o / ordinal-entity :value "2")) # ::id bio.chicago_2015.38566 # ::date 2015-10-27T21:20:00 # ::file bio_chicago_2015_38566.txt # ::snt NIK can interact in vivo with MEKK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (e2 / enzyme :name (n / name :op1 "NIK") :xref (x1 / xref :value "UNIPROT:M3K14_HUMAN" :prob "1.002")) :ARG1 (e / enzyme :name (n2 / name :op1 "MEKK1") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :manner (i2 / in-vivo))) # ::id bio.chicago_2015.38569 # ::date 2015-10-27T21:22:21 # ::file bio_chicago_2015_38569.txt # ::snt P120ctn is colocalized with Vav2 within growth cones and a subset of dendritic spines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / colocalize-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "P120ctn") :xref (x1 / xref :value "UNIPROT:CTND1_HUMAN" :prob "0.643")) :op2 (p2 / protein :name (n2 / name :op1 "Vav2") :xref (x / xref :value "UNIPROT:VAV2_HUMAN" :prob "0.604"))) :ARG2 (a / and :op1 (c2 / cone :mod (g / grow-01)) :op2 (s / subset :mod (s2 / spine :mod (d / dendrite))))) # ::id bio.chicago_2015.38579 # ::date 2015-10-27T21:26:31 # ::file bio_chicago_2015_38579.txt # ::snt In the present study, we have shown that TFIIB interacts with the AHR at a site (the region bordered by amino acids 81 and 183) that lies slightly adjacent to its ARNT dimerization motif as well as interacting with its carboxyl terminus. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (i / interact-01 :ARG0 (p3 / protein :name (n / name :op1 "TFIIB") :xref (x / xref :value "UNIPROT:TF2B_HUMAN" :prob "1.002")) :ARG1 (a5 / and :op1 (p / protein :name (n2 / name :op1 "AHR") :xref (x2 / xref :value "UNIPROT:AHR_HUMAN" :prob "1.003")) :op2 (p4 / protein-segment :name (n4 / name :op1 "carboxyl" :op2 "terminus") :part-of p3)) :location (s2 / site :ARG1-of (m2 / mean-01 :ARG2 (r / region :ARG2-of (b / border-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "81") :op2 (a3 / amino-acid :mod "183"))))) :ARG1-of (l / lay-01 :ARG2 (r2 / relative-position :op1 (m3 / motif :ARG0-of (d / dimerize-01 :ARG1 (p5 / protein :name (n3 / name :op1 "ARNT") :xref (x1 / xref :value "UNIPROT:ARNT_HUMAN" :prob "1.003"))) :part-of p3) :mod (a4 / adjacent :degree (s3 / slight)))))) :medium (s4 / study-01 :mod (p2 / present))) # ::id bio.chicago_2015.38598 # ::date 2015-10-27T21:42:45 # ::file bio_chicago_2015_38598.txt # ::snt Whereas removal of Ci activity from clones of cells was shown to result in the loss of expression of some Hh target genes, notably ptc (Dominguez et al. 1996 ), consistent with Hh activation of ptc transcription being mediated by Ci (Alexandre et al. 1996 ), other Hh targets, such as dpp, were found to be activated in the absence of Ci, albeit at a lower level than in their normal domain close to the compartment border. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (s / show-01 :ARG1 (r / remove-01 :ARG1 (a / activity-06 :ARG0 (p3 / protein :name (n / name :op1 "Ci"))) :ARG2 (c2 / clone-01 :ARG1 (c3 / cell))) :ARG1-of (r2 / result-01 :ARG2 (l / lose-02 :ARG1 (e / express-03 :ARG1 (g / gene :mod (s2 / some) :ARG1-of (t / target-01 :ARG0 (p5 / protein :name (n3 / name :op1 "Hh"))) :ARG2-of (n8 / notable-04 :ARG1 (g4 / gene :name (n9 / name :op1 "ptc") :ARG1-of (c4 / consistent-01 :ARG2 (a4 / activate-01 :ARG0 p5 :ARG1 (t2 / transcribe-01 :ARG1 g4 :ARG1-of (m3 / mediate-01 :ARG0 p3))) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and :op1 (p / person :name (n4 / name :op1 "Alexandre")) :op2 (p4 / person :mod (o2 / other)) :time "d"))) :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "0.603"))))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p2 / person :name (n7 / name :op1 "Dominguez")) :op2 p4 :time (d / date-entity :year "1996")))) :ARG2 (f / find-01 :ARG1 (g2 / gene :mod (o / other) :example (g3 / gene :name (n5 / name :op1 "dpp") :xref (x1 / xref :value "UNIPROT:DSPP_HUMAN" :prob "0.602")) :ARG1-of (a7 / activate-01 :condition (a8 / absent-01 :ARG1 p3) :concession (a3 / activate-01 :ARG1 g2 :degree (l3 / level :ARG1-of (l4 / low-04 :degree (m4 / more)) :compared-to (d5 / domain :ARG1-of (n6 / normal-02) :part-of p3) :location (c5 / close-06 :ARG2 (b / border-01 :ARG2 (c6 / compartment)))))) :ARG1-of (t3 / target-01 :ARG0 p5)))) # ::id bio.chicago_2015.38602 # ::date 2015-10-27T21:44:02 # ::file bio_chicago_2015_38602.txt # ::snt The mutation in the APPKPPR sequence (mPR) abolished the binding of CIZ to Cas SH3 (Fig. 3B, lanes 1, 2), strongly suggesting that this sequence was the binding site for Cas SH3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (a / abolish-01 :ARG0 (m / mutate-01 :ARG1 (d / dna-sequence :name (n / name :op1 "APPKPPR") :mod (t / this))) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n2 / name :op1 "CIZ") :xref (x1 / xref :value "UNIPROT:ZN384_HUMAN" :prob "1.002")) :ARG2 (p4 / protein-segment :name (n4 / name :op1 "SH3") :part-of (p3 / protein :name (n3 / name :op1 "Cas") :xref (x / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.603")) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3B") :op2 (l / lane :mod "1") :op3 (l2 / lane :mod "2"))))) :ARG0-of (s / suggest-01 :ARG1 (s3 / site :ARG1-of (b2 / bind-01 :ARG2 p4) :domain d) :ARG1-of (s2 / strong-02))) # ::id bio.chicago_2015.38616 # ::date 2015-10-27T21:54:46 # ::file bio_chicago_2015_38616.txt # ::snt The conclusion that spen is partially required for Wg-dependent bristle inhibition is complicated by the fact that loss of spen causes an increase in Ac expression in wild-type eyes as well ( Fig. 3E,F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / complicate-01 :ARG0 (f / fact :mod (c3 / cause-01 :ARG0 (l / lose-02 :ARG1 "p2") :ARG1 (i2 / increase-01 :ARG1 (e / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ac") :xref (x1 / xref :value "UNIPROT:ASAH1_HUMAN" :prob "0.602")) :ARG3 (e2 / eye :mod (w / wild-type)))) :mod (a / as-well))) :ARG1 (c2 / conclude-01 :ARG1 (r / require-01 :ARG0 (i / inhibit-01 :ARG1 (b / bristle-01) :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n / name :op1 "Wg")))) :ARG1 (p2 / protein :name (n3 / name :op1 "spen") :xref (x / xref :value "UNIPROT:MINT_HUMAN" :prob "0.602")) :degree (p / part))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "3E") :op2 (f3 / figure :mod "3F")))) # ::id bio.chicago_2015.38618 # ::date 2015-10-27T22:08:35 # ::file bio_chicago_2015_38618.txt # ::snt These findings indicate that DTRAF1 activates JNK, but -- in contrast to the activation of JNK by mammalian TRAFs 2, 5 and 6 -- this activation does not require either the Ring-finger or zinc-finger domains [10,11] . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (i / indicate-01 :ARG0 (t2 / thing :ARG1-of (f / find-01) :mod (t / this)) :ARG1 (c / contrast-01 :ARG1 (a / activate-01 :ARG0 (p3 / protein :name (n / name :op1 "DTRAF1") :xref (x1 / xref :value "UNIPROT:HBEGF_HUMAN" :prob "0.213")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :ARG2 (r / require-01 :polarity "-" :ARG0 a :ARG1 (o / or :op1 (p4 / protein-segment :name (n4 / name :op1 "ring-finger" :op2 "domain")) :op2 (p5 / protein-segment :name (n5 / name :op1 "zinc-finger" :op2 "domain"))) :ARG1-of (c2 / contrast-01 :ARG2 (a2 / activate-01 :ARG0 (a4 / and :op1 (p / protein :name (n3 / name :op1 "TRAF2") :xref (x4 / xref :value "UNIPROT:TRAF2_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n6 / name :op1 "TRAF5") :xref (x2 / xref :value "UNIPROT:TRAF5_HUMAN" :prob "1.003")) :op3 (p7 / protein :name (n7 / name :op1 "TRAF6") :xref (x3 / xref :value "UNIPROT:TRAF6_HUMAN" :prob "1.003")) :mod (m / mammal)) :ARG1 e2)) :mod (e / either))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 "10" :op2 "11"))))) # ::id bio.chicago_2015.38621 # ::date 2015-10-27T22:23:01 # ::file bio_chicago_2015_38621.txt # ::snt If the binding of c-Myb to S2 is important for silencer function, we could predict that the site-specific mutation of the c-Myb recognition site in S2 in the appropriate context would lead to abrogation of silencer function. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (h / have-condition-91 :ARG1 (p4 / possible-01 :ARG1 (p3 / predict-01 :ARG0 (w / we) :ARG1 (l / lead-03 :ARG0 (m / mutate-01 :ARG1 (s4 / site :ARG0-of (r / recognize-02 :ARG1 "p" :location "p2" :location (c / context :ARG1-of (a / appropriate-02)))) :ARG1-of (s2 / specific-02 :ARG2 (s3 / site))) :ARG2 (a2 / abrogate-01 :ARG1 "f")))) :ARG2 (i / important :domain (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "c-Myb") :xref (x / xref :value "UNIPROT:Q708E1_HUMAN" :prob "0.661")) :ARG2 (p2 / protein :name (n2 / name :op1 "S2"))) :purpose (f / function-01 :ARG0 (s / silencer)))) # ::id bio.chicago_2015.38629 # ::date 2015-10-27T22:32:42 # ::file bio_chicago_2015_38629.txt # ::snt Mammalian isopeptidase T, similar in its functional properties to yeast Ubp14 ( 351), stimulates the degradation of ubiquitinated proteins specifically by deconjugating free Lys-48 - linked Ub chains after the degradation of the target protein ( 281, 350, 375). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / stimulate-01 :ARG0 (e / enzyme :name (n4 / name :op1 "isopeptidase" :op2 "t") :mod (m / mammal) :ARG1-of (r2 / resemble-01 :ARG2 (e2 / enzyme :name (n / name :op1 "Ubp14") :mod (y2 / yeast) :xref (x / xref :value "UNIPROT:UBP14_HUMAN" :prob "0.633")) :topic (p / property :mod (f / function-01)) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 "351"))))) :ARG1 (d / degrade-01 :ARG1 (p2 / protein :ARG1-of (u / ubiquitinate-01)) :manner (c2 / conjugate-02 :polarity "-" :ARG1 (c / chain :mod (p5 / protein :name (n2 / name :op1 "Ub") :ARG1-of (l / link-01 :ARG2 (a3 / amino-acid :mod "48" :name (n3 / name :op1 "lysine") :xref (x1 / xref :value "PUBCHEM:866" :prob "11.053295"))) :ARG1-of (f2 / free-04))))) :time (a / after :op1 (d3 / degrade-01 :ARG1 (p4 / protein :ARG1-of (t / target-01)))) :ARG1-of (s3 / specific-02) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 "281" :op2 "350" :op3 "375"))))) # ::id bio.chicago_2015.38647 # ::date 2015-10-28T12:46:45 # ::file bio_chicago_2015_38647.txt # ::snt One such mutation, R89L, is located in the RBD and prevents the binding and activation of Raf-1 by Ras ( 17, 28, 29). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (b2 / be-located-at-91 :ARG1 (m / mutate-01 :value "R89L" :mod (o / one) :mod (s / such)) :ARG2 (p / protein-segment :name (n2 / name :op1 "RBD"))) :op2 (p2 / prevent-01 :ARG0 m :ARG1 (a2 / and :op1 (b / bind-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (e / enzyme :name (n3 / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :op2 (a3 / activate-01 :ARG0 e2 :ARG1 e))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 "17" :op2 "28" :op3 "29"))))) # ::id bio.chicago_2015.38657 # ::date 2015-10-28T12:59:00 # ::file bio_chicago_2015_38657.txt # ::snt In three experiments, the binding of Ras to Raf-1 peptide increased upon antigen stimulation and showed similar maximal increases at 1-2 min in both control (2.0 plus-or-minus 0.5-fold, mean plus-or-minus S.E.) and dexamethasone-treated (1.9 plus-or-minus 0.3-fold) cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (a / and :op1 (i / increase-01 :ARG1 (b2 / bind-01 :ARG1 (e3 / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (p / peptide :name (n2 / name :op1 "Raf-1"))) :time (s2 / stimulate-01 :ARG0 (a2 / antigen))) :op2 (s / show-01 :ARG0 b2 :ARG1 (i2 / increase-01 :ARG1-of (r / resemble-01 :ARG2 i) :mod (m / maximal) :time (a4 / after :op1 (t2 / temporal-quantity :quant (v4 / value-interval :op1 "1" :op2 "2") :unit (m2 / minute)))) :location (a3 / and :op1 (c / cell :ARG0-of (c2 / control-01) :ARG1-of (m3 / mean-01 :ARG2 (a5 / and :op1 (v2 / value-interval :op1 (a6 / add-02 :ARG1 (p4 / product-of :op1 "0.5") :ARG2 "2") :op2 (s3 / subtract-01 :ARG1 p4 :ARG2 "2")) :op2 (v3 / value-interval :op1 (a7 / add-02 :ARG1 (e / err-01 :ARG1-of (s5 / standard-02)) :ARG2 (m4 / mean)) :op2 (s6 / subtract-01 :ARG1 e :ARG2 m4))))) :op2 (c3 / cell :ARG1-of (t / treat-04 :ARG2 (s4 / small-molecule :name (n7 / name :op1 "dexamethasone") :xref (x1 / xref :value "PUBCHEM:5743" :prob "14.701785"))) :ARG1-of (m5 / mean-01 :ARG2 (v / value-interval :op1 (a8 / add-02 :ARG1 "1.9" :ARG2 (p2 / product-of :op1 "0.3")) :op2 (s7 / subtract-01 :ARG1 p2 :ARG2 "1.9")))))) :location (e2 / experiment-01 :quant "3")) # ::id bio.chicago_2015.38673 # ::date 2015-10-28T13:29:07 # ::file bio_chicago_2015_38673.txt # ::snt Data in Figure 5A show that Elk-1 phosphorylation was acutely stimulated by EGF with maximum phosphorylation occurring at 5 min. Co-transfection of KSR completely blocked EGF-stimulated Elk-1 phosphorylation (Figure 5B, panel pElk-1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (m3 / multi-sentence :snt1 (s / show-01 :ARG0 (d / data :location (f / figure :mod "5A")) :ARG1 (s2 / stimulate-01 :ARG0 (p4 / protein :name (n2 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "Elk-1") :xref (x / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :mod (m / maximum) :time (a3 / after :op1 (t2 / temporal-quantity :quant "5" :unit (m4 / minute)))) :manner (a2 / acute))) :snt2 (b / block-01 :ARG0 (c2 / cotransfect-01 :ARG2 (e / enzyme :name (n3 / name :op1 "KSR") :xref (x1 / xref :value "UNIPROT:KSR1_HUMAN" :prob "1.003"))) :ARG1 (p / phosphorylate-01 :ARG1 (p5 / protein :name (n4 / name :op1 "Elk-1") :xref (x4 / xref :value "UNIPROT:ELK1_HUMAN" :prob "0.592")) :ARG1-of (s3 / stimulate-01 :ARG0 (p6 / protein :name (n5 / name :op1 "EGF") :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG1-of (c / complete-02)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "5b") :op2 (p7 / panel :name (n6 / name :op1 "pElka-1"))))) # ::id bio.chicago_2015.38676 # ::date 2015-10-28T13:46:29 # ::file bio_chicago_2015_38676.txt # ::snt Binding features of DSL proteins to Notch2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (f / feature :mod (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "DSL")) :ARG2 (p2 / protein :name (n2 / name :op1 "Notch2") :xref (x / xref :value "UNIPROT:NOTC2_HUMAN" :prob "0.693")))) # ::id bio.chicago_2015.38704 # ::date 2015-10-28T13:56:09 # ::file bio_chicago_2015_38704.txt # ::snt To confirm the specific binding of magoh to Y14, we carried out in vitro binding assays using recombinant GST - magoh. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (h / have-purpose-91 :ARG1 (c2 / carry-out-03 :ARG0 (w / we) :ARG1 (a / assay-01 :ARG1 (b2 / bind-01)) :mod (i / in-vitro) :manner (u / use-01 :ARG0 w :ARG1 (p / protein :name (n3 / name :op1 "GST" :op2 "magoh") :ARG3-of (r2 / recombine-01)))) :ARG2 (c / confirm-01 :ARG0 w :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n2 / name :op1 "magoh") :xref (x / xref :value "UNIPROT:MGN_HUMAN" :prob "0.602")) :ARG2 (a2 / amino-acid :mod "14" :name (n / name :op1 "tyrosine") :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG1-of (s / specific-02)))) # ::id bio.chicago_2015.38710 # ::date 2015-10-28T14:04:18 # ::file bio_chicago_2015_38710.txt # ::snt Although PKB can phosphorylate GSK-3 at this site and inhibit its activity, our results also implicate a direct role for ILK in the regulation of GSK-3 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (h / have-concession-91 :ARG1 (i2 / implicate-01 :ARG0 (t2 / thing :ARG2-of (r / result-01 :ARG1 (w / we))) :ARG1 (r2 / role :topic (r3 / regulate-01 :ARG0 "e2" :ARG1 (a4 / activity-06 :ARG0 "e3")) :ARG1-of (d / direct-02) :poss (e2 / enzyme :name (n3 / name :op1 "ILK") :xref (x1 / xref :value "UNIPROT:ILK_HUMAN" :prob "1.004"))) :mod (a3 / also)) :ARG2 (p / possible-01 :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "GSK-3") :xref (x / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.262")) :ARG2 (e / enzyme :name (n / name :op1 "PKB") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003")) :location (s / site :mod (t / this))) :op2 (i / inhibit-01 :ARG0 e :ARG1 (a2 / activity-06 :ARG0 e3))))) # ::id bio.chicago_2015.38763 # ::date 2015-10-28T20:37:39 # ::file bio_chicago_2015_38763.txt # ::snt Phosphorylation of K Protein by JNK and ERK in Vivo-- To confirm phosphorylation of the K protein by JNK or ERK in vivo, we performed orthophosphate labeling of cells that had been transfected with the K protein and the respective upstream kinases for ERK, p38, or JNK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / multi-sentence :snt1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "K")) :ARG2 (a / and :op1 (e / enzyme :name (n3 / name :op1 "JNK") :xref (x4 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :manner (i / in-vivo)) :snt2 (p4 / perform-02 :ARG0 (w / we) :ARG1 (l / label-01 :ARG1 (c / cell :ARG1-of (t / transfect-01 :ARG2 (a2 / and :op1 "p5" :op2 (k / kinase :beneficiary (a3 / and :op1 "e5" :op2 (e3 / enzyme :name (n / name :op1 "p38") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op3 "e4") :direction (u / upstream) :mod (r / respective))))) :ARG2 (s / small-molecule :name (n8 / name :op1 "orthophosphate") :xref (x5 / xref :value "PUBCHEM:1061" :prob "9.399563"))) :purpose (c2 / confirm-01 :ARG0 w :ARG1 (p2 / phosphorylate-01 :ARG1 (p5 / protein :name (n5 / name :op1 "K")) :ARG2 (a4 / and :op1 (e4 / enzyme :name (n6 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op2 (e5 / enzyme :name (n7 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :manner (i2 / in-vivo)))))) # ::id bio.chicago_2015.38801 # ::date 2015-10-28T20:48:23 # ::file bio_chicago_2015_38801.txt # ::snt Insulin and PMA Induce Dissociation of the Grb2-SOS Complex-- Previous studies have observed that agents that activate the Ras/ Raf/ MEK/ ERK pathway can also induce the serine/ threonine phosphorylation of SOS and dissociation of the Grb2-SOS complex ( 29, 35, 36). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (m / multi-sentence :snt1 (i / induce-01 :ARG0 (a2 / and :op1 (i2 / insulin) :op2 (s / small-molecule :name (n3 / name :op1 "PMA") :xref (x6 / xref :value "PUBCHEM:4792" :prob "16.591986"))) :ARG2 (d / dissociate-01 :ARG1 (m2 / macro-molecular-complex :part (p7 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :part (p8 / protein :name (n8 / name :op1 "SOS") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.263"))))) :snt2 (o / observe-01 :ARG0 (s2 / study-01 :mod (p3 / previous)) :ARG1 (p4 / possible-01 :ARG1 (i3 / induce-01 :ARG0 (a3 / agent :ARG0-of (a4 / activate-01 :ARG1 (p6 / pathway :name (n4 / name :op1 "Ras/Raf/MEK/ERK")))) :ARG2 (a6 / and :op1 (p2 / phosphorylate-01 :ARG1 (s3 / slash :op1 (a5 / amino-acid :name (n5 / name :op1 "serine") :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a / amino-acid :name (n2 / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (p5 / protein :name (n6 / name :op1 "SOS") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.263")))) :op2 (d2 / dissociate-01 :ARG1 (m3 / macro-molecular-complex :part (p9 / protein :name (n9 / name :op1 "Grb2") :xref (x3 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :part p5))) :mod (a8 / also))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 (a7 / and :op1 "29" :op2 "35" :op3 "36")))))) # ::id bio.chicago_2015.38881 # ::date 2015-10-28T21:02:09 # ::file bio_chicago_2015_38881.txt # ::snt These data suggest that sens normally represses Ro in the differentiating R8 photoreceptor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (r / repress-01 :ARG0 (p4 / protein :name (n4 / name :op1 "sens")) :ARG1 (p2 / protein :name (n2 / name :op1 "Ro")) :ARG2 (d2 / differentiate-01 :ARG1 (p3 / photoreceptor :part-of (p / protein :name (n3 / name :op1 "R8")))) :ARG1-of (n / normal-02))) # ::id bio.chicago_2015.38884 # ::date 2015-10-28T21:07:02 # ::file bio_chicago_2015_38884.txt # ::snt Rather surprisingly, however, experiments with the deltaGP5 mutant indicate this did not require profilin binding to VASP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (c / contrast-01 :ARG2 (i / indicate-01 :ARG0 (e / experiment-01 :ARG1 (e2 / enzyme :name (n / name :op1 "deltaGP5") :ARG2-of (m2 / mutate-01) :xref (x2 / xref :value "UNIPROT:DLL3_HUMAN" :prob "0.253"))) :ARG1 (r / require-01 :polarity "-" :ARG0 (t / this) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n2 / name :op1 "profilin") :xref (x1 / xref :value "UNIPROT:B4DNH1_HUMAN" :prob "0.701")) :ARG2 (p2 / protein :name (n3 / name :op1 "VASP") :xref (x / xref :value "UNIPROT:VASP_HUMAN" :prob "1.003"))))) :ARG0-of (s / surprise-01 :degree (r2 / rather))) # ::id bio.chicago_2015.38908 # ::date 2015-10-28T21:13:33 # ::file bio_chicago_2015_38908.txt # ::snt One report shows that, in addition to activating Rho, Wnt signaling can also activate Rac but not Cdc42 (Habas et al., 2003 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (r / report :mod (o / one)) :ARG1 (a4 / and :op1 (a5 / activate-01 :ARG0 "p2" :ARG1 (p3 / protein :name (n4 / name :op1 "Rho") :xref (x2 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602"))) :op2 (p / possible-01 :ARG1 (c / contrast-01 :ARG1 (a / activate-01 :ARG0 (p2 / protein :name (n / name :op1 "Wnt") :ARG0-of (s2 / signal-07) :xref (x / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")) :ARG1 (e / enzyme :name (n2 / name :op1 "Rac") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG2 (a3 / activate-01 :polarity "-" :ARG0 p2 :ARG1 (p6 / protein :name (n3 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")))) :mod (a2 / also))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (p4 / person :name (n5 / name :op1 "Habas")) :op2 (p5 / person :mod (o2 / other)) :time (d / date-entity :year "2003")))) # ::id bio.chicago_2015.38917 # ::date 2015-10-28T21:26:04 # ::file bio_chicago_2015_38917.txt # ::snt Shank, a Novel Family of Postsynaptic Density Proteins that Binds to the NMDA Receptor/ PSD-95/GKAP Complex and Cortactin # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (p8 / protein-family :name (n2 / name :op1 "Shank") :mod (n / novel) :consist-of (p / protein :mod (d / density :mod (p2 / postsynaptic)) :ARG1-of (b / bind-01 :ARG2 (a / and :op1 (m / macro-molecular-complex :part (p4 / protein :name (n4 / name :op1 "NMDA" :op2 "Receptor") :xref (x1 / xref :value "UNIPROT:NAA15_HUMAN" :prob "0.252")) :part (p5 / protein :name (n5 / name :op1 "PSD-95") :xref (x2 / xref :value "UNIPROT:DLG4_HUMAN" :prob "1.003")) :part (p6 / protein :name (n6 / name :op1 "GKAP") :xref (x / xref :value "UNIPROT:DLGP1_HUMAN" :prob "1.002"))) :op2 (p3 / protein :name (n3 / name :op1 "cortactin") :xref (x3 / xref :value "UNIPROT:CORT_HUMAN" :prob "0.292")))))) # ::id bio.chicago_2015.38985 # ::date 2015-10-28T21:32:37 # ::file bio_chicago_2015_38985.txt # ::snt (D) Association between CIZ and Cas expressed in COS-7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (e / express-03 :li "D" :ARG2 (a2 / associate-01 :ARG1 (p / protein :name (n2 / name :op1 "CIZ") :xref (x1 / xref :value "UNIPROT:ZN384_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n3 / name :op1 "Cas") :xref (x / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.603"))) :ARG3 (c / cell-line :name (n / name :op1 "COS-7"))) # ::id bio.chicago_2015.39001 # ::date 2015-10-31T00:57:48 # ::file bio_chicago_2015_39001.txt # ::snt ORC and regulation of the metazoan cell cycle In yeast, where ORC remains stably bound to chromatin throughout the cell cycle (see Introduction), conversion of ORCs into pre-RCs is delayed until mitosis is completed, because Cdk1/cyclin B simultaneously promotes mitosis and inhibits binding of Cdc6 to ORC ( Dahmann et al., 1995; Piatti et al., 1996), apparently by phosphorylation of Cdc6 protein ( Jallepalli et al., 1997). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / multi-sentence :snt1 (a / and :op1 (m6 / macro-molecular-complex :name (n / name :op1 "ORC")) :op2 (r / regulate-01 :ARG1 (c / cycle :mod (c2 / cell :mod (m2 / metazoan))))) :snt2 (d4 / delay-01 :ARG1 (c3 / convert-01 :ARG1 (m4 / macro-molecular-complex :name (n2 / name :op1 "ORC")) :ARG2 (m5 / macro-molecular-complex :name (n3 / name :op1 "pre-RCs"))) :ARG2 (u / until :op1 (c4 / complete-01 :ARG1 (m3 / mitosis))) :location (y / yeast :location-of (r2 / remain-01 :ARG1 m4 :ARG3 (b / bind-01 :ARG1 m4 :ARG2 (m7 / macro-molecular-complex :name (n4 / name :op1 "chromatin")) :ARG1-of (s / stable-03)) :duration (c5 / cycle :mod (c6 / cell)) :ARG1-of (d7 / describe-01 :ARG0 (i2 / introduce-01 :ARG1-of (s2 / see-01 :ARG0 (y2 / you)))))) :ARG1-of (c7 / cause-01 :ARG0 (a2 / and :op1 (p2 / promote-01 :ARG0 (m8 / macro-molecular-complex :part (e / enzyme :name (n5 / name :op1 "Cdk1") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.603")) :part (p12 / protein :name (n6 / name :op1 "cyclin" :op2 "B") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322"))) :ARG1 m3) :op2 (i / inhibit-01 :ARG0 m8 :ARG1 (b2 / bind-01 :ARG1 (p4 / protein :name (n7 / name :op1 "Cdc6") :xref (x2 / xref :value "UNIPROT:CDC6_HUMAN" :prob "0.603")) :ARG2 m4)) :manner (p / phosphorylate-01 :ARG1 p4 :ARG1-of (a3 / appear-02) :ARG1-of (d6 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a7 / and :op1 (p11 / person :name (n10 / name :op1 "Jallepalli")) :op2 "p7") :time (d3 / date-entity :year "1997")))) :ARG1-of (d5 / describe-01 :ARG0 (a5 / and :op1 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n8 / name :op1 "Dahmann")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "1995")) :op2 (p8 / publication-91 :ARG0 (a6 / and :op1 (p9 / person :name (n9 / name :op1 "Piatti")) :op2 p7) :time (d2 / date-entity :year "1996")))) :manner (s3 / simultaneous))))) # ::id bio.chicago_2015.39049 # ::date 2015-10-31T01:01:57 # ::file bio_chicago_2015_39049.txt # ::snt The association of alpha-catenin with beta-catenin was also markedly increased in ApcMin/ adenoma cells (Fig. 8 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / increase-01 :ARG1 (a / associate-01 :ARG1 (p / protein :name (n / name :op1 "alpha-catenin") :xref (x1 / xref :value "UNIPROT:CTNA3_HUMAN" :prob "0.392")) :ARG2 (p2 / protein :name (n2 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))) :ARG2 (m / mark-01) :mod (a2 / also) :location (c / cell :mod (g / gene :name (n3 / name :op1 "ApcMin")) :mod (m2 / medical-condition :name (n4 / name :op1 "adenoma"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8B"))) # ::id bio.chicago_2015.39066 # ::date 2015-10-31T01:07:32 # ::file bio_chicago_2015_39066.txt # ::snt The disassembly of a Lys-48 - linked Ub chain by PA700 isopeptidase proceeds by sequentially removing the distal Ub moiety [ 346; Figure 6 b ( right)]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (p / proceed-01 :ARG0 (r / remove-01 :ARG1 (m / moiety :mod (p3 / protein :name (n4 / name :op1 "ubiquitin") :mod (d / distal) :xref (x1 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702"))) :manner (s / sequence)) :ARG1 (a / assemble-01 :polarity "-" :ARG0 (i / isopeptidase :name (n / name :op1 "PA700")) :ARG1 (c / chain :mod (p2 / protein :name (n2 / name :op1 "ubiquitin") :xref (x / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :ARG1-of (l / link-01 :ARG2 (a2 / amino-acid :mod "48" :name (n3 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6b" :ARG1-of (r2 / right-04))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "346")))) # ::id bio.chicago_2015.39083 # ::date 2015-10-31T01:26:13 # ::file bio_chicago_2015_39083.txt # ::snt Amphiphysin 1 can bind simultaneously to dynamin and either clathrin or AP-2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (p4 / possible-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Amphiphysin" :op2 "1") :xref (x3 / xref :value "UNIPROT:AMPH_HUMAN" :prob "0.392")) :ARG2 (a / and :op1 (p5 / protein :name (n2 / name :op1 "dynamin") :xref (x1 / xref :value "UNIPROT:DYN2_HUMAN" :prob "0.343")) :op2 (o / or :op1 (p2 / protein :name (n3 / name :op1 "clathrin") :xref (x / xref :value "UNIPROT:A0A087WVQ6_HUMAN" :prob "0.291")) :op2 (p3 / protein :name (n4 / name :op1 "AP-2") :xref (x2 / xref :value "UNIPROT:AP2A_HUMAN" :prob "1.002")))) :manner (s / simultaneous))) # ::id bio.chicago_2015.39129 # ::date 2015-10-31T06:23:24 # ::file bio_chicago_2015_39129.txt # ::snt MEKK1 Can Phosphorylate the N Terminus of p300 in Vitro-- Given the fact that JNK1 is not involved in the response of p300 to MEKK1, nor are the other potential downstream kinases such as p38 and IkappaBalpha, we considered the possibility that MEKK1delta may be able to directly phosphorylate p300. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (m / multi-sentence :snt1 (p / possible-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "N-Terminus") :part-of (p4 / protein :name (n3 / name :op1 "p300") :xref (x5 / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702"))) :ARG2 (e / enzyme :name (n / name :op1 "MEKK1") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :manner (i / in-vitro))) :snt2 (c / consider-01 :ARG0 (w / we) :ARG1 (p5 / possible-01 :ARG1 (c2 / capable-01 :ARG1 (p6 / phosphorylate-01 :ARG1 p4 :ARG2 (e2 / enzyme :name (n4 / name :op1 "MEKK1delta") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.263")) :ARG1-of (d2 / direct-02)))) :ARG1-of (c3 / cause-01 :ARG0 (i2 / involve-01 :polarity "-" :ARG1 (o / or :op1 (e3 / enzyme :name (n5 / name :op1 "JNK1") :xref (x2 / xref :value "UNIPROT:MK08_HUMAN" :prob "1.003")) :op2 (k / kinase :mod (o2 / other) :direction (d3 / downstream) :mod (p7 / potential) :ARG2-of (i3 / include-91 :ARG1 (a / and :op1 (k2 / kinase :name (n6 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op2 (k3 / kinase :name (n7 / name :op1 "IkappaBalpha") :xref (x / xref :value "UNIPROT:IKBA_HUMAN" :prob "1.003")))))) :ARG2 (r / respond-01 :ARG0 p4 :ARG1 e))))) # ::id bio.chicago_2015.39166 # ::date 2015-10-31T06:40:34 # ::file bio_chicago_2015_39166.txt # ::snt Cdk1/cyclin B simultaneously promotes mitosis and inhibits binding of Cdc6 to ORC by phosphorylating Cdc6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (p / promote-01 :ARG0 (m2 / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "Cdk1") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.603")) :part (p6 / protein :name (n2 / name :op1 "cyclin" :op2 "B") :xref (x2 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322"))) :ARG1 (m / mitosis)) :op2 (i / inhibit-01 :ARG0 m2 :ARG1 (b / bind-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Cdc6") :xref (x / xref :value "UNIPROT:CDC6_HUMAN" :prob "0.603")) :ARG2 (m3 / macro-molecular-complex :name (n4 / name :op1 "ORC")))) :manner (s2 / simultaneous) :manner (p5 / phosphorylate-01 :ARG1 p3 :ARG2 m2)) # ::id bio.chicago_2015.39206 # ::date 2015-10-31T06:52:26 # ::file bio_chicago_2015_39206.txt # ::snt Our genetic analyses suggest that the vein phenotype and wing shape alterations are due to an effect on the balance between TGF and Wnt signaling and the subsequent activation of JNK signaling that ensues. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (s / suggest-01 :ARG0 (a / analyze-01 :ARG0 (w / we) :ARG1 (g / genetics)) :ARG1 (c / cause-01 :ARG0 (a2 / affect-01 :ARG1 (b / balance-01 :ARG1 (s2 / signal-07 :ARG0 (a3 / and :op1 (p / protein :name (n / name :op1 "TGF") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.263")) :op2 (p2 / protein :name (n2 / name :op1 "Wnt") :xref (x / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")))) :ARG2 (a4 / activate-01 :ARG1 (s4 / signal-07 :ARG0 (e / enzyme :name (n3 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :mod (s3 / subsequent) :ARG1-of (e2 / ensue-01)))) :ARG1 (a5 / alter-01 :ARG1 (a6 / and :op1 (p3 / phenotype :mod (v / vein)) :op2 (s5 / shape :mod (w2 / wing)))))) # ::id bio.chicago_2015.39226 # ::date 2015-10-31T07:29:05 # ::file bio_chicago_2015_39226.txt # ::snt IKK recovery was determined by immunoblotting ( IB) with antibody to IKKgamma. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (d / determine-01 :ARG1 (r / recover-02 :ARG1 (e / enzyme :name (n / name :op1 "IKK") :xref (x / xref :value "UNIPROT:IKKA_HUMAN" :prob "0.262"))) :ARG2 (i / immunoblot-01 :ARG1 e :ARG3 (a / antibody :ARG0-of (o / oppose-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "IKKgamma") :xref (x1 / xref :value "UNIPROT:NEMO_HUMAN" :prob "0.692")))))) # ::id bio.chicago_2015.39236 # ::date 2015-10-31T07:35:58 # ::file bio_chicago_2015_39236.txt # ::snt Other studies showed that PI3K is also activated by small GTPase molecules such as Ras and Rac1 (Nishida et al., 1999 ; Rodriguez-Viciana et al., 1994 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (s2 / study-01 :mod (o / other)) :ARG1 (a / activate-01 :ARG0 (m / molecule :mod (p / protein-family :name (n / name :op1 "GTPase")) :mod (s3 / small) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (p2 / protein :name (n5 / name :op1 "Rac1") :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))))) :ARG1 (e / enzyme :name (n3 / name :op1 "PI3K") :xref (x2 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :mod (a3 / also)) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p3 / publication-91 :ARG0 (a5 / and :op1 (p4 / person :name (n6 / name :op1 "Nishida")) :op2 (p6 / person :mod (o2 / other))) :time (d / date-entity :year "1999")) :op2 (p7 / publication-91 :ARG0 (a6 / and :op1 (p8 / person :name (n4 / name :op1 "Rodriguez-Viciana")) :op2 p6) :time (d2 / date-entity :year "1994"))))) # ::id bio.chicago_2015.39239 # ::date 2015-10-31T07:51:51 # ::file bio_chicago_2015_39239.txt # ::snt The PI bound to PI-TPalpha is delivered as a substrate for phospholipase A2 ( PLA2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (d / deliver-01 :ARG1 (b / bind-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "PI") :xref (x2 / xref :value "PUBCHEM:448108" :prob "8.655408")) :ARG2 (p2 / protein :name (n2 / name :op1 "PI-TPalpha") :xref (x / xref :value "UNIPROT:PIPNA_HUMAN" :prob "0.693")) :purpose (s / substrate :beneficiary (e / enzyme :name (n3 / name :op1 "phospholipase" :op2 "A2") :xref (x1 / xref :value "UNIPROT:PA21B_HUMAN" :prob "0.702"))))) # ::id bio.chicago_2015.39287 # ::date 2015-11-01T01:30:58 # ::file bio_chicago_2015_39287.txt # ::snt sepA Is Required for Actin Ring Formation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (r / require-01 :ARG0 (f / form-01 :ARG1 (r2 / ring :mod (p2 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :ARG1 (p / protein :name (n / name :op1 "sepA") :xref (x1 / xref :value "UNIPROT:ESPL1_HUMAN" :prob "0.232"))) # ::id bio.chicago_2015.39301 # ::date 2015-11-01T01:35:15 # ::file bio_chicago_2015_39301.txt # ::snt In this study, we show that Cos2 inhibits Ci activity by tethering it in the cytoplasm via a 125 amino acid domain in the C-terminal region of Ci, whereas Su(fu) inhibits Ci nuclear import through the N-terminal region of Ci. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (c3 / contrast-01 :ARG1 (i3 / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "Cos2")) :ARG1 (a / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "Ci"))) :manner (t / tether-01 :ARG0 p :ARG1 p2 :location (c4 / cytoplasm :xref (x / xref :value "GO:0005737" :prob "0.8")) :manner (d / domain :mod (a2 / amino-acid :mod "125" :location (r / region :mod (p3 / protein-segment :name (n3 / name :op1 "C-terminus") :part-of p2)))))) :ARG2 (i4 / inhibit-01 :ARG0 (p4 / protein :name (n4 / name :op1 "Su(fu)")) :ARG1 (i5 / import-01 :ARG1 (n5 / nucleus :part-of p2 :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :location (r2 / region :mod (p5 / protein-segment :name (n6 / name :op1 "N-terminus") :part-of p2))))) :location (s2 / study-01 :mod (t2 / this))) # ::id bio.chicago_2015.39321 # ::date 2015-11-01T01:51:59 # ::file bio_chicago_2015_39321.txt # ::snt Therefore we analyzed the role of p38MAPK in TNF-induced inhibition of conventional kinesin and KLC hyperphosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (c / cause-01 :ARG1 (a / analyze-01 :ARG0 (w / we) :ARG1 (r / role :poss (e / enzyme :name (n / name :op1 "p38MAPK") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203")) :topic (i / inhibit-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "kinesin") :mod (c2 / conventional) :xref (x / xref :value "UNIPROT:KIF2A_HUMAN" :prob "0.332")) :op2 (h / hyperphosphorylate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "KLC") :xref (x2 / xref :value "UNIPROT:KLC1_HUMAN" :prob "1.002")))) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "TNF") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))))))) # ::id bio.chicago_2015.39324 # ::date 2015-11-01T01:59:48 # ::file bio_chicago_2015_39324.txt # ::snt The semiquantification in Fig. 2C and F shows that the ME significantly decreased the CRE-DNA binding activity of CREB to 77 and 63% of the control in the ipsilateral cerebral cortex on the third and seventh days, respectively, after the operation ( Fig. 2C), and to 74 and 59%, respectively, in the ipsilateral hippocampus ( Fig. 2F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (s / show-01 :ARG0 (q / quantify-01 :degree (s2 / semi) :location (a / and :op1 (f / figure :mod "2C") :op2 (f2 / figure :mod "F"))) :ARG1 (a3 / and :op1 (d / decrease-01 :ARG0 (m / medical-condition :name (n / name :op1 "microsphere" :op2 "embolism")) :ARG1 (a2 / activity-06 :ARG0 (p3 / protein :name (n2 / name :op1 "CREB") :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :ARG1 (b / bind-01 :ARG1 p3 :ARG2 (e / enzyme :name (n3 / name :op1 "CRE-DNA") :xref (x1 / xref :value "UNIPROT:CREB5_HUMAN" :prob "0.232")))) :ARG2 (s3 / significant-02) :ARG4 (a4 / and :op1 (p4 / percentage-entity :value "77") :op2 (p / percentage-entity :value "63") :quant-of (c / control-01 :ARG1 (c2 / cortex :mod (c3 / cerebral) :mod (i / ipsilateral)))) :time (a5 / and :op1 (d2 / day :ord (o2 / ordinal-entity :value "3")) :op2 (d3 / day :ord (o3 / ordinal-entity :value "7")) :manner (r / respective)) :time (a6 / after :op1 (o4 / operate-02)) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "2C"))) :op2 (d5 / decrease-01 :ARG0 m :ARG1 a2 :ARG2 s3 :ARG4 (a7 / and :op1 (p5 / percentage-entity :value "74") :op2 (p2 / percentage-entity :value "59") :manner r) :location (h / hippocampus :mod (i2 / ipsilateral)) :ARG1-of (d6 / describe-01 :ARG0 (f4 / figure :mod "2F"))))) # ::id bio.chicago_2015.39367 # ::date 2015-11-01T01:29:58 # ::file bio_chicago_2015_39367.txt # ::snt (d) NAK is activated by recombinant Nef and CDC42 in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (a / activate-01 :li "d" :ARG0 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Nef") :xref (x / xref :value "UNIPROT:NFL_HUMAN" :prob "0.203")) :op2 (p3 / protein :name (n3 / name :op1 "CDC42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "1.004")) :ARG3-of (r / recombine-01)) :ARG1 (p / protein :name (n / name :op1 "NAK") :xref (x2 / xref :value "UNIPROT:TBK1_HUMAN" :prob "1.002")) :manner (i / in-vitro)) # ::id bio.chicago_2015.39416 # ::date 2015-11-01T01:35:07 # ::file bio_chicago_2015_39416.txt # ::snt Furthermore, it has been shown that GSK-3beta phosphorylates APC and that the phosphorylation enhances the binding of APC to beta-catenin (Rubinfeld et al., 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (a / and :op2 (s / show-01 :ARG1 (a2 / and :op1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "APC") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")) :ARG2 (e / enzyme :name (n2 / name :op1 "GSK-3beta") :xref (x / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692"))) :op2 (e2 / enhance-01 :ARG0 p3 :ARG1 (b / bind-01 :ARG1 p4 :ARG2 (p5 / protein :name (n3 / name :op1 "beta-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n4 / name :op1 "Rubinfeld")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "1996"))))) # ::id bio.chicago_2015.39423 # ::date 2015-11-01T01:41:18 # ::file bio_chicago_2015_39423.txt # ::snt All the results indicate that the activation of MAPK through Ras inhibits Fas-mediated apoptosis in Balb3T3 cells, which may play a role in oncogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (a / all)) :ARG1 (i2 / inhibit-01 :ARG0 (a2 / activate-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (p / pathway :name (n / name :op1 "MAPK"))) :ARG1 (a3 / apoptosis :location (c / cell :name (n3 / name :op1 "Balb3T3")) :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "Fas") :xref (x / xref :value "UNIPROT:FAS_HUMAN" :prob "0.603")))) :ARG0-of (p4 / play-08 :ARG1 (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :ARG1-of (p5 / possible-01)))) # ::id bio.chicago_2015.39438 # ::date 2015-11-01T01:49:03 # ::file bio_chicago_2015_39438.txt # ::snt Mapping the region of HBO1 that interacts with MCM2 and ORC1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (m / map-01 :ARG1 (r / region :poss (e / enzyme :name (n / name :op1 "HBO1") :xref (x1 / xref :value "UNIPROT:KAT7_HUMAN" :prob "1.002")) :ARG0-of (i / interact-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "MCM2") :xref (x2 / xref :value "UNIPROT:MCM2_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n3 / name :op1 "ORC1") :xref (x / xref :value "UNIPROT:ORC1_HUMAN" :prob "1.003")))))) # ::id bio.chicago_2015.39496 # ::date 2015-11-01T01:52:30 # ::file bio_chicago_2015_39496.txt # ::snt To illustrate, elevated levels of cAMP that induce the activation of PKA can determine which Raf isoform will be engaged in a cell to stimulate MEKs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p2 / possible-01 :ARG1 (d / determine-01 :ARG0 (l / level :ARG1-of (e / elevate-01) :quant-of (s2 / small-molecule :name (n2 / name :op1 "cAMP") :ARG0-of (i / induce-01 :ARG2 (a / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")))) :xref (x2 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :ARG1 (e3 / engage-01 :ARG1 (a2 / amr-unknown :ARG1-of (i2 / include-91 :ARG2 (i3 / isoform :mod (e4 / enzyme :name (n / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))) :ARG2 (c / cell) :purpose (s / stimulate-01 :ARG0 a2 :ARG1 (p4 / protein-family :name (n4 / name :op1 "MEK")))) :purpose (i4 / illustrate-01))) # ::id bio.chicago_2015.39508 # ::date 2015-11-01T02:00:19 # ::file bio_chicago_2015_39508.txt # ::snt Phosphorylation of SR Proteins by SRPK1 and Clk/ty # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (p / phosphorylate-01 :ARG1 (p2 / protein-family :name (n / name :op1 "SR")) :ARG2 (a / and :op1 (e / enzyme :name (n2 / name :op1 "SRPK1") :xref (x / xref :value "UNIPROT:SRPK1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "Clk/ty")))) # ::id bio.chicago_2015.39510 # ::date 2015-11-01T02:02:43 # ::file bio_chicago_2015_39510.txt # ::snt Fzr can not activate the APC/C in these cells because cdk1 - cyclin B1 phosphorylates fzr and prevents its binding to the APC/C ( Zachariae et al., 1998; Lukas et al., 1999; Listovsky et al., 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c / cause-01 :ARG0 (a2 / and :op1 (p4 / phosphorylate-01 :ARG1 "p2" :ARG2 (m / macro-molecular-complex :part (e / enzyme :name (n3 / name :op1 "cdk1") :xref (x2 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.603")) :part (p14 / protein :name (n7 / name :op1 "cyclin" :op2 "B1") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.361")))) :op2 (p5 / prevent-01 :ARG0 m :ARG1 (b / bind-01 :ARG1 "p2" :ARG2 "p3"))) :ARG1 (p / possible-01 :polarity "-" :ARG1 (a / activate-01 :ARG0 (p2 / protein :name (n / name :op1 "Fzr") :xref (x / xref :value "UNIPROT:FZR_HUMAN" :prob "1.003")) :ARG1 (p3 / protein :name (n2 / name :op1 "APC/C")) :location (c2 / cell :mod (t / this)))) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and :op1 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n4 / name :op1 "Zachariae")) :op2 (p9 / person :mod (o / other))) :time (d / date-entity :year "1998")) :op2 (p10 / publication-91 :ARG0 (a5 / and :op1 (p11 / person :name (n5 / name :op1 "Lukas")) :op2 p9) :time (d2 / date-entity :year "1999")) :op3 (p12 / publication-91 :ARG0 (a6 / and :op1 (p13 / person :name (n6 / name :op1 "Listovsky")) :op2 p9) :time (d3 / date-entity :year "2000"))))) # ::id bio.chicago_2015.39521 # ::date 2015-11-01T02:11:05 # ::file bio_chicago_2015_39521.txt # ::snt SRF Activation by LIMK-1 Is Largely Dependent on RhoA # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (d / depend-01 :ARG0 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "LIMK-1") :xref (x1 / xref :value "UNIPROT:LIMK1_HUMAN" :prob "1.002")) :ARG1 (p / protein :name (n2 / name :op1 "SRF") :xref (x2 / xref :value "UNIPROT:SRF_HUMAN" :prob "1.003"))) :ARG1 (p2 / protein :name (n3 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :degree (l / large)) # ::id bio.chicago_2015.39527 # ::date 2015-11-01T02:21:05 # ::file bio_chicago_2015_39527.txt # ::snt APC appears to be critical for the rapid turnover of beta-catenin (Munemitsu et al., 1995 ), and phosphorylation of APC by GSK-3 appears to enhance the interaction of APC and beta-catenin (Rubinfeld et al., 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (a2 / and :op1 (a3 / appear-02 :ARG1 (c2 / critical-02 :ARG1 (p3 / protein :name (n / name :op1 "APC") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")) :ARG2 (t / turn-over-12 :ARG1 (p4 / protein :name (n2 / name :op1 "beta-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :mod (r / rapid))) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a4 / and :op1 (p5 / person :name (n3 / name :op1 "Munemitsu")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "1995")))) :op2 (a5 / appear-02 :ARG1 (e / enhance-01 :ARG0 (p8 / phosphorylate-01 :ARG1 p3 :ARG2 (e2 / enzyme :name (n4 / name :op1 "GSK-3") :xref (x / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.262"))) :ARG1 (i / interact-01 :ARG0 p3 :ARG1 p4)) :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a6 / and :op1 (p11 / person :name (n6 / name :op1 "Rubinfeld")) :op2 p6) :time (d2 / date-entity :year "1996"))))) # ::id bio.chicago_2015.39535 # ::date 2015-11-01T02:31:14 # ::file bio_chicago_2015_39535.txt # ::snt It is interesting to note that the results we obtained by assaying BDNF-induced c- fos expression in transient gene reporter assays were qualitatively similar to those we obtained by assaying BDNF-induced expression of endogenous Fos (compare Figure 1 and Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / interest-01 :ARG0 (n / note-01 :ARG1 (r2 / resemble-01 :ARG1 (t / thing :ARG2-of (r3 / result-01) :ARG1-of (o / obtain-01 :ARG0 (w / we) :ARG2 (a / assay-01 :ARG0 w :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "c-fos")) :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n3 / name :op1 "BDNF") :xref (x / xref :value "UNIPROT:BDNF_HUMAN" :prob "1.004"))) :location (a2 / assay-01 :ARG1 (g2 / gene :ARG1-of (t2 / transient-02) :ARG0-of (r / report-01))))))) :ARG2 (t3 / thing :ARG2-of (r5 / result-01 :ARG1-of (o2 / obtain-01 :ARG0 w :ARG2 (a3 / assay-01 :ARG0 w :ARG1 (e2 / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "Fos") :mod (e3 / endogenous) :xref (x1 / xref :value "UNIPROT:FOS_HUMAN" :prob "0.603")) :ARG2-of i2))))) :mod (q / qualitative))) :ARG1-of (d / describe-01 :ARG0 (c / compare-01 :ARG1 (f / figure :mod "1") :ARG2 (f2 / figure :mod "2")))) # ::id bio.chicago_2015.39542 # ::date 2015-11-01T02:45:22 # ::file bio_chicago_2015_39542.txt # ::snt amphiphysin binds to clathrin, AP2, synaptojanin, and dynamin, while epsin binds to AP2 and clathrin (reviewed by [34, 38] ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / contrast-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "amphiphysin") :xref (x5 / xref :value "UNIPROT:AMPH_HUMAN" :prob "0.702")) :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "clathrin") :xref (x / xref :value "UNIPROT:A0A087WVQ6_HUMAN" :prob "0.291")) :op2 (p3 / protein :name (n3 / name :op1 "AP2") :xref (x1 / xref :value "UNIPROT:AP2A_HUMAN" :prob "0.652")) :op3 (p4 / protein :name (n4 / name :op1 "synaptojanin") :xref (x2 / xref :value "UNIPROT:SYNJ1_HUMAN" :prob "0.382")) :op4 (p8 / protein :name (n5 / name :op1 "dynamin") :xref (x4 / xref :value "UNIPROT:DYN2_HUMAN" :prob "0.343")))) :ARG2 (b2 / bind-01 :ARG1 (p5 / protein :name (n6 / name :op1 "epsin") :xref (x3 / xref :value "UNIPROT:EPN4_HUMAN" :prob "0.302")) :ARG2 (a2 / and :op1 p3 :op2 p2)) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "34" :op2 "38")) :ARG0-of (r / review-01)))) # ::id bio.chicago_2015.39546 # ::date 2015-11-01T02:51:34 # ::file bio_chicago_2015_39546.txt # ::snt Indeed, FynKD is able to inhibit Cbl phosphorylation by Abl (unpublished result). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (c / capable-01 :ARG1 "p" :ARG2 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "FynKD")) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Cbl") :xref (x / xref :value "UNIPROT:CBL_HUMAN" :prob "0.604")) :ARG2 (p4 / protein :name (n3 / name :op1 "Abl") :xref (x1 / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603")))) :mod (i2 / indeed) :ARG1-of (d / describe-01 :ARG0 (t / thing :ARG2-of (r / result-01) :ARG1-of (p5 / publish-01 :polarity "-")))) # ::id bio.chicago_2015.39559 # ::date 2015-11-01T02:56:18 # ::file bio_chicago_2015_39559.txt # ::snt Because binding of p53 by mdm2 is required for mdm2-mediated p53 degradation ( 15, 16), these results suggest that TAFII31 either out-competes mdm2 for binding to p53 or excludes mdm2 from the p53 complex, thus preventing mdm2-mediated p53 degradation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (o / or :op1 (o2 / outcompete-00 :ARG0 (p / protein :name (n / name :op1 "TAFII31") :xref (x2 / xref :value "UNIPROT:TAF9_HUMAN" :prob "1.002")) :ARG1 (p2 / protein :name (n2 / name :op1 "mdm2") :xref (x / xref :value "UNIPROT:A7UKX7_HUMAN" :prob "1.001")) :ARG3 (b / bind-01 :ARG1 p :ARG2 (p3 / protein :name (n3 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :op1 (e / exclude-01 :ARG0 p :ARG1 p2 :ARG2 (c / complex :mod p3) :ARG0-of (p4 / prevent-01 :ARG1 (d / degrade-01 :ARG1 p3 :ARG1-of (m / mediate-01 :ARG0 p2))))) :ARG1-of (c2 / cause-01 :ARG0 (r2 / require-01 :ARG0 d :ARG1 b) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (a / and :op1 "15" :op2 "16")))))) # ::id bio.chicago_2015.39560 # ::date 2015-11-01T06:30:52 # ::file bio_chicago_2015_39560.txt # ::snt Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / initiate-01 :ARG0 (f / form-01 :ARG1 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "Apaf-1") :xref (x2 / xref :value "UNIPROT:APAF_HUMAN" :prob "0.622")) :part (e / enzyme :name (n2 / name :op1 "caspase-9") :xref (x1 / xref :value "UNIPROT:CASP9_HUMAN" :prob "0.702"))) :ARG0-of (d / depend-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "Cytochrome" :op2 "c") :xref (x / xref :value "UNIPROT:CYC_HUMAN" :prob "1.002")) :op2 (s / small-molecule :name (n4 / name :op1 "dATP") :xref (x3 / xref :value "PUBCHEM:15993" :prob "16.321695"))))) :ARG1 (c / cascade :mod (p2 / protease) :mod (a / apoptotic))) # ::id bio.chicago_2015.39589 # ::date 2015-11-01T06:39:30 # ::file bio_chicago_2015_39589.txt # ::snt kuz Is Required for the Proteolytic Processing of Notch # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (r / require-01 :ARG0 (p2 / process-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Notch") :xref (x / xref :value "UNIPROT:NOTC1_HUMAN" :prob "0.323")) :mod (p4 / proteolysis)) :ARG1 (p / protein :name (n / name :op1 "kuz") :xref (x1 / xref :value "UNIPROT:ADA10_HUMAN" :prob "0.603"))) # ::id bio.chicago_2015.39645 # ::date 2015-11-01T09:33:50 # ::file bio_chicago_2015_39645.txt # ::snt Because CI is caused by the presence of Wolbachia in male reproductive cells, this 10-fold difference alone would seem sufficient to explain the very low CI phenotype exhibited by Wien 5 males in contrast with the high CI exhibited by transinfected ME males. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (c3 / cause-01 :ARG0 (c4 / cause-01 :ARG0 (p / present-02 :ARG1 (o / organism :name (n2 / name :op1 "Wolbachia")) :ARG2 (c5 / cell :ARG0-of (c6 / cause-01 :ARG1 (r / reproduce-01)) :mod (m2 / male))) :ARG1 "c") :ARG1 (s / seem-01 :ARG1 (s2 / suffice-01 :ARG0 (d / differ-02 :mod (a / alone) :mod (p2 / product-of :op1 "10")) :ARG1 (e / explain-01 :ARG0 d :ARG1 (l / low-04 :ARG1 (p3 / phenotype :ARG1-of (e2 / exhibit-01 :ARG0 (m3 / male :mod (o3 / organism :name (n4 / name :op1 "Wien" :op2 "5")))) :mod (c / compatible :polarity "-" :mod (c2 / cytoplasm :xref (x / xref :value "GO:0005737" :prob "0.8")))) :degree (v / very) :ARG1-of (c7 / contrast-01 :ARG2 (h / high-02 :ARG1 (c8 / compatible :polarity "-" :ARG1-of (e3 / exhibit-01 :ARG0 (m4 / male :mod (o2 / organism :name (n6 / name :op1 "ME"))) :ARG1-of (t2 / transinfect-00)) :mod c2)))))))) # ::id bio.chicago_2015.39663 # ::date 2015-11-01T10:06:57 # ::file bio_chicago_2015_39663.txt # ::snt These results suggest that, although it strongly stimulates caspase activation, the cell death induced by the down-regulation of DIAP1 can be executed through a caspase-independent pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p / possible-01 :ARG1 (e / execute-02 :ARG1 (d / die-01 :ARG1 (c / cell) :ARG2-of (i / induce-01 :ARG0 (d2 / downregulate-01 :ARG1 (p2 / protein :name (n / name :op1 "DIAP1") :xref (x / xref :value "UNIPROT:DIAP1_HUMAN" :prob "1.004"))))) :ARG3 (p3 / pathway :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 (p4 / protein :name (n2 / name :op1 "caspase") :xref (x1 / xref :value "UNIPROT:A0A024R3C0_HUMAN" :prob "0.701")))) :concession (s2 / stimulate-01 :ARG0 d :ARG1 (a / activate-01 :ARG1 p4) :ARG1-of (s3 / strong-02))))) # ::id bio.chicago_2015.39706 # ::date 2015-11-01T10:18:44 # ::file bio_chicago_2015_39706.txt # ::snt TSH rapidly activated Rap1, an effect that was reproduced by cAMP elevating agents, but PKA independent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "TSH") :xref (x2 / xref :value "PUBCHEM:15303" :prob "10.703792")) :ARG1 (e3 / enzyme :name (n2 / name :op1 "Rap1") :xref (x / xref :value "UNIPROT:RABX5_HUMAN" :prob "0.603")) :manner (r / rapid) :ARG2-of (a2 / affect-01 :ARG1-of (r2 / reproduce-01 :ARG0 (a3 / agent :ARG0-of (e / elevate-01) :mod (s / small-molecule :name (n3 / name :op1 "cAMP") :xref (x3 / xref :value "PUBCHEM:6076" :prob "15.374314"))) :ARG1-of (c / contrast-01 :ARG2 (d / depend-01 :polarity "-" :ARG0 a2 :ARG1 (e2 / enzyme :name (n4 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))))))) # ::id bio.chicago_2015.39736 # ::date 2015-11-01T10:29:47 # ::file bio_chicago_2015_39736.txt # ::snt Phosphorylation of Cdc25 by Cds1 and/or Chk1 inhibits its activity and thereby prevents dephosphorylation and activation of Cdc2-Cyclin B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG0 (p / phosphorylate-01 :ARG1 (e4 / enzyme :name (n / name :op1 "Cdc25") :xref (x2 / xref :value "UNIPROT:RGRF1_HUMAN" :prob "0.633")) :ARG2 (a / and-or :op1 (e / enzyme :name (n2 / name :op1 "Cds1") :xref (x / xref :value "UNIPROT:CDS1_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n3 / name :op1 "Chk1") :xref (x4 / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604")))) :ARG1 (a2 / activity-06 :ARG0 e4) :ARG0-of (c / cause-01 :ARG1 (p3 / prevent-01 :ARG0 p :ARG1 (a3 / and :op1 (d / dephosphorylate-01 :ARG1 (m / macro-molecular-complex :part (e3 / enzyme :name (n4 / name :op1 "Cdc2") :xref (x3 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :part (p5 / protein :name (n5 / name :op1 "Cyclin" :op2 "B") :xref (x1 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.352")))) :op2 (a4 / activate-01 :ARG1 m))))) # ::id bio.chicago_2015.39738 # ::date 2015-11-01T10:44:19 # ::file bio_chicago_2015_39738.txt # ::snt GBP might sterically block access of protein substrates to the active site of GSK-3, and we are currently attempting to map the residues of Xgsk-3 that are important for GBP binding to Xgsk-3 to determine if GBP might bind in the region of Xgsk-3's active site. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a3 / and :op1 (p / possible-01 :ARG1 (b / block-01 :ARG0 (p4 / protein :name (n2 / name :op1 "GBP") :xref (x1 / xref :value "UNIPROT:PIAS1_HUMAN" :prob "1.002")) :ARG1 (a / access-01 :ARG0 (s / substrate :mod (p2 / protein)) :ARG1 (s2 / site :part-of (e / enzyme :name (n / name :op1 "GSK-3") :xref (x / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.262")) :ARG1-of (a2 / activity-06))) :manner (s3 / steric))) :op2 (a4 / attempt-01 :ARG0 (w / we) :ARG1 (m / map-02 :ARG0 w :ARG1 (r / residue :poss (p5 / protein :name (n3 / name :op1 "Xgsk-3")) :mod (i / important :topic (b2 / bind-01 :ARG1 p4 :ARG2 p5) :purpose (d / determine-01 :ARG0 w :ARG1 (p6 / possible-01 :mode "interrogative" :ARG1 (b3 / bind-01 :ARG1 p4 :ARG2 (r2 / region :poss (s4 / site :ARG1-of a2 :mod p5)))))))) :time (c / current))) # ::id bio.chicago_2015.39759 # ::date 2015-11-01T11:09:51 # ::file bio_chicago_2015_39759.txt # ::snt The defect appears to be caused by the lack of filamin, as reintroduction of filamin restores NF-kappaB activation by TNF and constitutively active TLR4 or TRAF6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (a / appear-02 :ARG1 (c / cause-01 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "filamin") :xref (x4 / xref :value "UNIPROT:FLNA_HUMAN" :prob "0.343"))) :ARG1 (d / defect)) :ARG1-of (c2 / cause-01 :ARG0 (r / restore-01 :ARG0 (r2 / reintroduce-02 :ARG1 p) :ARG1 (a2 / activate-01 :ARG0 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "TNF") :xref (x2 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (o / or :op1 (p4 / protein :name (n4 / name :op1 "TLR4") :xref (x / xref :value "UNIPROT:TLR4_HUMAN" :prob "1.004")) :op2 (p5 / protein :name (n5 / name :op1 "TRAF6") :xref (x3 / xref :value "UNIPROT:TRAF6_HUMAN" :prob "1.003")) :ARG0-of (a4 / activity-06 :mod (c3 / constitutive)))) :ARG1 (p2 / protein :name (n2 / name :op1 "NF-kappaB") :xref (x1 / xref :value "UNIPROT:IKBB_HUMAN" :prob "0.382")))))) # ::id bio.chicago_2015.39792 # ::date 2015-11-01T11:31:27 # ::file bio_chicago_2015_39792.txt # ::snt Residues 170 to 200 of YY1 are acetylated by p300 and PCAF, while the C-terminal zinc finger domain is acetylated only by PCAF (Fig. 9A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (c / contrast-01 :ARG1 (a / acetylate-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "p300") :xref (x / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")) :op2 (p3 / protein :name (n3 / name :op1 "PCAF") :xref (x1 / xref :value "UNIPROT:KAT2B_HUMAN" :prob "1.002"))) :ARG1 (r / residue :part-of (p / protein :name (n / name :op1 "YY1") :xref (x2 / xref :value "UNIPROT:TYY1_HUMAN" :prob "1.002")) :mod (v / value-interval :op1 "170" :op2 "200"))) :ARG2 (a3 / acetylate-01 :ARG0 p3 :ARG1 (p4 / protein-segment :name (n4 / name :op1 "C-terminal" :op2 "zinc" :op3 "finger" :op4 "domain")) :mod (o / only)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "9A"))) # ::id bio.chicago_2015.39808 # ::date 2015-11-01T11:45:25 # ::file bio_chicago_2015_39808.txt # ::snt Indeed, mutant analysis indicates that msh is repressed ventrally by DER (D'Alessio and Frasch 1996 ; Skeath 1998 ), by ind (Weiss et al. 1998 ), and by vnd (this work); ind is repressed by vnd (McDonald et al. 1998 ), and vnd and rho are repressed by snail (Ip et al. 1992 ; Mellerick and Nirenberg 1995 ), a mesoderm master gene that is expressed in the ventral-most region of the blastoderm. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a12 / and :op1 (i4 / indicate-01 :ARG0 (a / analyze-01 :ARG1 (m / mutate-01)) :ARG1 (a2 / and :op1 (r / repress-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "DER") :xref (x1 / xref :value "UNIPROT:DERL1_HUMAN" :prob "0.262")) :ARG1 (g2 / gene :name (n / name :op1 "msh") :xref (x2 / xref :value "UNIPROT:MSH2_HUMAN" :prob "0.202")) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n3 / name :op1 "D'Alessio")) :op2 (p7 / person :name (n4 / name :op1 "Frasch"))) :time (d / date-entity :year "1996")) :op2 (p8 / publication-91 :ARG0 (p9 / person :name (n5 / name :op1 "Skeath")) :time (d2 / date-entity :year "1998")))) :manner (v2 / ventral)) :op2 (r2 / repress-01 :ARG0 (p10 / protein :name (n6 / name :op1 "ind") :xref (x3 / xref :value "UNIPROT:I23O1_HUMAN" :prob "0.202")) :ARG1 g2 :ARG1-of (d4 / describe-01 :ARG0 (p11 / publication-91 :ARG0 (a5 / and :op1 (p12 / person :name (n7 / name :op1 "Weiss")) :op2 (p13 / person :mod (o2 / other))) :time d2))) :op3 (r3 / repress-01 :ARG0 (p14 / protein :name (n8 / name :op1 "vdn")) :ARG1 g2 :ARG1-of (d7 / describe-01 :ARG0 (w / work :mod (t / this))))) :mod (i / indeed)) :op2 (a6 / and :op1 (r4 / repress-01 :ARG0 p14 :ARG1 p10 :ARG1-of (d8 / describe-01 :ARG0 (p15 / publication-91 :ARG0 (a7 / and :op1 (p16 / person :name (n9 / name :op1 "McDonald")) :op2 p13) :time d2))) :op2 (r5 / repress-01 :ARG0 (g / gene :name (n10 / name :op1 "snail") :ARG1-of (e / express-03 :ARG3 (r6 / region :mod (v / ventral :degree (m5 / most)) :poss (b / blastoderm))) :mod (m3 / mesoderm) :mod (m4 / master) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1 (a8 / and :op1 p14 :op2 (p18 / protein :name (n11 / name :op1 "rho") :xref (x4 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602"))) :ARG1-of (d9 / describe-01 :ARG0 (a9 / and :op1 (p19 / publication-91 :ARG0 (a10 / and :op1 (p20 / person :name (n12 / name :op1 "Ip")) :op2 p13) :time (d5 / date-entity :year "1992")) :op2 (p21 / publication-91 :ARG0 (a11 / and :op1 (p22 / person :name (n13 / name :op1 "Mellerick")) :op2 (p23 / person :name (n14 / name :op1 "Nirenberg"))) :time (d6 / date-entity :year "1995"))))))) # ::id bio.chicago_2015.39809 # ::date 2015-11-01T12:21:53 # ::file bio_chicago_2015_39809.txt # ::snt the Ras-binding domain (RBD) of Raf-1, which specifically binds the active, GTP-bound form of Ras, and the Rap1-binding domain of Ral-GDS, which binds the GTP-bound form of Rap1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (p5 / protein-segment :name (n6 / name :op1 "RBD") :part-of (e / enzyme :name (n2 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG0-of (b2 / bind-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "Ras") :ARG0-of (a2 / activity-06) :ARG2-of (b3 / bind-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (s2 / specific-02))) :op2 (d2 / domain :part-of (p3 / protein :name (n4 / name :op1 "Ral-GDS") :xref (x / xref :value "UNIPROT:GNDS_HUMAN" :prob "0.693")) :ARG0-of (b5 / bind-01 :ARG1 (p4 / protein :name (n5 / name :op1 "Rap1") :ARG1-of b3 :xref (x2 / xref :value "UNIPROT:RABX5_HUMAN" :prob "0.603"))))) # ::id bio.chicago_2015.39838 # ::date 2015-11-01T12:42:17 # ::file bio_chicago_2015_39838.txt # ::snt Amphiphysin, a cytosolic protein that can simultaneously bind the AP2 alpha ear and dynamin through different domains ( 39), has been implicated in dynamin recruitment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (i / implicate-01 :ARG1 (p / protein :name (n / name :op1 "amphiphysin") :mod (c / cytosolic) :ARG0-of (b / bind-01 :ARG1 (a / and :op1 (p6 / protein-segment :name (n2 / name :op1 "ear") :part-of (p3 / protein :name (n3 / name :op1 "AP2" :op2 "alpha") :xref (x / xref :value "UNIPROT:AP2A_HUMAN" :prob "0.692"))) :op2 (p4 / protein :name (n4 / name :op1 "dynamin") :xref (x1 / xref :value "UNIPROT:DYN2_HUMAN" :prob "0.343"))) :ARG1-of (p2 / possible-01) :manner (s / simultaneous) :manner (d / domain :ARG1-of (d2 / differ-02)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "39")))) :xref (x2 / xref :value "UNIPROT:AMPH_HUMAN" :prob "0.702")) :ARG2 (r / recruit-01 :ARG1 p4)) # ::id bio.chicago_2015.39840 # ::date 2015-11-01T12:53:22 # ::file bio_chicago_2015_39840.txt # ::snt Cos2 inhibits Ci activity independent of Ci processing # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "Cos2")) :ARG1 (a / activity-06 :ARG1 (p2 / protein :name (n2 / name :op1 "Ci"))) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (p3 / process-01 :ARG1 p2))) # ::id bio.chicago_2015.39843 # ::date 2015-11-01T12:57:05 # ::file bio_chicago_2015_39843.txt # ::snt Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (c / control-01 :ARG0 (d / degrade-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Pds1p") :ARG0-of (i / inhibit-01 :ARG1 (a / anaphase))) :ARG0-of (d2 / depend-01 :ARG1 (p / protein :name (n / name :op1 "APC") :xref (x / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")))) :ARG1 (i2 / initiate-01 :ARG1 a :location (o / organism :name (n3 / name :op1 "Saccharomyces" :op2 "cerevisiae")))) # ::id bio.chicago_2015.39899 # ::date 2015-11-01T13:12:05 # ::file bio_chicago_2015_39899.txt # ::snt A reverse-function mutant of Nkx3.2 can block the induction of Sox9 and cartilage gene expression by Shh/ BMP signals # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (p / possible-01 :ARG1 (b / block-01 :ARG0 (m2 / mutate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "Nkx3.2") :xref (x3 / xref :value "UNIPROT:NKX32_HUMAN" :prob "0.592")) :ARG0-of (r / reverse-01 :ARG1 (f / function-01))) :ARG1 (i / induce-01 :ARG0 (s / signal-07 :ARG0 (m / macro-molecular-complex :part (p2 / protein :name (n2 / name :op1 "Shh") :xref (x / xref :value "UNIPROT:SHH_HUMAN" :prob "0.603")) :part (p3 / protein :name (n3 / name :op1 "BMP") :xref (x1 / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263")))) :ARG2 (e / express-03 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "Sox9") :xref (x2 / xref :value "UNIPROT:SOX9_HUMAN" :prob "0.603")) :op2 (g2 / gene :mod (c / cartilage))))))) # ::id bio.chicago_2015.39944 # ::date 2015-11-01T13:27:04 # ::file bio_chicago_2015_39944.txt # ::snt Thus, activation of TAK1 induces phosphorylation of TCF-4 through NLK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / cause-01 :ARG1 (i / induce-01 :ARG0 (a / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "TAK1") :xref (x / xref :value "UNIPROT:M3K7_HUMAN" :prob "1.002"))) :ARG2 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "TCF-4") :xref (x1 / xref :value "UNIPROT:ITF2_HUMAN" :prob "1.002")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "NLK") :xref (x2 / xref :value "UNIPROT:NLK_HUMAN" :prob "1.003"))))) # ::id bio.chicago_2015.39948 # ::date 2015-11-01T13:31:43 # ::file bio_chicago_2015_39948.txt # ::snt Indeed, phosphorylation of APC by GSK-3beta stimulates its ability to bind beta-catenin and overexpression of APC following transfection substantially reduces beta-catenin levels (Munemitsu et al. 1995 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (a2 / and :op1 (s / stimulate-01 :ARG0 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "APC") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")) :ARG2 (e / enzyme :name (n2 / name :op1 "GSK-3beta") :xref (x / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692"))) :ARG1 (c2 / capable-01 :ARG1 p4 :ARG2 (b / bind-01 :ARG0 p4 :ARG1 (p5 / protein :name (n3 / name :op1 "beta-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))))) :op2 (r / reduce-01 :ARG0 (o / overexpress-01 :ARG1 p4 :ARG1-of (f / follow-01 :ARG2 (t / transfect-01))) :ARG1 (l / level :quant-of p5) :ARG2 (s2 / substantial)) :mod (i / indeed) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n4 / name :op1 "Munemitsu")) :op2 (p8 / person :mod (o2 / other))) :time (d / date-entity :year "1995")))) # ::id bio.chicago_2015.39970 # ::date 2015-11-01T13:47:59 # ::file bio_chicago_2015_39970.txt # ::snt At low levels of expression, dynamin-2 specifically induces cell death. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "dynamin-2") :xref (x / xref :value "UNIPROT:DYN2_HUMAN" :prob "0.703")) :ARG2 (d / die-01 :ARG1 (c / cell)) :ARG1-of (s / specific-02) :condition (l / low-04 :ARG1 (l2 / level :quant-of (e / express-03 :ARG2 p)))) # ::id bio.chicago_2015.40024 # ::date 2015-11-01T13:50:51 # ::file bio_chicago_2015_40024.txt # ::snt Like TAK1, both MEKK1 and MLK3 also activate JNK through SEK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEKK1") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MLK3") :xref (x3 / xref :value "UNIPROT:M3K11_HUMAN" :prob "1.002"))) :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK") :xref (x4 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :mod (a3 / also) :instrument (e5 / enzyme :name (n4 / name :op1 "SEK1") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003")) :ARG1-of (r / resemble-01 :ARG2 (e4 / enzyme :name (n5 / name :op1 "TAK1") :xref (x2 / xref :value "UNIPROT:M3K7_HUMAN" :prob "1.002")))) # ::id bio.chicago_2015.40045 # ::date 2015-10-31T02:44:49 # ::file bio_chicago_2015_40045.txt # ::snt A, LEF1 represses Runx2-mediated activation of a mOG2-luc reporter lacking the LEF1 DNA binding site. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (r2 / repress-01 :li "a" :ARG0 (p2 / protein :name (n3 / name :op1 "LEF1") :xref (x / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.003")) :ARG1 (a / activate-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (r / report-01 :ARG1 (e / enzyme :name (n4 / name :op1 "mOG2-luc"))) :ARG0-of (l / lack-01 :ARG1 (s / site :ARG1-of (b / bind-01 :ARG2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA") :ARG0-of (e2 / encode-01 :ARG1 p2)))))) :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n5 / name :op1 "Runx2") :xref (x1 / xref :value "UNIPROT:RUNX2_HUMAN" :prob "0.603"))))) # ::id bio.chicago_2015.40110 # ::date 2015-10-31T03:42:12 # ::file bio_chicago_2015_40110.txt # ::snt Furthermore, we showed that CED-12 physically interacts with CED-5 and forms a ternary complex with CED-2 in vitro, with CED-5 bridging CED-2 and CED-12. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (a / and :op2 (s / show-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "CED-12") :xref (x2 / xref :value "UNIPROT:ELMO2_HUMAN" :prob "0.292")) :ARG1 (p3 / protein :name (n2 / name :op1 "CED-5") :xref (x / xref :value "UNIPROT:GULP1_HUMAN" :prob "0.212")) :manner (p2 / physical)) :op2 (f / form-01 :ARG0 p :ARG1 (c / complex :mod (t / ternary)) :accompanier (p4 / protein :name (n3 / name :op1 "CED-2") :xref (x1 / xref :value "UNIPROT:GULP1_HUMAN" :prob "0.212")) :manner (i2 / in-vitro) :manner (b / bridge-01 :ARG0 p3 :ARG1 p4 :ARG2 p))))) # ::id bio.chicago_2015.40137 # ::date 2015-10-31T04:25:09 # ::file bio_chicago_2015_40137.txt # ::snt The Drosophila endocycle is controlled by cyclin E and lacks a checkpoint ensuring S-phase completion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (c / control-01 :ARG0 (p / protein :name (n2 / name :op1 "cyclin" :op2 "E") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")) :ARG1 (e / endocycle :mod (o / organism :name (n / name :op1 "Drosophila")))) :op2 (l / lack-01 :ARG0 e :ARG1 (c2 / checkpoint :ARG0-of (e2 / ensure-01 :ARG1 (c3 / complete-01 :ARG1 (e3 / event :name (n3 / name :op1 "S-phase"))))))) # ::id bio.chicago_2015.40191 # ::date 2015-10-31T04:32:40 # ::file bio_chicago_2015_40191.txt # ::snt Because HC-Pro suppression of PTGS is accompanied by the loss of smRNAs [5, 6] , this viral protein can potentially provide a tool to study RNA requirements for RdDM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (c / cause-01 :ARG0 (a / accompany-01 :ARG0 (l / lose-02 :ARG1 (n5 / nucleic-acid :name (n6 / name :op1 "smRNA"))) :ARG1 (s / suppress-01 :ARG0 (p / protein :name (n3 / name :op1 "HC-Pro")) :ARG1 (p2 / protein-family :name (n4 / name :op1 "PTGS"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "5" :op2 "6"))))) :ARG1 (p4 / possible-01 :ARG1 (p5 / provide-01 :ARG0 (p6 / protein :mod (v / viral) :mod (t / this)) :ARG1 (t3 / thing :ARG3-of (t2 / tool-03) :instrument-of (s2 / study-01 :ARG1 (r / require-01 :ARG0 (t4 / thing :name (n7 / name :op1 "RdDM")) :ARG1 (n / nucleic-acid :wiki "RNA" :name (n2 / name :op1 "RNA"))))) :mod (p7 / potential)))) # ::id bio.chicago_2015.40291 # ::date 2015-10-31T04:42:40 # ::file bio_chicago_2015_40291.txt # ::snt Consistent with this localization, we have previously shown that in HeLa cells overexpression of GTP-bound forms of rab6 (wt rab6 and rab6 Q72L) affects transport of both membrane and secretory proteins between an alpha-mannosidase II-positive and a sialyl-transferase-positive Golgi compartment ( 15). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (w2 / we) :ARG1 (a / affect-01 :ARG0 (o / overexpress-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "Rab6") :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (p9 / protein :name (n4 / name :op1 "Rab6") :mod (w3 / wild-type) :xref (x2 / xref :value "UNIPROT:RAB6A_HUMAN" :prob "0.672")) :op2 (p3 / protein :name (n5 / name :op1 "Rab6") :ARG2-of (m / mutate-01 :value "Q72L") :xref (x1 / xref :value "UNIPROT:RAB6A_HUMAN" :prob "0.672")))) :ARG1-of (b / bind-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "GTP") :xref (x5 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :location (c / cell-line :name (n / name :op1 "HeLa"))) :ARG1 (t / transport-01 :ARG1 (a3 / and :op1 (p4 / protein :mod (m2 / membrane :xref (x4 / xref :value "GO:0016020" :prob "0.8"))) :op2 (p5 / protein :ARG0-of (s4 / secrete-01))) :ARG2 (c2 / compartment :mod (t3 / thing :name (n6 / name :op1 "Golgi")) :mod (p6 / positive) :mod (e2 / enzyme :name (n8 / name :op1 "alpha-mannosidase" :op2 "II") :xref (x / xref :value "UNIPROT:MA2A1_HUMAN" :prob "0.392"))) :ARG3 (c3 / compartment :mod t3 :mod (p7 / positive) :mod (e / enzyme :name (n7 / name :op1 "sialyl-transferase") :xref (x3 / xref :value "UNIPROT:SIA10_HUMAN" :prob "0.382"))))) :time (p / previous) :ARG1-of (c4 / consistent-01 :ARG2 (b2 / be-located-at-91 :mod (t2 / this))) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c5 / cite-01 :ARG2 "15")))) # ::id bio.chicago_2015.40308 # ::date 2015-10-31T05:13:01 # ::file bio_chicago_2015_40308.txt # ::snt Furthermore, simultaneous overexpression of both Hsp90 and Flag-p50Cdc37 did not increase the association of Hsp90 with tsHck499F above that seen upon overexpression of Flag-p50Cdc37 alone (Fig. 7A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 26, 2015 (a / and :op2 (i / increase-01 :polarity "-" :ARG0 (o / overexpress-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "Hsp90") :xref (x2 / xref :value "UNIPROT:HS90B_HUMAN" :prob "0.622")) :op2 (p2 / protein :name (n2 / name :op1 "p50Cdc37") :ARG1-of "t2" :xref (x / xref :value "UNIPROT:CDC37_HUMAN" :prob "1.003"))) :mod (s / simultaneous)) :ARG1 (a3 / associate-01 :ARG1 p :ARG2 (e / enzyme :name (n3 / name :op1 "tsHck499F") :ARG2-of (m / mutate-01))) :ARG2 (a4 / above :op1 (i2 / increase-01 :ARG1-of (s2 / see-01 :location (o2 / overexpress-01 :ARG1 (p3 / protein :name (n4 / name :op1 "p50Cdc37") :mod (a5 / alone) :ARG1-of (t2 / tag-01 :ARG2 (p4 / protein-segment :name (n5 / name :op1 "Flag"))) :xref (x1 / xref :value "UNIPROT:CDC37_HUMAN" :prob "1.003")))) :mod (t / that)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7A"))) # ::id bio.chicago_2015.40323 # ::date 2015-10-31T05:27:05 # ::file bio_chicago_2015_40323.txt # ::snt Together, these data suggest that intersectin regulates MAPK activation through regulation of EGFR endocytosis as well as Ras activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / suggest-01 :ARG0 (d / data :mod (t / this) :mod (t2 / together)) :ARG1 (r / regulate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "intersectin") :xref (x / xref :value "UNIPROT:ITSN1_HUMAN" :prob "0.383")) :ARG1 (a / activate-01 :ARG1 (p / pathway :name (n5 / name :op1 "MAPK"))) :manner (r2 / regulate-01 :ARG1 (a2 / and :op1 (e3 / endocytosis :mod (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op2 (a3 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) # ::id bio.chicago_2015.40343 # ::date 2015-10-31T05:32:42 # ::file bio_chicago_2015_40343.txt # ::snt Moreover, a wide variety of studies using both dominant negative mutants and SHP-2 mutant fibroblasts have shown that SHP-2 function is required for full activation of MAPK in response to growth factors, cytokines, antigen receptors, and integrin engagement. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a / and :op2 (s / show-01 :ARG0 (s2 / study-01 :mod (v / variety) :ARG1-of (w / wide-02) :ARG0-of (u / use-01 :ARG1 (a2 / and :op1 (m / mutate-01 :mod "-/-" :ARG0-of (d / dominate-01)) :op2 (f / fibroblasts :mod (p2 / protein :name (n3 / name :op1 "SHP-2") :ARG2-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")))))) :ARG1 (r / require-01 :ARG0 (a3 / activate-01 :ARG1 (p / pathway :name (n5 / name :op1 "MAPK")) :ARG1-of (f3 / full-09)) :ARG1 (f2 / function-01 :ARG0 (p3 / protein :name (n4 / name :op1 "SHP-2") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003"))) :ARG2-of (r2 / respond-01 :ARG1 (a4 / and :op1 (g / growth-factor) :op2 (c / cytokine) :op3 (r3 / receptor :mod (a5 / antigen)) :op4 (e2 / engage-01 :ARG1 (p4 / protein :name (n7 / name :op1 "integrin") :xref (x / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")))))))) # ::id bio.chicago_2015.40381 # ::date 2015-10-31T05:56:49 # ::file bio_chicago_2015_40381.txt # ::snt Phosphorylation site mapping studies performed in vitro also support the hypothesis that Cds1 and Chk1 inhibit Cdc25. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (s / support-01 :ARG0 (s2 / site :mod (p / phosphorylate-01) :ARG0-of (m / map-01 :ARG1 (s3 / study-01 :ARG1-of (p2 / perform-01 :manner (i / in-vitro))))) :ARG1 (h / hypothesize-01 :ARG1 (i2 / inhibit-01 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "Cds1") :xref (x / xref :value "UNIPROT:CDS1_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n2 / name :op1 "Chk1") :xref (x2 / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604"))) :ARG1 (e3 / enzyme :name (n3 / name :op1 "Cdc25") :xref (x1 / xref :value "UNIPROT:RGRF1_HUMAN" :prob "0.633")))) :mod (a / also)) # ::id bio.chicago_2015.40436 # ::date 2015-10-31T06:00:42 # ::file bio_chicago_2015_40436.txt # ::snt To examine the interaction of Duplin with beta-catenin using the purified proteins in vitro, GST-beta-catenin and its deletion mutants (0.5 muM) were incubated with MBP-Duplin-(482-749) (30 pmol) immobilized on amylose resin in 100 mul of reaction mixture (20 mM Tris/ Cl, pH 7.5, 1 mM DTT) for 1 h at 4 degrees C. MBP-Duplin was precipitated by centrifugation, and then the precipitates were probed with the anti-GST antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (m2 / multi-sentence :snt1 (i / incubate-01 :ARG1 (a / and :op1 (m3 / macro-molecular-complex :part (e / enzyme :wiki "Glutathione_S-transferase" :name (n / name :op1 "GST") :xref (x4 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :part (p / protein :wiki "Beta-catenin" :name (n2 / name :op1 "beta-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703"))) :op2 (m4 / mutate-01 :ARG0-of (d2 / delete-01) :quant (c / concentration-quantity :quant "0.5" :unit "m7"))) :ARG2 (m / macro-molecular-complex :part (p6 / protein :wiki "Maltose-binding_protein" :name (n9 / name :op1 "MBP") :xref (x2 / xref :value "UNIPROT:MBP_HUMAN" :prob "1.003")) :part (p9 / protein :wiki "-" :name (n10 / name :op1 "Duplin")) :quant (c2 / concentration-quantity :quant "30" :unit (p2 / picomol)) :ARG1-of (i2 / immobilize-01 :ARG0 (s2 / small-molecule :wiki "-" :name (n4 / name :op1 "amylose" :op2 "resin") :xref (x5 / xref :value "PUBCHEM:53477771" :prob "4.349396")) :duration (t / temporal-quantity :quant "1" :unit (h / hour)) :condition (t2 / temperature-quantity :quant "4" :scale (c5 / celsius)) :location (m5 / mul :value "100" :consist-of (m6 / mixture :ARG0-of (r / react-01) :consist-of (a2 / and :op1 (s3 / small-molecule :wiki "Tris" :name (n5 / name :op1 "Tris/Cl") :quant (c3 / concentration-quantity :quant "20" :unit (m7 / millimolar))) :op2 (s4 / small-molecule :wiki "Dithiothreitol" :name (n6 / name :op1 "DTT") :quant (c4 / concentration-quantity :quant "1" :unit m7) :xref (x6 / xref :value "PUBCHEM:19001" :prob "17.251232"))) :mod (a3 / acidity-quantity :quant "7.5" :scale (p3 / ph))))) :mod (v / value-interval :op1 "482" :op2 "749")) :purpose (e3 / examine-01 :ARG1 (i3 / interact-01 :ARG1 m :ARG2 p) :manner (u / use-01 :ARG1 (p7 / protein :ARG1-of (p8 / purify-01 :manner (i4 / in-vitro)))))) :snt2 (a4 / and :op1 (p4 / precipitate-01 :ARG0 (c6 / centrifugation) :ARG1 (m8 / macro-molecular-complex :part (p10 / protein :wiki "Maltose-binding_protein" :name (n3 / name :op1 "MBP") :xref (x3 / xref :value "UNIPROT:MBP_HUMAN" :prob "1.003")) :part (p11 / protein :wiki "-" :name (n11 / name :op1 "Duplin")))) :op2 (p5 / probe-01 :ARG1 p4 :instrument (a5 / antibody :ARG0-of (o / oppose-01 :ARG1 (e2 / enzyme :wiki "Glutathione_S-transferase" :name (n8 / name :op1 "GST") :xref (x1 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")))) :time (t3 / then)))) # ::id bio.chicago_2015.40510 # ::date 2015-10-31T06:36:45 # ::file bio_chicago_2015_40510.txt # ::snt Thus, both Sox9 and Nkx3.2 are induced by Shh, prior to the expression of cartilage differentiation markers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (c / cause-01 :ARG1 (i / induce-01 :ARG0 (p3 / protein :name (n3 / name :op1 "Shh") :xref (x / xref :value "UNIPROT:SHH_HUMAN" :prob "0.603")) :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "Sox9") :xref (x1 / xref :value "UNIPROT:SOX9_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n2 / name :op1 "Nkx3.2") :xref (x2 / xref :value "UNIPROT:NKX32_HUMAN" :prob "0.592"))) :time (p4 / prior :op1 (e / express-03 :ARG1 (m / marker :mod (d / differentiate-01 :ARG1 (c2 / cartilage))))))) # ::id bio.chicago_2015.40538 # ::date 2015-10-31T06:48:19 # ::file bio_chicago_2015_40538.txt # ::snt Resistance of RNA-mediated TGS to HC-Pro, a viral suppressor of PTGS, suggests alternative pathways for dsRNA processing. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (s / suggest-01 :ARG0 (r / resist-01 :ARG0 (p / protein :name (n / name :op1 "TGS") :ARG1-of (m / mediate-01 :ARG0 (n2 / nucleic-acid :name (n3 / name :op1 "RNA"))) :xref (x / xref :value "UNIPROT:LIN9_HUMAN" :prob "1.002")) :ARG1 (p2 / protein :name (n4 / name :op1 "HC-Pro") :ARG0-of (s2 / suppress-01 :ARG1 (p3 / protein-family :name (n5 / name :op1 "PTGS"))) :mod (v / viral))) :ARG1 (p4 / pathway :mod (a / alternative) :beneficiary (p5 / process-01 :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "dsRNA"))))) # ::id bio.chicago_2015.40555 # ::date 2015-10-31T07:14:45 # ::file bio_chicago_2015_40555.txt # ::snt Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / initiate-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "Cytochrome" :op2 "c") :xref (x2 / xref :value "UNIPROT:CYC_HUMAN" :prob "1.002")) :op2 (f / form-01 :ARG1 (m2 / macro-molecular-complex :part (p2 / protein :name (n2 / name :op1 "Apaf-1") :xref (x / xref :value "UNIPROT:APAF_HUMAN" :prob "0.622")) :part (e / enzyme :name (n3 / name :op1 "Caspase-9") :xref (x1 / xref :value "UNIPROT:CASP9_HUMAN" :prob "1.002"))) :ARG0-of (d / depend-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "dATP") :xref (x3 / xref :value "PUBCHEM:15993" :prob "16.321695"))))) :ARG1 (c2 / cascade :mod (p3 / protease :mod (a3 / apoptotic)))) # ::id bio.chicago_2015.40576 # ::date 2015-10-31T07:19:28 # ::file bio_chicago_2015_40576.txt # ::snt It remains possible, however, that the phosphorylation of Dsh by CK2 and by perhaps other unidentified kinases is required but not sufficient for the transduction of the Wg signal. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (h / have-concession-91 :ARG1 (r / remain-01 :ARG1 (p3 / possible-01 :ARG1 (c / contrast-01 :ARG1 (r2 / require-01 :ARG0 "t" :ARG1 (a2 / and :op1 (p / phosphorylate-01 :ARG0 (e / enzyme :name (n2 / name :op1 "CK2") :xref (x / xref :value "UNIPROT:CSK22_HUMAN" :prob "0.332")) :ARG1 (p4 / protein-family :name (n / name :op1 "Dsh"))) :op2 (p5 / phosphorylate-01 :ARG0 (k / kinase :ARG1-of (i / identify-01 :polarity "-") :mod (o / other)) :ARG1 p4 :ARG1-of (p6 / possible-01)))) :ARG2 (s / suffice-01 :polarity "-" :ARG0 a2 :ARG1 (t / transduce-01 :ARG1 (s2 / signal-07 :ARG1 (p7 / protein :name (n3 / name :op1 "Wg"))) :ARG2 a2)))))) # ::id bio.chicago_2015.53561 # ::date 2015-10-31T07:30:09 # ::file bio_chicago_2015_53561.txt # ::snt In control experiments, ERK2 was strongly activated by an activated Raf mutant, RafBxB, to phosphorylate MBP ( Fig. 4B), and p38 was activated by ultraviolet irradiation and cotransfection of a MKK6 expression vector ( Fig. 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / activate-01 :ARG0 (m / mutate-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "RafBxB") :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.203")) :ARG1-of (a3 / activate-01) :mod (e6 / enzyme :name (n / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK2") :xref (x5 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :purpose (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "MBP") :xref (x4 / xref :value "UNIPROT:MBP_HUMAN" :prob "1.003")) :ARG2 e) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B")) :ARG1-of (s / strong-02)) :op2 (a4 / activate-01 :ARG0 (a5 / and :op1 (i / irradiate-01 :ARG2 (u / ultraviolet)) :op2 (c / cotransfect-01 :ARG1 (e3 / express-03 :ARG1 (v / vector) :ARG2 (e4 / enzyme :name (n6 / name :op1 "MKK6") :xref (x / xref :value "UNIPROT:MP2K6_HUMAN" :prob "1.003"))))) :ARG1 (e7 / enzyme :name (n5 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4C"))) :location (t / thing :ARG1-of (e5 / experiment-01) :mod (c2 / control))) # ::id bio.chicago_2015.53577 # ::date 2015-10-31T08:39:44 # ::file bio_chicago_2015_53577.txt # ::snt To determine whether NIK mediates JNK activation by EphB1, we used the RevTet-On system to inducibly express NIK(KD) in P19 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (s / system :name (n / name :op1 "RevTet-On")) :ARG2 (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "NIK(KD)")) :ARG3 (c / cell :name (n3 / name :op1 "P19")) :manner (i / induce-01 :ARG1-of (p / possible-01))) :purpose (d / determine-01 :ARG0 w :ARG1 (m / mediate-01 :mode "interrogative" :ARG0 e2 :ARG1 (a / activate-01 :ARG0 (p2 / protein :name (n4 / name :op1 "EphB1") :xref (x / xref :value "UNIPROT:EPHB1_HUMAN" :prob "0.634")) :ARG1 (e3 / enzyme :name (n5 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")))))) # ::id bio.chicago_2015.53583 # ::date 2015-10-31T08:43:49 # ::file bio_chicago_2015_53583.txt # ::snt Regardless of the receptor-coupling mechanism involved, TGF-beta activation of JNK or p38 in some cell lines and conditions can be rapid and mediate transcriptional responses by activating AP-1 complexes via phosphorylation of c-Jun transcription factor (Hocevar et al. 1999 ) or CRE-regulatory complexes via phosphorylation of ATF2 transcription factor (Sano et al. 1999 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r5 / regardless-91 :ARG1 (a / and :op1 (p2 / possible-01 :ARG1 (r2 / rapid :domain (a2 / and :op1 (a3 / activate-01 :ARG0 (p14 / protein :name (n / name :op1 "TGF-beta") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.373")) :ARG1 (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "JNK") :xref (x3 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :op2 (e / enzyme :name (n3 / name :op1 "p38") :xref (x4 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))) :location (c2 / cell-line :quant (s / some))) :op2 (t / thing :ARG2-of (c3 / condition-01))))) :op2 (m2 / mediate-01 :ARG0 a2 :ARG1 (r3 / respond-01 :ARG2 (t2 / transcribe-01)) :manner (o3 / or :op1 (a4 / activate-01 :ARG0 (p / phosphorylate-01 :ARG1 (f / factor :ARG0-of (t3 / transcribe-01 :ARG1 (p5 / protein :name (n5 / name :op1 "c-Jun"))))) :ARG1 (c4 / complex :mod (p4 / protein :name (n4 / name :op1 "AP-1") :xref (x5 / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a5 / and :op1 (p7 / person :name (n6 / name :op1 "Hocevar")) :op2 (p8 / person :mod (o2 / other))) :time (d / date-entity :year "1999")))) :op2 (a6 / activate-01 :ARG0 (p9 / phosphorylate-01 :ARG1 (p10 / protein :name (n8 / name :op1 "ATF2") :xref (x1 / xref :value "UNIPROT:ATF2_HUMAN" :prob "1.003"))) :ARG1 (c5 / complex :ARG0-of (r4 / regulate-01 :ARG1 (e3 / enzyme :name (n7 / name :op1 "CRE") :xref (x / xref :value "UNIPROT:CREG1_HUMAN" :prob "0.262")))) :ARG1-of (d3 / describe-01 :ARG0 (p11 / publication-91 :ARG0 (a7 / and :op1 (p12 / person :name (n9 / name :op1 "Sano")) :op2 (p13 / person :mod (o4 / other))) :time d)))))) :ARG2 (i / involve-01 :ARG1 (m / mechanism :ARG0-of (c / couple-01 :ARG1 (r / receptor))))) # ::id bio.chicago_2015.53648 # ::date 2015-11-01T01:36:57 # ::file bio_chicago_2015_53648.txt # ::snt Activation of PKC with TPA leads to inactivation of GSK3 in the absence of a wnt signal and downregulation of PKC by prolonged treatment with TPA prevents wnt-mediated inactivation of GSK3 [ 113]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (l / lead-03 :ARG0 (a2 / activate-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA") :xref (x2 / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1 (e / enzyme :name (n / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))) :ARG2 (a3 / activate-01 :polarity "-" :ARG1 (e2 / enzyme :name (n3 / name :op1 "GSK3") :xref (x / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.312"))) :condition (a4 / absent-01 :ARG1 (s / signal-07 :ARG0 (p2 / pathway :name (n4 / name :op1 "wnt"))))) :op2 (p3 / prevent-01 :ARG0 (d / downregulate-01 :ARG1 e :ARG2 (t / treat-04 :ARG2 s2 :ARG1-of (p4 / prolong-01))) :ARG1 (a5 / activate-01 :polarity "-" :ARG1 e2 :ARG1-of (m / mediate-01 :ARG0 p2))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "113")))) # ::id bio.chicago_2015.53659 # ::date 2015-11-01T01:52:03 # ::file bio_chicago_2015_53659.txt # ::snt To confirm that p65 activates PI3K in vivo, 3-phosphorylated inositol lipid levels were measured in different cells expressing p65 or p85alpha. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / measure-01 :ARG1 (l / level :quant "3" :ARG1-of (p / phosphorylate-01) :quant-of (l3 / lipid :name (n5 / name :op1 "3-phosphorylated" :op2 "inositol"))) :location (c / cell :ARG1-of (d / differ-02) :ARG3-of (e / express-03 :ARG2 (o / or :op1 (p2 / protein :name (n2 / name :op1 "p65") :xref (x / xref :value "UNIPROT:SYT1_HUMAN" :prob "1.002")) :op2 (p3 / protein-segment :name (n3 / name :op1 "p85alpha"))))) :purpose (c2 / confirm-01 :ARG1 (a / activate-01 :ARG0 p2 :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :manner (i / in-vivo)))) # ::id bio.chicago_2015.53662 # ::date 2015-11-01T01:59:05 # ::file bio_chicago_2015_53662.txt # ::snt However, in slp mutants, in contrast to the slp+ situation, VP16En activates hh expression (compare Fig. 6D with Fig. 4B) and also that of en (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 26, 2015 (h / have-concession-91 :ARG1 (a2 / and :op1 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "VP16En")) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Hh"))) :ARG1-of (d / describe-01 :ARG0 (c / compare-01 :ARG1 (f / figure :mod "6D") :ARG2 (f2 / figure :mod "4B")))) :op2 (a3 / activate-01 :ARG0 p :ARG1 (e2 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "En"))) :ARG1-of (s / show-01 :polarity "-") :mod (a4 / also)) :location (g / gene :name (n4 / name :op1 "SLP") :ARG2-of (m / mutate-01) :ARG1-of (c2 / contrast-01 :ARG2 (s2 / situation :mod (g2 / gene :name (n5 / name :op1 "SLP") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:STML1_HUMAN" :prob "0.262")))) :xref (x1 / xref :value "UNIPROT:STML1_HUMAN" :prob "0.262")))) # ::id bio.chicago_2015.53694 # ::date 2015-11-01T03:20:52 # ::file bio_chicago_2015_53694.txt # ::snt A, Responses to 10 msec flashes recorded in WT photoreceptors in controls and in the presence of 8-Br- cGMP (5 mM), 8-Br-cAMP (5 mM), IBMX (100 muM), and photoreceptors from flies expressing activated Gsalpha (Gsalpha*). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (a2 / and :li "a" :op1 (t / thing :ARG2-of (r / respond-01 :ARG1 (f / flash-01 :duration (t2 / temporal-quantity :quant "10" :unit (m2 / millisecond)) :ARG1-of (r2 / record-01 :location (p / photoreceptor :mod (w / wild-type) :location (c / control) :ARG2-of (p2 / present-02 :ARG1 (a / and :op1 (s / small-molecule :name (n / name :op1 "8-Br-cGMP") :quant (c2 / concentration-quantity :quant "5" :unit (m3 / millmolar)) :xref (x3 / xref :value "PUBCHEM:104767" :prob "15.656431")) :op2 (s2 / small-molecule :name (n2 / name :op1 "8-Br-cAMP") :quant c2 :xref (x2 / xref :value "PUBCHEM:32014" :prob "15.339571")) :op3 (s3 / small-molecule :name (n3 / name :op1 "IBMX") :quant (c3 / concentration-quantity :quant "100" :unit (m4 / millimolar)) :xref (x1 / xref :value "PUBCHEM:3758" :prob "18.349844"))))))))) :op2 (p3 / photoreceptor :source (f2 / fly :ARG3-of (e / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "Gsalpha") :ARG1-of (a3 / activate-01) :xref (x / xref :value "UNIPROT:Q14455_HUMAN" :prob "0.201")))))) # ::id bio.chicago_2015.53701 # ::date 2015-11-01T03:31:33 # ::file bio_chicago_2015_53701.txt # ::snt Consistent with the findings in Drosophila, Habas et al. (2001) recently demonstrated biochemically in mammalian cells that Fz/Dvl (mouse Disheveled) signaling activates Rho and weakly Rac, but not Cdc42. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (d2 / demonstrate-01 :ARG1 (c / contrast-01 :ARG1 (a3 / and :op1 (a2 / activate-01 :ARG0 (s / signal-07 :ARG0 (p3 / pathway :name (n2 / name :op1 "Fz/Dvl")) :location (m / mouse :name (n3 / name :op1 "Disheveled"))) :ARG1 (p4 / protein :name (n4 / name :op1 "Rho") :xref (x1 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")) :manner (b / biochemical)) :op2 (a4 / activate-01 :ARG0 s :ARG1 (e / enzyme :name (n5 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1-of (w / weak-02)) :location (c2 / cell :mod (m2 / mammal))) :ARG2 (a5 / activate-01 :polarity "-" :ARG0 s :ARG1 (p5 / protein :name (n6 / name :op1 "Cdc42") :xref (x2 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :location c2)) :time (r / recent) :ARG1-of (c3 / consistent-01 :ARG2 (t / thing :ARG1-of (f / find-01) :location (o2 / organism :name (n7 / name :op1 "Drosophila")))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a / and :op1 (p / person :name (n / name :op1 "Habas")) :op2 (p2 / person :mod (o / other))) :time (d / date-entity :year "2001")))) # ::id bio.chicago_2015.53712 # ::date 2015-11-01T03:40:44 # ::file bio_chicago_2015_53712.txt # ::snt NPAT activates histone gene transcription # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "NPAT") :xref (x1 / xref :value "UNIPROT:NPAT_HUMAN" :prob "1.003")) :ARG1 (t / transcribe-01 :ARG1 (g2 / gene :name (n2 / name :op1 "histone") :xref (x / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332")))) # ::id bio.chicago_2015.53750 # ::date 2015-11-01T03:42:58 # ::file bio_chicago_2015_53750.txt # ::snt KN-CKI inhibited the activation of Lef-1 reporter by Wnt-1 (Fig. 3 c), suggesting the involvement of endogenous CKI during the Wnt signal. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (i / inhibit-01 :ARG0 (e / enzyme :name (n / name :op1 "KN-CKI")) :ARG1 (a / activate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Wnt-1") :xref (x / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.592")) :ARG1 (m / molecular-physical-entity :ARG0-of (r / report-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Lef-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "0.632"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3C")) :ARG0-of (s / suggest-01 :ARG1 (i2 / involve-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "CKI") :mod (e3 / endogenous) :xref (x2 / xref :value "UNIPROT:CHKA_HUMAN" :prob "1.002")) :time (s2 / signal-07 :ARG0 (p4 / pathway :name (n5 / name :op1 "Wnt")))))) # ::id bio.chicago_2015.53769 # ::date 2015-11-01T03:53:22 # ::file bio_chicago_2015_53769.txt # ::snt Initial integrin clustering results in rapid activation of Rac and Cdc42, and this activation of Rac and Cdc42 induces formation of lamellipodia and filopodia, leading to cell spreading and subsequent activation of Rho. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (i / induce-01 :ARG0 (r / result-01 :ARG1 (p / protein :name (n / name :op1 "integrin") :ARG0-of (c / cluster-01) :mod (i2 / initial) :xref (x3 / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")) :ARG2 (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n3 / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634"))) :mod (r2 / rapid))) :ARG2 (f / form-01 :ARG1 (a4 / and :op1 (l / lamellipodia) :op2 (f2 / filopodia))) :ARG0-of (l2 / lead-01 :ARG2 (a5 / and :op1 (s / spread-03 :ARG1 (c2 / cell)) :op2 (a6 / activate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "Rho") :xref (x1 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")) :mod (s2 / subsequent))))) # ::id bio.chicago_2015.53781 # ::date 2015-11-01T03:59:14 # ::file bio_chicago_2015_53781.txt # ::snt It is, therefore, possible that Ad2 activation of PKA involves both integrins and functional F-actin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (c / cause-01 :ARG1 (p / possible-01 :ARG1 (i / involve-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "integrin") :xref (x / xref :value "UNIPROT:A0A024DAE5_HUMAN" :prob "0.311")) :op2 (p4 / protein :name (n4 / name :op1 "F-actin") :ARG0-of (f / function-01) :xref (x3 / xref :value "UNIPROT:NEXN_HUMAN" :prob "0.252"))) :ARG2 (a / activate-01 :ARG0 (p2 / protein :name (n / name :op1 "Ad2") :xref (x2 / xref :value "UNIPROT:Q9Y6Z1_HUMAN" :prob "0.611")) :ARG1 (e / enzyme :name (n2 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")))))) # ::id bio.chicago_2015.53810 # ::date 2015-11-01T07:47:29 # ::file bio_chicago_2015_53810.txt # ::snt One answer to how PYK2 might activate Ras comes from analysis of a structurally homologous protein, the focal adhesion kinase (p125FAK or FAK). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / come-03 :ARG1 (a / answer-01 :quant "1" :ARG1 (t / thing :manner-of (a2 / activate-01 :ARG0 (e / enzyme :name (n2 / name :op1 "PYK2") :xref (x4 / xref :value "UNIPROT:FAK2_HUMAN" :prob "1.003")) :ARG1 (e2 / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (p / possible-01)))) :ARG2 (a3 / analyze-01 :ARG1 (p3 / protein :mod (h / homologous) :mod (s / structural) :ARG1-of (m / mean-01 :ARG2 (e5 / enzyme :name (n3 / name :op1 "focal" :op2 "adhesion" :op3 "kinase") :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 (e4 / enzyme :name (n4 / name :op1 "p125FAK") :xref (x1 / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")) :op1 (e3 / enzyme :name (n5 / name :op1 "FAK") :xref (x2 / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")))) :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "0.393")))))) # ::id bio.chicago_2015.53850 # ::date 2015-11-01T08:09:05 # ::file bio_chicago_2015_53850.txt # ::snt To test whether GSK-3 activity is required for this response, we tested the effect of LiCl in the `collapse assay` since it is an established inhibitor of both GSK-3alpha and GSK-3beta ( Stambolic et al., 1996) and can prevent the Sema 3A activation of GSK-3 ( Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (t2 / test-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "LiCl") :xref (x4 / xref :value "PUBCHEM:433294" :prob "18.167522")) :location (a2 / assay-01 :mod (c / collapse-01))) :ARG1-of (c2 / cause-01 :ARG0 (a3 / and :op1 (e / establish-01 :ARG1 s :ARG2 (i2 / inhibit-01 :ARG0 s :ARG1 (a4 / and :op1 (e2 / enzyme :name (n2 / name :op1 "GSK-3alpha") :xref (x2 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.692")) :op2 (e3 / enzyme :name (n3 / name :op1 "GSK-3beta") :xref (x1 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a5 / and :op1 (p2 / person :name (n4 / name :op1 "Stambolic")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "1996")))) :op2 (p4 / possible-01 :ARG1 (p5 / prevent-01 :ARG0 s :ARG1 (a6 / activate-01 :ARG0 (p6 / protein :name (n6 / name :op1 "Sema" :op2 "3A") :xref (x3 / xref :value "UNIPROT:SEM3A_HUMAN" :prob "0.612")) :ARG1 (e4 / enzyme :name (n5 / name :op1 "GSK-3") :xref (x / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.262")))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4"))))) :purpose (t3 / test-01 :ARG0 w :ARG1 (r / require-01 :mode "interrogative" :ARG0 (t4 / thing :ARG2-of (r2 / respond-01) :mod (t5 / this)) :ARG1 (a7 / activity-06 :ARG0 e4)))) # ::id bio.chicago_2015.53852 # ::date 2015-11-01T08:18:04 # ::file bio_chicago_2015_53852.txt # ::snt In support of this observation, when oligonucleotide C3-3PmA was used as 32P-labeled probe in the presence of a nuclear extract from PMA/ PHA activated fresh human T lymphocytes, no binding activity was observed ( lane 9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (o / observe-01 :ARG1 (a2 / activity-06 :polarity "-" :ARG1 (b / bind-01)) :time (u / use-01 :ARG1 (o3 / oligonucleotide :name (n / name :op1 "C3-3PmA")) :ARG2 (p3 / probe-01 :ARG1-of (l / label-01 :ARG2 (p4 / phosphorus :mod (m / molecular-mass :value "32")))) :manner (p / present-02 :ARG1 (e / extract-01 :ARG2 (c / cell :name (n4 / name :op1 "T" :op2 "lymphocytes") :mod (h / human) :ARG1-of (f / fresh-04) :ARG1-of (a / activate-01 :ARG0 (s / slash :op1 (s2 / small-molecule :name (n5 / name :op1 "PMA") :xref (x2 / xref :value "PUBCHEM:4792" :prob "16.591986")) :op2 (p2 / protein :name (n6 / name :op1 "PHA") :xref (x / xref :value "UNIPROT:PHAX_HUMAN" :prob "0.262"))))) :mod (n3 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8"))))) :ARG1-of (d / describe-01 :ARG0 (l2 / lane :mod "9")) :ARG0-of (s3 / support-01 :ARG1 (t / thing :ARG1-of (o2 / observe-01) :mod (t2 / this)))) # ::id bio.chicago_2015.53861 # ::date 2015-11-01T08:35:19 # ::file bio_chicago_2015_53861.txt # ::snt Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (a / activate-01 :ARG0 (a2 / and :op1 (p / protein :name (n / name :op1 "MEF2") :xref (x1 / xref :value "UNIPROT:MEF2A_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "bHLH") :mod (m2 / myogenic) :xref (x / xref :value "UNIPROT:MAX_HUMAN" :prob "0.283"))) :ARG1 (e / express-03 :ARG1 (g / gene :mod (m / muscle))) :ARG0-of (c / cooperate-01)) # ::id bio.chicago_2015.53933 # ::date 2015-11-01T08:39:31 # ::file bio_chicago_2015_53933.txt # ::snt Because the single channel conductances of GABAA receptors activated by GABA and pentobarbital are similar (Jackson et al., 1982 ; Akk and Steinbach, 2000 ), it is likely that the open states of receptors activated by either of these compounds have similar conformations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / cause-01 :ARG0 (r / resemble-01 :ARG1 (c2 / conduct-03 :ARG2 (r3 / receptor :name (n2 / name :op1 "GABAA") :ARG1-of (a / activate-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "GABA") :xref (x / xref :value "PUBCHEM:119" :prob "14.989469")))) :mod (c3 / channel) :ARG1-of (s / single-02)) :ARG2 (p2 / pentobarbital) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n4 / name :op1 "Jackson")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "1982")) :op2 (p6 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :name (n5 / name :op1 "Akk")) :op2 (p8 / person :name (n6 / name :op1 "Steinbach"))) :time (d2 / date-entity :year "2000"))))) :ARG1 (l / likely-01 :ARG1 (h / have-03 :ARG0 (s3 / state :ARG1-of (o2 / open-01) :mod (r2 / receptor :ARG1-of (a5 / activate-01 :ARG0 (c4 / compound :mod (e / either) :mod (t / this))))) :ARG1 (r4 / resemble-01 :ARG1 (c5 / conformation))))) # ::id bio.chicago_2015.53950 # ::date 2015-11-01T08:49:21 # ::file bio_chicago_2015_53950.txt # ::snt Activation of GCN2 by various starvation or stress conditions requires the tRNA binding activity of its HisRS-like domain (for review, see Hinnebusch and Natarajan 2002 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (r / require-01 :ARG0 (a / activate-01 :ARG0 (c / condition-02 :ARG1 (o / or :op1 (s / starve-01) :op2 (s2 / stress-02)) :quant (v / various)) :ARG1 (e / enzyme :name (n / name :op1 "GCN2") :xref (x / xref :value "UNIPROT:E2AK4_HUMAN" :prob "1.002"))) :ARG1 (a2 / activity-06 :ARG0 (p4 / protein-segment :name (n7 / name :op1 "HisRS-like" :op2 "domain")) :ARG1 (b / bind-01 :ARG1 (d2 / domain) :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "tRNA")))) :ARG1-of (r2 / review-01 :purpose-of (s4 / see-01 :ARG1 (p / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n5 / name :op1 "Hinnebusch")) :op2 (p3 / person :name (n6 / name :op1 "Natarajan"))) :time (d / date-entity :year "2002"))))) # ::id bio.chicago_2015.53994 # ::date 2015-11-01T08:58:35 # ::file bio_chicago_2015_53994.txt # ::snt Ubiquitination is a multi-step process that begins with the activation of a Ub molecule by an E1 or Ub-activating enzyme. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (p / process-02 :ARG1 (u / ubiquitinate-01) :mod (m / multistep) :ARG1-of (b / begin-01 :ARG2 (a / activate-01 :ARG0 (o / or :op1 (e / enzyme :name (n2 / name :op1 "E1") :xref (x / xref :value "UNIPROT:Q8V9K6_HUMAN" :prob "1.001")) :op2 (e2 / enzyme :ARG1-of (a2 / activate-01 :ARG0 "m2"))) :ARG1 (m2 / molecule :mod (p2 / protein :name (n / name :op1 "Ub")))))) # ::id bio.chicago_2015.54023 # ::date 2015-11-01T09:14:53 # ::file bio_chicago_2015_54023.txt # ::snt At this concentration forskolin slightly enhanced Rap1 activation by PDGF (e.g. 1.9- to 2.6-fold in Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-condition-91 :ARG1 (e / enhance-01 :ARG0 (s / small-molecule :name (n / name :op1 "forskolin") :xref (x2 / xref :value "PUBCHEM:47936" :prob "16.627077")) :ARG1 (a / activate-01 :ARG0 (p3 / protein :name (n2 / name :op1 "PDGF") :xref (x / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :ARG1 (e3 / enzyme :name (n3 / name :op1 "Rap1") :xref (x1 / xref :value "UNIPROT:RABX5_HUMAN" :prob "0.603"))) :ARG3 (v / value-interval :op1 (p / product-of :op1 "1.9") :op2 (p2 / product-of :op2 "2.6")) :degree (s2 / slight)) :ARG2 (c / concentrate-01 :mod (t / this)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id bio.chicago_2015.54073 # ::date 2015-11-01T09:19:07 # ::file bio_chicago_2015_54073.txt # ::snt For example, compared to native channels, -only channels have decreased Ca2+ permeability, less voltage dependence, a lack of Ca2+/calmodulin modulation, less flickery single-channel records, lower apparent affinity for cGMP, and minimal activation by cAMP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / compare-01 :ARG1 (c3 / channel :mod (n / native) :mod (o / only) :ARG0-of (h / have-03 :ARG1 (a / and :op1 (p / permeability :ARG1-of (d / decrease-01) :mod (c / calcium :ARG1-of (i / ionize-01 :value "2+"))) :op2 (d2 / depend-01 :ARG0 c3 :ARG1 (v / voltage) :mod (l2 / less)) :op3 (l3 / lack-01 :ARG0 c3 :ARG1 (m3 / modulate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "calmodulin") :xref (x / xref :value "UNIPROT:CALM_HUMAN" :prob "0.703")) :mod c)) :op4 (r / record :mod (c4 / channel :ARG1-of (s / single-02) :mod (f / flickery)) :mod l2) :op5 (a2 / affinity :beneficiary (s2 / small-molecule :name (n4 / name :op1 "cGMP") :xref (x2 / xref :value "PUBCHEM:24316" :prob "16.008038")) :ARG1-of (a3 / appear-02) :ARG1-of (l4 / low-04 :degree (m5 / more))) :op6 (a4 / activate-01 :ARG0 (s3 / small-molecule :name (n5 / name :op1 "cAMP") :xref (x1 / xref :value "PUBCHEM:6076" :prob "15.374314")) :ARG1 c3 :ARG1-of (m6 / minimal-02))))) :ARG0-of (e2 / exemplify-01)) # ::id bio.chicago_2015.54091 # ::date 2015-11-01T09:31:28 # ::file bio_chicago_2015_54091.txt # ::snt Upon stimulation of the bombesin receptors, KUZ increases the docking and activation of adaptors Src homology 2 domain - containing protein and Gab1 on the EGFR, and activation of Ras and Erk. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i / increase-01 :ARG0 (p3 / protein :name (n4 / name :op1 "KUZ") :xref (x3 / xref :value "UNIPROT:ADA10_HUMAN" :prob "1.003")) :ARG1 (a / and :op1 (d / dock-01 :ARG1 (a5 / and :op1 (a3 / adaptor :mod (p4 / protein :ARG0-of (c / contain-01 :ARG1 (p5 / protein-segment :name (n5 / name :op1 "Src" :op2 "homology" :op3 "2" :op4 "domain"))))) :op2 (p6 / protein :name (n6 / name :op1 "GAb1") :xref (x4 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.654"))) :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op2 (a2 / activate-01 :ARG0 e :ARG1 a5) :op3 (a4 / activate-01 :ARG1 (a6 / and :op1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :time (s / stimulate-01 :ARG1 (r / receptor :mod (s2 / small-molecule :name (n7 / name :op1 "bombesin") :xref (x5 / xref :value "PUBCHEM:5486814" :prob "9.993118"))))) # ::id bio.chicago_2015.54241 # ::date 2015-11-01T10:43:45 # ::file bio_chicago_2015_54241.txt # ::snt Tinman is a direct activator of D-mef2 in heart precursor cells and this regulation probably requires a Tinman co-activator protein, since Tinman expression in the dorsal mesoderm is much broader than D-mef2, and ectopic Tinman expression can activate the D-mef2 cardiac enhancer in some but not all regions of the embryo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a2 / and :op1 (a3 / activate-01 :ARG0 (p / protein :name (n / name :op1 "Tinman")) :ARG1 (p2 / protein :name (n2 / name :op1 "D-mef2")) :ARG1-of (d / direct-02) :location (c / cell :mod (p3 / precursor) :mod (h / heart))) :op2 (r / require-01 :ARG0 (r2 / regulate-01 :mod (t2 / this)) :ARG1 (p4 / protein :ARG0-of (c2 / coactivate-01 :ARG1 p)) :mod (p5 / probable)) :ARG1-of (c5 / cause-01 :ARG0 (a4 / and :op1 (b / broad-02 :ARG1 (e / express-03 :ARG2 p :ARG3 (m / mesoderm :mod (d2 / dorsal))) :degree (m2 / more) :compared-to (b2 / broad-02 :ARG1 (e2 / express-03 :ARG2 p2))) :op2 (p6 / possible-01 :ARG1 (a5 / activate-01 :ARG0 (e4 / express-03 :ARG2 p :mod (e3 / ectopic)) :ARG1 (m3 / molecular-physical-entity :ARG0-of (e5 / enhance-01 :ARG1 p2 :mod (c3 / cardiac))) :location (r3 / region :quant (s / some) :location (e6 / embryo)) :ARG1-of (c4 / contrast-01 :ARG2 (a6 / activate-01 :polarity "-" :ARG0 e4 :ARG1 m3 :location (r4 / region :mod (a7 / all) :location e6)))))))) # ::id bio.chicago_2015.54249 # ::date 2015-11-01T12:25:08 # ::file bio_chicago_2015_54249.txt # ::snt TAK1 activates p38-MAPK activity through MAPK kinase 4/SEK1 by a coupled kinase assay ( 16). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG0 (e / enzyme :name (n2 / name :op1 "TAK1") :xref (x / xref :value "UNIPROT:M3K7_HUMAN" :prob "1.002")) :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "p38-MAPK") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "0.203"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "16"))) :ARG1-of (s / say-01 :ARG0 (a3 / assay-01 :ARG1 (k / kinase) :ARG1-of (c / couple-01))) :path (p2 / pathway :name (n3 / name :op1 "MAPK" :op2 "kinase" :op3 "4/SEK1"))) # ::id bio.chicago_2015.54262 # ::date 2015-11-01T12:30:13 # ::file bio_chicago_2015_54262.txt # ::snt While only 4 deficiencies were identified as specifically inducing ectopic activation of the ems HRE, 11 were found to severely reduce [ Df(2L)al, Df(2L)dp-79b, Df(2L)TW84, Df(3L)lxd6, and Df(3R)B81] or abolish [ Df(2L)H20, Df(2R)H3E1, Df(2R)Jp1, Df(2R)AA21, Df(3L)h-i22, and Df(3R)e-R1] its activity [ Table 2; shown in Fig 5E and Fig F, and Fig 4C for Df(2L)dp-79b, Df(3R)e-F1, and Df(3R)B81]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i / identify-01 :ARG1 (m / molecular-physical-entity :quant "4" :ARG1-of (l / lack-01) :mod (o / only)) :ARG2 (i2 / induce-01 :ARG0 m :ARG2 (a / activate-01 :ARG1 (d2 / dna-sequence :name (n2 / name :op1 "HRE") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "ems") :xref (x / xref :value "UNIPROT:SRC8_HUMAN" :prob "0.202")))) :mod (e / ectopic)) :ARG1-of (s5 / specific-02))) :ARG2 (f / find-01 :ARG1 (m2 / molecular-physical-entity :quant "11" :ARG1-of (l2 / lack-01)) :ARG2 (o2 / or :op1 (r / reduce-01 :ARG0 (m3 / molecular-physical-entity :ARG1-of (i4 / include-91 :ARG2 m2) :ARG1-of (m4 / mean-01 :ARG2 (a4 / and :op1 (m5 / molecular-physical-entity :name (n4 / name :op1 "Df(2L)al")) :op2 (m6 / molecular-physical-entity :name (n5 / name :op1 "Df(2L)dp-79b") :ARG1-of (s2 / show-01 :ARG0 (f2 / figure :mod "5E"))) :op3 (m7 / molecular-physical-entity :name (n6 / name :op1 "Df(2L)TW84")) :op4 (m8 / molecular-physical-entity :name (n7 / name :op1 "Df(3L)lxd6")) :op5 (m9 / molecular-physical-entity :name (n8 / name :op1 "Df(3R)B81") :ARG1-of (s4 / show-01 :ARG0 (f4 / figure :mod "4C")))))) :ARG1 (a3 / activity-06 :ARG0 d2) :manner (s / severe)) :op2 (a2 / abolish-01 :ARG0 (m10 / molecular-physical-entity :ARG1-of (i3 / include-91 :ARG2 m2) :ARG1-of (m11 / mean-01 :ARG2 (a5 / and :op1 (m12 / molecular-physical-entity :name (n9 / name :op1 "Df(2L)H20")) :op2 (m13 / molecular-physical-entity :name (n10 / name :op1 "Df(2R)H3E1")) :op3 (m14 / molecular-physical-entity :name (n11 / name :op1 "Df(2R)Jp1")) :op4 (m15 / molecular-physical-entity :name (n12 / name :op1 "Df(2R)AA21")) :op5 (m16 / molecular-physical-entity :name (n13 / name :op1 "Df(3L)h-i22")) :op6 (m17 / molecular-physical-entity :name (n14 / name :op1 "Df(3R)e-R1") :ARG1-of (s3 / show-01 :ARG0 (f3 / figure :mod "5F")))))) :ARG1 a3))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "1"))) # ::id bio.chicago_2015.54288 # ::date 2015-11-01T13:02:46 # ::file bio_chicago_2015_54288.txt # ::snt Initially, ubiquitin is activated by the ATP-dependent formation of a high-energy thioester intermediate between the ubiquitin-activating enzyme (E1) and the C terminus of ubiquitin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / activate-01 :ARG0 (f / form-02 :ARG0 (a2 / and :op1 (e2 / enzyme :name (n5 / name :op1 "ubiquitin-activating" :op2 "enzyme") :xref (x1 / xref :value "UNIPROT:UBA3_HUMAN" :prob "0.392")) :op2 (p3 / protein-segment :name (n6 / name :op1 "C" :op2 "terminus") :part-of "p2")) :ARG1 (i / intermediate :mod (s2 / small-molecule :name (n4 / name :op1 "thioester") :mod (e / energy :ARG1-of (h / high-02)) :xref (x2 / xref :value "PUBCHEM:13526" :prob "8.563033"))) :ARG0-of (d / depend-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP") :xref (x3 / xref :value "PUBCHEM:5957" :prob "14.368295")))) :ARG1 (p2 / protein :name (n2 / name :op1 "ubiquitin") :xref (x / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :time (i2 / initial)) # ::id bio.chicago_2015.54303 # ::date 2015-11-01T13:10:11 # ::file bio_chicago_2015_54303.txt # ::snt To determine wether activation of JNK by SLK occurs through a known MEKK, transfections were performed in the presence of dominant negative versions of MEKK or SEK1, both upstream activators of JNK ( 13). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / perform-01 :ARG1 (t2 / transfect-01) :condition (p2 / present-02 :ARG1 (o / or :op1 (v / version :ARG0-of (d / dominate-01) :mod (e / enzyme :name (n2 / name :op1 "MEKK") :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003")) :ARG2-of (m / mutate-01 :mod "-/-")) :op2 (v2 / version :ARG0-of d :mod (e2 / enzyme :name (n3 / name :op1 "SEK1") :xref (x3 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003")) :ARG2-of m) :ARG0-of (a2 / activate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "JNK") :xref (x2 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :direction (u / upstream)))) :purpose (d2 / determine-01 :ARG1 (a3 / activate-01 :mode "interrogative" :ARG0 (e4 / enzyme :name (n5 / name :op1 "SLK") :xref (x1 / xref :value "UNIPROT:FYN_HUMAN" :prob "1.003")) :ARG1 e3 :manner (e5 / enzyme :name (n6 / name :op1 "MEKK") :ARG1-of (k / know-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "1.003"))))) # ::id bio.chicago_2015.54322 # ::date 2015-11-01T13:18:24 # ::file bio_chicago_2015_54322.txt # ::snt In PC12 cells, NGF activates CREB phosphorylation through sequential activation of Ras, Raf, MEK, ERK, and RSK ( Xing et al. 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG0 (p6 / protein :name (n5 / name :op1 "NGF") :xref (x4 / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")) :ARG1 (p / phosphorylate-01 :ARG1 (p7 / protein :name (n6 / name :op1 "CREB") :xref (x5 / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312"))) :manner (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "Ras") :xref (x6 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op3 (e3 / enzyme :name (n3 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op4 (e4 / enzyme :name (n4 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op5 (e5 / enzyme :name (n9 / name :op1 "RSK") :xref (x / xref :value "UNIPROT:KS6A1_HUMAN" :prob "0.262"))) :mod (s / sequential)) :location (c / cell-line :name (n7 / name :op1 "PC12")) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a4 / and :op1 (p9 / person :name (n8 / name :op1 "Xing")) :op2 (p10 / person :mod (o / other))) :time (d / date-entity :year "1996")))) # ::id bio.chicago_2015.54328 # ::date 2015-11-01T13:23:05 # ::file bio_chicago_2015_54328.txt # ::snt GTP-dependent adenylyl cyclase activity in control ( cn, ry) flies and flies expressing the activated Gsalpha subunit # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "adenylyl" :op2 "cyclase") :ARG0-of (d / depend-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x / xref :value "UNIPROT:ADCY1_HUMAN" :prob "0.392")) :location (a4 / and :op1 (f / fly :mod (c / control) :mod (o / organism :name (n4 / name :op1 "cn"))) :op2 (f3 / fly :mod c :mod (o2 / organism :name (n5 / name :op1 "ry"))))) :op2 (e2 / express-03 :ARG2 (s2 / subunit :part-of (p / protein :name (n3 / name :op1 "Gsalpha") :xref (x1 / xref :value "UNIPROT:Q14455_HUMAN" :prob "0.201")) :ARG1-of (a3 / activate-01)) :ARG3 (f2 / fly))) # ::id bio.chicago_2015.54349 # ::date 2015-11-01T13:30:45 # ::file bio_chicago_2015_54349.txt # ::snt (c) That Ephexin can also activate Cdc42 raises the possibility that it may function to control cytoskeletal dynamics downstream from attractant receptors through Pak activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (p2 / possible-01 :li "c" :ARG1 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "Ephexin") :xref (x2 / xref :value "UNIPROT:NGEF_HUMAN" :prob "0.363")) :ARG1 (p3 / protein :name (n2 / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :mod (a2 / also)) :ARG0-of (c / cause-01 :ARG1 (r / raise-01 :ARG1 (p4 / possible-01 :ARG1 (p5 / possible-01 :ARG1 (f / function-01 :ARG0 a :ARG1 (c2 / control-01 :ARG0 a :ARG1 (d2 / dynamic :mod (c3 / cytoskeletal)) :direction (d3 / downstream :op1 (r2 / receptor :ARG0-of (a3 / attract-01 :manner (a4 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Pak") :xref (x1 / xref :value "UNIPROT:PAK1_HUMAN" :prob "0.203"))))))))))))) # ::id bio.chicago_2015.54352 # ::date 2015-10-30T08:44:59 # ::file bio_chicago_2015_54352.txt # ::snt Since the expression of either active Rit or RGL3 is sufficient to induce Ral GDP/ GTP exchange, the amount of individual expression vectors was adjusted to limit endogenous Ral activation by either RitQ79L or RGL3 expression alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (a / adjust-01 :ARG1 (a2 / amount :quant-of (v / vector :ARG3-of (e / express-03) :mod (i / individual))) :ARG4 (l / limit-01 :ARG0 (o / or :op1 (e4 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "RitQ79L"))) :op2 (e5 / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "RGL3") :xref (x / xref :value "UNIPROT:RGL3_HUMAN" :prob "1.003"))) :mod (a4 / alone)) :ARG1 (a3 / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "Ral") :mod (e2 / endogenous) :xref (x2 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.603")))) :ARG1-of (c / cause-01 :ARG0 (s2 / suffice-01 :ARG0 (e3 / express-03 :ARG2 (o2 / or :op1 (p4 / protein :name (n5 / name :op1 "Rit") :xref (x1 / xref :value "UNIPROT:RIT1_HUMAN" :prob "0.603")) :op2 p2 :ARG1-of (a5 / activate-01))) :ARG1 (i2 / induce-01 :ARG0 e3 :ARG2 (e7 / exchange-01 :ARG0 p :ARG1 (s4 / small-molecule :name (n6 / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG3 (s / small-molecule :name (n / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645"))))))) # ::id bio.chicago_2015.54392 # ::date 2015-10-30T09:00:06 # ::file bio_chicago_2015_54392.txt # ::snt However, activation of Rap1 by both thrombin and TCR stimulation in platelets and T cells, respectively, displayed similar calcium dependences. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (d / display-01 :ARG0 (a / and :op1 (a2 / activate-01 :ARG0 (s2 / stimulate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "thrombin") :xref (x1 / xref :value "UNIPROT:THRB_HUMAN" :prob "0.292"))) :ARG1 (e / enzyme :name (n2 / name :op1 "Rap1") :xref (x2 / xref :value "UNIPROT:RABX5_HUMAN" :prob "0.603")) :location (c / cell :part-of (p / platelet))) :op2 (a3 / activate-01 :ARG0 (s3 / stimulate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "TCR") :xref (x / xref :value "UNIPROT:A2NZL2_HUMAN" :prob "1.001"))) :ARG1 e :location (c2 / cell :name (n5 / name :op1 "T"))) :mod (r / respective)) :ARG1 (d2 / depend-01 :ARG0 a :ARG1 (s / small-molecule :name (n / name :op1 "calcium") :xref (x3 / xref :value "PUBCHEM:5460341" :prob "10.601383")) :ARG1-of (r2 / resemble-01)))) # ::id bio.chicago_2015.54403 # ::date 2015-10-30T09:07:00 # ::file bio_chicago_2015_54403.txt # ::snt We demonstrate that inhibition of dMLK using gene silencing with RNAi specifically blocked JNK activation without inhibiting activation of p38 or ERK by ceramide (Figure 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (b / block-01 :ARG0 (i / inhibit-01 :ARG0 (u / use-01 :ARG1 (s / silence-01 :ARG0 (i2 / interfere-01 :ARG0 (n / nucleic-acid :name (n7 / name :op1 "RNA"))) :ARG1 (g / gene))) :ARG1 (e / enzyme :name (n2 / name :op1 "dMLK"))) :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK") :xref (x2 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :ARG1-of (s2 / specific-02) :manner (i3 / inhibit-01 :polarity "-" :ARG0 i :ARG1 (o / or :op1 (a2 / activate-01 :ARG0 (s3 / small-molecule :name (n6 / name :op1 "ceramide") :xref (x3 / xref :value "PUBCHEM:2498" :prob "8.570734")) :ARG1 (e3 / enzyme :name (n4 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))) :op2 (a3 / activate-01 :ARG0 s3 :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1E"))) # ::id bio.chicago_2015.54425 # ::date 2015-10-30T09:16:10 # ::file bio_chicago_2015_54425.txt # ::snt Activation of intracellular CaM-KII by GD3, GD1b, GT1b and its oligosaccharide. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / activate-01 :ARG0 (a2 / and :op1 (s / small-molecule :name (n2 / name :op1 "GD3") :xref (x3 / xref :value "PUBCHEM:45259178" :prob "10.138507")) :op2 (s2 / small-molecule :name (n3 / name :op1 "GD1b") :xref (x2 / xref :value "PUBCHEM:6450237" :prob "10.123801")) :op3 (s3 / small-molecule :name (n4 / name :op1 "GT1b") :xref (x1 / xref :value "PUBCHEM:45259176" :prob "16.321695")) :op4 (o / oligosaccharide :poss s3)) :ARG1 (e / enzyme :name (n / name :op1 "CaM-KII") :mod (i / intracellular) :xref (x / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.603"))) # ::id bio.chicago_2015.54432 # ::date 2015-10-30T09:21:50 # ::file bio_chicago_2015_54432.txt # ::snt All three RTKs are known to activate an overlapping set of intracellular signaling proteins, such as Ras, MAP kinase, PLC-gamma, and Src family kinases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (k / know-01 :ARG1 (a / activate-01 :ARG0 (e / enzyme :quant "3" :name (n2 / name :op1 "RTK") :mod (a2 / all) :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")) :ARG1 (s / set :ARG0-of (o / overlap-01) :consist-of (p2 / protein :mod (i / intracellular) :ARG0-of (s2 / signal-07) :example (a3 / and :op1 (p / protein-family :name (n / name :op1 "Ras")) :op2 (p3 / protein-family :name (n3 / name :op1 "MAP" :op2 "kinase")) :op3 (p4 / protein-family :name (n4 / name :op1 "PLC-gamma")) :op4 (p5 / protein-family :name (n5 / name :op1 "Src"))))))) # ::id bio.chicago_2015.54450 # ::date 2015-10-30T09:27:09 # ::file bio_chicago_2015_54450.txt # ::snt Because most extracellular stimuli that activate MKK7 also activate MKK4 in parallel, it is difficult to assess the function of MKK7 independently from MKK4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (d / difficult :domain (a / assess-01 :ARG1 (f / function-01 :ARG0 (e / enzyme :name (n / name :op1 "MKK7") :xref (x / xref :value "UNIPROT:MP2K7_HUMAN" :prob "1.003")) :manner (d2 / depend-01 :polarity "-" :ARG0 f :ARG1 (e2 / enzyme :name (n2 / name :op1 "MKK4") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003"))))) :ARG1-of (c / cause-01 :ARG0 (a2 / activate-01 :ARG0 (s / stimulus :quant (m / most) :mod (e3 / extracellular) :ARG0-of (a3 / activate-01 :ARG1 e)) :ARG1 e2 :mod (a4 / also) :manner (p / parallel)))) # ::id bio.chicago_2015.54455 # ::date 2015-10-30T09:32:05 # ::file bio_chicago_2015_54455.txt # ::snt induction of cyclin D1 is required for S-phase entry in Rb-expressing cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / require-01 :ARG0 (e / enter-01 :ARG0 (c / cell :ARG3-of (e2 / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "Rb") :xref (x / xref :value "UNIPROT:RB_HUMAN" :prob "1.003")))) :ARG1 (e3 / event :name (n3 / name :op1 "S-phase"))) :ARG1 (i / induce-01 :ARG2 (p / protein :name (n / name :op1 "cyclin" :op2 "D1") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")))) # ::id bio.chicago_2015.54458 # ::date 2015-10-30T09:35:21 # ::file bio_chicago_2015_54458.txt # ::snt Phosphoinositides, particularly PIP2, formed secondarily to ARF activation of phospholipase D, have been implicated in the recruitment of COPI coat proteins onto the membranes of the Golgi stacks ( Donaldson et al. 1992 ; Palmer et al. 1993 ; Ktistakis et al. 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / implicate-01 :ARG1 (a / and :op1 (s / small-molecule :name (n / name :op1 "phosphoinositide") :xref (x5 / xref :value "PUBCHEM:16738692" :prob "18.86067")) :op2 (s2 / small-molecule :name (n2 / name :op1 "PIP2") :manner (p / particular) :xref (x4 / xref :value "PUBCHEM:125105" :prob "8.592926")) :ARG1-of (f / form-01 :ARG2 (a2 / activate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "ARF") :xref (x / xref :value "UNIPROT:ARF_HUMAN" :prob "1.002")) :ARG1 (e / enzyme :name (n4 / name :op1 "phospholipase" :op2 "D") :xref (x2 / xref :value "UNIPROT:PLD1_HUMAN" :prob "0.393"))) :manner (s3 / secondary))) :ARG2 (r / recruit-01 :ARG1 (p10 / protein :name (n5 / name :op1 "COPI" :op2 "coat" :op3 "protein") :xref (x1 / xref :value "UNIPROT:ATOX1_HUMAN" :prob "0.202")) :ARG2 (m2 / membrane :part-of (s4 / stack :mod (t / thing :name (n9 / name :op1 "Golgi"))) :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and :op1 (p3 / publication-91 :ARG0 (a4 / and :op1 (p4 / person :name (n6 / name :op1 "Donaldson")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "1992")) :op2 (p6 / publication-91 :ARG0 (a5 / and :op1 (p7 / person :name (n7 / name :op1 "Palmer")) :op2 p5) :time (d2 / date-entity :year "1993")) :op3 (p8 / publication-91 :ARG0 (a6 / and :op1 (p9 / person :name (n8 / name :op1 "Ktistakis")) :op2 p5) :time (d3 / date-entity :year "1996"))))) # ::id bio.chicago_2015.54513 # ::date 2015-10-30T09:44:08 # ::file bio_chicago_2015_54513.txt # ::snt For example, in most pheochromocytoma 12 (PC12) cell lines, transient Erk activation [evoked by epidermal growth factor (EGF)] results in cell proliferation, whereas sustained Erk activation (evoked by NGF) causes these cells to leave the cell cycle and differentiate toward a neuronal phenotype (Traverse et al., 1992 ; Yaka et al., 1998 ; York et al., 1998 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / result-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "Erk") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :ARG1-of (t / transient-02) :ARG1-of (e3 / evoke-01 :ARG0 (p10 / protein :name (n3 / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703")))) :ARG2 (p2 / proliferate-01 :ARG0 "c7")) :ARG2 (c3 / cause-01 :ARG0 (a2 / activate-01 :ARG1 e :ARG1-of (s2 / sustain-01) :ARG1-of (e4 / evoke-01 :ARG0 (p11 / protein :name (n4 / name :op1 "NGF") :xref (x1 / xref :value "UNIPROT:NGF_HUMAN" :prob "1.004")))) :ARG1 (a3 / and :op1 (l / leave-11 :ARG0 "c7" :ARG1 (c2 / cycle-02 :ARG1 (c6 / cell))) :op2 (d3 / differentiate-101 :ARG1 "c7" :ARG3 (p / phenotype :mod (n5 / neuron))))) :ARG0-of (e5 / exemplify-01) :location (c7 / cell-line :name (n6 / name :op1 "pheochromocytoma" :op2 "12") :quant (m / most)) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and :op1 (p3 / publication-91 :ARG0 (a5 / and :op1 (p4 / person :name (n7 / name :op1 "Traverse")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "1992")) :op2 (p6 / publication-91 :ARG0 (a6 / and :op1 (p7 / person :name (n8 / name :op1 "Yaka")) :op2 p5) :time (d2 / date-entity :year "1998")) :op3 (p8 / publication-91 :ARG0 (a7 / and :op1 (p9 / person :name (n9 / name :op1 "York")) :op2 p5) :time d2)))) # ::id bio.chicago_2015.54546 # ::date 2015-10-30T09:56:15 # ::file bio_chicago_2015_54546.txt # ::snt Exchange of T145, Q156, K157, Q166, T167, K171, or H175 for alanine enhanced transactivation by Raf basal activity 1.5- to 2.5-fold and increased Ras(G12V)-induced Raf activation accordingly, to 1.5- to 2-fold over the activity achieved by activation of Raf(wt) by Ras(G12V) (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (a / and :op1 (e / enhance-01 :ARG0 (e2 / exchange-01 :ARG1 (o / or :op1 (a2 / amino-acid :mod "145" :name (n / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a3 / amino-acid :mod "156" :name (n2 / name :op1 "glutamine") :xref (x2 / xref :value "PUBCHEM:738" :prob "11.972775")) :op3 (a4 / amino-acid :mod "157" :name (n3 / name :op1 "lysine") :xref (x5 / xref :value "PUBCHEM:866" :prob "11.053295")) :op4 (a5 / amino-acid :mod "166" :name (n4 / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :op5 (a6 / amino-acid :mod "167" :name (n5 / name :op1 "glutamine") :xref (x7 / xref :value "PUBCHEM:738" :prob "11.972775")) :op7 (a7 / amino-acid :mod "171" :name (n6 / name :op1 "lysine") :xref (x6 / xref :value "PUBCHEM:866" :prob "11.053295")) :op8 (a8 / amino-acid :mod "175" :name (n7 / name :op1 "histidine") :xref (x9 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :ARG3 (a9 / amino-acid :name (n8 / name :op1 "alanine") :xref (x8 / xref :value "PUBCHEM:602" :prob "10.089661"))) :ARG1 (t / transactivate-01 :ARG2 (a10 / activity-06 :ARG0 (e3 / enzyme :name (n9 / name :op1 "Raf") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :mod (b / basal))) :ARG3 (v / value-interval :op1 (p / product-of :op1 "1.5") :op2 (p2 / product-of :op1 "2.5"))) :op2 (i / increase-01 :ARG0 e2 :ARG1 (a11 / activate-01 :ARG1 e3 :ARG2-of (i2 / induce-01 :ARG0 (e4 / enzyme :name (n10 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 v :ARG4 (m2 / more-than :op1 (a13 / activity-06 :ARG1-of (a14 / achieve-01 :ARG0 (a15 / activate-01 :ARG0 e4 :ARG1 e3)))) :manner (a12 / accordingly)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id bio.chicago_2015.54584 # ::date 2015-10-30T10:21:30 # ::file bio_chicago_2015_54584.txt # ::snt Previous studies have shown that rRNA transcription is up-regulated in both mammalian ( 1, 51) and Drosophila ( 54, 64) cells by the phorbol ester tetradecanoyl phorbol acetate ( TPA), a potent activator of protein kinase C (PKC). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (s2 / study-01 :time (p / previous)) :ARG1 (u / upregulate-01 :ARG1 (t2 / transcribe-01 :ARG1 (n5 / nucleic-acid :name (n / name :op1 "rRNA"))) :ARG2 (e / ester :name (n2 / name :op1 "tetradecanoyl" :op2 "phorbol" :op3 "acetate") :mod (s3 / small-molecule :name (n3 / name :op1 "phorbol") :xref (x1 / xref :value "PUBCHEM:290670" :prob "14.445852")) :ARG0-of (a5 / activate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "protein" :op2 "kinase" :op3 "C") :xref (x / xref :value "UNIPROT:A0A087X0I9_HUMAN" :prob "0.701")) :mod (p6 / potent))) :location (a2 / and :op1 (c / cell :mod (m / mammal) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "1")) :op2 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "51"))))) :op2 (c2 / cell :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "54")) :op2 (p5 / publication :ARG1-of (c6 / cite-01 :ARG2 "64")))) :mod (o / organism :name (n6 / name :op1 "Drosophila")))))) # ::id bio.chicago_2015.54586 # ::date 2015-10-31T09:37:26 # ::file bio_chicago_2015_54586.txt # ::snt S6k1 is one of the major cellular targets for the immunosuppressant rapamycin and it was recognised several years ago that IL-2 activation of p70S6k was blocked by rapamycin [ 28]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (a / and :op1 (t3 / thing :quant "1" :ARG1-of (t2 / target-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "rapamycin") :ARG0-of (s3 / suppress-01 :ARG1 (i / immunity)) :xref (x3 / xref :value "PUBCHEM:5040" :prob "15.003454")) :mod (c / cell)) :domain (e / enzyme :name (n3 / name :op1 "S6k1") :xref (x1 / xref :value "UNIPROT:KS6B1_HUMAN" :prob "0.653")) :ARG1-of (m / major-02)) :op2 (r / recognize-02 :ARG1 (b3 / block-01 :ARG0 s2 :ARG1 (a2 / activate-01 :ARG0 (p / protein :name (n5 / name :op1 "IL-2") :xref (x2 / xref :value "UNIPROT:IL2_HUMAN" :prob "1.003")) :ARG1 (p2 / protein :name (n6 / name :op1 "p70S6k") :xref (x / xref :value "UNIPROT:KS6B1_HUMAN" :prob "0.303")))) :time (b / before :op1 (n / now) :quant (s / several :op1 (t / temporal-quantity :quant "1" :unit (y / year))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "28")))) # ::id bio.chicago_2015.54598 # ::date 2015-10-31T09:50:46 # ::file bio_chicago_2015_54598.txt # ::snt We initially utilized the dsRNAi-mediated gene silencing method (Clemens et al., 2000 ) to identify an agonist that induces JNK activation through dMLK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (u / utilize-01 :ARG0 (w / we) :ARG1 (m / method :ARG0-of (s / silence-01 :ARG1 (g / gene)) :ARG1-of (m2 / mediate-01 :ARG0 (i2 / interfere-01 :ARG0 (n5 / nucleic-acid :name (n / name :op1 "dsRNA")))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n2 / name :op1 "Clemens")) :op2 (p3 / person :mod (o / other)) :time (d / date-entity :year "2000"))))) :time (i / initial) :purpose (i3 / identify-01 :ARG0 w :ARG1 (a2 / agonist :ARG0-of (i4 / induce-01 :ARG2 (a3 / activate-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "dMLK")) :ARG1 (e / enzyme :name (n3 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))))))) # ::id bio.chicago_2015.54639 # ::date 2015-10-31T09:56:07 # ::file bio_chicago_2015_54639.txt # ::snt This finding was unexpected, since in vitro aMKII, when compared to CaMKIV, is a more potent activator of CREB Ser133 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (e / expect-01 :polarity "-" :ARG1 (t2 / thing :mod (t3 / this) :ARG1-of (f / find-01)) :ARG1-of (c / cause-01 :ARG0 (e3 / enzyme :name (n / name :op1 "CaMKII") :ARG0-of (a2 / activate-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "133" :name (n2 / name :op1 "serine") :part-of (p / protein :name (n3 / name :op1 "CREB") :xref (x / xref :value "UNIPROT:CREB1_HUMAN" :prob "0.312")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :mod (p2 / potent :degree (m2 / more) :compared-to (e4 / enzyme :name (n4 / name :op1 "CaMKIV") :xref (x1 / xref :value "UNIPROT:KCC4_HUMAN" :prob "0.693"))) :manner (i / in-vitro)) :xref (x2 / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.643")))) # ::id bio.chicago_2015.54645 # ::date 2015-10-31T10:03:06 # ::file bio_chicago_2015_54645.txt # ::snt Whereas MKK4 also activates p38 MAPK, experiments with ectopically expressed or recombinant MKK7 revealed that it activates JNK but not ERK or p38 MAPKs in vivo and in vitro ( 3-6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c2 / contrast-01 :ARG1 (r / reveal-01 :ARG0 (e / experiment-01 :ARG2 (o / or :op1 (e2 / enzyme :name (n3 / name :op1 "MKK7") :ARG2-of (e3 / express-03 :manner (e4 / ectopic)) :xref (x3 / xref :value "UNIPROT:MP2K7_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n4 / name :op1 "MKK7") :ARG1-of (r2 / recombine-01) :xref (x1 / xref :value "UNIPROT:MP2K7_HUMAN" :prob "1.003")))) :ARG1 (c / contrast-01 :ARG1 (a / activate-01 :ARG0 o :ARG1 (e6 / enzyme :name (n5 / name :op1 "JNK") :xref (x2 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :ARG2 (a2 / activate-01 :polarity "-" :ARG0 o :ARG1 (o2 / or :op1 (p3 / protein-family :name (n6 / name :op1 "ERK")) :op2 (p2 / protein-family :name (n7 / name :op1 "p38" :op2 "MAPK")))) :manner (a3 / and :op1 (i / in-vivo) :op2 (i2 / in-vitro)))) :ARG2 (a4 / activate-01 :ARG0 (e9 / enzyme :name (n8 / name :op1 "MKK4") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003")) :ARG1 p2 :mod (a5 / also)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 "3" :op2 "6"))))) # ::id bio.chicago_2015.54654 # ::date 2015-10-31T10:09:50 # ::file bio_chicago_2015_54654.txt # ::snt Phototransduction in Drosophila is mediated by a phosphoinositide (PI) cascade, whereby absorption of light by rhodopsin activates sequentially a heterotrimeric Gq protein and phospholipase C (PLC) (reviewed by Hardie and Minke 1995 ; Minke and Selinger 1996 ; Scott and Zuker 1998a ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / contrast-01 :ARG1 (m / mediate-01 :ARG0 (c2 / cascade :mod (s / small-molecule :name (n / name :op1 "phosphoinositide") :xref (x2 / xref :value "PUBCHEM:16738692" :prob "18.86067"))) :ARG1 (t / transduce-01 :ARG1 "l") :location (o / organism :name (n10 / name :op1 "Drosophila"))) :ARG2 (a / activate-01 :ARG0 (a2 / absorb-01 :ARG0 (p2 / protein :name (n2 / name :op1 "rhodopsin") :xref (x / xref :value "UNIPROT:Q16415_HUMAN" :prob "1.001")) :ARG1 (l / light)) :ARG1 (a3 / and :op1 (p / protein :name (n3 / name :op1 "Gq") :mod (h / heterotrimeric)) :op2 (e / enzyme :name (n4 / name :op1 "phospholipase" :op2 "C") :xref (x1 / xref :value "UNIPROT:PLCB1_HUMAN" :prob "0.393"))) :manner (s2 / sequence)) :ARG1-of (d5 / describe-01 :ARG0 (a4 / and :op1 (p3 / publication-91 :ARG1-of (r / review-01 :ARG0 (a5 / and :op1 (p4 / person :name (n5 / name :op1 "Hardie")) :op2 (p5 / person :name (n6 / name :op1 "Minke")))) :time (d / date-entity :year "1995")) :op2 (p6 / publication-91 :ARG0 (a6 / and :op1 p5 :op2 (p7 / person :name (n7 / name :op1 "Selinger"))) :time (d2 / date-entity :year "1996")) :op3 (p8 / publication-91 :ARG0 (a7 / and :op1 (p9 / person :name (n8 / name :op1 "Scott")) :op2 (p10 / person :name (n9 / name :op1 "Zuker"))) :time (d3 / date-entity :year "1998"))))) # ::id bio.chicago_2015.54672 # ::date 2015-10-31T10:18:04 # ::file bio_chicago_2015_54672.txt # ::snt KSR inhibits ERK MAP kinase activation by activated forms of Ras, Raf, and MEK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (i / inhibit-01 :ARG0 (e / enzyme :name (n5 / name :op1 "KSR") :xref (x / xref :value "UNIPROT:KSR1_HUMAN" :prob "1.003")) :ARG1 (a / activate-01 :ARG0 (a2 / and :op1 (e2 / enzyme :name (n7 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n8 / name :op1 "Raf") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op3 (e4 / enzyme :name (n9 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (a3 / activate-01)) :ARG1 (k / kinase :name (n6 / name :op1 "ERK" :op2 "MAP") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.203")))) # ::id bio.chicago_2015.54723 # ::date 2015-10-31T10:20:18 # ::file bio_chicago_2015_54723.txt # ::snt From in vitro experiments using cultured cells and biochemical assays, Dbl is known to activate mainly Rho and Cdc42. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (k / know-01 :ARG1 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "Dbl") :xref (x2 / xref :value "UNIPROT:MCF2_HUMAN" :prob "0.603")) :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Rho") :xref (x / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")) :op2 (p3 / protein :name (n3 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634"))) :manner (m / main)) :ARG1-of (c / cause-01 :ARG0 (e2 / experiment-01 :manner (i / in-vitro) :ARG0-of (u / use-01 :ARG1 (a3 / and :op1 (c2 / cell :ARG1-of (c3 / culture-01)) :op2 (a4 / assay-01 :mod (b / biochemistry))))))) # ::id bio.chicago_2015.54732 # ::date 2015-10-31T10:25:08 # ::file bio_chicago_2015_54732.txt # ::snt At concentrations substantially greater than those required to modulate the GABA-evoked response, 5 3 (300 nM-10 M) directly (i.e. in the absence of GABA) activated all the recombinant GABAA receptors investigated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / activate-01 :ARG0 (a4 / amr-unintelligible :value "53") :ARG1 (p / protein :name (n / name :op1 "GABAA" :op2 "receptor") :ARG0-of (r / recombine-01) :mod (a2 / all) :ARG1-of (i / investigate-01) :xref (x / xref :value "UNIPROT:GBRR1_HUMAN" :prob "0.382")) :ARG1-of (d / direct-02 :ARG1-of (m2 / mean-01 :ARG2 (a3 / absent-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "GABA") :xref (x1 / xref :value "PUBCHEM:119" :prob "14.989469"))))) :condition (c / concentrate-02 :ARG1 a4 :mod (g / great :degree (m / more) :manner (s / substantial) :compared-to (c2 / concentrate-01 :ARG1-of (r2 / require-01 :ARG0 (m3 / modulate-01 :ARG1 (r3 / respond-01 :ARG1-of (e / evoke-01 :ARG0 s2)))))) :ARG1-of (m4 / mean-01 :ARG2 (v / value-interval :op1 (c4 / concentration-quantity :quant "300" :unit (n3 / nanomolar)) :op2 (c5 / concentration-quantity :quant "10" :unit (m5 / molar)))))) # ::id bio.chicago_2015.54762 # ::date 2015-10-31T10:35:16 # ::file bio_chicago_2015_54762.txt # ::snt However, TNF , IL-1, and LPS are potent activators of the IKK and JNK pathways, which lead to stimulation of NF- B and AP-1 activities. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (h / have-concession-91 :ARG1 (a2 / and :op1 (p / protein :wiki "Tumor_necrosis_factors" :name (n / name :op1 "TNF") :xref (x3 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (p2 / protein :wiki "Interleukin_1_family" :name (n2 / name :op1 "IL-1") :xref (x / xref :value "UNIPROT:I36RA_HUMAN" :prob "0.382")) :op3 (m / molecular-physical-entity :wiki "Lipopolysaccharide" :name (n3 / name :op1 "LPS") :xref (x4 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :ARG0-of (a3 / activate-01 :ARG1 (a4 / and :op1 (p4 / pathway :wiki "-" :name (n4 / name :op1 "IKK")) :op2 (p5 / pathway :wiki "-" :name (n5 / name :op1 "JNK")) :ARG0-of (l / lead-03 :ARG2 (s / stimulate-01 :ARG1 (a / and :op1 (a5 / activity-06 :ARG0 (p7 / protein :wiki "NF-κB" :name (n6 / name :op1 "NF-B") :xref (x2 / xref :value "UNIPROT:RRP5_HUMAN" :prob "0.202"))) :op2 (a6 / activity-06 :ARG0 (p6 / protein :wiki "AP-1_transcription_factor" :name (n7 / name :op1 "AP-1") :xref (x1 / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))))))) :mod (p3 / potent)))) # ::id bio.chicago_2015.54870 # ::date 2015-10-31T10:39:43 # ::file bio_chicago_2015_54870.txt # ::snt Note that importin beta, the importin alpha/ beta heterodimer, transportin, RanBP5 and RanBP7 all bound specifically to rpL23a. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (n / note-01 :mode "imperative" :ARG0 (y / you) :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "importin" :op2 "beta") :xref (x5 / xref :value "UNIPROT:TNPO1_HUMAN" :prob "0.393")) :op2 (h / heterodimer :part (p2 / protein :name (n3 / name :op1 "importin" :op2 "alpha") :xref (x / xref :value "UNIPROT:IMA3_HUMAN" :prob "0.382")) :part p) :op3 (p3 / protein :name (n4 / name :op1 "transportin") :xref (x3 / xref :value "UNIPROT:TNPO1_HUMAN" :prob "0.383")) :op4 (p4 / protein :name (n5 / name :op1 "RanBP5") :xref (x2 / xref :value "UNIPROT:IPO5_HUMAN" :prob "1.002")) :op5 (p5 / protein :name (n6 / name :op1 "RanBP7") :xref (x4 / xref :value "UNIPROT:RANB9_HUMAN" :prob "1.003")) :mod (a2 / all)) :ARG2 (p6 / protein :name (n7 / name :op1 "rpL23a") :xref (x1 / xref :value "UNIPROT:RL23A_HUMAN" :prob "0.622")) :ARG1-of (s / specific-02))) # ::id bio.chicago_2015.54875 # ::date 2015-10-31T10:44:33 # ::file bio_chicago_2015_54875.txt # ::snt Indeed, transcriptional repression by Gal4 fusions to PHO polypeptides that could bind PC [PHO(1-356) and PHO(118-172)] was markedly enhanced by overexpression of PC (Fig. 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (e / enhance-01 :ARG0 (o2 / overexpress-01 :ARG1 "p2") :ARG1 (r / repress-01 :ARG0 (f / fuse-01 :ARG1 (g / gene :name (n2 / name :op1 "Gal4") :xref (x1 / xref :value "UNIPROT:LEG4_HUMAN" :prob "0.672")) :ARG2 (p / polypeptide :name (n4 / name :op1 "PHO") :ARG1-of (b3 / bind-01 :ARG2 (p2 / protein :name (n5 / name :op1 "PC") :xref (x / xref :value "UNIPROT:PODXL_HUMAN" :prob "1.002")) :ARG1-of (p5 / possible-01)) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (p6 / protein-segment :quant (b / between :op1 "1" :op2 "356")) :op2 (p7 / protein-segment :quant (b2 / between :op1 "118" :op2 "172")) :part-of p)))) :ARG1 (t / transcribe-01)) :ARG1-of (m2 / mark-01) :mod (i / indeed) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "7B"))) # ::id bio.chicago_2015.54886 # ::date 2015-10-31T10:56:11 # ::file bio_chicago_2015_54886.txt # ::snt Binding of ERM Proteins to CD43 and ICAM-2 As Well As CD44 through Their Juxta-Membrane Positively Charged Amino Acid Clusters # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (c / charge-03 :ARG0 (b / bind-01 :ARG1 (p / protein-family :name (n / name :op1 "ERM")) :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "CD43") :xref (x / xref :value "UNIPROT:LEUK_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n3 / name :op1 "ICAM-2") :xref (x2 / xref :value "UNIPROT:ICAM2_HUMAN" :prob "1.002")) :op3 (p4 / protein :name (n4 / name :op1 "CD44") :xref (x1 / xref :value "UNIPROT:CD44_HUMAN" :prob "1.004"))) :ARG3 (m / membrane :mod (j / juxtra) :poss p :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :ARG1 (c2 / cluster-01 :ARG1 (a2 / amino-acid)) :manner (p5 / positive)) # ::id bio.chicago_2015.54932 # ::date 2015-10-31T11:00:12 # ::file bio_chicago_2015_54932.txt # ::snt Significant binding of Arp1 to the DI and DIII constructs was observed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (o / observe-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Arp1") :xref (x1 / xref :value "UNIPROT:ACTZ_HUMAN" :prob "0.602")) :ARG2 (a / and :op1 (c / construct-01 :ARG2 (p2 / protein :name (n2 / name :op1 "DI") :xref (x / xref :value "UNIPROT:B3AT_HUMAN" :prob "1.002"))) :op2 (c2 / construct-01 :ARG1 (p3 / protein :name (n3 / name :op1 "DIII")))) :ARG1-of (s / significant-02))) # ::id bio.chicago_2015.54956 # ::date 2015-10-31T11:03:18 # ::file bio_chicago_2015_54956.txt # ::snt The above data support the idea that eIF4G just binds a single eIF4A molecule, either eIF4AI or eIF4AII. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (s / support-01 :ARG0 (d / data :location (a / above)) :ARG1 (i / idea :topic (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "eIF4G") :xref (x2 / xref :value "UNIPROT:IF4G1_HUMAN" :prob "0.702")) :ARG2 (m / molecule :part-of (p2 / protein-family :name (n2 / name :op1 "eIF4A")) :ARG1-of (s2 / single-02) :ARG1-of (m2 / mean-01 :ARG2 (o / or :op1 (p3 / protein :name (n3 / name :op1 "eIF4AI") :xref (x1 / xref :value "UNIPROT:IF4A1_HUMAN" :prob "0.692")) :op2 (p4 / protein :name (n4 / name :op1 "eIF4AII") :xref (x / xref :value "UNIPROT:IF4A2_HUMAN" :prob "0.692"))))) :mod (j / just)))) # ::id bio.chicago_2015.54971 # ::date 2015-10-31T11:07:27 # ::file bio_chicago_2015_54971.txt # ::snt We have hypothesized that the binding of PP2A to the Axin complex might counteract the phosphorylation of beta-catenin by GSK3beta (Hsu et al., 1999 ) that could account for the increased ventralization activity in the absence of this domain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (h2 / hypothesize-01 :ARG0 (w2 / we) :ARG1 (p / possible-01 :ARG1 (c / counteract-01 :ARG0 (b / bind-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "PP2A") :xref (x1 / xref :value "UNIPROT:PP2AA_HUMAN" :prob "0.372")) :ARG2 (m / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "Axin") :xref (x2 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")))) :ARG1 (p2 / phosphorylate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "beta-catenin") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :ARG2 (e3 / enzyme :name (n5 / name :op1 "GSK3" :op2 "beta") :xref (x / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :ARG0-of (a / account-01 :ARG1 (a2 / activity-06 :ARG1 (v / ventralization) :ARG1-of (i / increase-01)) :ARG1-of (p5 / possible-01) :condition (a3 / absent-01 :ARG1 (d2 / domain :mod (t / this)))))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :name (n6 / name :op1 "Hsu")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "1999"))))) # ::id bio.chicago_2015.54984 # ::date 2015-10-31T11:14:39 # ::file bio_chicago_2015_54984.txt # ::snt CEP2 and CEP5 bind to Cdc42. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "CEP2") :xref (x2 / xref :value "UNIPROT:BORG1_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "CEP5") :xref (x / xref :value "UNIPROT:BORG3_HUMAN" :prob "1.002"))) :ARG2 (p3 / protein :name (n3 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634"))) # ::id bio.chicago_2015.55013 # ::date 2015-10-31T11:15:58 # ::file bio_chicago_2015_55013.txt # ::snt We also introduced two amino acid substitutions into the JNK-binding motif of JIP3 ( Kelkar et al., 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Oct 31, 2015 (i / introduce-02 :ARG0 (w / we) :ARG1 (s / substitute-01 :quant "2" :ARG1 (a2 / amino-acid) :location (p / protein-segment :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :part-of (p2 / protein :name (n2 / name :op1 "JIP3") :xref (x / xref :value "UNIPROT:JIP3_HUMAN" :prob "1.003")))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n3 / name :op1 "Kelkar")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2000")))) # ::id bio.chicago_2015.55022 # ::date 2015-10-31T11:19:21 # ::file bio_chicago_2015_55022.txt # ::snt NF-1 was detected as described for panel B. (D) GR and hSwi/ nf facilitation of binding of NF-1 to MMTV chromatin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / multi-sentence :snt1 (d / detect-01 :ARG1 (p / protein :name (n / name :op1 "NF-1") :xref (x3 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.653")) :ARG2-of (d2 / describe-01 :ARG1 (p2 / panel :ARG1-of (l / label-01 :ARG2 (s / string-entity :value "B"))))) :snt2 (f / facilitate-01 :li "D" :ARG0 (a / and :op1 (p3 / protein :name (n2 / name :op1 "GR") :xref (x / xref :value "UNIPROT:GCR_HUMAN" :prob "1.002")) :op2 (m2 / macro-molecular-complex :part (p4 / protein :name (n3 / name :op1 "hSwi")) :part (p5 / protein :name (n4 / name :op1 "hSnf") :xref (x2 / xref :value "UNIPROT:CHM4A_HUMAN" :prob "0.292")))) :ARG1 (b / bind-01 :ARG1 (p6 / protein :name (n5 / name :op1 "NF-1") :xref (x1 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.653")) :ARG2 (m3 / macro-molecular-complex :name (n7 / name :op1 "chromatin") :part-of (o / organism :name (n6 / name :op1 "MMTV")))))) # ::id bio.chicago_2015.55025 # ::date 2015-10-31T11:31:36 # ::file bio_chicago_2015_55025.txt # ::snt Effects of Tcf3 phosphorylation on its activity These experiments establish that both GSK3 and CK1epsilon can bind and phosphorylate Tcf3 and suggest a possible role for both GSK3 and CK1epsilon in modulating Tcf3 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (m / multi-sentence :snt1 (a / affect-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein :wiki "TCF3" :name (n / name :op1 "Tcf3") :xref (x / xref :value "UNIPROT:TF7L1_HUMAN" :prob "0.602"))) :ARG1 (a2 / activity-06 :ARG0 p2)) :snt2 (a3 / and :op1 (e / establish-01 :ARG0 (e2 / experiment-01 :mod (t / this)) :ARG1 (p3 / possible-01 :ARG1 (a5 / and :op1 (b / bind-01 :ARG1 (a4 / and :op1 (e3 / enzyme :wiki "GSK-3" :name (n2 / name :op1 "GSK3") :xref (x2 / xref :value "UNIPROT:GSK3A_HUMAN" :prob "0.312")) :op2 (p4 / protein :wiki "Casein_kinase_1_isoform_epsilon" :name (n3 / name :op1 "CK1epsilon") :xref (x3 / xref :value "UNIPROT:Q5R2U3_HUMAN" :prob "0.201"))) :ARG2 "p6") :op2 (p5 / phosphorylate-01 :ARG1 (p6 / protein :wiki "TCF3" :name (n4 / name :op1 "Tcf3") :xref (x1 / xref :value "UNIPROT:TF7L1_HUMAN" :prob "0.602")) :ARG2 a4)))) :op2 (s / suggest-01 :ARG0 e2 :ARG1 (r / role :ARG1-of (p7 / possible-01) :poss a4 :topic (m2 / modulate-01 :ARG0 a4 :ARG1 (a6 / activity-06 :ARG0 p6)))))) # ::id bio.chicago_2015.55068 # ::date 2015-10-31T11:42:23 # ::file bio_chicago_2015_55068.txt # ::snt As shown in Table I, RitS35N, which corresponds to the RasS17N dominant negative mutant and would be expected to be predominantly GDP-bound, showed no detectable interaction with RGL3-RBD, suggesting that RGL3 showed preferential binding to the active GTP-bound form of Rit. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / show-01 :ARG0 (p / protein :name (n / name :op1 "RitS35N") :ARG0-of (c / correspond-01 :ARG1 (p2 / protein :name (n2 / name :op1 "RasS17N") :ARG2-of (m / mutate-01 :mod "-/-") :ARG1-of (d / dominate-01))) :ARG1-of (b / bind-01 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG1-of (p3 / predominate-01 :ARG1-of (e / expect-01)))) :ARG1 (i / interact-01 :polarity "-" :ARG0 p :ARG1 (p5 / protein :name (n5 / name :op1 "RGL3-RBD") :xref (x1 / xref :value "UNIPROT:RGL3_HUMAN" :prob "0.262")) :ARG1-of (d2 / detect-01 :ARG1-of (p4 / possible-01))) :ARG0-of (s3 / suggest-01 :ARG1 (s4 / show-01 :ARG0 (p6 / protein :name (n6 / name :op1 "RGL3") :xref (x / xref :value "UNIPROT:RGL3_HUMAN" :prob "1.003")) :ARG1 (b2 / bind-01 :ARG1 p6 :ARG2 (p8 / protein :name (n7 / name :op1 "Rit") :ARG1-of (a / activate-01) :ARG1-of (b3 / bind-01 :ARG2 (s5 / small-molecule :name (n8 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x2 / xref :value "UNIPROT:RIT1_HUMAN" :prob "0.603")) :ARG1-of (p7 / prefer-01 :ARG0 p6)))) :ARG1-of (s6 / show-01 :medium (t / table :mod "I"))) # ::id bio.chicago_2015.55070 # ::date 2015-11-01T11:26:56 # ::file bio_chicago_2015_55070.txt # ::snt ( A) p120ctn isoforms bind to both GST-Prox and GST-FL. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (b / bind-01 :li "A" :ARG1 (i / isoform :mod (p / protein :name (n / name :op1 "p120ctn") :xref (x2 / xref :value "UNIPROT:CTND1_HUMAN" :prob "0.663"))) :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "GST-Prox") :xref (x / xref :value "UNIPROT:GSTP1_HUMAN" :prob "0.212")) :op2 (p3 / protein :name (n3 / name :op1 "GST-FL") :xref (x1 / xref :value "UNIPROT:CHST3_HUMAN" :prob "0.232")))) # ::id bio.chicago_2015.55128 # ::date 2015-11-01T11:28:46 # ::file bio_chicago_2015_55128.txt # ::snt In stark contrast to the Sly1p/Sed5p-complex, Munc18a binds syntaxin in the central cleft via interactions that involve both the Habc domain and the SNARE motif (Misura et al., 2000 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (b / bind-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Munc18a") :xref (x / xref :value "UNIPROT:UN13A_HUMAN" :prob "0.262")) :ARG2 (c2 / cleft :mod (c3 / center) :part-of (p4 / protein :name (n4 / name :op1 "syntaxin") :xref (x1 / xref :value "UNIPROT:STX2_HUMAN" :prob "0.352"))) :ARG3 (i / interact-01 :ARG0-of (i2 / involve-01 :ARG1 (a / and :op1 (p5 / protein-segment :name (n5 / name :op1 "Habc")) :op2 (p6 / protein-segment :name (n6 / name :op1 "SNARE")) :part-of p4))) :ARG1-of (c / contrast-01 :ARG2 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "Sly1p") :xref (x2 / xref :value "UNIPROT:SCFD1_HUMAN" :prob "1.002")) :part (p2 / protein :name (n2 / name :op1 "Sed5p"))) :mod (s / stark)) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a2 / and :op1 (p8 / person :name (n7 / name :op1 "Misura")) :op2 (p9 / person :mod (o / other))) :time (d / date-entity :year "2000")))) # ::id bio.chicago_2015.55187 # ::date 2015-11-01T11:35:51 # ::file bio_chicago_2015_55187.txt # ::snt (A) Gab1 mutants were expressed as LexA-tpr-met fusion proteins and tested for yeast two-hybrid interactions with substrates as in Fig 3 A. CBR represents the CRKL-binding region of Gab1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (m / multi-sentence :snt1 (a / and :li "A" :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Gab1") :ARG2-of (m2 / mutate-01) :xref (x2 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.604")) :manner (p2 / protein :name (n2 / name :op1 "LexA-tpr-met") :ARG1-of (f2 / fuse-01))) :op2 (t / test-01 :ARG1 p :ARG2 (i / interact-01 :ARG0 (h / hybrid :quant "2") :ARG1 (s / substrate) :location (y / yeast))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) :snt2 (r / represent-01 :ARG0 (p3 / protein-segment :name (n4 / name :op1 "CBR")) :ARG1 (r2 / region :ARG1-of (b / bind-01 :ARG2 (p4 / protein :name (n5 / name :op1 "CRKL") :xref (x / xref :value "UNIPROT:CRKL_HUMAN" :prob "1.004"))) :part-of (p5 / protein :name (n6 / name :op1 "Gab1") :xref (x1 / xref :value "UNIPROT:GAB1_HUMAN" :prob "0.604"))))) # ::id bio.chicago_2015.55208 # ::date 2015-11-01T11:43:40 # ::file bio_chicago_2015_55208.txt # ::snt Binding of Sp1 and Smad2, Smad3, Smad4 and Sp1 to the wild-type oligonucleotide, as was also done in (E), was compared with their binding to the corresponding mutant oligonucleotides, in which the SBEs and Sp1 binding sequences were mutated, as shown in Figure 3A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / compare-01 :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "Sp1") :xref (x3 / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001")) :op2 (p2 / protein :name (n2 / name :op1 "Smad2") :xref (x / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "Smad3") :xref (x1 / xref :value "UNIPROT:SMAD3_HUMAN" :prob "1.003")) :op4 (p4 / protein :name (n4 / name :op1 "Smad4") :xref (x2 / xref :value "UNIPROT:SMAD4_HUMAN" :prob "1.003")) :op5 p) :ARG2 (o / oligonucleotide :mod (w / wild-type)) :ARG1-of (d / do-02 :mod (a2 / also) :medium (f2 / figure :mod "E"))) :ARG2 (b2 / bind-01 :ARG1 a :ARG2 (o2 / oligonucleotide :ARG2-of (m / mutate-01) :ARG1-of (c2 / correspond-02) :location-of (m2 / mutate-01 :ARG1 (a3 / and :op1 (s / sequence :ARG1-of (b3 / bind-01 :ARG2 (p5 / protein-segment :name (n5 / name :op1 "SBE")))) :op2 (s2 / sequence :ARG1-of (b4 / bind-01 :ARG2 p))) :ARG1-of (s3 / show-01 :medium (f / figure :mod "3A")))))) # ::id bio.chicago_2015.55244 # ::date 2015-11-01T11:54:43 # ::file bio_chicago_2015_55244.txt # ::snt The finding that LARFN5C binds to LAR and the absence of the LARFN5C N-terminal sequence in LAR make the possibility of N-terminal to N-terminal isologous homophilic binding unlikely. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / make-02 :ARG0 (a / and :op1 (f / find-01 :ARG1 (b / bind-01 :ARG1 (p / protein-segment :name (n / name :op1 "LARFN5C")) :ARG2 (e / enzyme :name (n2 / name :op1 "LAR") :xref (x / xref :value "UNIPROT:PTPRF_HUMAN" :prob "1.002")))) :op2 (a2 / absent-01 :ARG1 (p3 / protein-segment :name (n3 / name :op1 "N-terminus") :part-of p) :ARG2 e)) :ARG1 (l / likely-01 :polarity "-" :ARG1 (p4 / possible-01 :ARG1 (b2 / bind-01 :ARG1 (p5 / protein-segment :name (n4 / name :op1 "N-terminus")) :ARG2 (i / isologus :mod p5) :mod (h / homophilic))))) # ::id bio.chicago_2015.55261 # ::date 2015-11-01T12:01:56 # ::file bio_chicago_2015_55261.txt # ::snt Dystroglycan, which binds to laminins, agrin, and perlecan through its subunit, has been another candidate for mediation of basement membrane assembly (Henry and Campbell, 1998 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (c / candidate :mod (a / another) :domain (p / protein :name (n / name :op1 "dystroglycan") :ARG1-of (b / bind-01 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "laminin") :xref (x / xref :value "UNIPROT:LM-111_HUMAN_COMPLEX" :prob "0.33")) :op2 (p3 / protein :name (n3 / name :op1 "agrin") :xref (x1 / xref :value "UNIPROT:AGRIN_HUMAN" :prob "0.703")) :op3 (p4 / protein :name (n4 / name :op1 "perlecan") :xref (x2 / xref :value "UNIPROT:PGBM_HUMAN" :prob "0.702"))) :ARG3 (p5 / protein-segment :part-of p)) :xref (x3 / xref :value "UNIPROT:DAG1_HUMAN" :prob "0.702")) :ARG0-of (m / mediate-01 :ARG1 (a3 / assemble-01 :ARG1 (m2 / membrane :mod (b2 / basement) :xref (x4 / xref :value "GO:0016020" :prob "0.8")))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :name (n5 / name :op1 "Henry")) :op2 (p8 / person :name (n6 / name :op1 "Campbell"))) :time (d / date-entity :year "1998")))) # ::id bio.chicago_2015.55278 # ::date 2015-11-01T12:06:59 # ::file bio_chicago_2015_55278.txt # ::snt Binding of the VHL protein and Elongin A to the Elongin BC complex is mutually exclusive in vitro ( 101). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (e / exclude-01 :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "VHL") :xref (x3 / xref :value "UNIPROT:VHL_HUMAN" :prob "1.003")) :ARG2 "m") :op2 (b2 / bind-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Elongin" :op2 "A") :xref (x / xref :value "UNIPROT:ELOA1_HUMAN" :prob "0.692")) :ARG2 (m / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "Elongin" :op2 "B") :xref (x2 / xref :value "UNIPROT:ELOB_HUMAN" :prob "0.692")) :part (p4 / protein :name (n4 / name :op1 "Elongin" :op2 "C") :xref (x1 / xref :value "UNIPROT:ELOC_HUMAN" :prob "0.692"))))) :manner (m2 / mutual) :manner (i / in-vitro) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "101")))) # ::id bio.chicago_2015.55289 # ::date 2015-11-01T12:13:13 # ::file bio_chicago_2015_55289.txt # ::snt Here, we have demonstrated that intact p140mDia can bind to profilin in vitro, and its distribution in vivo largely overlaps with that of profilin in cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (d / demonstrate-01 :ARG0 (w2 / we) :ARG1 (a / and :op1 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "p140mDia") :mod (i / intact) :xref (x / xref :value "UNIPROT:O78200_HUMAN" :prob "0.251")) :ARG2 (p3 / protein :name (n2 / name :op1 "profilin") :xref (x1 / xref :value "UNIPROT:B4DNH1_HUMAN" :prob "0.701")) :manner (i2 / in-vitro))) :op2 (o / overlap-01 :ARG0 (d2 / distribute-01 :ARG1 p2 :manner (i3 / in-vivo)) :ARG1 (d3 / distribute-01 :ARG0 p3 :location (c / cell)) :ARG2 (l / large))) :medium (h2 / here)) # ::id bio.chicago_2015.55319 # ::date 2015-11-01T12:17:55 # ::file bio_chicago_2015_55319.txt # ::snt The finding that p115 binding to GM130 is inhibited by phosphorylation of GM130 on serine 25 suggests that this residue must be dephosphorylated for Golgi reassembly to occur. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (s / suggest-01 :ARG0 (f / find-01 :ARG1 (i / inhibit-01 :ARG0 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "25" :name (n4 / name :op1 "serine") :part-of "p3" :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n2 / name :op1 "p115") :xref (x / xref :value "UNIPROT:RHG04_HUMAN" :prob "1.003")) :ARG2 (p3 / protein :name (n3 / name :op1 "GM130") :xref (x1 / xref :value "UNIPROT:GOGA2_HUMAN" :prob "1.002"))))) :ARG1 (o / obligate-01 :ARG2 (d / dephosphorylate-01 :ARG1 a2 :purpose (a3 / assemble-01 :ARG1 (t / thing :name (n / name :op1 "Golgi")) :mod (a4 / again))))) # ::id bio.chicago_2015.55330 # ::date 2015-11-01T12:21:57 # ::file bio_chicago_2015_55330.txt # ::snt Treatment with C3 exoenzyme (C3) may block m1 mAChR - mediated suppression of Kv1.2 or may disrupt the binding between RhoA and Kv1.2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (o / or :op1 (p / possible-01 :ARG1 (b / block-01 :ARG0 (t / treat-04 :ARG2 (e / enzyme :name (n / name :op1 "C3" :op2 "exoenzyme"))) :ARG1 (s / suppress-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Kv1.2") :xref (x / xref :value "UNIPROT:KV112_HUMAN" :prob "0.262")) :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "m1" :op2 "mAChR")))))) :op2 (p4 / possible-01 :ARG1 (d2 / disrupt-01 :ARG0 t :ARG1 (b2 / bind-01 :ARG1 (p5 / protein :name (n4 / name :op1 "RhoA") :xref (x1 / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604")) :ARG2 p3)))) # ::id bio.chicago_2015.55334 # ::date 2015-11-01T12:30:10 # ::file bio_chicago_2015_55334.txt # ::snt Reconstitution of the binding of alpha-actinin to VPMs in the presence of actin stress fibers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (r / reconstitute-01 :ARG1 (b / bind-01 :ARG1 (p / protein :wiki "Actinin,_alpha_1" :name (n / name :op1 "alpha-actinin") :xref (x1 / xref :value "UNIPROT:ACTN2_HUMAN" :prob "0.383")) :ARG2 (m / membrane :mod (p5 / plasma :mod (v / ventral)) :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :condition (p3 / present-02 :ARG1 (f / fiber :mod (s / stress) :consist-of (p4 / protein :wiki "Actin" :name (n3 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))))) # ::id bio.chicago_2015.55368 # ::date 2015-11-01T12:35:08 # ::file bio_chicago_2015_55368.txt # ::snt The binding of the native CaMKII to projectin (maximally bound CaMKII (native)/projectin=1.38 plus-or-minus 0.02 mol mol-1) had a higher stoichiometry than the in vitro autophosphorylated CaMKII (maximally bound CaMKII (autophosphorylated)/projectin=0.86 plus-or-minus 0.04 mol mol-1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (h / have-03 :ARG0 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "CaMKII") :mod (n3 / native) :xref (x1 / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.643")) :ARG2 (p / protein :name (n2 / name :op1 "projectin") :xref (x2 / xref :value "UNIPROT:CL17A_HUMAN" :prob "0.342")) :ARG1-of (m2 / mean-01 :ARG2 (b2 / bind-01 :ARG1 e :ARG2 p :degree (m3 / maximum) :quant (v / value-interval :op1 (a / add-02 :ARG1 "0.02" :ARG2 "1.38") :op2 (s2 / subtract-01 :ARG1 "0.02" :ARG2 "1.38") :unit (m5 / molar))))) :ARG1 (s / stoichiometry :ARG1-of (h2 / high-02 :degree (m / more) :compared-to (e2 / enzyme :name (n4 / name :op1 "CaMKII") :ARG1-of (p2 / phosphorylate-01 :ARG2 e2 :manner (i / in-vitro)) :xref (x / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.643")) :ARG1-of (m4 / mean-01 :ARG2 (b3 / bind-01 :ARG1 e2 :ARG2 p :degree m3 :quant (v2 / value-interval :op1 (a2 / add-02 :ARG1 "0.04" :ARG2 "0.86") :op2 (s3 / subtract-01 :ARG1 "0.04" :ARG2 "0.86") :unit (m6 / molar))))))) # ::id bio.chicago_2015.55380 # ::date 2015-11-01T12:39:29 # ::file bio_chicago_2015_55380.txt # ::snt Oct-1 binds to the PRL3 element. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 1, 2015 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Oct-1") :xref (x / xref :value "UNIPROT:PO2F1_HUMAN" :prob "1.002")) :ARG2 (e / element :mod (e2 / enzyme :name (n2 / name :op1 "PRL3") :xref (x1 / xref :value "UNIPROT:SMR3B_HUMAN" :prob "1.002")))) # ::id bio.chicago_2015.55448 # ::date 2015-11-01T12:41:08 # ::file bio_chicago_2015_55448.txt # ::snt However, the interaction between the mutated CtIP and GST-BRCT was unaffected (Fig. 4 A, compare lanes 3 and 7), suggesting that CtIP binds to CtBP and the BRCT repeats of BRCA1 using different motifs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (h / have-concession-91 :ARG1 (a / affect-01 :polarity "-" :ARG1 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "CtIP") :ARG2-of (m / mutate-01) :xref (x4 / xref :value "UNIPROT:COM1_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n2 / name :op1 "GST-BRCT") :xref (x / xref :value "UNIPROT:SO6A1_HUMAN" :prob "0.262"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A" :location-of (c2 / compare-01 :mode "imperative" :ARG0 (y / you) :ARG1 (l / lane :mod "3") :ARG2 (l2 / lane :mod "7")))) :ARG0-of (s / suggest-01 :ARG1 (b / bind-01 :ARG1 p :ARG2 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "CtBP") :xref (x1 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652")) :op2 (r / repeat-01 :ARG1 (p5 / protein :name (n5 / name :op1 "BRCA1") :xref (x3 / xref :value "UNIPROT:BRCA1_HUMAN" :prob "1.003")) :mod (p4 / protein :name (n4 / name :op1 "BRCT") :xref (x2 / xref :value "UNIPROT:ANR32_HUMAN" :prob "0.282")))) :ARG3 (u / use-01 :ARG0 p :ARG1 (p6 / protein-segment :ARG1-of (d2 / differ-02))))))) # ::id bio.chicago_2015.55495 # ::date 2015-11-01T12:48:21 # ::file bio_chicago_2015_55495.txt # ::snt In contrast, although the HDL binding activities of the COS[ mSR-BI] and COS[hCD36] cells differed by only ~50% in this experiment (see legend), there were essentially only control (background) levels of DiI uptake mediated by hCD36 in the COS[hCD36] cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (c5 / contrast-01 :ARG2 (p / present-02 :ARG1 (l / level :mod (c / control :ARG1-of (m / mean-01 :ARG2 (b / background))) :mod (o / only) :quant-of (u / uptake :mod (p2 / protein :name (n / name :op1 "DiI")) :ARG1-of (m2 / mediate-01 :ARG0 (p3 / protein :name (n2 / name :op1 "hCD36") :xref (x / xref :value "UNIPROT:ASAH2_HUMAN" :prob "0.232"))))) :manner (e / essential) :location (c2 / cell-line :name (n3 / name :op1 "COS[hCD36]")) :concession (d / differ-02 :ARG1 (a / activity-06 :ARG0 (c3 / cell-line :name (n5 / name :op1 "COS[mSR-BI]")) :ARG1 (b2 / bind-01 :ARG1 (p4 / protein :name (n4 / name :op1 "HDL") :xref (x1 / xref :value "UNIPROT:VIGLN_HUMAN" :prob "0.232")))) :ARG2 (a2 / activity-06 :ARG0 c2 :ARG1 b2) :condition (e2 / experiment-01 :mod (t / this) :ARG1-of (s / see-01 :mode "imperative" :ARG0 (y / you) :medium (l2 / legend))) :extent (a3 / approximately :op1 (p5 / percentage-entity :value "50" :mod o))))) # ::id bio.chicago_2015.55503 # ::date 2015-11-01T12:53:45 # ::file bio_chicago_2015_55503.txt # ::snt Second, noggin and follistatin bind BMPs with greater affinity than BMP receptors (Holley et al., 1996 ; Zimmerman et al., 1996 ; Fainsod et al., 1997 ; Iemura et al., 1998), so it is unlikely that the extracellular compartment contains significant levels of antagonist not complexed to BMPs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (a4 / and :op2 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "noggin") :xref (x2 / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702")) :op2 (p2 / protein :name (n2 / name :op1 "follistatin") :xref (x / xref :value "UNIPROT:FST_HUMAN" :prob "0.702"))) :ARG2 (p3 / protein :name (n3 / name :op1 "BMP") :xref (x1 / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263")) :manner (a2 / affinity :mod (g / great :degree (m / more) :compared-to (r / receptor :mod p3))) :ARG0-of (c / cause-01 :ARG1 (l / likely-01 :polarity "-" :ARG1 (c2 / contain-01 :ARG0 (c3 / compartment :mod (e / extracellular)) :ARG1 (l2 / level :ARG1-of (s / significant-02) :quant-of (a3 / antagonist :ARG2-of (h / have-part-91 :polarity "-" :ARG1 (m2 / macro-molecular-complex :part p3))))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (p4 / publication-91 :ARG0 (a6 / and :op1 (p5 / person :name (n4 / name :op1 "Holley")) :op2 (p6 / person :mod (o2 / other))) :time (d / date-entity :year "1996")) :op2 (p7 / publication-91 :ARG0 (a8 / and :op1 (p8 / person :name (n5 / name :op1 "Zimmerman")) :op2 p6) :time d) :op3 (p9 / publication-91 :ARG0 (a7 / and :op1 (p10 / person :name (n6 / name :op1 "Fainsod")) :op2 p6) :time (d3 / date-entity :year "1997")) :op4 (p11 / publication-91 :ARG0 (a9 / and :op1 (p12 / person :name (n7 / name :op1 "Iemura")) :op2 p6) :time (d4 / date-entity :year "1998")))))) # ::id bio.chicago_2015.55550 # ::date 2015-11-02T05:59:53 # ::file bio_chicago_2015_55550.txt # ::snt The lack of observed binding between Sog and alphaPS3 could result from a difficulty in detecting an alternatively processed form of Sog bound to alphaPS3, or may reflect an indirect mode of action of scb (e.g. by altering the abundance of interacting integrins such as alphaPS1betaPS or by binding to a different Bmp inhibitor). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 9, 2015 (o / or :op1 (p2 / possible-01 :ARG1 (r / result-01 :ARG1 (d / difficult :domain (d3 / detect-01 :ARG1 (p6 / protein :name (n3 / name :op1 "Sog") :ARG1-of (b2 / bind-01 :ARG2 (p7 / protein :name (n4 / name :op1 "alphaPS3") :xref (x1 / xref :value "UNIPROT:PCBP3_HUMAN" :prob "0.282")) :ARG1-of (o3 / observe-01)) :ARG1-of (p5 / process-01 :ARG1-of (a / alternate-01)) :xref (x3 / xref :value "UNIPROT:SOGA1_HUMAN" :prob "0.202")))) :ARG2 (l / lack-01 :ARG1 (b / bind-01 :ARG1 (p3 / protein :name (n / name :op1 "Sog") :xref (x2 / xref :value "UNIPROT:SOGA1_HUMAN" :prob "0.202")) :ARG2 p7)))) :op2 (p / possible-01 :ARG1 (r2 / reflect-01 :ARG1 l :ARG2 (m / mode :manner-of (a2 / act-01 :ARG0 (p8 / protein :name (n5 / name :op1 "scb")) :ARG1-of (d4 / direct-02 :polarity "-" :example (o2 / or :op1 (a3 / alter-01 :ARG0 p8 :ARG1 (a4 / abound-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "integrin") :ARG0-of (i3 / interact-01) :example (p9 / protein :name (n6 / name :op1 "alphaPS1betaPS") :xref (x4 / xref :value "UNIPROT:Q16367_HUMAN" :prob "0.201"))))) :op2 (b3 / bind-01 :ARG1 p8 :ARG2 (m4 / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 (p10 / protein :name (n7 / name :op1 "Bmp") :xref (x / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.203"))) :ARG1-of (d2 / differ-02)))))))))) # ::id bio.chicago_2015.55555 # ::date 2015-11-03T08:01:54 # ::file bio_chicago_2015_55555.txt # ::snt Screening a brain library demonstrates that the PDZ-containing domain of nNOS binds to PDZ repeats in postsynaptic density 95 (PSD-95) ( Cho et al., 1992 ) and a novel related protein, PSD-93. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (d2 / demonstrate-01 :ARG0 (s / screen-01 :ARG1 (l / library :mod (b / brain))) :ARG1 (b2 / bind-01 :ARG1 (p / protein-segment :part-of (e / enzyme :name (n2 / name :op1 "nNOS") :xref (x1 / xref :value "UNIPROT:NOS1_HUMAN" :prob "1.002")) :ARG0-of (c / contain-01 :ARG1 (p2 / protein-segment :name (n / name :op1 "PZD")))) :ARG2 (p8 / protein-segment :name (n8 / name :op1 "PDZ" :op2 "repeat")) :location (a / and :op1 (p3 / protein :name (n4 / name :op1 "postsynaptic" :op2 "density" :op3 "95") :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and :op1 (p6 / person :name (n7 / name :op1 "Cho")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "1992"))) :xref (x / xref :value "UNIPROT:DLG4_HUMAN" :prob "0.383")) :op2 (p4 / protein :name (n5 / name :op1 "PSD-93") :mod (n6 / novel) :ARG1-of (r2 / relate-01 :ARG2 p3) :xref (x2 / xref :value "UNIPROT:DLG4_HUMAN" :prob "0.293"))))) # ::id bio.chicago_2015.55576 # ::date 2015-11-03T08:13:11 # ::file bio_chicago_2015_55576.txt # ::snt Panel A, mutations introduced in the AP-2 and clathrin binding regions of amphiphysin 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (i / introduce-02 :ARG1 (m / mutate-01) :ARG2 (r / region :ARG2-of (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "AP-2") :xref (x2 / xref :value "UNIPROT:AP2A_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "clathrin") :xref (x / xref :value "UNIPROT:A0A087WVQ6_HUMAN" :prob "0.291")))) :part-of (p3 / protein :name (n3 / name :op1 "amphiphysin" :op2 "1") :xref (x1 / xref :value "UNIPROT:AMPH_HUMAN" :prob "0.382"))) :ARG1-of (d / describe-01 :ARG0 (p4 / panel :mod (s / string-entity :value "A")))) # ::id bio.chicago_2015.55580 # ::date 2015-11-03T08:18:37 # ::file bio_chicago_2015_55580.txt # ::snt These results argue that a factor that binds to poly-U Sepharose and that is eluted from the resin at 2 M KCl is necessary for efficient recruitment of U1 snRNP to msl-2 5 ss, but not for U1 snRNP binding to a consensus 5 ss lacking downstream U-rich sequences. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / argue-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (f / factor :ARG1-of (b / bind-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "poly-U" :op2 "Sepharose") :xref (x3 / xref :value "PUBCHEM:11966311" :prob "5.42615"))) :ARG1-of (e / elute-01 :ARG2 (r5 / resin) :condition (s3 / small-molecule :name (n3 / name :op1 "KCl") :quant (c / concentration-quantity :quant "2" :unit (m2 / molar)) :xref (x2 / xref :value "PUBCHEM:4873" :prob "16.914757"))) :ARG1-of (n4 / need-01 :ARG0 (r2 / recruit-01 :ARG1 (p / protein :name (n5 / name :op1 "U1" :op2 "snRNP") :xref (x1 / xref :value "UNIPROT:SNRPA_HUMAN" :prob "0.372")) :ARG2 (p4 / protein-segment :name (n6 / name :op1 "5'" :op2 "ss") :part-of (p2 / protein :name (n8 / name :op1 "msl-2") :xref (x / xref :value "UNIPROT:MSL2_HUMAN" :prob "0.632"))) :ARG2-of (e2 / efficient-01)) :ARG1-of (c2 / contrast-01 :ARG2 (n7 / need-01 :polarity "-" :ARG0 (r3 / recruit-01 :ARG1 p :ARG2 (d / dna-sequence :name (n / name :op1 "5'ss") :mod (c3 / consensus) :ARG0-of (l / lack-01 :ARG1 (s / sequence :name (n10 / name :op1 "U-rich") :direction (d2 / downstream))))) :ARG1 f))))) # ::id bio.chicago_2015.55595 # ::date 2015-11-03T08:32:06 # ::file bio_chicago_2015_55595.txt # ::snt Degradation of any endogenous ATP present in retinal extracts resulted in no change of binding activity of P112 to CLD (Fig. 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (d / degrade-01 :ARG1 (s / small-molecule :name (n / name :op1 "ATP") :mod (e2 / endogenous) :ARG1-of (p / present-02 :ARG2 (m / molecular-physical-entity :ARG1-of (e3 / extract-01 :ARG2 (r2 / retina)))) :mod (a2 / any) :xref (x2 / xref :value "PUBCHEM:5957" :prob "14.368295"))) :ARG2 (c / change-01 :polarity "-" :ARG1 (a / activity-06 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n2 / name :op1 "P112") :xref (x / xref :value "UNIPROT:EXOS6_HUMAN" :prob "0.222")) :ARG2 (p3 / protein :name (n3 / name :op1 "CLD") :xref (x1 / xref :value "UNIPROT:CLD1_HUMAN" :prob "0.262"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2"))) # ::id bio.chicago_2015.55666 # ::date 2015-11-03T09:03:35 # ::file bio_chicago_2015_55666.txt # ::snt We next tested the contribution of the IAP binding activity of Omi to its killing activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (t / test-01 :ARG0 (w / we) :ARG1 (c / contribute-01 :ARG0 (a / activity-06 :ARG0 "p2" :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Omi") :xref (x / xref :value "UNIPROT:HTRA2_HUMAN" :prob "0.602")) :ARG2 (p / protein :name (n2 / name :op1 "IAP") :xref (x1 / xref :value "UNIPROT:CD47_HUMAN" :prob "1.002")))) :ARG2 (a2 / activity-06 :ARG0 p2 :ARG1 (k / kill-01 :ARG0 p2))) :time (n / next)) # ::id bio.chicago_2015.55671 # ::date 2015-11-03T09:17:02 # ::file bio_chicago_2015_55671.txt # ::snt Although the binding experiments described above demonstrated that the C-terminal 378 residues of E6TP1, which lack the PDZ domain, were sufficient for E6 binding, it remained possible that the PDZ domain of E6TP1 could also bind to E6, either independently or cooperatively with the C-terminal region. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (h / have-concession-91 :ARG1 (r3 / remain-01 :ARG1 (p4 / possible-01 :ARG1 (b3 / bind-01 :ARG1 (p8 / protein-segment :name (n7 / name :op1 "PDZ" :op2 "domain") :part-of "p2") :ARG2 "p6" :manner (o / or :op1 (d3 / depend-01 :polarity "-" :ARG0 p8) :op2 (c / cooperate-01 :ARG0 p8 :ARG1 (p3 / protein-segment :name (n6 / name :op1 "C-terminus")))) :mod (a3 / also)))) :ARG2 (d / demonstrate-01 :ARG0 (e / experiment-01 :ARG1 (b / bind-01) :ARG1-of (d2 / describe-01 :location (a / above))) :ARG1 (s / suffice-01 :ARG0 (r2 / residue :ARG0-of (l / lack-01 :ARG1 p8) :mod (a2 / amino-acid :mod "378" :part-of (p / protein-segment :name (n / name :op1 "C-terminus") :part-of (p2 / protein :name (n2 / name :op1 "E6TP1") :xref (x / xref :value "UNIPROT:SI1L1_HUMAN" :prob "1.002"))))) :ARG1 (b2 / bind-01 :ARG2 (p6 / protein :name (n5 / name :op1 "E6") :xref (x1 / xref :value "UNIPROT:Q8V9K8_HUMAN" :prob "1.001")))))) # ::id bio.chicago_2015.55702 # ::date 2015-11-03T09:28:14 # ::file bio_chicago_2015_55702.txt # ::snt C, summary of the Rab binding specificity of the mouse or human Slp family (Slp1-5), the Slac2 family (Slac2-a/b/c), Rim1, Rim2, Noc2, and rabphilin (see also Fig. 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (s2 / summarize-01 :li "c" :ARG1 (s3 / specific-02 :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p2 / protein-family :name (n2 / name :op1 "Slp") :mod (m / mouse :op1-of (o / or :op2 (h / human))) :ARG1-of (m3 / mean-01 :ARG2 (v / value-interval :op1 (p10 / protein :name (n10 / name :op1 "Slp1") :xref (x / xref :value "UNIPROT:STML1_HUMAN" :prob "0.602")) :op2 (p11 / protein :name (n11 / name :op1 "Slp5") :xref (x1 / xref :value "UNIPROT:SYTL5_HUMAN" :prob "0.602"))))) :op2 (p3 / protein-family :name (n3 / name :op1 "Slac2") :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (p7 / protein :name (n7 / name :op1 "Slac2-a") :xref (x3 / xref :value "UNIPROT:MELPH_HUMAN" :prob "0.682")) :op2 (p8 / protein :name (n8 / name :op1 "Slac2-b") :xref (x6 / xref :value "UNIPROT:EXPH5_HUMAN" :prob "0.682")) :op3 (p9 / protein :name (n9 / name :op1 "Slac2-c") :xref (x7 / xref :value "UNIPROT:MYRIP_HUMAN" :prob "0.682"))))) :op3 (p4 / protein :name (n4 / name :op1 "Rim1") :xref (x4 / xref :value "UNIPROT:RIMS1_HUMAN" :prob "0.602")) :op4 (p5 / protein :name (n5 / name :op1 "Rim2") :xref (x5 / xref :value "UNIPROT:RIMS2_HUMAN" :prob "0.602")) :op5 (p6 / protein :name (n6 / name :op1 "Noc2") :xref (x2 / xref :value "UNIPROT:RPH3L_HUMAN" :prob "0.602")) :op6 (r / rabphilin)) :ARG2 (p / protein-family :name (n / name :op1 "Rab")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5" :ARG1-of (s4 / see-01 :mode "imperative" :ARG0 (y / you) :mod (a3 / also))))) # ::id bio.chicago_2015.55713 # ::date 2015-11-03T09:39:32 # ::file bio_chicago_2015_55713.txt # ::snt Exchange of the GDP bound to eIF2 with GTP is catalyzed by eIF2B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (c / catalyze-01 :ARG0 (p3 / protein :name (n4 / name :op1 "eIF2B") :xref (x1 / xref :value "UNIPROT:IF2B_HUMAN" :prob "0.702")) :ARG1 (e / exchange-01 :ARG1 (s / small-molecule :wiki "Guanosine_diphosphate" :name (n / name :op1 "GDP") :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n3 / name :op1 "eIF2") :xref (x / xref :value "UNIPROT:AGO2_HUMAN" :prob "0.332"))) :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG3 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")))) # ::id bio.chicago_2015.55730 # ::date 2015-11-03T09:58:21 # ::file bio_chicago_2015_55730.txt # ::snt Binding of PTB or PTB to uniformly labeled MSE1-4 RNA was assayed by UV crosslinking followed by immunoprecipitation using the AntiXpress antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (a / assay-01 :ARG1 (b / bind-01 :ARG1 (o / or :op1 (p / protein :name (n3 / name :op1 "PTB") :xref (x1 / xref :value "UNIPROT:PTBP1_HUMAN" :prob "1.002")) :op2 p) :ARG2 (n4 / nucleic-acid :name (n5 / name :op1 "RNA") :ARG1-of (l / label-01 :ARG1-of (u / uniform-02)) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n / name :op1 "MSE1-4") :xref (x / xref :value "UNIPROT:ENOB_HUMAN" :prob "0.212"))))) :manner (c / crosslink-00 :ARG0 (l2 / light :mod (u2 / ultraviolet)) :ARG2-of (f / follow-01 :ARG1 (i / immunoprecipitate-01 :ARG3 (a2 / antibody :name (n7 / name :op1 "AntiXpressdd")))))) # ::id bio.chicago_2015.55746 # ::date 2015-11-03T10:05:15 # ::file bio_chicago_2015_55746.txt # ::snt The N-terminal boundary for PABP binding resides between amino acids 132 and 139, because eIF4GI(132-329) bound PABP, but eIF4GI(139-329) did not (Figure 3B, compare lanes 3 and 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (c / cause-01 :ARG0 (c2 / contrast-01 :ARG1 (b6 / bind-01 :ARG1 "p2" :ARG2 (p3 / protein :name (n5 / name :op1 "eIF4GI") :part (a3 / amino-acid :mod (v / value-interval :op1 "132" :op2 "329")) :xref (x1 / xref :value "UNIPROT:IF4G1_HUMAN" :prob "0.702"))) :ARG2 (b7 / bind-01 :polarity "-" :ARG1 "p2" :ARG2 (p4 / protein :name (n6 / name :op1 "eIF4GI") :part (a4 / amino-acid :mod (v2 / value-interval :op1 "139" :op2 "329")) :xref (x2 / xref :value "UNIPROT:IF4G1_HUMAN" :prob "0.702")))) :ARG1 (r / reside-01 :ARG0 (b3 / boundary :mod (p / protein-segment :name (n / name :op1 "N-terminus")) :purpose (b4 / bind-01 :ARG2 (p2 / protein :name (n2 / name :op1 "PABP") :xref (x / xref :value "UNIPROT:A0A024R9C1_HUMAN" :prob "1.001")))) :ARG1 (b5 / between :op1 (a / amino-acid :mod "139") :op2 (a2 / amino-acid :mod "329"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B" :location-of (c3 / compare-01 :mode "imperative" :ARG0 (y / you) :ARG1 (l / lane :mod "3") :ARG2 (l2 / lane :mod "4"))))) # ::id bio.chicago_2015.55796 # ::date 2015-11-03T21:38:43 # ::file bio_chicago_2015_55796.txt # ::snt This sequence shows marked homology to the amino-terminal sequence determined here for processed Smac/ DIABLO bound to XIAP, AVPIAQ; Smac/ DIABLO has been processed here to remove the first 55 amino acids. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a3 / and :op1 (s / show-01 :ARG0 (s2 / sequence :mod (t / this)) :ARG1 (h / homologous :compared-to (s3 / sequence :ARG1-of (d / determine-01 :ARG2 (p / protein :name (n / name :op1 "Smac/DIABLO") :ARG1-of (p2 / process-01) :ARG1-of (b / bind-01 :ARG2 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "XIAP") :xref (x / xref :value "UNIPROT:XIAP_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n3 / name :op1 "AVPIAQ") :xref (x1 / xref :value "UNIPROT:AVPI1_HUMAN" :prob "0.262"))))) :location (h3 / here)) :mod (p6 / protein-segment :name (n4 / name :op1 "amino-terminus"))) :ARG1-of (m / mark-01))) :op2 (p5 / process-01 :ARG1 (p7 / protein :name (n5 / name :op1 "Smac/DIABLO")) :purpose (r / remove-01 :ARG0 p7 :ARG1 (a4 / amino-acid :quant "55" :ord (o / ordinal-entity :value "1"))) :location h3)) # ::id bio.chicago_2015.55877 # ::date 2015-11-03T22:10:46 # ::file bio_chicago_2015_55877.txt # ::snt Rab binding properties of the Slp family, the Slac2 family, Rim1, Rim2, Noc2, and rabphilin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (p / property :mod (b / bind-01 :ARG1 (a / and :op1 (p3 / protein-family :name (n2 / name :op1 "Slp")) :op2 (p4 / protein-family :name (n3 / name :op1 "Slac2")) :op3 (p5 / protein :name (n4 / name :op1 "Rim1") :xref (x2 / xref :value "UNIPROT:RIMS1_HUMAN" :prob "0.602")) :op4 (p6 / protein :name (n5 / name :op1 "Rim2") :xref (x / xref :value "UNIPROT:RIMS2_HUMAN" :prob "0.602")) :op5 (p7 / protein :name (n6 / name :op1 "Noc2") :xref (x1 / xref :value "UNIPROT:RPH3L_HUMAN" :prob "0.602")) :op6 (p8 / protein :name (n7 / name :op1 "rabphilin") :xref (x3 / xref :value "UNIPROT:WDR44_HUMAN" :prob "0.352"))) :ARG2 (p2 / protein-family :name (n / name :op1 "Rab")))) # ::id bio.chicago_2015.55886 # ::date 2015-11-03T22:16:41 # ::file bio_chicago_2015_55886.txt # ::snt Raf did not inhibit the binding of RGL to RasG12V/E37G under the condition that Raf inhibited that of RGL to RasG12V. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / inhibit-01 :polarity "-" :ARG0 (e4 / enzyme :name (n2 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n3 / name :op1 "RGL") :xref (x1 / xref :value "UNIPROT:RGL1_HUMAN" :prob "1.003")) :ARG2 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (m / mutate-01 :value "G12V") :ARG1-of (m2 / mutate-01 :value "E37G") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :condition (i2 / inhibit-01 :ARG0 e4 :ARG1 (b2 / bind-01 :ARG1 p :ARG2 (e / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (m3 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) # ::id bio.chicago_2015.55914 # ::date 2015-11-03T22:22:53 # ::file bio_chicago_2015_55914.txt # ::snt Because Src does not bind to Abl (not shown), its binding to Cbl in the presence of Abl could be explained by a modification of Cbl conformation induced by its binding to Abl. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / cause-01 :ARG0 (b / bind-01 :polarity "-" :ARG1 (p2 / protein :name (n / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :ARG2 (p4 / protein :name (n2 / name :op1 "Abl") :xref (x1 / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603")) :ARG1-of (s / show-01 :polarity "-")) :ARG1 (p / possible-01 :ARG1 (e / explain-01 :ARG1 (b2 / bind-01 :ARG1 p2 :ARG2 (p5 / protein :name (n3 / name :op1 "Cbl") :xref (x2 / xref :value "UNIPROT:CBL_HUMAN" :prob "0.604")) :condition (p3 / present-02 :ARG1 p4)) :manner (m / modify-01 :ARG1 (c2 / conform-01 :ARG1 p5) :ARG2-of (i / induce-01 :ARG0 (b3 / bind-01 :ARG1 p2 :ARG2 p4)))))) # ::id bio.chicago_2015.55915 # ::date 2015-11-03T22:28:39 # ::file bio_chicago_2015_55915.txt # ::snt In agreement with the published data [7,19] , we readily demonstrated that a PAK CRIB peptide can bind directly to both Cdc42 and Rac1, whereas an N-WASP CRIB peptide bound only to Cdc42. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (p2 / peptide :name (n / name :op1 "PAK" :op2 "CRIB")) :ARG2 (a / and :op1 (p3 / protein :name (n2 / name :op1 "Cdc42") :xref (x1 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :op2 (p7 / protein :name (n3 / name :op1 "Rac1") :xref (x / xref :value "UNIPROT:RAC1_HUMAN" :prob "0.604"))) :ARG1-of (d2 / direct-02))) :ARG2-of (r / ready-02)) :ARG2 (b2 / bind-01 :ARG1 (p4 / peptide :name (n4 / name :op1 "N-WASP" :op2 "CRIB")) :ARG2 p3 :mod (o / only)) :ARG1-of (a2 / agree-01 :ARG2 (d3 / data :ARG1-of (p5 / publish-01) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "7" :op2 "19"))))))) # ::id bio.chicago_2015.55927 # ::date 2015-11-03T22:34:52 # ::file bio_chicago_2015_55927.txt # ::snt TLP can bind TFIIA and TFIIB, like TBP, but does not bind to the TATA sequence ( 40, 42, 48, 57). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "TFIIA") :xref (x1 / xref :value "UNIPROT:TF3A_HUMAN" :prob "0.392")) :op2 (p4 / protein :name (n3 / name :op1 "TFIIB") :xref (x3 / xref :value "UNIPROT:TF2B_HUMAN" :prob "1.002"))) :ARG2 (p2 / protein :name (n / name :op1 "TLP") :ARG1-of (r / resemble-01 :ARG2 (p5 / protein :name (n4 / name :op1 "TBP") :xref (x4 / xref :value "UNIPROT:TBP_HUMAN" :prob "1.003"))) :xref (x / xref :value "UNIPROT:TBPL1_HUMAN" :prob "1.002")))) :ARG2 (b2 / bind-01 :polarity "-" :ARG1 (p7 / protein :name (n6 / name :op1 "TLP") :xref (x2 / xref :value "UNIPROT:TBPL1_HUMAN" :prob "1.002")) :ARG2 (d2 / dna-sequence :name (n5 / name :op1 "TATA"))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "40" :op2 "42" :op3 "48" :op4 "57"))))) # ::id bio.chicago_2015.55934 # ::date 2015-11-03T22:59:14 # ::file bio_chicago_2015_55934.txt # ::snt For this, nonspecific binding of the PTN radioligand to 32D/control cells was subtracted from the total binding to 32D/ALK cells to obtain the amount of PTN bound to ALK at different concentrations of PTN. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / subtract-01 :ARG1 (b / bind-01 :ARG1 (r / radioligand :mod (p2 / protein :name (n3 / name :op1 "PTN") :xref (x / xref :value "UNIPROT:PTN_HUMAN" :prob "1.003"))) :ARG2 (s3 / slash :op1 (c / cell-line :name (n2 / name :op1 "32D")) :op2 (c6 / cell :ARG0-of (c2 / control-01))) :ARG1-of (s2 / specific-02 :polarity "-")) :ARG2 (b2 / bind-01 :ARG2 (s4 / slash :op1 c :op2 (c4 / cell :mod "e")) :mod (t / total)) :purpose (o / obtain-01 :ARG1 (a / amount :quant-of (p / protein :name (n5 / name :op1 "PTN") :ARG1-of (b3 / bind-01 :ARG2 (e / enzyme :name (n6 / name :op1 "ALK") :xref (x1 / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003")) :condition (c5 / concentrate-02 :ARG1-of (d / differ-02))) :xref (x2 / xref :value "UNIPROT:PTN_HUMAN" :prob "1.003")))) :purpose (t2 / this)) # ::id bio.chicago_2015.55945 # ::date 2015-11-03T23:15:26 # ::file bio_chicago_2015_55945.txt # ::snt The crystal structures of both the GDP- and GTP-bound forms of ARF1 have been solved ( 1, 20, 21). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s2 / solve-01 :ARG1 (s3 / structure-01 :ARG1 (a3 / and :op1 (p / protein :name (n / name :op1 "ARF1") :ARG1-of (b2 / bind-01 :ARG2 (a / and :op1 (s4 / small-molecule :name (n2 / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257")))) :xref (x1 / xref :value "UNIPROT:ARF1_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n5 / name :op1 "ARF1") :ARG1-of (b3 / bind-01 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x / xref :value "UNIPROT:ARF1_HUMAN" :prob "1.004"))) :ARG2 (c / crystal)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "1" :op2 "20" :op3 "21"))))) # ::id bio.chicago_2015.55950 # ::date 2015-11-03T23:21:22 # ::file bio_chicago_2015_55950.txt # ::snt Pins nearly completely abolishes the binding between Galphai and Gbeta13F. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / abolish-01 :ARG0 (p3 / protein :name (n2 / name :op1 "Pins") :xref (x1 / xref :value "UNIPROT:DYL1_HUMAN" :prob "0.202")) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n3 / name :op1 "Galphai") :xref (x2 / xref :value "UNIPROT:GNA11_HUMAN" :prob "0.273")) :ARG2 (p2 / protein :name (n4 / name :op1 "Gbeta13F") :xref (x / xref :value "UNIPROT:GBB5_HUMAN" :prob "0.273"))) :ARG1-of (c / complete-02 :degree (n / near))) # ::id bio.chicago_2015.55988 # ::date 2015-11-03T23:25:06 # ::file bio_chicago_2015_55988.txt # ::snt Crk Binding to CAS Is Required for the Induction of Cell Migration # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (r / require-01 :ARG0 (i / induce-01 :ARG1 (c / cell) :ARG2 (m / migrate-01 :ARG0 c)) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "Crk") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "0.604")) :ARG2 (p / protein :name (n2 / name :op1 "CAS") :xref (x1 / xref :value "UNIPROT:BCAR1_HUMAN" :prob "1.003")))) # ::id bio.chicago_2015.56033 # ::date 2015-11-03T23:33:53 # ::file bio_chicago_2015_56033.txt # ::snt These results indicate that FAST2 constitutively binds the gsc promoter and that Smad2 and Smad4 expressed in mammalian cells cannot interact directly with the element. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "FAST2") :xref (x / xref :value "UNIPROT:FOXH1_HUMAN" :prob "1.002")) :ARG2 (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (p4 / protein :name (n2 / name :op1 "gsc") :xref (x2 / xref :value "UNIPROT:GSC_HUMAN" :prob "0.603")))) :manner (c / constitutive)) :op2 (p / possible-01 :polarity "-" :ARG1 (i2 / interact-01 :ARG0 (a2 / and :op1 (p5 / protein :name (n3 / name :op1 "Smad2") :xref (x3 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n4 / name :op1 "Smad4") :xref (x1 / xref :value "UNIPROT:SMAD4_HUMAN" :prob "1.003")) :ARG2-of (e / express-03 :ARG3 (c2 / cell :mod (m2 / mammal)))) :ARG1 m :ARG1-of (d / direct-02))))) # ::id bio.chicago_2015.56052 # ::date 2015-11-03T23:41:20 # ::file bio_chicago_2015_56052.txt # ::snt This observation suggests that APP may play an important role in neurotransmitter release at nerve terminals or that Mint-2 may regulate the binding ability of X11L to APP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s / suggest-01 :ARG0 (o / observe-01 :mod (t2 / this)) :ARG1 (o2 / or :op1 (p / possible-01 :ARG1 (p2 / play-02 :ARG0 (p3 / protein :name (n / name :op1 "APP") :xref (x / xref :value "UNIPROT:A4_HUMAN" :prob "1.002")) :ARG1 (r / role :mod (i / important) :purpose (r2 / release-01 :ARG1 (n2 / neurotransmitter) :location (t / terminal :part-of (n3 / nerve)))))) :op2 (p4 / possible-01 :ARG1 (r3 / regulate-01 :ARG0 (p6 / protein :name (n4 / name :op1 "Mint-2") :xref (x1 / xref :value "UNIPROT:APBA2_HUMAN" :prob "1.002")) :ARG1 (c / capable-01 :ARG1 (p5 / protein :name (n5 / name :op1 "X11L") :xref (x2 / xref :value "UNIPROT:APBA2_HUMAN" :prob "1.002")) :ARG2 (b / bind-01 :ARG1 p5 :ARG2 p3)))))) # ::id bio.chicago_2015.56121 # ::date 2015-11-03T23:49:26 # ::file bio_chicago_2015_56121.txt # ::snt SLBP associated with the pre-mRNA stabilizes the binding of U7 snRNP, suggesting that SLBP bound to the pre-mRNA might interact with one of the U7 snRNP specific proteins (Dominski et al. 1999 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s / stabilize-01 :ARG0 (p7 / protein :name (n / name :op1 "SLBP") :ARG1-of (a / associate-01 :ARG2 (n2 / nucleic-acid :name (n3 / name :op1 "pre-mRNA"))) :xref (x / xref :value "UNIPROT:SLBP_HUMAN" :prob "1.003")) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n4 / name :op1 "U7" :op2 "snRNP"))) :ARG0-of (s2 / suggest-01 :ARG1 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (p8 / protein :name (n5 / name :op1 "SLBP") :ARG1-of (b2 / bind-01 :ARG2 n2) :xref (x1 / xref :value "UNIPROT:SLBP_HUMAN" :prob "1.003")) :ARG1 (p3 / protein :ARG1-of (s3 / specific-02 :ARG2 p2))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n6 / name :op1 "Dominski")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "1999")))) # ::id bio.chicago_2015.56140 # ::date 2015-11-04T00:00:36 # ::file bio_chicago_2015_56140.txt # ::snt We have shown that the region downstream of the DNA -binding domain in D-Myb binds to dCBP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s / show-01 :ARG0 (w2 / we) :ARG1 (b / bind-01 :ARG1 (r / region :location (r2 / relative-position :op1 (d2 / domain :ARG2-of (b2 / bind-01 :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "DNA"))) :location (p2 / protein :name (n5 / name :op1 "D-Myb"))) :direction (d / downstream))) :ARG2 (p / protein :name (n6 / name :op1 "dCBP")))) # ::id bio.chicago_2015.56172 # ::date 2015-11-04T00:06:06 # ::file bio_chicago_2015_56172.txt # ::snt The inhibition of Sp1 binding by EDTA was not abrogated by the addition of ZnCl2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / abrogate-01 :polarity "-" :ARG0 (a3 / add-02 :ARG1 (s / small-molecule :name (n3 / name :op1 "ZnCl2") :xref (x2 / xref :value "PUBCHEM:84962" :prob "9.565825"))) :ARG1 (i / inhibit-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Sp1") :xref (x / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "EDTA") :xref (x1 / xref :value "PUBCHEM:6049" :prob "14.194091"))))) # ::id bio.chicago_2015.56218 # ::date 2015-11-04T00:12:24 # ::file bio_chicago_2015_56218.txt # ::snt ( B) Binding of Dfd and Dfd-VP16 to the 2xD site (see Figure 4 for sequence) in EMSAs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "Dfd")) :op2 (p2 / protein :name (n2 / name :op1 "Dfd-VP16"))) :ARG2 (p3 / protein-segment :name (n5 / name :op1 "2xD" :op2 "site") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4" :ARG1-of (s2 / see-01 :mode "imperative" :ARG0 (y / you) :purpose (s3 / sequence))))) :location (a2 / assay-01 :instrument (t / thing :name (n3 / name :op1 "EMSA"))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "B"))) # ::id bio.chicago_2015.56261 # ::date 2015-11-04T00:16:40 # ::file bio_chicago_2015_56261.txt # ::snt Actin binds so tightly to Brg1 that only denaturing conditions will separate them, and it has not been established that Brg is active as an ATPase in the absence of actin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (a / and :op1 (c / cause-01 :ARG0 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Actin") :xref (x2 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.332")) :ARG2 (p2 / protein :name (n2 / name :op1 "Brg1") :xref (x / xref :value "UNIPROT:SMCA4_HUMAN" :prob "0.602")) :ARG1-of (t / tight-05 :degree (s2 / so))) :ARG1 (s / separate-01 :ARG0 (c2 / condition :ARG0-of (d / denaturate-00) :mod (o / only)) :ARG1 (a2 / and :op1 p :op2 p2))) :op2 (e / establish-01 :polarity "-" :ARG1 (a3 / activity-06 :ARG0 (p3 / protein :name (n3 / name :op1 "Brg") :xref (x1 / xref :value "UNIPROT:SMCA4_HUMAN" :prob "0.202")) :ARG1 (e2 / enzyme :name (n4 / name :op1 "ATPase") :xref (x3 / xref :value "UNIPROT:Q0ZFE3_HUMAN" :prob "0.361")) :condition (a4 / absent-01 :ARG1 p)))) # ::id bio.chicago_2015.56319 # ::date 2015-11-04T00:23:55 # ::file bio_chicago_2015_56319.txt # ::snt Transcription factor IIE binds preferentially to RNA polymerase IIA and recruits TFIIH a model for promoter clearance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (a / and :op1 (b / bind-01 :ARG1 (f / factor :name (n3 / name :op1 "IIE") :ARG0-of (t / transcribe-01)) :ARG2 (e2 / enzyme :name (n6 / name :op1 "RNA" :op2 "polymerase" :op3 "IIA") :xref (x1 / xref :value "UNIPROT:RPB2_HUMAN" :prob "0.342")) :ARG1-of (p / prefer-01)) :op2 (r / recruit-01 :ARG0 f :ARG1 (p2 / protein :name (n5 / name :op1 "TFIIH") :ARG1-of (m / mean-01 :ARG2 (m2 / model-01 :ARG2 (c / clear-02 :ARG1 (m3 / molecular-physical-entity :ARG0-of (p3 / promote-01))))) :xref (x / xref :value "UNIPROT:TCEA3_HUMAN" :prob "0.332")))) # ::id bio.chicago_2015.56329 # ::date 2015-11-04T00:28:48 # ::file bio_chicago_2015_56329.txt # ::snt Binding of both SLBP and U7 snRNP to the pre-mRNA results in formation of a stable complex due to interaction between these two factors and their mutual stabilization on the substrate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (c / cause-01 :ARG0 (a2 / and :op1 (i / interact-01 :ARG0 "p2" :ARG1 "p") :op2 (s2 / stabilize-01 :ARG1 (a4 / and :op1 "p" :op2 "p2") :location (s3 / substrate) :mod (m2 / mutual))) :ARG1 (r / result-01 :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "SLBP") :xref (x / xref :value "UNIPROT:SLBP_HUMAN" :prob "1.003")) :op2 (p / protein :name (n2 / name :op1 "U7" :op2 "snRNP"))) :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "pre-mRNA"))) :ARG2 (f / form-01 :ARG1 (m / macro-molecular-complex :ARG1-of (s / stable-03))))) # ::id bio.chicago_2015.56330 # ::date 2015-11-04T00:34:48 # ::file bio_chicago_2015_56330.txt # ::snt Yeast two-hybrid liquid assays, affinity chromatography, and coimmunoprecipitation experiments confirm binding between PS2 and calmyrin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / confirm-01 :ARG0 (a / and :op1 (a2 / assay-01 :mod (l / liquid) :mod (h / hybrid :quant "2") :mod (y / yeast)) :op2 (c2 / chromatography :mod (a3 / affinity)) :op3 (e / experiment-01 :ARG2 (c3 / coimmunoprecipitate-01))) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "PS2") :xref (x / xref :value "UNIPROT:PSN2_HUMAN" :prob "1.002")) :ARG2 (p / protein :name (n2 / name :op1 "calmyrin") :xref (x1 / xref :value "UNIPROT:CIB1_HUMAN" :prob "0.702")))) # ::id bio.chicago_2015.56367 # ::date 2015-11-04T00:39:23 # ::file bio_chicago_2015_56367.txt # ::snt It is not clear whether PS1 binds directly to E-cadherin; their interaction might be mediated by other components of the cadherin/ catenin system. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / and :op1 (c / clear-06 :polarity "-" :ARG1 (b / bind-01 :mode "interrogative" :ARG1 (p3 / protein :name (n / name :op1 "PS1") :xref (x1 / xref :value "UNIPROT:PSN1_HUMAN" :prob "1.002")) :ARG2 (p2 / protein :name (n2 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG1-of (d / direct-02))) :op2 (p / possible-01 :ARG1 (m / mediate-01 :ARG0 (c2 / component :part-of (s / system :part (p4 / protein :name (n3 / name :op1 "cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "0.353")) :part (p5 / protein :name (n4 / name :op1 "catenin") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.283"))) :mod (o / other)) :ARG1 (i / interact-01 :ARG0 p3 :ARG1 p2)))) # ::id bio.chicago_2015.56383 # ::date 2015-11-04T00:44:25 # ::file bio_chicago_2015_56383.txt # ::snt While a highly purified preparation of TFII-I bound to an intact Inr element (Fig. 2B, lane 2), the binding of TFII-I to the mutant Inr probe is nearly abrogated (about fivefold less as revealed by densitometric measurements) (Fig. 2B, lane 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / contrast-01 :ARG1 (b / bind-01 :ARG1 (t / thing :ARG1-of (p / prepare-01 :ARG2 (p2 / protein :name (n / name :op1 "TFII-I") :xref (x / xref :value "UNIPROT:GTF2I_HUMAN" :prob "1.002"))) :ARG1-of (p3 / purify-01 :ARG1-of (h / high-02))) :ARG2 (m5 / molecular-physical-entity :mod (i / intact) :mod (e / element) :ARG0-of (i2 / initiate-01)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2B") :op2 (l / lane :mod "2")))) :ARG2 (a2 / abrogate-01 :ARG1 (b2 / bind-01 :ARG1 p2 :ARG2 (m4 / molecular-physical-entity :ARG2-of (m / mutate-01) :ARG1-of (p4 / probe-01) :ARG1-of i2)) :degree (n3 / near) :ARG1-of (m2 / mean-01 :ARG2 (l2 / less :quant (p5 / product-of :op1 "5") :ARG1-of (r / reveal-01 :ARG0 (m3 / measure-01 :mod (d2 / densitometric))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "2B") :op2 (l3 / lane :mod "5"))))) # ::id bio.chicago_2015.56386 # ::date 2015-11-04T00:52:47 # ::file bio_chicago_2015_56386.txt # ::snt In contrast, a specific binding of GST-HP1 to the linker histone H1, isolated from either calf thymus ( Figure 4D, lane 5) or P19 nuclei ( Figure 4D, lane 6), was observed, indicating that HP1 , but neither HP1 nor HP1 ( Figures 4E and 4F, lane 5), can bind to both H3 and H1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (b / bind-01 :ARG1 (p4 / protein :name (n / name :op1 "GST-HP1") :xref (x1 / xref :value "UNIPROT:GSTP1_HUMAN" :prob "0.322")) :ARG2 (p5 / protein :name (n2 / name :op1 "histone" :op2 "H1") :ARG0-of (l / link-01) :xref (x2 / xref :value "UNIPROT:H10_HUMAN" :prob "0.692")) :ARG1-of (s / specific-02) :ARG1-of (i / isolate-01 :ARG2 (o2 / or :op1 (d / dna-sequence :name (n3 / name :op1 "calf" :op2 "thymus") :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "4D") :op2 (l2 / lane :mod "5")))) :op2 (n4 / nucleus :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 f :op2 (l3 / lane :mod "6"))) :part-of (c3 / cell :name (n5 / name :op1 "P19")) :xref (x4 / xref :value "GO:0005634" :prob "0.8"))))) :ARG0-of (i2 / indicate-01 :ARG1 (c2 / contrast-01 :ARG1 (b2 / bind-01 :ARG1 (p / protein :name (n6 / name :op1 "HP1") :xref (x3 / xref :value "UNIPROT:DEF1_HUMAN" :prob "1.002")) :ARG2 (a3 / and :op1 (p2 / protein :name (n7 / name :op1 "H3")) :op2 (p3 / protein :name (n8 / name :op1 "H1") :xref (x / xref :value "UNIPROT:Q76N68_HUMAN" :prob "0.651")))) :ARG2 (b3 / bind-01 :polarity "-" :ARG1 (o3 / or :op1 p :op2 p) :ARG2 a3 :ARG1-of (d4 / describe-01 :ARG0 (a4 / and :op1 (a5 / and :op1 (f2 / figure :mod "4E") :op2 (f3 / figure :mod "4F")) :op2 (l4 / lane :mod "5")))))))) # ::id bio.chicago_2015.56388 # ::date 2015-11-04T01:02:50 # ::file bio_chicago_2015_56388.txt # ::snt Our data further suggest that this element might be an NES because its activity is inhibited by the antibiotic LMB, which specifically binds to the NES receptor, CRM1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / cause-01 :ARG0 (i / inhibit-01 :ARG0 (a3 / antibiotic :name (n2 / name :op1 "LMB") :ARG1-of (b / bind-01 :ARG2 (r / receptor :name (n3 / name :op1 "CRM1") :mod "p2") :ARG1-of (s2 / specific-02))) :ARG1 (a2 / activity-06 :ARG0 "e")) :ARG1 (s / suggest-01 :ARG0 (d / data :poss (w / we)) :ARG1 (p / possible-01 :ARG1 (e / element :mod (t / this) :mod (p2 / protein-segment :name (n / name :op1 "NES")))) :mod (f / further))) # ::id bio.chicago_2015.56477 # ::date 2015-11-04T01:08:08 # ::file bio_chicago_2015_56477.txt # ::snt In the presence of the anti-STII-C2B antibody, the IP binding activity of both GST-STII-C2B and purified synaptotagmin II was completely inhibited dose dependently ( Fig. 1, B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (i4 / inhibit-01 :ARG1 (a / activity-06 :ARG0 (a3 / and :op1 (p / protein :name (n / name :op1 "GST-STII-C2B")) :op2 (p2 / protein :name (n2 / name :op1 "synaptotagmin" :op2 "II") :ARG1-of (p3 / purify-01) :xref (x / xref :value "UNIPROT:SYT2_HUMAN" :prob "0.702"))) :ARG1 (b / bind-01) :mod (i3 / immunoprecipitate-01)) :ARG1-of (c / complete-01) :ARG0-of (d / depend-01 :ARG1 (d2 / dose)) :condition (p4 / present-02 :ARG1 (a4 / antibody :ARG0-of (o2 / oppose-01 :ARG1 (p5 / protein :name (n3 / name :op1 "STII-C2B"))))) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and :op1 (f / figure :mod "1") :op2 (f2 / figure :mod "B") :op3 (f3 / figure :mod "C")))) # ::id bio.chicago_2015.56492 # ::date 2015-11-02T07:53:20 # ::file bio_chicago_2015_56492.txt # ::snt Because the proline-rich core of Mena binds to the profilin, WW, and SH3 domains, it will be important to determine which of these interactions are compatible and which are competitive. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (b / bind-01 :ARG1 (c2 / core :part-of (p / protein :name (n / name :op1 "Mena") :xref (x1 / xref :value "UNIPROT:ENAH_HUMAN" :prob "0.602")) :mod (r / rich :mod (a / amino-acid :name (n2 / name :op1 "proline") :xref (x2 / xref :value "PUBCHEM:614" :prob "10.45396")))) :ARG2 (a2 / and :op1 (p2 / protein-segment :part-of (p5 / protein :name (n3 / name :op1 "profilin") :xref (x / xref :value "UNIPROT:B4DNH1_HUMAN" :prob "0.701"))) :op2 (p3 / protein-segment :name (n4 / name :op1 "WW")) :op2 (p4 / protein-segment :name (n5 / name :op1 "SH3")))) :ARG1 (i / important :domain (d / determine-01 :ARG1 (a3 / and :op1 (c3 / compatible :domain (i2 / interact-01 :mod (t / this))) :op2 (c4 / compete-01 :ARG0 i2))))) # ::id bio.chicago_2015.56510 # ::date 2015-11-02T08:24:39 # ::file bio_chicago_2015_56510.txt # ::snt The checkpoint-resistant Cdc20 mutants greatly diminished the binding of Mad2 and Mad3 to Cdc20 (Fig. 3C) but had no effect on the overall level of Mad1, Mad2, or Mad3 in the cell ( 21). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (c / contrast-01 :ARG1 (d / diminish-01 :ARG0 (p6 / protein :name (n / name :op1 "Cdc20") :ARG2-of (m / mutate-01) :ARG0-of (r / resist-01 :ARG1 (c2 / checkpoint)) :xref (x2 / xref :value "UNIPROT:CDC20_HUMAN" :prob "0.633")) :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "Mad2") :xref (x4 / xref :value "UNIPROT:MD2L1_HUMAN" :prob "0.602")) :op2 (p2 / protein :name (n3 / name :op1 "Mad3") :xref (x / xref :value "UNIPROT:SMAD3_HUMAN" :prob "1.002"))) :ARG2 (p5 / protein :name (n4 / name :op1 "Cdc20") :xref (x3 / xref :value "UNIPROT:CDC20_HUMAN" :prob "0.633"))) :degree (g2 / great) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3C"))) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 p6 :ARG1 (o2 / or :op1 (l2 / level :mod (o / overall) :location (c3 / cell) :quant-of (p3 / protein :name (n5 / name :op1 "Mad1") :xref (x1 / xref :value "UNIPROT:MAD1_HUMAN" :prob "0.603"))) :op2 (l3 / level :mod o :location c3 :quant-of p) :op3 (l4 / level :mod o :location c3 :quant-of p2)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "21"))))) # ::id bio.chicago_2015.56529 # ::date 2015-11-02T08:58:42 # ::file bio_chicago_2015_56529.txt # ::snt Corto binds to ESC and E(Z), two members of the PcG initiation complex We first performed GST pull-down assays to check the interactions between Corto and ESC and between Corto and E(Z). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Corto") :xref (x2 / xref :value "UNIPROT:SHAN2_HUMAN" :prob "0.242")) :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "ESC") :xref (x / xref :value "UNIPROT:DB118_HUMAN" :prob "0.232")) :op2 (p3 / protein :name (n3 / name :op1 "E(Z)")) :ARG1-of (i / include-91 :ARG2 (m2 / macro-molecular-complex :ARG0-of (i2 / initiate-01 :ARG1 (p7 / protein :name (n4 / name :op1 "PcG"))))))) :snt2 (p4 / perform-02 :ARG0 (w / we) :ARG1 (a2 / assay-01 :ARG1 (p5 / pull-down-08 :ARG1 (e / enzyme :name (n5 / name :op1 "GST") :xref (x1 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")))) :purpose (c / check-01 :ARG0 w :ARG1 (a4 / and :op1 (i3 / interact-01 :ARG0 p :ARG1 p2) :op2 (i4 / interact-01 :ARG0 p :ARG1 p3))) :time (f / first))) # ::id bio.chicago_2015.56563 # ::date 2015-11-02T09:23:06 # ::file bio_chicago_2015_56563.txt # ::snt Moreover, it has been shown that mutations in the N-terminal region of actin, which yielded a change of charge, affect myosin S1 binding to actin and thereby reduce in vitro motility (Aspenstrom and Karlsson, 1991 ; Aspenstrom et al., 1992 ; Sutoh et al., 1991 ; Miller et al., 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / and :op2 (s / show-01 :ARG1 (a2 / affect-01 :ARG0 (m / mutate-01 :ARG1 (p / protein-segment :name (n / name :op1 "N-terminus") :part-of (p2 / protein :name (n2 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :ARG0-of (y / yield-01 :ARG1 (c / change-01 :ARG1 (c2 / charge-03)))) :ARG1 (b / bind-01 :ARG1 (p3 / protein-segment :name (n3 / name :op1 "S1") :part-of (p4 / protein :name (n4 / name :op1 "myosin") :xref (x1 / xref :value "UNIPROT:MYH1_HUMAN" :prob "0.322"))) :ARG2 p2) :ARG0-of (c3 / cause-01 :ARG1 (r / reduce-01 :ARG0 m :ARG1 (m2 / motility :mod (i / in-vitro))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (p6 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :name (n6 / name :op1 "Aspenstrom")) :op2 (p8 / person :name (n7 / name :op1 "Karlsson"))) :time (d2 / date-entity :year "1991")) :op2 (p9 / publication-91 :ARG0 (a5 / and :op1 p7 :op2 (p11 / person :mod (o / other))) :time (d3 / date-entity :year "1992")) :op3 (p12 / publication-91 :ARG0 (a6 / and :op1 (p13 / person :name (n9 / name :op1 "Sutoh")) :op2 (p14 / person :mod (o2 / other))) :time d2) :op4 (p15 / publication-91 :ARG0 (a7 / and :op1 (p16 / person :name (n10 / name :op1 "Miller")) :op2 (p17 / person :mod (o3 / other))) :time (d5 / date-entity :year "1996")))))) # ::id bio.chicago_2015.56580 # ::date 2015-11-02T10:03:21 # ::file bio_chicago_2015_56580.txt # ::snt Dimerization of Rabaptin-5 could also form a divalent Rab5-binding site, since single Rabaptin-5 chains can bind Rab5 (Horiuchi et al., 1997). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (c / cause-01 :ARG0 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (c2 / chain-01 :ARG0 (p2 / protein :name (n / name :op1 "Rabaptin-5") :xref (x / xref :value "UNIPROT:RABE1_HUMAN" :prob "1.002")) :ARG1-of (s / single-02)) :ARG2 (p3 / protein :name (n2 / name :op1 "Rab5") :xref (x1 / xref :value "UNIPROT:RAB5A_HUMAN" :prob "0.603")))) :ARG1 (p4 / possible-01 :ARG1 (f / form-01 :ARG0 (d / dimerize-01 :ARG1 p2) :ARG1 (s2 / site :ARG1-of (b2 / bind-01 :ARG2 p3) :mod (d2 / divalent))) :mod (a / also)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and :op1 (p6 / person :name (n3 / name :op1 "Horiuchi")) :op2 (p7 / person :mod (o / other))) :time (d4 / date-entity :year "1997")))) # ::id bio.chicago_2015.56582 # ::date 2015-11-02T10:23:34 # ::file bio_chicago_2015_56582.txt # ::snt Originally identified by virtue of its physical binding to Src, the mDab1 protein also binds other nonreceptor tyrosine kinases such as Fyn and Abl (Howell et al., 1997a ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "mDab1") :xref (x4 / xref :value "UNIPROT:TM190_HUMAN" :prob "0.212")) :ARG2 (e / enzyme :name (n2 / name :op1 "nonreceptor" :op2 "tyrosine" :op3 "kinase") :example (a2 / and :op1 (k2 / kinase :name (n3 / name :op1 "Fyn") :xref (x / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604")) :op2 (k / kinase :name (n4 / name :op1 "Abl") :xref (x3 / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603"))) :xref (x2 / xref :value "UNIPROT:TNK1_HUMAN" :prob "0.342")) :mod (a / also) :ARG1-of (i / identify-01 :ARG1-of (c / cause-01 :ARG0 (b2 / bind-01 :ARG1 p :ARG2 (p2 / protein :name (n5 / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")) :mod (p3 / physical))) :mod (o / original)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n6 / name :op1 "Howell")) :op2 (p6 / person :mod (o2 / other))) :time (d2 / date-entity :year "1997" :li "a")))) # ::id bio.chicago_2015.56594 # ::date 2015-11-02T10:36:00 # ::file bio_chicago_2015_56594.txt # ::snt Evidently, the peptide only slightly affected binding of c-Cbl to EGFR, but it almost completely abolished the interaction with the shorter viral form of Cbl. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (c / contrast-01 :ARG1 (a / affect-01 :ARG0 (p / peptide) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "c-Cbl") :xref (x / xref :value "UNIPROT:Q6LB30_HUMAN" :prob "0.601")) :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :degree (s / slight :mod (o / only))) :ARG2 (a2 / abolish-01 :ARG0 p :ARG1 (i / interact-01 :ARG1 (f / form :mod (v / viral) :ARG1-of (s2 / short-07 :degree (m / more)) :mod (p3 / protein :name (n3 / name :op1 "Cbl") :xref (x2 / xref :value "UNIPROT:CBL_HUMAN" :prob "0.604")))) :ARG1-of (c2 / complete-02 :degree (a3 / almost))) :ARG1-of (e2 / evidence-01)) # ::id bio.chicago_2015.56667 # ::date 2015-11-02T10:47:06 # ::file bio_chicago_2015_56667.txt # ::snt These data prompted us to test for a disruption of TFIID binding to various DCE mutations (Fig. 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (p / prompt-02 :ARG0 (d / data :mod (t / this)) :ARG1 (w / we) :ARG2 (t2 / test-01 :ARG0 w :ARG2 (d2 / disrupt-01 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "TFIID") :xref (x / xref :value "UNIPROT:TBP_HUMAN" :prob "1.002")) :ARG2 (m / mutate-01 :ARG2 (p3 / protein :name (n2 / name :op1 "DCE") :xref (x1 / xref :value "UNIPROT:DCE1_HUMAN" :prob "0.262")) :mod (v / various))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "6"))) # ::id bio.chicago_2015.56680 # ::date 2015-11-02T10:59:30 # ::file bio_chicago_2015_56680.txt # ::snt Hence, it can be predicted that BAG4 binds Hsc70 in a manner analogous to BAG1 ( 3, 15). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (c2 / cause-01 :ARG1 (p4 / possible-01 :ARG1 (p / predict-01 :ARG1 (b / bind-01 :ARG1 (p5 / protein :name (n / name :op1 "BAG4") :xref (x2 / xref :value "UNIPROT:BAG4_HUMAN" :prob "1.003")) :ARG2 (p2 / protein :name (n2 / name :op1 "Hsc70") :xref (x / xref :value "UNIPROT:HSP7C_HUMAN" :prob "0.633")) :ARG1-of (r / resemble-01 :ARG2 (b2 / bind-01 :ARG1 (p7 / protein :name (n3 / name :op1 "BAG1") :xref (x1 / xref :value "UNIPROT:BAG1_HUMAN" :prob "1.003"))))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 "3" :op2 "15"))))) # ::id bio.chicago_2015.56736 # ::date 2015-11-02T11:25:56 # ::file bio_chicago_2015_56736.txt # ::snt Western blotting confirmed that the Cdc11 septin binds to the Gin4 affinity column (Fig. 2 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (c / confirm-01 :ARG0 (t / thing :name (n / name :op1 "Western" :op2 "blotting")) :ARG1 (b / bind-01 :ARG1 (s / septin :name (n2 / name :op1 "Cdc11")) :ARG2 (c2 / column :mod (a2 / affinity) :mod (p / protein :name (n3 / name :op1 "Gin4") :xref (x / xref :value "UNIPROT:SLD5_HUMAN" :prob "0.232")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id bio.chicago_2015.56738 # ::date 2015-11-02T11:33:41 # ::file bio_chicago_2015_56738.txt # ::snt HMG-I(Y) and NF-kappaB subunit p50 bind to the iNOS promoter/enhancer and form a ternary DNA-protein complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (b / bind-01 :ARG1 (a2 / and :op1 (p6 / protein :name (n / name :op1 "p50") :part-of (m2 / macro-molecular-complex :name (n2 / name :op1 "HMG-I(Y)")) :xref (x1 / xref :value "UNIPROT:E4F1_HUMAN" :prob "0.212")) :op2 (p7 / protein :name (n3 / name :op1 "p50") :part-of (m5 / macro-molecular-complex :name (n4 / name :op1 "NF-kappaB")) :xref (x2 / xref :value "UNIPROT:E4F1_HUMAN" :prob "0.212"))) :ARG2 (s3 / slash :op1 (m3 / molecular-physical-entity :ARG0-of (p4 / promote-02 :ARG1 (e2 / enzyme :name (n5 / name :op1 "iNOS") :xref (x / xref :value "UNIPROT:NOS2_HUMAN" :prob "1.002")))) :op2 (m4 / molecular-physical-entity :ARG0-of (e / enhance-01 :ARG1 e2)))) :op2 (f / form-01 :ARG0 a2 :ARG1 (m / macro-molecular-complex :part (p5 / protein) :part (n6 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA")) :mod (t / ternary)))) # ::id bio.chicago_2015.56780 # ::date 2015-11-02T11:47:34 # ::file bio_chicago_2015_56780.txt # ::snt Despite the fact that myo-D and P/CAF bind to distinct CBP/ p300 sites, both interactions are disrupted by E1A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (h / have-concession-91 :ARG1 (d2 / disrupt-01 :ARG0 (p5 / protein :name (n5 / name :op1 "E1A") :xref (x2 / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.262")) :ARG1 "b") :ARG2 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "myo-D") :xref (x3 / xref :value "UNIPROT:MYOD1_HUMAN" :prob "0.592")) :op2 (e / enzyme :name (n2 / name :op1 "P/CAF"))) :ARG2 (a2 / and :op1 (s / site :mod (p3 / protein :name (n3 / name :op1 "CBP") :xref (x / xref :value "UNIPROT:CBP_HUMAN" :prob "1.003")) :mod (d / distinct)) :op2 (s2 / site :mod (p4 / protein :name (n4 / name :op1 "p300") :xref (x1 / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702")) :mod d)))) # ::id bio.chicago_2015.56853 # ::date 2015-11-02T12:07:42 # ::file bio_chicago_2015_56853.txt # ::snt In mammals, however, there has been no evidence that eIF4G binds PABP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (h / have-concession-91 :ARG1 (e / evidence-01 :polarity "-" :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "eIF4G") :xref (x1 / xref :value "UNIPROT:IF4G1_HUMAN" :prob "0.702")) :ARG2 (p2 / protein :name (n2 / name :op1 "PABP") :xref (x / xref :value "UNIPROT:A0A024R9C1_HUMAN" :prob "1.001"))) :location (m / mammal))) # ::id bio.chicago_2015.56858 # ::date 2015-11-02T13:05:52 # ::file bio_chicago_2015_56858.txt # ::snt A mutation within the 6-aa motif that mediates the binding between CtBP and HPC2 results in a significant but only small decrease in the repressing abilities of HPC2 (Fig. 9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (r / result-01 :ARG1 (m / mutate-01 :ARG1 (d3 / dna-sequence :name (n / name :op1 "6-aa" :op2 "motif") :ARG0-of (m2 / mediate-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n2 / name :op1 "CtBP") :xref (x1 / xref :value "UNIPROT:CTBP1_HUMAN" :prob "0.652")) :ARG2 (p2 / protein :name (n3 / name :op1 "HPC2") :xref (x / xref :value "UNIPROT:RNZ2_HUMAN" :prob "1.002")))))) :ARG2 (d / decrease-01 :ARG1 (c2 / capable-01 :ARG1 p2 :ARG2 (r2 / repress-01 :ARG0 p2)) :ARG1-of (s / significant-02 :ARG1-of (c / contrast-01 :ARG2 (s2 / small :mod (o / only))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "9"))) # ::id bio.chicago_2015.56861 # ::date 2015-11-02T13:37:31 # ::file bio_chicago_2015_56861.txt # ::snt Each binding site in eIF4G can bind either eIF4AI or eIF4AII. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (s / site :mod (e / each) :ARG2-of (b2 / bind-01) :location (p2 / protein :name (n / name :op1 "eIF4G") :xref (x / xref :value "UNIPROT:IF4G1_HUMAN" :prob "0.702"))) :ARG2 (o / or :op1 (p3 / protein :name (n2 / name :op1 "eIF4AI") :xref (x1 / xref :value "UNIPROT:IF4A1_HUMAN" :prob "0.692")) :op2 (p4 / protein :name (n3 / name :op1 "eIF4AII") :xref (x2 / xref :value "UNIPROT:IF4A2_HUMAN" :prob "0.692"))))) # ::id bio.chicago_2015.56879 # ::date 2015-11-02T13:51:27 # ::file bio_chicago_2015_56879.txt # ::snt ura4+ at 30 and 32 degrees C, where the effects of the mts3-1 mutation will be greater than at 25 degrees C, is due to the lack of polyubiquitin binding by Pus1N5 to bind conjugates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / cause-01 :ARG0 (l / lack-01 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Pus1N5") :xref (x / xref :value "UNIPROT:TRUA_HUMAN" :prob "0.222")) :ARG2 (p / protein :name (n2 / name :op1 "polyubiquitin") :xref (x2 / xref :value "UNIPROT:UBB_HUMAN" :prob "0.392")) :ARG1-of (b2 / bind-01 :ARG2 (m / molecular-physical-entity :ARG3-of (c3 / conjugate-02))))) :ARG1 (g / gene :name (n / name :op1 "ura4+") :ARG0-of (c4 / cause-01 :ARG1 (a2 / affect-01 :ARG0 (m2 / mutate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "mts3-1") :xref (x1 / xref :value "UNIPROT:CD2A1_HUMAN" :prob "0.262"))) :mod (g3 / great :degree (m3 / more) :compared-to (t3 / temperature-quantity :quant "25" :scale (c5 / celsius))))) :mod (t / temperature-quantity :quant "30" :scale (c2 / celsius)) :mod (t2 / temperature-quantity :quant "32" :scale c2))) # ::id bio.chicago_2015.56963 # ::date 2015-11-03T00:38:39 # ::file bio_chicago_2015_56963.txt # ::snt We also find that three lysine-rich boxes in the N-terminal segment of eIF2beta mediate the binding of eIF2 to both eIF5 and eIF2B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (m / mediate-01 :ARG0 (b / box :quant "3" :mod (r / rich :mod (a / amino-acid :name (n / name :op1 "lysine") :xref (x4 / xref :value "PUBCHEM:866" :prob "11.053295"))) :location (p / protein-segment :name (n2 / name :op1 "N-terminus") :part-of (p2 / protein :name (n3 / name :op1 "eIF2beta") :xref (x / xref :value "UNIPROT:IF2B_HUMAN" :prob "0.672")))) :ARG1 (b2 / bind-01 :ARG1 (p3 / protein :name (n4 / name :op1 "eIF2") :xref (x2 / xref :value "UNIPROT:AGO2_HUMAN" :prob "0.332")) :ARG2 (a3 / and :op1 (p4 / protein :name (n5 / name :op1 "eIF5") :xref (x1 / xref :value "UNIPROT:IF5_HUMAN" :prob "0.702")) :op2 (p5 / protein :name (n6 / name :op1 "eIF2B") :xref (x3 / xref :value "UNIPROT:IF2B_HUMAN" :prob "0.702"))))) :mod (a2 / also)) # ::id bio.chicago_2015.56965 # ::date 2015-11-03T00:46:28 # ::file bio_chicago_2015_56965.txt # ::snt DAG binding to UNC-13 is required to stimulate acetylcholine release. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (r / require-01 :ARG0 (s / stimulate-01 :ARG1 (r2 / release-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "acetylcholine") :xref (x1 / xref :value "PUBCHEM:187" :prob "16.403933")))) :ARG1 (b / bind-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "DAG") :xref (x2 / xref :value "PUBCHEM:2784000" :prob "12.363392")) :ARG2 (p2 / protein :name (n2 / name :op1 "UNC-13") :xref (x / xref :value "UNIPROT:UN13B_HUMAN" :prob "0.682")))) # ::id bio.chicago_2015.56989 # ::date 2015-11-03T00:51:55 # ::file bio_chicago_2015_56989.txt # ::snt In contrast, minimal binding of Arp1 to the DII and GST columns was observed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Arp1") :xref (x1 / xref :value "UNIPROT:ACTZ_HUMAN" :prob "0.602")) :ARG2 (a / and :op1 (c2 / column :mod (p2 / protein :name (n2 / name :op1 "DII"))) :op2 (c3 / column :mod (e / enzyme :name (n3 / name :op1 "GST") :xref (x / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")))) :ARG1-of (m / minimal-02)))) # ::id bio.chicago_2015.56998 # ::date 2015-11-03T00:57:35 # ::file bio_chicago_2015_56998.txt # ::snt Ena is phosphorylated on multiple tyrosine residues, most of which are found near proline-rich sequences that mediate Ena's binding to the Abl and Src SH3 domains. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / phosphorylate-01 :ARG1 (r / residue :mod (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "Ena") :xref (x / xref :value "UNIPROT:SCNNA_HUMAN" :prob "0.232")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :quant (m / multiple) :ARG2-of (i / include-91 :ARG1 (r2 / residue :ARG1-of (f / find-01 :ARG1-of (n3 / near-02 :ARG2 (s / sequence :mod (r3 / rich :mod (a3 / amino-acid :name (n4 / name :op1 "proline") :xref (x3 / xref :value "PUBCHEM:614" :prob "10.45396"))) :ARG0-of (m3 / mediate-01 :ARG1 (b / bind-01 :ARG1 p2 :ARG2 (a2 / and :op1 (p4 / protein-segment :name (n5 / name :op1 "SH3") :part-of (p6 / protein :name (n7 / name :op1 "Abl") :xref (x2 / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603"))) :op1 (p7 / protein-segment :name (n8 / name :op1 "SH3") :part-of (p5 / protein :name (n6 / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604")))))))))) :mod (m2 / most)))) # ::id bio.chicago_2015.57043 # ::date 2015-11-03T01:34:44 # ::file bio_chicago_2015_57043.txt # ::snt Complex Formation of GSK-3beta, AKAP220, PKA, and PP1-- It has been shown that AKAP220 binds to PP1 in addition to PKA ( 29). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (m / multi-sentence :snt1 (f / form-01 :ARG1 (m2 / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "GSK-3beta") :xref (x3 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.692")) :part (p / protein :name (n2 / name :op1 "AKAP220") :xref (x6 / xref :value "UNIPROT:AKA11_HUMAN" :prob "1.002")) :part (e2 / enzyme :name (n3 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :part (p2 / protein :name (n4 / name :op1 "PP1") :xref (x2 / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002")))) :snt2 (s / show-01 :ARG1 (b / bind-01 :ARG1 (p4 / protein :name (n5 / name :op1 "AKAP220") :xref (x4 / xref :value "UNIPROT:AKA11_HUMAN" :prob "1.002")) :ARG2 (a / and :op1 (p5 / protein :name (n6 / name :op1 "PP1") :xref (x5 / xref :value "UNIPROT:NPY4R_HUMAN" :prob "1.002")) :op2 (e3 / enzyme :name (n7 / name :op1 "PKA") :xref (x / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "29"))))) # ::id bio.chicago_2015.57105 # ::date 2015-11-03T03:39:24 # ::file bio_chicago_2015_57105.txt # ::snt The GTP-bound form of ARF1 recruits protein coats, including the clathrin-associated adaptor proteins AP-1 and AP-3 and the nonclathrin coatomer, to membranes and initiates budding of the membrane vesicles (Lenhard et al., 1992 ; Donaldson and Klausner, 1994 ; Boman and Kahn, 1995 ; Dittie et al., 1996 ; Ooi et al., 1998 ; Springer et al., 1999 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (a4 / and :op1 (r / recruit-01 :ARG0 (p / protein :name (n2 / name :op1 "ARF1") :ARG2-of (b / bind-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x2 / xref :value "UNIPROT:ARF1_HUMAN" :prob "1.004")) :ARG1 (c / coat-01 :ARG2 (p2 / protein) :ARG2-of (i / include-01 :ARG1 (a / and :op1 (p3 / protein :name (n3 / name :op1 "AP-1") :mod (a2 / adaptor) :ARG1-of (a3 / associate-01 :ARG2 (p5 / protein :name (n5 / name :op1 "clathrin") :xref (x1 / xref :value "UNIPROT:A0A087WVQ6_HUMAN" :prob "0.291"))) :xref (x / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652")) :op2 (p4 / protein :name (n4 / name :op1 "AP-3") :mod a2 :ARG1-of a3) :op3 (p6 / protein :name (n6 / name :op1 "nonclathrin" :op2 "coatomer"))))) :purpose (m / membrane :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :op2 (i2 / initiate-01 :ARG0 p :ARG1 (b2 / bud-01 :ARG1 (v / vesicle :mod m))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (p7 / publication-91 :ARG0 (a6 / and :op1 (p8 / person :name (n7 / name :op1 "Lenhard")) :op2 (p9 / person :mod (o / other))) :time (d2 / date-entity :year "1992")) :op2 (p10 / publication-91 :ARG0 (a7 / and :op1 (p11 / person :name (n8 / name :op1 "Donaldson")) :op2 (p12 / person :name (n9 / name :op1 "Klausner"))) :time (d3 / date-entity :year "1994")) :op3 (p13 / publication-91 :ARG0 (a8 / and :op1 (p14 / person :name (n10 / name :op1 "Boman")) :op2 (p15 / person :name (n11 / name :op1 "Kahn"))) :time (d4 / date-entity :year "1995")) :op4 (p16 / publication-91 :ARG0 (a9 / and :op1 (p17 / person :name (n12 / name :op1 "Dittie")) :op2 (p18 / person :mod (o2 / other))) :time (d5 / date-entity :year "1996")) :op5 (p19 / publication-91 :ARG0 (a10 / and :op1 (p20 / person :name (n13 / name :op1 "Ooi")) :op2 (p21 / person :mod (o3 / other))) :time (d6 / date-entity :year "1998")) :op6 (p22 / publication-91 :ARG0 (a11 / and :op1 (p23 / person :name (n14 / name :op1 "Springer")) :op2 (p24 / person :mod (o4 / other))) :time (d7 / date-entity :year "1999"))))) # ::id bio.chicago_2015.57113 # ::date 2015-11-03T04:23:18 # ::file bio_chicago_2015_57113.txt # ::snt This analysis revealed specific in vivo binding of NFAT5 to the TNF proximal promoter and the aldose reductase enhancer in response to hypertonic stimulation, either alone or in combination with PMA ( Figure 6D, right, top and middle panels, lanes 5 and 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :mod (t / this)) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "NFAT5") :xref (x2 / xref :value "UNIPROT:NFAT5_HUMAN" :prob "1.003")) :ARG2 (a2 / and :op1 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n2 / name :op1 "TNF") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002"))) :mod (p4 / proximal)) :op2 (m2 / molecular-physical-entity :ARG0-of (e / enhance-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "aldose" :op2 "reductase") :xref (x / xref :value "UNIPROT:ALDR_HUMAN" :prob "0.702"))))) :ARG1-of (s / specific-02) :manner (i / in-vivo) :ARG2-of (r2 / respond-01 :ARG1 (o / or :op1 (s2 / stimulate-01 :ARG0 (h / hypertonic) :mod (a3 / alone)) :op2 (c / combine-01 :ARG1 s2 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "PMA") :xref (x3 / xref :value "PUBCHEM:4792" :prob "16.591986")))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (a5 / and :op1 (l / lane :mod "5") :op2 (l2 / lane :mod "6")) :op2 (a6 / and :op1 (p5 / panel :ARG1-of (r3 / right-04)) :op2 (p6 / panel :location (t2 / top)) :op3 (p7 / panel :location (m3 / middle))) :part-of (f / figure :mod "6D")))) # ::id bio.chicago_2015.57142 # ::date 2015-11-03T07:33:46 # ::file bio_chicago_2015_57142.txt # ::snt C, DNA binding of Smad5 and Smad4 to the GC-rich sequence is shown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / show-01 :ARG1 (b / bind-01 :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")) :ARG1 (a / and :op1 (p2 / protein :name (n4 / name :op1 "Smad5") :xref (x / xref :value "UNIPROT:SMAD5_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n5 / name :op1 "Smad4") :xref (x1 / xref :value "UNIPROT:SMAD4_HUMAN" :prob "1.003"))) :ARG2 (s2 / sequence :mod (r / rich :op1 (s3 / small-molecule :name (n / name :op1 "guanine") :xref (x2 / xref :value "PUBCHEM:764" :prob "13.358051")) :op2 (s4 / small-molecule :name (n6 / name :op1 "cytosine") :xref (x3 / xref :value "PUBCHEM:597" :prob "13.428404"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id bio.chicago_2015.57166 # ::date 2015-11-03T07:45:15 # ::file bio_chicago_2015_57166.txt # ::snt Because Sec15p also binds to activated Sec4p, the exocyst might be an effector for this Rab-like GTPase that is necessary for the targeting or tethering of secretory vesicles to sites of secretion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (c / cause-01 :ARG0 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Sec15p") :xref (x4 / xref :value "UNIPROT:EXOC6_HUMAN" :prob "0.232")) :ARG2 (p2 / protein :name (n2 / name :op1 "Sec4p") :ARG1-of (a / activate-01) :xref (x1 / xref :value "UNIPROT:RB40B_HUMAN" :prob "0.212")) :mod (a3 / also)) :ARG1 (p3 / possible-01 :ARG1 (e / effector :domain (p4 / protein :name (n3 / name :op1 "exocyst") :xref (x2 / xref :value "UNIPROT:EXOC8_HUMAN" :prob "0.222")) :beneficiary (e2 / enzyme :name (n4 / name :op1 "GTPase") :ARG1-of (r / resemble-01 :ARG2 (p5 / protein :name (n5 / name :op1 "Rab") :xref (x3 / xref :value "UNIPROT:AGFG1_HUMAN" :prob "0.602"))) :ARG1-of (n6 / need-01 :ARG0 (o / or :op1 (t / target-01 :ARG0 (v / vesicle :ARG0-of (s / secrete-01)) :ARG1 (s2 / site :location-of (s3 / secrete-01))) :op2 (t2 / tether-01 :ARG0 v :ARG1 s2))) :mod (t3 / this) :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312"))))) # ::id bio.chicago_2015.57186 # ::date 2015-11-03T08:22:51 # ::file bio_chicago_2015_57186.txt # ::snt Calmodulin binding activities of the adducin recombinant polypeptides and the MARCKS-related domain peptide were inhibited by PKA and PKC phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG0 (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332")) :op2 (e2 / enzyme :name (n2 / name :op1 "PKC") :xref (x3 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")))) :ARG1 (a2 / and :op1 (a3 / activity-06 :ARG0 (p5 / polypeptide :name (n4 / name :op1 "adducin" :op2 "recombinant")) :ARG1-of (b / bind-01 :ARG2 (p4 / protein :name (n3 / name :op1 "calmodulin") :xref (x2 / xref :value "UNIPROT:CALM_HUMAN" :prob "0.703")))) :op2 (p6 / peptide :part-of (d / domain :ARG1-of (r / relate-01 :ARG2 (p7 / protein :name (n5 / name :op1 "MARCKS") :xref (x / xref :value "UNIPROT:MARCS_HUMAN" :prob "1.002"))))))) # ::id bio.chicago_2015.57199 # ::date 2015-11-03T08:48:31 # ::file bio_chicago_2015_57199.txt # ::snt All of these results indicate that the binding of Axin to Dvl is probably mediated by two interactions; one between DvlN and AxinC and the other between DvlPDZ and an N-terminal sequence of Axin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this) :mod (a / all)) :ARG1 (m / mediate-01 :ARG0 (a2 / and :op1 (i2 / interact-01 :ARG0 (p3 / protein :name (n3 / name :op1 "DvlN") :xref (x / xref :value "UNIPROT:DVLP1_HUMAN" :prob "0.202")) :ARG1 (p5 / protein :name (n4 / name :op1 "AxinC") :xref (x3 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.272"))) :op2 (i3 / interact-01 :ARG0 (p4 / protein :name (n5 / name :op1 "DvlPDZ") :xref (x2 / xref :value "UNIPROT:DNM1L_HUMAN" :prob "0.222")) :ARG1 (p7 / protein-segment :name (n7 / name :op1 "N-terminus") :part-of "p6"))) :ARG1 (b / bind-01 :ARG1 (p6 / protein :name (n / name :op1 "Axin") :xref (x1 / xref :value "UNIPROT:AXIN1_HUMAN" :prob "0.602")) :ARG2 (p / protein :name (n2 / name :op1 "Dvl") :xref (x4 / xref :value "UNIPROT:DVLP1_HUMAN" :prob "0.602"))) :mod (p2 / probable))) # ::id bio.chicago_2015.57217 # ::date 2015-11-03T09:04:37 # ::file bio_chicago_2015_57217.txt # ::snt TIF1alpha and TIF1beta bind directly to HP1alpha, - beta and -gamma in vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "TIF1" :op2 "alpha") :xref (x4 / xref :value "UNIPROT:TIF1A_HUMAN" :prob "0.692")) :op2 (p2 / protein :name (n2 / name :op1 "TIF1" :op2 "beta") :xref (x / xref :value "UNIPROT:TIF1B_HUMAN" :prob "0.692"))) :ARG2 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "HP1" :op2 "alpha") :xref (x2 / xref :value "UNIPROT:CBX5_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n4 / name :op1 "HP1" :op2 "beta") :xref (x1 / xref :value "UNIPROT:CBX1_HUMAN" :prob "1.002")) :op3 (p5 / protein :name (n5 / name :op1 "HP1" :op2 "gamma") :xref (x3 / xref :value "UNIPROT:CBX3_HUMAN" :prob "1.002"))) :ARG1-of (d / direct-02) :manner (i / in-vitro)) # ::id bio.chicago_2015.57274 # ::date 2015-11-03T09:25:42 # ::file bio_chicago_2015_57274.txt # ::snt The mechanism of indirect binding of ERM proteins to integral membrane proteins has also been reported. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (r / report-01 :ARG1 (m / mechanism :instrument-of (b / bind-01 :ARG1 (p / protein-family :name (n / name :op1 "ERM")) :ARG2 (p2 / protein :name (n2 / name :op1 "integral" :op2 "membrane" :op3 "protein") :xref (x / xref :value "UNIPROT:STT3A_HUMAN" :prob "0.392")) :ARG1-of (d / direct-02 :polarity "-"))) :mod (a / also)) # ::id bio.chicago_2015.57316 # ::date 2015-11-03T09:32:12 # ::file bio_chicago_2015_57316.txt # ::snt The Tyr43/Asp49 conformational switch is the most probable explanation for the GTP-dependent binding of Sec5 to RalA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (e / explain-01 :ARG0 (s / switch-01 :ARG1-of (c / conform-01 :ARG2 (s2 / slash :op1 (a / amino-acid :mod "43" :name (n6 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a2 / amino-acid :mod "49" :name (n / name :op1 "aspartic" :op2 "acid") :xref (x4 / xref :value "PUBCHEM:424" :prob "7.741247"))))) :ARG1 (b / bind-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Sec5") :xref (x / xref :value "UNIPROT:EXOC2_HUMAN" :prob "0.602")) :ARG2 (p4 / protein :name (n4 / name :op1 "RalA") :xref (x1 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604")) :ARG0-of (d / depend-01 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :mod (p5 / probable :degree (m / most))) # ::id bio.chicago_2015.57334 # ::date 2015-11-03T09:50:51 # ::file bio_chicago_2015_57334.txt # ::snt In our studies no increase in endogenous plakoglobin levels was detected in response to the expression of E-cadherin in L cells, despite the fact that plakoglobin can effectively bind to E-cadherin in other cell types ( 24, 25). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (h / have-concession-91 :ARG1 (d / detect-01 :polarity "-" :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "plakoglobin") :mod (e / endogenous))) :ARG2-of (r / respond-01 :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG3 (c / cell :name (n3 / name :op1 "L"))))) :ARG2 (s / study-01 :ARG0 (w / we))) :ARG2 (p3 / possible-01 :ARG1 (b / bind-01 :ARG1 p :ARG2 p2 :ARG1-of (e3 / effective-04) :location (c4 / cell :mod (t / type) :mod (o / other)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (a / and :op1 "24" :op2 "25"))))) # ::id bio.chicago_2015.57387 # ::date 2015-11-03T10:39:45 # ::file bio_chicago_2015_57387.txt # ::snt Binding of Smad3 and Sp1 was demonstrated upon immunodetection with specific antibodies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (d / demonstrate-01 :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "Smad3") :xref (x1 / xref :value "UNIPROT:SMAD3_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "Sp1") :xref (x / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001")))) :time (i / immunodetect-01 :ARG3 (a2 / antibody :ARG1-of (s / specific-02)))) # ::id bio.chicago_2015.57447 # ::date 2015-11-03T10:43:43 # ::file bio_chicago_2015_57447.txt # ::snt While the homeodomain alone of Pbx1 or exd binds DNA cooperatively with Hox proteins, studies with Pbx1 have shown that a 16-residue C-terminal tail, which is conserved in exd, is required for maximal cooperative interactions with Hox partners (Chang et al., 1995 ; Lu and Kamps, 1996 ; Green et al., 1998 ) and for maximal binding of monomeric Pbx1 homeodomain to DNA (Lu and Kamps, 1996 ; Green et al., 1998 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (s / show-01 :ARG0 (s2 / study-01 :ARG1 (p / protein :name (n / name :op1 "Pbx1") :xref (x1 / xref :value "UNIPROT:PBX1_HUMAN" :prob "0.603"))) :ARG1 (r / require-01 :ARG0 (a / and :op1 (i / interact-01 :ARG1 (p3 / partner-01 :ARG1 (p2 / protein-family :name (n3 / name :op1 "Hox"))) :degree (m / maximal) :manner (c2 / cooperate-01) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p7 / publication-91 :ARG0 (a4 / and :op1 (p10 / person :name (n8 / name :op1 "Chang")) :op2 (p11 / person :mod (o2 / other))) :time (d2 / date-entity :year "1995")) :op2 (p8 / publication-91 :ARG0 (a5 / and :op1 (p12 / person :name (n9 / name :op1 "Lu")) :op2 (p13 / person :name (n10 / name :op1 "Kamps"))) :time (d3 / date-entity :year "1996")) :op3 (p9 / publication-91 :ARG0 (a6 / and :op1 (p14 / person :name (n11 / name :op1 "Green")) :op2 (p15 / person :mod (o3 / other))) :time (d4 / date-entity :year "1998"))))) :op2 (b / bind-01 :ARG1 (h4 / homeodomain :part-of (p5 / protein :name (n4 / name :op1 "Pbx1") :mod (m3 / monomeric) :xref (x / xref :value "UNIPROT:PBX1_HUMAN" :prob "0.603"))) :ARG2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")) :degree m :ARG1-of (d5 / describe-01 :ARG0 (a7 / and :op1 p8 :op2 p9)))) :ARG1 (t / tail :mod (r2 / residue :mod "16") :ARG1-of (c / conserve-01 :location (p6 / protein :name (n7 / name :op1 "edx"))) :part-of (p16 / protein-segment :name (n12 / name :op1 "C-terminus"))))) :ARG2 (b2 / bind-01 :ARG1 (o / or :op1 (h2 / homeodomain :part-of p :mod (a3 / alone)) :op2 (h3 / homeodomain :part-of p6 :mod a3)) :ARG2 n5 :ARG3 p2 :ARG2-of c2)) # ::id bio.chicago_2015.57503 # ::date 2015-11-03T11:40:02 # ::file bio_chicago_2015_57503.txt # ::snt Incubation of wild-type Tsg protein with Chordin and BMP4 generated a ternary complex corresponding to a Tsg dimer bound to a BMP4 dimer and Chordin ( Fig. 4D, lane 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (g / generate-01 :ARG0 (i / incubate-01 :ARG1 (p / protein :name (n / name :op1 "Tsg") :mod (w / wild-type) :xref (x4 / xref :value "UNIPROT:TWSG1_HUMAN" :prob "0.602")) :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "Chordin") :xref (x / xref :value "UNIPROT:CHRD_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n3 / name :op1 "BMP4") :xref (x1 / xref :value "UNIPROT:BMP4_HUMAN" :prob "1.004")))) :ARG1 (m / macro-molecular-complex :mod (t / ternary) :ARG1-of (c / correspond-02 :ARG2 (p5 / protein :name (n4 / name :op1 "Tsg") :ARG1-of (b / bind-01 :ARG2 (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "BMP4") :ARG3-of (d2 / dimerize-01) :xref (x2 / xref :value "UNIPROT:BMP4_HUMAN" :prob "1.004")) :op2 p2)) :ARG3-of (d / dimerize-01) :xref (x3 / xref :value "UNIPROT:TWSG1_HUMAN" :prob "0.602")))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "4D" :location (l / lane :mod "3")))) # ::id bio.chicago_2015.57541 # ::date 2015-11-03T12:01:08 # ::file bio_chicago_2015_57541.txt # ::snt (C) Differential binding of recombinant s-synaphin constructs to syntaxin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (b / bind-01 :ARG1 (c / construct :mod (p / protein :name (n / name :op1 "s-synaphin") :ARG3-of (r / recombine-01))) :ARG2 (p2 / protein :name (n2 / name :op1 "syntaxin") :xref (x / xref :value "UNIPROT:STX2_HUMAN" :prob "0.352")) :ARG1-of (d2 / differ-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"))) # ::id bio.chicago_2015.57550 # ::date 2015-11-03T12:23:40 # ::file bio_chicago_2015_57550.txt # ::snt Binding of actin to tropomyosin is directly demonstrated by cosedimentation and SDS-gel electrophoresis ( Fig. 1 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (d / demonstrate-01 :ARG0 (a / and :op1 (c / cosedimentation) :op2 (e / electrophoresis :instrument (t / thing :name (n3 / name :op1 "SDS" :op2 "gel")))) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG2 (p2 / protein :name (n2 / name :op1 "tropomyosin") :xref (x / xref :value "UNIPROT:TPM1_HUMAN" :prob "0.382"))) :ARG1-of (d2 / direct-02) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1"))) # ::id bio.chicago_2015.57613 # ::date 2015-11-03T12:35:28 # ::file bio_chicago_2015_57613.txt # ::snt As Fig. 4 b shows, the amount of MYPT bound to phosphorylated myosin was two to three times higherR using MYPT phosphorylated with mitotic extracts compared to the MYPT phosphorylated by interphase extracts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (h2 / high-02 :ARG1 (a / amount :quant-of (p / protein :name (n / name :op1 "MYPT") :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n2 / name :op1 "myosin") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:MYH1_HUMAN" :prob "0.322"))) :xref (x3 / xref :value "UNIPROT:MYPT1_HUMAN" :prob "0.312"))) :degree (m / more) :degree (b2 / between :op1 (p4 / product-of :op1 "2") :op2 (p5 / product-of :op2 "3")) :condition (u / use-01 :ARG1 (p6 / protein :name (n3 / name :op1 "MYPT") :ARG3-of (p7 / phosphorylate-01 :ARG2 (m3 / molecular-physical-entity :ARG1-of (e / extract-01 :time (m2 / mitosis)))) :xref (x1 / xref :value "UNIPROT:MYPT1_HUMAN" :prob "0.312")) :compared-to (p8 / protein :name (n4 / name :op1 "MYPT") :ARG3-of (p9 / phosphorylate-01 :ARG2 (m4 / molecular-physical-entity :ARG1-of (e2 / extract-01 :time (i / interphase)))) :xref (x2 / xref :value "UNIPROT:MYPT1_HUMAN" :prob "0.312"))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "4b"))) # ::id bio.chicago_2015.57633 # ::date 2015-11-03T13:08:47 # ::file bio_chicago_2015_57633.txt # ::snt Finally, NIMA can phosphorylate histone H3 at Ser-10 in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (p / possible-01 :li "-1" :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod "10" :name (n / name :op1 "serine") :part-of (p3 / protein :name (n2 / name :op1 "histone" :op2 "H3") :xref (x1 / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "0.701")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e / enzyme :name (n3 / name :op1 "NIMA") :xref (x / xref :value "UNIPROT:NIM1_HUMAN" :prob "0.222")) :manner (i / in-vitro))) # ::id bio.chicago_2015.57664 # ::date 2015-11-03T13:17:12 # ::file bio_chicago_2015_57664.txt # ::snt Although Pax6 is phosphorylated by two members of the MAPK family (ERK and p38), it is not phosphorylated by JNK (Mikkola et al. 1999 ); JNK-dependent Pax6 regulation may therefore be indirect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / infer-01 :ARG1 (p7 / possible-01 :ARG1 (d3 / direct-02 :polarity "-" :ARG1 (r / regulate-01 :ARG1 "p2" :ARG0-of (d4 / depend-01 :ARG1 "e4")))) :ARG2 (h / have-concession-91 :ARG1 (p3 / phosphorylate-01 :polarity "-" :ARG1 "p2" :ARG2 (e4 / enzyme :name (n5 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n6 / name :op1 "Mikkola")) :op2 (p5 / person :mod (o / other))) :time (d2 / date-entity :year "1999")))) :ARG2 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "Pax6") :xref (x3 / xref :value "UNIPROT:PAX6_HUMAN" :prob "0.603")) :ARG2 (a / and :op1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG1-of (i2 / include-91 :ARG2 (p8 / protein-family :name (n4 / name :op1 "MAPK"))))))) # ::id bio.chicago_2015.57688 # ::date 2015-11-03T13:41:50 # ::file bio_chicago_2015_57688.txt # ::snt Importantly, we found a weak but direct interaction between Pelle and dTRAF2 in vitro, and showed that dTRAF2 can be phosphorylated by Pelle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 7, 2015 (a / and :op1 (f / find-01 :ARG0 (w / we) :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "Pelle") :xref (x / xref :value "UNIPROT:PELI1_HUMAN" :prob "0.222")) :ARG1 (p2 / protein :name (n2 / name :op1 "dTRAF2")) :manner (i2 / in-vitro) :ARG1-of (w2 / weak-02 :ARG1-of (c / contrast-01 :ARG2 (d / direct-02 :ARG1 i))))) :op2 (s / show-01 :ARG0 w :ARG1 (p3 / possible-01 :ARG1 (p4 / phosphorylate-01 :ARG1 p2 :ARG2 e))) :mod (i3 / important)) # ::id bio.chicago_2015.57709 # ::date 2015-11-04T05:36:45 # ::file bio_chicago_2015_57709.txt # ::snt This view is consistent with previous data that suggest ATM phosphorylates Nbs1 when it is bound to DNA damage ( 37) (Fig. 8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / consistent-01 :ARG1 (v / view-02 :mod (t / this)) :ARG2 (d3 / data :ARG0-of (s / suggest-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "Nbs1") :xref (x / xref :value "UNIPROT:NALP2_HUMAN" :prob "0.602")) :ARG2 (e / enzyme :name (n / name :op1 "ATM") :xref (x1 / xref :value "UNIPROT:ATM_HUMAN" :prob "1.003")) :time (b2 / bind-01 :ARG1 p3 :ARG2 (d4 / damage-01 :ARG1 (n2 / nucleic-acid :name (n3 / name :op1 "DNA")))))) :time (p4 / previous)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8")) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "37")))) # ::id bio.chicago_2015.57767 # ::date 2015-11-04T06:51:20 # ::file bio_chicago_2015_57767.txt # ::snt The data presented in Fig. 1 suggest that KSR is phosphorylated by MAPK in response to Ras activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / suggest-01 :ARG0 (d / data :ARG1-of (p / present-01 :location (f / figure :op1 "1"))) :ARG1 (p4 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "KSR") :xref (x2 / xref :value "UNIPROT:KSR1_HUMAN" :prob "1.003")) :ARG2 (e / enzyme :name (n4 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2-of (r / respond-01 :ARG1 (a / activate-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) # ::id bio.chicago_2015.57774 # ::date 2015-11-04T07:08:10 # ::file bio_chicago_2015_57774.txt # ::snt PTP2C inhibits PLC tyrosine phosphorylation by c-Src. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (i / inhibit-01 :ARG0 (e / enzyme :name (n / name :op1 "PTP2C") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (e3 / enzyme :name (n2 / name :op1 "PLC") :xref (x1 / xref :value "UNIPROT:PGBM_HUMAN" :prob "1.002")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (e2 / enzyme :name (n3 / name :op1 "c-Src") :xref (x2 / xref :value "UNIPROT:CSK_HUMAN" :prob "0.212")))) # ::id bio.chicago_2015.57802 # ::date 2015-11-04T07:13:02 # ::file bio_chicago_2015_57802.txt # ::snt Previous data from Wahba and colleagues ( Dholakia and Wahba, 1988) suggested that phosphorylation of eIF2Bepsilon by CK2 increased its activity in nucleotide exchange, and our findings thus provide an explanation of this effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (a / and :op1 (s / suggest-01 :ARG0 (d2 / data :time (p3 / previous) :source (a3 / and :op1 (p4 / person :name (n2 / name :op1 "Wahba")) :op2 (c / colleagues)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n / name :op1 "Dholakia")) :op2 p4) :time (d / date-entity :year "1988")))) :ARG1 (i / increase-01 :ARG0 (p / phosphorylate-01 :ARG1 (p7 / protein :name (n3 / name :op1 "eIF2Bepsilon") :xref (x / xref :value "UNIPROT:EIF3F_HUMAN" :prob "0.352")) :ARG2 (e3 / enzyme :name (n4 / name :op1 "CK2") :xref (x1 / xref :value "UNIPROT:CSK22_HUMAN" :prob "0.332"))) :ARG1 (a5 / activity-06 :ARG0 p7 :ARG1 (e2 / exchange-01 :ARG1 (n5 / nucleotide))))) :op2 (p2 / provide-01 :ARG0 (t2 / thing :ARG1-of (f / find-01 :ARG0 (w / we))) :ARG1 (e / explain-01 :ARG1-of (a2 / affect-01 :mod (t / this))) :ARG1-of (c2 / cause-01))) # ::id bio.chicago_2015.57826 # ::date 2015-11-05T08:00:56 # ::file bio_chicago_2015_57826.txt # ::snt The regulation of Chk1 is perhaps best characterized in Xenopus, where it has been demonstrated that Chk1 is phosphorylated and activated by ATR and that the ATR-Chk1 pathway responds to unreplicated DNA and UV-damaged DNA ( 26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / characterize-01 :ARG1 (r / regulate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Chk1") :xref (x1 / xref :value "UNIPROT:CHK1_HUMAN" :prob "0.604"))) :ARG1-of (p3 / possible-01) :ARG1-of (g / good-02 :degree (m / most)) :location (o / organism :name (n4 / name :op1 "Xenopus") :location-of (a / and :op1 (d / demonstrate-01 :ARG1 (a3 / and :op1 (p / phosphorylate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n9 / name :op1 "ATR") :xref (x / xref :value "UNIPROT:ATR_HUMAN" :prob "1.004"))) :op1 (a4 / activate-01 :ARG0 e2 :ARG1 e))) :op2 (r2 / respond-01 :ARG0 (p4 / pathway :name (n5 / name :op1 "ATR-Chk1")) :ARG1 (a2 / and :op1 (n / nucleic-acid :name (n2 / name :op1 "DNA") :ARG1-of (r3 / replicate-01 :polarity "-")) :op2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA") :ARG1-of (d2 / damage-01 :polarity "-" :ARG0 (l / light :mod (u / ultraviolet)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "26")))) # ::id bio.chicago_2015.57852 # ::date 2015-11-05T06:03:46 # ::file bio_chicago_2015_57852.txt # ::snt In addition to JNK, JNKK1 also phosphorylates p38 in in-vitro kinase assay and activates p38 in cotransfection assay ( Derijard et al., 1995; Lin et al., 1995). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a5 / and :op1 (p / phosphorylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "p38") :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :location (a4 / assay-01 :ARG1 (k / kinase) :manner (i / in-vitro))) :ARG2 (e2 / enzyme :name (n2 / name :op1 "JNKK1") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "1.003")) :mod (a / also) :ARG1-of (a2 / add-02 :ARG2 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG2 e2))) :op2 (a6 / activate-01 :ARG0 e2 :ARG1 e :location (a7 / assay-01 :ARG1 (c / cotransfect-01))) :ARG1-of (d2 / describe-01 :ARG0 (a8 / and :op1 (p3 / publication-91 :ARG0 (a9 / and :op1 (p5 / person :name (n4 / name :op1 "Derijard")) :op2 (p8 / person :mod (o / other)))) :op2 (p4 / publication-91 :ARG0 (a10 / and :op1 (p7 / person :name (n5 / name :op1 "Lin")) :op2 p8)) :time (d / date-entity :year "1995")))) # ::id bio.chicago_2015.57855 # ::date 2015-11-04T06:30:38 # ::file bio_chicago_2015_57855.txt # ::snt Hsc70 Is Not Phosphorylated by p16 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (p / phosphorylate-01 :polarity "-" :ARG1 (p2 / protein :name (n / name :op1 "Hsc70") :xref (x / xref :value "UNIPROT:HSP7C_HUMAN" :prob "0.633")) :ARG2 (p3 / protein :name (n2 / name :op1 "p16") :xref (x1 / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262"))) # ::id bio.chicago_2015.57886 # ::date 2015-11-04T06:33:15 # ::file bio_chicago_2015_57886.txt # ::snt ( B) Tryptic peptide map of MBP phosphorylated by GST - LKB1 and GST - LKB1/flag-STRAD (left panel), and the corresponding Edman degradation diagram (right panel) and PAA analysis (insert). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :li "B" :op1 (m / map-01 :ARG1 (p2 / protein :name (n6 / name :op1 "MBP") :ARG1-of (p3 / phosphorylate-01 :ARG2 (a2 / and :op1 (p4 / protein :name (n2 / name :op1 "GST-LKB1") :xref (x1 / xref :value "UNIPROT:GSTO1_HUMAN" :prob "0.232")) :op2 (s / slash :op1 p4 :op2 (p6 / protein :name (n4 / name :op1 "Flag-STRAD") :ARG1-of (d / describe-01 :ARG0 (p5 / panel :ARG1-of (l / left-20))))))) :xref (x / xref :value "UNIPROT:MBP_HUMAN" :prob "1.003")) :mod (p / peptide :name (n / name :op1 "trypsin"))) :op2 (a3 / and :op1 (d2 / diagram-01 :ARG1 (d3 / degrade-01 :mod (p7 / person :name (n3 / name :op1 "Edman"))) :ARG1-of (d4 / describe-01 :ARG0 (p9 / panel :ARG1-of (r / right-04))) :ARG1-of (c / correspond-01)) :op2 (a4 / analyze-01 :name (n5 / name :op1 "PAA") :ARG1-of (d5 / describe-01 :ARG0 (i / insert))))) # ::id bio.chicago_2015.57908 # ::date 2015-11-04T21:37:37 # ::file bio_chicago_2015_57908.txt # ::snt Src family kinases phosphorylate c-Abl # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "c-Abl") :xref (x / xref :value "UNIPROT:CABL1_HUMAN" :prob "0.223")) :ARG2 (p2 / protein-family :name (n / name :op1 "Src" :op2 "kinase"))) # ::id bio.chicago_2015.57910 # ::date 2015-11-04T05:47:42 # ::file bio_chicago_2015_57910.txt # ::snt Overexpression of PTC1 did not inhibit Tyr phosphorylation of Hog1, suggesting it does not act on Pbs2 (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (i / inhibit-01 :polarity "-" :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :wiki "Ptc1" :name (n / name :op1 "PTC1") :xref (x1 / xref :value "UNIPROT:PTC1_HUMAN" :prob "1.003"))) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :wiki "Tyrosine" :name (n2 / name :op1 "tyrosine") :part-of (p2 / protein :wiki "-" :name (n3 / name :op1 "Hog1") :xref (x / xref :value "UNIPROT:HOGA1_HUMAN" :prob "0.232")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A")) :ARG0-of (s / suggest-01 :ARG1 (a2 / act-02 :polarity "-" :ARG0 o :ARG1 (e2 / enzyme :wiki "-" :name (n4 / name :op1 "Pbs2"))))) # ::id bio.chicago_2015.57934 # ::date 2015-11-04T06:29:36 # ::file bio_chicago_2015_57934.txt # ::snt The plus sign (+) indicates the serine residue potentially phosphorylated by casein kinase II. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (i / indicate-01 :ARG0 (s / sign :mod (s2 / string-entity :value "+")) :ARG1 (p2 / phosphorylate-01 :ARG1 (r / residue :mod (a / amino-acid :name (n / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG2 (e / enzyme :name (n2 / name :op1 "casein" :op2 "kinase" :op3 "II") :xref (x / xref :value "UNIPROT:CSK2B_HUMAN" :prob "0.302")) :mod (p3 / potential))) # ::id bio.chicago_2015.57958 # ::date 2015-11-04T22:52:13 # ::file bio_chicago_2015_57958.txt # ::snt TFIIH phosphorylates CDC2, CDK2, TFIIF, TFIIE, TATA-binding protein (TBP) and the CTD (Lu et al., 1992; Serizawa et al., 1992; Ohkuma and Roeder, 1994; Serizawa et al., 1995; Shiekhattar et al., 1995). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "CDC2") :xref (x3 / xref :value "UNIPROT:CDK1_HUMAN" :prob "1.002")) :op2 (e2 / enzyme :name (n3 / name :op1 "CDK2") :xref (x2 / xref :value "UNIPROT:CDK2_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n4 / name :op1 "TFIIF") :xref (x4 / xref :value "UNIPROT:TF2B_HUMAN" :prob "0.282")) :op4 (p5 / protein :name (n5 / name :op1 "TFIIE") :xref (x5 / xref :value "UNIPROT:TF2B_HUMAN" :prob "0.282")) :op5 (p6 / protein :name (n6 / name :op1 "TATA-binding" :op2 "protein") :xref (x1 / xref :value "UNIPROT:TBP_HUMAN" :prob "0.382")) :op6 (p3 / protein-segment :name (n7 / name :op1 "C-terminus"))) :ARG2 (p2 / protein :name (n / name :op1 "TFIIH") :xref (x / xref :value "UNIPROT:TCEA3_HUMAN" :prob "0.332")) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p8 / publication-91 :ARG0 (a3 / and :op1 (p13 / person :name (n8 / name :op1 "Lu")) :op2 (p18 / person :mod (o / other))) :time "d") :op2 (p9 / publication-91 :ARG0 (a4 / and :op1 (p14 / person :name (n9 / name :op1 "Serizawa")) :op2 p18) :time (d / date-entity :year "1992")) :op3 (p10 / publication-91 :ARG0 (a5 / and :op1 (a8 / and :op1 (p15 / person :name (n10 / name :op1 "Ohkuma")) :op2 (p23 / person :name (n13 / name :op1 "Roeder")) :time (d3 / date-entity :year "1994")) :op2 p18)) :op4 (p11 / publication-91 :ARG0 (a6 / and :op1 p14 :op2 p18 :time "d4")) :op5 (p12 / publication-91 :ARG0 (a7 / and :op1 (p17 / person :name (n12 / name :op1 "Shiekhattar")) :op2 p18) :time (d4 / date-entity :year "1995"))))) # ::id bio.chicago_2015.57959 # ::date 2015-11-04T22:04:03 # ::file bio_chicago_2015_57959.txt # ::snt Tyrosine phosphorylation of the Kv1.3 potassium channel. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "Tyrosine") :part-of (p2 / protein :name (n / name :op1 "Kv1.3" :op2 "potassium" :op3 "channel")) :xref (x / xref :value "PUBCHEM:1153" :prob "11.081481"))) # ::id bio.chicago_2015.57964 # ::date 2015-11-04T22:14:23 # ::file bio_chicago_2015_57964.txt # ::snt Experiments with transgenic mice also support a crucial role of CaM-KII phosphorylation of GluR1 as an important component of CA1 LTP in mature animals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (s / support-01 :ARG0 (e / experiment-01 :ARG1 (m / mouse :mod (t / transgenic))) :ARG1 (r / role :mod (c / crucial) :poss (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "GluR1") :xref (x / xref :value "UNIPROT:GRIA1_HUMAN" :prob "0.682")) :ARG2 (e2 / enzyme :name (n / name :op1 "CaM-KII") :xref (x2 / xref :value "UNIPROT:KCC2G_HUMAN" :prob "0.603"))) :domain (c2 / component :mod (i / important) :purpose (p3 / potentiate-01 :ARG1 (g / gene :name (n3 / name :op1 "CA1") :xref (x1 / xref :value "UNIPROT:CAH1_HUMAN" :prob "1.002")) :location (a2 / animal :ARG1-of (m2 / mature-01)) :ARG1-of (l / long-03)))) :mod (a / also)) # ::id bio.chicago_2015.58014 # ::date 2015-11-04T22:21:51 # ::file bio_chicago_2015_58014.txt # ::snt Phosphorylation of Myosin VI by PAK In Vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "Myosin" :op2 "VI") :xref (x / xref :value "UNIPROT:MYH1_HUMAN" :prob "0.292")) :ARG2 (e / enzyme :name (n2 / name :op1 "PAK") :xref (x1 / xref :value "UNIPROT:PAK1_HUMAN" :prob "0.263")) :manner (i / in-vitro)) # ::id bio.chicago_2015.58026 # ::date 2015-11-04T06:52:30 # ::file bio_chicago_2015_58026.txt # ::snt dTRAF2 Is Phosphorylated by Pelle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "dTRAF2")) :ARG2 (e / enzyme :name (n2 / name :op1 "Pelle") :xref (x / xref :value "UNIPROT:PELI1_HUMAN" :prob "0.222"))) # ::id bio.chicago_2015.58031 # ::date 2015-11-04T06:55:02 # ::file bio_chicago_2015_58031.txt # ::snt Thus, the phosphorylation of MEF2 by p38 MAP kinase and ERK5/BMK1 may precede or stabilise the Smad - MEF2 interaction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (c / cause-01 :ARG1 (o / or :op1 (p2 / precede-01 :ARG1 (p3 / phosphorylate-01 :ARG1 "p" :ARG2 (a / and :op1 (k / kinase :name (n / name :op1 "p38" :op2 "MAP" :op3 "kinase")) :op2 (p5 / pathway :name (n2 / name :op1 "ERK5/BMK1")))) :ARG2 (i / interact-01 :ARG0 (p6 / protein :name (n4 / name :op1 "Smad") :xref (x / xref :value "UNIPROT:SMAD1_HUMAN" :prob "0.312")) :ARG1 (p / protein :name (n5 / name :op1 "MEF2") :xref (x1 / xref :value "UNIPROT:MEF2A_HUMAN" :prob "1.002")))) :op2 (s / stabilize-01 :ARG0 p3 :ARG1 i) :ARG1-of (p4 / possible-01))) # ::id bio.chicago_2015.58034 # ::date 2015-11-04T08:51:50 # ::file bio_chicago_2015_58034.txt # ::snt A number of transcription factors are phosphorylated in response to SAPK activation; for example, the c-Jun factor is regulated by JNK (Hibi et al., 1993 ; Derijard et al., 1994 ; Kyriakis et al., 1994 ) but not by p38, whereas ATF2 is phosphorylated and regulated by both JNK (Gupta et al., 1995 ; Livingstone et al., 1995 ; van Dam et al., 1995 ) and p38 (Raingeaud et al., 1995 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (m / multi-sentence :snt1 (p / phosphorylate-01 :ARG1 (f / factor :ARG0-of (t / transcribe-01) :quant (n13 / number)) :ARG2-of (r / respond-01 :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "SAPK") :xref (x1 / xref :value "UNIPROT:MK08_HUMAN" :prob "0.313"))))) :snt2 (c / contrast-01 :ARG1 (e3 / exemplify-01 :ARG0 (r2 / regulate-01 :ARG0 (e / enzyme :name (n4 / name :op1 "JNK") :xref (x3 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")) :ARG1 (p2 / protein :name (n3 / name :op1 "c-Jun"))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p5 / publication-91 :ARG0 (a5 / and :op1 (p8 / person :name (n6 / name :op1 "Hibi")) :op2 (p9 / person :mod (o / other))) :time (d / date-entity :year "1993")) :op2 (p6 / publication-91 :ARG0 (a6 / and :op1 (p10 / person :name (n7 / name :op1 "Derijard")) :op2 p9) :time (d2 / date-entity :year "1994")) :op3 (p7 / publication-91 :ARG0 (a7 / and :op1 (p12 / person :name (n8 / name :op1 "Kyriakis")) :op2 p9) :time d2)))) :ARG2 (r3 / regulate-01 :polarity "-" :ARG0 (e4 / enzyme :name (n5 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG1 p2) :ARG1-of (c2 / contrast-01 :ARG2 (a2 / and :op1 (p4 / phosphorylate-01 :ARG1 (p3 / protein :name (n14 / name :op1 "ATF2") :xref (x2 / xref :value "UNIPROT:ATF2_HUMAN" :prob "1.003")) :ARG2 (a3 / and :op1 e :op2 e4) :ARG1-of (d5 / describe-01 :ARG0 (a8 / and :op1 (p14 / publication-91 :ARG0 (a9 / and :op1 (p17 / person :name (n9 / name :op1 "Gupta")) :op2 p9) :time (d4 / date-entity :year "1995")) :op2 (p15 / publication-91 :ARG0 (a10 / and :op1 (p19 / person :name (n10 / name :op1 "Livingstone")) :op2 p9) :time d4) :op3 (p16 / publication-91 :ARG0 (a11 / and :op1 (p21 / person :name (n11 / name :op1 "Van" :op2 "Dam")) :op2 p9) :time d4)))) :op2 (r4 / regulate-01 :ARG0 a3 :ARG1 p3 :ARG1-of (d6 / describe-01 :ARG0 (p23 / publication-91 :ARG0 (a12 / and :op1 (p24 / person :name (n12 / name :op1 "Raingeaud") :op2 p9)) :time d4))))))) # ::id bio.chicago_2015.58063 # ::date 2015-11-05T06:58:31 # ::file bio_chicago_2015_58063.txt # ::snt To determine whether Src family kinases could directly phosphorylate c-Abl, we produced Src and Fyn in baculovirus-infected Sf9 insect cells, and incubated Src or Fyn immunoprecipitates with various GST-Abl fragments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (p2 / produce-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p / protein-family :name (n3 / name :op1 "Src")) :op2 (e / enzyme :name (n4 / name :op1 "Fyn") :xref (x1 / xref :value "UNIPROT:FYN_HUMAN" :prob "0.604"))) :location (c / cell-line :name (n / name :op1 "Sf9") :part-of (i / insect :ARG1-of (i2 / infect-01 :ARG2 (o2 / organism :name (n6 / name :op1 "baculovirus")))))) :op2 (i3 / incubate-01 :ARG0 w :ARG1 (o / or :op1 (i4 / immunoprecipitate-01 :ARG1 p) :op2 (i5 / immunoprecipitate-01 :ARG1 e)) :ARG2 (f / fragment-01 :ARG1 (p8 / protein :name (n5 / name :op1 "GST-Abl") :xref (x2 / xref :value "UNIPROT:GSTA1_HUMAN" :prob "0.222")) :ARG1-of (v / vary-01))) :purpose (d / determine-01 :ARG0 w :ARG1 (p5 / possible-01 :mode "interrogative" :ARG1 (p3 / phosphorylate-01 :ARG1 (p6 / protein :name (n2 / name :op1 "c-Abl") :xref (x / xref :value "UNIPROT:CABL1_HUMAN" :prob "0.223")) :ARG2 (k / kinase :mod p) :ARG1-of (d2 / direct-02))))) # ::id bio.chicago_2015.58067 # ::date 2015-11-04T08:06:09 # ::file bio_chicago_2015_58067.txt # ::snt Our lab and others have recently identified S6K2, a homolog of S6K1 that phosphorylates S6 in vitro ( 4-7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / identify-01 :ARG0 (a / and :op1 (l / lab :poss (w / we)) :op2 (l2 / lab :mod (o / other))) :ARG1 (e / enzyme :name (n / name :op1 "S6K2") :domain (h / homolog :poss (e2 / enzyme :name (n2 / name :op1 "S6K1") :ARG2-of (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "S6")) :manner (i2 / in-vitro)) :xref (x1 / xref :value "UNIPROT:KS6B1_HUMAN" :prob "1.003"))) :xref (x / xref :value "UNIPROT:KS6B2_HUMAN" :prob "1.002")) :time (r / recent) :ARG1-of (d / describe-01 :ARG0 (p3 / publication) :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 "4" :op2 "7")))) # ::id bio.chicago_2015.58101 # ::date 2015-11-04T08:15:12 # ::file bio_chicago_2015_58101.txt # ::snt Myosin II was phosphorylated by MLCK in the presence of various concentrations of isolated RLC-GFP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "Myosin" :op2 "II") :xref (x / xref :value "UNIPROT:MYO3A_HUMAN" :prob "0.332")) :ARG2 (e / enzyme :name (n2 / name :op1 "MLCK") :xref (x1 / xref :value "UNIPROT:MYLK3_HUMAN" :prob "1.002")) :ARG2-of (p3 / present-02 :ARG1 (c / concentrate-02 :ARG1 (m / macro-molecular-complex :name (n3 / name :op1 "RLC-GFP") :ARG1-of (i / isolate-01)) :ARG1-of (v / vary-01)))) # ::id bio.chicago_2015.58172 # ::date 2015-11-04T08:27:38 # ::file bio_chicago_2015_58172.txt # ::snt This initial phosphorylation of Rb by cyclin D/Cdk4 also disrupts its interaction with HDAC, thereby relieving the repression of the cyclin E gene and allowing further progression into S phase ( Zhang et al., 2000). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (d2 / disrupt-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "Rb") :xref (x2 / xref :value "UNIPROT:RB_HUMAN" :prob "1.003")) :ARG2 (m / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "Cyclin" :op2 "D") :xref (x4 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.352")) :part (e2 / enzyme :name (n7 / name :op1 "Cdk4") :xref (x1 / xref :value "UNIPROT:CDK4_HUMAN_DNA" :prob "0.701"))) :mod (i / initial) :mod (t / this)) :ARG1 (i2 / interact-01 :ARG0 p2 :ARG1 (e / enzyme :name (n3 / name :op1 "HDAC") :xref (x3 / xref :value "UNIPROT:HDAC1_HUMAN" :prob "0.312"))) :mod (a / also)) :ARG1 (a2 / and :op1 (r / relieve-01 :ARG0 p2 :ARG1 (r2 / repress-01 :ARG0 (g / gene :name (n4 / name :op1 "cyclin" :op2 "E") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")))) :op2 (a3 / allow-01 :ARG0 p2 :ARG1 (p5 / progress-01 :ARG3 (p6 / phase :name (n6 / name :op1 "S")) :degree (f / further)))) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a4 / and :op1 (p / person :name (n5 / name :op1 "Zhang")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "2000")))) # ::id bio.chicago_2015.58176 # ::date 2015-11-04T21:57:56 # ::file bio_chicago_2015_58176.txt # ::snt Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / and :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "myosin") :xref (x / xref :value "UNIPROT:MYH1_HUMAN" :prob "0.322")) :ARG2 (e / enzyme :name (n2 / name :op1 "Rho-associated" :op2 "kinase") :xref (x1 / xref :value "UNIPROT:D9ZGF8_HUMAN" :prob "0.371"))) :op2 (a2 / activate-01 :ARG0 e :ARG1 p2)) # ::id bio.chicago_2015.58200 # ::date 2015-11-04T22:03:06 # ::file bio_chicago_2015_58200.txt # ::snt p34 cdc2 phosphorylated the threonine residue located in the tail domain that is conserved within the bimC family of kinesin-related protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (p / phosphorylate-01 :ARG1 (r / residue :mod (a2 / amino-acid :name (n3 / name :op1 "threonine") :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :location (d / domain :mod (t / tail) :ARG1-of (c / conserve-01 :location (p2 / protein-family :name (n4 / name :op1 "BimC") :ARG1-of (r2 / relate-01 :ARG2 (p3 / protein :name (n / name :op1 "kinesin") :xref (x / xref :value "UNIPROT:KIF2A_HUMAN" :prob "0.332"))))))) :ARG2 (e / enzyme :name (n2 / name :op1 "p34" :op2 "cdc2") :xref (x1 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602"))) # ::id bio.chicago_2015.58215 # ::date 2015-11-04T08:30:12 # ::file bio_chicago_2015_58215.txt # ::snt It is possible, however, that Myt1 can phosphorylate Cdk2 that has been initially phosphorylated on Tyr15, as has been previously suggested ( 11). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (p / possible-01 :ARG1 (p2 / possible-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Cdk2") :part-of (a / amino-acid :mod "15" :name (n3 / name :op1 "Tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG3-of (p6 / phosphorylate-01 :time (i / initial) :ARG1-of (s / suggest-01 :time (p7 / previous))) :xref (x / xref :value "UNIPROT:CDK2_HUMAN" :prob "0.603")) :ARG2 (p4 / protein :name (n / name :op1 "Myt1") :xref (x1 / xref :value "UNIPROT:MYT1_HUMAN" :prob "0.653")))) :ARG2-of (c2 / contrast-01) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c / cite-01 :ARG2 "11")))) # ::id bio.chicago_2015.58274 # ::date 2015-11-04T08:38:57 # ::file bio_chicago_2015_58274.txt # ::snt ( B) Similar amounts of Cdc2 can be precipitated from either wild-type or mutant embryos using anti-Cyclin B antibodies but the fast migrating ( Thr-161 phosphorylated) isoform of Cdc2 (Edgar et al. 1994 ) is reduced in the cdk7ts embryos as compared to wild type. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (c / contrast-01 :li "B" :ARG1 (p / possible-01 :ARG1 (p2 / precipitate-01 :ARG1 (a / amount-01 :ARG1 (e5 / enzyme :name (n / name :op1 "Cdc2") :xref (x / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :ARG1-of (r / resemble-01)) :source (o / or :op1 (e / embryo :mod (w / wild-type)) :op2 (e2 / embryo :ARG2-of (m / mutate-01))) :instrument (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p4 / protein :name (n2 / name :op1 "Cyclin" :op2 "B") :xref (x1 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.352")))))) :ARG2 (r2 / reduce-01 :ARG1 (i / isoform :ARG0-of (m2 / migrate-01 :ARG1-of (f / fast-02)) :mod e5 :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n3 / name :op1 "Edgar")) :op2 (p7 / person :mod (o2 / other))) :time (d / date-entity :year "1994"))) :part (a4 / amino-acid :mod "161" :name (n5 / name :op1 "Threonine") :ARG3-of (p3 / phosphorylate-01) :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))) :location (e3 / embryo :mod (p8 / protein :name (n4 / name :op1 "cdk7ts") :xref (x2 / xref :value "UNIPROT:CDK7_HUMAN" :prob "0.222"))) :ARG1-of (c3 / compare-01 :ARG2 e))) # ::id bio.chicago_2015.58292 # ::date 2015-11-05T06:37:58 # ::file bio_chicago_2015_58292.txt # ::snt To confirm further the specific phosphorylation of MARCKS by PKC, we included the PKC inhibitor peptide (19-31) in the phosphorylation assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i2 / include-01 :ARG0 (w / we) :ARG1 (p2 / peptide :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "PKC") :xref (x / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263"))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 "19" :op2 "31"))))) :ARG2 (a / assay-01 :ARG1 (p / phosphorylate-01)) :purpose (c / confirm-01 :ARG0 w :ARG1 (p3 / phosphorylate-01 :ARG1 (p5 / protein :name (n2 / name :op1 "MARCKS") :xref (x1 / xref :value "UNIPROT:MARCS_HUMAN" :prob "1.002")) :ARG2 e :ARG1-of (s / specific-02)) :degree (f / further))) # ::id bio.chicago_2015.58296 # ::date 2015-11-05T06:41:32 # ::file bio_chicago_2015_58296.txt # ::snt N-terminal KSR was phosphorylated by Nm23-H1 only under the specific conditions of transfection with Pyo-tagged N-terminal KSR, immunoprecipitation with anti-Pyo, and incubation with wild type autophosphorylated Nm23-H1 ( upper panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 26, 2015 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "N-terminal" :op2 "KSR") :xref (x1 / xref :value "UNIPROT:SOGA1_HUMAN" :prob "0.322")) :ARG2 (p4 / protein :name (n2 / name :op1 "Nm23-H1") :xref (x2 / xref :value "UNIPROT:NDKA_HUMAN" :prob "0.683")) :condition (a / and :op1 (t / transfect-01 :ARG1 e :ARG2 (e2 / enzyme :name (n3 / name :op1 "N-terminal" :op2 "KSR") :ARG1-of (t2 / tag-01 :ARG2 "s") :xref (x / xref :value "UNIPROT:SOGA1_HUMAN" :prob "0.322"))) :op2 (i / immunoprecipitate-01 :ARG1 e :ARG3 (m / molecular-physical-entity :ARG0-of (c / counter-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "Pyo") :xref (x4 / xref :value "PUBCHEM:1561" :prob "11.258356"))))) :op3 (i2 / incubate-01 :ARG1 e :ARG2 (p5 / protein :name (n5 / name :op1 "Nm23-H1") :mod (w / wild-type) :ARG1-of (p3 / phosphorylate-01 :ARG2 p4) :xref (x3 / xref :value "UNIPROT:NDKA_HUMAN" :prob "0.683"))) :ARG1-of (s2 / specific-02)) :ARG1-of (d / describe-01 :ARG0 (p2 / panel :mod (u / upper))) :mod (o / only)) # ::id bio.chicago_2015.58306 # ::date 2015-11-04T22:53:25 # ::file bio_chicago_2015_58306.txt # ::snt PKC directly phosphorylates GluR2 but not GluR2S880A mutant fusion proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (c / contrast-01 :ARG1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "GluR2") :xref (x2 / xref :value "UNIPROT:GRIA2_HUMAN" :prob "0.682")) :ARG2 (e / enzyme :name (n / name :op1 "PKC") :xref (x1 / xref :value "UNIPROT:KPCZ_HUMAN" :prob "0.263")) :ARG1-of (d / direct-02)) :ARG2 (p2 / phosphorylate-01 :polarity "-" :ARG1 (p3 / protein :name (n3 / name :op1 "GluR2S880A") :ARG1-of (f / fuse-01) :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:GRIA2_HUMAN" :prob "0.242")) :ARG2 e)) # ::id bio.chicago_2015.58325 # ::date 2015-11-04T07:25:49 # ::file bio_chicago_2015_58325.txt # ::snt It did, however, inhibit the phosphorylation and binding of endogenous Shc to MT and Grb2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (i / inhibit-01 :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (p / protein :name (n / name :op1 "Sch") :mod (e / endogenous) :xref (x2 / xref :value "UNIPROT:MERL_HUMAN" :prob "0.602"))) :op2 (b / bind-01 :ARG1 p :ARG2 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "MT") :xref (x1 / xref :value "UNIPROT:FABD_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n3 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))))) # ::id bio.chicago_2015.58328 # ::date 2015-11-04T07:49:30 # ::file bio_chicago_2015_58328.txt # ::snt Taken together, Frat-1 prefers Dvl-1 phosphorylated by CKIepsilon, and the amino acid region 228-250 of Dvl-1 is necessary for the direct binding of Dvl-1 to Frat-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / and :op1 (p / prefer-01 :ARG0 (p2 / protein :name (n3 / name :op1 "Frat-1") :xref (x / xref :value "UNIPROT:FRAT1_HUMAN" :prob "0.622")) :ARG1 (p4 / phosphorylate-01 :ARG1 (p5 / protein :name (n5 / name :op1 "Dvl-1") :xref (x2 / xref :value "UNIPROT:DVL1_HUMAN" :prob "0.593")) :ARG2 (e / enzyme :name (n4 / name :op1 "CKIepsilon") :xref (x1 / xref :value "UNIPROT:KC1E_HUMAN" :prob "0.692")))) :op2 (n2 / need-01 :ARG0 (b2 / bind-01 :ARG1 p5 :ARG2 p2 :ARG1-of (d / direct-02)) :ARG1 (r / region :mod (a2 / amino-acid) :part-of p5 :mod (v / value-interval :op1 "228" :op2 "250"))) :ARG1-of (t2 / take-01 :manner (t / together))) # ::id bio.chicago_2015.58338 # ::date 2015-11-04T06:56:09 # ::file bio_chicago_2015_58338.txt # ::snt In contrast, PKG phosphorylation of SF1-C4 completely inhibited spliceosome assembly (Figure 7B, lanes 7-9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / contrast-01 :ARG2 (i / inhibit-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "SF1-C4") :xref (x / xref :value "UNIPROT:SF01_HUMAN" :prob "0.212")) :ARG2 (e / enzyme :name (n2 / name :op1 "PKG"))) :ARG1 (a / assembly :mod (s / spliceosome :xref (x1 / xref :value "GO:0005681" :prob "0.8"))) :ARG1-of (c2 / complete-02)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "7B") :op2 (l / lane :mod (v / value-interval :op1 "7" :op2 "9"))))) # ::id bio.chicago_2015.62138 # ::date 2015-11-04T07:00:05 # ::file bio_chicago_2015_62138.txt # ::snt ( A) Emi1 can bind Cdc20 and Cdh1 already associated with the APC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p2 / possible-01 :li "A" :ARG1 (b / bind-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "Emi1")) :ARG2 (a2 / and :op1 (p4 / protein :name (n2 / name :op1 "Cdc20") :xref (x / xref :value "UNIPROT:CDC20_HUMAN" :prob "0.633")) :op2 (p5 / protein :name (n3 / name :op1 "Cdh1") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "0.603")) :ARG1-of (a / associate-01 :ARG2 (p / protein :name (n / name :op1 "APC") :xref (x2 / xref :value "UNIPROT:APC_HUMAN" :prob "1.004")) :time (a3 / already))))) # ::id bio.chicago_2015.68191 # ::date 2015-11-04T22:45:52 # ::file bio_chicago_2015_68191.txt # ::snt As shown in Fig. 2D, M. tuberculosis stimulation of J774 cells results in the inducible binding of ATF-2, c-jun, Ets-1/2, Egr-1, and Sp1 to the TNF-alpha promoter in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s / show-01 :ARG0 (f / figure :mod "2D") :ARG1 (r / result-01 :ARG1 (s2 / stimulate-01 :ARG0 (o / organism :name (n / name :op1 "M." :op2 "tuberculosis")) :ARG1 (c / cell-line :name (n2 / name :op1 "J774"))) :ARG2 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n3 / name :op1 "ATF-2") :xref (x3 / xref :value "UNIPROT:ATF2_HUMAN" :prob "0.672")) :op2 (p2 / protein :name (n4 / name :op1 "c-jun")) :op3 (p3 / protein :name (n5 / name :op1 "Ets-1/2")) :op4 (p4 / protein :name (n6 / name :op1 "Egr-1") :xref (x1 / xref :value "UNIPROT:A0A089VKS7_HUMAN" :prob "1.001")) :op5 (p5 / protein :name (n7 / name :op1 "Sp1") :xref (x2 / xref :value "UNIPROT:C4PGM0_HUMAN" :prob "1.001"))) :ARG2 (m / molecular-physical-entity :ARG0-of (p6 / promote-02 :ARG1 (p7 / protein :name (n8 / name :op1 "TNF-alpha") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))) :ARG2-of (i2 / induce-01 :ARG1-of (p8 / possible-01)) :manner (i / in-vivo)))) # ::id bio.chicago_2015.68528 # ::date 2015-11-05T06:42:18 # ::file bio_chicago_2015_68528.txt # ::snt This result again supports the notion that binding of the GATA family factors to the GATA motif is important for E4bp4 expression in IL-3-dependent Ba/F3 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / support-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG1 (n / notion :topic (i / important :domain (b / bind-01 :ARG1 (f / factor :mod (p / protein-family :name (n2 / name :op1 "GATA"))) :ARG2 (m / motif :part-of p)) :purpose (e / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "E4bp4") :xref (x / xref :value "UNIPROT:NFIL3_HUMAN" :prob "0.632")) :ARG3 (c / cell-line :name (n6 / name :op1 "Ba/F3") :ARG0-of (d / depend-01 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-3") :xref (x1 / xref :value "UNIPROT:IL3_HUMAN" :prob "1.003"))))))) :mod (a / again)) # ::id bio.chicago_2015.68624 # ::date 2015-11-04T05:39:52 # ::file bio_chicago_2015_68624.txt # ::snt We tested cells growing in low and high serum for mDia1 and mDia2 associated Src activity (shown in pairs). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (t / test-01 :ARG0 (w / we) :ARG1 (c / cell :ARG1-of (g / grow-01 :location (a / and :op1 (s / serum :ARG1-of (l / low-04)) :op2 (s2 / serum :ARG1-of (h / high-02))))) :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "mDia1") :xref (x2 / xref :value "UNIPROT:DIAP3_HUMAN" :prob "0.252")) :op2 (p2 / protein :name (n3 / name :op1 "mDia2") :xref (x / xref :value "UNIPROT:DIAP3_HUMAN" :prob "0.702")) :ARG1-of (a3 / associate-01 :ARG2 (a4 / activity-06 :ARG0 (p3 / protein :name (n2 / name :op1 "Src") :xref (x1 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))))) :ARG1-of (s3 / show-01 :manner (p4 / pair))) # ::id bio.chicago_2015.69904 # ::date 2015-11-04T05:47:11 # ::file bio_chicago_2015_69904.txt # ::snt The oxysterol binding protein and beta-spectrin PH domains bound PtdIns-3,4,5-P3 and PtdIns-4,5-P2 with similar affinities. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (b / bind-01 :ARG1 (a / and :op1 (p / protein :ARG1-of (b2 / bind-01 :ARG2 (o / oxysterol))) :op2 (d / domain :name (n / name :op1 "beta-spectrin" :op2 "PH"))) :ARG2 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "PtdIns-3,4,5-P3") :xref (x / xref :value "UNIPROT:TM55B_HUMAN" :prob "0.242")) :op2 (e2 / enzyme :name (n3 / name :op1 "PtdIns-4,5-P2") :xref (x1 / xref :value "UNIPROT:TM55B_HUMAN" :prob "0.322"))) :ARG3 (a3 / affinity :ARG1-of (r / resemble-01))) # ::id bio.chicago_2015.70184 # ::date 2015-11-04T22:59:58 # ::file bio_chicago_2015_70184.txt # ::snt Effect of okadaic acid on apoB and apoA-I secretion by CaCo-2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (a / affect-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "okadaic" :op2 "acid") :xref (x2 / xref :value "PUBCHEM:4584" :prob "10.68039")) :ARG1 (s / secrete-01 :ARG0 (c2 / cell-line :name (n3 / name :op1 "CaCo-2")) :ARG1 (a3 / and :op1 (p2 / protein :name (n / name :op1 "apoB") :xref (x / xref :value "UNIPROT:APOB_HUMAN" :prob "0.603")) :op2 (p / protein :name (n2 / name :op1 "apoA-I") :xref (x1 / xref :value "UNIPROT:APOA1_HUMAN" :prob "0.702"))))) # ::id bio.chicago_2015.70354 # ::date 2015-11-04T23:05:52 # ::file bio_chicago_2015_70354.txt # ::snt A simple alfalfa seedling infection model for Pseudomonas aeruginosa strains associated with cystic fibrosis shows AlgT (sigma-22) and RhlR contribute to pathogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / show-01 :ARG0 (m / model-01 :ARG1 (s2 / strain-01 :ARG0 (o / organism :name (n / name :op1 "Pseudomonas" :op2 "aeruginosa")) :ARG1-of (a2 / associate-01 :ARG2 (d / disease :name (n5 / name :op1 "cystic" :op2 "fibrosis")))) :topic (i / infect-01 :ARG1 (s3 / seedling :mod (o2 / organism :name (n3 / name :op1 "Alfalfa")))) :ARG1-of (s4 / simple-02)) :ARG1 (c / contribute-01 :ARG0 (a / and :op1 (p4 / protein :name (n6 / name :op1 "AlgT" :op2 "sigma-22")) :op2 (p3 / protein :name (n4 / name :op1 "RhlR"))) :ARG2 (p / pathogenesis))) # ::id bio.chicago_2015.70864 # ::date 2015-11-05T00:13:01 # ::file bio_chicago_2015_70864.txt # ::snt Concurrently, gp41 dissociates from gp120, associates with the target membrane and mediates fusion of the viral and the cellular membranes by a process that involves the N-terminal hydrophobic region of gp41, termed the fusion peptide (Gallaher, 1987 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / and :op1 (d3 / dissociate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "gp41") :xref (x / xref :value "UNIPROT:CD36_HUMAN" :prob "0.202")) :ARG2 (p4 / protein :name (n3 / name :op1 "gp120") :xref (x1 / xref :value "UNIPROT:ITIH4_HUMAN" :prob "0.702"))) :op2 (a2 / associate-01 :ARG1 p3 :ARG2 (m2 / membrane :ARG1-of (t / target-01) :xref (x4 / xref :value "GO:0016020" :prob "0.8"))) :op3 (m / mediate-01 :ARG0 p3 :ARG1 (f / fuse-01 :ARG1 (a3 / and :op1 (m3 / membrane :mod (v / viral) :xref (x3 / xref :value "GO:0016020" :prob "0.8")) :op2 (m4 / membrane :mod (c2 / cell) :xref (x2 / xref :value "GO:0016020" :prob "0.8")))) :manner (p5 / process-02 :ARG2-of (i / involve-01 :ARG1 (r / region :mod (h / hydrophobic) :part-of p3 :mod (p7 / protein-segment :name (n4 / name :op1 "N-terminus")))) :ARG1-of (t2 / term-01 :ARG0 (p6 / peptide :ARG0-of (f2 / fuse-01))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (p2 / person :name (n / name :op1 "Gallaher")) :time (d / date-entity :year "1987"))) :ARG1-of (c / concurrent-02)) # ::id bio.chicago_2015.70878 # ::date 2015-11-04T22:35:05 # ::file bio_chicago_2015_70878.txt # ::snt AAK1 localizes to regions active in endocytosis AAK1 binds directly to AP2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (m / multi-sentence :snt1 (l / localize-01 :ARG1 (p2 / protein :name (n / name :op1 "AAK1") :xref (x / xref :value "UNIPROT:AAK1_HUMAN" :prob "1.003")) :location (r / region :ARG0-of (a / activity-06 :ARG1 (e / endocytosis)))) :snt2 (b / bind-01 :ARG1 (p3 / protein :name (n3 / name :op1 "AAK1") :xref (x1 / xref :value "UNIPROT:AAK1_HUMAN" :prob "1.003")) :ARG2 (p / protein :name (n2 / name :op1 "AP2") :xref (x2 / xref :value "UNIPROT:AP2A_HUMAN" :prob "0.652")) :ARG1-of (d / direct-02))) # ::id bio.chicago_2015.70927 # ::date 2015-11-04T08:53:46 # ::file bio_chicago_2015_70927.txt # ::snt Characterization of a novel member of the DOK family that binds and modulates Abl signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c / characterize-01 :ARG1 (m / member :mod (n / novel) :poss (p / protein-family :name (n2 / name :op1 "DOK")) :ARG0-of (b / bind-01 :ARG1 (s / signal-07 :ARG0 (p2 / protein :name (n3 / name :op1 "Abl") :xref (x / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603")))) :ARG0-of (m2 / modulate-01 :ARG1 s))) # ::id bio.chicago_2015.71093 # ::date 2015-11-04T14:02:00 # ::file bio_chicago_2015_71093.txt # ::snt The tyrosine phosphatase PTP1C associates with Vav, Grb2, and mSos1 in hematopoietic cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (a / associate-01 :ARG1 (e / enzyme :name (n / name :op1 "tyrosine" :op2 "phosphatase" :op3 "PTP1C") :xref (x2 / xref :value "UNIPROT:UBS3B_HUMAN" :prob "0.272")) :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Vav") :xref (x / xref :value "UNIPROT:VAV_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p4 / protein :name (n4 / name :op1 "Sos1") :part-of (m / mouse) :xref (x3 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.604"))) :location (c / cell :mod (h / hematopoietic))) # ::id bio.chicago_2015.71185 # ::date 2015-11-04T14:14:30 # ::file bio_chicago_2015_71185.txt # ::snt S phase induction and c-MYC RNA and c-JUN protein in quiescent MCF10A cells infected at 20 pfu/cell with dl1500 (wild-type E1A) and dl2-36 ( mutant E1A that does not bind to p300). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (i / induce-01 :ARG2 (p / phase :name (n / name :op1 "S"))) :op2 (a2 / and :op1 (n3 / nucleic-acid :name (n4 / name :op1 "RNA") :ARG0-of (e3 / encode-01 :ARG1 (p7 / protein :name (n2 / name :op1 "c-MYC") :xref (x1 / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.601")))) :op2 (p2 / protein :name (n5 / name :op1 "c-JUN"))) :location (c / cell-line :name (n6 / name :op1 "MCF10A") :mod (q / quiescent) :ARG1-of (i2 / infect-01 :ARG2 (a3 / and :op1 (v / virus :name (n7 / name :op1 "dl1500") :ARG1-of (e / express-03 :ARG2 (p3 / protein :name (n8 / name :op1 "E1A") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.262")))) :op2 (v2 / virus :name (n9 / name :op1 "dl2-36") :ARG1-of (e2 / express-03 :ARG2 (p4 / protein :name (n10 / name :op1 "E1A") :ARG2-of (m3 / mutate-01) :ARG1-of (b / bind-01 :polarity "-" :ARG2 (p5 / protein :name (n11 / name :op1 "p300") :xref (x3 / xref :value "UNIPROT:EP300_HUMAN" :prob "0.702"))) :xref (x2 / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.262"))))) :mod (r / rate-entity-91 :ARG1 (u / unit :quant "20" :ARG0-of (f / form-01 :ARG1 (p6 / plaque))) :ARG2 (c2 / cell :quant "1"))))) # ::id bio.chicago_2015.71284 # ::date 2015-11-05T05:58:33 # ::file bio_chicago_2015_71284.txt # ::snt Characterization of a representative U2OS clone conditionally coexpressing Rbdeltacdk with cyclin E (clone B3B4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / characterize-01 :ARG1 (c2 / clone-01 :ARG1 (c3 / cell :name (n / name :op1 "U2OS")) :ARG0-of (r / represent-01) :ARG3-of (c4 / coexpress-01 :ARG2 (a / and :op1 (p / protein :name (n2 / name :op1 "RbΔcdk")) :op2 (p2 / protein :name (n3 / name :op1 "cyclin" :op2 "E") :ARG1-of (m / mean-01 :ARG2 (c5 / clone-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "cyclin" :op2 "B3") :xref (x2 / xref :value "UNIPROT:CNNM3_HUMAN" :prob "0.312")) :op2 (p4 / protein :name (n5 / name :op1 "cyclin" :op2 "B4") :xref (x1 / xref :value "UNIPROT:CNNM4_HUMAN" :prob "0.312"))))) :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322"))) :ARG1-of (c6 / condition-01)))) # ::id bio.chicago_2015.71299 # ::date 2015-11-05T06:48:51 # ::file bio_chicago_2015_71299.txt # ::snt In summary, the results of these experiments are consistent with previous studies in the Hepa-1 cell line (Gassmann et al., 1997 ) and support the hypothesis that the formation of AHR/ ARNT complexes capable of binding DNA is not affected by conditions in which up to 15% of the ARNT protein pool has been recruited to the hypoxia signaling pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / and :op1 (c / consistent-01 :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (e / experiment-01 :mod (t2 / this)))) :ARG2 (s / study-01 :ARG1 (c2 / cell-line :name (n / name :op1 "Hepa-1")) :time (p / previous)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n2 / name :op1 "Gassmann")) :op2 (p4 / person :mod (o / other))) :time (d2 / date-entity :year "1997")))) :op2 (s2 / support-01 :ARG0 t :ARG1 (h / hypothesize-01 :ARG1 (a3 / affect-01 :polarity "-" :ARG0 (c3 / condition-01 :ARG2 (r2 / recruit-01 :ARG1 (p5 / pool-01 :ARG1 (p6 / protein :name (n3 / name :op1 "ARNT") :xref (x1 / xref :value "UNIPROT:ARNT_HUMAN" :prob "1.003")) :quant (u / up-to :op1 (p7 / percentage-entity :value "15"))) :ARG2 (p8 / pathway :name (n4 / name :op1 "hypoxia") :ARG0-of (s3 / signal-07)))) :ARG1 (f / form-01 :ARG1 (m / macro-molecular-complex :part (p9 / protein :name (n5 / name :op1 "AHR") :xref (x / xref :value "UNIPROT:AHR_HUMAN" :prob "1.003")) :part p6 :ARG1-of (c4 / capable-01 :ARG2 (b / bind-01 :ARG0 m :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "DNA"))))))))) :ARG2-of (s4 / summarize-01)) # ::id bio.chicago_2015.71300 # ::date 2015-11-05T07:23:14 # ::file bio_chicago_2015_71300.txt # ::snt To independently prove that IkappaBalpha is linked to ubiquitin, cells were treated with TNFalpha and Z-LLL-H, and extracts were immunoprecipitated with antibodies to IkappaBalpha, NF-kappaB p50, NF-kappaB p65, or nonimmune serum prior to detection of bound ubiquitin by Western blotting with a monoclonal antibody directed against ubiquitin( 59) . # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (t / treat-04 :ARG1 (c / cell) :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "TNFα") :xref (x4 / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.652")) :op2 (s2 / small-molecule :name (n2 / name :op1 "Z-LLL-H") :xref (x5 / xref :value "PUBCHEM:462382" :prob "15.717797")))) :op2 (i / immunoprecipitate-01 :ARG2 (m2 / molecular-physical-entity :ARG1-of (e / extract-01)) :ARG3 (o / or :op1 (a3 / and :op1 (a4 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IκBα")))) :op2 (a5 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p3 / protein :name (n4 / name :op1 "p50") :part-of (m3 / macro-molecular-complex :name (n5 / name :op1 "NF-κB")) :xref (x1 / xref :value "UNIPROT:E4F1_HUMAN" :prob "0.212")))) :op3 (a6 / antibody :ARG0-of (c4 / counter-01 :ARG1 (p4 / protein :name (n6 / name :op1 "p65") :part-of m3 :xref (x2 / xref :value "UNIPROT:SYT1_HUMAN" :prob "1.002"))))) :op2 (s / serum :ARG1-of (i2 / immune-02 :polarity "-")))) :time (p5 / prior :op1 (d / detect-01 :ARG1 (p6 / protein :name (n8 / name :op1 "ubiquitin") :ARG1-of (b / bind-01) :xref (x3 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :ARG2 (i3 / immunoblot-01 :ARG3 (a7 / antibody :mod (m4 / monoclonal) :ARG1-of (d2 / direct-01 :ARG2 (a8 / against :op1 (p7 / protein :name (n9 / name :op1 "ubiquitin") :xref (x / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")))))))) :purpose (p8 / prove-01 :ARG1 (l / link-01 :ARG1 p2 :ARG2 p7) :ARG0-of (d3 / depend-01 :polarity "-")) :ARG1-of (d4 / describe-01 :ARG0 (p9 / publication :ARG1-of (c5 / cite-01 :ARG2 "59")))) # ::id bio.chicago_2015.71532 # ::date 2015-11-10T02:27:42 # ::file bio_chicago_2015_71532.txt # ::snt Skb1 and Shk1 Associate with Cdc2 in S. pombe. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (a / associate-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "Skb1") :xref (x1 / xref :value "UNIPROT:ANM5_HUMAN" :prob "0.602")) :op2 (p2 / protein :name (n2 / name :op1 "Shk1") :xref (x / xref :value "UNIPROT:SHKB1_HUMAN" :prob "0.232"))) :ARG2 (e2 / enzyme :name (n3 / name :op1 "Cdc2") :xref (x2 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.602")) :location (o / organism :name (n4 / name :op1 "Schizosaccharomyces" :op2 "pombe"))) # ::id bio.chicago_2015.71733 # ::date 2015-11-10T02:41:43 # ::file bio_chicago_2015_71733.txt # ::snt The labels RNAP IIO and IIA represent hyperphosphorylated and hypophosphorylated forms of the RNAP II larger subunit, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 17, 2015 (a / and :op1 (r / represent-01 :ARG0 (e / enzyme :name (n / name :op1 "RNAP" :op2 "IIO") :ARG2-of (l / label-01)) :ARG1 (s / subunit :ARG1-of (h / hyperphosphorylate-01) :mod (e2 / enzyme :name (n2 / name :op1 "RNAP" :op2 "II") :xref (x / xref :value "UNIPROT:RNC_HUMAN" :prob "0.252")) :mod (l2 / large :degree (m / more)))) :op2 (r2 / represent-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "RNAP" :op2 "IIA") :ARG2-of l) :ARG1 (s2 / subunit :ARG1-of (h2 / hypophosphorylate-00) :mod e2 :mod l2))) # ::id bio.chicago_2015.71734 # ::date 2015-11-10T02:53:49 # ::file bio_chicago_2015_71734.txt # ::snt The fluorescent microscopy method has allowed us to examine how quickly caldesmon coupled with TM can disassemble preformed fascin-actin bundles. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (a / allow-01 :ARG0 (m / method :mod (m2 / microscopy :mod (f / fluoresce-01))) :ARG1 (e / examine-01 :ARG0 (w / we) :ARG1 (q / quick-02 :ARG1 (p / possible-01 :ARG1 (d / disassemble-01 :ARG0 (p2 / protein :wiki "Caldesmon" :name (n2 / name :op1 "caldesmon") :ARG1-of (c / couple-01 :ARG2 (p3 / protein :wiki "Tropomyosin" :name (n3 / name :op1 "tropomyosin") :xref (x1 / xref :value "UNIPROT:TPM1_HUMAN" :prob "0.382"))) :xref (x / xref :value "UNIPROT:CALD1_HUMAN" :prob "0.702")) :ARG1 (b / bundle-01 :ARG2 (a2 / and :op1 (p4 / protein :wiki "Fascin" :name (n4 / name :op1 "fascin") :xref (x2 / xref :value "UNIPROT:FSCN1_HUMAN" :prob "0.702")) :op2 (p5 / protein :wiki "Actin" :name (n5 / name :op1 "actin") :xref (x3 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302"))) :ARG1-of (p6 / preform-01)))) :degree (a3 / amr-unknown)))) # ::id bio.chicago_2015.71778 # ::date 2015-11-10T03:28:07 # ::file bio_chicago_2015_71778.txt # ::snt As determined by immunoprecipitation, these affinity-purified antisera detected a single protein band of ~43 kDa in an SDS-PAGE using in vitro translated Spy1 (Figure 3A, lane 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (d / detect-01 :ARG0 (a / antiserum :ARG1-of (p / purify-01 :ARG2 (a2 / affinity)) :mod (t / this)) :ARG1 (b / band :mod (p2 / protein :quant (a3 / approximately :op1 (m / mass-quantity :quant "43" :unit (k / kilodalton)))) :ARG1-of (s / single-02)) :ARG2 (t2 / thing :name (n / name :op1 "SDS-PAGE")) :ARG2-of (u / use-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Spy1") :ARG2-of (t3 / translate-02 :manner (i / in-vitro)) :xref (x / xref :value "UNIPROT:SPDYA_HUMAN" :prob "1.002"))) :ARG1-of (d2 / determine-01 :ARG0 (i2 / immunoprecipitate-01)) :ARG1-of (d3 / describe-01 :ARG0 (l / lane :mod "4" :part-of (f / figure :mod "3A")))) # ::id bio.chicago_2015.71791 # ::date 2015-11-10T04:28:36 # ::file bio_chicago_2015_71791.txt # ::snt Actin depolymerization with latrunculin delocalized myosin II and anillin, as expected, and had little effect on the organization of cytokinesis-associated microtubules. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (d / delocalize-01 :ARG0 (d2 / depolymerize-00 :ARG1 (p / protein :name (n / name :op1 "actin") :xref (x1 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :instrument (s / small-molecule :name (n4 / name :op1 "latrunculin") :xref (x2 / xref :value "PUBCHEM:3892" :prob "10.32831"))) :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "myosin" :op2 "II") :xref (x / xref :value "UNIPROT:MYO3A_HUMAN" :prob "0.312")) :op2 (p3 / protein :name (n3 / name :op1 "anillin"))) :ARG1-of (e / expect-01)) :op2 (a3 / affect-01 :ARG0 d2 :ARG1 (o / organize-01 :ARG1 (m2 / microtubule :ARG1-of (a4 / associate-01 :ARG2 (c / cytokinesis)))) :degree (l2 / little))) # ::id bio.chicago_2015.71819 # ::date 2015-11-10T04:41:34 # ::file bio_chicago_2015_71819.txt # ::snt The synergistic interaction between cofilin and Arp2/3, where Arp2/3 caps and stabilizes short filaments produced by cofilin severing activity, may resolve the inconsistencies inherent in the above two mechanisms ( Bailly et al. 1999 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / possible-01 :ARG1 (r / resolve-01 :ARG0 (i / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "cofilin") :xref (x / xref :value "UNIPROT:COF1_HUMAN" :prob "0.342")) :ARG1 (m / macro-molecular-complex :part (p3 / protein :name (n2 / name :op1 "Arp2") :xref (x1 / xref :value "UNIPROT:ARP2_HUMAN" :prob "0.603")) :part (p4 / protein :name (n3 / name :op1 "Arp3") :xref (x2 / xref :value "UNIPROT:ARP3_HUMAN" :prob "0.603"))) :ARG0-of (s / synergize-01) :location-of (a / and :op1 (c / cap-02 :ARG0 m :ARG1 (f / filament :ARG1-of (s2 / short-07) :ARG1-of (p5 / produce-01 :ARG0 (a2 / activity-06 :ARG0 p2 :ARG1 (s3 / sever-01 :ARG0 p2))))) :op2 (s4 / stabilize-01 :ARG0 m :ARG1 f))) :ARG1 (c2 / consistent-01 :polarity "-" :ARG1 c :ARG2 s4 :mod (i2 / inherent))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n4 / name :op1 "Bailly")) :op2 (p8 / person :mod (o / other))) :time (d2 / date-entity :year "1999")))) # ::id bio.chicago_2015.72000 # ::date 2015-11-10T05:23:18 # ::file bio_chicago_2015_72000.txt # ::snt In the MSI( ) tumors, 11 of 37 (30%) displayed methylation of p16, and, in contrast, in sporadic MSI(+) tumors hypermethylation of p16 was observed in 14 of 20 (70%) ( P < 0.05 versus MSI-negative). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / contrast-01 :ARG1 (d / display-01 :ARG0 (t / tumor :quant "11" :ARG1-of (s3 / stable-03 :mod (m2 / microsatellite)) :ARG1-of (i / include-91 :ARG2 (t3 / tumor :quant "37" :ARG1-of s3) :ARG3 (p / percentage-entity :value "30"))) :ARG1 (m / methylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "p16") :xref (x / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262")))) :ARG2 (o / observe-01 :ARG1 (h / hypermethylate-01 :ARG2 p2) :location (t4 / tumor :quant "14" :ARG1-of (s2 / stable-03 :polarity "-" :mod m2) :mod (s / sporadic) :ARG1-of (i2 / include-91 :ARG2 (t6 / tumor :quant "20" :ARG1-of s2 :mod s) :ARG3 (p3 / percentage-entity :value "70"))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05") :ARG5 t))) # ::id bio.chicago_2015.72003 # ::date 2015-11-10T06:20:45 # ::file bio_chicago_2015_72003.txt # ::snt This is true for intraphylum splits in many animal groups ( 19, 33), the origin and divergences of major insect clades ( 34), early (Paleozoic) splits among basal vertebrates ( 35) and tetrapods ( 12, 32), and most intraordinal splits among birds ( 28, 29) and mammals ( 32, 36, 37). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 17, 2015 (t / true-01 :ARG1 (t2 / this) :ARG2 (a / and :op1 (s / split-01 :mod (i / intraphylum) :location (g / group-01 :ARG2 (a2 / animal) :quant (m / many)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "19" :op2 "33"))))) :op2 (a4 / and :op1 (o / originate-01 :ARG1 (c2 / clade :mod (i2 / insect) :ARG1-of (m2 / major-02))) :op2 (d2 / diverge-01 :ARG0 c2) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "34")))) :op3 (s2 / split-01 :ARG2 (a5 / and :op1 (v / vertebrate :mod (b / basal) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "35")))) :op2 (t3 / tetrapod :ARG1-of (d5 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 (a6 / and :op1 "12" :op2 "32")))))) :time (e / early :ARG1-of (m3 / mean-01 :ARG2 (e2 / era :name (n / name :op1 "Paleozoic"))))) :op4 (s3 / split-01 :ARG2 (a7 / and :op1 (b2 / bird :ARG1-of (d6 / describe-01 :ARG0 (p5 / publication :ARG1-of (c6 / cite-01 :ARG2 (a8 / and :op1 "28" :op2 "29"))))) :op2 (m4 / mammal :ARG1-of (d7 / describe-01 :ARG0 (p6 / publication :ARG1-of (c7 / cite-01 :ARG2 (a9 / and :op1 "32" :op2 "36" :op3 "37")))))) :mod (i3 / intraordinal) :quant (m5 / most)))) # ::id bio.chicago_2015.72086 # ::date 2015-11-10T06:55:23 # ::file bio_chicago_2015_72086.txt # ::snt A membrane location for this a-factor NH2-terminal protease is consistent with our previous observation that all COOH-terminally prenylated a-factor intermediates, including P1, are membrane associated ( Chen, 1993 ; Chen et al., 1997 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / consistent-01 :ARG1 (b / be-located-at-91 :ARG1 (e / enzyme :name (n / name :op1 "protease") :part (p / protein-segment :name (n2 / name :op1 "NH2-terminus")) :mod (g / gene :name (n3 / name :op1 "a-factor")) :mod (t / this) :xref (x / xref :value "UNIPROT:VP113_HUMAN" :prob "0.702")) :ARG2 (m2 / membrane :xref (x1 / xref :value "GO:0016020" :prob "0.8"))) :ARG2 (o / observe-01 :ARG0 (w / we) :ARG1 (a / associate-01 :ARG1 (i / intermediate :mod g :ARG1-of (p2 / prenylate-00 :location (p3 / protein-segment :name (n4 / name :op1 "COOH-terminus"))) :mod (a2 / all) :ARG2-of (i2 / include-91 :ARG1 (i3 / intermediate :name (n5 / name :op1 "P1")))) :ARG2 m2) :time (p4 / previous)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (p5 / publication-91 :ARG0 (p6 / person :name (n6 / name :op1 "Chen")) :time (d2 / date-entity :year "1993")) :op2 (p7 / publication-91 :ARG0 (a4 / and :op1 p6 :op2 (p8 / person :mod (o2 / other))) :time (d3 / date-entity :year "1997"))))) # ::id bio.chicago_2015.72090 # ::date 2015-11-10T15:06:55 # ::file bio_chicago_2015_72090.txt # ::snt If Ste5 constrains Ste11 and Ste7 to within, say, 10 nm of each other, then the effective concentration of the scaffold-bound Ste7 in the eyes of the scaffold-bound Ste11 will be 250,000 molecules per fl, an increase of more than 104-fold. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (c / concentrate-01 :ARG2 (e / enzyme :name (n / name :op1 "Ste7") :ARG1-of (b / bind-01 :ARG2 (s / scaffold)) :quant (c2 / concentration-quantity :quant "250000" :unit (m / molecule-per-femtoliter) :ARG1-of (i / increase-01 :ARG2 (m2 / more-than :op1 (p / product-of :op1 "104")))) :xref (x2 / xref :value "UNIPROT:ST1E1_HUMAN" :prob "0.202")) :ARG0-of (e2 / effective-04) :compared-to (c3 / concentrate-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ste11") :ARG1-of b :xref (x1 / xref :value "UNIPROT:STEA1_HUMAN" :prob "0.212"))) :condition (c4 / constrain-01 :ARG0 (e4 / enzyme :name (n3 / name :op1 "Ste5") :xref (x / xref :value "UNIPROT:ST1E1_HUMAN" :prob "0.202")) :ARG1 (a / and :op1 e3 :op2 e) :degree (w / within :example (r / relative-position :op1 a :quant (d / distance-quantity :quant "10" :unit (n4 / nanometer)))))) # ::id bio.chicago_2015.72096 # ::date 2015-11-10T16:04:22 # ::file bio_chicago_2015_72096.txt # ::snt Figure 2 shows that all Gcn4 genes tested here, i.e., TRP3, ARG1, HIS3, CPA1, and CPA2, displayed H3 hyperacetylation similar to HIS3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (s / show-01 :ARG0 (f / figure :mod "2") :ARG1 (d / display-01 :ARG0 (g / gene :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "Gcn4") :xref (x / xref :value "UNIPROT:GCNT4_HUMAN" :prob "0.232"))) :mod (a / all) :ARG1-of (t / test-01 :location (h / here)) :example (a2 / and :op1 (g2 / gene :name (n3 / name :op1 "TRP3") :xref (x5 / xref :value "UNIPROT:TRPC3_HUMAN" :prob "1.002")) :op2 (g3 / gene :name (n4 / name :op1 "ARG1") :xref (x4 / xref :value "UNIPROT:ARGI1_HUMAN" :prob "1.002")) :op3 (g4 / gene :name (n5 / name :op1 "HIS3") :xref (x3 / xref :value "UNIPROT:HIS3_HUMAN" :prob "1.003")) :op4 (g5 / gene :name (n6 / name :op1 "CPA1") :xref (x2 / xref :value "UNIPROT:CBPA1_HUMAN" :prob "1.002")) :op5 (g6 / gene :name (n7 / name :op1 "CPA2") :xref (x1 / xref :value "UNIPROT:CBPA2_HUMAN" :prob "1.002")))) :ARG1 (h2 / hyperacetylate-00 :ARG1 (p2 / protein :name (n8 / name :op1 "H3")) :ARG1-of (r / resemble-01 :ARG2 (h3 / hyperacetylate-00 :ARG1 g4))))) # ::id bio.chicago_2015.72107 # ::date 2015-11-10T16:20:21 # ::file bio_chicago_2015_72107.txt # ::snt AD designated as the sole or principal cause and no contributing cerebrovascular disease; AD with contributing cerebrovascular disease (CVD); VaD as the sole or principal cause without any apparent AD component; and other dementias attributed to Parkinson s disease, progressive supranuclear palsy, subdural hematoma, trauma, and vitamin B12 deficiency. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (m / multi-sentence :snt1 (a / and :op1 (d / designate-01 :ARG1 (d2 / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer's")) :ARG2 (c / cause-01 :mod (o / or :op1 (s / sole) :op2 (p / principal)))) :op2 (d3 / disease :mod (c2 / cerebrovascular) :ARG0-of (c3 / contribute-01 :polarity "-"))) :snt2 (d4 / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's") :accompanier (d5 / disease :mod (c4 / cerebrovascular) :ARG0-of (c5 / contribute-01))) :snt3 (m2 / medical-condition :name (n3 / name :op1 "vascular" :op2 "dementia") :ARG0-of (c6 / cause-01 :mod (o2 / or :op1 (s2 / sole) :op2 (p2 / principal))) :accompanier (c7 / component :polarity "-" :mod (d7 / disease :wiki "Alzheimer's_disease" :name (n4 / name :op1 "Alzheimer's")) :ARG1-of (a2 / appear-01) :mod (a3 / any))) :snt4 (a4 / and :op2 (d8 / dementia :mod (o3 / other) :ARG1-of (a5 / attribute-01 :ARG2 (a6 / and :op1 (d9 / disease :wiki "Parkinson's_disease" :name (n5 / name :op1 "Parkinson's")) :op2 (d10 / disease :name (n6 / name :op1 "progressive" :op2 "supranuclear" :op3 "palsy")) :op3 (h / hematoma :mod (s3 / subdural)) :op4 (t / trauma) :op5 (d11 / deficiency :mod (v / vitamin :name (n7 / name :op1 "B12")))))))) # ::id bio.chicago_2015.72190 # ::date 2015-11-11T01:40:26 # ::file bio_chicago_2015_72190.txt # ::snt Of 22 omp-1 paralogs examined by RT-PCR, omp-1B was the only omp-1 transcript detected in all 16 groups of tick tissues (Fig. 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (t / transcript :mod (p / protein :name (n / name :op1 "omp-1") :xref (x / xref :value "UNIPROT:NUAK1_HUMAN" :prob "0.212")) :domain (p2 / protein :name (n2 / name :op1 "omp-1B") :mod (o / only) :ARG1-of (d / detect-01 :location (g / group-01 :quant "16" :ARG2 (t2 / tissue :mod (t3 / tick)) :mod (a / all))) :ARG1-of (i / include-91 :ARG2 (p3 / paralog :quant "22" :mod p :ARG1-of (e / examine-01 :instrument (t4 / thing :name (n3 / name :op1 "RT-PCR")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2"))) # ::id bio.chicago_2015.72229 # ::date 2015-11-11T01:53:39 # ::file bio_chicago_2015_72229.txt # ::snt However, Southern analysis following 5-azaC treatment ruled out the demethylation of RI and RII genes as a contributor to RI and RII expression ( 14, 16). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (h / have-concession-91 :ARG2 (r / rule-out-02 :ARG0 (t / thing :name (n / name :op1 "Southern" :op2 "analysis") :ARG1-of (f / follow-01 :ARG2 (t2 / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "5-azaC") :xref (x1 / xref :value "PUBCHEM:9444" :prob "12.533094"))))) :ARG1 (c / contribute-01 :ARG0 (d / demethylate-01 :ARG1 (a / and :op1 (g / gene :name (n3 / name :op1 "RI")) :op2 (g2 / gene :name (n4 / name :op1 "RII") :xref (x / xref :value "UNIPROT:RIAD1_HUMAN" :prob "0.212")))) :ARG2 (e / express-03 :ARG1 a))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "14" :op2 "16"))))) # ::id bio.chicago_2015.72242 # ::date 2015-11-11T02:14:46 # ::file bio_chicago_2015_72242.txt # ::snt Other less exquisitely specific proteases produced by some bacteria (e.g., Pseudomonas aeruginosa, Porphyromonas gingivalis, or Proteus mirabilis) can completely break down IgA and other Igs ( 9, 14, 24) but do not achieve this effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (b / break-down-12 :ARG0 (e / enzyme :name (n / name :op1 "protease") :ARG1-of (s / specific-02 :degree (e2 / exquisite :degree (l / less))) :ARG1-of (p2 / produce-01 :ARG0 (b2 / bacteria :quant (s2 / some) :example (o / or :op1 (o2 / organism :name (n2 / name :op1 "Pseudomonas" :op2 "aeruginosa")) :op2 (o3 / organism :name (n3 / name :op1 "Porphyromonas" :op2 "gingivalis")) :op3 (o4 / organism :name (n4 / name :op1 "Proteus" :op2 "mirabilis"))))) :mod (o5 / other) :xref (x1 / xref :value "UNIPROT:VP113_HUMAN" :prob "0.702")) :ARG1 (a / and :op1 (p3 / protein :name (n5 / name :op1 "IgA") :xref (x / xref :value "UNIPROT:CD79A_HUMAN" :prob "0.623")) :op2 (p4 / protein :name (n6 / name :op1 "Ig") :mod (o6 / other))) :ARG1-of (c2 / complete-02)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 "9" :op2 "14" :op3 "24"))))) :ARG2 (a3 / achieve-01 :polarity "-" :ARG0 e :ARG1 (a4 / affect-01 :ARG2 b))) # ::id bio.chicago_2015.72284 # ::date 2015-11-11T02:43:43 # ::file bio_chicago_2015_72284.txt # ::snt UBPs also have been found to stimulate protein degradation by editing the size of polyubiquitin chains, releasing ubiquitin after the protein has been targeted to the proteasome, or disassembling polyubiquitin chains to restore the cellular pool of free ubiquitin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (f / find-01 :ARG1 (s / stimulate-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "UBP") :xref (x3 / xref :value "PUBCHEM:16219277" :prob "17.656696")) :ARG1 (d / degrade-01 :ARG1 (p / protein)) :ARG2 (o / or :op1 (e / edit-01 :ARG0 s3 :ARG1 (s2 / size-01 :ARG1 (c / chain-01 :ARG1 (p2 / protein :name (n2 / name :op1 "polyubiquitin") :xref (x / xref :value "UNIPROT:UBB_HUMAN" :prob "0.392"))))) :op2 (r / release-01 :ARG0 s3 :ARG1 (p3 / protein :name (n3 / name :op1 "ubiquitin") :xref (x1 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :time (a / after :op1 (t / target-01 :ARG0 s3 :ARG1 p3))) :op3 (d2 / disassemble-01 :ARG0 s3 :ARG1 c :purpose (r2 / restore-02 :ARG0 s3 :ARG1 (p4 / pool-01 :ARG1 (p5 / protein :name (n4 / name :op1 "ubiquitin") :ARG1-of (f2 / free-04) :xref (x2 / xref :value "UNIPROT:RL40_HUMAN" :prob "0.702")) :mod (c2 / cell)))))) :mod (a2 / also)) # ::id bio.chicago_2015.72524 # ::date 2015-11-11T03:06:30 # ::file bio_chicago_2015_72524.txt # ::snt B, Rats were restrained for the indicated time ( x axis), then returned to their cages for the remainder of the time period (up to 60 minutes), at which time they were euthanatized and analyzed for hsp70 expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (r / restrain-01 :ARG1 (r2 / rat) :duration (t / time :ARG1-of (i / indicate-01 :ARG0 (a2 / axis :ARG1-of (l / label-01 :ARG2 (s / string-entity :value "x")))))) :op2 (r3 / return-04 :ARG1 r2 :ARG2 (c / cage-01 :ARG1 r2) :duration (r4 / remain-01 :ARG1 (p / period :mod (t2 / time-01 :ARG2 (u / up-to :op1 (t3 / temporal-quantity :quant "60" :unit (m / minute))))) :time-of (a3 / and :op1 (e / euthanize-00 :ARG1 r2) :op2 (a4 / analyze-01 :ARG1 r2 :purpose (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "hsp70") :xref (x / xref :value "UNIPROT:HSP77_HUMAN" :prob "0.252")))))) :time (t4 / then)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"))) # ::id bio.chicago_2015.72571 # ::date 2015-11-11T03:33:16 # ::file bio_chicago_2015_72571.txt # ::snt So, although both the GAPDH and CA genes exhibit hyperacetylation of H3 and H4 only at the 5''-end of the genes, in contrast to the betaA-globin gene, it is not at present possible to conclude that this is a promoter-specific effect, particularly as regards histone H4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / infer-01 :ARG1 (p / possible-01 :polarity "-" :ARG1 (c / conclude-01 :ARG1 (a / affect-01 :ARG2 (t / this) :ARG1-of (s / specific-02 :ARG2 (m / molecular-physical-entity :ARG0-of (p2 / promote-01))) :ARG0-of (r / regard-01 :ARG1 (p3 / protein :name (n / name :op1 "histone" :op2 "H4") :xref (x1 / xref :value "UNIPROT:H4_HUMAN" :prob "0.702")) :mod (p4 / particular)))) :time (p5 / present) :concession (c2 / contrast-01 :ARG1 (e / exhibit-01 :ARG0 (a2 / and :op1 (g / gene :name (n2 / name :op1 "GAPDH") :xref (x2 / xref :value "UNIPROT:G3P_HUMAN" :prob "1.002")) :op2 (g2 / gene :name (n3 / name :op1 "CA"))) :ARG1 (h / hyperacetylate-00 :ARG1 (a3 / and :op1 (p6 / protein :name (n4 / name :op1 "H3")) :op2 p3)) :location (d / dna-sequence :name (n6 / name :op1 "5''-end") :mod (o / only) :part-of a2)) :ARG2 (e3 / exhibit-01 :polarity "-" :ARG0 (g3 / gene :name (n5 / name :op1 "betaA-globin") :xref (x / xref :value "UNIPROT:HBB_HUMAN" :prob "0.392")) :ARG1 h)))) # ::id bio.chicago_2015.72676 # ::date 2015-11-11T03:50:57 # ::file bio_chicago_2015_72676.txt # ::snt In hepatocytes, inhibition of cAMP-PDE activity in the absence of additional effectors has no effect on the activity of PKA (attributable to a low basal level of adenylate cyclase activity). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :polarity "-" :ARG0 (i / inhibit-01 :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "PDE") :xref (x2 / xref :value "UNIPROT:PDE5A_HUMAN" :prob "0.262")) :ARG1-of (s / specific-02 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "cAMP") :xref (x3 / xref :value "PUBCHEM:6076" :prob "15.374314")))) :ARG2-of (a3 / absent-01 :ARG1 (e2 / effector :ARG1-of (a4 / add-02)))) :ARG1 (a5 / activity-06 :ARG0 (e3 / enzyme :name (n3 / name :op1 "PKA") :xref (x1 / xref :value "UNIPROT:KAPCA_HUMAN" :prob "0.332"))) :ARG1-of (a6 / attribute-01 :ARG2 (l / level :quant-of (a7 / activity-06 :ARG0 (e4 / enzyme :name (n4 / name :op1 "adenylate" :op2 "cyclase") :xref (x / xref :value "UNIPROT:ADCYA_HUMAN" :prob "0.362"))) :mod (b / basal) :ARG1-of (l2 / low-04)) :ARG1-of (p / possible-01)) :location (c / cell :name (n5 / name :op1 "hepatocyte"))) # ::id bio.chicago_2015.72680 # ::date 2015-11-11T04:03:05 # ::file bio_chicago_2015_72680.txt # ::snt However, bypassing this reaction with pyruvate, dihydroxyacetone, or glycerol uncovers constraints imposed by mitochondrial metabolism, each of which attains a similar maximal limit of insulin secretion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (h / have-concession-91 :ARG2 (u / uncover-01 :ARG0 (b / bypass-01 :ARG0 (o / or :op1 (s2 / small-molecule :wiki "Pyruvic_acid" :name (n / name :op1 "pyruvate") :xref (x2 / xref :value "PUBCHEM:1060" :prob "14.909428")) :op2 (s3 / small-molecule :wiki "Dihydroxyacetone" :name (n2 / name :op1 "dihydroxyacetone") :xref (x1 / xref :value "PUBCHEM:670" :prob "16.348362")) :op3 (s4 / small-molecule :wiki "Glycerol" :name (n3 / name :op1 "glycerol") :xref (x3 / xref :value "PUBCHEM:753" :prob "10.520293")) :ARG0-of (a / attain-01 :ARG1 (l / limit-01 :ARG1 (s / secrete-01 :ARG1 (p / protein :wiki "Insulin" :name (n4 / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :mod (m4 / maximal) :ARG1-of (r / resemble-01)) :mod (e / each))) :ARG1 (r2 / react-01 :mod (t / this))) :ARG1 (t2 / thing :ARG1-of (c / constrain-01) :ARG1-of (i2 / impose-01 :ARG0 (m5 / metabolize-01 :ARG1 (m6 / mitochondrium)))))) # ::id bio.chicago_2015.72720 # ::date 2015-11-11T04:26:22 # ::file bio_chicago_2015_72720.txt # ::snt p53 may act synergistically with E2A, to activate p21 expression in wild-type cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / possible-01 :ARG1 (s / synergize-01 :ARG0 (p2 / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1 (p3 / protein :name (n2 / name :op1 "E2A") :xref (x1 / xref :value "UNIPROT:TFE2_HUMAN" :prob "1.002")) :ARG2 (a3 / activate-01 :ARG0 (a2 / and :op1 p2 :op2 p3) :ARG1 (e / express-03 :ARG2 (p4 / protein :name (n3 / name :op1 "p21") :xref (x2 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002"))) :location (c / cell :mod (w / wild-type))))) # ::id bio.chicago_2015.72786 # ::date 2015-11-11T04:33:58 # ::file bio_chicago_2015_72786.txt # ::snt Earlier studies also reported that ERK depolymerizes interphase microtubules and forms mitotic microtubules in Xenopus cell extracts ( 19). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / report-01 :ARG0 (t / thing :ARG1-of (s / study-01 :time (e / early :degree (m / more)))) :ARG1 (a / and :op1 (d / depolymerize-00 :ARG0 (e2 / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1 (m2 / microtubule :mod (i / interphase))) :op2 (f / form-01 :ARG0 e2 :ARG1 (m3 / microtubule :mod (m4 / mitosis))) :location (c / cell :ARG1-of (e3 / extract-01) :part-of (o / organism :name (n2 / name :op1 "Xenopus")))) :mod (a2 / also) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "19")))) # ::id bio.chicago_2015.72820 # ::date 2015-11-11T04:43:24 # ::file bio_chicago_2015_72820.txt # ::snt Cytochalasin D disassembles bcl10 filament and bcl10-induced NF-kappaB activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (d / disassemble-01 :ARG0 (s / small-molecule :name (n / name :op1 "Cytochalasin" :op2 "D") :xref (x1 / xref :value "PUBCHEM:30956" :prob "10.399279")) :ARG1 (a / and :op1 (f / filament :mod (p / protein :name (n2 / name :op1 "bcl10") :xref (x / xref :value "UNIPROT:BCL10_HUMAN" :prob "0.653"))) :op2 (a2 / activate-01 :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "NF-kappaB")) :ARG2-of (i / induce-01 :ARG0 p)))) # ::id bio.chicago_2015.72824 # ::date 2015-11-11T04:51:24 # ::file bio_chicago_2015_72824.txt # ::snt The insert encodes the cleavage site of TEV protease that can proteolyze target proteins in vivo, in vitro, or on the extracellular side of whole cells when the recognition sequence is surface accessible. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (e / encode-01 :ARG0 (t / thing :ARG1-of (i / insert-01)) :ARG1 (s / site :mod (c / cleave-01 :ARG1 (e2 / enzyme :name (n / name :op1 "TEV" :op2 "protease"))) :ARG0-of (p / proteolyze-00 :ARG1 (p2 / protein :ARG1-of (t2 / target-01)) :manner (o / or :op1 (i2 / in-vivo) :op2 (i3 / in-vitro)) :location (o2 / or :op2 (s2 / side :mod (e3 / extracellular) :part-of (c2 / cell :mod (w / whole)))) :ARG1-of (p3 / possible-01) :time (p4 / possible-01 :ARG1 (a / access-01 :ARG1 (s3 / sequence :ARG1-of (r / recognize-02))) :mod (s4 / surface))))) # ::id bio.chicago_2015.72930 # ::date 2015-11-11T05:06:35 # ::file bio_chicago_2015_72930.txt # ::snt LC spontaneous discharge and activation by intracerebroventricularly administered CRF, hypotensive challenge, sciatic nerve stimulation, and carbachol were compared in adrenalectomized and sham-operated halothane-anesthetized rats. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / compare-01 :ARG1 (d / discharge-101 :ARG0 (c3 / ceruleus :mod (l / locus)) :manner (s / spontaneous)) :ARG2 (a / activate-01 :ARG0 (a2 / and :op1 (s5 / small-molecule :name (n2 / name :op1 "CRF") :ARG1-of (a3 / administer-01 :manner (i / intracerebroventricularly)) :xref (x2 / xref :value "PUBCHEM:45382193" :prob "17.014843")) :op2 (c2 / challenge-01 :ARG1 (m / molecular-physical-entity) :mod (h / hypotensive)) :op3 (s2 / stimulate-01 :ARG1 (n3 / nerve :mod (s3 / sciatic))) :op4 (s7 / small-molecule :name (n4 / name :op1 "carbachol") :xref (x / xref :value "PUBCHEM:5831" :prob "17.068911"))) :ARG1 m) :location (r / rat :ARG1-of (a4 / adrenalectomize-00) :ARG1-of (a5 / anesthetize-01 :ARG2 (s6 / small-molecule :name (n5 / name :op1 "halothane") :xref (x1 / xref :value "PUBCHEM:3562" :prob "17.879841"))) :ARG1-of (o / operate-02 :manner (s4 / sham)))) # ::id bio.chicago_2015.73032 # ::date 2015-11-11T05:06:44 # ::file bio_chicago_2015_73032.txt # ::snt In order to investigate the importance of the chitin deacetylation process to cell wall assembly, we took advantage of the natural fluorescence that wild type spores emit when excited by ultraviolet light, as well as their resistance to hydrolytic enzymes, ether, and heat shock ( 8, 10). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 18, 2015 (t / take-01 :ARG0 (w / we) :ARG1 (a / advantage) :ARG2 (a2 / and :op1 (f / fluorescence :ARG1-of (n / natural-03) :ARG1-of (e / emit-01 :ARG0 (s / spore :mod (w2 / wild-type)) :time (e2 / excite-01 :ARG0 (l / light :mod (u / ultraviolet)) :ARG1 s))) :op2 (r / resist-01 :ARG0 s :ARG1 (a3 / and :op1 (e3 / enzyme :mod (h / hydrolytic)) :op2 (e4 / ether) :op3 (s2 / shock-01 :ARG0 (h2 / heat) :ARG1 s)))) :purpose (i / investigate-01 :ARG0 w :ARG1 (i2 / importance :poss (p / process-01 :ARG1 (d / deacetylate-01 :ARG1 (m / macro-molecular-complex :name (n2 / name :op1 "chitin")))) :beneficiary (a4 / assemble-01 :ARG1 (w3 / wall :mod (c / cell))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 "8" :op2 "10"))))) # ::id bio.chicago_2015.73037 # ::date 2015-11-04T08:59:26 # ::file bio_chicago_2015_73037.txt # ::snt Spontaneous or induced deamination of cytosine, adenine, guanine or 5-methylcytosine converts these bases to the miscoding uracil, hypoxanthine, xanthine and thymine, respectively 4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / convert-01 :ARG0 (o / or :op1 (d / deaminate-01 :ARG1 "o2" :mod (s / spontaneous)) :op2 (d2 / deaminate-01 :ARG1 (o2 / or :op1 (s2 / small-molecule :name (n / name :op1 "cytosine") :xref (x3 / xref :value "PUBCHEM:597" :prob "13.428404")) :op2 (s3 / small-molecule :name (n2 / name :op1 "adenine") :xref (x2 / xref :value "PUBCHEM:190" :prob "12.636771")) :op3 (s4 / small-molecule :name (n3 / name :op1 "guanine") :xref (x7 / xref :value "PUBCHEM:764" :prob "13.358051")) :op4 (s5 / small-molecule :name (n4 / name :op1 "5-methylcytosine") :xref (x6 / xref :value "PUBCHEM:65040" :prob "11.894562"))) :ARG2-of (i / induce-01))) :ARG1 (b / base :mod (t / this)) :ARG2 (a / and :op1 (s6 / small-molecule :name (n5 / name :op1 "uracil") :xref (x5 / xref :value "PUBCHEM:1174" :prob "12.491339")) :op2 (s7 / small-molecule :name (n6 / name :op1 "hypoxanthine") :xref (x4 / xref :value "PUBCHEM:790" :prob "14.285957")) :op3 (s8 / small-molecule :name (n7 / name :op1 "xanthine") :xref (x1 / xref :value "PUBCHEM:1188" :prob "14.032355")) :op4 (s9 / small-molecule :name (n8 / name :op1 "thymine") :xref (x / xref :value "PUBCHEM:1135" :prob "13.198867")) :ARG0-of (m9 / miscode-00) :manner (r / respective)) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "4")))) # ::id bio.chicago_2015.73068 # ::date 2015-11-05T12:21:05 # ::file bio_chicago_2015_73068.txt # ::snt pRb indicates hypophosphorylated retinoblastoma protein; ppRb, hyperphosphorylated pRb. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (a / and :op1 (i / indicate-01 :ARG0 (p / protein :name (n / name :op1 "pRb") :xref (x3 / xref :value "UNIPROT:RB_HUMAN" :prob "1.002")) :ARG1 (p4 / protein :name (n4 / name :op1 "retinoblastoma" :op2 "protein") :ARG1-of (h / hypophosphorylate-00) :xref (x2 / xref :value "UNIPROT:RBL1_HUMAN" :prob "0.362"))) :op2 (i2 / indicate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "ppRb") :xref (x / xref :value "UNIPROT:PPR1B_HUMAN" :prob "0.232")) :ARG1 (p3 / protein :name (n3 / name :op1 "pRb") :ARG1-of (h2 / hyperphosphorylate-01) :xref (x1 / xref :value "UNIPROT:RB_HUMAN" :prob "1.002")))) # ::id bio.chicago_2015.73070 # ::date 2015-11-05T12:24:54 # ::file bio_chicago_2015_73070.txt # ::snt Toll receptors, CD14, and macrophage activation and deactivation by LPS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (a / and :op1 (p / protein-family :name (n / name :op1 "Toll" :op2 "receptor")) :op2 (p2 / protein :name (n2 / name :op1 "CD14") :xref (x / xref :value "UNIPROT:CD14_HUMAN" :prob "1.003")) :op1 (a2 / and :op1 (a3 / activate-01 :ARG0 (m / molecular-physical-entity :name (n3 / name :op1 "LPS") :xref (x1 / xref :value "PUBCHEM:53481794" :prob "9.905254")) :ARG1 (m2 / macrophage)) :op2 (d / deactivate-01 :ARG0 m :ARG1 m2))) # ::id bio.chicago_2015.73119 # ::date 2015-11-05T12:32:14 # ::file bio_chicago_2015_73119.txt # ::snt CpG island methylation and deacetylation of histone are involved in the creation of transcription suppressive domains ( 54). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (i / involve-01 :ARG1 (a / and :op1 (m / methylate-01 :ARG1 (d / dna-sequence :name (n / name :op1 "CpG" :op2 "island"))) :op2 (d2 / deacetylate-01 :ARG1 (p / protein :name (n2 / name :op1 "histone") :xref (x / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332")))) :ARG2 (c / create-01 :ARG1 (d3 / domain :ARG0-of (s / suppress-01 :ARG1 (t / transcribe-01)))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "54")))) # ::id bio.chicago_2015.73121 # ::date 2015-11-05T12:37:18 # ::file bio_chicago_2015_73121.txt # ::snt The signaling from Ras through Raf prompted us to ask whether Raf itself could elicit senescence. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p4 / prompt-01 :ARG0 (s / signal-07 :ARG0 (e2 / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :path (e3 / enzyme :name (n2 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG1 (a / ask-01 :ARG0 (w / we) :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (e / elicit-01 :ARG0 e3 :ARG1 (s2 / senescence))))) # ::id bio.chicago_2015.73158 # ::date 2015-11-05T12:42:47 # ::file bio_chicago_2015_73158.txt # ::snt Assuming a 100% increase in LC discharge rate as the maximum effect produced by CRF (Curtis et al., 1997 ), the CRF ED50 value in naive rats was 0.9 mug, similar to the value previously reported by this laboratory (Curtis et al., 1997 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (h / have-percentage-maximal-effective-dose-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "CRF") :xref (x / xref :value "PUBCHEM:45382193" :prob "17.014843")) :ARG2 "50" :ARG4 (m4 / mass-quantity :quant "0.9" :unit (m5 / microgram) :ARG1-of (r3 / resemble-01 :ARG2 (v2 / value :ARG1-of (r4 / report-01 :ARG0 (l / laboratory :mod (t2 / this)) :time (p / previous)) :ARG1-of (d4 / describe-01 :ARG0 "a3")))) :ARG5 (r2 / rat :mod (n3 / naive)) :condition (a / assume-01 :ARG1 (a2 / affect-01 :mod (m3 / maximum) :ARG1-of (p3 / produce-01 :ARG0 s)) :ARG2 (i / increase-01 :ARG1 (r5 / rate :degree-of (d2 / discharge-01 :ARG0 (c2 / ceruleus :mod (l2 / locus)))) :ARG2 (p2 / percentage-entity :value "100")) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n5 / name :op1 "Curtis")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "1997"))))) # ::id bio.chicago_2015.73159 # ::date 2015-11-05T13:12:30 # ::file bio_chicago_2015_73159.txt # ::snt HPLC was used to resolve the 3H-labeled inositol phosphates ( polarity Ins P2) in DDT1 MF-2 cells (Figure 2); there were three diphosphorylated compounds ( PP-Ins P4, peak v; PP-Ins P5, peak vii; [PP]2-Ins P4, peak viii), all of which have been observed previously in other mammalian cells (Menniti et al., 1993 ; # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m / multi-sentence :snt1 (u / use-01 :ARG1 (t / thing :name (n / name :op1 "HPLC")) :ARG2 (r / resolve-03 :ARG0 t :ARG1 (s / small-molecule :name (n2 / name :op1 "inositol" :op2 "phosphates") :ARG1-of (l / label-01 :ARG0 (s5 / small-molecule :name (n3 / name :op1 "3H") :xref (x2 / xref :value "PUBCHEM:104752" :prob "6.488818"))) :mod (p / polarity :mod (t3 / thing :name (n4 / name :op1 "Ins" :op2 "P2"))) :xref (x4 / xref :value "PUBCHEM:1061" :prob "6.696162")) :location (c / cell :name (n5 / name :op1 "DDT1" :op2 "MF-2")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2")))) :snt2 (o / observe-01 :ARG1 (c2 / compound :quant "3" :ARG1-of (m3 / mean-01 :ARG2 (a3 / and :op1 (s2 / small-molecule :name (n7 / name :op1 "PP-Ins" :op2 "P4") :ARG1-of (d5 / describe-01 :ARG0 (p6 / peak :li "v")) :xref (x1 / xref :value "PUBCHEM:123286" :prob "3.36179")) :op2 (s3 / small-molecule :name (n8 / name :op1 "PP-Ins" :op2 "P5") :ARG1-of (d6 / describe-01 :ARG0 (p7 / peak :li "vii")) :xref (x / xref :value "PUBCHEM:44278493" :prob "2.397001")) :op3 (s4 / small-molecule :name (n9 / name :op1 "[PP]2-Ins" :op2 "P4") :ARG1-of (d7 / describe-01 :ARG0 (p8 / peak :li "viii")) :xref (x3 / xref :value "PUBCHEM:123286" :prob "3.160067")))) :ARG1-of (d3 / diphosphorylate-00) :mod (a / all)) :time (p2 / previous) :location (c3 / cell :mod (m2 / mammal) :mod (o2 / other)) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n6 / name :op1 "Menniti")) :op2 (p5 / person :mod (o3 / other))) :time (d / date-entity :year "1993"))))) # ::id bio.chicago_2015.73189 # ::date 2015-11-05T13:56:12 # ::file bio_chicago_2015_73189.txt # ::snt Gfi-1B was in vitro transcribed and translated by the TNTtm T7 coupled reticulocyte lysate system (Promega). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (a / and :op1 (t / transcribe-01 :ARG0 (t3 / thing :name (n2 / name :op1 "TNTtm" :op2 "T7" :op3 "coupled" :op4 "reticulocyte" :op5 "lysate" :op6 "system") :mod (c / company :name (n3 / name :op1 "Promega"))) :ARG1 (g / gene :name (n / name :op1 "Gfi-1B") :xref (x / xref :value "UNIPROT:GFI1B_HUMAN" :prob "0.622"))) :op2 (t2 / translate-02 :ARG1 g) :manner (i / in-vitro)) # ::id bio.chicago_2015.73212 # ::date 2015-11-05T14:03:16 # ::file bio_chicago_2015_73212.txt # ::snt This would suggest that the capacity for anaerobic glycolysis is adequate to stoichiometrically replace the ATP attributable to oxidative metabolism. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (s / suggest-01 :ARG0 (t / this) :ARG1 (a / adequate :domain (c / capacity :prep-for (g / glycolysis :mod (a2 / anaerobic))) :purpose (r / replace-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "ATP") :ARG1-of (a3 / attribute-01 :ARG2 (m / metabolize-01 :ARG1-of (o / oxidize-01)) :ARG1-of (p / possible-01)) :xref (x / xref :value "PUBCHEM:5957" :prob "14.368295")) :manner (s2 / stoichiometric)))) # ::id bio.chicago_2015.73264 # ::date 2015-11-05T14:12:57 # ::file bio_chicago_2015_73264.txt # ::snt NE10790 specifically inhibits Rab prenylation by Rab GGTase, demonstrating for the first time that Rab proteins are also required for osteoclastic bone resorption. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "NE10790") :xref (x1 / xref :value "PUBCHEM:10014835" :prob "19.266134")) :ARG1 (p / prenylate-00 :ARG0 (e / enzyme :name (n3 / name :op1 "Rab" :op2 "GGTase") :xref (x / xref :value "UNIPROT:PGTB2_HUMAN" :prob "0.342")) :ARG1 (p2 / protein-family :name (n2 / name :op1 "Rab"))) :ARG1-of (s2 / specific-02) :ARG0-of (d / demonstrate-01 :ARG1 (r / require-01 :ARG0 (r2 / resorb-01 :ARG0 (o2 / osteoclast) :ARG1 (b / bone)) :ARG1 p2 :mod (a / also)) :ord (o / ordinal-entity :value "1"))) # ::id bio.chicago_2015.73355 # ::date 2015-11-05T14:25:08 # ::file bio_chicago_2015_73355.txt # ::snt It has been shown that both Tris-HCl and sodium phosphate buffers hydrolyse FDA to fluorescein and neither are particularly suitable for use in the FDA assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / show-01 :ARG1 (a / and :op1 (h / hydrolyze-01 :ARG1 (s6 / small-molecule :name (n3 / name :op1 "FDA") :xref (x1 / xref :value "PUBCHEM:525" :prob "10.055051")) :ARG2 (a2 / and :op1 (b / buffer :mod (m / macro-molecular-complex :name (n / name :op1 "Tris-HC1"))) :op2 (b2 / buffer :mod (s3 / small-molecule :name (n2 / name :op1 "sodium" :op2 "phosphate") :xref (x / xref :value "PUBCHEM:24243" :prob "7.520881")))) :ARG3 (s4 / small-molecule :name (n4 / name :op1 "fluorescein") :xref (x2 / xref :value "PUBCHEM:16850" :prob "14.021746"))) :op2 (s5 / suit-01 :polarity "-" :ARG1 a2 :ARG2 (u / use-01 :ARG1 a2 :ARG2 (a3 / assay-01 :ARG1 s6)) :manner (p / particular)))) # ::id bio.chicago_2015.73390 # ::date 2015-11-05T14:38:03 # ::file bio_chicago_2015_73390.txt # ::snt Divergence times for hedgehog and primate apo(a)s were calculated according to Li and Graur ( 15), by using the divergence times for the rhesus/ human split (25 Myr ago), rodent/ primate split (75 Myr), and cow/ primate split (80 Myr) of Li et al. ( 16). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 27, 2015 (c / calculate-01 :ARG1 (t / time :time-of (d / diverge-01 :ARG0 (p / protein :name (n2 / name :op1 "Apo(a)") :mod (h / hedgehog)) :ARG1 (p2 / protein :name (n3 / name :op1 "Apo(a)") :mod (p3 / primate)))) :manner (t2 / thing :ARG1-of (s / say-01 :ARG0 (a / and :op1 (p4 / person :name (n4 / name :op1 "Li")) :op2 (p5 / person :name (n5 / name :op1 "Graur")))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "15")))) :manner (u / use-01 :ARG1 (a2 / and :op1 (t3 / time :time-of (d5 / diverge-01 :ARG1 (s2 / split-01 :ARG1 (r / rhesus) :ARG3 (h2 / human) :time (b2 / before :op1 (n6 / now) :duration (t4 / temporal-quantity :quant "25000000" :unit (y / year)))))) :op2 (t7 / time :time-of (d6 / diverge-01 :ARG1 (s3 / split-01 :ARG1 (r2 / rodent) :ARG3 p3 :time (b / before :op1 n6 :duration (t5 / temporal-quantity :quant "75000000" :unit y))))) :op3 (t8 / time :time-of (d7 / diverge-01 :ARG1 (s4 / split-01 :ARG1 (c3 / cow) :ARG3 p3 :time (b3 / before :op1 n6 :duration (t6 / temporal-quantity :quant "80000000" :unit y))))) :poss (a3 / and :op1 p4 :op2 (p9 / person :mod (o / other)) :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication :ARG1-of (c4 / cite-01 :ARG2 "16"))))))) # ::id bio.chicago_2015.73401 # ::date 2015-11-05T14:59:54 # ::file bio_chicago_2015_73401.txt # ::snt Within these tumors, one subgroup (a) had additional methylation in HOXA5, WT1, and uPA loci, whereas the other subgroup (b) acquired frequent hypermethylation of 3OST3B, BRCA1, and DAPK1 genes (see Figure 5B ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / contrast-01 :ARG1 (h / have-03 :ARG0 (s / subgroup :quant "1" :li "a" :ARG1-of (i / include-91 :ARG2 (t / tumor :mod (t2 / this)))) :ARG1 (m / methylate-01 :ARG1 (a3 / and :op1 (l / locus :mod (g4 / gene :name (n / name :op1 "HOXA5") :xref (x2 / xref :value "UNIPROT:HXA5_HUMAN" :prob "1.002"))) :op2 (l2 / locus :mod (g5 / gene :name (n2 / name :op1 "WT1") :xref (x1 / xref :value "UNIPROT:WT1_HUMAN" :prob "1.003"))) :op3 (l3 / locus :mod (g6 / gene :name (n3 / name :op1 "uPA") :xref (x / xref :value "UNIPROT:UROK_HUMAN" :prob "1.003")))) :mod (a2 / additional))) :ARG2 (a4 / acquire-01 :ARG0 (s2 / subgroup :li "b" :mod (o / other) :ARG1-of i) :ARG1 (h2 / hypermethylate-01 :ARG2 (a5 / and :op1 (g / gene :name (n4 / name :op1 "3OST3B") :xref (x5 / xref :value "UNIPROT:HS3SB_HUMAN" :prob "0.652")) :op2 (g2 / gene :name (n5 / name :op1 "BRCA1") :xref (x4 / xref :value "UNIPROT:BRCA1_HUMAN" :prob "1.003")) :op3 (g3 / gene :name (n6 / name :op1 "DAPK1") :xref (x3 / xref :value "UNIPROT:DAPK1_HUMAN" :prob "1.003"))) :ARG1-of (f2 / frequent-02))) :ARG1-of (s3 / see-01 :medium (f / figure :mod "5B"))) # ::id bio.chicago_2015.73405 # ::date 2015-11-06T09:56:02 # ::file bio_chicago_2015_73405.txt # ::snt Recombinant ADAM 12-S partially purified from conditioned medium on a heparin-Sepharose column also proteolyzed IGFBP-3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / proteolyze-00 :ARG0 (e / enzyme :name (n / name :op1 "ADAM" :op2 "12-S") :ARG1-of (p3 / purify-01 :ARG2 (m / medium :ARG1-of (c / condition-02) :location (c2 / column :consist-of (a2 / and :op1 (s / small-molecule :name (n4 / name :op1 "heparin") :xref (x3 / xref :value "PUBCHEM:32756" :prob "9.875249")) :op2 (s2 / small-molecule :name (n5 / name :op1 "Sepharose") :xref (x2 / xref :value "PUBCHEM:11966311" :prob "17.394333"))))) :degree (p2 / part)) :ARG3-of (r / recombine-01) :xref (x / xref :value "UNIPROT:ADA12_HUMAN" :prob "0.352")) :ARG1 (p5 / protein :name (n3 / name :op1 "IGFBP-3") :xref (x1 / xref :value "UNIPROT:IBP3_HUMAN" :prob "1.002")) :mod (a / also)) # ::id bio.chicago_2015.73467 # ::date 2015-11-06T10:15:39 # ::file bio_chicago_2015_73467.txt # ::snt High and nonperiodic APC-Cdh1 activity apparently supported progressive accumulation of Skp2 F-box protein, a crucial SCF component, and thus created conditions permissive for a rapid turnover of p27 CDK inhibitor that would otherwise restrain S-phase-promoting CDK activities. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (s / support-01 :ARG0 (a2 / activity-06 :ARG0 (p / protein :name (n / name :op1 "APC-Cdh1") :xref (x3 / xref :value "UNIPROT:APCD1_HUMAN" :prob "0.222")) :ARG1-of (h / high-02) :frequency (p2 / periodic :polarity "-")) :ARG1 (a4 / accumulate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "Skp2" :op2 "F-box") :mod (c / component :mod (p8 / protein :name (n3 / name :op1 "SCF") :xref (x2 / xref :value "UNIPROT:SCF_HUMAN" :prob "1.004")) :mod (c2 / crucial)) :xref (x1 / xref :value "UNIPROT:SKP2_HUMAN" :prob "0.202")) :ARG1-of (p3 / progress-01)) :ARG1-of (a3 / appear-02) :ARG0-of (c3 / cause-01 :ARG1 (c4 / create-01 :ARG0 a2 :ARG1 (c5 / condition-01 :ARG0-of (p5 / permit-01 :ARG1 (t2 / turn-over-12 :ARG1 (p6 / protein :name (n5 / name :op1 "p27") :ARG0-of (r2 / restrain-01 :ARG1 (a / activity-06 :ARG0 "e" :ARG1 (p7 / promote-01 :ARG1 (e2 / event :name (n6 / name :op1 "S-phase")))) :mod (o / otherwise)) :ARG0-of (i2 / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "CDK") :xref (x4 / xref :value "UNIPROT:CDK1_HUMAN" :prob "0.262"))) :xref (x / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003")) :mod (r / rapid))))))) # ::id bio.chicago_2015.73500 # ::date 2015-11-06T10:35:41 # ::file bio_chicago_2015_73500.txt # ::snt The activated insulin-like growth factor I receptor induces depolarization in breast epithelial cells characterized by actin filament disassembly and tyrosine dephosphorylation of FAK, Cas, and paxillin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / induce-01 :ARG0 (p5 / protein :name (n / name :op1 "growth" :op2 "factor" :op3 "I" :op4 "receptor") :ARG1-of (a / activate-01) :ARG1-of (r / resemble-01 :ARG2 (p6 / protein :name (n7 / name :op1 "insulin") :xref (x2 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :xref (x4 / xref :value "UNIPROT:GRAP2_HUMAN" :prob "0.303")) :ARG2 (d / depolarize-00 :ARG1 (c / cell :mod (e / epithelium) :mod (b / breast)) :ARG1-of (c2 / characterize-01 :ARG2 (a2 / and :op1 (d2 / disassemble-01 :ARG0 (f / filament :mod (p / protein :name (n2 / name :op1 "actin") :xref (x5 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :op2 (d3 / dephosphorylate-01 :ARG1 (a4 / and :op1 (e2 / enzyme :name (n4 / name :op1 "FAK") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n5 / name :op1 "Cas") :xref (x1 / xref :value "UNIPROT:BCAR1_HUMAN" :prob "0.603")) :op3 (p4 / protein :name (n6 / name :op1 "paxillin") :xref (x3 / xref :value "UNIPROT:PAXI_HUMAN" :prob "0.703"))) :ARG2 (a3 / amino-acid :name (n3 / name :op1 "tyrosine") :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481"))))))) # ::id bio.chicago_2015.73683 # ::date 2015-11-06T10:44:09 # ::file bio_chicago_2015_73683.txt # ::snt Myristoylated ARF1 and ARF6 (referred in the text as ARF1 and ARF6), myristoylated ARF1 mutant N52R-ARF1 (referred in the text as N52R-ARF1), and PITPalpha were expressed in Escherichia coli and purified exactly as described ( 7, 37). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (a / and :op1 (e / express-03 :ARG2 (a2 / and :op1 (a3 / and :op1 (p2 / protein :name (n / name :op1 "ARF1") :xref (x / xref :value "UNIPROT:ARF1_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n2 / name :op1 "ARF6") :xref (x1 / xref :value "UNIPROT:ARF6_HUMAN" :prob "1.004")) :ARG1-of (m / myristoylate-00) :ARG1-of (r / refer-01 :ARG2 (a4 / and :op1 p2 :op2 p3) :location (t / text))) :op2 (p4 / protein :name (n3 / name :op1 "N52R-ARF1") :ARG2-of (m2 / mutate-01 :ARG1 p2) :ARG1-of m :ARG1-of (r2 / refer-01 :ARG2 p4 :location t)) :op3 (p5 / protein :name (n4 / name :op1 "PITPalpha") :xref (x2 / xref :value "UNIPROT:PIPNA_HUMAN" :prob "0.673"))) :ARG3 (o / organism :name (n5 / name :op1 "Escherichia" :op2 "coli"))) :op2 (p / purify-01 :ARG1 p5 :manner (e2 / exact) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a5 / and :op1 "7" :op2 "37")))))) # ::id bio.chicago_2015.73782 # ::date 2015-11-06T10:58:30 # ::file bio_chicago_2015_73782.txt # ::snt Confirmation that Narf specifically recognizes preAct, and not just a prenylated cysteine residue, came from in vitro binding assays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / come-03 :ARG1 (c2 / confirm-01 :ARG1 (c3 / contrast-01 :ARG1 (r / recognize-02 :ARG0 (p / protein :name (n2 / name :op1 "Narf") :xref (x / xref :value "UNIPROT:NARF_HUMAN" :prob "0.603")) :ARG1 (s2 / small-molecule :name (n / name :op1 "preAct")) :ARG1-of (s / specific-02)) :ARG2 (r3 / recognize-02 :polarity "-" :ARG0 p :ARG1 (r2 / residue :mod (a2 / amino-acid :name (n3 / name :op1 "cysteine") :ARG1-of (p2 / prenylate-00) :xref (x1 / xref :value "PUBCHEM:594" :prob "11.272514"))) :mod (j / just)))) :ARG2 (a3 / assay-01 :ARG1 (b / bind-01) :manner (i / in-vitro))) # ::id bio.chicago_2015.73823 # ::date 2015-11-06T11:08:11 # ::file bio_chicago_2015_73823.txt # ::snt Esterified lipids of LDL are hydrolysed by lipases like phospholipase A2 or lipoprotein lipase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (h / hydrolyze-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "lipase") :example (o / or :op1 (e3 / enzyme :name (n3 / name :op1 "phospholipase" :op2 "A2") :xref (x2 / xref :value "UNIPROT:PA21B_HUMAN" :prob "0.702")) :op2 (e4 / enzyme :name (n4 / name :op1 "lipoprotein" :op2 "lipase") :xref (x1 / xref :value "UNIPROT:LIPL_HUMAN" :prob "0.702"))) :xref (x3 / xref :value "UNIPROT:A8K2H6_HUMAN" :prob "0.701")) :ARG1 (l / lipid :ARG1-of (e / esterify-00) :mod (p / protein :name (n / name :op1 "LDL") :xref (x / xref :value "UNIPROT:COG1_HUMAN" :prob "0.262")))) # ::id bio.chicago_2015.73906 # ::date 2015-11-06T11:12:55 # ::file bio_chicago_2015_73906.txt # ::snt Enlargement of plant cells is constrained by a resistant cell wall composed of cellulose microfibrils, crosslinked by other polysaccharides such as xyloglucans ( 16). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / constrain-01 :ARG0 (w / wall :mod (c2 / cell) :ARG0-of (r / resist-01) :ARG1-of (c4 / compose-01 :ARG2 (m / microfibril :mod (c5 / cellulose) :ARG1-of (c6 / crosslink-00 :ARG0 (p3 / polysaccharide :mod (o / other) :example (s / small-molecule :name (n2 / name :op1 "xyloglucan") :xref (x / xref :value "PUBCHEM:6444001" :prob "10.871458"))))))) :ARG1 (e / enlarge-01 :ARG1 (c3 / cell :mod (p / plant))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c7 / cite-01 :ARG2 "16")))) # ::id bio.chicago_2015.73940 # ::date 2015-11-06T11:24:19 # ::file bio_chicago_2015_73940.txt # ::snt Only sagittal and oblique sections following BDA injections in the rostral prelimbic area are presented here because coronal sections severed most of the rostral prelimbic PFC to NAc projecting fibers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / present-01 :ARG1 (a / and :op1 (s / section-01 :mod (s2 / sagittal)) :op2 (s3 / section-01 :mod (o / oblique)) :mod (o2 / only) :ARG1-of (f2 / follow-01 :ARG2 (i / inject-01 :ARG1 (s4 / small-molecule :name (n / name :op1 "BDA") :xref (x / xref :value "PUBCHEM:3008895" :prob "17.656696")) :ARG2 (a3 / area :mod (p2 / prelimb :mod (r / rostral)))))) :medium (h / here) :ARG1-of (c / cause-01 :ARG0 (s5 / sever-01 :ARG0 (s6 / section-01 :mod (c2 / coronal)) :ARG1 (f / fiber :ARG1-of (p3 / project-01 :mod (t2 / thing :name (n3 / name :op1 "NAc"))) :mod (t / thing :name (n2 / name :op1 "PFC") :mod p2) :quant (m / most))))) # ::id bio.chicago_2015.73959 # ::date 2015-11-06T11:48:52 # ::file bio_chicago_2015_73959.txt # ::snt ( C) Both N-terminal bacterially expressed hCdc20 and hCdh1 bind the N-terminal fragment of Xenopus cyclin B containing the D box, but fail to recover the D-box deleted N-terminal cyclin B. ( D) In vitro-translated cyc A binds MTCdc20 and MTCdh1, but not to MT alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt1 (c / contrast-01 :li "C" :ARG1 (b / bind-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "hCdc20") :xref (x7 / xref :value "UNIPROT:FBXW7_HUMAN" :prob "0.262")) :op2 (p2 / protein :name (n2 / name :op1 "hCdh1") :xref (x / xref :value "UNIPROT:FZR_HUMAN" :prob "0.632")) :ARG1-of (e / express-03 :manner (b2 / bacterial)) :mod (p9 / protein-segment :name (n10 / name :op1 "N-terminal"))) :ARG2 (f / fragment :part-of (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "B") :mod (o / organism :name (n11 / name :op1 "Xenopus")) :xref (x3 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322")) :ARG0-of (c2 / contain-01 :ARG1 (t / thing :name (n4 / name :op1 "D" :op2 "box"))) :mod p9)) :ARG2 (f2 / fail-01 :ARG0 a :ARG1 (r / recover-02 :ARG0 a :ARG1 (p4 / protein :name (n5 / name :op1 "cyclin" :op2 "B") :ARG1-of (d / delete-01 :ARG0 t) :mod p9 :xref (x4 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.322"))))) :snt2 (c3 / contrast-01 :li "D" :ARG1 (b3 / bind-01 :ARG1 (p5 / protein :name (n6 / name :op1 "cyc" :op2 "A") :ARG2-of (t2 / translate-02 :manner (i / in-vitro)) :xref (x1 / xref :value "UNIPROT:CYC_HUMAN" :prob "0.202")) :ARG2 (a2 / and :op1 (p6 / protein :name (n7 / name :op1 "MTCdc20") :xref (x5 / xref :value "UNIPROT:NTRK1_HUMAN" :prob "0.203")) :op2 (p7 / protein :name (n8 / name :op1 "MTCdh1") :xref (x2 / xref :value "UNIPROT:MTCH1_HUMAN" :prob "0.302")))) :ARG2 (b4 / bind-01 :polarity "-" :ARG1 p5 :ARG2 (p8 / protein :name (n9 / name :op1 "MT") :xref (x6 / xref :value "UNIPROT:FABD_HUMAN" :prob "1.002")) :mod (a3 / alone)))) # ::id bio.chicago_2015.73961 # ::date 2015-11-06T13:44:38 # ::file bio_chicago_2015_73961.txt # ::snt In the case of histone H3, both RPD3 and HDA1 deacetylate the five lysines (K9, K14, K18, K23 and K27; Figure 1D) that are acetylated by GCN5 (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (d / deacetylate-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "RPD3") :xref (x3 / xref :value "UNIPROT:HDAC3_HUMAN" :prob "0.292")) :op2 (p2 / protein :name (n2 / name :op1 "HDA1") :xref (x / xref :value "UNIPROT:HDA11_HUMAN" :prob "0.372"))) :ARG1 (a2 / amino-acid :quant "5" :name (n3 / name :op1 "lysine") :ARG2-of (m / mean-01 :ARG1 (a3 / and :op1 (a4 / amino-acid :mod "9" :name (n4 / name :op1 "lysine") :xref (x6 / xref :value "PUBCHEM:866" :prob "11.053295")) :op2 (a5 / amino-acid :mod "14" :name (n5 / name :op1 "lysine") :xref (x5 / xref :value "PUBCHEM:866" :prob "11.053295")) :op3 (a6 / amino-acid :mod "18" :name (n6 / name :op1 "lysine") :xref (x8 / xref :value "PUBCHEM:866" :prob "11.053295")) :op4 (a7 / amino-acid :mod "23" :name (n7 / name :op1 "lysine") :xref (x7 / xref :value "PUBCHEM:866" :prob "11.053295")) :op5 (a8 / amino-acid :mod "27" :name (n8 / name :op1 "lysine") :xref (x9 / xref :value "PUBCHEM:866" :prob "11.053295")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1D")) :ARG1-of (a9 / acetylate-01 :ARG2 (p3 / protein :name (n9 / name :op1 "GCN5") :xref (x1 / xref :value "UNIPROT:KAT2A_HUMAN" :prob "1.002")) :ARG1-of (d3 / describe-01 :ARG0 f)) :xref (x4 / xref :value "PUBCHEM:866" :prob "11.053295")) :topic (p4 / protein :name (n10 / name :op1 "histone" :op2 "H3") :xref (x2 / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "0.701"))) # ::id bio.chicago_2015.73964 # ::date 2015-11-06T13:55:01 # ::file bio_chicago_2015_73964.txt # ::snt Loss of DNA methylation may also result from active mechanisms involving either an enzymatic activity, which removes methylcytosine and replaces it by cytosine, or a deamination of methylated CpGs, creating a mismatch that is then repaired (Jost and Saluz 1993 ; Weiss et al. 1996 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / possible-01 :ARG1 (r / result-01 :ARG1 (m2 / mechanism :ARG0-of (a / activity-06) :ARG2-of (i / involve-01 :ARG1 (o / or :op1 (a2 / activity-06 :ARG1 (e / enzymatic) :ARG0-of (r2 / remove-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "methylcytosine") :xref (x1 / xref :value "PUBCHEM:65040" :prob "10.029536"))) :ARG0-of (r3 / replace-01 :ARG1 s :ARG2 (s2 / small-molecule :name (n4 / name :op1 "cytosine") :xref (x / xref :value "PUBCHEM:597" :prob "13.428404")))) :op2 (d5 / deaminate-01 :ARG1 (d6 / dna-sequence :name (n5 / name :op1 "CpG") :ARG1-of (m3 / methylate-01)) :ARG0-of (c / create-01 :ARG1 (m4 / mismatch :ARG1-of (r4 / repair-01 :time (t / then)))))))) :ARG2 (l / lose-02 :ARG1 (m / methylate-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"))))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and :op1 (p2 / publication-91 :ARG0 (a5 / and :op1 (p4 / person :name (n6 / name :op1 "Jost")) :op2 (p5 / person :name (n8 / name :op1 "Saluz"))) :time (d2 / date-entity :year "1993")) :op2 (p3 / publication-91 :ARG0 (a6 / and :op1 (p6 / person :name (n7 / name :op1 "Weiss")) :op2 (p7 / person :mod (o2 / other))) :time (d3 / date-entity :year "1996")))) :mod (a7 / also)) # ::id bio.chicago_2015.74011 # ::date 2015-11-06T14:09:36 # ::file bio_chicago_2015_74011.txt # ::snt This demonstrates the testis-specific demethylation of the Pgk-2/CAT transgenes, the ubiquitous hypomethylation of the transferrin/ CAT transgene, and the ubiquitous hypermethylation of the CAT-only transgene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (d / demonstrate-01 :ARG0 (t / this) :ARG1 (a / and :op1 (d2 / demethylate-01 :ARG1 (t3 / transgene :name (n / name :op1 "Pgk-2/CAT")) :ARG1-of (s / specific-02 :ARG2 (t2 / testis))) :op2 (h / hypomethylate-00 :ARG1 (t4 / transgene :name (n2 / name :op1 "transferrin/CAT")) :mod (u / ubiquitous)) :op3 (h2 / hypermethylate-01 :ARG2 (t5 / transgene :name (n3 / name :op1 "CAT-only")) :mod u))) # ::id bio.chicago_2015.74036 # ::date 2015-11-06T14:14:22 # ::file bio_chicago_2015_74036.txt # ::snt When a lesion is detected, the UvrB protein hydrolyses its bound ATP molecule, leading to formation of the pro-pre-incision complex ( Moolenaar et al., 2000b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "ATP") :ARG1-of (b / bind-01) :poss "p" :xref (x / xref :value "PUBCHEM:5957" :prob "14.368295")) :ARG2 (p / protein :name (n / name :op1 "UvrB")) :ARG0-of (l / lead-03 :ARG1 (f / form-01 :ARG1 (c / complex :ARG0-of (f2 / favor-01 :ARG1 (p2 / preincise-00))))) :time (d2 / detect-01 :ARG1 (l2 / lesion)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and :op1 (p4 / person :name (n3 / name :op1 "Moolenaar")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2000" :li "b")))) # ::id bio.chicago_2015.74144 # ::date 2015-11-06T14:20:21 # ::file bio_chicago_2015_74144.txt # ::snt As phosphatidylinositol (PI) 3-kinase and Akt play a critical role in survival pathways in response to both growth factors and extracellular stimuli, these observations prompted us to explore whether E-cadherins could affect intracellular molecules regulating the activity of the PI 3-kinase/Akt signaling cascade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (c / cause-01 :ARG0 (p2 / play-02 :ARG0 (a5 / and :op1 (e3 / enzyme :name (n2 / name :op1 "phosphatidylinositol" :op2 "3-kinase") :xref (x1 / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.701")) :op2 (e4 / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG1 (r / role :ARG1-of (c3 / critical-02) :topic (p3 / pathway :mod (s / survive-01))) :ARG2-of (r2 / respond-01 :ARG1 (a / and :op1 (g / growth-factor) :op2 (s3 / stimulus :mod (e / extracellular))))) :ARG1 (p4 / prompt-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (e2 / explore-01 :ARG0 (w / we) :ARG1 (p5 / possible-01 :mode "interrogative" :ARG1 (a2 / affect-01 :ARG0 (p / protein :name (n4 / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG1 (m / molecule :ARG0-of (r3 / regulate-01 :ARG1 (a3 / activity-06 :ARG1 (p6 / pathway :name (n5 / name :op1 "PI" :op2 "3-kinase/Akt") :ARG0-of (s4 / signal-07)))) :mod (i / intracellular))))))) # ::id bio.chicago_2015.74146 # ::date 2015-11-06T14:34:34 # ::file bio_chicago_2015_74146.txt # ::snt Furthermore, HDL inhibited thromboxane A2 liberation, and addition of HDL to clotting blood diminished platelet thromboxane A2 formation capacity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (a2 / and :op1 (i / inhibit-01 :ARG0 (p2 / protein :name (n / name :op1 "HDL") :xref (x / xref :value "UNIPROT:VIGLN_HUMAN" :prob "0.232")) :ARG1 (l / liberate-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "thromboxane" :op2 "A2") :xref (x2 / xref :value "PUBCHEM:5280497" :prob "12.963704")))) :op2 (d / diminish-01 :ARG0 (a3 / add-02 :ARG1 p2 :ARG2 (b / blood :ARG0-of (c / clot-00))) :ARG1 (c2 / capable-01 :ARG2 (f / form-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "thromboxane" :op2 "A2") :mod (p / platelet) :xref (x1 / xref :value "PUBCHEM:5280497" :prob "12.963704"))))))) # ::id bio.chicago_2015.74199 # ::date 2015-11-06T14:45:26 # ::file bio_chicago_2015_74199.txt # ::snt These data indicate that NHERF-1 specifically associates with Pin1, but only when NHERF-1 is hyperphosphorylated by cyclin-dependent kinases in mitosis phase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (d / data :mod (t / this)) :ARG1 (a / associate-01 :ARG1 (p / protein :name (n2 / name :op1 "NHERF-1") :xref (x1 / xref :value "UNIPROT:NHRF1_HUMAN" :prob "1.003")) :ARG2 (e2 / enzyme :name (n3 / name :op1 "Pin1") :xref (x2 / xref :value "UNIPROT:PIN1_HUMAN" :prob "0.603")) :ARG1-of (s / specific-02) :condition (h / hyperphosphorylate-01 :ARG1 p :ARG2 (k / kinase :ARG0-of (d2 / depend-01 :ARG1 (p2 / protein :name (n4 / name :op1 "cyclin") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.702")))) :time (p3 / phase :mod (m / mitosis)) :mod (o / only)))) # ::id bio.chicago_2015.74221 # ::date 2015-11-06T14:51:07 # ::file bio_chicago_2015_74221.txt # ::snt Elafin also reduces the liberation of matrix-bound growth factors which may be responsible for the proliferation of vascular smooth muscle cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (r / reduce-01 :ARG0 (p / protein :name (n2 / name :op1 "elafin") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.702")) :ARG1 (l / liberate-01 :ARG1 (g / growth-factor :ARG1-of (b / bind-01 :ARG2 (m / matrix)))) :mod (a / also) :ARG0-of (r2 / responsible-01 :ARG1 (p3 / proliferate-01 :ARG0 (c / cell :mod (m2 / muscle :mod (s2 / smooth)) :mod (v / vascular))) :ARG1-of (p2 / possible-01))) # ::id bio.chicago_2015.74264 # ::date 2015-11-08T01:07:28 # ::file bio_chicago_2015_74264.txt # ::snt Such bacteria may be responsible for the high rates of H2-dependent 14CO2 reduction to formate observed in the P1 section of C. orthognathus (Fig. 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / possible-01 :ARG1 (r / responsible-01 :ARG0 (b / bacteria :mod (s / such)) :ARG1 (r2 / rate :ARG1-of (h / high-02) :degree-of (r3 / reduce-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "14CO2")) :ARG4 (s4 / small-molecule :name (n3 / name :op1 "formate") :xref (x1 / xref :value "PUBCHEM:283" :prob "10.573729")) :ARG0-of (d2 / depend-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "H2") :xref (x / xref :value "PUBCHEM:783" :prob "11.245043")))) :ARG1-of (o / observe-01 :location (s5 / section :mod "P1" :part-of (o2 / organism :name (n5 / name :op1 "C." :op2 "orthognathus")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id bio.chicago_2015.74340 # ::date 2015-11-08T01:14:07 # ::file bio_chicago_2015_74340.txt # ::snt The PLC- isozymes have a multidomain array (a PH domain split by two SH2 domains and an SH3 domain) inserted between two halves of the catalytic domain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 21, 2015 (h / have-03 :ARG0 (i2 / isozyme :name (n / name :op1 "PLC")) :ARG1 (a / array-01 :ARG1 (m2 / multidomain) :ARG1-of (m3 / mean-01 :ARG2 (p / protein-segment :name (n2 / name :op1 "PH") :ARG1-of (s / split-01 :ARG2 (a2 / and :op1 (p3 / protein-segment :quant "2" :name (n3 / name :op1 "SH2")) :op2 (p2 / protein-segment :name (n4 / name :op1 "SH3")))))) :ARG1-of (i / insert-01 :ARG2 (h2 / half :quant "2" :mod (d4 / domain :mod (c / catalysis)))))) # ::id bio.chicago_2015.74386 # ::date 2015-11-08T01:23:14 # ::file bio_chicago_2015_74386.txt # ::snt Recent accumulating evidences suggest that induction of histone hyperacetylation by HDAC inhibitors is responsible for the antiproliferative activity and reversal of neoplastic characteristics through selective induction of genes, which play important roles in the cell cycle and cell morphology ( 14). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (s / suggest-01 :ARG0 (e / evidence-01 :ARG1-of (a / accumulate-01) :time (r / recent)) :ARG1 (r2 / responsible-01 :ARG0 (i2 / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "HDAC") :ARG0-of (i / inhibit-01) :xref (x / xref :value "UNIPROT:HDAC1_HUMAN" :prob "0.312")) :ARG2 (h / hyperacetylate-00 :ARG1 (p / protein :name (n / name :op1 "histone") :xref (x1 / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332")))) :ARG1 (a2 / and :op1 (a3 / activity-06 :ARG1 (c / counter-01 :ARG1 (p2 / proliferate-01))) :op1 (r3 / reverse-01 :ARG1 (t / thing :ARG2-of (c2 / characteristic-02 :ARG1 (n3 / neoplasm)))) :manner (i3 / induce-01 :ARG1 (g / gene) :mod (s2 / selective)) :ARG0-of (p3 / play-02 :ARG1 (r4 / role :mod (i4 / important) :time (a4 / and :op1 (c3 / cycle-02 :mod (c4 / cell)) :op2 (m / morphology :mod c4)))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "14")))) # ::id bio.chicago_2015.74432 # ::date 2015-11-08T01:32:45 # ::file bio_chicago_2015_74432.txt # ::snt Treatment with DNase I failed to liberate GAPDH from the nuclear fraction (Fig. 6 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (f / fail-01 :ARG1 (t / treat-04 :ARG2 (e / enzyme :name (n / name :op1 "DNase" :op2 "I") :xref (x / xref :value "UNIPROT:DNAS1_HUMAN" :prob "1.002"))) :ARG2 (l / liberate-01 :ARG0 t :ARG1 (e2 / enzyme :name (n2 / name :op1 "GAPDH") :xref (x1 / xref :value "UNIPROT:G3P_HUMAN" :prob "1.002")) :ARG2 (f2 / fraction-01 :ARG1 (n3 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "6B"))) # ::id bio.chicago_2015.74470 # ::date 2015-11-08T01:35:48 # ::file bio_chicago_2015_74470.txt # ::snt Here, we report that a short incubation of control cells with the F-actin depolymerizing agent cytochalasin D triggered cytochrome c release and procaspase 3-like activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (r / report-01 :ARG0 (w / we) :ARG1 (t / trigger-01 :ARG0 (i / incubate-01 :ARG1 (c / cell :mod (c2 / control)) :ARG2 (s2 / small-molecule :name (n / name :op1 "cytochalasin" :op2 "D") :mod (a / agent) :ARG0-of (d / depolymerize-00 :ARG1 (p / protein :name (n2 / name :op1 "F-actin") :xref (x1 / xref :value "UNIPROT:NEXN_HUMAN" :prob "0.252"))) :xref (x2 / xref :value "PUBCHEM:30956" :prob "10.399279")) :ARG1-of (s / short-07)) :ARG1 (a2 / and :op1 (r2 / release-01 :ARG1 (p2 / protein :name (n3 / name :op1 "cytochrome" :op2 "c"))) :op2 (a3 / activate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "procaspase" :op2 "3-like") :xref (x / xref :value "UNIPROT:RD3L_HUMAN" :prob "0.232"))))) :medium (h / here)) # ::id bio.chicago_2015.74541 # ::date 2015-11-08T01:46:22 # ::file bio_chicago_2015_74541.txt # ::snt p-Nitroanilines liberated by trypsin activity were measured with a spectrophotometer at 410 nm. Dependency of the reactions on enterokinase activation was studied by performing the same reaction in the absence of enterokinase and comparing the results. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m3 / multi-sentence :snt1 (m / measure-01 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "p-Nitroaniline") :ARG1-of (l / liberate-01 :ARG0 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "trypsin") :xref (x1 / xref :value "UNIPROT:TRY1_HUMAN" :prob "0.342")))) :xref (x2 / xref :value "PUBCHEM:7475" :prob "11.36176")) :ARG2 (s / spectrophotometer) :condition (f / frequence :value "410" :unit (n3 / nanometer))) :snt2 (s2 / study-01 :ARG1 (d / depend-01 :ARG0 (r / react-01) :ARG1 (a3 / activate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "enterokinase") :xref (x / xref :value "UNIPROT:ENTK_HUMAN" :prob "0.702")))) :manner (a6 / and :op1 (p / perform-01 :ARG1 (r2 / react-01 :ARG1-of (s3 / same-01)) :condition (a4 / absent-01 :ARG1 e2)) :op2 (c / compare-01 :ARG1 (t / thing :ARG2-of (r3 / result-01)))))) # ::id bio.chicago_2015.74615 # ::date 2015-11-08T01:57:37 # ::file bio_chicago_2015_74615.txt # ::snt Proteins in the pathways that regulate contractility and actin depolymerization downstream of Rho and ROK, such as myosin light-chain kinase and phosphatase and cofilin, are candidate targets for aPKCs, but the precise mechanism by which Cdc42 and aPKCs regulate stress fibers is not yet clear. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 21, 2015 (c / contrast-01 :ARG1 (t / thing :mod (c2 / candidate) :ARG1-of (t2 / target-01 :ARG0 (e / enzyme :name (n7 / name :op1 "aPKC"))) :domain (p / protein :part-of (p2 / pathway) :ARG0-of (r / regulate-01 :ARG1 (a / and :op1 (c3 / contractility) :op2 (d / depolymerize-00 :ARG1 (p3 / protein :name (n / name :op1 "actin") :xref (x3 / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :location (r3 / relative-position :op1 (a2 / and :op1 (p4 / protein :name (n2 / name :op1 "Rho") :xref (x4 / xref :value "UNIPROT:OPSD_HUMAN" :prob "0.602")) :op2 (p5 / protein :name (n3 / name :op1 "ROK") :xref (x5 / xref :value "UNIPROT:DDX52_HUMAN" :prob "0.262"))) :direction (d2 / downstream))) :example (a3 / and :op1 (e2 / enzyme :name (n4 / name :op1 "myosin" :op2 "light-chain" :op3 "kinase") :xref (x2 / xref :value "UNIPROT:MYLK3_HUMAN" :prob "0.392")) :op2 (e3 / enzyme :name (n5 / name :op1 "phosphatase") :xref (x1 / xref :value "UNIPROT:Q59GM9_HUMAN" :prob "0.291")) :op3 (p8 / protein :name (n6 / name :op1 "cofilin") :xref (x6 / xref :value "UNIPROT:COF1_HUMAN" :prob "0.342"))))) :ARG2 (c4 / clear-06 :polarity "-" :ARG1 (m / mechanism :mod (p9 / precise) :instrument-of (r2 / regulate-01 :ARG0 (a4 / and :op1 (p10 / protein :name (n8 / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :op2 e) :ARG1 (f / fiber :mod (s / stress)))) :time (y / yet))) # ::id bio.chicago_2015.74675 # ::date 2015-11-08T02:16:34 # ::file bio_chicago_2015_74675.txt # ::snt Strikingly, while Bdf1 prefers hyperacetylated forms of histone H4, Bdf2 binds equally well to all histone H4 species (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (c / contrast-01 :ARG1 (b / bind-01 :ARG1 (p4 / protein :name (n3 / name :op1 "Bdf2")) :ARG2 (s / species :mod "p3" :mod (a / all)) :ARG1-of (g / good-02 :degree (e / equal))) :ARG2 (p / prefer-01 :ARG0 (p2 / protein :name (n / name :op1 "Bdf1")) :ARG1 (f / form :ARG1-of (h / hyperacetylate-00) :mod (p3 / protein :name (n2 / name :op1 "histone" :op2 "H4") :xref (x / xref :value "UNIPROT:H4_HUMAN" :prob "0.702")))) :ARG1-of (s2 / strike-04) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2B"))) # ::id bio.chicago_2015.74682 # ::date 2015-11-08T02:24:32 # ::file bio_chicago_2015_74682.txt # ::snt Reasoning that dC dU deamination of the retroviral reverse transcripts ( cDNA) could give rise to inactivating mutations of the GFP gene, we speculated that some of the GFP-negative target cells could nevertheless have been infected but with the GFP gene having been rendered nonfunctional by CEM15/APOBEC3G-induced mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c / cause-01 :ARG0 (r / reason-01 :ARG0 (w / we) :ARG1 (p2 / possible-01 :ARG1 (g / give-rise-to-10 :ARG0 (d / deaminate-01 :ARG1 (t / transcript :mod (r2 / reverse-01) :mod (r3 / retrovirus)) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "dC" :op2 "dU") :xref (x3 / xref :value "PUBCHEM:297" :prob "3.187958"))) :ARG2 (m / mutate-01 :ARG1 (g2 / gene :name (n / name :op1 "GFP") :xref (x2 / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")) :ARG0-of (a / activate-01 :polarity "-"))))) :ARG1 (s / speculate-01 :ARG0 w :ARG1 (p / possible-01 :ARG1 (h / have-concession-91 :ARG1 (i / infect-01 :ARG0 (g4 / gene :name (n5 / name :op1 "GFP") :ARG1-of (r4 / render-01 :ARG0 (m3 / mutate-01 :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n6 / name :op1 "CEM15/APOBEC3G")))) :ARG2 (f / function-01 :polarity "-" :ARG0 g4)) :xref (x / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")) :ARG1 (c3 / cell :quant (s2 / some) :ARG1-of (i3 / include-91 :ARG2 (c2 / cell :ARG1-of (t2 / target-01) :mod (g3 / gene :name (n3 / name :op1 "GFP") :ARG2-of (m4 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")))))))))) # ::id bio.chicago_2015.74687 # ::date 2015-11-08T02:43:50 # ::file bio_chicago_2015_74687.txt # ::snt Compared with PMNs receiving inputs that lacked oscillations ( Fig. 2 F), discharge patterns of PMNs receiving inputs with consistent oscillations showed much less variability for consecutive spontaneous bursts ( Fig. 2 E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (s / show-01 :ARG0 (p / pattern :mod (d / discharge-01) :mod (c / cell :name (n / name :op1 "PMN") :ARG0-of (r / receive-01 :ARG1 (i / input :ARG1-of (o / oscillate-01 :ARG1-of (c2 / consistent-02))))) :compared-to (c4 / cell :name (n2 / name :op1 "PMN") :ARG0-of (r2 / receive-01 :ARG1 (i2 / input :ARG0-of (l2 / lack-01 :ARG1 (o2 / oscillate-01)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2F")))) :ARG1 (v / variability :degree (l / less :quant (m / much)) :mod (b / burst-01 :mod (s2 / spontaneous) :mod (c3 / consecutive)) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2E")))) # ::id bio.chicago_2015.74732 # ::date 2015-11-08T13:10:25 # ::file bio_chicago_2015_74732.txt # ::snt In addition to GST-CIIS, the S. pombe FTase also efficiently farnesylated another C AAX protein, S. cerevisiae Rho3, while prenylating two different C AAL proteins, Cdc42 and RhoA, with very low efficiency (Fig. 3 C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (a4 / and :op1 (f / farnesylate-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "GST-CIIS") :xref (x1 / xref :value "UNIPROT:GSTCD_HUMAN" :prob "0.212")) :op2 (p5 / protein :mod (a3 / another) :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n3 / name :op1 "C" :op2 "AAX"))) :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n4 / name :op1 "Rho3") :mod (o2 / organism :name (n9 / name :op1 "S." :op2 "cerevisiae")) :xref (x2 / xref :value "UNIPROT:LMO3_HUMAN" :prob "0.232"))))) :ARG2 (e / enzyme :name (n / name :op1 "FTase") :mod (o / organism :name (n8 / name :op1 "S." :op2 "pombe")) :xref (x3 / xref :value "UNIPROT:FNTB_HUMAN" :prob "0.272")) :mod (a / also) :ARG1-of (e2 / efficient-01)) :op2 (p4 / prenylate-00 :ARG1 (p6 / protein :quant "2" :ARG1-of (d / differ-02) :ARG1-of (i2 / include-91 :ARG2 (p7 / protein-family :name (n5 / name :op1 "C" :op2 "AAL"))) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (p8 / protein :name (n6 / name :op1 "Cdc42") :xref (x4 / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")) :op2 (p9 / protein :name (n7 / name :op1 "RhoA") :xref (x / xref :value "UNIPROT:RHOA_HUMAN" :prob "0.604"))))) :ARG2 e :ARG1-of (e3 / efficient-01 :ARG1-of (l / low-04 :degree (v / very)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3C"))) # ::id bio.chicago_2015.74770 # ::date 2015-11-08T13:23:09 # ::file bio_chicago_2015_74770.txt # ::snt In the case of I B, which holds the transcription factor NF B in an inactive cytoplasmic complex, cytokines induce the phosphorylation of the two serine residues (Ser32 and Ser36) in the I B destruction motif, leading to its ubiquitination by SCF -TrCP1, destruction by the proteasome, and liberation of NF B (Winston et al., 1999a ; Yaron et al., 1998 ; Li and Verma, 2002 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "cytokine") :xref (x / xref :value "UNIPROT:RED_HUMAN" :prob "0.342")) :ARG2 (p3 / phosphorylate-01 :ARG1 (r / residue :quant "2" :mod (a / amino-acid :name (n / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (a3 / amino-acid :mod "32" :name (n3 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "36" :name (n5 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784"))))) :ARG0-of (l / lead-03 :ARG2 (a5 / and :op1 (u / ubiquitinate-01 :ARG1 "m2" :ARG2 (p / protein :name (n6 / name :op1 "SCF-TrCP1"))) :op2 (d4 / destroy-01 :ARG0 (m4 / macro-molecular-complex :name (n7 / name :op1 "proteasome")) :ARG1 "m2") :op3 (l2 / liberate-01 :ARG0 "m2" :ARG1 "f2"))) :location (m2 / motif :ARG0-of (d6 / destroy-01) :mod "p6")) :ARG1-of (d5 / describe-01 :ARG0 (a7 / and :op1 (p8 / publication-91 :ARG0 (a8 / and :op1 (p11 / person :name (n11 / name :op1 "Winston")) :op2 (p12 / person :mod (o / other))) :time (d / date-entity :year "1999" :li "a")) :op2 (p9 / publication-91 :ARG0 (a9 / and :op1 (p13 / person :name (n12 / name :op1 "Yaron")) :op2 (p14 / person :mod (o2 / other))) :time (d2 / date-entity :year "1998")) :op3 (p10 / publication-91 :ARG0 (a10 / and :op1 (p15 / person :name (n13 / name :op1 "Li")) :op2 (p16 / person :name (n14 / name :op1 "Verma"))) :time (d3 / date-entity :year "2002")))) :topic (p6 / protein :name (n9 / name :op1 "I" :op2 "B") :ARG0-of (h / hold-01 :ARG1 (f2 / factor :name (n10 / name :op1 "NF" :op2 "B") :ARG0-of (t2 / transcribe-01)) :ARG3 (m3 / macro-molecular-complex :mod (c3 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :ARG0-of (a6 / activity-06 :polarity "-"))))) # ::id bio.chicago_2015.74847 # ::date 2015-11-08T13:47:47 # ::file bio_chicago_2015_74847.txt # ::snt It is conceivable that Mxi2 could somehow interfere with MEK retrophosphorylation by ERKs, something that would hinder the negative feedback control of MEK exerted by ERKs ( 2), resulting in prolonged MEK activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p3 / possible-01 :ARG1 (c / conceive-01 :ARG1 (p4 / possible-01 :ARG1 (i / interfere-01 :ARG0 (p5 / protein :name (n2 / name :op1 "Mxi2") :xref (x1 / xref :value "UNIPROT:MK14_HUMAN" :prob "0.602")) :ARG1 (r / retrophosphorylate-00 :ARG1 (e3 / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG2 (p / protein-family :name (n3 / name :op1 "ERK"))) :ARG0-of (h / hinder-01 :ARG1 (c2 / control-01 :ARG0 e3 :mod (f / feedback :ARG0-of (n4 / negative-03)) :ARG1-of (e2 / exert-01 :ARG0 p)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "2"))) :ARG1-of (r2 / result-01 :ARG2 (a / activity-06 :ARG1 e3 :ARG1-of (p7 / prolong-01)))) :manner (s / somehow))))) # ::id bio.chicago_2015.74892 # ::date 2015-11-08T13:53:32 # ::file bio_chicago_2015_74892.txt # ::snt Injection of lefty into mouse blastocysts leads to neurogenesis, a function attributable to BMP inhibitors such as chordin, noggin, and follistatin ( 41, 44-47). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (l / lead-03 :ARG0 (i2 / inject-01 :ARG1 (p / protein :name (n / name :op1 "lefty") :xref (x4 / xref :value "UNIPROT:A0A0A0N0K8_HUMAN" :prob "0.301")) :ARG2 (b2 / blastocyst :mod (m / mouse))) :ARG2 (n2 / neurogenesis :mod (f / function-01 :ARG1-of (a / attribute-01 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein :name (n3 / name :op1 "BMP") :xref (x / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263"))) :example (a2 / and :op1 (p4 / protein :name (n4 / name :op1 "chordin") :xref (x2 / xref :value "UNIPROT:CHRD_HUMAN" :prob "0.702")) :op2 (p5 / protein :name (n5 / name :op1 "noggin") :xref (x3 / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702")) :op3 (p6 / protein :name (n6 / name :op1 "follistatin") :xref (x1 / xref :value "UNIPROT:FST_HUMAN" :prob "0.702")))) :ARG1-of (p2 / possible-01)))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "41" :op2 (v / value-interval :quant (b / between :op1 "44" :op2 "47"))))))) # ::id bio.chicago_2015.74899 # ::date 2015-11-08T13:59:54 # ::file bio_chicago_2015_74899.txt # ::snt The ADAM 12 propeptide remains bound to the protease after cleavage by furin [ 9], therefore the cysteine switch is potentially still functional in furin-cleaved ADAM 12-S. Cu(II) could conceivably disengage the cysteine switch by binding to or oxidizing Cys179, similar to the way in which ADAM 12 or MMP proforms can be activated by alkylation of the free cysteine in the propeptide [ 11 and 13]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (r2 / remain-01 :ARG1 (p2 / propeptide :name (n / name :op1 "ADAM" :op2 "12")) :ARG3 (b / bind-01 :ARG1 p2 :ARG2 (e2 / enzyme :name (n2 / name :op1 "protease") :xref (x3 / xref :value "UNIPROT:VP113_HUMAN" :prob "0.702"))) :time (a / after :op1 (c / cleave-01 :ARG0 (p3 / protein :name (n3 / name :op1 "furin") :xref (x4 / xref :value "UNIPROT:FURIN_HUMAN" :prob "0.703")) :ARG1 p2)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "9"))) :ARG0-of (c3 / cause-01 :ARG1 (f / function-01 :ARG0 (s / switch-01 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "cysteine") :xref (x7 / xref :value "PUBCHEM:594" :prob "11.272514"))) :manner (p5 / potential) :mod (s2 / still) :location (e3 / enzyme :name (n5 / name :op1 "ADAM" :op2 "12-S") :ARG1-of (c4 / cleave-01 :ARG0 p3) :xref (x2 / xref :value "UNIPROT:ADA12_HUMAN" :prob "0.352"))))) :snt2 (p6 / possible-01 :ARG1 (d2 / disengage-01 :ARG0 (s3 / small-molecule :name (n6 / name :op1 "Cu(II)")) :ARG1 (s4 / switch-01 :ARG1 (a3 / amino-acid :name (n7 / name :op1 "cysteine") :xref (x6 / xref :value "PUBCHEM:594" :prob "11.272514"))) :manner (o / or :op1 (b2 / bind-01 :ARG1 s3 :ARG2 (a8 / amino-acid :mod "179" :name (n8 / name :op1 "cysteine") :xref (x5 / xref :value "PUBCHEM:594" :prob "11.272514"))) :op2 (o2 / oxidize-01 :ARG0 s3 :ARG1 a8)) :ARG1-of (r3 / resemble-01 :ARG2 (w / way :manner-of (p7 / possible-01 :ARG1 (a4 / activate-01 :ARG1 (o4 / or :op1 (p / proform :mod (e4 / enzyme :name (n9 / name :op1 "ADAM" :op2 "12") :xref (x1 / xref :value "UNIPROT:ADA12_HUMAN" :prob "1.002"))) :op2 (p11 / proform :mod (e5 / enzyme :name (n10 / name :op1 "MMP") :xref (x / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263")))) :manner (a5 / alkylate-01 :ARG1 (a6 / amino-acid :name (n11 / name :op1 "cysteine") :ARG1-of (f2 / free-04) :xref (x8 / xref :value "PUBCHEM:594" :prob "11.272514")) :location (p9 / propeptide))))))) :ARG1-of (c5 / conceive-01) :ARG1-of (d3 / describe-01 :ARG0 (p10 / publication :ARG1-of (c6 / cite-01 :ARG2 (a7 / and :op1 "11" :op2 "13")))))) # ::id bio.chicago_2015.74919 # ::date 2015-11-08T14:22:55 # ::file bio_chicago_2015_74919.txt # ::snt The 432-bp 2 coding sequence is interrupted by two introns, the first ( I1) splitting codon 32 and the second ( I2) separating codons 101 and 102. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 21, 2015 (i / interrupt-01 :ARG0 (d / dna-sequence :quant "2" :name (n / name :op1 "intron") :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (i2 / intron :ARG0-of (s / split-01 :ARG1 (c / codon :mod "32")) :ord (o / ordinal-entity :value "1") :ARG1-of (l / label-01 :ARG2 (n4 / name :op1 "I1"))) :op2 (i3 / intron :ARG0-of (s2 / separate-01 :ARG1 (a2 / and :op1 (c2 / codon :mod "101") :op2 (c3 / codon :mod "102"))) :ord (o2 / ordinal-entity :value "2") :ARG1-of (l2 / label-01 :ARG2 (n3 / name :op1 "I2")))))) :ARG1 (d2 / dna-sequence :name (n2 / name :op1 "432-bp" :op2 "2") :ARG0-of (c4 / code-01))) # ::id bio.chicago_2015.75018 # ::date 2015-11-08T02:44:47 # ::file bio_chicago_2015_75018.txt # ::snt COX-1 mediates epithelial regeneration in a model of irradiation-induced intestinal injury in mice ( 9), which supports the cytoprotective role attributed to COX-1 in gastrointestinal inflammation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Nov 21, 2015 (m / mediate-01 :ARG0 (e / enzyme :name (n / name :op1 "COX-1") :xref (x / xref :value "UNIPROT:PGH1_HUMAN" :prob "1.002")) :ARG1 (r / regenerate-01 :ARG1 (e2 / epithelium) :location (m2 / model-01 :ARG1 (i / injure-01 :ARG1 (i2 / intestine) :ARG2-of (i3 / induce-01 :ARG0 (i4 / irradiate-01)) :location (m3 / mouse))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "9"))) :ARG0-of (s / support-01 :ARG1 (r2 / role :mod (c2 / cytoprotective) :ARG1-of (a / attribute-01 :ARG2 e :time (i5 / inflame-01 :ARG1 (g / gastrointestine))))))) # ::id bio.chicago_2015.75030 # ::date 2015-11-05T05:30:30 # ::file bio_chicago_2015_75030.txt # ::snt The initial observations that marijuana produced unique behavioral and pharmacological effects in humans and laboratory animals prompted chemists to prepare synthetic agonists and antagonists. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (p / prompt-01 :ARG0 (o / observe-01 :ARG1 (p2 / produce-01 :ARG0 (m / marijuana) :ARG1 (a / affect-01 :ARG0 m :ARG1 (a3 / and :op1 (h / human) :op2 (a4 / animal :mod (l / laboratory))) :ARG2 (a2 / and :op1 (b / behave-01) :op2 (p3 / pharmacology)) :mod (u / unique))) :time (i / initial)) :ARG1 (p4 / prepare-01 :ARG0 (c / chemist) :ARG1 (a5 / and :op1 (a6 / agonist) :op2 (a7 / antagonist) :mod (s / synthetic)))) # ::id bio.chicago_2015.75156 # ::date 2015-11-05T05:37:14 # ::file bio_chicago_2015_75156.txt # ::snt The uniqueness of the incomplete inhibition by BoNT A was indicated by the finding that Tetx or BoNT B and BoNT C, which extensively proteolyzed synaptobrevin and syntaxin, respectively (not shown), completely inhibited Ca2+-activated secretion in ATP-primed cells (Fig. 4 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (i / indicate-01 :ARG0 (f / find-01 :ARG1 (i3 / inhibit-01 :ARG0 (o2 / or :op1 (p2 / protein :name (n2 / name :op1 "Tetx")) :op2 (a / and :op1 (p3 / protein :name (n3 / name :op1 "BoNT" :op2 "B") :ARG0-of (p5 / proteolyze-00 :ARG1 (p6 / protein :name (n5 / name :op1 "synaptobrevin") :xref (x / xref :value "UNIPROT:VAMP1_HUMAN" :prob "0.392")) :ARG1-of (e / extensive-03))) :op2 (p4 / protein :name (n4 / name :op1 "BoNT" :op2 "C") :ARG0-of (p7 / proteolyze-00 :ARG1 (p8 / protein :name (n6 / name :op1 "syntaxin") :xref (x1 / xref :value "UNIPROT:STX2_HUMAN" :prob "0.352")) :ARG1-of e)) :manner (r / respective) :ARG1-of (s / show-01 :polarity "-"))) :ARG1 (s2 / secrete-01 :ARG0 (c3 / cell :ARG1-of (p9 / prime-01 :ARG0 (s4 / small-molecule :name (n8 / name :op1 "ATP") :xref (x3 / xref :value "PUBCHEM:5957" :prob "14.368295")))) :ARG1-of (a2 / activate-01 :ARG0 (s3 / small-molecule :name (n7 / name :op1 "calcium") :ARG1-of (i4 / ionize-01 :value "2+") :xref (x2 / xref :value "PUBCHEM:5460341" :prob "10.601383")))) :ARG1-of (c2 / complete-02))) :ARG1 (u / uniqueness :poss (i2 / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "BoNT" :op2 "A")) :ARG1-of (c / complete-02 :polarity "-"))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4B"))) # ::id bio.chicago_2015.75158 # ::date 2015-11-05T05:52:24 # ::file bio_chicago_2015_75158.txt # ::snt These results indicated that LPA-induced actin depolymerization through alpha-actinin was involved in regulation of growth cone morphology of primary neurons. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (i / indicate-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG1 (i2 / involve-01 :ARG1 (p / polymerize-01 :polarity "-" :ARG1 (p2 / protein :name (n / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG2 (p3 / protein :name (n3 / name :op1 "alpha-actinin") :xref (x1 / xref :value "UNIPROT:ACTN2_HUMAN" :prob "0.383")) :ARG2-of (i3 / induce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "LPA") :xref (x2 / xref :value "PUBCHEM:62707" :prob "9.981436")))) :ARG2 (r2 / regulate-01 :ARG1 (m / morphology :poss (c / cone :mod (g / growth) :part-of (n4 / neuron :mod (p4 / primary))))))) # ::id bio.chicago_2015.75270 # ::date 2015-11-05T05:59:47 # ::file bio_chicago_2015_75270.txt # ::snt IKACh activation by adenosine may be responsible for the profound transient bradycardia and atrioventricular block seen in humans after administration of adenosine ( DiMarco et al. 1983 ; Clemo and Belardinelli 1986 ; Kurachi et al. 1986 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (p / possible-01 :ARG1 (r / responsible-03 :ARG0 (a2 / activate-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "adenosine") :xref (x1 / xref :value "PUBCHEM:60961" :prob "11.072318")) :ARG1 (p2 / protein :name (n / name :op1 "IKACh") :xref (x / xref :value "UNIPROT:ELP1_HUMAN" :prob "0.202"))) :ARG1 (a3 / and :op1 (b / bradycardia :ARG1-of (t / transient-02) :mod (p3 / profound)) :op2 (b2 / block-01 :mod (a / atrioventricular)) :ARG1-of (s2 / see-01 :location (h / human) :time (a6 / after :op1 (a7 / administer-01 :ARG1 s))))) :ARG1-of (d4 / describe-01 :ARG0 (a8 / and :op1 (p4 / publication-91 :ARG0 (a9 / and :op1 (p5 / person :name (n3 / name :op1 "Di" :op2 "Marco")) :op1 (p6 / person :mod (o / other))) :time (d2 / date-entity :year "1983")) :op2 (p7 / publication-91 :ARG0 (a10 / and :op1 (p8 / person :name (n4 / name :op1 "Clemo")) :op2 (p9 / person :name (n5 / name :op1 "Belardinelli"))) :time (d3 / date-entity :year "1986")) :op3 (p10 / publication-91 :ARG0 (a11 / and :op1 (p11 / person :name (n6 / name :op1 "Kurachi")) :op2 p6) :time d3)))) # ::id bio.chicago_2015.75329 # ::date 2015-11-05T06:08:19 # ::file bio_chicago_2015_75329.txt # ::snt The global burden of disease and injury attributable to selected risk factors in 1990 ( 12). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (b / burden-01 :ARG2 (a / and :op1 (d2 / disease) :op2 (i / injure-01)) :mod (g / globe) :ARG1-of (a2 / attribute-01 :ARG2 (f / factor :mod (r / risk) :ARG1-of (s / select-01)) :ARG1-of (p / possible-01) :time (d / date-entity :year "1990")) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "12")))) # ::id bio.chicago_2015.75347 # ::date 2015-11-05T06:11:11 # ::file bio_chicago_2015_75347.txt # ::snt Abeta peptides (amyloid plaques), hyperphosphorylated tau proteins (NFTs, NTs), and alpha-synuclein (LBs, GCIs). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (p / protein-segment :name (n / name :op1 "abeta" :op2 "peptide") :part-of (p2 / plaque :mod (a4 / amyloid))) :op2 (p4 / protein :name (n3 / name :op1 "tau") :ARG1-of (h / hyperphosphorylate-01) :part-of (a2 / and :op1 (p3 / protein-family :name (n4 / name :op1 "NFT")) :op2 (p5 / protein-family :name (n5 / name :op1 "NT"))) :xref (x1 / xref :value "UNIPROT:TAU_HUMAN" :prob "0.603")) :op3 (p7 / protein :name (n6 / name :op1 "alpha-synuclein") :part-of (a3 / and :op1 (p6 / protein-family :name (n8 / name :op1 "LB")) :op2 (p8 / protein-family :name (n7 / name :op1 "GCI"))) :xref (x / xref :value "UNIPROT:SYUA_HUMAN" :prob "0.702"))) # ::id bio.chicago_2015.75367 # ::date 2015-11-05T06:19:53 # ::file bio_chicago_2015_75367.txt # ::snt It contains all six motifs ( PM1-PM3, G1-G3) involved in nucleotide binding ( Valencia et al., 1991), and a recombinant protein isolated from E. coli indeed binds and hydrolyses GTP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (a / and :op1 (c / contain-01 :ARG0 (i / it) :ARG1 (p / protein-segment :quant "6" :mod (a2 / all) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (p2 / protein-segment :mod (v / value-interval :op1 (p8 / protein-segment :name (n5 / name :op1 "PM1")) :op2 (p9 / protein-segment :name (n6 / name :op1 "PM3")))) :op2 (p3 / protein-segment :mod (v2 / value-interval :op1 (p10 / protein-segment :name (n7 / name :op1 "G1")) :op2 (p11 / protein-segment :name (n8 / name :op1 "G3")))))) :ARG1-of (i2 / involve-01 :ARG2 (b / bind-01 :ARG1 p :ARG2 (n2 / nucleotide)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and :op1 (p5 / person :name (n3 / name :op1 "Valencia")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "1991")))) :op2 (a5 / and :op1 (b2 / bind-01 :ARG1 (p7 / protein :ARG1-of (r / recombine-01) :ARG1-of (i3 / isolate-01 :ARG2 (o2 / organism :name (n4 / name :op1 "E." :op2 "coli")))) :ARG2 "s") :op2 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG2 p7) :mod (i4 / indeed))) # ::id bio.chicago_2015.75388 # ::date 2015-11-05T07:00:28 # ::file bio_chicago_2015_75388.txt # ::snt In budding yeast, Mad1p becomes hyperphosphorylated and associates with Bub1p and Bub3p, and the formation of this complex occurs in a Mad2p- and Mps1p-dependent fashion and is crucial for checkpoint function ( 8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (a / and :op1 (a2 / and :op1 (b / become-01 :ARG1 (p / protein :name (n / name :op1 "Mad1p") :xref (x4 / xref :value "UNIPROT:MAD1_HUMAN" :prob "0.232")) :ARG2 (h / hyperphosphorylate-01 :ARG1 p)) :op2 (a3 / associate-01 :ARG1 p :ARG2 (a4 / and :op1 (e / enzyme :name (n2 / name :op1 "Bub1p") :xref (x3 / xref :value "UNIPROT:BUB1_HUMAN" :prob "0.232")) :op2 (e2 / enzyme :name (n3 / name :op1 "Bub3p") :xref (x1 / xref :value "UNIPROT:BUB3_HUMAN" :prob "0.232"))))) :op2 (f / form-01 :ARG1 (m / macro-molecular-complex :part p :part e :part e2 :mod (t / this)) :ARG0-of (d / depend-01 :ARG1 (a5 / and :op1 (p2 / protein :name (n4 / name :op1 "Mad2p") :xref (x2 / xref :value "UNIPROT:MD2L1_HUMAN" :prob "0.232")) :op2 (e3 / enzyme :name (n5 / name :op1 "Mps1p") :xref (x / xref :value "UNIPROT:RS27_HUMAN" :prob "0.232"))))) :op3 (c / crucial :domain f :purpose (f3 / function-01 :ARG1 (c2 / checkpoint))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "8"))) :location (y / yeast :ARG1-of (b2 / bud-01))) # ::id bio.chicago_2015.75391 # ::date 2015-11-05T07:09:42 # ::file bio_chicago_2015_75391.txt # ::snt The structural and functional conservation of basal transcription machineries between yeast and mammals prompted us to investigate whether TFIIH is involved in rDNA transcription in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (p / prompt-01 :ARG0 (c / conserve-01 :ARG1 (a / and :op1 (s / structure-01 :ARG1 (m / machinery :ARG0-of (t / transcribe-01) :mod (b / basal))) :op2 (f / function-01 :ARG0 m)) :location (a2 / and :op1 (y / yeast) :op2 (m2 / mammal))) :ARG1 (i / investigate-01 :ARG0 (w / we) :ARG1 (i2 / involve-01 :mode "interrogative" :ARG1 (p2 / protein :name (n / name :op1 "TFIIH") :xref (x / xref :value "UNIPROT:TCEA3_HUMAN" :prob "0.332")) :ARG2 (t2 / transcribe-01 :ARG1 (n2 / nucleic-acid :name (n3 / name :op1 "rDNA"))) :manner (i3 / in-vivo)))) # ::id bio.chicago_2015.75414 # ::date 2015-11-05T07:40:44 # ::file bio_chicago_2015_75414.txt # ::snt Of the 30 tests (data not shown), all but 1 received P values > 0.05, and the one exception, reductase constrained to the ammonia ligase consensus, received a P value of 0.0338. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / and :op1 (r / receive-01 :ARG0 (t2 / test :mod (a2 / all) :ARG1-of (i / include-01 :ARG2 (t / test :quant "30" :ARG1-of (d2 / describe-01 :ARG0 (d / data :ARG1-of (s / show-01 :polarity "-"))))) :ARG2-of (e / except-01 :ARG1 (t3 / test :quant "1" :ARG1-of (m2 / mean-01 :ARG2 (c / constrain-01 :ARG0 (c2 / consent-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "ammonia" :op2 "ligase"))) :ARG1 (e2 / enzyme :name (n / name :op1 "reductase"))))))) :ARG1 (s2 / statistical-test-91 :ARG1 t2 :ARG2 (m / more-than :op1 "0.05"))) :op2 (r2 / receive-01 :ARG0 t3 :ARG1 (s3 / statistical-test-91 :ARG1 t3 :ARG2 "0.0338"))) # ::id bio.chicago_2015.75551 # ::date 2015-11-05T08:06:35 # ::file bio_chicago_2015_75551.txt # ::snt GLP-1-(1-36)-amide and GLP-1(1137) synthetic peptides were iodinated by the chloramine-T method. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (i / iodinate-00 :ARG0 (m / method :mod (s2 / small-molecule :name (n3 / name :op1 "chloramine-T") :xref (x / xref :value "PUBCHEM:3641960" :prob "15.844507"))) :ARG1 (a / and :op1 (p / peptide :name (n / name :op1 "GLP-1-(1-36)-amide")) :op2 (p2 / peptide :name (n2 / name :op1 "GLP-1(1137)")) :mod (s / synthetic))) # ::id bio.chicago_2015.79572 # ::date 2015-11-05T08:11:56 # ::file bio_chicago_2015_79572.txt # ::snt A strong FRET signal is detected from DABCYL-tagged PLCbeta2 in the presence of coumarin-tagged prenylated betagamma complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (d / detect-01 :ARG1 (s / signal-07 :ARG0 (e / enzyme :name (n2 / name :op1 "PLCbeta2") :ARG1-of (t2 / tag-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "DABCYL") :xref (x3 / xref :value "PUBCHEM:22650" :prob "17.068911"))) :xref (x2 / xref :value "UNIPROT:PLCB2_HUMAN" :prob "0.673")) :ARG1 (t / thing :name (n / name :op1 "FRET")) :ARG1-of (s2 / strong-02)) :condition (p / present-02 :ARG1 (m / macro-molecular-complex :part (p2 / protein :name (n4 / name :op1 "beta") :xref (x / xref :value "UNIPROT:Q15866_HUMAN" :prob "0.291")) :part (p3 / protein :name (n5 / name :op1 "gamma") :xref (x1 / xref :value "UNIPROT:IL2RG_HUMAN" :prob "0.333")) :ARG1-of (p4 / prenylate-00) :ARG1-of (t3 / tag-01 :ARG0 (s4 / small-molecule :name (n6 / name :op1 "coumarin") :xref (x4 / xref :value "PUBCHEM:323" :prob "12.668988")))))) # ::id bio.chicago_2015.79887 # ::date 2015-11-05T08:20:20 # ::file bio_chicago_2015_79887.txt # ::snt Elevated A{beta}42 in Skeletal Muscle of Alzheimer Disease Patients Suggests Peripheral Alterations of A{beta}PP Metabolism. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / suggest-01 :ARG0 (p / protein :name (n2 / name :op1 "A-beta" :op2 "42") :ARG1-of (e / elevate-01) :location (m / muscle :mod (s2 / skeleton) :poss (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :ARG0-of (h2 / have-03 :ARG1 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer" :op2 "disease")))))) :ARG1 (a / alter-01 :ARG1 (m2 / metabolize-01 :ARG1 (p5 / protein :name (n3 / name :op1 "A-beta" :op2 "PP"))) :mod (p4 / peripheral))) # ::id bio.chicago_2015.79978 # ::date 2015-11-05T08:26:23 # ::file bio_chicago_2015_79978.txt # ::snt Cystic Fibrosis Phenotype Associated with Pancreatic Insufficiency Does Not Always Reflect the cAMP-dependent Chloride Conductive Pathway Defect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (r / reflect-01 :polarity "-" :ARG1 (p / phenotype :mod (d / disease :name (n / name :op1 "cystic" :op2 "fibrosis")) :ARG1-of (a / associate-01 :ARG2 (m2 / medical-condition :name (n2 / name :op1 "pancreatic" :op2 "insufficiency")))) :ARG2 (d3 / defect-01 :ARG0 (p2 / pathway :mod (s2 / small-molecule :name (n3 / name :op1 "chloride") :xref (x / xref :value "PUBCHEM:312" :prob "7.750597")) :ARG1-of (c / conduct-03) :ARG0-of (d4 / depend-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "cAMP") :xref (x1 / xref :value "PUBCHEM:6076" :prob "15.374314"))))) :time (a2 / always)) # ::id bio.chicago_2015.80319 # ::date 2015-11-05T08:34:49 # ::file bio_chicago_2015_80319.txt # ::snt Potential Mechanisms for Exacerbation of Diabetic Retinopathy by Hypertension. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (m / mechanism :mod (p / potential) :instrument-of (e / exacerbate-01 :ARG0 (h / hypertension) :ARG1 (r / retinopathy :mod (d / disease :name (n / name :op1 "diabetes"))))) # ::id bio.chicago_2015.80327 # ::date 2015-11-05T08:36:39 # ::file bio_chicago_2015_80327.txt # ::snt D, HT-induced phosphorylation of myrAkt delta4-129-ER. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :li "D" :ARG1 (g / gene :name (n / name :op1 "myrAKT" :op2 "Delta4-129-ER")) :ARG2-of (i / induce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "HT") :xref (x / xref :value "PUBCHEM:2805" :prob "9.451874")))) # ::id bio.chicago_2015.80330 # ::date 2015-11-05T08:43:03 # ::file bio_chicago_2015_80330.txt # ::snt In vivo, iNOS concentrations increase in parallel with diabetes onset in a model of T-cell transfer 69 and after cyclophosphamide treatment of insulitic animals 70; moreover, an inhibitor of iNOS activity can block diabetes transfer 69. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (m / multi-sentence :snt1 (i2 / increase-01 :ARG1 (c / concentrate-02 :ARG1 (e / enzyme :name (n / name :op1 "iNOS") :xref (x1 / xref :value "UNIPROT:NOS2_HUMAN" :prob "1.002"))) :manner (i3 / in-vivo) :ARG0-of (p / parallel-01 :ARG1 (o / onset :mod (d4 / disease :name (n2 / name :op1 "diabetes")))) :location (m2 / model :mod (t2 / transfer-01 :ARG1 (c2 / cell :name (n4 / name :op1 "T"))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "69")))) :time (a / after :op1 (t3 / treat-04 :ARG1 (a2 / animal :mod (i4 / insulitic)) :ARG2 (s / small-molecule :name (n3 / name :op1 "cyclophosphamide") :xref (x2 / xref :value "PUBCHEM:2907" :prob "15.481944"))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "70"))))) :snt2 (a3 / and :op2 (p4 / possible-01 :ARG1 (b / block-01 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i5 / inhibit-01 :ARG1 (a4 / activity-06 :ARG0 (e2 / enzyme :name (n5 / name :op1 "iNOS") :xref (x / xref :value "UNIPROT:NOS2_HUMAN" :prob "1.002"))))) :ARG1 (t4 / transfer-01 :ARG1 (d6 / disease :name (n6 / name :op1 "diabetes"))))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication :ARG1-of (c5 / cite-01 :ARG2 "69"))))) # ::id bio.chicago_2015.80669 # ::date 2015-11-05T08:59:36 # ::file bio_chicago_2015_80669.txt # ::snt Consistent with this prediction, when families were divided into two groups according to the presence or absence in the probands of the risk allele of SNP V26 (the most significant SNP in BLOCK I), significance of the schizophrenia associations with BLOCK I SNPs V23-27 increased dramatically in families with the V26 risk allele present. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i / increase-01 :ARG1 (s / signify-01 :ARG0 (a / associate-01 :ARG1 (m2 / medical-condition :name (n / name :op1 "schizophrenia")) :ARG2 (p5 / polymorphism :mod (n4 / nucleotide :ARG1-of (s3 / single-02)) :mod (v / value-interval :op1 (m3 / molecular-physical-entity :ARG1-of (s4 / substitute-01 :value "V23")) :op2 (m4 / molecular-physical-entity :ARG1-of (s5 / substitute-01 :value "V27"))) :location "b"))) :ARG2 (d2 / dramatic) :location (f / family :ARG2-of (p / present-02 :ARG1 "a2")) :ARG1-of (c / consistent-01 :ARG2 (t2 / thing :ARG1-of (p2 / predict-01) :mod (t3 / this))) :time (d3 / divide-02 :ARG1 (f2 / family) :ARG2 (g / group :quant "2") :ARG1-of (a3 / accord-02 :ARG2 (o2 / or :op1 (p3 / present-02 :ARG1 (a2 / allele :mod (r / risk) :mod (p6 / polymorphism :mod n4 :ARG1-of (s2 / significant-02 :degree (m / most) :location (b / block :ord (o / ordinal-entity :value "1"))) :mod (m5 / molecular-physical-entity :ARG1-of (s6 / substitute-01 :value "V26")))) :ARG2 (p4 / proband)) :op2 (a4 / absent-01 :ARG1 a2 :ARG2 p4))))) # ::id bio.chicago_2015.80727 # ::date 2015-11-05T09:22:20 # ::file bio_chicago_2015_80727.txt # ::snt Mice and rats with spontaneously occurring Lepr mutations affecting the expression of all ( db3J, dbPas, faf, fa), or only one ( db), of the LEPR isoforms have provided useful models for determining the physiological function(s) of LEPR isoforms in various tissues. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / provide-01 :ARG0 (a / and :op1 (m / mouse) :op2 (r / rat) :ARG0-of (h / have-03 :ARG1 (m2 / mutate-01 :ARG1 (p7 / protein :wiki "Leptin_receptor" :name (n / name :op1 "Lepr") :xref (x / xref :value "UNIPROT:LEPR_HUMAN" :prob "0.603")) :mod (s / spontaneous) :ARG0-of (a2 / affect-01 :ARG1 (a3 / and :op1 (e / express-03 :ARG2 (i / isoform :mod (a4 / all) :ARG1-of (m3 / mean-01 :ARG2 (a5 / and :op1 (i6 / isoform :name (n2 / name :op1 "db3J")) :op2 (i7 / isoform :name (n3 / name :op1 "dbPas")) :op3 (i8 / isoform :name (n4 / name :op1 "faf")) :op4 (i9 / isoform :name (n5 / name :op1 "fa")))) :ARG1-of (i4 / include-91 :ARG2 (i3 / isoform :mod p7)))) :op2 (e2 / express-03 :ARG2 (i2 / isoform :quant "1" :mod (o / only) :ARG1-of (m4 / mean-01 :ARG2 (i10 / isoform :name (n6 / name :op1 "db"))) :ARG1-of i4))))))) :ARG1 (m5 / model :ARG1-of (u / useful-05 :ARG2 (d / determine-01 :ARG1 (f / function-01 :ARG0 (i5 / isoform :mod p7) :mod (p8 / physiology) :location (t / tissue :mod (v / various))))))) # ::id bio.chicago_2015.80768 # ::date 2015-11-05T09:26:37 # ::file bio_chicago_2015_80768.txt # ::snt Linkage and association of tumor necrosis factor receptor 2 locus with hypertension, hypercholesterolemia and plasma shed receptor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / and :op1 (l / link-01 :ARG1 (l2 / locus :ARG0-of (c / contain-01 :ARG1 (p / protein :name (n / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "receptor" :op5 "2") :xref (x / xref :value "UNIPROT:TNR1B_HUMAN" :prob "0.702")))) :ARG2 (a3 / and :op1 (h / hypertension) :op2 (h2 / hypercholesterolemia) :op3 (p2 / protein :name (n2 / name :op1 "shed" :op2 "receptor") :mod (p3 / plasma)))) :op2 (a2 / associate-01 :ARG1 l2 :ARG2 a3)) # ::id bio.chicago_2015.80775 # ::date 2015-11-06T00:13:21 # ::file bio_chicago_2015_80775.txt # ::snt However, little is known about how chronic hypoxia and/or pulmonary hypertension affect PDE expression and activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (h / have-concession-91 :ARG1 (k / know-01 :ARG1 (t / thing :manner-of (a / affect-01 :ARG0 (a2 / and-or :op1 (h2 / hypoxia :mod (c / chronic)) :op2 (h3 / hypertension :mod (l2 / lung))) :ARG1 (a3 / and :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "PDE") :xref (x / xref :value "UNIPROT:PDE5A_HUMAN" :prob "0.262"))) :op2 (a4 / activity-06 :ARG0 e2))) :degree (l / little)))) # ::id bio.chicago_2015.80886 # ::date 2015-11-06T00:19:20 # ::file bio_chicago_2015_80886.txt # ::snt Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / associate-01 :ARG1 (s / schizophrenia) :ARG2 (p / polymorphism :mod (g / gene :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n / name :op1 "5-hydroxytryptamine" :op2 "type" :op3 "2a-receptor") :xref (x / xref :value "UNIPROT:5HT2A_HUMAN" :prob "0.372"))) :ARG1-of (m / mutate-01 :value "T102C")))) # ::id bio.chicago_2015.80961 # ::date 2015-11-06T00:22:53 # ::file bio_chicago_2015_80961.txt # ::snt PPL in the NIDDM group resulted in the production of TG rich lipoproteins, with AUC for TG content of HDL, LDL and VLDL being significantly greater in the NIDDM group than controls ( Table 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (a3 / and :op1 (r / result-01 :ARG1 (d4 / disease :wiki "-" :name (n8 / name :op1 "postprandial" :op2 "lipaemia") :location (g2 / group :mod (d / disease :wiki "Diabetes_mellitus_type_2" :name (n / name :op1 "diabetes" :op2 "mellitus" :op3 "type" :op4 "2")))) :ARG2 (p / produce-01 :ARG1 (p2 / protein :wiki "Lipoprotein" :name (n3 / name :op1 "lipoprotein") :mod (r2 / rich :topic (s / small-molecule :wiki "Triglyceride" :name (n4 / name :op1 "triglyceride") :xref (x4 / xref :value "PUBCHEM:6050" :prob "10.042163"))) :xref (x / xref :value "UNIPROT:LIPL_HUMAN" :prob "0.332")))) :op2 (h / have-03 :ARG0 (c2 / contain-01 :ARG0 (a2 / and :op1 (p3 / protein :wiki "Lipoprotein" :name (n5 / name :op1 "lipoprotein") :mod (d2 / density :ARG1-of (h2 / high-02)) :xref (x1 / xref :value "UNIPROT:LIPL_HUMAN" :prob "0.332")) :op2 (p4 / protein :wiki "Lipoprotein" :name (n6 / name :op1 "lipoprotein") :mod (d5 / density :ARG1-of (l / low-04)) :xref (x2 / xref :value "UNIPROT:LIPL_HUMAN" :prob "0.332")) :op3 (p5 / protein :wiki "Lipoprotein" :name (n7 / name :op1 "lipoprotein") :mod (d6 / density :ARG1-of (l2 / low-04 :degree (v / very))) :xref (x3 / xref :value "UNIPROT:LIPL_HUMAN" :prob "0.332"))) :ARG1 s) :ARG1 (a / area :location (u / under :op1 (c / curve))) :mod (g3 / great :degree (m2 / more) :ARG1-of (s2 / significant-02) :location g2 :compared-to (c3 / control))) :ARG1-of (d3 / describe-01 :ARG0 (t / table :mod "3"))) # ::id bio.chicago_2015.81024 # ::date 2015-11-06T00:33:33 # ::file bio_chicago_2015_81024.txt # ::snt To examine this point, tetanic stimulation of the CF in current clamp mode was applied twice with a 5 min interval ( Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (a / apply-02 :ARG1 (s / stimulate-01 :ARG1 (f2 / fiber :ARG0-of (c4 / climb-01)) :mod (t / tetanic) :manner (m / mode :mod (c2 / clamp-01 :ARG1 (c3 / current)))) :purpose (e / examine-01 :ARG1 (p / point :mod (t3 / this))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3")) :frequency (r / rate-entity-91 :ARG1 (t4 / twice) :ARG3 (i / interval :duration (t2 / temporal-quantity :quant "5" :unit (m2 / minute))))) # ::id bio.chicago_2015.81034 # ::date 2015-11-06T00:43:17 # ::file bio_chicago_2015_81034.txt # ::snt In fact, our results indicate that DNA derived from the sputum of patients with cystic fibrosis initiates an inflammatory response in the lower respiratory tract. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / indicate-01 :ARG0 (t / thing :poss (w / we) :ARG2-of (r / result-01)) :ARG1 (i2 / initiate-01 :ARG0 (n3 / nucleic-acid :name (n4 / name :op1 "DNA") :ARG1-of (d / derive-01 :ARG2 (s / sputum :poss (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :name (n5 / name :op1 "cystic" :op2 "fibrosis"))))))) :ARG1 (r2 / respond-01 :ARG2 (i3 / inflame-01)) :location (t2 / tract :ARG1-of (l / low-04 :degree (m / more)) :ARG0-of (r3 / respire-01))) :mod (i4 / in-fact)) # ::id bio.chicago_2015.81265 # ::date 2015-11-06T00:48:43 # ::file bio_chicago_2015_81265.txt # ::snt After exclusion of subjects who were being treated for hypertension, hypercholesterolemia, or diabetes, substitution of SBP, HDL and LDL cholesterol, and blood glucose levels for hypertension, hypercholesterolemia, and diabetes, respectively, yielded very close results. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (y / yield-01 :ARG0 (a / and :op1 (s / substitute-01 :ARG1 (p / pressure-01 :ARG0 "b" :mod (s11 / systole)) :ARG2 (h / hypertension)) :op2 (s3 / substitute-01 :ARG1 (a2 / and :op1 (s4 / small-molecule :name (n2 / name :op1 "HDL" :op2 "cholesterol") :xref (x2 / xref :value "PUBCHEM:6323542" :prob "6.902719")) :op2 (s5 / small-molecule :name (n3 / name :op1 "LDL" :op2 "cholesterol") :xref (x1 / xref :value "PUBCHEM:304" :prob "3.702857"))) :ARG2 (h2 / hypercholesterolemia)) :op3 (s6 / substitute-01 :ARG1 (l3 / level :quant-of (s7 / small-molecule :name (n5 / name :op1 "glucose") :mod (b / blood) :xref (x / xref :value "PUBCHEM:206" :prob "11.89276"))) :ARG2 (d / disease :name (n / name :op1 "diabetes"))) :manner (r2 / respective)) :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (c / close-10 :degree (v / very))) :time (a3 / after :op1 (e / exclude-01 :ARG1 (o / or :op1 (s8 / subject :ARG1-of (t2 / treat-03 :ARG2 h)) :op2 (s9 / subject :ARG1-of (t3 / treat-03 :ARG2 h2)) :op3 (s10 / subject :ARG1-of (t4 / treat-03 :ARG2 d)))))) # ::id bio.chicago_2015.81467 # ::date 2015-11-06T01:07:49 # ::file bio_chicago_2015_81467.txt # ::snt Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "neutrophil" :op2 "elastase") :location (f / fluid :ARG0-of (l / line-01 :ARG1 (e2 / epithelium :ARG0-of (r / respire-01) :part-of (i2 / individual :ARG0-of (h / have-03 :ARG1 (d / disease :name (n2 / name :op1 "cystic" :op2 "fibrosis"))))))) :xref (x / xref :value "UNIPROT:ELNE_HUMAN" :prob "0.702")) :ARG2 (e3 / express-03 :ARG1 (g / gene :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "interleukin-8") :xref (x1 / xref :value "UNIPROT:IL8_HUMAN" :prob "0.703")))) :ARG3 (c / cell-line :part-of (e5 / epithelium :part-of (b / bronchus :mod (h2 / human)))))) # ::id bio.chicago_2015.81509 # ::date 2015-11-06T01:15:45 # ::file bio_chicago_2015_81509.txt # ::snt Hypertension Associated with Decreased Testosterone Levels in Natriuretic Peptide Receptor-A Gene-Knockout and Gene-Duplicated Mutant Mouse Models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (a / associate-01 :ARG1 (h / hypertension) :ARG2 (l / level :ARG1-of (d / decrease-01) :quant-of (s / small-molecule :name (n / name :op1 "testosterone") :xref (x1 / xref :value "PUBCHEM:6013" :prob "13.752706"))) :location (a2 / and :op1 (m / model :mod (m5 / mouse :mod (g / gene :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "natriuretic" :op2 "peptide" :op3 "receptor-A") :xref (x / xref :value "UNIPROT:ANF_HUMAN" :prob "0.342"))) :ARG1-of (k / knock-out-03)) :ARG1-of "m4")) :op2 (m2 / model :mod (m3 / mouse :ARG2-of (m4 / mutate-01) :mod (g3 / gene :ARG1-of (d2 / duplicate-01)))))) # ::id bio.chicago_2015.81555 # ::date 2015-11-06T01:23:08 # ::file bio_chicago_2015_81555.txt # ::snt APL modulation of spontaneous diabetes in NOD mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (m / modulate-01 :ARG0 (p / protein :name (n / name :op1 "APL") :xref (x / xref :value "UNIPROT:TNFL6_HUMAN" :prob "1.002")) :ARG1 (d2 / disease :name (n2 / name :op1 "diabetes") :mod (s / spontaneous)) :location (m2 / mouse :mod (o / obese :polarity "-") :mod d2)) # ::id bio.chicago_2015.81850 # ::date 2015-11-06T01:26:36 # ::file bio_chicago_2015_81850.txt # ::snt Refractory hypertension is associated with the haptoglobin 2-2 phenotype. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (a / associate-01 :ARG1 (h / hypertension :mod (r / refractory)) :ARG2 (p / phenotype :mod (p2 / protein :name (n / name :op1 "haptoglobin" :op2 "2-2") :xref (x / xref :value "UNIPROT:HPT_HUMAN" :prob "0.362")))) # ::id bio.chicago_2015.81979 # ::date 2015-11-06T01:27:59 # ::file bio_chicago_2015_81979.txt # ::snt 14 Studies in men revealed a dose-dependent vasodilation of forearm arterioles in healthy subjects as well as in patients with essential hypertension, which was inhibited by the NOS inhibitor L-NMMA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / reveal-01 :ARG0 (s / study-01 :quant "14" :ARG1 (m / man)) :ARG1 (d3 / dilate-01 :ARG1 (a / arteriole :part-of (f / forearm)) :ARG0-of (d / depend-01 :ARG1 (d2 / dose-01)) :ARG1-of (i / inhibit-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "L-NMMA") :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "NOS") :xref (x / xref :value "UNIPROT:Q3Y9M1_HUMAN" :prob "1.001"))) :xref (x1 / xref :value "PUBCHEM:132862" :prob "15.442354")))) :location (a2 / and :op1 (s2 / subject :mod (h / healthy)) :op2 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h3 / have-03 :ARG1 (h4 / hypertension :mod (e / essential)))))) # ::id bio.chicago_2015.82087 # ::date 2015-11-06T01:34:30 # ::file bio_chicago_2015_82087.txt # ::snt Subgroup analysis on men showed a significant association of tPA and diabetes, smoking, hypertension, BMI, cholesterol, and apoA-I in multivariate conditional logistic regression, whereas no significant association could be shown when PAI-1, vWF, TM, or DHEAS was included in the model (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (m / man :mod (s2 / subgroup))) :ARG1 (a2 / associate-01 :ARG1 (e / enzyme :name (n / name :op1 "tPA") :xref (x2 / xref :value "UNIPROT:TPA_HUMAN" :prob "1.003")) :ARG2 (a3 / and :op1 (d4 / disease :name (n8 / name :op1 "diabetes")) :op2 (s4 / smoke-02) :op3 (h / hypertension) :op4 (i2 / index-01 :ARG1 (m4 / mass :mod (b2 / body))) :op5 (s5 / small-molecule :name (n2 / name :op1 "cholesterol") :xref (x6 / xref :value "PUBCHEM:304" :prob "13.332563")) :op6 (p2 / protein :name (n3 / name :op1 "apoA-I") :xref (x / xref :value "UNIPROT:APOA1_HUMAN" :prob "0.702"))) :ARG1-of (s3 / significant-02)) :condition (r / regress-01 :mod (l / logistic) :mod (c2 / condition) :mod (m2 / multivariate))) :ARG2 (p / possible-01 :polarity "-" :ARG1 (s6 / show-01 :ARG1 (a4 / associate-01 :ARG1-of (s7 / significant-02))) :time (i / include-01 :ARG1 (o / or :op1 (p3 / protein :name (n4 / name :op1 "PAI-1") :xref (x1 / xref :value "UNIPROT:PAI1_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n5 / name :op1 "vWF") :xref (x3 / xref :value "UNIPROT:VWF_HUMAN" :prob "1.003")) :op3 (p5 / protein :name (n6 / name :op1 "TM") :xref (x4 / xref :value "UNIPROT:ENR1_HUMAN" :prob "1.002")) :op4 (s8 / small-molecule :name (n7 / name :op1 "DHEAS") :xref (x5 / xref :value "PUBCHEM:12594" :prob "18.86067"))) :ARG2 (m3 / model))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s9 / show-01 :polarity "-")))) # ::id bio.chicago_2015.82191 # ::date 2015-11-06T01:45:18 # ::file bio_chicago_2015_82191.txt # ::snt The observation that the hypophosphorylated CUG-BP/ hNab50 form (CUG-BP2) was accumulated in the nuclei of patients with DM (containing low levels of DMPK) suggested that DMPK activity may be required for CUG-BP/ hNab50 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / suggest-01 :ARG0 (o / observe-01 :ARG1 (a / accumulate-01 :ARG0 (n2 / nucleus :poss (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG0-of (h2 / have-03 :ARG1 (d / dystrophy :mod (m / myotonic)))) :ARG0-of (c2 / contain-01 :ARG1 (l2 / level :ARG1-of (l3 / low-04) :quant-of (e / enzyme :name (n3 / name :op1 "DMPK") :xref (x / xref :value "UNIPROT:DMPK_HUMAN" :prob "1.003")))) :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :ARG1 (p2 / protein :name (n / name :op1 "CUG-BP/hNab50") :ARG1-of (l / label-01 :ARG2 (n5 / name :op1 "CUG-BP2")) :ARG1-of (h3 / hypophosphorylate-00)))) :ARG1 (p5 / possible-01 :ARG1 (r / require-01 :ARG0 (p / phosphorylate-01 :ARG1 p2) :ARG1 (a2 / activity-06 :ARG0 e)))) # ::id bio.chicago_2015.82428 # ::date 2015-11-06T01:58:16 # ::file bio_chicago_2015_82428.txt # ::snt These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of A peptides terminating at 42(43), species that foster A deposition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (p / provide-01 :ARG0 (s / study-01 :mod (t / this)) :ARG1 (s2 / support-01 :ARG0 s :ARG1 (v / view-02 :ARG1 (m / mechanism :quant "1" :instrument-of (c2 / cause-01 :ARG0 (p2 / protein :name (n / name :op1 "PS1") :ARG1-of (m2 / mutate-01) :mod t :xref (x / xref :value "UNIPROT:PSN1_HUMAN" :prob "1.002")) :ARG1 (d2 / disease :wiki "Alzheimer's_disease" :name (n3 / name :op1 "Alzheimer's"))) :domain (i / increase-01 :ARG0 p2 :ARG1 (c3 / concentrate-02 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "Abeta" :op2 "peptide") :ARG1-of (t2 / terminate-01 :location (a2 / amino-acid :mod "42")) :mod (s3 / species :ARG0-of (f / foster-01 :ARG1 (d / depose-03 :ARG1 p3)))) :mod (e / extracellular)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "43")))))) :ARG0-of (c / compel-01))) # ::id bio.chicago_2015.83036 # ::date 2015-11-06T02:10:09 # ::file bio_chicago_2015_83036.txt # ::snt Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (i / increase-01 :ARG0 (m / mutate-01 :ARG1 (p / protein :name (n2 / name :op1 "beta-amyloid" :op2 "precursor") :xref (x1 / xref :value "UNIPROT:A4_HUMAN" :prob "0.292")) :location (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer") :mod (f / family))) :ARG1 (p2 / produce-01 :ARG1 (p3 / protein :name (n4 / name :op1 "beta") :xref (x / xref :value "UNIPROT:Q15866_HUMAN" :prob "0.291")))) # ::id bio.chicago_2015.83072 # ::date 2015-11-06T02:12:04 # ::file bio_chicago_2015_83072.txt # ::snt Wnt/{ beta}-Catenin/ cf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (i / induce-01 :ARG0 (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Wnt/beta-catenin/Tcf"))) :ARG2 (t / transcribe-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Axin2") :ARG2-of (d / downregulate-01 :ARG1 p) :xref (x / xref :value "UNIPROT:AXIN2_HUMAN" :prob "0.683")))) # ::id bio.chicago_2015.83176 # ::date 2015-11-06T02:16:33 # ::file bio_chicago_2015_83176.txt # ::snt Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / associate-01 :ARG1 (d3 / disease :name (n2 / name :op1 "diabetes") :mod (m / mellitus) :ARG0-of (d2 / depend-01 :ARG1 (p3 / protein :name (n3 / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :ARG1-of (l / label-01 :ARG2 (n4 / name :op1 "IDDM"))) :ARG2 (p / polymorphism :mod (p2 / protein :name (n / name :op1 "CTLA4") :xref (x / xref :value "UNIPROT:CTLA4_HUMAN" :prob "1.003"))) :location (e2 / ethnic-group :mod (m2 / multiple))) # ::id bio.chicago_2015.83187 # ::date 2015-11-06T02:19:16 # ::file bio_chicago_2015_83187.txt # ::snt Although the underlying mechanisms remain unknown, based on our results that A , an AD-related molecule, upregulated SCD-1 in macrophages, it can be considered that there is a link between SCD-1 and AD. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (h / have-concession-91 :ARG1 (p / possible-01 :ARG1 (c / consider-01 :ARG1 (l / link-01 :ARG1 (p2 / protein :name (n / name :op1 "SCD-1") :xref (x / xref :value "UNIPROT:ACOD_HUMAN" :prob "0.252")) :ARG2 (d / disease :wiki "Alzheimer's_disease" :name (n3 / name :op1 "Alzheimer's")))) :ARG1-of (b / base-02 :ARG2 (t / thing :ARG2-of (r2 / result-01) :poss (w / we) :topic (u2 / upregulate-01 :ARG1 p2 :ARG2 (p3 / protein :name (n2 / name :op1 "Abeta") :ARG1-of (r3 / relate-01 :ARG2 d)) :location (m2 / macrophage))))) :ARG2 (r / remain-01 :ARG1 (m / mechanism :ARG0-of (u / underlie-01)) :ARG3 (k / know-01 :polarity "-" :ARG1 m))) # ::id bio.chicago_2015.83472 # ::date 2015-11-06T02:28:11 # ::file bio_chicago_2015_83472.txt # ::snt The column, absorbed with bc1 complexes, was then subjected to a sequence of washings with TN buffer (50 mM Tris-Cl (pH 8.0 at 4 degrees C) and 200 mM NaCl) containing 0.01% DM, TN buffer containing 5 mM histidine and 0.01% DM, and TN buffer containing 5 mM histidine and 0.5% octyl glucoside. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s / subject-01 :ARG1 (c / column :ARG0-of (a2 / absorb-01 :ARG1 (m4 / macro-molecular-complex :name (n2 / name :op1 "bc1")))) :ARG2 (s2 / sequence :consist-of (a3 / and :op1 (w / wash-01 :ARG1 c :ARG2 (b / buffer :mod (s3 / small-molecule :name (n3 / name :op1 "TN") :consist-of (a4 / and :op1 (s5 / small-molecule :name (n / name :op1 "tris(hydroxymethyl)aminomethane") :quant (c3 / concentration-quantity :quant "50" :unit (m5 / millimolar)) :mod (a5 / acidity-quantity :quant "8.0" :scale (p4 / ph)) :mod (t / temperature-quantity :quant "4" :scale (c5 / celsius))) :op2 (s6 / small-molecule :name (n5 / name :op1 "sodium" :op2 "chloride") :quant (c4 / concentration-quantity :quant "200" :unit m5) :xref (x2 / xref :value "PUBCHEM:5234" :prob "7.137103"))) :xref (x / xref :value "PUBCHEM:119" :prob "7.243538")) :ARG0-of (c2 / contain-01 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "DM") :quant (p2 / percentage-entity :value "0.01") :xref (x3 / xref :value "PUBCHEM:2968" :prob "9.14767"))))) :op2 (w2 / wash-01 :ARG1 c :ARG2 (b2 / buffer :mod s3 :ARG0-of (c6 / contain-01 :ARG1 (a6 / and :op1 (a7 / amino-acid :name (n7 / name :op1 "histidine") :quant (c8 / concentration-quantity :quant "5" :unit m5) :xref (x4 / xref :value "PUBCHEM:6274" :prob "11.959939")) :op2 s4)))) :op3 (w3 / wash-01 :ARG1 c :ARG2 (b3 / buffer :mod s3 :ARG0-of (c7 / contain-01 :ARG1 (a8 / and :op1 a7 :op2 (s7 / small-molecule :name (n8 / name :op1 "octyl" :op2 "glucoside") :quant (p5 / percentage-entity :value "0.5") :xref (x1 / xref :value "PUBCHEM:62080" :prob "9.593014")))))))) :time (t2 / then)) # ::id bio.chicago_2015.83519 # ::date 2015-11-06T02:56:33 # ::file bio_chicago_2015_83519.txt # ::snt Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / secrete-01 :ARG0 (p2 / person :ARG0-of (c / carry-01 :ARG1 (v / vary-01 :ARG1 (g / gene :ARG0-of (e / encode-01 :ARG1 (p3 / protein :name (n / name :op1 "sulphonylurea" :op2 "receptor") :xref (x / xref :value "UNIPROT:ABCC8_HUMAN" :prob "0.362"))))))) :ARG1 (p4 / protein :name (n2 / name :op1 "insulin") :xref (x1 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :ARG1-of (r / reduce-01) :time (p / phase :ord (o2 / ordinal-entity :value "2")) :ARG1-of (a / associate-01 :ARG2 (d2 / disease :name (n3 / name :op1 "diabetes") :mod (m / mellitus) :mod (t / type :ord o2)))) # ::id bio.chicago_2015.83813 # ::date 2015-11-06T03:03:37 # ::file bio_chicago_2015_83813.txt # ::snt In humans, insulin-receptor mutations cause diabetes rather than longevity; however, these mutations lead ultimately to a severe loss of insulin production and so may not mimic the weak signalling mutations of C. elegans. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (a / and :op1 (l2 / lead-03 :ARG0 "m" :ARG2 (l3 / lose-01 :ARG1 (p2 / produce-01 :ARG1 (p4 / protein :name (n3 / name :op1 "insulin") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :ARG2 (s / severe)) :time (u / ultimate)) :op2 (p3 / possible-01 :ARG1 (m2 / mimic-01 :polarity "-" :ARG0 "m" :ARG1 (m3 / mutate-01 :ARG1 (o / organism :name (n2 / name :op1 "C" :op2 "elegan")) :ARG1-of (w / weak-02) :ARG0-of (s2 / signal-07))) :ARG1-of (c2 / cause-01 :ARG0 l3))) :ARG2 (c / cause-01 :ARG0 (m / mutate-01 :ARG1 (p / protein :name (n / name :op1 "insulin" :op2 "receptor") :xref (x1 / xref :value "UNIPROT:INSR_HUMAN" :prob "0.703"))) :ARG1 (d2 / diabetes :ARG1-of (i / instead-of-91 :ARG2 (l / longevity))) :location (h2 / human))) # ::id bio.chicago_2015.83846 # ::date 2015-11-06T03:12:15 # ::file bio_chicago_2015_83846.txt # ::snt We conclude that lack of HNF-6 results in diabetes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / conclude-01 :ARG0 (w / we) :ARG1 (r / result-01 :ARG1 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "HNF-6") :xref (x / xref :value "UNIPROT:HNF6_HUMAN" :prob "1.002"))) :ARG2 (d2 / disease :name (n2 / name :op1 "diabetes")))) # ::id bio.chicago_2015.83848 # ::date 2015-11-06T03:13:37 # ::file bio_chicago_2015_83848.txt # ::snt Early-onset type-II diabetes mellitus (MODY4) linked to IPF-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (l / link-01 :ARG1 (d2 / disease :name (n2 / name :op1 "diabetes") :mod (m / mellitus) :mod (o / onset :time (e / early)) :mod (t / type :ord (o2 / ordinal-entity :value "2")) :ARG1-of (l2 / label-01 :ARG2 (n3 / name :op1 "MODY4"))) :ARG2 (p / protein :name (n / name :op1 "IPF-1") :xref (x / xref :value "UNIPROT:PDX1_HUMAN" :prob "1.002"))) # ::id bio.chicago_2015.84036 # ::date 2015-11-06T03:15:44 # ::file bio_chicago_2015_84036.txt # ::snt Two Novel Mutations of the Vasopressin Gene Associated with Familial Diabetes Insipidus and Identification of an Asymptomatic Carrier Infant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / associate-01 :ARG1 (m / mutate-01 :quant "2" :ARG1 (g / gene :ARG0-of (e / encode-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "vasopressin") :xref (x / xref :value "PUBCHEM:5772" :prob "8.737748")))) :mod (n / novel)) :ARG2 (a2 / and :op1 (d / disease :name (n4 / name :op1 "familial" :op2 "diabetes")) :op2 (i2 / identify-01 :ARG1 (i3 / infant :mod (s2 / symptom :polarity "-") :mod (c / carrier :mod m))))) # ::id bio.chicago_2015.84144 # ::date 2015-11-06T03:18:45 # ::file bio_chicago_2015_84144.txt # ::snt Confirmation of the genetic association of interleukin-1A with early onset sporadic Alzheimer's disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (c / confirm-01 :ARG1 (a / associate-01 :ARG1 (p / protein :name (n2 / name :op1 "interleukin-1A") :xref (x / xref :value "UNIPROT:IL17_HUMAN" :prob "0.393")) :ARG2 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer") :mod (o / onset :time (e / early)) :mod (s / sporadic)) :mod (g / gene))) # ::id bio.chicago_2015.84177 # ::date 2015-11-06T03:20:03 # ::file bio_chicago_2015_84177.txt # ::snt Specifically, LTD was induced by low-frequency pairing of CF and PF activity, while PF-mediated Ca2+ signals were measured following high-frequency PF activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 15, 2015 (c2 / contrast-01 :ARG1 (i2 / induce-01 :ARG0 (p / pair-01 :ARG1 (a / activity-06 :ARG0 (f4 / fiber :ARG0-of (c / climb-01))) :ARG2 (a2 / activity-06 :ARG0 (f5 / fiber :mod (p3 / parallel))) :mod (f / frequency :ARG1-of (l2 / low-04))) :ARG2 (d / depress-01 :ARG1 (s4 / synapse) :duration (t / term :ARG1-of (l3 / long-03)))) :ARG2 (m / measure-01 :ARG1 (s / signal-07 :ARG0 (s2 / small-molecule :name (n / name :op1 "calcium") :ARG1-of (i / ionize-01 :value "2+") :xref (x / xref :value "PUBCHEM:5460341" :prob "10.601383")) :ARG1-of (m2 / mediate-01 :ARG0 f5)) :ARG1-of (f2 / follow-01 :ARG2 (a3 / activity-06 :ARG0 f5 :mod (f3 / frequency :ARG1-of (h / high-02))))) :ARG1-of (s3 / specific-02)) # ::id bio.chicago_2015.84183 # ::date 2015-11-06T03:27:30 # ::file bio_chicago_2015_84183.txt # ::snt The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 11, 2015 (s / suggest-01 :ARG0 (d / distribute-01 :ARG1 (h / haplotype :mod (p / protein :name (n / name :op1 "DR4") :xref (x1 / xref :value "UNIPROT:2B14_HUMAN" :prob "1.002"))) :location (c / country-region :name (n2 / name :op1 "Sardinia"))) :ARG1 (a / associate-01 :ARG1 (d3 / disease :name (n5 / name :op1 "diabetes") :mod (t / type :ord (o / ordinal-entity :value "1"))) :ARG2 (a2 / and :op1 (l / locus :mod (g / gene :name (n3 / name :op1 "DRB1") :xref (x / xref :value "UNIPROT:RBM45_HUMAN" :prob "1.002"))) :op2 (l2 / locus :mod (g2 / gene :name (n4 / name :op1 "DQB1") :xref (x2 / xref :value "UNIPROT:DQB1_HUMAN" :prob "1.003")))) :mod (p2 / primary))) # ::id bio.chicago_2015.84212 # ::date 2015-11-06T01:51:06 # ::file bio_chicago_2015_84212.txt # ::snt The identification of APP, PS1, and PS2 mutations associated with hereditary Alzheimer's disease [ 34] has increased our understanding of its molecular basis [ 32]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (i / increase-01 :ARG0 (i2 / identify-01 :ARG1 (m / mutate-01 :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "APP") :xref (x / xref :value "UNIPROT:A4_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n3 / name :op1 "PS1") :xref (x1 / xref :value "UNIPROT:PSN1_HUMAN" :prob "1.002")) :op3 (p5 / protein :name (n4 / name :op1 "PS2") :xref (x2 / xref :value "UNIPROT:PSN2_HUMAN" :prob "1.002"))) :ARG1-of (a2 / associate-01 :ARG2 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer") :mod (h / hereditary)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "34")))))) :ARG1 (u / understand-01 :ARG0 (w / we) :ARG1 (b / basis :mod (m2 / molecule) :poss d)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "32")))) # ::id bio.chicago_2015.84243 # ::date 2015-11-08T06:31:12 # ::file bio_chicago_2015_84243.txt # ::snt No association between DLST gene and Alzheimer s disease or Wernicke - Korsakoff syndrome. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / associate-01 :polarity "-" :ARG1 (g / gene :name (n2 / name :op1 "DLST") :xref (x / xref :value "UNIPROT:ODO2_HUMAN" :prob "1.002")) :ARG2 (o / or :op1 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer")) :op2 (d2 / disease :name (n3 / name :op1 "Wernicke-Kirsakoff" :op2 "syndrome")))) # ::id bio.chicago_2015.84567 # ::date 2015-11-08T06:50:49 # ::file bio_chicago_2015_84567.txt # ::snt A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (i / induce-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "insulin" :op2 "2") :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.333")) :ARG0-of (c / cause-01 :ARG1 (f / function-01 :polarity "-" :ARG1 (c2 / cell :name (n3 / name :op1 "beta-cell") :mod (p / pancreas)) :degree (s / severe) :location (o / organism :name (n4 / name :op1 "Mody" :op2 "mouse"))))) :ARG2 (d / disease :name (n2 / name :op1 "diabetes"))) # ::id bio.chicago_2015.84636 # ::date 2015-11-08T06:57:44 # ::file bio_chicago_2015_84636.txt # ::snt The ob gene and leptin Recessive mutations in the mouse obese ( ob) and diabetes ( db) genes result in obesity and diabetes in a syndrome resembling morbid human obesity 3, 7. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m3 / multi-sentence :snt1 (a3 / and :op1 (g / gene :name (n / name :op1 "ob") :xref (x1 / xref :value "UNIPROT:LEP_HUMAN" :prob "0.602")) :op2 (p2 / protein :name (n3 / name :op1 "leptin") :xref (x / xref :value "UNIPROT:LEP_HUMAN" :prob "0.702"))) :snt2 (r / result-01 :ARG1 (m / mutate-01 :ARG1 (a2 / and :op1 (g3 / gene :mod "m2" :mod "m6") :op2 (g2 / gene :mod (m2 / mouse) :mod "d2")) :ARG0-of (r2 / recede-01)) :ARG2 (a / and :op1 (m6 / medical-condition :name (n5 / name :op1 "obesity")) :op2 (d2 / disease :name (n6 / name :op1 "diabetes")) :ARG1-of (m4 / mean-01 :ARG2 (s2 / syndrome :ARG1-of (r3 / resemble-01 :ARG2 (m7 / medical-condition :name (n7 / name :op1 "obesity") :mod (h / human) :mod (m5 / morbid)))))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 "3" :op2 "7")))))) # ::id bio.chicago_2015.84698 # ::date 2015-11-08T07:20:08 # ::file bio_chicago_2015_84698.txt # ::snt Lane 1, GST-Grb2; lane 2, GST only; lane 3, GST-neuron isoform (containing exons AD); and lane 4, GST-astrocyte isoform (containing exons BD). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a / and :op1 (m / macro-molecular-complex :location (l / lane :mod "1") :part (e2 / enzyme :name (n / name :op1 "GST") :xref (x / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :part (p / protein :name (n3 / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :op2 (e / enzyme :name (n2 / name :op1 "GST") :mod (o / only) :location (l2 / lane :mod "2") :xref (x1 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :op3 (i / isoform :name (n4 / name :op1 "GST-neuron") :ARG0-of (c / contain-01 :ARG1 (e3 / exon :name (n5 / name :op1 "AD"))) :location (l3 / lane :mod "3")) :op4 (i2 / isoform :name (n6 / name :op1 "GST-astrocyte") :ARG0-of (c2 / contain-01 :ARG1 (e4 / exon :name (n7 / name :op1 "BD"))) :location (l4 / lane :mod "4"))) # ::id bio.chicago_2015.84741 # ::date 2015-11-08T07:33:13 # ::file bio_chicago_2015_84741.txt # ::snt A P387L Variant in Protein Tyrosine Phosphatase-1B (PTP-1B) Is Associated With Type 2 Diabetes and Impaired Serine Phosphorylation of PTP-1B In Vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (a2 / associate-01 :ARG1 (p3 / protein-segment :name (n4 / name :op1 "P387L") :part-of (p2 / protein :name (n3 / name :op1 "Tyrosine" :op2 "Phosphatase-1B") :xref (x / xref :value "UNIPROT:PTN1_HUMAN" :prob "0.263"))) :ARG2 (a3 / and :op1 (d / disease :wiki "Diabetes_mellitus_type_2" :name (n / name :op1 "type" :op2 "2" :op3 "diabetes")) :op2 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "serine") :part-of p2 :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (i / impair-01) :manner (i2 / in-vitro)))) # ::id bio.chicago_2015.85035 # ::date 2015-11-08T07:47:05 # ::file bio_chicago_2015_85035.txt # ::snt Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / associate-01 :ARG1 (m / mutate-01 :mod "-/-" :ARG1 (p / protein :name (n / name :op1 "PPARgamma") :mod (h / human) :xref (x / xref :value "UNIPROT:PPARG_HUMAN" :prob "0.692")) :ARG0-of (d / dominate-01)) :ARG2 (a2 / and :op1 (r / resist-01 :ARG1 (i / insulin) :degree (s / severe)) :op2 (d2 / disease :name (n3 / name :op1 "diabetes" :op2 "mellitus")) :op3 (h2 / hypertension))) # ::id bio.chicago_2015.85089 # ::date 2015-11-08T07:52:59 # ::file bio_chicago_2015_85089.txt # ::snt Among the genes induced by TNF-alpha, secreted VCAM-1, fibronectin, tenascin C, ceruloplasmin, PAI-1, and adrenomedullin have been associated with type 2 diabetes or an excessive rate of cardiovascular diseases ( 51 - 53). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (a / associate-01 :ARG1 (a2 / and :op1 (g / gene :name (n2 / name :op1 "VCAM-1") :ARG1-of (s / secrete-01) :xref (x5 / xref :value "UNIPROT:VCAM1_HUMAN" :prob "1.002")) :op2 (g2 / gene :name (n3 / name :op1 "fibronectin") :xref (x4 / xref :value "UNIPROT:FINC_HUMAN" :prob "0.703")) :op2 (g6 / gene :name (n7 / name :op1 "adrenomedullin") :xref (x / xref :value "UNIPROT:ADML_HUMAN" :prob "0.702")) :op3 (g3 / gene :name (n4 / name :op1 "tenascin" :op2 "C") :xref (x3 / xref :value "UNIPROT:TENA_HUMAN" :prob "0.673")) :op4 (g4 / gene :name (n5 / name :op1 "ceruloplasmin") :xref (x2 / xref :value "UNIPROT:CERU_HUMAN" :prob "0.702")) :op5 (g5 / gene :name (n6 / name :op1 "PAI-1") :xref (x1 / xref :value "UNIPROT:PAI1_HUMAN" :prob "1.002")) :ARG1-of (i / include-91 :ARG2 (g7 / gene :ARG2-of (i2 / induce-01 :ARG0 (p / protein :name (n8 / name :op1 "TNF-alpha") :xref (x6 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")))))) :ARG2 (o / or :op1 (d / disease :wiki "Diabetes_mellitus_type_2" :name (n / name :op1 "type" :op2 "2" :op3 "diabetes")) :op2 (r / rate :ARG1-of (e / excessive-02) :mod (d2 / disease :mod (c2 / cardiovascular)))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 "51" :op2 "53"))))) # ::id bio.chicago_2015.85434 # ::date 2015-11-08T08:10:11 # ::file bio_chicago_2015_85434.txt # ::snt The findings that both SR-A and SR-BI are expressed by monocytes and macrophages from adult mice and humans, 1, 7- 9 by microglia from newborn mice, 36 and Bell et al 13 , but not by adult mouse or human microglia, and that SR-A, but not SR-BI, is expressed on microglia associated with senile plaques in AD brains, 2, 3 indicate that microglia can regulate SR-A and SR-BI expression by independent mechanisms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (i / indicate-01 :ARG0 (f / find-01 :ARG1 (a / and :op1 (e / express-03 :ARG2 (a3 / and :op1 (p / protein :name (n3 / name :op1 "SR-A") :xref (x1 / xref :value "UNIPROT:SFR19_HUMAN" :prob "0.292")) :op2 (p2 / protein :name (n4 / name :op1 "SR-BI") :xref (x / xref :value "UNIPROT:SCRB1_HUMAN" :prob "1.002"))) :ARG3 (a2 / and :op1 (c / cell :name (n / name :op1 "monocytes")) :op2 (c2 / cell :name (n2 / name :op1 "macrophages")) :source (a5 / and :op1 (m / mouse :mod (a4 / adult)) :op2 (h / human))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 "1" :op2 (v / value-interval :op1 "7" :op2 "9")))))) :op2 (e2 / express-03 :ARG2 a3 :ARG3 (c4 / cell :name (n5 / name :op1 "microglia") :source (m2 / mouse :mod (n6 / newborn))) :ARG1-of (d2 / describe-01 :ARG0 (a7 / and :op1 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "36")) :op2 (p5 / publication-91 :ARG0 (a8 / and :op1 (p6 / person :name (n7 / name :op1 "Bell")) :op2 (p7 / person :mod (o / other))) :ARG1-of (c6 / cite-01 :ARG2 "13")))) :ARG1-of (c7 / contrast-01 :ARG2 (e3 / express-03 :ARG1 (c8 / cell :name (n8 / name :op1 "microglia") :source a5)))) :op3 (e4 / express-03 :ARG2 p :ARG3 (c9 / cell :name (n9 / name :op1 "microglia") :ARG1-of (a9 / associate-01 :ARG2 (p8 / plaque :mod (s / senile) :location (b2 / brain :mod (d3 / disease :wiki "Alzheimer's_disease" :name (n10 / name :op1 "Alzheimer's")))))) :ARG1-of (d4 / describe-01 :ARG0 (p9 / publication :ARG1-of (c10 / cite-01 :ARG2 (a10 / and :op1 "2" :op2 "3")))) :ARG1-of (c11 / contrast-01 :ARG2 (e6 / express-03 :polarity "-" :ARG2 p2))))) :ARG1 (p10 / possible-01 :ARG1 (r / regulate-01 :ARG0 c4 :ARG1 (e5 / express-03 :ARG2 a3) :instrument (m3 / mechanism :ARG0-of (d5 / depend-01 :polarity "-"))))) # ::id bio.chicago_2015.85464 # ::date 2015-11-08T08:43:12 # ::file bio_chicago_2015_85464.txt # ::snt Localization of P. aeruginosa and beads in transported and stationary ASL (mucus) produced by planar CF cultures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (l / localize-01 :ARG1 (a / and :op1 (o / organism :name (n / name :op1 "Pseudomonas" :op2 "aeruginosa")) :op2 (b / bead) :location (l2 / liquid :ARG1-of (m / mean-01 :ARG2 (m2 / mucus)) :mod (s / stationary) :ARG1-of (t2 / transport-01) :ARG1-of (p / produce-01 :ARG0 (c / culture :mod (p2 / planar) :mod (d / disease :name (n3 / name :op1 "cystic" :op2 "fibrosis")))) :mod (s2 / surface :part-of (a2 / airway))))) # ::id bio.chicago_2015.85539 # ::date 2015-11-08T09:08:09 # ::file bio_chicago_2015_85539.txt # ::snt Here we show that mab-23 encodes a DM (Doublesex/ MAB-3) domain transcription factor necessary for specific aspects of differentiation in sex-specific tissues of the male. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (e / encode-01 :ARG0 (g / gene :name (n2 / name :op1 "mab-23") :xref (x / xref :value "UNIPROT:MB213_HUMAN" :prob "0.232")) :ARG1 (p / protein-segment :name (n4 / name :op1 "doublesex/mab-3" :op2 "transcription" :op3 "factor") :ARG1-of (n / need-01 :ARG0 (a / aspect :ARG1-of (s2 / specific-02 :ARG2 (d / differentiate-101 :ARG1 (t / tissue :ARG1-of (s3 / specific-02 :ARG2 (s4 / sex)) :poss (m / male)))))))) :location (h / here)) # ::id bio.chicago_2015.85555 # ::date 2015-11-08T10:49:04 # ::file bio_chicago_2015_85555.txt # ::snt We then used the radiometric technique to test the hypothesis that P. aeruginosa in CF sputum produces acyl-HSL signals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (t2 / technique :mod (r / radiometric)) :ARG2 (t3 / test-01 :ARG0 (w2 / we) :ARG1 (h / hypothesize-01 :ARG0 w :ARG1 (p / produce-01 :ARG0 (o / organism :name (n / name :op1 "P." :op2 "aeruginosa") :location (s / sputum :mod (d / disease :name (n2 / name :op1 "cystic" :op2 "fibrosis")))) :ARG1 (s2 / signal-07 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "acyl-HSL")))))) :time (t / then)) # ::id bio.chicago_2015.85798 # ::date 2015-11-08T11:20:59 # ::file bio_chicago_2015_85798.txt # ::snt Interestingly, it is this stretch of amino acids in GRF2 that contains the PEST region and the DB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (c / contain-01 :ARG0 (s / stretch :poss (a / amino-acid :part-of (p / protein :name (n / name :op1 "GRF2") :xref (x / xref :value "UNIPROT:RGRF2_HUMAN" :prob "1.003"))) :mod (t / this)) :ARG1 (a2 / and :op1 (p2 / protein-segment :name (n2 / name :op1 "PEST")) :op2 (p3 / protein-segment :name (n3 / name :op1 "DB"))) :ARG2-of (i / interest-01)) # ::id bio.chicago_2015.85825 # ::date 2015-11-08T11:31:54 # ::file bio_chicago_2015_85825.txt # ::snt Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (l / link-01 :ARG1 (o / onset :poss (d / disease :name (n2 / name :op1 "type-II" :op2 "diabetes" :op3 "mellitus")) :time (e / early)) :ARG2 (p / protein :name (n / name :op1 "IPF1") :xref (x / xref :value "UNIPROT:PDX1_HUMAN" :prob "1.002"))) # ::id bio.chicago_2015.85926 # ::date 2015-11-08T11:38:43 # ::file bio_chicago_2015_85926.txt # ::snt The PGE2-induced sensitization of the HT MS channels was presumably mediated by the cAMP-dependent protein kinase pathway, because the pretreatment of sensory neurons with H-89 (10 muM), a membrane-permeable inhibitor of protein kinase A, completely blocked the sensitization of the channel by PGE2 (Fig. 7 B,C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / mediate-01 :ARG0 (p / pathway :name (n / name :op1 "cAMP-dependent" :op2 "protein" :op3 "kinase")) :ARG1 (s / sensitize-01 :ARG1 (c / channel :mod (m2 / mechanosensitive) :mod (t2 / threshold :ARG1-of (h / high-02))) :ARG2-of (i2 / induce-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "PGE2") :xref (x2 / xref :value "PUBCHEM:5280360" :prob "15.07648")))) :ARG1-of (p2 / presume-01) :ARG1-of (c2 / cause-01 :ARG0 (b / block-01 :ARG0 (p3 / pretreat-01 :ARG1 (n3 / neuron :mod (s4 / sensory)) :ARG3 (s5 / small-molecule :name (n4 / name :op1 "H-89") :quant (c3 / concentration-quantity :quant "10" :unit (m3 / micromolar)) :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n5 / name :op1 "protein" :op2 "kinase" :op3 "A") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.393"))) :mod (p4 / permeable :mod (m4 / membrane :xref (x1 / xref :value "GO:0016020" :prob "0.8"))) :xref (x3 / xref :value "PUBCHEM:449241" :prob "11.151844"))) :ARG1 (s3 / sensitize-01 :ARG0 s2 :ARG1 c) :ARG1-of (c4 / complete-02))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "7B") :op2 (f2 / figure :mod "7C")))) # ::id bio.chicago_2015.86087 # ::date 2015-11-08T12:20:15 # ::file bio_chicago_2015_86087.txt # ::snt Twenty-three of the 33 sera contained antibodies against PcrV, a protein involved in translocation of type III cytotoxins into eukaryotic cells, and 11 of 33 had antibodies against ExoS, while most CF sera contained antibodies against PopB and PopD, components of the type III apparatus. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c4 / contrast-01 :ARG1 (a2 / and :op1 (c / contain-01 :ARG0 (s / serum :quant "23" :ARG1-of (i / include-91 :ARG2 (s2 / serum :quant "33"))) :ARG1 (a / antibody :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n / name :op1 "PcrV") :ARG1-of (i2 / involve-01 :ARG2 (t / translocate-01 :ARG1 (c8 / cytotoxins) :ARG2 (c3 / cell :mod (e / eukaryotic)))))))) :op2 (h / have-03 :ARG0 (s4 / serum :quant "11" :ARG1-of i) :ARG1 (a3 / antibody :ARG0-of (c5 / counter-01 :ARG1 (p2 / protein :name (n4 / name :op1 "ExoS") :xref (x / xref :value "UNIPROT:EXOS1_HUMAN" :prob "0.232")))))) :ARG2 (c6 / contain-01 :ARG0 (s5 / serum :mod (d / disease :name (n5 / name :op1 "cystic" :op2 "fibrosis")) :quant (m / most)) :ARG1 (a4 / antibody :ARG0-of (c7 / counter-01 :ARG1 (a5 / and :op1 (p3 / protein :name (n6 / name :op1 "PopB")) :op2 (p4 / protein :name (n7 / name :op1 "PopD") :xref (x1 / xref :value "UNIPROT:POPD1_HUMAN" :prob "0.232")) :ARG1-of (i3 / include-91 :ARG2 (p5 / protein-family :name (n8 / name :op1 "type" :op2 "III" :op3 "apparatus")))))))) # ::id bio.chicago_2015.86563 # ::date 2015-11-08T12:38:59 # ::file bio_chicago_2015_86563.txt # ::snt Interaction of Tau Isoforms with Alzheimer's Disease Abnormally Hyperphosphorylated Tau and in Vitro Phosphorylation into the Disease -like Protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (h / hyperphosphorylate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "Tau") :xref (x / xref :value "UNIPROT:TAU_HUMAN" :prob "0.603")) :ARG2 (i / interact-01 :ARG0 (i2 / isoform :mod p2) :ARG1 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"))) :ARG1-of (n3 / normal-02 :polarity "-")) :op2 (p / phosphorylate-01 :ARG1 (p3 / protein :ARG1-of (r / resemble-01 :ARG2 d)) :manner (i3 / in-vitro))) # ::id bio.chicago_2015.87018 # ::date 2015-11-08T12:50:04 # ::file bio_chicago_2015_87018.txt # ::snt Scopolamine has been used as a pharmacological tool for understanding pathological impairments such as AD, because it produces amnesiac effects similar to those identified in AD (Sakhakian et al., 1987 ). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Nov 8, 2015 (c / cause-01 :ARG0 (p3 / produce-01 :ARG0 "s" :ARG1 (a / affect-01 :ARG0 "s" :ARG2 (a2 / amnesia) :ARG1-of (r / resemble-01 :ARG2 (a3 / affect-01 :ARG1-of (i2 / identify-01 :location "d2"))))) :ARG1 (u / use-01 :ARG1 (s / small-molecule :name (n / name :op1 "scopolamine") :xref (x / xref :value "PUBCHEM:5184" :prob "14.794495")) :ARG2 (t / tool :mod (p2 / pharmacologic) :purpose (u2 / understand-01 :ARG1 (i / impair-01 :example (d2 / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's")) :mod (p / pathology))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and :op1 (p5 / person :name (n3 / name :op1 "Sakhakian")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "1987")))) # ::id bio.chicago_2015.87155 # ::date 2015-11-08T13:10:50 # ::file bio_chicago_2015_87155.txt # ::snt If the pancreas is allowed to develop with an intact pdx1 gene, and the pdx1 gene is disrupted only in mature beta cells, diabetes ensues due to impaired beta-cell function ( 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (h / have-condition-91 :ARG1 (e / ensue-01 :ARG1 (d3 / disease :name (n3 / name :op1 "diabetes")) :ARG1-of (c2 / cause-01 :ARG0 (f / function-01 :ARG0 (c4 / cell :name (n4 / name :op1 "beta")) :ARG1-of (i2 / impair-01)))) :ARG2 (a2 / and :op1 (a / allow-01 :ARG1 (d / develop-02 :ARG1 (p / pancreas) :condition (h2 / have-03 :ARG0 p :ARG1 (g / gene :name (n / name :op1 "pdx1") :mod (i / intact) :xref (x / xref :value "UNIPROT:PDX1_HUMAN" :prob "0.603"))))) :op2 (d2 / disrupt-01 :ARG1 g :location (c / cell :name (n2 / name :op1 "beta") :ARG1-of (m / mature-01)) :mod (o / only))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "3")))) # ::id bio.chicago_2015.87157 # ::date 2015-11-08T13:19:59 # ::file bio_chicago_2015_87157.txt # ::snt Neurons in AD brains express fetal antigens, including the fetal type of tau antigen ( 112), the A68 protein recognized by the monoclonal antibody ALZ-50 ( 113), gangliosides recognized by the monoclonal antibody A2B5 ( 114), and a fetal form of alpha-tubulin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (e / express-03 :ARG2 (a / antigen :mod (f / fetus) :ARG2-of (i / include-01 :ARG1 (a2 / and :op1 (a3 / antigen :mod (p / protein :name (n3 / name :op1 "tau") :xref (x1 / xref :value "UNIPROT:TAU_HUMAN" :prob "0.603")) :mod (t / type :mod f) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "112")))) :op2 (p3 / protein :name (n4 / name :op1 "A68") :ARG1-of (r / recognize-01 :ARG0 (a4 / antibody :name (n5 / name :op1 "ALZ-50") :mod (m / monoclonal))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "113")))) :op3 (s / small-molecule :name (n6 / name :op1 "ganglioside") :ARG1-of (r2 / recognize-01 :ARG0 (a5 / antibody :name (n7 / name :op1 "A2B5") :mod m)) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "114"))) :xref (x2 / xref :value "PUBCHEM:445946" :prob "8.633095")) :op4 (f2 / form :mod f :poss (p6 / protein :name (n8 / name :op1 "alpha-tubulin") :xref (x / xref :value "UNIPROT:TBA4A_HUMAN" :prob "0.393")))))) :ARG3 (n / neuron :part-of (b / brain :mod (d / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's"))))) # ::id bio.chicago_2015.87198 # ::date 2015-11-08T13:34:41 # ::file bio_chicago_2015_87198.txt # ::snt To elucidate the role of C-AD in a physiological situation, full-length and C-AD-truncated NDRFs were analysed in the mouse IP3R1 promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / analyze-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "NDRF") :mod (l / length :ARG1-of (f / full-09)) :xref (x1 / xref :value "UNIPROT:NDF2_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "NDRF") :ARG1-of (t / truncate-01 :ARG2 (p3 / protein-segment :name (n3 / name :op1 "C-AD"))) :xref (x / xref :value "UNIPROT:NDF2_HUMAN" :prob "1.002"))) :purpose (e / elucidate-01 :ARG1 (r / role :ARG1-of (h / have-03 :ARG0 p3) :topic (s / situation :mod (p4 / physiology)))) :location (m2 / molecular-physical-entity :ARG0-of (p5 / promote-01 :ARG1 (p6 / protein :name (n4 / name :op1 "IP3R1") :mod (m / mouse) :xref (x2 / xref :value "UNIPROT:ITPR1_HUMAN" :prob "0.682"))))) # ::id bio.chicago_2015.87332 # ::date 2015-11-08T13:47:57 # ::file bio_chicago_2015_87332.txt # ::snt The major known genetic risk factor for late-onset AD is the 4 allele of the apolipoprotein E (ApoE) gene (ApoE4); however, at least half of the people who develop AD do not carry ApoE4, and not all who carry ApoE4 develop AD. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (m / multi-sentence :snt1 (a2 / allele :quant "4" :part-of (g / gene :name (n / name :op1 "apolipoprotein" :op2 "E") :xref (x1 / xref :value "UNIPROT:APOE_HUMAN" :prob "0.702")) :domain (f / factor :ARG1-of (m2 / major-02) :mod (g2 / genetics) :ARG1-of (k / know-02) :mod (r / risk-01 :ARG2 (o / onset :mod (l / late) :mod (d / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's")))))) :snt2 (h / have-concession-91 :ARG1 (a3 / and :op1 (c / carry-01 :polarity "-" :ARG0 (p / person :quant (a / at-least :op1 (h2 / half)) :ARG1-of (i / include-91 :ARG2 (p2 / person :ARG0-of (d2 / develop-02 :ARG1 "d4")))) :ARG1 (g3 / gene :name (n3 / name :op1 "ApoE4") :xref (x / xref :value "UNIPROT:APOE_HUMAN" :prob "0.262"))) :op2 (d3 / develop-02 :polarity "-" :ARG0 (p4 / person :mod (a4 / all) :ARG0-of (c2 / carry-01 :ARG1 g3)) :ARG1 (d4 / disease :wiki "Alzheimer's_disease" :name (n4 / name :op1 "Alzheimer's")))))) # ::id bio.chicago_2015.87380 # ::date 2015-11-08T14:01:38 # ::file bio_chicago_2015_87380.txt # ::snt In addition, AD patients have increased serum levels of TNF and IL-6 have been established in [ 20 and 47]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-org-role-91 :ARG2 (p2 / patient)) :mod (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer's"))) :ARG1 (l / level :mod (s / serum) :ARG1-of (i / increase-01) :quant-of (a / and :op1 (p3 / protein :name (n2 / name :op1 "TNF") :xref (x1 / xref :value "UNIPROT:TNFA_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (e / establish-01)) :ARG1-of (a2 / add-02) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "20" :op2 "47"))))) # ::id bio.chicago_2015.87430 # ::date 2015-11-08T14:11:43 # ::file bio_chicago_2015_87430.txt # ::snt Indeed, Lad/Ad interacts with the receptor tyrosine kinases PDGFR and vascular endothelial cell growth factor receptor (VEGFR) KDR, as well as several components of receptor signaling networks, including Grb2, phosphatidylinositol 3-kinase, and phospholipase Cgamma ( PLC-gamma) ( 11, 41, 58). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / interact-01 :ARG0 (p / protein :name (n2 / name :op1 "Lad/Ad")) :ARG1 (a / and :op1 (p2 / protein :name (n3 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinases" :op4 "PDGFR") :xref (x / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.362")) :op2 (p3 / protein :name (n4 / name :op1 "vascular" :op2 "endothelial" :op3 "cell" :op4 "growth" :op5 "factor" :op6 "receptor") :xref (x2 / xref :value "UNIPROT:NRP2_HUMAN" :prob "0.392")) :op3 (c / component :quant (s2 / several) :poss (n / network :ARG0-of (s / signal-07) :ARG2-of (i2 / include-01 :ARG1 (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "Grb2") :xref (x4 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (e / enzyme :name (n6 / name :op1 "phosphatidylinositol" :op2 "3-kinase") :xref (x3 / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.701")) :op3 (e2 / enzyme :name (n7 / name :op1 "phospholipase" :op2 "Cgamma") :xref (x1 / xref :value "UNIPROT:PLCG1_HUMAN" :prob "0.393"))))))) :mod (i3 / indeed) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "11" :op2 "41" :op3 "58"))))) # ::id bio.chicago_2015.87520 # ::date 2015-11-08T14:30:53 # ::file bio_chicago_2015_87520.txt # ::snt Importantly, at least 10 of those known genes have been previously characterized in AD, which include p21ras, mitogen-activated protein kinase (MAPK) kinase 1, alpha-enolase 1, carbonyl reductase, apolipoprotein D, transferrin, phosphotriesterase protein, glutamate dehydrogenase, calpain, and Cu/Zn superoxide dismutase (SOD1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (c / characterize-01 :ARG1 (g / gene :quant (a / at-least :op1 "10") :ARG1-of (i / include-91 :ARG2 (g2 / gene :ARG1-of (k / know-01) :ARG2-of (i2 / include-01 :ARG1 (a3 / and :op1 (g3 / gene :name (n4 / name :op1 "p21ras") :xref (x4 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :op2 (g4 / gene :name (n5 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase" :op4 "1") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.703")) :op3 (g5 / gene :name (n6 / name :op1 "alpha-enolase" :op2 "1") :xref (x2 / xref :value "UNIPROT:ENOA_HUMAN" :prob "0.392")) :op4 (g6 / gene :name (n7 / name :op1 "carbonyl" :op2 "reductase") :xref (x1 / xref :value "UNIPROT:DCXR_HUMAN" :prob "0.392")) :op5 (g7 / gene :name (n8 / name :op1 "apolipoprotein" :op2 "D") :xref (x / xref :value "UNIPROT:APOD_HUMAN" :prob "0.702")) :op6 (g8 / gene :name (n9 / name :op1 "transferrin") :xref (x6 / xref :value "UNIPROT:TRFE_HUMAN" :prob "0.702")) :op7 (g9 / gene :name (n10 / name :op1 "phosphotriesterase") :xref (x5 / xref :value "UNIPROT:PTER_HUMAN" :prob "0.312")) :op8 (g10 / gene :name (n11 / name :op1 "glutamate" :op2 "dehydrogenase") :xref (x8 / xref :value "UNIPROT:B3KT18_HUMAN" :prob "0.701")) :op9 (g11 / gene :name (n12 / name :op1 "calpain") :xref (x7 / xref :value "UNIPROT:CAN3_HUMAN" :prob "0.342")) :op10 (g12 / gene :name (n13 / name :op1 "Cu/Zn" :op2 "superoxide" :op3 "dismutase")))) :mod (t / that)))) :time (p3 / previous) :location (d / disease :wiki "Alzheimer's_disease" :name (n3 / name :op1 "Alzheimer's")) :mod (i3 / important)) # ::id bio.chicago_2015.88023 # ::date 2015-11-08T14:44:07 # ::file bio_chicago_2015_88023.txt # ::snt Furthermore, cortical neurons of AD patients express p75NTR, but this receptor is only infrequently expressed in cortical neurons of nonaffected aged-matched controls ( 15). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op2 (c / contrast-01 :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "75NTR") :ARG3-of (p4 / phosphorylate-01)) :ARG3 (n / neuron :mod (c2 / cortex) :part-of (p / person :ARG0-of (h / have-org-role-91 :ARG2 (p2 / patient)) :mod (d / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's"))))) :ARG2 (e2 / express-03 :ARG2 p3 :ARG3 (n4 / neuron :mod c2 :poss (c3 / control :ARG1-of (a2 / affect-01 :polarity "-") :ARG1-of (m / match-01 :ARG2 (a3 / age)))) :ARG1-of (f / frequent-02 :polarity "-" :mod (o / only)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 "14")))) # ::id bio.chicago_2015.88844 # ::date 2015-11-08T14:51:27 # ::file bio_chicago_2015_88844.txt # ::snt Considering the increasing evidence for neuronal apoptosis in Alzheimer's disease ( 50-54), the transcriptional control of PS1 and its down-regulation by p53 may relate directly to the pathology of the disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (p / possible-01 :ARG1 (r / relate-01 :ARG1 (a / and :op1 (c / control-01 :ARG0 "p4" :ARG1 (p3 / protein :name (n2 / name :op1 "PS1") :xref (x / xref :value "UNIPROT:PSN1_HUMAN" :prob "1.002")) :ARG0-of (t / transcribe-01)) :op2 (d4 / downregulate-01 :ARG1 p3 :ARG2 (p4 / protein :name (n3 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :ARG2 (p2 / pathology :mod "d2") :ARG1-of (d3 / direct-02)) :condition (c2 / consider-02 :ARG1 (e / evidence-01 :ARG1 (a2 / apoptosis :mod (n4 / neuron) :location (d2 / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"))) :ARG1-of (i / increase-01)) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 "50" :op2 "54")))))) # ::id bio.chicago_2015.88939 # ::date 2015-11-08T05:13:19 # ::file bio_chicago_2015_88939.txt # ::snt Recombinant Adenoviral Vectors and Adenoviral Infection-- The recombinant adenovirus vector AdCox-2, expressing COX-2, was constructed from replication-deficient adenovirus type 5(Ad5) with deletions in the E1 and E3 genes, Ad dl327, and a plasmid containing Ad5 sequences from 22 to 5790 with a deletion of the E1 region from bp 342 to 3523, a polycloning site under control of the cytomegalovirus promoter, the COX-2 cDNA, and the simian virus 40 polyadenylation signal. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / multi-sentence :snt1 (a / and :op1 (v / vector :mod (a6 / adenovirus :ARG3-of (r / recombine-01))) :op2 (i / infect-01 :ARG2 (a7 / adenovirus))) :snt2 (c2 / construct-01 :ARG1 (v3 / vector :name (n3 / name :op1 "AdCox-2") :mod (a2 / adenovirus :ARG3-of (r2 / recombine-01)) :ARG1-of (e / express-03 :ARG2 (e2 / enzyme :name (n4 / name :op1 "COX-2") :xref (x1 / xref :value "UNIPROT:PGH2_HUMAN" :prob "1.003")))) :ARG2 (a4 / and :op1 (a8 / adenovirus :mod "5" :ARG0-of (l / lack-01 :ARG1 (r3 / replicate-01 :ARG1 a8)) :ARG2-of (d / delete-01 :ARG1 (a3 / and :op1 (g / gene :name (n6 / name :op1 "E1") :xref (x / xref :value "UNIPROT:Q8V9K6_HUMAN" :prob "1.001")) :op2 (g2 / gene :name (n7 / name :op1 "E3"))))) :op2 (s / small-molecule :name (n8 / name :op1 "Ad-dl327")) :op3 (p / plasmid :ARG0-of (c3 / contain-01 :ARG1 (s2 / sequence :mod (v6 / value-interval :op1 "22" :op2 "5790") :mod (d3 / dna-sequence :name (n9 / name :op1 "Ad5") :ARG2-of (d2 / delete-01 :ARG1 (p3 / protein-segment :mod (v7 / value-interval :op1 "342" :op2 "3523") :ARG1-of (m2 / mean-01 :ARG2 (s3 / site :mod (p4 / polyclone) :ARG1-of (c4 / control-01 :ARG0 (a5 / and :op1 (n5 / nucleic-acid :name (n / name :op1 "cDNA") :ARG0-of (p7 / promote-01 :ARG1 (v8 / virus :name (n13 / name :op1 "cytomegalovirus"))) :mod e2) :op2 (s4 / signal-07 :ARG0 (s5 / small-molecule :name (n12 / name :op1 "simian" :op2 "virus" :op3 "40") :xref (x2 / xref :value "PUBCHEM:71571515" :prob "1.531738")) :mod (p6 / polyadenylation)))))) :part-of g))))))))) # ::id biomed_0004.1 # ::date 2015-07-28T06:55:43 # ::file biomed_0004_1.txt # ::snt The receptor tyrosine kinase EGFR binds the growth factor ligand EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (b / bind-01 :ARG1 (r / receptor-tyrosine-kinase :name (n3 / name :op1 "EGFR")) :ARG2 (g / growth-factor-ligand :name (n / name :op1 "EGF"))) # ::id biomed_0004.2 # ::date 2015-07-28T10:28:16 # ::file biomed_0004_2.txt # ::snt The EGFR-EGF complex binds another EGFR-EGF complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (b / bind-01 :ARG1 (m / macro-molecular-complex :part (e / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :part (p / protein :wiki "Epidermal_growth_factor" :name (n2 / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG2 (m2 / macro-molecular-complex :part e :part p :mod (a / another))) # ::id biomed_0004.3 # ::date 2015-07-28T10:41:40 # ::file biomed_0004_3.txt # ::snt EGFR, bound to EGFR, transphosphorylates itself on a tyrosine residue. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (t / transphosphorylate-01 :ARG0 (e / enzyme :name (n / name :op1 "EGFR") :ARG1-of (b / bind-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1 (r / residue :mod (a / amino-acid :name (n2 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :part-of e)) # ::id biomed_0004.4 # ::date 2015-07-28T10:50:58 # ::file biomed_0004_4.txt # ::snt The adaptor protein GRB2 can bind EGFR that is phosphorylated on tyrosine. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n2 / name :op1 "GRB2") :mod (a2 / adaptor) :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "1.004")) :ARG2 (e / enzyme :name (n3 / name :op1 "EGFR") :ARG3-of (p3 / phosphorylate-01 :ARG1 (a / amino-acid :name (n4 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) # ::id biomed_0004.5 # ::date 2015-07-28T10:57:58 # ::file biomed_0004_5.txt # ::snt EGFR-bound GRB2 binds SOS1 and the SOS1-GRB2 complex binds HRAS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "GRB2") :ARG1-of (b2 / bind-01 :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "1.004")) :ARG2 (p2 / protein :name (n3 / name :op1 "SOS1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "1.004"))) :op2 (b3 / bind-01 :ARG1 (m / macro-molecular-complex :part p2 :part p) :ARG2 (e2 / enzyme :name (n4 / name :op1 "HRAS") :xref (x3 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))) # ::id biomed_0004.6 # ::date 2015-07-28T11:02:51 # ::file biomed_0004_6.txt # ::snt HRAS, bound to SOS1, binds GTP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (b / bind-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HRAS") :ARG1-of (b2 / bind-01 :ARG2 (p / protein :name (n3 / name :op1 "SOS1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "1.004"))) :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG2 (s / small-molecule :name (n4 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) # ::id biomed_0004.7 # ::date 2015-07-28T11:06:15 # ::file biomed_0004_7.txt # ::snt HRAS, bound to GTP, binds RAF1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (b / bind-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HRAS") :ARG1-of (b2 / bind-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :ARG2 (e2 / enzyme :name (n4 / name :op1 "RAF1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.004"))) # ::id biomed_0004.8 # ::date 2015-07-28T11:08:03 # ::file biomed_0004_8.txt # ::snt RAF1, bound to HRAS, phosphorylates itself at Thr491 and Ser494. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "491" :name (n3 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a3 / amino-acid :mod "494" :name (n4 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of "e") :ARG2 (e / enzyme :name (n / name :op1 "RAF1") :ARG1-of (b / bind-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "HRAS") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003"))) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.004"))) # ::id biomed_0004.9 # ::date 2015-07-28T11:12:36 # ::file biomed_0004_9.txt # ::snt RAF1 phosphorylated at Thr491 and Ser494 is activated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "RAF1") :ARG3-of (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "491" :name (n2 / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a4 / amino-acid :mod "494" :name (n3 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.004"))) # ::id biomed_0004.10 # ::date 2015-07-28T11:16:55 # ::file biomed_0004_10.txt # ::snt Active RAF1 phosphorylates MEK1 at Ser218 and Ser222. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "218" :name (n / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :mod "222" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG2 (e2 / enzyme :name (n4 / name :op1 "RAF1") :ARG0-of (a4 / activity-06) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.004"))) # ::id biomed_0004.11 # ::date 2015-07-28T11:19:40 # ::file biomed_0004_11.txt # ::snt MEK1 phosphorylated at Ser218 and Ser222 is activated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK1") :ARG3-of (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "218" :name (n2 / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "222" :name (n3 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")))) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) # ::id biomed_0004.12 # ::date 2015-07-28T11:21:29 # ::file biomed_0004_12.txt # ::snt Active MEK1 phosphorylates ERK2 at Tyr187 and Thr185. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a / and :op1 (a3 / amino-acid :mod "187" :name (n2 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a4 / amino-acid :mod "185" :name (n3 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (e2 / enzyme :name (n4 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG2 (e / enzyme :name (n / name :op1 "MEK1") :ARG0-of (a2 / activity-06) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) # ::id biomed_0004.13 # ::date 2015-07-28T11:24:07 # ::file biomed_0004_13.txt # ::snt Ras bound to GTP binds to BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (b2 / bind-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (e2 / enzyme :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id biomed_0004.14 # ::date 2015-07-28T11:25:12 # ::file biomed_0004_14.txt # ::snt BRAF bound to Ras transphosphorylates itself at Thr598 and Ser601. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (t / transphosphorylate-01 :ARG0 (e / enzyme :name (n2 / name :op1 "BRAF") :ARG1-of (b / bind-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (a / and :op1 (a2 / amino-acid :mod "598" :name (n4 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a3 / amino-acid :mod "601" :name (n / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of e)) # ::id biomed_0004.15 # ::date 2015-07-28T11:27:51 # ::file biomed_0004_15.txt # ::snt Phosphorylation at Thr598 and Ser601 activates BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / activate-01 :ARG0 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "598" :name (n / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a4 / amino-acid :mod "601" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of "e")) :ARG1 (e / enzyme :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id biomed_0004.16 # ::date 2015-07-28T11:29:40 # ::file biomed_0004_16.txt # ::snt BRAF is activated by being phosphorylated at Thr598 and Ser601. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / activate-01 :ARG0 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "598" :name (n2 / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a4 / amino-acid :mod "601" :name (n3 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of "e")) :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id biomed_0004.17 # ::date 2015-07-28T11:32:19 # ::file biomed_0004_17.txt # ::snt Active BRAF phosphorylates MEK1 at Ser218 and Ser222. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "218" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "222" :name (n3 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of (e2 / enzyme :name (n4 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG2 (e / enzyme :name (n / name :op1 "BRAF") :ARG0-of (a / activity-06) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id biomed_0004.18 # ::date 2015-07-28T11:34:12 # ::file biomed_0004_18.txt # ::snt Phosphorylation at Ser218 and Ser222 activates MEK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / activate-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "218" :name (n / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "222" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of "e")) :ARG1 (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) # ::id biomed_0004.19 # ::date 2015-07-28T11:35:32 # ::file biomed_0004_19.txt # ::snt MEK1 is activated by being phosphorylated at Ser218 and Ser222. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / activate-01 :ARG0 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "218" :name (n2 / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "222" :name (n3 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of "e")) :ARG1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) # ::id biomed_0004.20 # ::date 2015-07-28T11:37:24 # ::file biomed_0004_20.txt # ::snt Active MEK1 phosphorylates ERK2 at Thr202 and Thr185. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "202" :name (n2 / name :op1 "threonine") :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a4 / amino-acid :mod "185" :name (n3 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :part-of (e2 / enzyme :name (n4 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG2 (e / enzyme :name (n / name :op1 "MEK1") :ARG0-of (a / activity-06) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) # ::id biomed_0004.21 # ::date 2015-07-28T11:39:01 # ::file biomed_0004_21.txt # ::snt BRAF bound to Ras transphosphorylates itself at Thr598. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (t / transphosphorylate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "BRAF") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (a / amino-acid :mod "598" :name (n3 / name :op1 "threonine") :part-of e2 :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252"))) # ::id biomed_0004.22 # ::date 2015-07-28T11:40:37 # ::file biomed_0004_22.txt # ::snt BRAF bound to Ras transphosphorylates itself at Ser601. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (t / transphosphorylate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "BRAF") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (a / amino-acid :mod "601" :name (n4 / name :op1 "serine") :part-of e2 :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) # ::id biomed_0004.23 # ::date 2015-07-28T11:42:48 # ::file biomed_0004_23.txt # ::snt Active BRAF phosphorylates MEK1 at Ser222. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "222" :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e / enzyme :name (n / name :op1 "BRAF") :ARG0-of (a / activity-06) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id biomed_0004.24 # ::date 2015-07-28T11:44:03 # ::file biomed_0004_24.txt # ::snt Active MEK1 phosphorylates ERK2 at Thr202. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "202" :name (n2 / name :op1 "threonine") :part-of (e2 / enzyme :name (n3 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 (e / enzyme :name (n / name :op1 "MEK1") :ARG0-of (a / activity-06) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) # ::id biomed_0004.25 # ::date 2015-07-28T11:45:10 # ::file biomed_0004_25.txt # ::snt Active MEK1 phosphorylates ERK2 at Thr185. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "185" :name (n2 / name :op1 "threonine") :part-of (e2 / enzyme :name (n3 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 (e / enzyme :name (n / name :op1 "MEK1") :ARG0-of (a / activity-06) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) # ::id biomed_0004.26 # ::date 2015-07-28T11:46:24 # ::file biomed_0004_26.txt # ::snt Phosphorylation of BRAF at Thr598 and Ser601 activates it. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / activate-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "598" :wiki "Threonine" :name (n / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a4 / amino-acid :mod "601" :wiki "Serine" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of (e / enzyme :wiki "-" :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1 e) # ::id biomed_0004.27 # ::date 2015-07-28T11:48:52 # ::file biomed_0004_27.txt # ::snt Active BRAF phosphorylates MEK1 at Ser218. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "218" :name (n / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e / enzyme :name (n2 / name :op1 "BRAF") :ARG0-of (a2 / activity-06) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id biomed_0004.28 # ::date 2015-07-28T11:50:06 # ::file biomed_0004_28.txt # ::snt Phosphorylation of MEK1 at Ser218 and Ser222 activates it. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (a / activate-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod "218" :name (n / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a4 / amino-acid :mod "222" :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :part-of (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG1 e) # ::id pmid_1177_7939.30 # ::date 2015-02-26T03:44:12 # ::file pmid_1177_7939_30.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 30, 2015 (t2 / thing :ARG2-of (r / result-01)) # ::id pmid_1177_7939.31 # ::date 2015-02-26T23:04:30 # ::file pmid_1177_7939_31.txt # ::snt The S/E/E8 complex exists under physiological conditions # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / exist-01 :ARG1 (m / macro-molecular-complex :part (s / slash :op1 (p / protein :name (n / name :op1 "S") :xref (x / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :op2 (p2 / protein :name (n2 / name :op1 "E")) :op2 (p3 / protein :name (n3 / name :op1 "E8")))) :condition (p4 / physiology)) # ::id pmid_1177_7939.32 # ::date 2015-02-27T00:14:25 # ::file pmid_1177_7939_32.txt # ::snt In previous studies, we showed that Sos-1, E3b1, and Eps8 could form a trimeric complex in vivo upon concomitant overexpression of the three proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (f / form-01 :ARG0 (a / and :op1 (p2 / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :op2 (p3 / protein :name (n2 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op3 (e2 / enzyme :name (n3 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :ARG1 (m / macro-molecular-complex :mod (t / trimeric)) :ARG1-of (p / possible-01) :manner (i / in-vivo) :condition (o / overexpress-01 :ARG1 a :ARG2 (c / concomitant))) :medium (s2 / study :time (p5 / previous))) # ::id pmid_1177_7939.33 # ::date 2015-02-27T01:01:41 # ::file pmid_1177_7939_33.txt # ::snt However, we failed to detect the existence of an endogenous S/E/E8 complex (Scita et al., 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (f / fail-01 :ARG1 (w / we) :ARG2 (d / detect-01 :ARG0 w :ARG1 (e / exist-01 :ARG1 (m / macro-molecular-complex :mod (e2 / endogenous) :part (s / slash :op1 (p / protein :name (n / name :op1 "S") :xref (x / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :op2 (p2 / protein :name (n2 / name :op1 "E")) :op3 (p3 / protein :name (n3 / name :op1 "E8"))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a / and :op1 (p5 / person :name (n4 / name :op1 "Scita")) :op2 (p6 / person :mod (o / other))) :time (d3 / date-entity :year "1999")))) # ::id pmid_1177_7939.34 # ::date 2015-02-28T11:06:35 # ::file pmid_1177_7939_34.txt # ::snt We reasoned that this could be due to the low efficiency of the immunoprecipitating antibodies used. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 26, 2015 (r / reason-01 :ARG0 (w / we) :ARG1 (p2 / possible-01 :ARG1 (c / cause-01 :ARG0 (e / efficient-01 :ARG1 (a / antibody :ARG1-of (u / use-01 :ARG2 (i2 / immunoprecipitate-01))) :ARG1-of (l / low-04)) :ARG1 (t / this)))) # ::id pmid_1177_7939.35 # ::date 2015-03-01T22:52:23 # ::file pmid_1177_7939_35.txt # ::snt We thus sought to exploit the availability of eps8−/− fibroblasts to circumvent this problem. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (s / seek-01 :ARG0 (w / we) :ARG1 (e / exploit-01 :ARG0 w :ARG1 (a / available-02 :ARG2 (f2 / fibroblast :ARG0-of (c3 / contain-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "eps8") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) :purpose (c2 / circumvent-01 :ARG0 w :ARG1 (p / problem :mod (t / this)))) :ARG0-of (c / cause-01)) # ::id pmid_1177_7939.36 # ::date 2015-03-02T23:59:41 # ::file pmid_1177_7939_36.txt # ::snt To this end, we performed immunoprecipitation experiments using eps8−/− fibroblasts in which the expression of Eps8 was restored, to physiological levels, with an expression vector encoding a myc epitope-tagged Eps8 (−/− [Eps8myc] cells). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / perform-02 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG2 (i / immunoprecipitate-01 :ARG2 (f / fibroblast :location-of (r / restore-01 :ARG1 (e2 / express-03 :ARG2 (e4 / enzyme :name (n2 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :ARG2 (l / level :mod (p3 / physiology)) :instrument (v / vector :ARG0-of (e3 / encode-01 :ARG1 (e6 / enzyme :name (n / name :op1 "Eps8") :ARG1-of (t2 / tag-01 :ARG2 (e7 / epitope :mod (p2 / protein :name (n3 / name :op1 "myc") :xref (x3 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")))) :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :ARG2-of (e8 / express-03))) :ARG0-of (c2 / contain-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "eps8") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))))) :purpose (t / this)) # ::id pmid_1177_7939.37 # ::date 2015-03-02T01:22:46 # ::file pmid_1177_7939_37.txt # ::snt We selected transfected clones in which the levels of expression of Eps8myc were very similar to those present in wild-type fibroblasts (Fig. 1 A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (s / select-01 :ARG0 (w / we) :ARG1 (c / clone :ARG1-of (t / transfect-01) :ARG3-of (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Eps8myc") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.213")) :degree (l / level :ARG1-of (r / resemble-01 :ARG2 (l2 / level :ARG1-of (p / present-02 :ARG2 (f / fibroblast :mod (w2 / wild-type)))) :degree (v / very))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1A"))))) # ::id pmid_1177_7939.38 # ::date 2015-03-02T22:29:39 # ::file pmid_1177_7939_38.txt # ::snt Endogenous Sos-1 and E3b1 could be detected in anti-myc immunoprecipitates from lysates of Eps8myc-reconstituted, but not from eps8−/− fibroblasts (Fig. 1 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (p / possible-01 :ARG1 (d / detect-01 :ARG1 (a / and :op1 (p3 / protein :name (n / name :op1 "Sos-1") :xref (x3 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :op2 (p4 / protein :name (n2 / name :op1 "E3b1") :xref (x4 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :mod (e / endogenous)) :location (p5 / protein :ARG1-of (i3 / immunoprecipitate-01 :ARG2 (l / lysate :source (f3 / fibroblast :ARG0-of (c5 / contain-01 :ARG1 (p7 / protein :name (n7 / name :op1 "Eps8myc") :ARG1-of (r / reconstitute-01) :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.213")))))) :ARG0-of (c / counter-01 :ARG1 (p2 / protein :name (n3 / name :op1 "myc") :xref (x2 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")))) :ARG1-of (c4 / contrast-01 :ARG2 (d2 / detect-01 :polarity "-" :ARG1 a :location (p6 / protein :ARG1-of (i / immunoprecipitate-01 :ARG2 (f / fibroblast :ARG0-of (c2 / contain-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "eps8") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "1B"))) # ::id pmid_1177_7939.39 # ::date 2015-03-03T01:38:00 # ::file pmid_1177_7939_39.txt # ::snt To determine whether E3b1 mediates the interaction between Eps8 and Sos-1, as it would be expected according to the tricomplex model, we performed coimmunoprecipitation experiments under conditions in which the association between Eps8 and E3b1 was disrupted. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (p / perform-02 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG2 (c / coimmunoprecipitate-01) :condition (d / disrupt-01 :ARG1 (a / associate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :ARG2 (p3 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))))) :purpose (d2 / determine-01 :ARG0 w :ARG1 (m / mediate-01 :mode "interrogative" :ARG0 p3 :ARG1 (i / interact-01 :ARG0 (a2 / and :op1 e3 :op2 (p4 / protein :name (n3 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :ARG1-of (e2 / expect-01 :ARG1-of (s / say-01 :ARG0 (m2 / model :mod (t / tricomplex))))))) # ::id pmid_1177_7939.40 # ::date 2015-03-04T01:03:03 # ::file pmid_1177_7939_40.txt # ::snt The binding site of E3b1 to the SH3 domain of Eps8 was previously mapped to the amino acid sequence, PPPPPVDYTEDEE, where the D and the Y residues are critical for efficient binding (Mongiovi et al., 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / map-02 :ARG1 (p / protein-segment :part-of (p3 / protein :name (n8 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1-of (b / bind-01 :ARG2 (p2 / protein-segment :name (n2 / name :op1 "SH3" :op2 "domain") :part-of (e / enzyme :name (n3 / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) :ARG2 (d3 / dna-sequence :name (n / name :op1 "PPPPPVDYTEDEE") :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (r3 / residue :mod (a4 / amino-acid :name (n5 / name :op1 "aspartic" :op2 "acid") :xref (x3 / xref :value "PUBCHEM:424" :prob "7.741247"))) :op2 (r / residue :mod (a5 / amino-acid :name (n6 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (c / critical-02 :ARG3 (e2 / efficient-01 :ARG2 b)))) :mod (a / amino-acid)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n7 / name :op1 "Mongiovi")) :op2 (p6 / person :mod (o / other))) :time (d2 / date-entity :year "1999"))) :time (p7 / previous)) # ::id pmid_1177_7939.41 # ::date 2015-03-04T02:21:56 # ::file pmid_1177_7939_41.txt # ::snt Thus, a peptide encompassing this region should specifically disrupt the Eps8–E3b1 association. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / infer-01 :ARG1 (r / recommend-01 :ARG1 (d / disrupt-01 :ARG0 (p / peptide :ARG0-of (e / encompass-01 :ARG1 (r2 / region :mod (t / this)))) :ARG1 (a / associate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :ARG2 (p3 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG1-of (s / specific-02)))) # ::id pmid_1177_7939.42 # ::date 2015-03-05T00:13:57 # ::file pmid_1177_7939_42.txt # ::snt Indeed, no E3b1could be recovered in anti-myc immunoprecipitates from lysates of Eps8myc-reconstituted cells, when the immunoprecipitation was performed in the presence of an excess of the competing peptide. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (p / possible-01 :polarity "-" :ARG1 (r / recover-02 :ARG1 (p2 / protein :name (n / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :location (p6 / protein :ARG1-of (i3 / immunoprecipitate-01 :ARG2 (l / lysate :source (c5 / cell :ARG0-of (c6 / contain-01 :ARG1 (p8 / protein :name (n5 / name :op1 "Eps8myc") :ARG1-of (r2 / reconstitute-01) :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.213"))))) :ARG0-of (c3 / counter-01 :ARG1 (p4 / protein :name (n4 / name :op1 "myc") :xref (x1 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")))))) :mod (i2 / indeed) :condition (p3 / perform-02 :ARG1 (i / immunoprecipitate-01) :condition (p7 / present-02 :ARG1 (e / exceed-01 :ARG0 (p5 / peptide :ARG0-of (c4 / compete-01)))))) # ::id pmid_1177_7939.43 # ::date 2015-03-06T22:25:08 # ::file pmid_1177_7939_43.txt # ::snt The association was, however, preserved when a control peptide, bearing a Y→A substitution and unable to bind to Eps8 (Mongiovi et al., 1999), was used (Fig. 1 C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jun 1, 2015 (c / contrast-01 :ARG2 (p / preserve-01 :ARG1 (a / associate-01) :condition (u / use-01 :ARG1 (p2 / peptide :purpose (c2 / control-01) :ARG0-of (b / bear-01 :ARG1 (s / substitute-01 :ARG1 (a3 / amino-acid :name (n2 / name :op1 "alanine") :xref (x1 / xref :value "PUBCHEM:602" :prob "10.089661")) :ARG2 (a2 / amino-acid :name (n / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :ARG1-of (b2 / bind-01 :ARG2 (e / enzyme :name (n3 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :ARG1-of (p4 / possible-01 :polarity "-"))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1C"))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n4 / name :op1 "Mongiovi")) :op2 (p7 / person :mod (o / other))) :time (d2 / date-entity :year "1999"))))) # ::id pmid_1177_7939.44 # ::date 2015-03-07T00:28:58 # ::file pmid_1177_7939_44.txt # ::snt Similarly, no Sos-1 could be recovered in anti-myc immunoprecipitates in the presence of the competing, but not of the control, peptide (Fig. 1 C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / possible-01 :polarity "-" :ARG1 (r2 / recover-02 :ARG1 (p2 / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :location (p5 / protein :ARG0-of (c / counter-01 :ARG1 (p3 / protein :name (n2 / name :op1 "myc") :xref (x1 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604"))) :ARG1-of (i / immunoprecipitate-01))) :ARG1-of (r / resemble-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1C")) :ARG1-of (c4 / contrast-01 :ARG2 (p7 / possible-01 :ARG1 r2 :condition (p6 / peptide :ARG0-of (c3 / control-01)))) :condition (p8 / present-02 :ARG1 (p4 / peptide :ARG0-of (c2 / compete-01)))) # ::id pmid_1177_7939.45 # ::date 2015-03-07T02:10:56 # ::file pmid_1177_7939_45.txt # ::snt Thus, under physiological conditions, the coimmunoprecipitation of Eps8 and Sos-1 depends on the integrity of the Eps8–E3b1 interaction, pointing to the existence of a physiological S/E/E8 complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / infer-01 :ARG1 (d / depend-01 :ARG0 (c / coimmunoprecipitate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :ARG2 (p3 / protein :name (n2 / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :ARG1 (i2 / integrity :mod (i3 / interact-01 :ARG0 e2 :ARG1 (p4 / protein :name (n3 / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :condition (p / physiology) :ARG0-of (p2 / point-01 :ARG1 (e / exist-01 :ARG1 (m / macro-molecular-complex :mod (p5 / physiology) :part (s / slash :op1 (p6 / protein :name (n4 / name :op1 "S") :xref (x1 / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :op2 (p7 / protein :name (n5 / name :op1 "E")) :op3 (p8 / protein :name (n6 / name :op1 "E8")))))))) # ::id pmid_1177_7939.46 # ::date 2015-03-07T03:24:51 # ::file pmid_1177_7939_46.txt # ::snt It cannot be formally excluded that Eps8, E3b1, and Sos-1 associate after cell lysis, thus allowing coimmunoprecipitation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (p / possible-01 :polarity "-" :ARG1 (e / exclude-01 :ARG1 (a / associate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG2 (p4 / protein :name (n3 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :time (a3 / after :op1 (l / lyse-01 :ARG1 (c / cell))) :ARG0-of (a4 / allow-01 :ARG1 (c3 / coimmunoprecipitate-01 :ARG1 a2 :ARG2 p4))) :mod (f / formal))) # ::id pmid_1177_7939.47 # ::date 2015-03-07T03:51:17 # ::file pmid_1177_7939_47.txt # ::snt However, we have previously demonstrated (Scita et al., 2001) that the three endogenous proteins also colocalize in vivo in dynamic actin structures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / contrast-01 :ARG2 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (c2 / colocalize-01 :ARG1 (p5 / protein :quant "3" :mod (e / endogenous)) :ARG2 (s / structure :mod (d4 / dynamic) :mod (a3 / actin)) :mod (a2 / also) :manner (i / in-vivo)) :time (p / previous) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n / name :op1 "Scita")) :op2 (p4 / person :mod (o / other))) :time (d3 / date-entity :year "2001"))))) # ::id pmid_1177_7939.48 # ::date 2015-03-07T08:59:18 # ::file pmid_1177_7939_48.txt # ::snt Thus, the sum of our results strongly argues in favor of the existence of a physiological S/E/E8 complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / infer-01 :ARG1 (a / argue-01 :ARG0 (s3 / sum :mod (t / thing :ARG2-of (r / result-01) :poss (w / we))) :ARG1 (e / exist-01 :ARG1 (m / macro-molecular-complex :mod (p / physiology) :part (s2 / slash :op1 (p2 / protein :name (n / name :op1 "S") :xref (x / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :op2 (p3 / protein :name (n2 / name :op1 "E")) :op3 (p4 / protein :name (n3 / name :op1 "E8"))))) :ARG1-of (s / strong-02))) # ::id pmid_1177_7939.49 # ::date 2015-03-07T09:35:14 # ::file pmid_1177_7939_49.txt # ::snt Similarly, it cannot be formally excluded that other interactors of the SH3 domain of Eps8, besides E3b1, mediate the formation of the endogenous trimeric complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 1, 2015 (p / possible-01 :polarity "-" :ARG1-of (r / resemble-01) :ARG1 (e / exclude-01 :ARG1 (m / mediate-01 :ARG0 (i / interact-01 :ARG0 (p4 / protein-segment :name (n3 / name :op1 "SH3" :op2 "domain") :part-of (e4 / enzyme :name (n2 / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :mod (o / other) :ARG2-of (e2 / except-01 :ARG1 (p2 / protein :name (n / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :ARG1 (f2 / form-01 :ARG1 (m2 / macro-molecular-complex :mod (t / trimeric) :mod (e3 / endogenous)))) :mod (f / formal))) # ::id pmid_1177_7939.50 # ::date 2015-03-08T01:31:45 # ::file pmid_1177_7939_50.txt # ::snt This is, however, unlikely since no coimmunoprecipitation between Eps8 and Sos-1 could be detected when the two proteins were overexpressed in cell lines with relative low levels of E3b1 (Scita et al., 1999; unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / contrast-01 :ARG2 (l3 / likely-01 :polarity "-" :ARG1 (t / this) :ARG1-of (c2 / cause-01 :ARG0 (p / possible-01 :polarity "-" :ARG1 (d / detect-01 :ARG1 (c3 / coimmunoprecipitate-01 :ARG1 (e2 / enzyme :wiki "EPS8" :name (n / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :ARG2 (p3 / protein :wiki "SOS1" :name (n2 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :condition (o3 / overexpress-01 :ARG1 (a4 / and :op1 e2 :op2 p3) :location (c4 / cell-line :part (p4 / protein :wiki "-" :name (n3 / name :op1 "E3b1") :quant (l / level :ARG1-of (l2 / low-04 :ARG2-of (r / relative-05))) :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p5 / publication-91 :ARG0 (a2 / and :op1 (p6 / person :wiki "-" :name (n4 / name :op1 "Scita")) :op2 (p7 / person :mod (o2 / other))) :time (d3 / date-entity :year "1999")) :op2 (d4 / data :ARG1-of (p8 / publish-01 :polarity "-"))))) # ::id pmid_1177_7939.51 # ::date 2015-03-08T04:35:20 # ::file pmid_1177_7939_51.txt # ::snt Moreover, neither RN-tre, nor JIK, two other known interactors of the SH3 domain of Eps8 (Biesova et al., 1997; Mongiovi et al., 1999), were able to bind to Sos-1 (unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (a / and :op2 (p / possible-01 :polarity "-" :ARG1 (b / bind-01 :ARG1 (a2 / and :op1 (p4 / protein :name (n3 / name :op1 "RN-tre") :xref (x2 / xref :value "UNIPROT:US6NL_HUMAN" :prob "1.003")) :op2 (p5 / protein :name (n4 / name :op1 "JIK") :xref (x3 / xref :value "UNIPROT:TAOK3_HUMAN" :prob "1.002")) :ARG0-of (i2 / interact-01 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "SH3" :op2 "domain") :part-of (e / enzyme :name (n5 / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :mod (o / other) :ARG1-of (k / know-01)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n6 / name :op1 "Biesova")) :op2 (p9 / person :mod (o2 / other))) :time (d2 / date-entity :year "1997")) :op2 (p10 / publication-91 :ARG0 (a5 / and :op1 (p11 / person :name (n7 / name :op1 "Mongiovi")) :op2 (p12 / person :mod (o3 / other))) :time (d3 / date-entity :year "1999"))))) :ARG2 (p2 / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :ARG1-of (p13 / publish-01 :polarity "-")) # ::id pmid_1177_7939.52 # ::date 2015-03-04T23:27:16 # ::file pmid_1177_7939_52.txt # ::snt The adaptor molecules, E3b1 and Grb2, compete for binding to Sos-1 both in vitro and in vivo # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 1, 2015 (a3 / and :op1 (c / compete-01 :ARG0 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op2 (p4 / protein :name (n4 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :mod (a4 / adaptor)) :ARG2 (b2 / bind-01 :ARG1 a2 :ARG2 (p / protein :name (n / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :manner (i / in-vitro)) :op2 (c2 / compete-01 :ARG0 a2 :ARG1 b2 :manner (i2 / in-vivo))) # ::id pmid_1177_7939.53 # ::date 2015-03-07T10:57:15 # ::file pmid_1177_7939_53.txt # ::snt Sos-1 has been shown to be part of a signaling complex with Grb2, which mediates the activation of Ras upon RTK stimulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (s / show-01 :ARG1 (h / have-part-91 :ARG1 (m / macro-molecular-complex :ARG0-of (s2 / signal-07) :part (p2 / protein :name (n2 / name :op1 "Grb2") :ARG0-of (m2 / mediate-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :condition (s3 / stimulate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "RTK") :xref (x3 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262"))))) :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :ARG2 (p / protein :name (n / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) # ::id pmid_1177_7939.54 # ::date 2015-03-08T05:24:21 # ::file pmid_1177_7939_54.txt # ::snt Our finding that, under physiological conditions, Sos-1 also participates in a complex with Eps8 and E3b1 raises the question of the physical and functional relationships between these two Sos-1–containing complexes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 11, 2015 (r / raise-01 :ARG0 (f / find-01 :ARG0 (w / we) :ARG1 (m / macro-molecular-complex :part (a / and :op1 (p2 / protein :name (n / name :op1 "Sos-1") :mod (a2 / also) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :op2 (e / enzyme :name (n2 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :op3 (p4 / protein :name (n3 / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :condition (p / physiology))) :ARG1 (q / question-01 :ARG1 (r2 / relation-03 :ARG0 a :ARG1 (a5 / and :op1 (p5 / physical) :op2 (f2 / functional)) :ARG2 (m2 / macro-molecular-complex :part (a3 / and :op1 p2 :op2 (p6 / protein :name (n4 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))))) # ::id pmid_1177_7939.55 # ::date 2015-03-08T06:32:20 # ::file pmid_1177_7939_55.txt # ::snt To gain insight into this issue, we initially mapped the region of E3b1 responsible for the interaction with Sos-1 by using a series of deletion mutants of E3b1 fused to glutathione S-transferase (GST). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m / map-01 :ARG0 (w / we) :ARG1 (r2 / region :part-of (p / protein :name (n / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG0-of (r / responsible-01 :ARG1 (i2 / interact-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :manner (u2 / use-01 :ARG0 w :ARG1 (p3 / protein :name (n3 / name :op1 "E3b1") :ARG1-of (f / fuse-01 :ARG3 (e2 / enzyme :name (n5 / name :op1 "glutathione" :op2 "S-transferase") :xref (x / xref :value "UNIPROT:HPGDS_HUMAN" :prob "0.702"))) :quant (s / series) :ARG2-of (m2 / mutate-01 :manner (d3 / delete-01)) :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))))) :purpose (u / understand-01 :ARG0 w :ARG1 (i3 / issue-02 :mod (t / this))) :time (i / initial)) # ::id pmid_1177_7939.56 # ::date 2015-03-04T06:08:23 # ::file pmid_1177_7939_56.txt # ::snt Native Sos-1 could be efficiently recovered onto GST-E3b1 full length (Fig. 2 A, amino acids [aa] 2–480). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p2 / possible-01 :ARG1 (r / recover-02 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :mod (n2 / native) :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG2-of (e / efficient-01) :manner (l / length :degree (f / full) :poss (p3 / protein :name (n3 / name :op1 "GST-E3b1") :xref (x / xref :value "UNIPROT:GSTO1_HUMAN" :prob "0.232")))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2A" :mod (b / between :op1 (a2 / amino-acid :value "2") :op2 (a3 / amino-acid :value "480"))))) # ::id pmid_1177_7939.57 # ::date 2015-03-04T06:17:25 # ::file pmid_1177_7939_57.txt # ::snt Further mapping revealed that the SH3 domain of E3b1 (aa 416–480) was necessary and sufficient for binding (Fig. 2 A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 10, 2015 (r / reveal-01 :ARG0 (m / map-01 :degree (f / further)) :ARG1 (a / and :op1 (n / need-01 :ARG0 (b / bind-01 :ARG2 "p") :ARG1 (p / protein-segment :name (n2 / name :op1 "SH3") :part-of (p2 / protein :name (n3 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :consist-of (b2 / between :op1 (a3 / amino-acid :value "416") :op2 (a4 / amino-acid :value "480")))) :op2 (s / suffice-01 :ARG0 p :ARG1 b)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2A"))) # ::id pmid_1177_7939.58 # ::date 2015-03-04T06:26:20 # ::file pmid_1177_7939_58.txt # ::snt We have previously shown that E3b1 binds to the proline-rich, COOH-terminal tail of Sos-1 (aa 1131–1333) (Scita et al., 1999), which also binds to the SH3 of Grb2 (Li et al., 1993; Cussac et al., 1994). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 10, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG2 (t / tail :part-of (p2 / protein-segment :name (n2 / name :op1 "COOH-terminus") :mod (r / rich :topic (a / amino-acid :name (n3 / name :op1 "proline") :xref (x3 / xref :value "PUBCHEM:614" :prob "10.45396"))) :part-of (p3 / protein :name (n4 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (b2 / bind-01 :ARG2 (p7 / protein-segment :name (n6 / name :op1 "SH3") :part-of (p8 / protein :name (n7 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :mod (a3 / also) :ARG1-of (d5 / describe-01 :ARG0 (a4 / and :op1 (p9 / publication-91 :ARG0 (a5 / and :op1 (p10 / person :name (n8 / name :op1 "Li")) :op2 (p11 / person :mod (o2 / other))) :time (d2 / date-entity :year "1993")) :op2 (p12 / publication-91 :ARG0 (a6 / and :op1 (p13 / person :name (n9 / name :op1 "Cussac")) :op2 (p14 / person :mod (o3 / other))) :time (d3 / date-entity :year "1994"))))) :ARG1-of (m / mean-01 :ARG2 (b3 / between :op1 (a8 / amino-acid :value "1131") :op2 (a9 / amino-acid :value "1333"))))) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n5 / name :op1 "Scita")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "1999")))) :time (p15 / previous)) # ::id pmid_1177_7939.59 # ::date 2015-03-04T06:42:22 # ::file pmid_1177_7939_59.txt # ::snt Thus, Grb2 and E3b1 might compete for binding to Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 9, 2015 (i / infer-01 :ARG1 (p / possible-01 :ARG1 (c / compete-01 :ARG0 (p2 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG1 (p3 / protein :name (n2 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG2 (b / bind-01 :ARG1 (a / and :op1 p2 :op2 p3) :ARG2 (p4 / protein :name (n3 / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))))) # ::id pmid_1177_7939.60 # ::date 2015-03-04T06:45:24 # ::file pmid_1177_7939_60.txt # ::snt This hypothesis was validated by a series of experiments performed both in vitro and in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (v / validate-01 :ARG0 (s / series :consist-of (e / experiment-01 :ARG1-of (p / perform-02 :manner (a / and :op1 (i / in-vitro) :op2 (i2 / in-vivo))))) :ARG1 (t / thing :ARG1-of (h / hypothesize-01) :mod (t2 / this))) # ::id pmid_1177_7939.61 # ::date 2015-03-04T06:49:10 # ::file pmid_1177_7939_61.txt # ::snt We could demonstrate that (a) the SH3 of Grb2, but not of Eps8, efficiently competed with the SH3 of E3b1 for binding to the proline-rich COOH-terminal tail of Sos-1 in vitro (Fig. 2 B); (b) the Sos-1 peptide VPVPPPVPPRRR, known to constitute a Grb2-SH3 binding site (Li et al., 1993; Cussac et al., 1994), competed equally well the binding of the COOH-terminal tail of Sos-1 to the SH3s of Grb2 or E3b1 (Fig. 2 C); (c) the binding constants of the interaction between the proline rich COOH-terminal tail of Sos-1 and the SH3 domains of Grb2 and E3b1 were very similar (Fig. 2 D); (d) overexpression of Grb2 abolished the ability of GST-E3b1 to bind to native Sos-1 (Fig. 3 A); and (e) overexpression of E3b1 significantly decreased the coimmunoprecipitation between Grb2 and Sos-1 (Fig. 3 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 25, 2016 (p / possible-01 :ARG1 (d3 / demonstrate-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (c / compete-01 :li "a" :ARG0 (p2 / protein-segment :name (n2 / name :op1 "SH3") :part-of (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x3 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG1-of (i / instead-of-91 :ARG2 (p4 / protein-segment :name (n4 / name :op1 "SH3") :part-of (e3 / enzyme :name (n5 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) :ARG1 (p6 / protein-segment :name (n6 / name :op1 "SH3") :part-of (p7 / protein :name (n7 / name :op1 "E3b1") :xref (x4 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG2 (b / bind-01 :ARG2 (t2 / tail :part-of (p8 / protein-segment :name (n8 / name :op1 "COOH-terminus") :part-of (p19 / protein :name (n9 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :mod (r2 / rich :topic (a3 / amino-acid :name (n10 / name :op1 "proline") :xref (x6 / xref :value "PUBCHEM:614" :prob "10.45396"))))) :manner (i2 / in-vitro)) :ARG2-of (e / efficient-01 :ARG1 p2) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "2B"))) :op2 (c2 / compete-01 :li "b" :ARG0 (p10 / peptide :name (n15 / name :op1 "VPVPPPVPPRRR") :part-of p19 :ARG0-of (c3 / constitute-01 :ARG1 (p9 / protein-segment :ARG1-of (b2 / bind-01 :ARG2 p2)) :ARG1-of (d5 / describe-01 :ARG0 (a5 / and :op1 (p11 / publication-91 :ARG0 (a4 / and :op1 (p12 / person :name (n11 / name :op1 "Li")) :op2 (p13 / person :mod (o / other))) :time (d / date-entity :year "1993")) :op2 (p14 / publication-91 :ARG0 (a6 / and :op1 (p15 / person :name (n12 / name :op1 "Cussac")) :op2 (p16 / person :mod (o2 / other))) :time (d2 / date-entity :year "1994")))) :ARG1-of (k / know-01))) :ARG1 (b3 / bind-01 :ARG1 t2 :ARG2 (o3 / or :op1 p2 :op2 p6)) :mod (w2 / well :degree (e2 / equal)) :ARG1-of (d6 / describe-01 :ARG0 (f2 / figure :mod "2C"))) :op3 (r / resemble-01 :li "c" :ARG1 (c4 / constant :value-of (i3 / interact-01 :ARG0 t2 :ARG1 p2 :ARG0-of (b4 / bind-01))) :ARG2 (c5 / constant :value-of (i4 / interact-01 :ARG0 t2 :ARG1 p6 :ARG0-of (b5 / bind-01))) :degree (v / very) :ARG1-of (d7 / describe-01 :ARG0 (f3 / figure :mod "2D"))) :op4 (a / abolish-01 :li "d" :ARG0 (o4 / overexpress-01 :ARG1 p3) :ARG1 (c7 / capable-01 :ARG1 (p18 / protein :name (n / name :op1 "GST-E3b1") :xref (x / xref :value "UNIPROT:GSTO1_HUMAN" :prob "0.232")) :ARG2 (b6 / bind-01 :ARG1 p18 :ARG2 (p20 / protein :name (n13 / name :op1 "Sos-1") :mod (n14 / native) :xref (x5 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :ARG1-of (d8 / describe-01 :ARG0 (f4 / figure :mod "3A"))) :op5 (d9 / decrease-01 :li "e" :ARG0 (o5 / overexpress-01 :ARG1 p7) :ARG1 (p17 / precipitate-01 :ARG0 (a7 / antibody) :ARG1 (m / macro-molecular-complex :part p3 :part p19)) :ARG2 (s / significant-02) :ARG1-of (d10 / describe-01 :ARG0 (f5 / figure :mod "3B")))))) # ::id pmid_1177_7939.62 # ::date 2015-03-04T07:36:03 # ::file pmid_1177_7939_62.txt # ::snt Thus, Sos-1 binds either E3b1 or Grb2, in a mutually exclusive fashion, suggesting that two distinct pools of Sos-1 exist in the cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / infer-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG2 (o / or :op1 (p2 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op2 (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :ARG0-of (e / exclusive-02 :mod (m / mutual)) :ARG0-of (s / suggest-01 :ARG1 (e2 / exist-01 :ARG1 (p4 / pool :quant "2" :consist-of p :mod (d / distinct)) :location (c / cell))))) # ::id pmid_1177_7939.63 # ::date 2015-03-04T07:46:27 # ::file pmid_1177_7939_63.txt # ::snt To test this possibility in vivo, we set out to perturb the equilibrium between the Sos-1–E3b1 (S/E) and Sos-1–Grb2 (S/G) complexes, by increasing the levels of E3b1 within the cell. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Dec 19, 2015 (s / set-out-06 :ARG0 (w / we) :ARG1 (p / perturb-01 :ARG0 w :ARG1 (e / equilibrate-01 :ARG1 (a / and :op1 (m / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :part (p3 / protein :name (n2 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :op2 (m2 / macro-molecular-complex :part p2 :part (p4 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))) :instrument (i / increase-01 :ARG0 w :ARG1 (l / level :quant-of p3) :location (c / cell))) :purpose (t / test-01 :ARG0 w :ARG1 (p5 / possible-01 :ARG1 (t2 / this)) :manner (i2 / in-vivo))) # ::id pmid_1177_7939.64 # ::date 2015-03-04T07:55:20 # ::file pmid_1177_7939_64.txt # ::snt If the two complexes are functionally distinct, then the overexpression of E3b1, by competing the S/G interaction, should result in (a) reduced Sos-1 recruitment in vivo to active EGFR, (b) consequent reduction in Ras activation, as measured by reduced Ras-GTP levels, (c) reduced activation of Ras-dependent pathways, as measured by activation of MAPK, and finally (d) reduced proliferative response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / recommend-01 :ARG1 (r2 / result-01 :ARG1 (o / overexpress-01 :ARG1 (p2 / protein :name (n4 / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG2 (a / and :op1 (r3 / recruit-01 :li "a" :ARG1 "p3" :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :ARG0-of (a2 / activity-06) :xref (x4 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (r4 / reduce-01) :manner (i2 / in-vivo)) :op2 (r5 / reduce-01 :li "b" :ARG1 (a3 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (c2 / cause-01 :ARG0 r3) :ARG1-of (m / measure-01 :ARG2 (l / level :quant-of (m2 / macro-molecular-complex :part e2 :part (s / small-molecule :name (n7 / name :op1 "GTP") :xref (x5 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG1-of (r6 / reduce-01)))) :op3 (a4 / activate-01 :li "c" :ARG1 (p5 / pathway :ARG0-of (d / depend-01 :ARG1 e2)) :ARG1-of (r7 / reduce-01) :ARG1-of (m3 / measure-01 :ARG2 (a5 / activate-01 :ARG1 (p / pathway :name (n3 / name :op1 "MAPK"))))) :op4 (r8 / respond-01 :li "d" :li "-1" :ARG1-of (r9 / reduce-01) :mod (p6 / proliferate-01))) :manner (c / compete-01 :ARG0 o :ARG1 (i / interact-01 :ARG0 (p3 / protein :name (n5 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1 (p4 / protein :name (n6 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))) :condition (f2 / function-01 :ARG0 (m4 / macro-molecular-complex :quant "2") :mod (d2 / distinct))) # ::id pmid_1177_7939.65 # ::date 2015-03-04T08:25:57 # ::file pmid_1177_7939_65.txt # ::snt All of these predictions were confirmed experimentally (Fig. 4, A–C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / confirm-01 :ARG1 (t / thing :ARG1-of (p / predict-01) :mod (a / all) :mod (t2 / this)) :manner (e / experiment-01) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "A") :op2 (f2 / figure :mod "B") :op3 (f3 / figure :mod "C")))) # ::id pmid_1177_7939.66 # ::date 2015-03-04T08:29:36 # ::file pmid_1177_7939_66.txt # ::snt We note that our mapping data are at variance with those recently reported by Fan and Goff (2000), who concluded that, in vivo, the interaction between Sos-1 and E3b1–Abi-1 is mediated by the NH2-terminal portion of the latter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (n2 / note-02 :ARG0 (w / we) :ARG1 (v / vary-01 :ARG1 (d3 / data :topic (m / map-01) :poss w) :compared-to (d4 / data :mod (t / that) :ARG1-of (r / report-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Fan")) :op2 (p3 / person :name (n3 / name :op1 "Goff")) :ARG0-of (c / conclude-01 :ARG1 (m2 / mediate-01 :ARG0 (p6 / protein-segment :name (n7 / name :op1 "NH2-terminus") :part-of "p4") :ARG1 (i / interact-01 :ARG0 (p5 / protein :name (n4 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1 (p4 / protein :name (n5 / name :op1 "E3b1–Abi-1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.223"))) :manner (i2 / in-vivo)))) :time (d / date-entity :year "2000")) :time (r2 / recent))))) # ::id pmid_1177_7939.67 # ::date 2015-03-04T08:42:04 # ::file pmid_1177_7939_67.txt # ::snt Consistently, Fan and Goff (2000) did not observe competition in vivo between Grb2 and E3b1 for binding to Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (o / observe-01 :polarity "-" :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Fan")) :op2 (p3 / person :name (n2 / name :op1 "Goff")) :ARG0-of (p / publication-91 :time (d / date-entity :year "2000"))) :ARG1 (c / compete-01 :ARG0 (p4 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG1 (p5 / protein :name (n4 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG2 (b / bind-01 :ARG2 (p6 / protein :name (n5 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :manner (c2 / consistent-02) :manner (i / in-vivo)) # ::id pmid_1177_7939.68 # ::date 2015-03-04T08:49:13 # ::file pmid_1177_7939_68.txt # ::snt Although we cannot exclude that the NH2-terminal region of E3b1–Abi-1 participates in binding, in vivo, we were not able to observe a high-affinity binding surface in that region by in vitro binding experiments (Fig. 2 A; Scita et al., 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (p / possible-01 :polarity "-" :ARG1 (o / observe-01 :ARG0 (w / we) :ARG1 (s / surface :location-of (b / bind-01) :mod (a / affinity :ARG1-of (h / high-02))) :location (r / region :mod (t / that)) :manner (e / experiment-01 :ARG1 (b2 / bind-01) :manner (i / in-vitro))) :concession (p2 / possible-01 :polarity "-" :ARG1 (e2 / exclude-01 :ARG0 w :ARG1 (p3 / participate-01 :ARG0 (p4 / protein-segment :name (n / name :op1 "NH2-terminus") :part-of (p5 / protein :name (n2 / name :op1 "E3b1–Abi-1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.223"))) :ARG1 (b3 / bind-01) :manner (i2 / in-vivo)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p6 / publication-91 :ARG0 (a2 / and :op1 (p7 / person :name (n4 / name :op1 "Scita")) :op2 (p8 / person :mod (o2 / other))) :time (d / date-entity :year "1999")) :op2 (f / figure :mod "2A")))) # ::id pmid_1177_7939.69 # ::date 2015-03-04T08:58:23 # ::file pmid_1177_7939_69.txt # ::snt Conversely, under our conditions of analysis, the efficient competition of the SH3 domains of Grb2 and E3b1 for binding to the same Sos-1 peptide, coupled to the readily detectable biological competition, strongly suggests that the SH3-mediated contact is the major determinant of the interaction between Sos-1 and E3b1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / suggest-01 :ARG0 (c / compete-01 :ARG0 (p8 / protein-segment :name (n6 / name :op1 "SH3" :op2 "domain") :part-of (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :ARG1 (p / protein-segment :name (n / name :op1 "SH3" :op2 "domain") :part-of (p4 / protein :name (n4 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG2 (b / bind-01 :ARG2 (p5 / peptide :ARG1-of (s3 / same-01) :part-of (p6 / protein :name (n5 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :ARG2-of (e / efficient-01 :ARG1 p) :ARG1-of (c2 / couple-01 :ARG2 (c3 / compete-01 :mod (b2 / biology) :ARG1-of (d / detect-01 :ARG1-of (p7 / possible-01) :manner (r / ready))))) :ARG1 (d2 / determine-01 :ARG0 (c4 / contact :ARG1-of (m / mediate-01 :ARG0 (p2 / protein-segment :name (n8 / name :op1 "SH3")))) :ARG1 (i / interact-01 :ARG0 p6 :ARG1 p4) :ARG1-of (m2 / major-02)) :ARG1-of (s2 / strong-02) :ARG2-of (c6 / contrast-01) :condition (c5 / condition :mod (a / analyze-01) :poss (w / we))) # ::id pmid_1177_7939.70 # ::date 2015-03-04T09:13:40 # ::file pmid_1177_7939_70.txt # ::snt E3b1 is a limiting factor in Rac activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 4, 2015 (f / factor :ARG0-of (l / limit-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :domain (p / protein :name (n / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) # ::id pmid_1177_7939.71 # ::date 2015-03-04T09:16:18 # ::file pmid_1177_7939_71.txt # ::snt The competition between E3b1 and Grb2 for the same binding site on Sos-1 implies that an individual Sos-1 molecule can only be part of one GEF complex at a time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 23, 2016 (i / imply-01 :ARG0 (c / compete-01 :ARG0 (p / protein :name (n / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2 (p7 / protein-segment :ARG1-of (s2 / same-01) :ARG1-of (b / bind-01) :part-of (p3 / protein :name (n3 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :ARG1 (p4 / possible-01 :ARG1 (h / have-part-91 :ARG1 (m / macro-molecular-complex :quant "1" :part (p6 / protein :name (n4 / name :op1 "GEF") :xref (x2 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002"))) :ARG2 (m2 / molecule :mod p3 :mod (i2 / individual)) :mod (a / at-a-time) :mod (o / only)))) # ::id pmid_1177_7939.72 # ::date 2015-03-04T09:29:37 # ::file pmid_1177_7939_72.txt # ::snt However, different pools of Sos-1, either bound to Grb2 or to E3b1, could exist in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / contrast-01 :ARG2 (p / possible-01 :ARG1 (e / exist-01 :ARG1 (p2 / pool :ARG1-of (d / differ-02) :consist-of (p3 / protein :name (n / name :op1 "Sos-1") :ARG1-of (b / bind-01 :ARG2 (o / or :op1 (p4 / protein :name (n2 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p5 / protein :name (n3 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :manner (i / in-vivo))) # ::id pmid_1177_7939.73 # ::date 2015-03-04T09:33:14 # ::file pmid_1177_7939_73.txt # ::snt We tried to gain insight into this issue. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (t2 / try-01 :ARG0 (w / we) :ARG1 (g / gain-02 :ARG0 w :ARG1 (i2 / insight :topic (i / issue-02 :mod (t / this))))) # ::id pmid_1177_7939.74 # ::date 2015-03-04T09:34:54 # ::file pmid_1177_7939_74.txt # ::snt We showed that BIAcore measurements revealed similar kinetic parameters for the SH3-mediated S/G and S/E interactions (Fig. 2 D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (r2 / reveal-01 :ARG0 (t / thing :ARG1-of (m / measure-01 :ARG0 (c / company :name (n / name :op1 "BIAcore")))) :ARG1 (p / parameter :ARG1-of (r / resemble-01 :ARG2 (i2 / interact-01 :ARG0 (a / and :op1 "p5" :op2 (p4 / protein :name (n5 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG1-of "m2")) :mod (k / kinetic) :topic (i / interact-01 :ARG0 (p5 / protein :name (n3 / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1 (p3 / protein :name (n4 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG1-of (m2 / mediate-01 :ARG0 (p2 / protein-segment :name (n2 / name :op1 "SH3")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2D"))) # ::id pmid_1177_7939.75 # ::date 2015-03-04T09:46:33 # ::file pmid_1177_7939_75.txt # ::snt However, when we measured the relative abundance of S/G and S/E complexes within the cell, we found a 10-fold excess of the former (Fig. 5 A), under conditions in which quantitative immunoprecipitation of the adaptor molecules, Grb2 and E3b1, was achieved (Fig. 5 A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (c3 / contrast-01 :ARG2 (f / find-01 :ARG0 (w / we) :ARG1 (e / exceed-01 :ARG0 (m / macro-molecular-complex :part (p5 / protein :name (n / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :part (p / protein :name (n2 / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :ARG1 (m2 / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :part p5) :ARG2 (p3 / product-of :op1 "10") :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5A")) :condition (a2 / achieve-01 :ARG1 (i / immunoprecipitate-01 :ARG1 (a5 / and :op1 p :op2 p2 :mod (a4 / adaptor)) :mod (q / quantity)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "5A")))) :time (m3 / measure-01 :ARG1 (a / abound-01 :ARG1 (a6 / and :op1 m :op2 m2) :ARG2 (c / cell) :ARG2-of (r / relative-05))))) # ::id pmid_1177_7939.76 # ::date 2015-03-04T09:51:03 # ::file pmid_1177_7939_76.txt # ::snt Thus, the data indicate that two pools of Sos-1, associated with different adaptors, exist simultaneously in the cell. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 9, 2015 (i / infer-01 :ARG1 (i2 / indicate-01 :ARG0 (d / data) :ARG1 (e / exist-01 :ARG1 (p / pool :quant "2" :consist-of (p2 / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (a / associate-01 :ARG2 (a2 / adaptor :ARG1-of (d2 / differ-02)))) :manner (s / simultaneous) :location (c / cell)))) # ::id pmid_1177_7939.77 # ::date 2015-02-26T23:45:48 # ::file pmid_1177_7939_77.txt # ::snt They further suggest that the pool of E3b1, available for binding to Sos-1, is reduced relative to that of Grb2, and may be rate-limiting. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (s / suggest-01 :ARG0 (t / they) :ARG1 (a3 / and :op1 (r / reduce-01 :ARG1 (p / pool :consist-of (p3 / protein :name (n / name :op1 "E3b1") :ARG2-of (a / available-02 :purpose (b / bind-01 :ARG1 p :ARG2 (p4 / protein :name (n2 / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :compared-to (p5 / pool :consist-of (p6 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")))) :op2 (p2 / possible-01 :ARG1 (l / limit-01 :ARG0 p :ARG1 (r2 / rate)))) :degree (f / further)) # ::id pmid_1177_7939.78 # ::date 2015-02-27T01:24:36 # ::file pmid_1177_7939_78.txt # ::snt Indeed, overexpression of E3b1 resulted in increased PAK65 activity, an indicator of Rac activation (Manser et al., 1994) (Fig. 5 B), which was abrogated by a dominant negative Rac mutant (Fig. 5 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (p4 / protein :name (n / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG2 (a / activity-06 :ARG0 (e4 / enzyme :name (n2 / name :op1 "PAK65") :xref (x / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003")) :ARG1-of (i2 / increase-01) :ARG0-of (i / indicate-01 :ARG1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1-of (a3 / abrogate-01 :ARG2 (e3 / enzyme :name (n5 / name :op1 "Rac") :ARG0-of (d4 / dominate-01) :ARG1-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1-of (d5 / describe-01 :ARG0 "f2"))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (p / publication-91 :ARG0 (a4 / and :op1 (p2 / person :name (n4 / name :op1 "Manser")) :op2 (p5 / person :mod (o2 / other))) :time (d3 / date-entity :year "1994")) :op2 (f2 / figure :mod "5B"))) :mod (i3 / indeed)) # ::id pmid_1177_7939.79 # ::date 2015-02-27T07:47:51 # ::file pmid_1177_7939_79.txt # ::snt On the other hand, overexpression of Sos-1 did not lead to increased PAK65 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (c / contrast-01 :ARG2 (l / lead-03 :polarity "-" :ARG0 (o2 / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :ARG2 (a / activity-06 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PAK65") :xref (x1 / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003")) :ARG1-of (i2 / increase-01)))) # ::id pmid_1177_7939.80 # ::date 2015-02-28T11:11:55 # ::file pmid_1177_7939_80.txt # ::snt An additional corollary of this hypothesis is that the overexpression of E3b1, by facilitating the formation of a trimeric complex with Eps8 and Sos-1, should directly lead to activation of Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / corollary :domain (r / recommend-01 :ARG1 (l / lead-03 :ARG0 (o / overexpress-01 :ARG1 (p2 / protein :name (n2 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG2 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "Rac") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG1-of (d / direct-02) :manner (f / facilitate-01 :ARG0 o :ARG1 (f2 / form-01 :ARG1 (m / macro-molecular-complex :part p2 :part (e2 / enzyme :name (n3 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :part (p3 / protein :name (n4 / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :mod (t3 / trimer)))))) :ARG0-of (a2 / add-01 :ARG1 (t2 / thing :ARG1-of (h / hypothesize-01) :mod (t / this)))) # ::id pmid_1177_7939.81 # ::date 2015-02-28T11:17:40 # ::file pmid_1177_7939_81.txt # ::snt To test this prediction E3b1 or a mutant of E3b1 (E3b1-DY), bearing alanine substitutions of the DY residues critical for the interaction with Eps8 (Mongiovi et al., 1999), were used to infect wild-type and eps8−/− fibroblasts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 25, 2016 (u / use-01 :ARG1 (o / or :op1 (p / protein :name (n2 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n3 / name :op1 "E3b1-DY") :ARG2-of (m / mutate-01 :ARG1 p) :ARG0-of (b / bear-01 :ARG1 (s / substitute-01 :ARG1 (a / amino-acid :name (n / name :op1 "alanine") :xref (x3 / xref :value "PUBCHEM:602" :prob "10.089661")) :ARG2 (r / residue :mod (p8 / protein-segment :name (n4 / name :op1 "DY")) :ARG1-of (c / critical-02 :ARG3 (i / interact-01 :ARG0 p2 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))))) :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.213"))) :ARG2 (i2 / infect-01 :ARG1 (a2 / and :op1 (f / fibroblast :mod (w / wild-type)) :op2 (f2 / fibroblast :ARG0-of (m2 / mutate-01 :ARG1 e2))) :ARG2 o :purpose (t2 / test-01 :ARG1 (t3 / thing :ARG1-of (p3 / predict-01) :mod (t4 / this)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n7 / name :op1 "Mongiovi")) :op2 (p7 / person :mod (o2 / other))) :time (d3 / date-entity :year "1999")))))) # ::id pmid_1177_7939.82 # ::date 2015-03-01T03:29:06 # ::file pmid_1177_7939_82.txt # ::snt The levels of GTP-bound Rac were then determined by in vitro binding assays using the immobilized CRIB domain of PAK65 (Manser et al., 1994). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d2 / determine-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "Rac") :ARG2-of (b / bind-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG2 (a / assay-01 :ARG1 (b2 / bind-01) :ARG0-of (u / use-01 :ARG1 (p5 / protein-segment :name (n6 / name :op1 "CRIB" :op2 "domain") :ARG1-of (m / mobilize-01 :polarity "-") :ARG1-of (i2 / immobilize-01) :part-of (e2 / enzyme :name (n4 / name :op1 "PAK65") :xref (x / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003")))) :manner (i / in-vitro)) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n3 / name :op1 "Manser")) :op2 (p6 / person :mod (o / other))) :time (d5 / date-entity :year "1994"))) :time (t / then)) # ::id pmid_1177_7939.83 # ::date 2015-03-02T01:43:31 # ::file pmid_1177_7939_83.txt # ::snt E3b1, but not the E3b1 mutant impaired in Eps8 binding, caused a readily detectable increase in Rac-GTP levels in wild type, but not in eps8−/− fibroblasts (Fig. 5 C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (c / cause-01 :ARG0 (p / protein :name (n / name :op1 "E3b1") :xref (x4 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (m3 / macro-molecular-complex :part (e2 / enzyme :name (n2 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :part (s / small-molecule :name (n6 / name :op1 "GTP") :xref (x5 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :ARG1-of (d3 / detect-01 :ARG1-of (p3 / possible-01) :manner (r / ready)) :ARG1-of (b2 / be-located-at-91 :ARG2 (f4 / fibroblast :mod (w2 / wild-type)) :ARG1-of (c2 / contrast-01 :ARG2 (b3 / be-located-at-91 :polarity "-" :ARG1 i :ARG2 (f3 / fibroblast :mod (e / enzyme :name (n3 / name :op1 "eps8") :ARG2-of (m2 / mutate-01 :mod "−/−") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))))))) :ARG2 (c4 / cause-01 :polarity "-" :ARG0 (p4 / protein :name (n4 / name :op1 "E3b1") :ARG1-of (m / mutate-01) :ARG1-of (i2 / impair-01 :ARG0 (b / bind-01 :ARG1 p4 :ARG2 (e3 / enzyme :name (n5 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))) :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1 i) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id pmid_1177_7939.84 # ::date 2015-03-02T02:27:43 # ::file pmid_1177_7939_84.txt # ::snt Thus, the overexpression of E3b1 is sufficient to activate Rac and this effect is strictly dependent on Eps8. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i2 / infer-01 :ARG1 (a2 / and :op1 (s / suffice-01 :ARG0 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG1 (a / activate-01 :ARG0 o :ARG1 (e / enzyme :name (n2 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :op2 (d / depend-01 :ARG0 (e2 / effect :mod (t / this)) :ARG1 (e3 / enzyme :name (n3 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :mod (s2 / strict)))) # ::id pmid_1177_7939.85 # ::date 2015-03-02T05:24:26 # ::file pmid_1177_7939_85.txt # ::snt The indispensability of E3b1 in the cascade of events leading to Rac activation and Rac-dependent actin reorganization was further analyzed at the biological level. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / analyze-01 :ARG1 (i / indispensable-01 :ARG1 (e / enzyme :name (n / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG2 (c / cascade-01 :subevent (e2 / event :ARG0-of (l / lead-03 :ARG2 (a4 / and :op1 (a2 / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :op2 (r / reorganize-01 :ARG1 (p2 / protein :name (n3 / name :op1 "actin") :ARG0-of (d2 / depend-01 :ARG1 e3) :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))))))) :time (f / further) :manner (l2 / level :mod (b / biology))) # ::id pmid_1177_7939.86 # ::date 2015-03-02T05:50:46 # ::file pmid_1177_7939_86.txt # ::snt We have previously shown that interference with E3b1 functions, by microinjection of anti-E3b1 antibodies, inhibited PDGF-induced ruffles (Scita et al. 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / show-01 :ARG0 (w2 / we) :ARG1 (i3 / inhibit-01 :ARG0 (i / interfere-01 :ARG1 (f / function-01 :ARG0 (p6 / protein :name (n / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :manner (m / microinject-01 :ARG1 (a / antibody :ARG0-of (c / counter-01 :ARG1 f)) :ARG2 f)) :ARG1 (r / ruffle-02 :ARG2-of (i4 / induce-01 :ARG0 (p5 / protein :name (n3 / name :op1 "PDGF") :xref (x1 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313"))))) :time (p / previous) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n2 / name :op1 "Scita")) :op2 (p3 / person :mod (o / other))) :time (d3 / date-entity :year "1999")))) # ::id pmid_1177_7939.87 # ::date 2015-03-02T06:26:55 # ::file pmid_1177_7939_87.txt # ::snt We also showed that in eps8−/− cells, ruffling induced by PDGF and activated Ras, but not by activated Rac, was inhibited. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG1 (r / ruffle-02 :ARG2-of (i2 / induce-01 :ARG0 (a2 / and :op1 (p / protein :name (n3 / name :op1 "PDGF") :xref (x1 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :op2 (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (a3 / activate-01) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (c2 / contrast-01 :ARG2 (i3 / induce-01 :polarity "-" :ARG0 (e3 / enzyme :name (n5 / name :op1 "Rac") :ARG1-of a3 :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG2 r))))) :mod (a / also) :location (c / cell :part (e / enzyme :name (n / name :op1 "eps8") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))) # ::id pmid_1177_7939.88 # ::date 2015-03-02T06:41:11 # ::file pmid_1177_7939_88.txt # ::snt Ruffling, however, could be restored upon reexpression of Eps8, but not of an Eps8 mutant unable to bind to E3b1 (Scita et al., 1999), suggesting that the Eps8–E3b1-based complex is implicated in the transmission of signal between Ras and Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / contrast-01 :ARG2 (p / possible-01 :ARG1 (r / restore-01 :ARG0 (e2 / express-03 :ARG2 (e5 / enzyme :name (n2 / name :op1 "Eps8") :ARG1-of (c4 / contrast-01 :ARG2 (p6 / possible-01 :polarity "-" :ARG1 (r3 / restore-01 :ARG0 (e6 / express-03 :ARG2 (e7 / enzyme :name (n3 / name :op1 "Eps8") :ARG1-of (m / mutate-01) :ARG1-of (b / bind-01 :ARG2 (p7 / protein :name (n4 / name :op1 "E3b1") :xref (x4 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1-of (p4 / possible-01 :polarity "-")) :xref (x3 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :ARG1 "r2" :mod "a2"))) :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :mod (a2 / again)) :ARG1 (r2 / ruffle-02)) :ARG0-of (s / suggest-01 :ARG1 (i / implicate-01 :ARG1 (c / complex :ARG1-of (b2 / base-02 :ARG2 (a / and :op1 e5 :op2 p7))) :ARG2 (t / transmit-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (s2 / signal-07) :ARG2 (e4 / enzyme :name (n6 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n7 / name :op1 "Scita")) :op2 (p3 / person :mod (o / other))) :time (d3 / date-entity :year "1999")))) # ::id pmid_1177_7939.89 # ::date 2015-03-02T07:42:31 # ::file pmid_1177_7939_89.txt # ::snt Thus, one might predict that a mutant of E3b1 unable to associate to Eps8 should function as a dominant negative on Ras-induced Rac-dependent ruffling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (i2 / infer-01 :ARG1 (p5 / possible-01 :ARG1 (p6 / predict-01 :ARG0 (o / one) :ARG1 (r2 / recommend-01 :ARG1 (f / function-01 :ARG0 (p2 / protein :name (n / name :op1 "E3b1") :ARG1-of (m / mutate-01) :ARG1-of (a / associate-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :ARG1-of (p / possible-01 :polarity "-")) :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1 (m2 / mutate-01 :mod "-/-" :ARG0-of (d / dominate-01) :time (r3 / ruffle-02 :ARG2-of (i / induce-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG0-of (d2 / depend-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))))))))) # ::id pmid_1177_7939.90 # ::date 2015-03-02T08:13:46 # ::file pmid_1177_7939_90.txt # ::snt To test this, we cotransfected the activated versions of either Ras or Rac, together with E3b1 or the E3b1DY mutant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (c / cotransfect-01 :ARG0 (w / we) :ARG2 (a3 / and :op1 (o2 / or :op1 (v / version :ARG1-of (a / activate-01) :mod (e4 / enzyme :name (n5 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (v2 / version :mod (e3 / enzyme :name (n2 / name :op1 "Rac") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1-of (a2 / activate-01))) :op2 (o / or :op1 (p / protein :name (n3 / name :op1 "E3b1") :ARG1-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op2 (p2 / protein :name (n4 / name :op1 "E3b1DY") :ARG1-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.223")))) :purpose (t3 / test-01 :ARG0 w :ARG1 (t4 / this))) # ::id pmid_1177_7939.91 # ::date 2015-03-02T08:27:52 # ::file pmid_1177_7939_91.txt # ::snt RasV12-induced, but not RacQL-induced, ruffles were efficiently inhibited by the coexpression of E3b1DY, but not of E3b1 wild type (Fig. 6), supporting the contention that the ability of E3b1 to form a complex with Eps8 is required to transmit signals from Ras to Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / inhibit-01 :ARG0 (c / coexpress-01 :ARG2 (p / protein :wiki "-" :name (n4 / name :op1 "E3b1") :ARG2-of (m4 / mutate-01 :value "DY") :xref (x6 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG1 (r / ruffle-02 :ARG2-of (i2 / induce-01 :ARG0 (e3 / enzyme :wiki "Ras_subfamily" :name (n2 / name :op1 "Ras") :ARG1-of (c2 / contrast-01 :ARG2 (i4 / induce-01 :ARG0 (e4 / enzyme :polarity "-" :wiki "Rac_(GTPase)" :name (n3 / name :op1 "Rac") :ARG2-of (m3 / mutate-01 :value "QL") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :ARG2-of (m2 / mutate-01 :value "V12") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2-of (e / efficient-01 :ARG1 c) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6")) :ARG0-of (s / support-01 :ARG1 (c4 / contend-01 :ARG1 (r2 / require-01 :ARG1 (p3 / possible-01 :ARG1 (f2 / form-01 :ARG1 (m / macro-molecular-complex :part p :part (e2 / enzyme :wiki "EPS8" :name (n6 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) :purpose (t2 / transmit-01 :ARG0 (e6 / enzyme :wiki "Ras_subfamily" :name (n7 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (s2 / signal-07) :ARG2 (e7 / enzyme :wiki "Rac_(GTPase)" :name (n8 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))))) :ARG1-of (c3 / contrast-01 :ARG2 (i3 / inhibit-01 :polarity "-" :ARG0 (c5 / coexpress-01 :polarity "-" :ARG2 (p2 / protein :wiki "-" :name (n5 / name :op1 "E3b1") :mod (w / wild-type) :xref (x5 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))))) # ::id pmid_1177_7939.92 # ::date 2015-03-02T08:58:46 # ::file pmid_1177_7939_92.txt # ::snt In conclusion, our data show that two pools of Sos-1 exist in the cell, coupled respectively to Grb2 or E3b1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / conclude-02 :ARG1 (s / show-01 :ARG0 (d / data :poss (w / we)) :ARG1 (e / exist-01 :ARG1 (p / pool :quant "2" :consist-of (p2 / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (c3 / couple-01 :ARG2 (o / or :op1 (p4 / protein :name (n2 / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n3 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :mod (r / respective))) :location (c2 / cell)))) # ::id pmid_1177_7939.93 # ::date 2015-03-02T09:07:15 # ::file pmid_1177_7939_93.txt # ::snt In addition, the availability of E3b1, but not of Sos-1, is indispensable and rate limiting in the pathway leading to Rac activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (a / and :op2 (a2 / and :op1 (i / indispensable-01 :ARG1 (a5 / available-02 :ARG2 (p / protein :name (n / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG1-of (c2 / contrast-01 :ARG2 (d / dispense-01 :ARG1 (a3 / available-02 :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))))) :op2 (l / limit-01 :ARG0 a5 :ARG1 (r / rate) :ARG1-of (c / contrast-01 :ARG2 (l3 / limit-01 :polarity "-" :ARG0 (a6 / available-02 :ARG2 p2) :ARG1 r)) :location (p3 / pathway :ARG0-of (l2 / lead-03 :ARG2 (a4 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))))))) # ::id pmid_1177_7939.94 # ::date 2015-03-03T12:58:05 # ::file pmid_1177_7939_94.txt # ::snt The dual GEF activity of Sos-1 depends on its presence in distinct complexes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (d / depend-01 :ARG0 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1 (p3 / protein :name (n2 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :mod (d2 / dual)) :ARG1 (p2 / present-02 :ARG1 p :ARG2 (c / complex :mod (d3 / distinct)))) # ::id pmid_1177_7939.95 # ::date 2015-03-03T13:41:36 # ::file pmid_1177_7939_95.txt # ::snt The existence of Sos-1 in two physically and functionally distinct pools suggests the hypothesis that its presence in a S/G or a S/E/E8 complex could dictate its Ras- or Rac-specific GEF activities, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / suggest-01 :ARG0 (e5 / exist-01 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :xref (x4 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :location (p2 / pool :quant "2" :ARG0-of (f / function-01 :manner (d / distinct)) :mod (p3 / physical))) :ARG1 (h / hypothesize-01 :ARG1 (p4 / possible-01 :ARG1 (d2 / dictate-01 :ARG0 (p7 / present-02 :ARG1 p :ARG2 (o / or :op1 (m / macro-molecular-complex :part p :part (p5 / protein :name (n2 / name :op1 "Grb2") :xref (x3 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :op2 (m2 / macro-molecular-complex :part p :part (p6 / protein :name (n3 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :part (e / enzyme :name (n4 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) :ARG1 (a / activity-06 :ARG0 p :ARG1 (p8 / protein :name (n5 / name :op1 "GEF") :xref (x2 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :mod (r / respective) :ARG1-of (s2 / specific-02 :ARG2 (o2 / or :op1 (p9 / protein-family :name (n6 / name :op1 "Ras")) :op2 (p10 / protein-family :name (n7 / name :op1 "Rac"))))))))) # ::id pmid_1177_7939.96 # ::date 2015-03-03T15:27:23 # ::file pmid_1177_7939_96.txt # ::snt To explore this possibility, we used an in vitro assay that can score GEF activities in Sos-1–containing immunoprecipitates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (a / assay-01 :ARG0-of (s / score-01 :ARG1 (a2 / activity-06 :ARG0 (p4 / protein :name (n / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :location (m / molecular-physical-entity :ARG1-of (i / immunoprecipitate-01) :ARG0-of (c / contain-01 :ARG1 (p / protein :name (n2 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))) :ARG1-of (p2 / possible-01)) :manner (i2 / in-vitro)) :ARG2 (e2 / explore-01 :ARG0 w :ARG1 (p3 / possible-01 :mod (t / this)))) # ::id pmid_1177_7939.97 # ::date 2015-03-04T03:33:04 # ::file pmid_1177_7939_97.txt # ::snt Cells were transfected with either Sos-1 alone (SosTfx) or a combination of S/E/E8 (Triple Tfx) (Fig. 7 A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 10, 2015 (t / transfect-01 :ARG1 (c / cell) :ARG2 (o / or :op1 (p / protein :name (n / name :op1 "Sos-1") :mod (a / alone) :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :op2 (c2 / combine-01 :ARG3 (m / macro-molecular-complex :part p :part (p2 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :part (e / enzyme :name (n3 / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7A"))) # ::id pmid_1177_7939.98 # ::date 2015-03-04T05:11:10 # ::file pmid_1177_7939_98.txt # ::snt When Sos-1 was immunoprecipitated from SosTfx, it displayed Ras-GEF, but not Rac-GEF, activity (Fig. 7 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / cause-01 :ARG0 (i / immunoprecipitate-01 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG2 (p2 / protein :name (n2 / name :op1 "SosTfx") :xref (x / xref :value "UNIPROT:SOST_HUMAN" :prob "0.222"))) :ARG1 (c2 / contrast-01 :ARG1 (d / display-01 :ARG0 p :ARG1 (a / activity-06 :ARG0 (p3 / protein :name (n4 / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (e2 / enzyme :name (n5 / name :op1 "Ras") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (d3 / display-01 :polarity "-" :ARG0 p :ARG1 (a2 / activity-06 :ARG0 p3 :ARG1 (e3 / enzyme :name (n7 / name :op1 "Rac") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7B"))) # ::id pmid_1177_7939.99 # ::date 2015-03-04T06:28:34 # ::file pmid_1177_7939_99.txt # ::snt Of note, little E3b1 and no Eps8 could be detected in Sos-1 immunoprecipitates (Fig. 7 A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a2 / and :op1 (p / possible-01 :ARG1 (d / detect-01 :ARG1 (p2 / protein :name (n / name :op1 "E3b1") :quant (l / little) :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :location (p3 / protein :name (n4 / name :op1 "Sos-1") :ARG1-of (i / immunoprecipitate-01) :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :op2 (p4 / possible-01 :polarity "-" :ARG1 (d3 / detect-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :location p3)) :ARG1-of (n3 / note-01 :ARG1-of (r / recommend-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7A"))) # ::id pmid_1177_7939.100 # ::date 2015-03-04T07:02:28 # ::file pmid_1177_7939_100.txt # ::snt Conversely, Grb2 was readily recovered from the same immunoprecipitates (unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / contrast-01 :ARG2 (r / recover-02 :ARG1 (p / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2 (m / molecular-physical-entity :ARG1-of (i / immunoprecipitate-01) :ARG1-of (s / same-01)) :manner (r2 / ready) :ARG1-of (d2 / describe-01 :ARG0 (d / data :ARG1-of (p2 / publish-01 :polarity "-"))))) # ::id pmid_1177_7939.101 # ::date 2015-03-04T15:00:32 # ::file pmid_1177_7939_101.txt # ::snt We then used the Triple Tfx and coimmunoprecipitated Sos-1 with anti-Eps8 antibodies (Fig. 7, A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (a / and :op1 (u / use-01 :ARG0 (w / we) :ARG1 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :part (p2 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :part (e / enzyme :name (n4 / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :ARG2-of (t2 / transfect-01)) :time (t / then)) :op2 (c / coimmunoprecipitate-01 :ARG1 p :ARG3 (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 e))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7B")))) # ::id pmid_1177_7939.102 # ::date 2015-03-04T16:06:19 # ::file pmid_1177_7939_102.txt # ::snt Under these conditions, all of the coimmunoprecipitated Sos-1 is present in the S/E/E8 tricomplex (Scita et al., 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 14, 2015 (h / have-condition-91 :ARG1 (p6 / present-02 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :mod (a / all) :ARG1-of (c / coimmunoprecipitate-01) :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG2 (m / macro-molecular-complex :part p :part (p2 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :part (e / enzyme :name (n3 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))) :ARG2 (t / this) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n4 / name :op1 "Scita")) :op2 (p5 / person :mod (o / other))) :time (d2 / date-entity :year "1999")))) # ::id pmid_1177_7939.103 # ::date 2015-03-04T16:34:23 # ::file pmid_1177_7939_103.txt # ::snt Despite lower levels of Sos-1 in the coimmunoprecipitate (with respect to a Sos-1 immunoprecipitate from SosTfx), Rac-GEF activity was now present (Fig. 7 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / present-02 :ARG1 (a / activity-06 :ARG0 (m3 / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :part (e2 / enzyme :name (n3 / name :op1 "Rac") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :time (n4 / now) :topic (i / immunoprecipitate-01 :ARG1 "p2" :ARG2 (p3 / protein :name (n5 / name :op1 "SosTfx") :xref (x / xref :value "UNIPROT:SOST_HUMAN" :prob "0.222"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7B")) :concession (l2 / low-04 :ARG1 (l / level :location (m2 / molecular-physical-entity :ARG1-of (c / coimmunoprecipitate-01)) :quant-of (p2 / protein :name (n / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :degree (m / more))) # ::id pmid_1177_7939.104 # ::date 2015-03-04T17:13:18 # ::file pmid_1177_7939_104.txt # ::snt Conversely, no Ras-GEF activity could be detected (Fig. 7 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG2 (p / possible-01 :polarity "-" :ARG1 (d / detect-01 :ARG1 (a / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :beneficiary (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7B"))))) # ::id pmid_1177_7939.105 # ::date 2015-03-04T17:22:59 # ::file pmid_1177_7939_105.txt # ::snt The lack of Ras-GEF activity was not due to the low levels of Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / cause-01 :polarity "-" :ARG0 (l / level :ARG1-of (l2 / low-04 :quant-of (p / protein :name (n / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :ARG1 (l3 / lack-01 :ARG1 (a / activity-06 :ARG0 (p2 / protein :name (n3 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) # ::id pmid_1177_7939.106 # ::date 2015-03-05T01:18:29 # ::file pmid_1177_7939_106.txt # ::snt To prove this point, we immunoprecipitated from SosTfx an amount of Sos-1 comparable to that present in anti-Eps8 immunoprecipitates from Triple Tfx (Fig. 7, A and B, lanes SosTfx1/10). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / immunoprecipitate-01 :ARG0 (w / we) :ARG1 (p / protein :name (n / name :op1 "SosTfx") :xref (x4 / xref :value "UNIPROT:SOST_HUMAN" :prob "0.222")) :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1") :quant (a / amount :ARG1-of (c / comparable-03 :ARG2 (p3 / protein :name (n3 / name :op1 "Sos-1") :quant-of (a2 / amount :ARG1-of (p8 / present-02 :ARG2 (m / molecular-physical-entity :ARG1-of (i2 / immunoprecipitate-01 :ARG2 (m2 / macro-molecular-complex :part p3 :part (p4 / protein :name (n5 / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :part "e" :ARG2-of (t3 / transfect-01))) :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n4 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :mod (t / that)))) :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (p5 / possible-01))) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :purpose (p6 / prove-01 :ARG0 w :ARG1 (p7 / point :mod (t2 / this))) :ARG1-of (d / describe-01 :ARG0 (l2 / lane :ARG1-of (l / label-01 :ARG2 (s / string-entity :value "SosTfx1/10")) :part-of (a3 / and :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7B"))))) # ::id pmid_1177_7939.107 # ::date 2015-03-05T13:41:12 # ::file pmid_1177_7939_107.txt # ::snt Under these conditions, Ras-GEF activity was readily detectable (Fig. 7 B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (h / have-condition-91 :ARG1 (a / activity-06 :ARG0 (p / protein :name (n2 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (d / detect-01 :ARG1-of (p2 / possible-01) :manner (r / ready))) :ARG2 (t / this) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7B"))) # ::id pmid_1177_7939.108 # ::date 2015-03-05T13:59:01 # ::file pmid_1177_7939_108.txt # ::snt The detection of Rac-specific GEF activity in anti-Eps8 immunoprecipitates strictly required the presence of Sos-1, since no GEF activity was detected in Eps8 immunoprecipitates, in the absence of coexpressed Sos-1 (Scita et al., 1999; unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (r / require-01 :ARG0 (d / detect-01 :ARG1 (a / activity-06 :ARG0 (p7 / protein :name (n2 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :location (m / molecular-physical-entity :ARG1-of (i / immunoprecipitate-01) :ARG0-of (c / counter-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))) :ARG1-of (s / specific-02 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))))) :ARG1 (p2 / present-02 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :ARG2-of (c3 / coexpress-01) :xref (x3 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :manner (s2 / strict) :ARG1-of (c2 / cause-01 :ARG0 (d2 / detect-01 :polarity "-" :ARG1 (a2 / activity-06 :ARG0 p7) :manner (a3 / absent-01 :ARG1 p) :location (m2 / molecular-physical-entity :ARG1-of (i2 / immunoprecipitate-01 :ARG2 e3)))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p3 / publication-91 :ARG0 (a5 / and :op1 (p4 / person :name (n6 / name :op1 "Scita")) :op2 (p5 / person :mod (o / other))) :time (d4 / date-entity :year "1999")) :op2 (d5 / data :ARG1-of (p6 / publish-01 :polarity "-"))))) # ::id pmid_1177_7939.109 # ::date 2015-03-05T14:53:09 # ::file pmid_1177_7939_109.txt # ::snt Furthermore, no Rac-GEF activity could be detected in Eps8 immunoprecipitates from lysates of cells transfected with Sos-1, E3b1, and an Eps8 mutant that is impaired in its ability to bind E3b1 and thereby cannot form a trimeric complex (Scita et al., 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op2 (p / possible-01 :polarity "-" :ARG1 (d / detect-01 :ARG1 (a2 / activity-06 :ARG0 (p9 / protein :name (n2 / name :op1 "GEF") :xref (x5 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (e2 / enzyme :name (n3 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :name (n7 / name :op1 "Scita")) :op2 (p8 / person :mod (o / other))) :time (d3 / date-entity :year "1999"))) :location (e3 / enzyme :name (n4 / name :op1 "Eps8") :ARG1-of (i / immunoprecipitate-01 :ARG2 (l / lysate :domain (c / cell) :ARG1-of (t / transfect-01 :ARG2 (a3 / and :op1 (p2 / protein :name (n / name :op1 "Sos-1") :xref (x3 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :op2 (p3 / protein :name (n5 / name :op1 "E3b1") :xref (x4 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op3 (e4 / enzyme :name (n6 / name :op1 "Eps8") :ARG1-of (m2 / mutate-01) :ARG0-of (b / bind-01 :ARG1 p3 :ARG1-of (p4 / possible-01 :ARG1-of (i2 / impair-01 :ARG0-of (c2 / cause-01 :ARG1 (p5 / possible-01 :polarity "-" :ARG1 (f / form-01 :ARG0 e4 :ARG1 (m3 / macro-molecular-complex :mod (t2 / trimer)))))))) :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))))) :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) # ::id pmid_1177_7939.110 # ::date 2015-03-05T14:53:27 # ::file pmid_1177_7939_110.txt # ::snt At this stage, we cannot formally exclude that an unknown GEF, coprecipitating with Sos-1, is responsible for the observed activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (p / possible-01 :polarity "-" :ARG1 (e / exclude-01 :ARG0 (w / we) :ARG1 (r / responsible-01 :ARG0 (p3 / protein :name (n2 / name :op1 "GEF") :ARG1-of (k / know-01 :polarity "-") :op1-of (a2 / and :op2 (p2 / protein :name (n3 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (c / coprecipitate-01)) :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (a / activity-06 :ARG1-of (o / observe-01))) :time (s / stage :mod (t / this)) :manner (f / formal))) # ::id pmid_1177_7939.111 # ::date 2015-03-05T16:08:58 # ::file pmid_1177_7939_111.txt # ::snt However, such a hypothetical protein should not only be associated with Sos-1, but also be active only in the presence of Eps8 and E3b1, which are both required for the formation of the trimeric complex endowed with Rac-specific GEF activity (Scita et al., 1999), making this possibility unlikely. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG2 (a / and :op1 (r / recommend-01 :ARG1 (a2 / associate-01 :ARG1 (p / protein :ARG1-of (h / hypothetical-02) :mod (s / such)) :ARG2 (p2 / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :mod (o / only))) :op2 (a3 / activity-06 :ARG0 p :mod (a4 / also) :condition (p3 / present-02 :ARG1 (a5 / and :op1 (e / enzyme :name (n2 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :op2 (p4 / protein :name (n3 / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1-of (r2 / require-01 :purpose (f / form-01 :ARG1 (m / macro-molecular-complex :mod (t / trimer) :ARG2-of (e2 / endow-01 :ARG1 (a6 / activity-06 :ARG0 (p9 / protein :name (n4 / name :op1 "GEF") :xref (x4 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1-of (s2 / specific-02 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))))))))))) :ARG0-of (m2 / make-02 :ARG1 (l / likely-01 :polarity "-" :ARG1 (p5 / possible-01 :ARG1 p :mod (t2 / this))))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a7 / and :op1 (p7 / person :name (n6 / name :op1 "Scita")) :op2 (p8 / person :mod (o2 / other))) :time (d2 / date-entity :year "1999")))) # ::id pmid_1177_7939.112 # ::date 2015-03-05T16:09:22 # ::file pmid_1177_7939_112.txt # ::snt It is reasonable, therefore, to propose that Sos-1 alone (or complexed with proteins, such as Grb2) is endowed with Ras-GEF activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / cause-01 :ARG1 (r / reasonable-02 :ARG1 (p / propose-01 :ARG1 (e3 / endow-01 :ARG1 (a / activity-06 :ARG0 (p5 / protein :name (n3 / name :op1 "GEF") :xref (x2 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 (o / or :op1 (p2 / protein :name (n / name :op1 "Sos-1") :mod (a2 / alone) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :op2 (m / macro-molecular-complex :part p2 :part (p3 / protein :example (p4 / protein :name (n2 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))))))) # ::id pmid_1177_7939.113 # ::date 2015-03-06T01:55:36 # ::file pmid_1177_7939_113.txt # ::snt However, upon interaction with Eps8 and E3b1, its specificity is switched toward Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (h / have-concession-91 :ARG1 (s / switch-01 :ARG1 (s2 / specificity :poss (i2 / it)) :ARG2 (e3 / enzyme :name (n3 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :time (i / interact-01 :ARG0 i2 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))))) # ::id pmid_1177_7939.114 # ::date 2015-03-06T06:56:14 # ::file pmid_1177_7939_114.txt # ::snt A common feature of proteins endowed with GEF catalytic activity is their ability to bind to their specific nucleotide-depleted GTPase with relative high affinities. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (f / feature :ARG1-of (s2 / share-01 :ARG0 "p") :domain (c / capable-01 :ARG1 (p / protein :ARG2-of (e2 / endow-01 :ARG1 (a / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (c2 / catalysis)))) :ARG2 (b / bind-01 :ARG1 p :ARG2 (e / enzyme :name (n / name :op1 "GTPase") :ARG1-of (s3 / specific-02) :ARG1-of (d / deplete-01 :ARG2 (n3 / nucleotide)) :poss p :xref (x1 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :manner (a2 / affinity :ARG1-of (h / high-02 :ARG2-of (r / relative-05)))))) # ::id pmid_1177_7939.115 # ::date 2015-03-06T09:11:13 # ::file pmid_1177_7939_115.txt # ::snt Thus, one might postulate that Sos-1 associates with the nucleotide-free form of Rac exclusively when engaged in the S/E/E8 complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / cause-01 :ARG1 (p8 / possible-01 :ARG1 (p5 / postulate-01 :ARG0 (p6 / person) :ARG1 (a / associate-01 :ARG1 (p7 / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG2 (f / form :ARG1-of (f2 / free-04 :ARG2 (n2 / nucleotide)) :mod (e / enzyme :name (n3 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG0-of (e2 / exclusive-02) :time (e3 / engage-01 :ARG1 p7 :ARG2 (m / macro-molecular-complex :part (p / protein :name (n4 / name :op1 "S") :xref (x1 / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :part (p3 / protein :name (n5 / name :op1 "E")) :part (p4 / protein :name (n6 / name :op1 "E8")))))))) # ::id pmid_1177_7939.116 # ::date 2015-03-06T09:48:01 # ::file pmid_1177_7939_116.txt # ::snt Purified and nucleotide depleted, GST-Rac and GST-Cdc42 proteins were therefore used to test their ability to interact with Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 12, 2015 (c2 / cause-01 :ARG1 (u2 / use-01 :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "GST-Rac") :xref (x / xref :value "UNIPROT:CHST3_HUMAN" :prob "0.212")) :op2 (p3 / protein :name (n3 / name :op1 "GST-Cdc42") :xref (x2 / xref :value "UNIPROT:CHST2_HUMAN" :prob "0.252")) :ARG1-of (p / purify-01) :ARG1-of (d / deplete-01 :ARG2 (n / nucleotide))) :ARG2 (t2 / test-01 :ARG1 (c / capable-01 :ARG1 a :ARG2 (i / interact-01 :ARG0 a :ARG1 (p4 / protein :name (n4 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))))) # ::id pmid_1177_7939.117 # ::date 2015-03-07T13:01:08 # ::file pmid_1177_7939_117.txt # ::snt Native Sos-1, present in lysates of −/− [Eps8myc] fibroblasts, could be specifically recovered with nucleotide-depleted immobilized GST-Rac, but not with GST-Cdc42 or GST alone (Fig. 7 C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (c / contrast-01 :ARG1 (r / recover-01 :ARG1 (p2 / protein :name (n / name :op1 "Sos-1") :mod (n2 / native) :ARG1-of (p6 / present-02 :ARG2 (l / lysate :mod (f / fibroblast :mod (p5 / protein :name (n3 / name :op1 "Eps8myc") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x4 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.213"))))) :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :instrument (p4 / protein :name (n4 / name :op1 "GST-Rac") :ARG1-of (i / immobilize-01) :ARG1-of (d / deplete-01 :ARG2 (n7 / nucleotide)) :xref (x3 / xref :value "UNIPROT:CHST3_HUMAN" :prob "0.212")) :ARG1-of (s / specific-02)) :ARG2 (r2 / recover-01 :polarity "-" :ARG1 p2 :instrument (o / or :op1 (p3 / protein :name (n5 / name :op1 "GST-Cdc42") :xref (x2 / xref :value "UNIPROT:CHST2_HUMAN" :prob "0.252")) :op2 (e2 / enzyme :name (n12 / name :op1 "GST") :xref (x / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :mod (a / alone)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "7C"))) # ::id pmid_1177_7939.118 # ::date 2015-03-08T03:48:57 # ::file pmid_1177_7939_118.txt # ::snt Conversely, no Sos-1 could be recovered with GST-Rac from lysates of eps8−/− cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 1, 2015 (p / possible-01 :ARG1 (r / recover-02 :ARG1 (p2 / protein :polarity "-" :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG2 (l / lysate :mod (c2 / cell :mod (e / enzyme :name (n3 / name :op1 "eps8") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))) :instrument (p3 / protein :name (n2 / name :op1 "GST-Rac") :xref (x1 / xref :value "UNIPROT:CHST3_HUMAN" :prob "0.212"))) :manner (c / converse)) # ::id pmid_1177_7939.119 # ::date 2015-03-06T09:48:54 # ::file pmid_1177_7939_119.txt # ::snt Thus, Eps8 is required for the association between Sos-1 and nucleotide-free Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (c / cause-01 :ARG1 (r / require-01 :ARG1 (e / enzyme :name (n / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :purpose (a / associate-01 :ARG1 (p / protein :name (n2 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG2 (e2 / enzyme :name (n3 / name :op1 "Rac") :ARG1-of (f / free-04 :ARG2 (n4 / nucleotide)) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))))) # ::id pmid_1177_7939.120 # ::date 2015-03-07T05:48:04 # ::file pmid_1177_7939_120.txt # ::snt Furthermore, under conditions in which the Eps8–E3b1 or the E3b1–Sos-1 interactions were disrupted by specifically competing peptides, a reduction of >80% in the amount of Sos-1 bound to nucleotide-depleted Rac was observed (Fig. 7 C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a2 / and :op2 (o / observe-01 :ARG1 (r / reduce-01 :ARG1 (a / amount :quant-of (p3 / protein :name (n / name :op1 "Sos-1") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Rac") :ARG1-of (d / deplete-01 :ARG2 (n3 / nucleotide)) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :ARG2 (p / percentage-entity :value "80" :degree (m / more))) :condition (d2 / disrupt-01 :ARG0 (p2 / peptide :ARG0-of (c / compete-01 :ARG1-of (s / specific-02))) :ARG1 (o2 / or :op1 (i / interact-01 :ARG0 (a3 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :op2 (p5 / protein :name (n5 / name :op1 "E3b1") :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :op2 (i2 / interact-01 :ARG0 (a4 / and :op1 p5 :op2 p3))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "7C"))) # ::id pmid_1177_7939.121 # ::date 2015-03-08T04:14:26 # ::file pmid_1177_7939_121.txt # ::snt This latter result strongly suggests that an intact S/E/E8 complex is required for binding to Rac, providing a molecular basis for the catalytic specificity of the complex. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (l / latter) :mod (t2 / this)) :ARG1 (r2 / require-01 :ARG1 (m2 / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "S") :xref (x / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :part (p3 / protein :name (n2 / name :op1 "E")) :part (p4 / protein :name (n3 / name :op1 "E8")) :mod (i / intact) :ARG0-of (p / provide-01 :ARG1 (b2 / basis :mod (m / molecule)) :ARG2 (s3 / specificity :mod (c / catalysis) :poss m2))) :purpose (b / bind-01 :ARG2 (e / enzyme :name (n4 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :ARG1-of (s2 / strong-02)) # ::id pmid_1177_7939.122 # ::date 2015-03-06T08:14:47 # ::file pmid_1177_7939_122.txt # ::snt RTK activation differentially regulates the S/G and S/E/E8 complexes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 12, 2015 (r / regulate-01 :ARG0 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "RTK") :xref (x1 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262"))) :ARG1 (a2 / and :op1 (m / macro-molecular-complex :part (p / protein :name (n2 / name :op1 "S") :xref (x2 / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :part (p2 / protein :name (n3 / name :op1 "G") :xref (x / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601"))) :op2 (m2 / macro-molecular-complex :part p :part (p3 / protein :name (n4 / name :op1 "E")) :part (p4 / protein :name (n5 / name :op1 "E8")))) :manner (d / differential)) # ::id pmid_1177_7939.123 # ::date 2015-03-06T08:28:35 # ::file pmid_1177_7939_123.txt # ::snt Since S/G and S/E complexes are present in the cells simultaneously, then both Sos-1-dependent Ras- and Rac-GEF activities are present at the same time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a5 / and :op1 (a2 / activity-06 :ARG0 (m / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part (p5 / protein :name (n2 / name :op1 "GEF") :xref (x3 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG0-of (d / depend-01 :ARG1 (p6 / protein :name (n3 / name :op1 "Sos-1") :xref (x4 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))) :op2 (a / activity-06 :ARG0 (m2 / macro-molecular-complex :part (e3 / enzyme :name (n4 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :part p5)) :ARG1-of (c / cause-01 :ARG0 (a4 / and :op1 (m3 / macro-molecular-complex :part (p / protein :name (n6 / name :op1 "S") :xref (x5 / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :part (p2 / protein :name (n7 / name :op1 "G") :xref (x / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601"))) :ARG1-of (p4 / present-02 :ARG2 (c2 / cell) :time (s / simultaneous)))) :ARG1-of (p3 / present-02 :time (t / time :ARG1-of (s3 / same-01)))) # ::id pmid_1177_7939.124 # ::date 2015-03-06T06:57:04 # ::file pmid_1177_7939_124.txt # ::snt The question remains as to how these two complexes, and the ensuing Ras and Rac activities, are coordinated to achieve propagation of signals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (q / question-01 :ARG1 (t / thing :manner-of (c / coordinate-01 :ARG1 (a2 / and :op1 (m / macro-molecular-complex :quant "2" :mod (t2 / this)) :op2 (a3 / and :op1 (a5 / act-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (a4 / act-02 :ARG0 (e4 / enzyme :name (n3 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG1-of (e2 / ensue-01))) :purpose (a / achieve-01 :ARG0 m :ARG1 (p / propagate-01 :ARG1 (s / signal))))) :ARG1-of (r / remain-01)) # ::id pmid_1177_7939.125 # ::date 2015-03-06T07:12:35 # ::file pmid_1177_7939_125.txt # ::snt We therefore looked for evidence of differential regulation of the S/G and S/E complex upon RTK stimulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 21, 2015 (c / cause-01 :ARG1 (l2 / look-01 :ARG0 (w / we) :ARG1 (e / evidence-01 :ARG1 (r / regulate-01 :ARG1 (a / and :op1 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "S") :xref (x1 / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :part (p2 / protein :name (n2 / name :op1 "G") :xref (x / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601"))) :op2 (m2 / macro-molecular-complex :part (p4 / protein :name (n5 / name :op1 "E")) :part p)) :mod (d / differential) :condition (s / stimulate-01 :ARG2 (e4 / enzyme :name (n3 / name :op1 "RTK") :xref (x2 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262"))))))) # ::id pmid_1177_7939.126 # ::date 2015-03-06T08:02:20 # ::file pmid_1177_7939_126.txt # ::snt Upon PDGF stimulation, we observed decreased coimmunoprecipitation between Grb2 and Sos-1 and consequently between PDGFR and Sos-1 (Fig. 8, A and B), which correlated with the appearance of a mobility-retarded form of Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (a / and :op1 (c / coimmunoprecipitate-01 :ARG1 (p4 / protein :name (n / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2 (p3 / protein :name (n2 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (d / decrease-01)) :op2 (c3 / coimmunoprecipitate-01 :ARG1 (p / protein :name (n3 / name :op1 "PDGFR") :xref (x3 / xref :value "UNIPROT:PGFRB_HUMAN" :prob "1.003")) :ARG2 p3 :ARG1-of (c2 / cause-01 :ARG0 c)) :ARG1-of (c4 / correlate-01 :ARG2 (a2 / appear-01 :ARG1 (f4 / form :mod p3 :ARG1-of (r / retard-01 :ARG2 (m / mobility))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "8A") :op2 (f2 / figure :mod "8B")))) :condition (s / stimulate-01 :ARG0 (p2 / protein :name (n4 / name :op1 "PDGF") :xref (x / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")))) # ::id pmid_1177_7939.127 # ::date 2015-03-08T08:55:41 # ::file pmid_1177_7939_127.txt # ::snt This likely represents a hyperphosphorylated form of Sos-1, as previously demonstrated (Baltensperger et al., 1993; Cherniack et al., 1994; Pronk et al., 1994). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (l / likely-01 :ARG1 (r / represent-01 :ARG0 (t / this) :ARG1 (f / form :ARG3-of (h / hyperphosphorylate-01) :mod (p / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :compared-to (d3 / demonstrate-01 :time (p2 / previous))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (p3 / publication-91 :ARG0 (a2 / and :op1 (p6 / person :name (n2 / name :op1 "Baltensperger")) :op2 (p9 / person :mod (o / other))) :time (d / date-entity :year "1993")) :op2 (p4 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n3 / name :op1 "Cherniack")) :op2 (p10 / person :mod (o2 / other))) :time (d2 / date-entity :year "1994")) :op3 (p5 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n4 / name :op1 "Pronk")) :op2 (p11 / person :mod (o3 / other))) :time (d5 / date-entity :year "1994"))))) # ::id pmid_1177_7939.128 # ::date 2015-03-07T03:43:20 # ::file pmid_1177_7939_128.txt # ::snt Conversely, under identical conditions, the coimmunoprecipitation between E3b1 and Sos-1 was not affected (Fig. 8 A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (a / affect-01 :polarity "-" :ARG1 (c4 / coimmunoprecipitate-01 :ARG1 (p3 / protein :name (n / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8A")) :mod (c / converse) :condition (c3 / condition :ARG1-of (i / identical-01))) # ::id pmid_1177_7939.129 # ::date 2015-03-07T12:11:25 # ::file pmid_1177_7939_129.txt # ::snt Similarly, the stability of the endogenous trimeric complex, Sos-1/Eps8/E3b1 was not affected by treatment of cells with growth factors (Fig. 8 C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a / affect-01 :polarity "-" :ARG0 (t / treat-04 :ARG1 (c / cell) :ARG2 (g / growth-factor)) :ARG1 (s2 / stable-03 :ARG1 (m / macro-molecular-complex :mod (t2 / trimeric) :mod (e / endogenous) :part (p / protein :name (n / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :part (e2 / enzyme :name (n2 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :part (p3 / protein :name (n3 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8C")) :ARG1-of (r / resemble-01)) # ::id pmid_1177_7939.130 # ::date 2015-03-06T08:32:08 # ::file pmid_1177_7939_130.txt # ::snt The above data indicate that, as a consequence of activation of RTKs, the S/G complex is disrupted, whereas the S/E/E8 complex persists in the cell. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 12, 2015 (i / indicate-01 :ARG0 (d / data :location (a / above)) :ARG1 (c / contrast-01 :ARG1 (d2 / disrupt-01 :ARG1 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "S") :xref (x1 / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :part (p2 / protein :name (n2 / name :op1 "G") :xref (x / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601")))) :ARG2 (p3 / persist-01 :ARG1 (m2 / macro-molecular-complex :part (p5 / protein :name (n4 / name :op1 "E")) :part (p6 / protein :name (n5 / name :op1 "E8")) :part p) :location (c2 / cell)) :ARG1-of (c3 / cause-01 :ARG0 (a2 / activate-01 :ARG1 (e / enzyme :name (n6 / name :op1 "RTK") :xref (x2 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")))))) # ::id pmid_1177_7939.131 # ::date 2015-03-06T08:03:19 # ::file pmid_1177_7939_131.txt # ::snt This might lead to a transient peak in Ras activity vis a vis a more prolonged activation of Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (p / possible-01 :ARG1 (l / lead-03 :ARG0 (t / this) :ARG2 (p2 / peak-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (t2 / transient-02)) :purpose (a2 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1-of (p3 / prolong-01 :degree (m / more))))) # ::id pmid_1177_7939.132 # ::date 2015-03-06T12:52:24 # ::file pmid_1177_7939_132.txt # ::snt Therefore, we measured the kinetic of RTK-induced activation of Ras and Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / cause-01 :ARG1 (m / measure-01 :ARG0 (w / we) :ARG1 (k / kinetics :mod (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n2 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG2-of (i / induce-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "RTK") :xref (x1 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262"))))))) # ::id pmid_1177_7939.133 # ::date 2015-03-06T13:02:18 # ::file pmid_1177_7939_133.txt # ::snt As shown in Fig. 8 D, activation of Ras was rapid and short lived, whereas activation of Rac was sustained over a longer period of time, compatible with the differential regulation of the corresponding activating complexes, S/G and S/E/E8. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (a / and :op1 (r / rapid :domain (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (l / live-01 :ARG0 a2 :ARG1-of (s / short-07))) :ARG2 (s2 / sustain-01 :ARG1 (a3 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG1-of (l2 / long-03 :degree (m / more) :mod (c2 / compatible :prep-with (r2 / regulate-01 :ARG1 (a4 / and :op1 (m2 / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "S") :xref (x / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :part (p3 / protein :name (n5 / name :op1 "G") :xref (x2 / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601"))) :op2 (m3 / macro-molecular-complex :part (p5 / protein :name (n6 / name :op1 "E")) :part (p6 / protein :name (n7 / name :op1 "E8")) :part p2) :ARG0-of (a5 / activate-01 :ARG1-of (c3 / correspond-02))) :ARG1-of (d / differ-02))))) :ARG1-of (s3 / show-01 :ARG0 (f / figure :mod "8D"))) # ::id pmid_1177_7939.198 # ::date 2015-03-06T14:02:57 # ::file pmid_1177_7939_198.txt # ::snt Figure 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 6, 2015 (f / figure :mod "1") # ::id pmid_1177_7939.199 # ::date 2015-03-06T14:03:38 # ::file pmid_1177_7939_199.txt # ::snt The S/E/E8 complex exists under physiological conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (e / exist-01 :ARG1 (m / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "S") :xref (x / xref :value "UNIPROT:Q0EFA5_HUMAN" :prob "1.001")) :part (p3 / protein :name (n2 / name :op1 "E")) :part (p4 / protein :name (n3 / name :op1 "E8"))) :condition (p / physiology)) # ::id pmid_1177_7939.200 # ::date 2015-03-06T14:07:31 # ::file pmid_1177_7939_200.txt # ::snt (A) Eps8−/− cells were transfected with a control vector (−/− lanes) or a vector coding a myc epitope–tagged Eps8 (−/− [Eps8myc] lanes), both carrying a hygromicin resistance gene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (t / transfect-01 :li "A" :ARG1 (c / cell :ARG0-of (c6 / contain-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Eps8") :ARG2-of "m4" :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))) :ARG2 (o / or :op1 (v / vector :ARG0-of (c2 / control-01) :ARG1-of (d / describe-01 :ARG2 (l / lane :ARG2-of (m4 / mutate-01 :mod "−/−")))) :op2 (v2 / vector :ARG0-of (c3 / code-01 :ARG1 (c4 / cell :ARG0-of (c7 / contain-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Eps8") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :ARG1-of (t2 / tag-01 :ARG2 (e / epitope :mod (p / protein :name (n3 / name :op1 "myc") :xref (x3 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")))))) :ARG1-of (m2 / mean-01 :ARG2 (l2 / lane :mod (p2 / protein :name (n5 / name :op1 "Eps8myc") :ARG2-of m4 :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.213"))))) :ARG0-of (c5 / carry-01 :ARG1 (g / gene :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "hygromicin"))))))) # ::id pmid_1177_7939.201 # ::date 2015-03-06T14:21:18 # ::file pmid_1177_7939_201.txt # ::snt Hygromicin-resistant single-cell clones were established after 10 d of selection with hygromicin (0.2 mg/ml). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (e / establish-01 :ARG1 (c2 / cell :ARG1-of (s / single-02) :ARG0-of (r / resist-01 :ARG1 (s4 / small-molecule :name (n / name :op1 "hygromicin"))) :ARG1-of (c / clone-01)) :time (a / after :op1 (s2 / select-01 :ARG1 c2 :instrument (s3 / small-molecule :quant "0.2" :name (n2 / name :op1 "hygromicin") :quant (c3 / concentration-quantity :quant "0.2" :unit (m3 / milligram-per-milliliter)))) :quant (t / temporal-quantity :quant "10" :unit (d / day)))) # ::id pmid_1177_7939.202 # ::date 2015-03-06T14:37:14 # ::file pmid_1177_7939_202.txt # ::snt The levels of Eps8, PDGFR, and EGFR in individual clones of eps8−/−, −/− [Eps8myc], or in wild-type (WT) cells were determined by immunoblotting analysis of equal amounts of total cellular lysates (50 μg) using the indicated antibodies (WB), and clones with levels of expression of Eps8, PDGFR, and EGFR similar to wild-type fibroblasts were used. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (d / determine-01 :ARG0 (a3 / analyze-01 :ARG1 (a4 / amount :ARG1-of (e2 / equal-01) :quant-of (l4 / lysate :mod (c3 / cell) :ARG1-of (t / total-01 :ARG2 (m / mass-quantity :quant "50" :unit (m2 / microgram))))) :manner (i2 / immunoblot-01) :manner (u / use-01 :ARG1 (a5 / antibody :ARG1-of (i3 / indicate-01) :ARG1-of (d3 / describe-01 :ARG2 (n6 / name :op1 "WB"))))) :ARG1 (a2 / and :op1 (l / level :quant-of (e8 / enzyme :name (n2 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :op2 (l2 / level :quant-of (e4 / enzyme :name (n3 / name :op1 "PDGFR") :xref (x1 / xref :value "UNIPROT:PGFRB_HUMAN" :prob "1.003"))) :op3 (l3 / level :quant-of (e3 / enzyme :name (n4 / name :op1 "EGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :location (o / or :op1 (c / clone-01 :ARG1 (c5 / cell :ARG0-of (c6 / contain-01 :ARG1 (e7 / enzyme :name (n5 / name :op1 "Eps8") :ARG2-of (m3 / mutate-01 :mod "−/−") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))) :mod (i / individual)) :op2 (c7 / clone-01 :ARG1 (c8 / cell :ARG0-of (c9 / contain-01 :ARG1 (p / protein :name (n / name :op1 "Eps8myc") :ARG2-of m3 :xref (x4 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.213"))))) :op3 (c10 / clone-01 :ARG1 (c2 / cell :mod (w / wild-type :ARG1-of (d2 / describe-01 :ARG2 (n7 / name :op1 "WT")))))))) :op2 (u2 / use-01 :ARG1 (c4 / clone :poss-of (a6 / and :op1 (l5 / level :degree-of (e / express-01 :ARG1 e8)) :op2 (l6 / level :degree-of (e5 / express-01 :ARG1 e4)) :op3 (l7 / level :degree-of (e6 / express-01 :ARG1 e3)) :ARG1-of (r / resemble-01 :ARG2 (f / fibroblast :mod w)))))) # ::id pmid_1177_7939.203 # ::date 2015-03-07T01:35:14 # ::file pmid_1177_7939_203.txt # ::snt (B) Total cellular lysates (10 mg), obtained from the transfectants described in A, were immunoprecipitated (IP) with the antibody indicated at the bottom (ctr, irrelevant antibody), followed by immunoblot with indicated antibodies (WB). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / immunoprecipitate-01 :ARG1 (l / lysate :mod (c / cell) :ARG1-of (t / total-01 :ARG2 (m / mass-quantity :quant "10" :unit (m2 / milligram))) :ARG1-of (o / obtain-01 :ARG2 (m3 / molecular-physical-entity :ARG1-of (t2 / transfect-01) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "1A"))))) :ARG3 (a2 / antibody :ARG1-of (i2 / indicate-01 :location (b / bottom)) :ARG1-of (r / relevant-01 :polarity "-") :ARG1-of (d3 / describe-01 :ARG2 (c2 / control))) :ARG2-of (f / follow-01 :ARG1 (i3 / immunoblot-01 :ARG2 l :ARG3 (a3 / antibody :ARG1-of (i4 / indicate-01)))) :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure :mod "1B"))) # ::id pmid_1177_7939.204 # ::date 2015-03-07T01:48:19 # ::file pmid_1177_7939_204.txt # ::snt The indicated lanes (lysates) were loaded with 100 μg of total cellular lysates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (l / load-01 :ARG1 (l2 / lane :ARG1-of (i / indicate-01) :ARG1-of (d / describe-01 :ARG2 (l4 / lysate))) :ARG2 (l3 / lysate :mod (c / cell) :ARG1-of (t / total-01 :ARG2 (m / mass-quantity :quant "100" :unit (m2 / microgram))))) # ::id pmid_1177_7939.205 # ::date 2015-03-07T01:52:36 # ::file pmid_1177_7939_205.txt # ::snt (C) Total cellular lysates (10 mg) obtained from −/− [Eps8myc] cells were immunoprecipitated (IP) with the antibody indicated at the top (ctr, irrelevant antibody) in the presence or absence (−) of 40 ng/ml of the indicated peptides (peptides). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / immunoprecipitate-01 :ARG2 (l / lysate :mod (c / cell) :ARG1-of (t / total-01 :ARG2 (m / mass-quantity :quant "10" :unit (m2 / milligram))) :ARG1-of (o / obtain-01 :ARG2 (c2 / cell :ARG0-of (c4 / contain-01 :ARG1 (p2 / protein :name (n / name :op1 "EPS8myc") :ARG2-of (m3 / mutate-01 :mod "−/−") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.263")))))) :ARG3 (a / antibody :ARG1-of (i2 / indicate-01 :location (t2 / top)) :ARG1-of (r / relevant-01 :polarity "-")) :condition (o2 / or :op1 (p3 / present-02 :ARG1 (p / peptide :ARG1-of (i3 / indicate-01) :quant (c6 / concentration-quantity :quant "40" :unit (n3 / nanogram-per-milliliter)))) :op2 (a2 / absent-01 :ARG1 p)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"))) # ::id pmid_1177_7939.206 # ::date 2015-03-07T02:02:49 # ::file pmid_1177_7939_206.txt # ::snt The peptides used were PPPPPVDYTEDEE (PXXDY) and PPPPPVDATEDEE (PXXDA, used as a control). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (u / use-01 :ARG1 (a / and :op1 (p / peptide :name (n / name :op1 "PPPPPVDYTEDEE") :ARG1-of (d / describe-01 :ARG2 (n3 / name :op1 "PXXDY"))) :op2 (p2 / peptide :name (n2 / name :op1 "PPPPPVDATEDEE") :ARG1-of (u2 / use-01 :ARG2 (c / control-01 :ARG0 p2)) :ARG1-of (d2 / describe-01 :ARG2 (n4 / name :op1 "PXXDA"))))) # ::id pmid_1177_7939.207 # ::date 2015-03-07T02:04:58 # ::file pmid_1177_7939_207.txt # ::snt Immunoblotting was with the indicated antibodies (WB). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (i / immunoblot-01 :ARG3 (a / antibody :ARG1-of (i2 / indicate-01) :ARG1-of (d / describe-01 :ARG2 (n / name :op1 "WB")))) # ::id pmid_1177_7939.208 # ::date 2015-03-07T02:06:04 # ::file pmid_1177_7939_208.txt # ::snt The indicated lanes (lysates) were loaded with 100 μg of total cellular lysates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (l / load-01 :ARG1 (l2 / lane :ARG1-of (i / indicate-01) :ARG1-of (d / describe-01 :ARG2 (l4 / lysate))) :ARG2 (l3 / lysate :ARG1-of (t / total-01 :ARG2 (m / mass-quantity :quant "100" :unit (m2 / microgram))) :mod (c / cell))) # ::id pmid_1177_7939.209 # ::date 2015-03-07T02:07:31 # ::file pmid_1177_7939_209.txt # ::snt Figure 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 7, 2015 (f / figure :mod "2") # ::id pmid_1177_7939.210 # ::date 2015-03-07T02:08:33 # ::file pmid_1177_7939_210.txt # ::snt In vitro competition between E3b1 and Grb2 for binding to Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 8, 2015 (c / compete-01 :ARG0 (p / protein :name (n / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2 (b / bind-01 :ARG2 (p3 / protein :name (n3 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :manner (i / in-vitro)) # ::id pmid_1177_7939.211 # ::date 2015-03-07T02:15:27 # ::file pmid_1177_7939_211.txt # ::snt (A, Top) schematic of E3b1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (s / schematic :poss (p / protein :name (n / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1-of (d / describe-01 :location (f / figure :mod "A" :location (t / top)))) # ::id pmid_1177_7939.212 # ::date 2015-03-07T02:20:03 # ::file pmid_1177_7939_212.txt # ::snt The ruler shows amino acid positions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (s / show-01 :ARG0 (r / ruler) :ARG1 (l / location :ARG2-of (p / position-01 :ARG1 (a / amino-acid)))) # ::id pmid_1177_7939.213 # ::date 2015-03-07T02:21:15 # ::file pmid_1177_7939_213.txt # ::snt (Bottom) In vitro binding of various fragments of E3b1 (all engineered as GST fusions, amino acid boundaries are indicated on the top) to Sos-1 from lysates of Sos-1–transfected Cos-7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (m / multi-sentence :snt1 (b / bind-01 :ARG1 (p2 / protein-segment :part-of (p / protein :name (n / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :mod (v / various)) :ARG2 (p4 / protein :name (n3 / name :op1 "Sos-1") :source (l / lysate :mod (c / cell-line :name (n4 / name :op1 "Cos-7") :ARG1-of (t / transfect-01 :ARG2 p4))) :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :location (b2 / bottom) :manner (i / in-vitro)) :snt2 (a2 / and :op1 (e / engineer-01 :ARG1 (a / all) :ARG2 (p3 / protein :name (n2 / name :op1 "GST" :op2 "fusion") :xref (x / xref :value "UNIPROT:GSTA1_HUMAN" :prob "0.232"))) :op2 (i2 / indicate-01 :ARG1 (b3 / boundary :poss (a3 / amino-acid)) :location (t2 / top)))) # ::id pmid_1177_7939.214 # ::date 2015-03-06T14:38:11 # ::file pmid_1177_7939_214.txt # ::snt Detection was with anti–Sos-1 antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (d / detect-01 :ARG2 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))) # ::id pmid_1177_7939.215 # ::date 2015-03-06T14:39:01 # ::file pmid_1177_7939_215.txt # ::snt The lane “lysate” was loaded with 50 μg of total cellular lysates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (l / load-01 :ARG1 (l2 / lane :ARG1-of (d / describe-01 :ARG2 (l4 / lysate))) :ARG2 (l3 / lysate :mod (c / cell) :ARG1-of (t / total-01 :ARG2 (m / mass-quantity :quant "50" :unit (m2 / microgram))))) # ::id pmid_1177_7939.216 # ::date 2015-03-06T14:47:40 # ::file pmid_1177_7939_216.txt # ::snt P Rich, proline rich region; SH3, SH3 domain. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (a2 / and :op1 (n4 / name :op1 "P" :op2 "Rich" :ARG2-of (d / describe-01 :ARG1 (r2 / rich :mod "a" :domain (r3 / region) :mod (a / amino-acid :name (n / name :op1 "proline") :xref (x / xref :value "PUBCHEM:614" :prob "10.45396"))))) :op2 (n5 / name :op1 "SH3" :ARG2-of (d2 / describe-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "SH3" :op2 "domain"))))) # ::id pmid_1177_7939.217 # ::date 2015-03-06T14:55:25 # ::file pmid_1177_7939_217.txt # ::snt (B) A His-tagged COOH-terminal fragment (His-Sos, aa 1131–1333) of Sos-1 (10 pmoles) was bound to 60 pmoles of either immobilized GST (GST) or GST-E3b1–331–480 in the presence of increasing concentrations of the NH2-terminal SH3 domain of Grb2 or of Eps8 (SH3s, 0, 10, 100, 1,000 pmoles, as indicated on the top). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (m4 / multi-sentence :snt1 (b / bind-01 :li "B" :ARG1 (p / protein-segment :name (n / name :op1 "COOH-terminus") :part-of (p2 / protein :name (n2 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (t / tag-01 :ARG2 (a / amino-acid :name (n3 / name :op1 "histidine") :xref (x5 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :quant (m / mass-quantity :quant "10" :unit (p3 / picomole)) :consist-of (a2 / amino-acid :mod (v / value-interval :op1 "1131" :op2 "1333"))) :ARG2 (o / or :op1 (e / enzyme :name (n4 / name :op1 "GST") :ARG1-of (i3 / immobilize-01) :quant (m3 / mass-quantity :quant "60" :unit (p4 / picomole)) :xref (x2 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :op2 (p5 / protein :name (n5 / name :op1 "GST-E3b1") :consist-of (a3 / amino-acid :mod (v2 / value-interval :op1 "331" :op2 "480")) :xref (x4 / xref :value "UNIPROT:GSTO1_HUMAN" :prob "0.232"))) :condition (p9 / present-02 :ARG1 (c / concentrate-02 :ARG1 (o2 / or :op1 (p15 / protein-segment :name (n11 / name :op1 "SH3" :op2 "domain") :part-of (p6 / protein-segment :name (n6 / name :op1 "NH2-terminus") :part-of (p7 / protein :name (n7 / name :op1 "Grb2") :xref (x3 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")))) :op2 (p16 / protein-segment :name (n12 / name :op1 "SH3" :op2 "domain") :part-of (p8 / protein-segment :name (n8 / name :op1 "NH2-terminus") :part-of (e2 / enzyme :name (n9 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) :ARG1-of (i / increase-01)))) :snt2 (a4 / and :op1 (p10 / protein-segment :name (n10 / name :op1 "SH3")) :op2 (m5 / mass-quantity :quant "0" :unit (p11 / picomole)) :op3 (m6 / mass-quantity :quant "10" :unit (p12 / picomole)) :op4 (m7 / mass-quantity :quant "100" :unit (p13 / picomole)) :op5 (m8 / mass-quantity :quant "1000" :unit (p14 / picomole)) :ARG1-of (i2 / indicate-01 :location (t2 / top)))) # ::id pmid_1177_7939.218 # ::date 2015-03-07T05:59:53 # ::file pmid_1177_7939_218.txt # ::snt Detection was with antihistidine antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (d / detect-01 :ARG2 (a / antibody :ARG0-of (c / counter-01 :ARG1 (a2 / amino-acid :name (n / name :op1 "histidine") :xref (x / xref :value "PUBCHEM:6274" :prob "11.959939"))))) # ::id pmid_1177_7939.219 # ::date 2015-03-07T06:01:10 # ::file pmid_1177_7939_219.txt # ::snt I, input, 10 pmoles of His-Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / input :mod (p / protein :name (n / name :op1 "Sos-1") :ARG1-of (t / tag-01 :ARG2 (a / amino-acid :name (n2 / name :op1 "histidine") :xref (x1 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :quant (m / mass-quantity :quant "10" :unit (p2 / picomole)) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (d / describe-01 :ARG2 (n3 / name :op1 "I"))) # ::id pmid_1177_7939.220 # ::date 2015-03-07T06:27:33 # ::file pmid_1177_7939_220.txt # ::snt (C) His-Sos (10 pmoles) was bound to 60 pmoles of GST fusions encompassing the SH3s of either E3b1 (○ and •) or of Grb2 (□ and ▪). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (b / bind-01 :ARG1 (p / protein :name (n2 / name :op1 "Sos") :ARG1-of (t / tag-01 :ARG2 (a / amino-acid :name (n / name :op1 "histidine") :xref (x4 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :quant (m2 / mass-quantity :quant "10" :unit (p2 / picomole)) :xref (x3 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203")) :ARG2 (p3 / protein :name (n3 / name :op1 "GST" :op2 "fusion") :quant (m3 / mass-quantity :quant "60" :unit (p4 / picomole)) :ARG0-of (e / encompass-01 :ARG1 (o / or :op1 (p5 / protein-segment :name (n4 / name :op1 "SH3") :part-of (p6 / protein :name (n5 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :op2 (p7 / protein-segment :name (n6 / name :op1 "SH3") :part-of (p8 / protein :name (n7 / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))) :xref (x1 / xref :value "UNIPROT:GSTA1_HUMAN" :prob "0.232")) :li "C") # ::id pmid_1177_7939.221 # ::date 2015-03-07T10:11:20 # ::file pmid_1177_7939_221.txt # ::snt Binding was in the presence of the indicated amounts of the competing peptide NH2-VPVPPPVPPRRR-COOH (derived from the sequence of Sos-1, • and ▪), or of a scrambled control peptide (○ and □). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (b / bind-01 :condition (p2 / present-02 :ARG1 (o / or :op1 (a / amount :quant-of (p / peptide :name (n / name :op1 "NH2-VPVPPPVPPRRR-COOH") :ARG0-of (c / compete-01) :ARG1-of (d / derive-01 :ARG2 (s2 / sequence :mod (p3 / protein :name (n2 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))))) :op2 (a2 / amount :quant-of (p4 / peptide :ARG0-of (c2 / control-01) :ARG1-of (s / scramble-02))) :ARG1-of (i / indicate-01)))) # ::id pmid_1177_7939.222 # ::date 2015-03-07T06:34:50 # ::file pmid_1177_7939_222.txt # ::snt Detection was by immunoblot with anti-His, followed by densitometric scanning. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (d / detect-01 :ARG2 (i / immunoblot-01 :ARG3 (a / antibody :ARG0-of (c / counter-01 :ARG1 (h / histidine))) :ARG2-of (f / follow-01 :ARG1 (s / scan-01 :mod (d2 / densitometric))))) # ::id pmid_1177_7939.223 # ::date 2015-03-07T06:36:41 # ::file pmid_1177_7939_223.txt # ::snt (D) Kinetic analysis and rate constants for the binding of the SH3 domains of Grb2 and E3b1 to the proline-rich COOH-terminal of Sos-1 (aa 1131–1333). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :li "D" :op1 (a2 / analyze-01 :ARG1 (k / kinetics)) :op2 (c / constant :mod (r / rate)) :purpose (b / bind-01 :ARG1 (a3 / and :op1 (p / protein-segment :name (n / name :op1 "SH3" :op2 "domain") :part-of (p2 / protein :name (n2 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :op2 (p3 / protein-segment :name (n3 / name :op1 "SH3" :op2 "domain") :part-of (p4 / protein :name (n4 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :ARG2 (p5 / protein-segment :name (n5 / name :op1 "COOH-terminus") :part-of (p6 / protein :name (n6 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :consist-of (a4 / amino-acid :mod (b2 / between :op1 "1131" :op2 "1333")) :mod (r2 / rich :mod (a5 / amino-acid :name (n7 / name :op1 "proline") :xref (x3 / xref :value "PUBCHEM:614" :prob "10.45396")))))) # ::id pmid_1177_7939.224 # ::date 2015-03-07T07:02:44 # ::file pmid_1177_7939_224.txt # ::snt Increasing concentrations (10–400 nM) of His-Sos-1 were passed over the immobilized GST fusion proteins (GST-SH3-Grb2 and GST-SH3-E3b1) for 2.5 min at a flow rate of 50 μl/min. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / pass-08 :ARG0 (c / concentration :ARG1-of (i / increase-01) :mod (p2 / protein :name (n2 / name :op1 "Sos-1") :ARG1-of (t3 / tag-01 :ARG2 (a / amino-acid :name (n / name :op1 "histidine") :xref (x4 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :quant (c2 / concentration-quantity :quant (b / between :op1 "10" :op2 "400") :unit (n3 / nanomolar))) :ARG1 (p3 / protein :name (n4 / name :op1 "GST" :op2 "fusion") :ARG1-of (i2 / immobilize-01) :ARG0-of (m3 / mean-01 :ARG1 (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "GST-SH3-Grb2") :xref (x2 / xref :value "UNIPROT:CHST2_HUMAN" :prob "0.212")) :op2 (p5 / protein :name (n6 / name :op1 "GST-SH3-E3b1") :xref (x3 / xref :value "UNIPROT:CHST1_HUMAN" :prob "0.212")))) :xref (x1 / xref :value "UNIPROT:GSTA1_HUMAN" :prob "0.232")) :duration (t / temporal-quantity :quant "2.5" :unit (m4 / minute)) :frequency (r / rate-entity-91 :ARG1 (v / volume-quantity :quant "50" :unit (m5 / microliter)) :ARG2 (t2 / temporal-quantity :quant "1" :unit (m6 / minute)))) # ::id pmid_1177_7939.225 # ::date 2015-03-07T09:28:34 # ::file pmid_1177_7939_225.txt # ::snt The kinetics of binding are shown in the graphs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (s / show-01 :ARG0 (g / graph) :ARG1 (k / kinetics :mod (b / bind-01))) # ::id pmid_1177_7939.226 # ::date 2015-03-07T09:29:55 # ::file pmid_1177_7939_226.txt # ::snt Coupling of equal amounts of the GST fusion proteins was performed with a goat anti-GST antibody covalently linked to CM5 sensor chip according to the manufacturer's instructions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (p / perform-02 :ARG1 (c / couple-01 :ARG1 (a / amount :quant-of (p2 / protein :name (n / name :op1 "GST" :op2 "fusion") :xref (x / xref :value "UNIPROT:GSTA1_HUMAN" :prob "0.232")) :ARG1-of (e / equal-01)) :ARG2 (a2 / antibody :mod (g / goat) :ARG0-of (c5 / counter-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "GST") :xref (x1 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002"))) :ARG1-of (l / link-01 :ARG2 (c3 / chip :name (n3 / name :op1 "CM5") :mod (s / sensor)) :manner (c2 / covalent)))) :ARG1-of (s2 / say-01 :ARG0 (i / instruct-01 :ARG0 (c4 / company :ARG0-of (m / manufacture-01))))) # ::id pmid_1177_7939.227 # ::date 2015-03-07T09:49:18 # ::file pmid_1177_7939_227.txt # ::snt kon and koff kinetic rates were obtained by simple Langmuir fitting model (biaevaluation software v2.1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (o / obtain-01 :ARG1 (a / and :op1 (r / rate :mod (k / kinetics :ARG1-of (o2 / on-01))) :op2 (r2 / rate :mod (k2 / kinetics :mod (o3 / off)))) :manner (m / model :name (n / name :op1 "Langmuir") :ARG0-of (f / fit-01) :ARG1-of (s / simple-02)) :instrument (s2 / software :mod (b / biaevaluation) :mod (v / version :mod "2.1"))) # ::id pmid_1177_7939.228 # ::date 2015-03-07T05:01:41 # ::file pmid_1177_7939_228.txt # ::snt Figure 3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 7, 2015 (f / figure :mod "3") # ::id pmid_1177_7939.229 # ::date 2015-03-07T05:05:11 # ::file pmid_1177_7939_229.txt # ::snt In vivo competition between E3b1 and Grb2 for binding to Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 7, 2015 (c / compete-01 :ARG0 (p / protein :name (n / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2 (b / bind-01 :ARG2 (p3 / protein :name (n3 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :manner (i / in-vivo)) # ::id pmid_1177_7939.230 # ::date 2015-03-07T05:28:20 # ::file pmid_1177_7939_230.txt # ::snt (A, Top) GST-E3b1-331–480, or control GST, was bound to Sos-1 present in Cos-7 cells transfected (Tfx) with either Sos-1 or S/G. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (b / bind-01 :ARG1 (o / or :op1 (m / macro-molecular-complex :consist-of (a / amino-acid :mod (v / value-interval :op1 "331" :op2 "480")) :part (e2 / enzyme :name (n / name :op1 "GST") :xref (x1 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :part (p4 / protein :name (n8 / name :op1 "E3b1") :xref (x4 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :op2 (e / enzyme :name (n2 / name :op1 "GST") :ARG0-of (c / control-01) :xref (x3 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002"))) :ARG2 (p2 / protein :name (n3 / name :op1 "Sos-1") :ARG1-of (p5 / present-02 :ARG2 (c2 / cell-line :name (n4 / name :op1 "Cos-7") :ARG1-of (t / transfect-01 :ARG2 (o2 / or :op1 (p3 / protein :name (n5 / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :op2 (m2 / macro-molecular-complex :part p3 :part (p / protein :name (n7 / name :op1 "Grb2") :xref (x5 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))))) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "A" :location (t2 / top)))) # ::id pmid_1177_7939.231 # ::date 2015-03-07T02:26:19 # ::file pmid_1177_7939_231.txt # ::snt Detection was with anti–Sos-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (d / detect-01 :ARG2 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))) # ::id pmid_1177_7939.232 # ::date 2015-03-07T02:27:29 # ::file pmid_1177_7939_232.txt # ::snt (Bottom) The same cellular lysates (50 μg) were detected with anti-Grb2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (d / detect-01 :ARG1 (l / lysate :mod (c / cell) :ARG1-of (s / same-01) :quant (m / mass-quantity :quant "50" :unit (m2 / microgram))) :ARG2 (a / antibody :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")))) :location (b / bottom)) # ::id pmid_1177_7939.233 # ::date 2015-03-07T02:30:07 # ::file pmid_1177_7939_233.txt # ::snt (B) Lysates, from 293T cells transfected (Tfx) with E3b1 or a control vector (ctr), were immunoprecipitated (IP) with anti-Grb2 or an irrelevant antibody (ctr), followed by detection (WB) with anti–Sos-1 (top) or anti-Grb2 (middle). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (i / immunoprecipitate-01 :ARG1 (l / lysate) :ARG2 (c / cell-line :name (n / name :op1 "293T") :ARG1-of (t / transfect-01 :ARG2 (o / or :op1 (p / protein :name (n2 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op2 (v / vector :ARG0-of (c2 / control-01))))) :ARG3 (o2 / or :op1 (a / antibody :ARG0-of (c3 / counter-01 :ARG1 "p3")) :op2 (a2 / antibody :ARG1-of (r / relevant-01 :polarity "-"))) :ARG2-of (f / follow-01 :ARG1 (d / detect-01 :ARG1 l :ARG2 (o3 / or :op1 (a3 / antibody :ARG0-of (c4 / counter-01 :ARG1 (p2 / protein :name (n4 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :ARG1-of (d7 / describe-01 :location (t2 / top))) :op2 (a4 / antibody :ARG0-of (c5 / counter-01 :ARG1 (p3 / protein :name (n10 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :ARG1-of (d6 / describe-01 :location (m / middle)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "B"))) # ::id pmid_1177_7939.234 # ::date 2015-03-07T02:36:43 # ::file pmid_1177_7939_234.txt # ::snt The expression of E3b1 (bottom) was detected with an anti-E3b1 antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (d / detect-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG1-of (d2 / describe-01 :location (b / bottom))) :ARG2 (a / antibody :ARG0-of (c / counter-01 :ARG1 p))) # ::id pmid_1177_7939.235 # ::date 2015-03-11T19:34:50 # ::file pmid_1177_7939_235.txt # ::snt Figure 4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 11, 2015 (f / figure :mod "4") # ::id pmid_1177_7939.236 # ::date 2015-03-11T19:34:24 # ::file pmid_1177_7939_236.txt # ::snt The S/G and the S/E complexes are functionally distinct. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 11, 2015 (f / function-01 :ARG0 (a / and :op1 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :part (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :op2 (m2 / macro-molecular-complex :part p :part (p2 / protein :name (n2 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :mod (d / distinct)) # ::id pmid_1177_7939.237 # ::date 2015-03-11T19:48:23 # ::file pmid_1177_7939_237.txt # ::snt (A) Cos-7 cells were transfected with the indicated cDNAs (Tfx), and treated with EGF (3 min, +) or mock treated (−). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :li "A" :op1 (t / transfect-01 :ARG1 (c / cell-line :name (n / name :op1 "Cos-7")) :ARG2 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA") :ARG1-of (c2 / complement-01) :ARG1-of (i / indicate-01))) :op2 (o / or :op1 (t2 / treat-04 :ARG1 c :ARG2 (p / protein :name (n2 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :duration (t3 / temporal-quantity :quant "3" :unit (m / minute)) :ARG1-of (d2 / describe-01 :ARG2 (s3 / string-entity :value "+"))) :op2 (t4 / treat-04 :ARG1 c :mod (m2 / mock) :ARG1-of (d3 / describe-01 :ARG2 (s2 / string-entity :value "−"))))) # ::id pmid_1177_7939.238 # ::date 2015-03-11T20:24:32 # ::file pmid_1177_7939_238.txt # ::snt Immunoprecipitates (IP) with anti-EGFR or preimmune sera (ctr) were analyzed by immunoblotting (WB) with anti–EGFR or HA (for Sos-1 detection). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / analyze-01 :ARG1 (p / protein :ARG1-of (i / immunoprecipitate-01 :ARG3 (o / or :op1 (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :op2 (s2 / serum :mod (p2 / preimmune))))) :manner (o4 / or :op1 (i2 / immunoblot-01 :ARG3 a2) :op2 (i3 / immunoblot-01 :ARG3 (a3 / antibody :ARG0-of (c / counter-01 :ARG1 (p4 / protein :name (n2 / name :op1 "HA") :xref (x2 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))))) :purpose (d / detect-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))) # ::id pmid_1177_7939.239 # ::date 2015-03-11T21:04:18 # ::file pmid_1177_7939_239.txt # ::snt Lysates (50 μg) were analyzed by immunoblotting with anti-EGFR, anti-HA (for Sos-1 detection), or anti-E3b1 antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (a / analyze-01 :ARG1 (l / lysate :quant (m / mass-quantity :quant "50" :unit (m2 / microgram))) :manner (o5 / or :op1 (i / immunoblot-01 :ARG2 l :ARG3 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) :op2 (i2 / immunoblot-01 :ARG2 l :ARG3 (a3 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n2 / name :op1 "HA") :xref (x3 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002")))) :purpose (d / detect-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")))) :op3 (i3 / immunoblot-01 :ARG2 l :ARG3 (a4 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p3 / protein :name (n4 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))))))) # ::id pmid_1177_7939.240 # ::date 2015-03-11T21:17:43 # ::file pmid_1177_7939_240.txt # ::snt HA-Sos, HA-epitope tagged Sos-1 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 23, 2015 (m / mean-01 :ARG1 (p / protein :name (n / name :op1 "HA-Sos") :xref (x2 / xref :value "UNIPROT:HYAS1_HUMAN" :prob "0.222")) :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1") :ARG1-of (t / tag-01 :ARG2 (e / epitope :mod (p3 / protein :name (n3 / name :op1 "HA") :xref (x1 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002")))) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) # ::id pmid_1177_7939.241 # ::date 2015-03-11T21:39:04 # ::file pmid_1177_7939_241.txt # ::snt (B) Cos-7 cells were cotransfected (Tfx) with E3b1 (or a control empty vector, ctr) and either a myc-tagged Ras (left) or HA-tagged MAPK (right), followed by treatment with EGF (5 min, +) or mock-treatment (−). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / cotransfect-01 :ARG1 (c2 / cell-line :name (n3 / name :op1 "Cos-7")) :ARG2 (a / and :op1 (o / or :op1 (p2 / protein :name (n4 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op2 (v / vector :ARG1-of (e2 / empty-02) :ARG2-of (c3 / control-01))) :op2 (o2 / or :op1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (t / tag-01 :ARG2 (p / protein :name (n2 / name :op1 "myc") :xref (x5 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604"))) :ARG1-of (d / describe-01 :ARG1-of (l / left-20)) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK") :ARG1-of (t2 / tag-01 :ARG2 (p4 / protein :name (n6 / name :op1 "HA") :xref (x4 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :ARG1-of (d2 / describe-01 :ARG1-of (r / right-04)) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :ARG2-of (f3 / follow-01 :ARG1 (o3 / or :op1 (t3 / treat-04 :ARG2 (p3 / protein :name (n7 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :duration (t4 / temporal-quantity :quant "5" :unit (m / minute)) :ARG1-of (d3 / describe-01 :ARG2 (s3 / string-entity :value "+"))) :op2 (t5 / treat-04 :mod (m2 / mock) :ARG1-of (d4 / describe-01 :ARG2 (s2 / string-entity :value "−"))))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "B"))) # ::id pmid_1177_7939.242 # ::date 2015-03-11T22:10:16 # ::file pmid_1177_7939_242.txt # ::snt (Top, left) Ras-GTP was recovered with the GST-RBD of Raf-1 followed by immunodetection with anti-myc antibodies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (r / recover-02 :ARG1 (m / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG1-of (d / describe-01 :location (a / and :op1 (t / top) :op2 (l / left-20))) :manner (p / protein-segment :name (n3 / name :op1 "GST-RBD") :part-of (e2 / enzyme :name (n4 / name :op1 "Raf-1") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG2-of (f2 / follow-01 :ARG1 (i2 / immunodetect-01 :ARG1 m :ARG3 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p2 / protein :name (n5 / name :op1 "myc") :xref (x / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")))))))) # ::id pmid_1177_7939.243 # ::date 2015-03-12T00:15:55 # ::file pmid_1177_7939_243.txt # ::snt (Top, right) Anti-HA immunoprecipitation, followed by immunodetection with an anti–phosphorylated MAPK antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Dec 19, 2015 (i / immunoprecipitate-01 :ARG3 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "HA") :xref (x1 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002")))) :ARG2-of (f / follow-01 :ARG1 (i3 / immunodetect-01 :ARG3 (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MAPK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))))) :ARG1-of (d2 / describe-01 :location (t / top) :ARG1-of (r / right-04))) # ::id pmid_1177_7939.244 # ::date 2015-03-12T00:31:07 # ::file pmid_1177_7939_244.txt # ::snt The levels of expression of myc-Ras and HA-MAPK (middle) and E3b1 (bottom) are also shown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 23, 2015 (s / show-01 :ARG1 (l / level :mod (e / express-03 :ARG2 (a / and :op1 (a3 / and :op1 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "myc") :xref (x4 / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")) :part (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (m2 / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "HA") :xref (x / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002")) :part (e3 / enzyme :name (n4 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG1-of (d / describe-01 :location (m3 / middle))) :op2 (p4 / protein :name (n5 / name :op1 "E3b1") :ARG1-of (d2 / describe-01 :location (b / bottom)) :xref (x3 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))))) :mod (a2 / also)) # ::id pmid_1177_7939.245 # ::date 2015-03-12T00:43:07 # ::file pmid_1177_7939_245.txt # ::snt (C) Quiescent NIH-3T3 fibroblasts were microinjected with an empty vector together with rabbit IgG (left) or with an HA-tagged E3b1 expression vector (right) followed by treatment with 10% serum. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (m / microinject-01 :li "C" :ARG1 (o / or :op1 (v / vector :ARG1-of (e / empty-02) :accompanier (p2 / protein :name (n2 / name :op1 "IgG") :mod (r / rabbit) :xref (x / xref :value "UNIPROT:Q9Y298_HUMAN" :prob "0.211")) :ARG1-of (d / describe-01 :location (l / left-20))) :op2 (v2 / vector :ARG1-of (e2 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "E3b1") :ARG1-of (t / tag-01 :ARG2 (p4 / protein :name (n4 / name :op1 "HA") :xref (x2 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG1-of (d2 / describe-01 :ARG1-of (r2 / right-04)) :ARG2-of (f2 / follow-01 :ARG1 (t2 / treat-04 :ARG2 (s / serum :mod (p / percentage-entity :value "10")))))) :ARG2 (f / fibroblast :mod (c / cell-line :name (n / name :op1 "NIH-3T3")) :mod (q / quiescent))) # ::id pmid_1177_7939.246 # ::date 2015-03-12T01:15:23 # ::file pmid_1177_7939_246.txt # ::snt After 15 h, BrdU was added and 3 h later the cells were fixed and stained to detect BrdU incorporation (top), E3b1 (anti-HA), or control (anti-IgG). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / add-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU") :xref (x3 / xref :value "PUBCHEM:6035" :prob "18.013371")) :time (a4 / after :op1 (t / temporal-quantity :quant "15" :unit (h / hour)))) :op2 (a3 / and :op1 (f / fix-02 :ARG1 (c / cell)) :op2 (s / stain-01 :ARG1 c) :purpose (d / detect-01 :ARG1 (o / or :op1 (i / incorporate-02 :ARG1 s2 :ARG1-of (d2 / describe-01 :location (t2 / top))) :op2 (p2 / protein :name (n2 / name :op1 "E3b1") :ARG0-of (c3 / counter-01 :ARG1 (p3 / protein :name (n3 / name :op1 "HA") :xref (x1 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op3 (c2 / control-01 :ARG0-of (c4 / counter-01 :ARG1 (p4 / protein :name (n4 / name :op1 "IgG") :xref (x2 / xref :value "UNIPROT:Q9Y298_HUMAN" :prob "0.211")))))) :time (l2 / late :op1 (t3 / temporal-quantity :quant "3" :unit (h2 / hour)) :degree (m2 / more)))) # ::id pmid_1177_7939.247 # ::date 2015-03-12T01:34:53 # ::file pmid_1177_7939_247.txt # ::snt Nuclei were counterstained with Dapi (bottom). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / stain-01 :ARG1 (n / nucleus :xref (x / xref :value "GO:0005634" :prob "0.8")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Dapi") :xref (x1 / xref :value "PUBCHEM:2954" :prob "18.167522")) :ARG1-of (c / counter-01) :ARG1-of (d / describe-01 :location (b / bottom))) # ::id pmid_1177_7939.248 # ::date 2015-03-12T01:53:22 # ::file pmid_1177_7939_248.txt # ::snt A quantitative analysis of BrdU incorporation into control (empty bar) and E3b1 (closed bar) injected cells is shown on the right. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG1 (a / analyze-01 :ARG1 (i / incorporate-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU") :xref (x1 / xref :value "PUBCHEM:6035" :prob "18.013371")) :ARG2 (a2 / and :op1 (c / cell :mod (c3 / control-01) :ARG1-of (m / mean-01 :ARG2 (b / bar :ARG1-of (e / empty-02)))) :op2 (c2 / cell :ARG1-of (m2 / mean-01 :ARG2 (b2 / bar :ARG1-of (c4 / close-01))) :ARG2-of (i2 / inject-01 :ARG1 (p2 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))))) :mod (q / quantity)) :ARG1-of (r / right-04)) # ::id pmid_1177_7939.249 # ::date 2015-03-12T02:04:43 # ::file pmid_1177_7939_249.txt # ::snt The data are the mean ± SEM of three independent experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (e4 / equal-01 :ARG1 (d / data) :ARG2 (v / value-interval :op1 (e / error :ARG1-of (s2 / standard-02 :ARG1-of (a / add-02 :ARG2 (m / mean :poss (e3 / experiment-01 :quant "3" :ARG0-of (d2 / depend-01 :polarity "-")))))) :op2 (e2 / error :ARG1-of (s / standard-02) :ARG1-of (s3 / subtract-01 :ARG2 m)))) # ::id pmid_1177_7939.250 # ::date 2015-03-12T02:15:51 # ::file pmid_1177_7939_250.txt # ::snt Results are expressed as a percentage of injected cells incorporating BrdU respect to uninjected ones. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / express-01 :ARG1 (t / thing :ARG2-of (r / result-01)) :manner (p / percentage :quant-of (c / cell :ARG2-of (i / inject-01) :ARG2-of (i2 / incorporate-02 :ARG1 (s / small-molecule :name (n / name :op1 "BrdU") :xref (x / xref :value "PUBCHEM:6035" :prob "18.013371")))) :compared-to (c2 / cell :ARG2-of (i3 / inject-01 :polarity "-")))) # ::id pmid_1177_7939.251 # ::date 2015-03-12T02:27:26 # ::file pmid_1177_7939_251.txt # ::snt Serum treatment induces BrdU incorporation in >95% of not injected cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / induce-01 :ARG0 (t / treat-04 :ARG2 (s / serum)) :ARG2 (i2 / incorporate-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU") :xref (x / xref :value "PUBCHEM:6035" :prob "18.013371")) :ARG2 (c / cell :ARG2-of (i3 / inject-01 :polarity "-") :quant (m / more-than :op1 (p2 / percentage-entity :value "95"))))) # ::id pmid_1177_7939.252 # ::date 2015-03-12T02:39:11 # ::file pmid_1177_7939_252.txt # ::snt Figure 5. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 12, 2015 (f / figure :mod "5") # ::id pmid_1177_7939.253 # ::date 2015-03-12T02:39:39 # ::file pmid_1177_7939_253.txt # ::snt E3b1 is a limiting factor in Rac activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 24, 2015 (f / factor :ARG0-of (l / limit-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :domain (p / protein :name (n / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) # ::id pmid_1177_7939.254 # ::date 2015-03-12T02:48:39 # ::file pmid_1177_7939_254.txt # ::snt (Top, left) Lysates of Cos-7 cells were immunoprecipitated (IP) with the antibody indicated on the top and immunoblotted with the antibody indicated on the right. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (i / immunoprecipitate-01 :ARG1 (l / lysate) :ARG2 (c / cell-line :wiki "COS_cells" :name (n / name :op1 "Cos-7")) :ARG3 (a2 / antibody :ARG1-of (i2 / indicate-01 :location (t / top)))) :op2 (i3 / immunoblot-01 :ARG1 l :ARG3 (a3 / antibody :ARG1-of (i4 / indicate-01 :ARG1-of (r / right-04)))) :ARG1-of (d / describe-01 :location (a4 / and :op1 t :op2 (l2 / left-20)))) # ::id pmid_1177_7939.255 # ::date 2015-03-12T04:34:09 # ::file pmid_1177_7939_255.txt # ::snt Lysate, 50 μg of total cellular lysate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 24, 2015 (l / lysate :quant (m / mass-quantity :quant "50" :unit (m2 / microgram)) :ARG1-of (i / include-91 :ARG2 (l2 / lysate :mod (c / cell) :ARG2-of (t / total-01)))) # ::id pmid_1177_7939.256 # ::date 2015-03-12T04:44:11 # ::file pmid_1177_7939_256.txt # ::snt (Top, right) The efficiency of Grb2 and E3b1 immunoprecipitations was >95%, as determined by immunoblot analysis of the supernatants of the immunoprecipitations performed with either the specific antibody with (Grb2 and E3b1, respectively, as indicated) or with an irrelevant (ctr) antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (e / efficient-01 :ARG1 (i / immunoprecipitate-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :degree (m / more-than :op1 (p / percentage-entity :value "95")) :ARG1-of (d / determine-01 :ARG0 (a2 / analyze-01 :ARG1 (s / supernatant :mod (i3 / immunoprecipitate-01 :ARG1-of (p4 / perform-02 :instrument (o / or :op1 (a3 / antibody :ARG1-of (s2 / specific-02) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 p2 :op2 p3) :mod (r / respective) :ARG1-of (i4 / indicate-01))) :op2 (a5 / antibody :ARG1-of (r2 / relevant-01 :polarity "-") :ARG1-of (m3 / mean-01 :ARG2 (c / control-01))))))) :manner (i2 / immunoblot-01))) :ARG1-of (d2 / describe-01 :location (t / top) :ARG1-of (r3 / right-04))) # ::id pmid_1177_7939.257 # ::date 2015-03-12T05:10:43 # ::file pmid_1177_7939_257.txt # ::snt (Middle) Cos-7 cells were transfected (Tfx) with HA-tagged PAK65 (all lanes) together with the plasmids indicated on the top (ctr, empty vector) and serum starved for 24 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a3 / and :op1 (t / transfect-01 :ARG1 (c / cell-line :name (n / name :op1 "Cos-7")) :ARG2 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "PAK65") :ARG1-of (t2 / tag-01 :ARG2 (p2 / protein :name (n3 / name :op1 "HA") :xref (x1 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :ARG1-of (m / mean-01 :ARG2 (l / lane :mod (a / all))) :xref (x / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003")) :op2 (p3 / plasmid :ARG1-of (i / indicate-01 :location (t3 / top)) :ARG1-of (m2 / mean-01 :ARG2 (v / vector :ARG2-of (c2 / control-01) :ARG1-of (e / empty-02)))))) :op2 (s / starve-01 :ARG1 c :ARG2 (s2 / serum) :duration (t4 / temporal-quantity :quant "24" :unit (h / hour))) :ARG1-of (d / describe-01 :location (m3 / middle))) # ::id pmid_1177_7939.258 # ::date 2015-03-12T05:25:17 # ::file pmid_1177_7939_258.txt # ::snt Equal amounts of anti-HA immunoprecipitated PAK65 were subjected to an in vitro kinase assay using myelin basic protein (MBP) as a substrate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / subject-01 :ARG1 (e2 / enzyme :name (n / name :op1 "PAK65") :quant (a / amount :ARG1-of (e / equal-01)) :ARG1-of (i / immunoprecipitate-01 :ARG3 (a3 / antibody :ARG0-of (c / counter-01 :ARG1 (p2 / protein :name (n2 / name :op1 "HA") :xref (x / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))))) :xref (x2 / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003")) :ARG2 (a2 / assay-01 :ARG1 (k / kinase) :mod (i2 / in-vitro) :ARG0-of (u / use-01 :ARG1 (p3 / protein :name (n3 / name :op1 "myelin" :op2 "basic" :op3 "protein") :xref (x1 / xref :value "UNIPROT:MBP_HUMAN" :prob "0.702")) :ARG2 (s2 / substrate)))) # ::id pmid_1177_7939.259 # ::date 2015-03-12T05:37:46 # ::file pmid_1177_7939_259.txt # ::snt The levels of immunoprecipitated PAK65 and the expression of Sos-1, E3b1, and HARacN17 in the various transfectants are also shown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG1 (a / and :op1 (l / level :quant-of (e2 / enzyme :name (n / name :op1 "PAK65") :ARG1-of (i / immunoprecipitate-01) :xref (x3 / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003"))) :op2 (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :op2 (p3 / protein :name (n3 / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op3 (p4 / protein :name (n4 / name :op1 "HARacN17") :xref (x1 / xref :value "UNIPROT:CD37L_HUMAN" :prob "0.202"))) :ARG3 (c / cell :mod (v / various) :ARG1-of (t / transfect-01)))) :mod (a3 / also)) # ::id pmid_1177_7939.260 # ::date 2015-03-12T05:51:19 # ::file pmid_1177_7939_260.txt # ::snt Similar results were obtained using Cos-7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 24, 2015 (o / obtain-01 :ARG1 (t / thing :ARG1-of (r / result-01) :ARG1-of (r2 / resemble-01)) :manner (u / use-01 :ARG1 (c / cell-line :name (n / name :op1 "Cos-7")))) # ::id pmid_1177_7939.261 # ::date 2015-03-12T05:54:56 # ::file pmid_1177_7939_261.txt # ::snt (Bottom) Wild-type (+/+) and eps8−/− (−/−) mouse embryo fibroblasts were infected with retroviral vectors coding for E3b1 (E3b1) or the mutant of E3b1-DY (E3b1-DY), or with an empty vector as a control (ctr). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (i / infect-01 :ARG1 (a / and :op1 (f / fibroblast :mod (w / wild-type) :source (e / embryo :mod (m2 / mouse))) :op2 (f2 / fibroblast :ARG2-of (m / mutate-01 :mod "−/−") :source e :ARG0-of (c3 / contain-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "eps8") :ARG2-of (m4 / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))))) :ARG2 (o / or :op1 (v / vector :mod (r / retrovirus) :ARG0-of (c2 / code-01 :ARG1 (p / protein :name (n / name :op1 "E3b1") :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :op2 (p2 / protein :name (n2 / name :op1 "E3b1-DY") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.213")) :op3 (v2 / vector :ARG1-of (e2 / empty-02) :ARG2-of (c / control-01))) :ARG1-of (d / describe-01 :location (b / bottom))) # ::id pmid_1177_7939.262 # ::date 2015-03-12T06:40:40 # ::file pmid_1177_7939_262.txt # ::snt >95% of the cells expressed the infected cDNA, as determined by immunostaining with anti-E3b1 (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (e / express-03 :ARG2 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA") :ARG1-of (c2 / complement-01) :ARG1-of (i / infect-01)) :ARG3 (c / cell :quant (m / more-than :op1 (p / percentage-entity :value "95"))) :ARG1-of (d2 / determine-01 :ARG2 (i2 / immunostain-01 :ARG2 (a / antibody :ARG0-of (c3 / counter-01 :ARG1 (p2 / protein :name (n / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))))) :ARG1-of (s / show-01 :polarity "-")) # ::id pmid_1177_7939.263 # ::date 2015-03-12T08:10:23 # ::file pmid_1177_7939_263.txt # ::snt Equal amounts of lysates were subjected to in vitro binding assays with the immobilized CRIB domain of PAK65. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / subject-01 :ARG1 (a3 / and :op1 (l / lysate :quant (a / amount :ARG1-of (e / equal-01))) :op2 (p3 / protein-segment :name (n3 / name :op1 "CRIB" :op2 "domain") :ARG1-of (i2 / immobilize-01) :part-of (e2 / enzyme :name (n2 / name :op1 "PAK65") :xref (x / xref :value "UNIPROT:PAK2_HUMAN" :prob "1.003")))) :ARG2 (a2 / assay-01 :ARG1 (b / bind-01) :manner (i / in-vitro))) # ::id pmid_1177_7939.264 # ::date 2015-03-12T09:36:05 # ::file pmid_1177_7939_264.txt # ::snt After washing, bound proteins were resolved by SDS-PAGE and immunoblotted with anti-Rac antibodies (Rac-GTP). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 31, 2016 (a / and :op1 (r / resolve-03 :ARG1 (p / protein :ARG1-of (b / bind-01)) :ARG3 (t / thing :name (n / name :op1 "SDS-PAGE"))) :op2 (i / immunoblot-01 :ARG1 p :ARG3 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG1-of (m2 / mean-01 :ARG2 (m3 / macro-molecular-complex :part e :part (s / small-molecule :name (n3 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")))))) :time (a3 / after :op1 (w / wash-01))) # ::id pmid_1177_7939.265 # ::date 2015-03-12T10:11:05 # ::file pmid_1177_7939_265.txt # ::snt The levels of total Rac (Rac) and E3b1 proteins are also shown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG1 (a2 / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "Rac") :mod (t / total) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :op2 (l2 / level :quant-of (p2 / protein :name (n2 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :mod (a / also)) # ::id pmid_1177_7939.266 # ::date 2015-03-12T10:34:26 # ::file pmid_1177_7939_266.txt # ::snt Figure 6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 12, 2015 (f / figure :mod "6") # ::id pmid_1177_7939.267 # ::date 2015-03-12T10:40:08 # ::file pmid_1177_7939_267.txt # ::snt The E3b1DY mutant inhibits actin remodeling induced by activated Ras, but not by activated Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "E3b1DY") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.223")) :ARG1 (r / remodel-01 :ARG1 (a / actin) :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (c2 / contrast-01 :ARG2 (i3 / induce-01 :polarity "-" :ARG0 (e2 / enzyme :name (n3 / name :op1 "Rac") :ARG1-of a2 :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))))))) # ::id pmid_1177_7939.268 # ::date 2015-03-12T11:08:21 # ::file pmid_1177_7939_268.txt # ::snt Mouse embryo fibroblasts were transfected, as indicated on the top, with expression vectors for either RasV12 or RacQL, together with ECFP-tagged versions of either E3b1 or the E3b1DY mutant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t / transfect-01 :ARG1 (f / fibroblast :source (e / embryo :mod (m / mouse))) :ARG2 (v / vector :ARG1-of (e2 / express-03 :ARG2 (o / or :op1 (e3 / enzyme :name (n / name :op1 "RasV12") :xref (x / xref :value "UNIPROT:RASLC_HUMAN" :prob "0.252")) :op2 (e4 / enzyme :name (n2 / name :op1 "RacQL")))) :accompanier (o2 / or :op1 (p2 / protein :name (n3 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :op2 (p3 / protein :name (n4 / name :op1 "E3b1DY") :ARG2-of (m2 / mutate-01) :xref (x2 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.223")) :ARG1-of (t3 / tag-01 :ARG2 (p4 / protein :name (n5 / name :op1 "ECFP"))))) :ARG1-of (i / indicate-01 :location (t2 / top))) # ::id pmid_1177_7939.269 # ::date 2015-03-12T12:16:51 # ::file pmid_1177_7939_269.txt # ::snt After serum starvation, cells were fixed and stained with rhodamine-conjugated phalloidine to detect F-actin (top, red). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (f / fix-02 :ARG1 (c / cell)) :op2 (s / stain-01 :ARG1 c :ARG2 (s4 / small-molecule :name (n / name :op1 "phalloidine") :ARG1-of (c2 / conjugate-02 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "rhodamine") :xref (x1 / xref :value "PUBCHEM:6694" :prob "14.36086"))) :xref (x2 / xref :value "PUBCHEM:4752" :prob "18.572987"))) :purpose (d / detect-01 :ARG1 (p / protein :name (n2 / name :op1 "F-actin") :xref (x / xref :value "UNIPROT:NEXN_HUMAN" :prob "0.252"))) :time (a2 / after :op1 (s2 / starve-01 :ARG1 c :ARG2 (s3 / serum))) :ARG1-of (d2 / describe-01 :location (t / top) :mod (r / red))) # ::id pmid_1177_7939.270 # ::date 2015-03-12T12:30:21 # ::file pmid_1177_7939_270.txt # ::snt Expression of the transfected proteins was detected (bottom, green) with either anti-Ras or anti-Rac antibodies or by epifluorescence (ECFP). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (d / detect-01 :ARG1 (e / express-03 :ARG2 (p / protein :ARG2-of (t / transfect-01))) :ARG2 (o / or :op1 (a / antibody :ARG0-of (c / counter-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 (e4 / enzyme :name (n2 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :op3 (e3 / epifluorescence)) :ARG1-of (d2 / describe-01 :location (b / bottom)) :ARG1-of (g / green-02)) # ::id pmid_1177_7939.271 # ::date 2015-03-12T13:20:31 # ::file pmid_1177_7939_271.txt # ::snt In the cotransfection experiments a molar ratio of 1:3 of the activated GTPases to the ECFP-E3b1 constructs was used, such as that all of the epifluorescent cells expressed also the corresponding GTPase (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (u / use-01 :ARG0 (e3 / experiment-01 :ARG1 (c / cotransfect-01)) :ARG1 (r / ratio-of :op1 (m2 / molar :quant-of (e2 / enzyme :name (n2 / name :op1 "GTPase") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312"))) :op2 (m3 / molar :quant-of (m / macro-molecular-complex :part (p / protein :name (n3 / name :op1 "ECFP")) :part (p2 / protein :name (n4 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :ARG1-of (e7 / equal-01 :ARG2 "1/3")) :ARG0-of (c2 / cause-01 :ARG1 (e4 / express-03 :ARG2 (e6 / enzyme :name (n5 / name :op1 "GTPase") :ARG1-of (c4 / correspond-02) :xref (x2 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :ARG3 (c3 / cell :mod (a2 / all) :mod (e / epifluorescent)) :mod (a3 / also))) :ARG1-of (s / show-01 :polarity "-")) # ::id pmid_1177_7939.272 # ::date 2015-03-12T13:59:38 # ::file pmid_1177_7939_272.txt # ::snt The percent of transfected cells (mean ± SEM) undergoing ruffling was as follow: RasV12 = 65 ± 3%; RasV12 + E3b1 WT = 62 ± 4%; RasV12 + E3b1DY = 16 ± 2%; RacQL = 93 ± 3%; RacQL + E3b1 WT = 90 ± 4%; RacQL + E3b1DY = 95 ± 5%. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m3 / multi-sentence :snt1 (f / follow-04 :ARG1 (p4 / percentage-entity :quant-of (c / cell :ARG1-of (t / transfect-01) :ARG1-of (u / undergo-28 :ARG2 (r / ruffle-02)) :ARG1-of (m / mean-01 :ARG2 (m2 / mean :mod (s / slash :op1 (e / error :ARG1-of (s2 / standard-02)) :op2 (e2 / error :polarity "-" :ARG1-of s2))))))) :snt2 (e3 / equal-01 :ARG1 (s3 / sum-of :op1 "65" :op2 (s4 / slash :op1 (p / percentage-entity :value "3") :op2 (p2 / percentage-entity :value "-3"))) :ARG2 (e4 / enzyme :name (n / name :op1 "RasV12") :xref (x2 / xref :value "UNIPROT:RASLC_HUMAN" :prob "0.252"))) :snt3 (e5 / equal-01 :ARG1 (s6 / sum-of :op1 "62" :op2 (s7 / slash :op1 (p5 / percentage-entity :value "4") :op2 (p6 / percentage-entity :value "-4"))) :ARG2 (s5 / sum-of :op1 (e6 / enzyme :name (n2 / name :op1 "RasV12") :xref (x3 / xref :value "UNIPROT:RASLC_HUMAN" :prob "0.252")) :op2 (p3 / protein :name (n3 / name :op1 "E3b1") :mod (w / wild-type) :xref (x4 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :snt4 (e7 / equal-01 :ARG1 (s9 / sum-of :op1 "16" :op2 (s10 / slash :op1 (p8 / percentage-entity :value "2") :op2 (p9 / percentage-entity :value "-2"))) :ARG2 (s8 / sum-of :op1 (e8 / enzyme :name (n4 / name :op1 "RasV12") :xref (x1 / xref :value "UNIPROT:RASLC_HUMAN" :prob "0.252")) :op2 (p7 / protein :name (n5 / name :op1 "E3b1DY") :xref (x5 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.223")))) :snt5 (e9 / equal-01 :ARG1 (s11 / sum-of :op1 "93" :op2 (s12 / slash :op1 (p11 / percentage-entity :value "3") :op2 (p12 / percentage-entity :value "-3"))) :ARG2 (e14 / enzyme :name (n6 / name :op1 "RacQL"))) :snt6 (e10 / equal-01 :ARG1 (s14 / sum-of :op1 "90" :op2 (s15 / slash :op1 (p15 / percentage-entity :value "4") :op2 (p16 / percentage-entity :value "-4"))) :ARG2 (s13 / sum-of :op1 (e13 / enzyme :name (n7 / name :op1 "RacQL")) :op2 (p14 / protein :name (n8 / name :op1 "E3b1") :mod (w2 / wild-type) :xref (x6 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")))) :snt7 (e11 / equal-01 :ARG1 (s17 / sum-of :op1 "95" :op2 (s18 / slash :op1 (p19 / percentage-entity :value "5") :op2 (p20 / percentage-entity :value "-5"))) :ARG2 (s16 / sum-of :op1 (e12 / enzyme :name (n9 / name :op1 "RacQL")) :op2 (p18 / protein :name (n10 / name :op1 "E3b1DY") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.223"))))) # ::id pmid_1177_7939.273 # ::date 2015-03-12T14:53:36 # ::file pmid_1177_7939_273.txt # ::snt Bar, 10 μm. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (b / bar :mod (d / distance-quantity :quant "10" :unit (m / micrometer))) # ::id pmid_1177_7939.274 # ::date 2015-03-10T09:17:11 # ::file pmid_1177_7939_274.txt # ::snt Figure 7. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 10, 2015 (f / figure :mod "7") # ::id pmid_1177_7939.275 # ::date 2015-03-10T09:22:02 # ::file pmid_1177_7939_275.txt # ::snt The bifunctional guanine nucleotide exchange activity of Sos-1 is regulated by its assembly into distinct molecular complexes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / regulate-01 :ARG0 (a / assemble-02 :ARG0 (p2 / protein :name (n2 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG1 (c / complex :mod (d / distinct) :mod (m / molecule))) :ARG1 (a2 / activity-06 :ARG0 p2 :ARG1 (p / protein :name (n / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor") :ARG0-of (f / function-01 :quant "2") :xref (x1 / xref :value "UNIPROT:PKHG5_HUMAN" :prob "0.393")))) # ::id pmid_1177_7939.276 # ::date 2015-03-10T10:35:56 # ::file pmid_1177_7939_276.txt # ::snt (A) Cos-7 cells were transfected with expression vectors for Sos-1 (SosTfx) or for Sos-1, E3b1, and Eps8 (TripleTfx) or with the corresponding empty vectors (mock). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t / transfect-01 :ARG1 (c / cell-line :name (n / name :op1 "Cos-7")) :ARG2 (o2 / or :op1 (v / vector :ARG1-of (e / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :ARG1-of (d2 / describe-01 :ARG2 (s / string-entity :value "SosTfx"))) :op2 (v3 / vector :ARG1-of (e3 / express-03 :ARG2 (m2 / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :part (e4 / enzyme :name (n4 / name :op1 "Eps8") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")) :part p4)) :ARG1-of (d3 / describe-01 :ARG2 (s2 / string-entity :value "TripleTfx"))) :op3 (v2 / vector :ARG1-of (e2 / empty-02) :ARG1-of (c2 / correspond-02) :ARG1-of (d4 / describe-01 :ARG2 (m3 / mock)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"))) # ::id pmid_1177_7939.277 # ::date 2015-03-10T11:21:06 # ::file pmid_1177_7939_277.txt # ::snt Total cellular lysates (100 μg, left), or immunoprecipitates (IP, right) with the antibody indicated on the top (ctr, irrelevant antibody), were immunoblotted (WB) with the indicated antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / immunoblot-01 :ARG1 (a / and :op1 (l / lysate :mod (c / cell) :quant (m / mass-quantity :quant "100" :unit (m2 / microgram)) :ARG1-of (d / describe-01 :ARG0 (f / figure :ARG1-of (l2 / left-20))) :mod (t2 / total)) :op2 (p / protein :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :ARG1-of (r / right-04))) :ARG1-of (i2 / immunoprecipitate-01 :ARG3 (a2 / antibody :ARG1-of (i4 / indicate-01 :location (f4 / figure :mod (t / top))) :ARG1-of (r2 / relevant-01 :polarity "-"))))) :ARG3 a2) # ::id pmid_1177_7939.278 # ::date 2015-03-10T13:20:46 # ::file pmid_1177_7939_278.txt # ::snt 5 mg of total cellular lysates were used for the immunoprecipitations, except in the SosTfx 1/10 lanes, in which 0.5 mg were used. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (u / use-01 :ARG1 (l / lysate :mod (t / total) :mod (c / cell) :quant (m / mass-quantity :quant "5" :unit (m2 / milligram))) :ARG2 (i / immunoprecipitate-01) :ARG2-of (e / except-01 :ARG1 (u2 / use-01 :ARG1 (l3 / lysate :quant (m3 / mass-quantity :quant "0.5" :unit (m4 / milligram))) :location (l2 / lane :ARG1-of (d / describe-01 :ARG2 (n / name :op1 "SosTfx 1/10")))))) # ::id pmid_1177_7939.279 # ::date 2015-03-10T13:50:48 # ::file pmid_1177_7939_279.txt # ::snt (B) Ras-GEF (empty bars) and Rac-GEF (closed bars) activities in aliquots of the same immunoprecipitates (IP) shown in B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a2 / and :op1 (a3 / activity-06 :ARG0 (p / protein :name (n3 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor") :xref (x2 / xref :value "UNIPROT:PKHG5_HUMAN" :prob "0.393")) :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (d2 / describe-01 :ARG2 (b / bar :ARG1-of (e3 / empty-02))) :location (a / aliquot :ARG1-of (i / include-91 :ARG2 (p2 / protein :ARG1-of (i2 / immunoprecipitate-01) :ARG1-of (s / same-01))))) :op2 (a4 / activity-06 :ARG0 p :ARG1 (e2 / enzyme :name (n2 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :ARG1-of (d3 / describe-01 :ARG2 (b2 / bar :ARG1-of (c / close-01))) :location a) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "B"))) # ::id pmid_1177_7939.280 # ::date 2015-03-10T14:13:52 # ::file pmid_1177_7939_280.txt # ::snt Data are expressed as described in Material and methods. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 1, 2015 (r / resemble-01 :ARG1 (e / express-01 :ARG1 (d2 / data)) :ARG2 (d / describe-01 :ARG0 (t2 / thing :ARG1-of (t / title-01 :ARG2 (a / and :op1 (m / material) :op2 (m2 / method)))))) # ::id pmid_1177_7939.281 # ::date 2015-03-10T14:21:29 # ::file pmid_1177_7939_281.txt # ::snt (C) Immobilized, purified GST-Rac (Rac) and GST-Cdc42 (Cdc42) were depleted of guanine nucleotide by extensive washing in 10 mM EDTA as described in Material and methods. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (d2 / deplete-01 :ARG1 (a / and :op1 (m4 / macro-molecular-complex :ARG1-of (d3 / describe-01 :ARG2 (n7 / name :op1 "Rac")) :ARG1-of (i / immobilize-01) :ARG1-of (p / purify-01) :part (e3 / enzyme :name (n / name :op1 "GST") :xref (x1 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :part (e / enzyme :name (n5 / name :op1 "Rac") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :op2 (m5 / macro-molecular-complex :ARG1-of (d4 / describe-01 :ARG2 (n8 / name :op1 "Cdc42")) :ARG1-of i :ARG1-of p :part e3 :part (p2 / protein :name (n2 / name :op1 "Cdc42") :xref (x / xref :value "UNIPROT:CDC42_HUMAN" :prob "0.634")))) :ARG2 (n6 / nucleotide :mod (s / small-molecule :name (n3 / name :op1 "guanine") :xref (x4 / xref :value "PUBCHEM:764" :prob "13.358051"))) :manner (w / wash-01 :ARG1 (a2 / and :op1 m4 :op2 m5) :ARG2 (s2 / small-molecule :name (n4 / name :op1 "EDTA") :mod (c / concentration-quantity :quant "10" :unit (m / millimolar)) :xref (x3 / xref :value "PUBCHEM:6049" :prob "14.194091")) :ARG1-of (d5 / describe-01 :ARG0 (t2 / thing :ARG1-of (t / title-01 :ARG2 (a3 / and :op1 (m6 / material) :op2 (m7 / method))))) :ARG1-of (e2 / extensive-03)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"))) # ::id pmid_1177_7939.282 # ::date 2015-03-11T04:40:16 # ::file pmid_1177_7939_282.txt # ::snt Equal amounts of the nucleotide-free GST-GTPases or GST alone (GST) were incubated with total cellular lysates from eps8−/− fibroblasts (−/−) or eps8−/− stably expressing Eps8myc (−/−[Eps8myc]) in the presence or absence (−) of the 40 ng/ml of the indicated peptides (peptides). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (i / incubate-01 :ARG0 (l / lysate :mod (t / total) :mod (c / cell) :ARG1-of (o / obtain-01 :ARG2 (o2 / or :op1 (f2 / fibroblast :part (e6 / enzyme :name (n4 / name :op1 "eps8") :ARG2-of (m4 / mutate-01 :mod "−/−") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604"))) :op2 (f3 / fibroblast :ARG3-of (e5 / express-03 :ARG2 (p3 / protein :name (n5 / name :op1 "Eps8myc") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.213")) :ARG1-of (s / stable-03)) :ARG1-of (d3 / describe-01 :ARG2 (s3 / string-entity :value "−/−[Eps8myc]")) :part e6)))) :ARG1 (a / and :op1 (a2 / amount :quant-of (m / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "GST") :xref (x3 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")) :part (e2 / enzyme :name (n2 / name :op1 "GTPase") :xref (x1 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :ARG1-of (f / free-04 :ARG2 (n6 / nucleotide)))) :op2 (a4 / amount :quant-of e) :ARG1-of (e4 / equal-01)) :ARG2 (o3 / or :op1 (p4 / present-02 :ARG1 (p / peptide :ARG1-of (i2 / indicate-01) :ARG1-of (d4 / describe-01 :ARG2 (p2 / peptide)) :mod (m3 / mass-quantity :quant "40" :unit (n7 / nanogram-per-milliliter)))) :op2 (a3 / absent-01 :ARG1 p :ARG1-of (d5 / describe-01 :ARG2 (s2 / string-entity :value "−"))))) # ::id pmid_1177_7939.283 # ::date 2015-03-11T12:15:46 # ::file pmid_1177_7939_283.txt # ::snt The peptide used were PPPPPPVDATEDEE (PXXDA), used as control (see text and Fig. 1); PPPPPVDYTEDEE (PXXDY), which corresponds to the E3b1 binding site for the SH3 domain of Eps8 and prevents Eps8-E3b1 association (refer to Fig. 1 B); VPVPPPVPPRRR (PXXP), which corresponds to the Sos-1 binding site for the SH3 domain of E3b1 and readily competes the interaction between Sos-1 and E3b1 (refer to Fig. 2 C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jun 13, 2015 (u / use-01 :ARG1 (a / and :op1 (p / peptide :name (n / name :op1 "PPPPPPVDATEDEE") :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (t / text) :op2 (f / figure :mod "1") :ARG1-of (s / see-01 :mode "imperative" :ARG0 "y")) :ARG2 (n7 / name :op1 "PXXDA")) :ARG0-of (c / control-01)) :op2 (p2 / peptide :name (n2 / name :op1 "PPPPPVDYTEDEE") :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1B" :ARG1-of (r2 / refer-03 :mode "imperative" :ARG0 (y / you))) :ARG2 (n10 / name :op1 "PXXDY")) :ARG0-of (p4 / prevent-01 :ARG1 (a3 / associate-01 :ARG1 (p6 / protein :name (n5 / name :op1 "E3b1") :xref (x / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603")) :ARG2 (e / enzyme :name (n4 / name :op1 "Eps8") :xref (x2 / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.604")))) :ARG1-of (b2 / bind-01 :ARG2 (p9 / protein-segment :name (n8 / name :op1 "SH3" :op2 "domain") :part-of e) :ARG1-of (i3 / instead-of-91 :ARG2 (b3 / bind-01 :ARG1 p6 :ARG2 e)))) :op3 (p3 / peptide :name (n3 / name :op1 "VPVPPPVPPRRR") :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "2C") :ARG2 (n11 / name :op1 "PXXP")) :ARG0-of (c3 / compete-01 :ARG1 (p7 / protein :name (n6 / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633")) :ARG2 (i2 / interact-01 :ARG0 (a4 / and :op1 p7 :op2 p6)) :manner (r / ready)) :ARG1-of (b4 / bind-01 :ARG2 (p5 / protein-segment :name (n9 / name :op1 "SH3" :op2 "domain") :part-of p6) :ARG1-of (i4 / instead-of-91 :ARG2 (b5 / bind-01 :ARG1 p7 :ARG2 p6)))))) # ::id pmid_1177_7939.284 # ::date 2015-03-11T07:10:31 # ::file pmid_1177_7939_284.txt # ::snt Bound proteins were resolved by SDS-PAGE. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 31, 2016 (r / resolve-03 :ARG1 (p / protein :ARG1-of (b / bind-01)) :ARG3 (t / thing :name (n / name :op1 "SDS-PAGE"))) # ::id pmid_1177_7939.285 # ::date 2015-03-11T07:15:04 # ::file pmid_1177_7939_285.txt # ::snt Detection was with anti–Sos-1 antibody (Sos-1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 18, 2015 (d / detect-01 :ARG0 (a / antibody :ARG1-of (d2 / describe-01 :ARG2 (n2 / name :op1 "Sos-1")) :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))) # ::id pmid_1177_7939.286 # ::date 2015-03-11T07:17:42 # ::file pmid_1177_7939_286.txt # ::snt The indicted lanes (lysate) were loaded with 50 μg of total cellular lysates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (l / load-01 :ARG1 (l2 / lane :ARG1-of (i / indicate-01) :ARG1-of (d / describe-01 :ARG2 (l5 / lysate))) :ARG2 (l3 / lysate :mod (t / total) :mod (c / cell) :mod (m / mass-quantity :quant "50" :unit (m2 / microgram)))) # ::id pmid_1177_7939.287 # ::date 2015-03-11T07:09:30 # ::file pmid_1177_7939_287.txt # ::snt Figure 8. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 11, 2015 (f / figure :mod "8") # ::id pmid_1177_7939.288 # ::date 2015-03-11T12:53:51 # ::file pmid_1177_7939_288.txt # ::snt The differential regulation of the S/G and S/E/E8 complexes by RTKs correlates with the kinetics of activation of Ras and Rac. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 16, 2015 (c / correlate-01 :ARG1 (r / regulate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "RTK") :xref (x2 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")) :ARG1 (a2 / and :op1 (m / macro-molecular-complex :name (n3 / name :op1 "S/G")) :op2 (m2 / macro-molecular-complex :name (n4 / name :op1 "S/E/E8"))) :ARG1-of (d / differ-02)) :ARG2 (k / kinetics :mod (a / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n5 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))))) # ::id pmid_1177_7939.289 # ::date 2015-03-11T11:55:17 # ::file pmid_1177_7939_289.txt # ::snt (A) Mouse embryo fibroblasts cells were treated with PDGF for 15 min (+) or mock treated (−). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :li "A" :op1 (t / treat-03 :ARG1 (f / fibroblast :part-of (e / embryo :mod (m / mouse))) :ARG3 (p / protein :name (n / name :op1 "PDGF") :ARG1-of (d / describe-01 :ARG2 (s2 / string-entity :value "+")) :xref (x / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :duration (t3 / temporal-quantity :quant "15" :unit (m2 / minute))) :op2 (t2 / treat-04 :polarity "-" :ARG1 f :ARG2 (m3 / mock) :ARG1-of (d2 / describe-01 :ARG2 (s / string-entity :value "−")))) # ::id pmid_1177_7939.290 # ::date 2015-03-13T04:54:45 # ::file pmid_1177_7939_290.txt # ::snt Lysates were immunoprecipitated (IP) with anti-Grb2 (left) or anti-E3b1 (right) antibody and detected with anti–Sos-1 antibody (top) or anti-Grb2 (bottom, left), or anti-E3b1 (bottom, right). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (i / immunoprecipitate-01 :ARG1 (l / lysate) :ARG3 (o / or :op1 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p3 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :ARG1-of (l2 / left-20)) :op2 (a9 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p4 / protein :name (n2 / name :op1 "E3b1") :xref (x1 / xref :value "UNIPROT:ABI1_HUMAN" :prob "0.603"))) :ARG1-of (r2 / right-04)))) :op2 (d / detect-01 :ARG1 l :ARG2 (o2 / or :op1 (a7 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p / protein :name (n3 / name :op1 "Sos-1") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))) :location (t / top)) :op2 (a10 / antibody :ARG0-of (c4 / counter-01 :ARG1 p3) :location (b / bottom :ARG1-of l2)) :op3 (a4 / antibody :ARG0-of (c5 / counter-01 :ARG1 p4) :location (b2 / bottom :ARG1-of r2))))) # ::id pmid_1177_7939.291 # ::date 2015-03-13T07:50:52 # ::file pmid_1177_7939_291.txt # ::snt The indicated lanes (lysate) (50 μg) were detected with anti–Sos-1 antibody to show the mobility shift after PDGF stimulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 27, 2015 (h / have-purpose-91 :ARG1 (d / detect-01 :ARG1 (l / lane :ARG1-of (i / indicate-01) :quant (m2 / mass-quantity :quant "50" :unit (m3 / microgram)) :ARG1-of (d2 / describe-01 :ARG2 (n3 / name :op1 "lysate"))) :ARG2 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Sos-1") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))) :ARG2 (s / show-01 :ARG1 (s2 / shift-01 :ARG1 (m / mobility) :time (a / after :op1 (s4 / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "PDGF") :xref (x1 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313"))))))) # ::id pmid_1177_7939.292 # ::date 2015-03-13T07:59:15 # ::file pmid_1177_7939_292.txt # ::snt Similar results were obtained upon EGF stimulation in Cos-7 cells (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 20, 2015 (o / obtain-01 :ARG1 (t / thing :ARG2-of (r2 / result-01 :ARG1 (s / stimulate-01 :ARG0 (p / protein :name (n / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :location (c / cell-line :mod "7" :name (n2 / name :op1 "Cos")))) :ARG1-of (r / resemble-01)) :ARG1-of (s2 / show-01 :polarity "-")) # ::id pmid_1177_7939.293 # ::date 2015-03-13T08:05:11 # ::file pmid_1177_7939_293.txt # ::snt (B) Fibroblasts were treated with PDGF for the indicated lengths of time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (t / treat-04 :li "B" :ARG0 (p / protein :name (n / name :op1 "PDGF") :xref (x / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :ARG1 (f / fibroblast) :duration (t2 / temporal-quantity :ARG1-of (i / indicate-01))) # ::id pmid_1177_7939.294 # ::date 2015-03-13T08:08:34 # ::file pmid_1177_7939_294.txt # ::snt Lysates were immunoprecipitated (IP) with anti-PDGFR (PDGFR) or an irrelevant antibody as a control (ctr) and detected with the indicated antibodies (WB). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (i / immunoprecipitate-01 :ARG1 (l / lysate) :ARG3 "o") :op2 (d / detect-01 :ARG0 (o / or :op1 (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n / name :op1 "PDGFR") :xref (x / xref :value "UNIPROT:PGFRB_HUMAN" :prob "1.003")))) :op2 (a3 / antibody :ARG1-of (r / relevant-01 :polarity "-") :ARG0-of (a4 / act-01 :ARG1 (c / control-01))) :ARG1-of (i3 / indicate-01)) :ARG1 l)) # ::id pmid_1177_7939.295 # ::date 2015-03-13T09:35:36 # ::file pmid_1177_7939_295.txt # ::snt (C) −/− [Eps8myc] cells were treated with 20 ng/ml of PDGF (+) or mock treated (−), and total cellular lysates were prepared. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (o / or :op1 (t / treat-04 :ARG1 (p / protein :name (n / name :op1 "PDGF") :quant (c4 / concentration-quantity :quant "20" :unit (n3 / nanogram-per-milliliter)) :ARG1-of (d2 / describe-01 :ARG2 (s / string-entity :name (n4 / name :op1 "+"))) :xref (x1 / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :ARG2 (c / cell :part (p3 / protein :name (n2 / name :op1 "Eps8myc") :ARG2-of (m3 / mutate-01 :mod "−/−") :xref (x / xref :value "UNIPROT:EPS8_HUMAN" :prob "0.213")))) :op2 (t3 / treat-04 :ARG1 c :manner (m / mock-01) :ARG1-of (d / describe-01 :ARG2 (s2 / string-entity :name (n5 / name :op1 "−"))))) :op2 (p2 / prepare-01 :ARG1 (l / lysate :mod (c2 / cellular :mod (t2 / total)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "C"))) # ::id pmid_1177_7939.296 # ::date 2015-03-13T09:40:49 # ::file pmid_1177_7939_296.txt # ::snt Immmunoprecipitations (IP) were performed with anti-myc antibody or with an irrelevant (ctr) antibody, followed by immunoblot with the antibody indicated on the right (WB). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / perform-02 :ARG1 (i / immunoprecipitate-01 :ARG3 (o / or :op1 (a / antibody :ARG0-of (c3 / counter-01 :ARG1 (p2 / protein :name (n / name :op1 "myc") :xref (x / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604")))) :op2 (a2 / antibody :ARG2-of (r2 / relevant-01 :polarity "-")))) :ARG2-of (f / follow-01 :ARG1 (i3 / immunoblot-01 :ARG3 (a3 / antibody :ARG1-of (i4 / indicate-01 :ARG1-of (r / right-04)))))) # ::id pmid_1177_7939.297 # ::date 2015-03-13T09:44:27 # ::file pmid_1177_7939_297.txt # ::snt The indicated lanes (lysates) were loaded with 100 μg of total cellular lysates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (l / load-01 :ARG1 (l2 / lane :ARG1-of (i / indicate-01) :ARG1-of (d / describe-01 :ARG2 (l3 / lysate))) :ARG2 (l4 / lysate :ARG1-of (t / total-01 :ARG2 (m / mass-quantity :quant "100" :unit (m2 / microgram))) :mod (c / cell))) # ::id pmid_1177_7939.298 # ::date 2015-03-13T09:45:07 # ::file pmid_1177_7939_298.txt # ::snt (D) Fibroblasts were treated with PDGF for the indicated lengths of time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (t / treat-04 :li "D" :ARG1 (f / fibroblast) :ARG2 (p / protein :name (n / name :op1 "PDGF") :xref (x / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313")) :duration (t2 / temporal-quantity :ARG1-of (i / indicate-01))) # ::id pmid_1177_7939.299 # ::date 2015-03-14T12:13:21 # ::file pmid_1177_7939_299.txt # ::snt The levels of Ras-GTP and Rac-GTP in total cellular lysates were determined by affinity precipitation using GST-RBD and GST-CRIB, as described in Materials and methods. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 1, 2015 (d / determine-01 :ARG1 (l / level :quant-of (a / and :op1 (m3 / macro-molecular-complex :part (s2 / small-molecule :name (n3 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645")) :part (e / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (m4 / macro-molecular-complex :part (e2 / enzyme :name (n4 / name :op1 "Rac") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")) :part s2)) :location (l3 / lysate :quant (t / total) :source (c / cell))) :ARG2 (p / precipitate-01 :mod (a2 / affinity) :manner (u / use-01 :ARG1 (a5 / and :op1 (p2 / protein :name (n2 / name :op1 "GST-RBD") :xref (x / xref :value "UNIPROT:GSTCD_HUMAN" :prob "0.252")) :op2 (p3 / protein :name (n5 / name :op1 "GST-CRIB") :xref (x2 / xref :value "UNIPROT:GSTCD_HUMAN" :prob "0.212"))))) :ARG1-of (d2 / describe-01 :location (a4 / and :op1 (m / material) :op2 (m2 / method)))) # ::id pmid_1177_7939.300 # ::date 2015-03-14T12:27:42 # ::file pmid_1177_7939_300.txt # ::snt Elevated levels of Rac-GTP could be observed ≤30 min of RTK stimulation (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 26, 2015 (p / possible-01 :ARG1 (o / observe-01 :ARG1 (l / level :degree-of (m / macro-molecular-complex :part (s / small-molecule :name (n / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")) :part (e / enzyme :name (n2 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603"))) :ARG1-of (e2 / elevate-01)) :time (b2 / before :op1 (s2 / stimulate-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "RTK") :xref (x1 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262"))) :duration (t / temporal-quantity :quant "30" :unit (m2 / minute)))) :ARG1-of (s3 / show-01 :polarity "-")) # ::id pmid_1177_7939.301 # ::date 2015-03-14T12:33:52 # ::file pmid_1177_7939_301.txt # ::snt The expression levels of Ras (total Ras) and Rac (total Rac), in the same lysates, were determined by immunoblotting with anti-Ras and anti-Rac antibodies, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (d / determine-01 :ARG1 (e2 / express-03 :ARG1 (l / level :degree-of (a / and :op1 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (d2 / describe-01 :ARG2 (t / total-01 :ARG1 e3)) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e4 / enzyme :name (n3 / name :op1 "Rac") :ARG1-of (d3 / describe-01 :ARG2 (t2 / total-01 :ARG1 e4)) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :location (l2 / lysate :ARG1-of (s / same-01))) :manner (i / immunoblot-01 :ARG1 e3 :ARG2 l2 :ARG3 (a2 / and :op1 (a3 / antibody :ARG0-of (c / counter-01 :ARG1 e3)) :op2 (a4 / antibody :ARG0-of (c2 / counter-01 :ARG1 e4))))) # ::id pmid_1177_7939.302 # ::date 2015-03-14T12:38:20 # ::file pmid_1177_7939_302.txt # ::snt The kinetic of the mobility shift of Sos-1, after PDGF stimulation, was determined by immunoblotting with anti–Sos-1 antibodies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (d / determine-01 :ARG1 (k / kinetics :poss (s / shift-01 :mod (m / mobility :poss (p / protein :name (n / name :op1 "Sos-1") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.633"))))) :ARG2 (i / immunoblot-01 :ARG1 p :ARG3 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 p))) :time (a / after :op1 (s2 / stimulate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "PDGF") :xref (x / xref :value "UNIPROT:PDGFA_HUMAN" :prob "0.313"))))) # ::id pmid_1563_0473.1 # ::date 2015-03-17T07:32:50 # ::file pmid_1563_0473_1.txt # ::snt A Signaling Pathway Involving TGF-β2 and Snail in Hair Follicle Morphogenesis (PMID:15630473) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / involve-01 :ARG0 (p / pathway :ARG0-of (s / signal-07)) :ARG1 (a / and :op1 (p3 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :op2 (p4 / protein :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG2 (m / morphogenesis :mod (f / follicle :mod (h / hair))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID15630473"))) # ::id pmid_1563_0473.2 # ::date 2015-03-17T07:45:03 # ::file pmid_1563_0473_2.txt # ::snt In a common theme of organogenesis, certain cells within a multipotent epithelial sheet exchange signals with their neighbors and develop into a bud structure. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (a / and :op1 (e / exchange-01 :ARG0 (c / cell :location (s / sheet :mod (m / multipotent) :mod (e2 / epithelium)) :mod (c2 / certain)) :ARG1 (t2 / thing :ARG1-of (s2 / signal-07)) :ARG2 (c4 / cell :ARG1-of (n / neighbor-01 :ARG2 c))) :op2 (d / develop-02 :ARG1 (s3 / structure :mod (b / bud)) :ARG2 c) :subevent-of (t / theme :mod (c3 / common) :purpose (g / genesis :mod (o / organ)))) # ::id pmid_1563_0473.3 # ::date 2015-03-17T07:54:47 # ::file pmid_1563_0473_3.txt # ::snt Using hair bud morphogenesis as a paradigm, we employed mutant mouse models and cultured keratinocytes to dissect the contributions of multiple extracellular cues in orchestrating adhesion dynamics and proliferation to shape the cluster of cells involved. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (e / employ-02 :ARG0 (w / we) :ARG1 (a / and :op1 (m / model :topic (m2 / mouse) :ARG1-of (m3 / mutate-01)) :op2 (c / cell :name (n / name :op1 "keratinocyte") :ARG1-of (c2 / culture-01))) :purpose (d / dissect-01 :ARG0 w :ARG1 (c3 / contribute-01 :ARG0 (c6 / cue :location (e3 / extracellular) :quant (m4 / multiple)) :ARG2 (o / orchestrate-01 :ARG1 (a2 / and :op1 (d2 / dynamic :mod (a3 / adhere-01)) :op2 (p / proliferate-01)) :purpose (s / shape-01 :ARG0 c6 :ARG1 (c4 / cluster :consist-of (c5 / cell) :ARG1-of (i / involve-01)))))) :manner (u / use-01 :ARG1 (m5 / morphogenesis :mod (b / bud :mod (h / hair))) :ARG2 (p2 / paradigm))) # ::id pmid_1563_0473.4 # ::date 2015-03-17T08:16:50 # ::file pmid_1563_0473_4.txt # ::snt We found that transforming growth factor β2 signaling is necessary to transiently induce the transcription factor Snail and activate the Ras-mitogen-activated protein kinase (MAPK) pathway in the bud. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (n2 / need-01 :ARG1 (s2 / signal-07 :ARG0 (p2 / protein :name (n / name :op1 "transforming" :op2 "growth" :op3 "factor" :op4 "β2") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.393"))) :purpose (a / and :op1 (i / induce-01 :ARG2 (p3 / protein :name (n4 / name :op1 "Snail") :mod (f2 / factor :ARG0-of (t2 / transcribe-01)) :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (t / transient-02)) :op2 (a2 / activate-01 :ARG1 (p / pathway :name (n3 / name :op1 "Ras-mitogen-activated" :op2 "protein" :op3 "kinase")) :location (b / bud))))) # ::id pmid_1563_0473.5 # ::date 2015-03-17T08:25:10 # ::file pmid_1563_0473_5.txt # ::snt In the epidermis, Snail misexpression leads to hyperproliferation and a reduction in intercellular adhesion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (l / lead-03 :ARG0 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (w / wrong-04)) :ARG2 (a / and :op1 (p / proliferate-01 :degree (h / hyper)) :op2 (r / reduce-01 :ARG1 (a2 / adhere-01 :ARG1 (c / cell) :ARG2 (c2 / cell)))) :location (e3 / epidermis)) # ::id pmid_1563_0473.6 # ::date 2015-03-17T08:31:52 # ::file pmid_1563_0473_6.txt # ::snt When E-cadherin is transcriptionally down-regulated, associated adhesion proteins with dual functions in signaling are released from cell-cell contacts, a process which we demonstrate leads to Ras-MAPK activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / release-01 :ARG1 (p / proteins :ARG0-of (a / adhere-01) :ARG1-of (a2 / associate-01) :ARG0-of (f / function-01 :ARG1 (s / signal-07) :mod (d / dual))) :ARG2 (c / contact-01 :ARG0 (c2 / cell) :ARG1 (c3 / cell)) :time (d2 / downregulate-01 :ARG1 (g / gene :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :manner (t / transcribe-01)) :ARG0-of (l / lead-03 :ARG1 (a3 / activate-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "Ras-MAPK"))) :ARG1-of (d3 / demonstrate-01 :ARG0 (w / we)))) # ::id pmid_1563_0473.7 # ::date 2015-03-17T08:43:27 # ::file pmid_1563_0473_7.txt # ::snt These studies provide insights into how multipotent cells within a sheet are stimulated to undergo transcriptional changes that result in proliferation, junctional remodeling, and bud formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 25, 2015 (p / provide-01 :ARG0 (s / study :mod (t / this)) :ARG1 (i / insight :topic (t3 / thing :manner-of (s2 / stimulate-01 :ARG1 (c / cell :mod (m2 / multipotent) :location (s3 / sheet)) :purpose (u / undergo-28 :ARG1 c :ARG2 (c2 / change-01 :ARG1 (t2 / transcribe-01) :ARG1-of (r / result-01 :ARG2 (a / and :op1 (p2 / proliferate-01 :ARG0 c) :op2 (r2 / remodel-01 :ARG1 c :mod (j / junction)) :op3 (f / form-01 :ARG1 (b / bud)))))))))) # ::id pmid_1563_0473.8 # ::date 2015-03-17T08:58:08 # ::file pmid_1563_0473_8.txt # ::snt This novel signaling pathway further weaves together the web of different morphogens and downstream transcriptional events that guide hair bud formation within the developing skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 25, 2015 (w / weave-01 :ARG0 (p / pathway :ARG0-of (s / signal-07) :mod (n / novel) :mod (t / this)) :ARG1 (w2 / web :consist-of (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "morphogen") :ARG1-of (d / differ-02) :xref (x / xref :value "PUBCHEM:123902" :prob "9.430335")) :op2 (e / event :mod (t2 / transcribe-01) :location (d2 / downstream)) :ARG0-of (g / guide-01 :ARG1 (f2 / form-01 :ARG1 (b / bud :mod (h / hair)) :location (s3 / skin :ARG1-of (d3 / develop-02)))))) :degree (f / further)) # ::id pmid_1563_0473.9 # ::date 2015-03-17T09:07:12 # ::file pmid_1563_0473_9.txt # ::snt The study of hair follicle morphogenesis provides insights into how cells within a sheet can be triggered to proliferate, remodel, and form buds - a recurring theme in development # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / provide-01 :ARG0 (s / study-01 :ARG1 (m / morphogenesis :mod (f / follicle :mod (h / hair)))) :ARG1 (i / insight :topic (t / thing :manner-of (p2 / possible-01 :ARG1 (t4 / trigger-01 :ARG1 (c / cell :location (s2 / sheet)) :purpose (a / and :op1 (p3 / proliferate-01 :ARG0 t4) :op2 (r / remodel-01 :ARG1 t4) :op3 (f2 / form-01 :ARG0 t4 :ARG1 (b / bud)) :ARG1-of (m2 / mean-01 :ARG2 (t3 / theme :ARG0-of (r2 / recur-01) :subevent-of (d / develop-02))))))))) # ::id pmid_1563_0473.10 # ::date 2015-03-17T09:15:05 # ::file pmid_1563_0473_10.txt # ::snt Introduction # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 25, 2015 (i / introduce-01) # ::id pmid_1563_0473.11 # ::date 2015-03-17T09:15:29 # ::file pmid_1563_0473_11.txt # ::snt Mammalian development involves the morphogenesis of complex three-dimensional structures from seemingly uniform sheets or masses of cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (i / involve-01 :ARG0 (d / develop-02 :ARG1 (m / mammal)) :ARG1 (m2 / morphogenesis :mod (s / structure :mod (c / complex) :mod (d2 / dimension :quant "3")) :source (o / or :op1 (s2 / sheet) :op2 (m3 / mass) :ARG1-of (u / uniform-02 :ARG1-of (s3 / seem-01)) :consist-of (c2 / cell)))) # ::id pmid_1563_0473.12 # ::date 2015-03-17T09:21:44 # ::file pmid_1563_0473_12.txt # ::snt A simple bud-like structure initiates the formation of many organs, including lungs, spinal cord, mammary glands, and hair follicles [1]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (i / initiate-01 :ARG0 (s / structure :ARG1-of (r / resemble-01 :ARG2 (b / bud)) :ARG1-of (s2 / simple-02)) :ARG1 (f / form-01 :ARG1 (o / organ :quant (m / many) :ARG2-of (i2 / include-01 :ARG1 (a / and :op1 (l / lung) :op2 (c / cord :mod (s3 / spine)) :op3 (g / gland :source (b2 / breast)) :op4 (f2 / follicle :mod (h / hair)))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG1-of (c2 / cite-01 :ARG2 "1")))) # ::id pmid_1563_0473.13 # ::date 2015-03-17T09:26:06 # ::file pmid_1563_0473_13.txt # ::snt The multipotent, adhering epithelial cells are typically attached to an underlying basal lamina that polarizes the epithelial sheet and separates it from surrounding mesenchyme. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (a / attach-01 :ARG1 (c / cell :part-of (e / epithelium) :mod (m / multipotent) :ARG1-of (a2 / adhere-01)) :ARG2 (l / lamina :ARG0-of (u / underlay-01 :ARG1 c) :mod (b / basal) :ARG0-of (p / polarize-01 :ARG1 (s / sheet :mod e)) :ARG0-of (s2 / separate-01 :ARG1 s :ARG2 (m2 / mesenchyme :ARG1-of (s3 / surround-01 :ARG2 s)))) :ARG1-of (t / typical-02)) # ::id pmid_1563_0473.14 # ::date 2015-03-17T09:39:04 # ::file pmid_1563_0473_14.txt # ::snt Budding morphogenesis is guided by a reciprocal exchange of signals between epithelium and mesenchyme to specify the identity of the organ that will form and to govern its growth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 25, 2015 (g / guide-01 :ARG0 (e / exchange-01 :ARG0 (e2 / epithelium) :ARG1 (t / thing :ARG0-of (s / signal-07)) :ARG2 (m2 / mesenchyme) :mod (r / reciprocal)) :ARG1 (m / morphogenesis :ARG1-of (b / bud-01)) :purpose (a / and :op1 (s2 / specify-01 :ARG1 (i / identity :mod (o / organ :ARG1-of (f / form-01)))) :op2 (g2 / govern-01 :ARG1 (g3 / grow-01 :ARG1 o)))) # ::id pmid_1563_0473.15 # ::date 2015-03-17T09:45:22 # ::file pmid_1563_0473_15.txt # ::snt At the helm of these molecular communication pathways are Wnts, bone morphogenic proteins (BMPs), transforming growth factor βs (TGF-βs), and fibroblast growth factors (FGFs). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (b / be-located-at-91 :ARG1 (a / and :op1 (p / pathway :name (n2 / name :op1 "Wnt")) :op2 (p2 / protein :name (n / name :op1 "bone" :op2 "morphogenic" :op3 "protein") :xref (x / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.383")) :op3 (p4 / protein :name (n3 / name :op1 "transforming" :op2 "growth" :op3 "factor" :op4 "β") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.393")) :op4 (p5 / protein :name (n4 / name :op1 "fibroblast" :op2 "growth" :op3 "factor") :xref (x2 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "0.701"))) :ARG2 (h / helm :location (r / relative-position :op1 (p3 / pathway :mod (t / this) :path-of (c / communication :mod (m / molecule)))))) # ::id pmid_1563_0473.16 # ::date 2015-03-17T09:52:24 # ::file pmid_1563_0473_16.txt # ::snt Through activation of cell surface transmembrane receptors, these external signaling molecules trigger distinct cascades of intracellular events that culminate in changes in gene expression, growth, and differentiation [2]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 18, 2015 (t / trigger-01 :ARG0 (m / molecule :mod (t2 / this) :mod (e / external) :ARG0-of (s / signal-07)) :ARG1 (c / cascade :consist-of (e2 / event :location (c2 / cell)) :mod (d / distinct) :ARG1-of (c3 / culminate-01 :ARG2 (c4 / change-01 :ARG1 (a / and :op1 (e3 / express-03 :ARG1 (g / gene)) :op2 (g2 / grow-01 :ARG1 c2) :op3 (d2 / differentiate-01 :ARG1 c2))))) :ARG2 (a2 / activate-01 :ARG1 (r / receptor :mod (t3 / transmembrane) :location (s2 / surface :poss (c5 / cell)))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG1-of (c6 / cite-01 :ARG2 "2")))) # ::id pmid_1563_0473.17 # ::date 2015-03-17T10:01:41 # ::file pmid_1563_0473_17.txt # ::snt How this constellation of signals collaborates in tailoring each budding process so that it executes a distinct morphogenetic program has yet to be comprehensively defined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (h / have-11 :ARG1 (y / yet) :ARG2 (d / define-01 :ARG1 (t / thing :manner-of (c2 / collaborate-01 :ARG0 (c3 / constellation :consist-of (t3 / thing :ARG1-of (s / signal-07)) :mod (t4 / this)) :ARG2 (t2 / tailor-01 :ARG1 (p / process-02 :ARG1 (b / bud-01) :mod (e / each))) :purpose (e2 / execute-02 :ARG0 p :ARG1 (p2 / program :topic (m / morphogenesis) :mod (d2 / distinct))))) :manner (c / comprehensive))) # ::id pmid_1563_0473.18 # ::date 2015-03-17T10:12:27 # ::file pmid_1563_0473_18.txt # ::snt However, the process appears to be patterned at the initial stages of bud formation, since the relative importance of these pathways and their downstream effectors differ as buds begin to develop and cell fates are specified. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / contrast-01 :ARG2 (a / appear-02 :ARG1 (p / process-02 :ARG1-of (p2 / pattern-01 :time (s / stage :mod (i / initial) :subevent-of (f / form-01 :ARG1 (b / bud))))) :ARG1-of (c2 / cause-01 :ARG0 (d / differ-02 :ARG1 (i2 / important :ARG2-of (r / relative-05) :domain (p3 / pathway :mod (t / this))) :ARG2 (e / effector :location (d2 / downstream) :poss p3) :condition (a3 / and :op1 (b2 / begin-01 :ARG0 b :ARG1 (d3 / develop-01 :ARG2 b)) :op2 (s2 / specify-01 :ARG1 (f2 / fate-01 :ARG1 (c3 / cell)))))))) # ::id pmid_1563_0473.19 # ::date 2015-03-17T10:25:12 # ::file pmid_1563_0473_19.txt # ::snt The development of a bud requires a number of coordinated changes in the behavior of the targeted cells within an epithelial sheet. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 19, 2015 (r / require-01 :ARG0 (d / develop-02 :ARG1 (b / bud)) :ARG1 (c / change-01 :ARG1 (b2 / behave-01 :ARG0 (c3 / cell :ARG1-of (t / target-01) :location (s / sheet :mod (e / epithelium)))) :quant (n / number) :ARG1-of (c2 / coordinate-01))) # ::id pmid_1563_0473.20 # ::date 2015-03-17T10:29:25 # ::file pmid_1563_0473_20.txt # ::snt The process must be accompanied by alterations in the proliferation, polarity, shape, and adhesiveness of selected cells, as well as by modifications in their underlying basal lamina. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (o / obligate-01 :ARG2 (a / accompany-01 :ARG0 (a5 / and :op1 (a2 / alter-01 :ARG1 (a3 / and :op1 (p2 / proliferate-01 :ARG0 (c / cell :ARG1-of (s2 / select-01))) :op2 (p3 / polarity :poss c) :op3 (s / shape :poss c) :op4 (c2 / capable-01 :ARG1 c :ARG2 (a4 / adhere-01)))) :op2 (m / modify-01 :ARG1 (l / lamina :ARG0-of (u / underlay-01 :ARG1 c) :mod (b / base)))) :ARG1 (p / process-02))) # ::id pmid_1563_0473.21 # ::date 2015-03-17T10:36:22 # ::file pmid_1563_0473_21.txt # ::snt Thus, extracellular epithelial-mesenchymal crosstalk must be intricately orchestrated to couple the determination of distinct cell fates with the contemporaneous remodeling of the physical and structural properties of the cell. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (i / infer-01 :ARG1 (o / obligate-01 :ARG2 (o2 / orchestrate-01 :ARG1 (c / crosstalk :mod (e / extracellular) :location (b / between :op1 (e2 / epithelium) :op2 (m / mesenchyme))) :manner (i2 / intricate) :purpose (c2 / couple-01 :ARG1 (d / determine-01 :ARG1 (f / fate-01 :ARG1 (c3 / cell) :mod (d2 / distinct))) :ARG2 (r / remodel-01 :ARG1 (a / and :op1 (p / property :mod (p2 / physical) :poss c3) :op2 (p3 / property :mod (s / structure) :poss c3)) :mod (c4 / contemporaneous)))))) # ::id pmid_1563_0473.22 # ::date 2015-03-17T10:44:13 # ::file pmid_1563_0473_22.txt # ::snt Among the few dispensable organs, hair follicles offer an excellent model system to study epithelial bud formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (o / offer-01 :ARG0 (f / follicle :mod (h / hair) :ARG1-of (i / include-91 :ARG2 (o2 / organ :quant (f3 / few) :ARG1-of (d / dispense-01 :ARG1-of (p / possible-01))))) :ARG1 (s / system :mod (m / model) :ARG1-of (e / excellent-02 :ARG2 (s2 / study-01 :ARG1 (f2 / form-01 :ARG1 (b / bud) :location (e2 / epithelium)))))) # ::id pmid_1563_0473.23 # ::date 2015-03-17T14:17:30 # ::file pmid_1563_0473_23.txt # ::snt Mammalian skin epithelium begins as a single sheet of multipotent ectodermal cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (b / begin-01 :ARG1 (e / epithelium :part-of (s / skin :part-of (m / mammal))) :ARG2 (s2 / sheet :consist-of (c / cell :mod (m2 / multipotent) :part-of (e2 / ectoderm)) :ARG1-of (s3 / single-02))) # ::id pmid_1563_0473.24 # ::date 2015-03-17T14:19:18 # ::file pmid_1563_0473_24.txt # ::snt During development, specialized mesenchymal cells populate the skin in a spatially defined pattern to initiate the complex epithelial-mesenchymal crosstalk that will specify the bud [3]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (p / populate-01 :ARG1 (s2 / skin) :ARG2 (c / cell :part-of (m / mesenchyme) :ARG0-of (s / specialize-01)) :manner (p2 / pattern :ARG1-of (d / define-01 :mod (s3 / space))) :purpose (i / initiate-01 :ARG0 c :ARG1 (c2 / crosstalk :mod (c3 / complex) :location (b / between :op1 (e / epithelium) :op2 m) :ARG0-of (s4 / specify-01 :ARG1 (b2 / bud-01)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "3"))) :time (d3 / develop-02)) # ::id pmid_1563_0473.25 # ::date 2015-03-17T14:20:25 # ::file pmid_1563_0473_25.txt # ::snt Once committed, a small cluster of epithelial cells, the placode, instructs a group of underlying mesenchymal cells to condense and form the nascent dermal papilla, which will be a permanent fixture of the hair follicle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (i / instruct-01 :ARG0 (c / cluster-01 :ARG1 (c2 / cell :part-of (e / epithelium)) :mod (s / small) :ARG1-of (m2 / mean-01 :ARG2 (p3 / placode))) :ARG1 (g / group :consist-of (c3 / cell :part-of (m / mesenchyme) :ARG0-of (u / underlay-01))) :ARG2 (a / and :op1 (c4 / condense-01 :ARG1 c3) :op2 (f / form-01 :ARG0 c3 :ARG1 (p / papilla :part-of (d / dermis) :ARG1-of (b / bear-02) :ARG0-of (f2 / fix-03 :ARG1 (f3 / follicle :mod (h / hair)) :manner (p2 / permanent))))) :time (a2 / after :op1 (c5 / commit-01 :ARG1 c))) # ::id pmid_1563_0473.26 # ::date 2015-03-17T14:22:00 # ::file pmid_1563_0473_26.txt # ::snt Subsequent exchanges between the placode and nascent dermal papilla result in further growth of the follicle into the underlying dermis, or down-growth, and eventual differentiation into the six concentric layers of the mature follicle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / result-01 :ARG1 (e / exchange-01 :ARG0 (p / placode) :ARG2 (p2 / papilla :ARG1-of (b / bear-02) :part-of "d") :time (s / subsequent)) :ARG2 (a / and :op1 (o / or :op1 (g / grow-01 :ARG1 (f2 / follicle) :ARG2 (f / further) :direction (d / dermis :ARG0-of (u5 / underlay-01))) :op2 (g2 / grow-01 :ARG1 f2 :ARG1-of (d2 / down-03))) :op2 (d3 / differentiate-01 :ARG1 f2 :direction (l / layer :quant "6" :mod (c / concentric) :part-of (f3 / follicle :ARG1-of (m / mature-02))) :time (e2 / eventual)))) # ::id pmid_1563_0473.27 # ::date 2015-03-17T14:25:15 # ::file pmid_1563_0473_27.txt # ::snt Previously, we delineated how two respective epithelial and mesenchymal signals, Wnts and the BMP-inhibitory factor noggin, function in concert to induce lymphoid enhancer factor-1/β-catenin (LEF-1/β-catenin)-mediated gene transcription within the follicle placode [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (d / delineate-01 :ARG0 (w / we) :ARG1 (t / thing :manner-of (f / function-01 :ARG0 (t3 / thing :quant "2" :ARG1-of (s / signal-07) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (p5 / pathway :name (n2 / name :op1 "Wnt") :source (e / epithelium)) :op2 (p / protein :name (n3 / name :op1 "noggin") :ARG0-of (i2 / inhibit-01 :ARG1 (p6 / protein :name (n4 / name :op1 "BMP") :xref (x / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263"))) :source (m3 / mesenchyme) :xref (x1 / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702"))) :manner (r / respective))) :manner (i3 / in-concert) :purpose (i / induce-01 :ARG0 t3 :ARG2 (t2 / transcribe-01 :ARG1 (g / gene) :ARG1-of (m2 / mediate-01 :ARG0 (p7 / pathway :name (n5 / name :op1 "lymphoid" :op2 "enhancer" :op3 "factor-1/β-catenin"))) :location (p2 / placode :part-of (f2 / follicle)))))) :time (p3 / previous) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 "4")))) # ::id pmid_1563_0473.28 # ::date 2015-03-17T14:33:33 # ::file pmid_1563_0473_28.txt # ::snt The downstream changes elicited through convergence of these two early signaling pathways include down-regulation of the gene encoding E-cadherin, the prototypical epithelial cadherin that forms the transmembrane core of intercellular adherens junctions (AJs) [5]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 27, 2015 (i / include-01 :ARG1 (d / downregulate-01 :ARG1 (g / gene :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin") :ARG1-of (m / mean-01 :ARG2 (p4 / protein :name (n2 / name :op1 "cadherin") :location (e4 / epithelium) :mod (p3 / prototype) :ARG0-of (f / form-01 :ARG1 (c3 / core :mod (t2 / transmembrane) :part-of (m3 / macro-molecular-complex :name (n4 / name :op1 "adherens" :op2 "junction") :location (i2 / intercellular)))) :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "0.353"))) :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :ARG2 (c / change-01 :location (d2 / downstream) :ARG1-of (e / elicit-01 :ARG0 (c2 / converge-01 :ARG0 (p / pathway :quant "2" :mod (t / this) :time (e2 / early) :ARG0-of (s / signal-07))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "5")))) # ::id pmid_1563_0473.29 # ::date 2015-03-17T14:37:12 # ::file pmid_1563_0473_29.txt # ::snt We subsequently showed that when E-cadherin is transgenically elevated in mouse skin, hair follicle morphogenesis is blocked, suggesting that E-cadherin down-regulation is a critical event in governing the adhesion dynamics necessary for budding morphogenesis [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (b / block-01 :ARG1 (m / morphogenesis :mod (f / follicle :mod (h / hair))) :ARG0-of (s2 / suggest-01 :ARG1 (c / critical-02 :ARG1 (d / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG2 (g / govern-01 :ARG1 (d2 / dynamic :ARG0-of (a / adhere-01) :ARG1-of (n3 / need-01 :purpose (m2 / morphogenesis :ARG1-of (b2 / bud-01))))))) :time (e2 / elevate-01 :ARG1 p :manner (t / transgene) :location (s4 / skin :part-of (m3 / mouse)))) :time (s3 / subsequent) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 "4")))) # ::id pmid_1563_0473.30 # ::date 2015-03-19T10:01:38 # ::file pmid_1563_0473_30.txt # ::snt Like LEF-1, E-cadherin also binds to β-catenin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (b / bind-01 :ARG1 (p3 / protein :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG2 (p / protein :name (n2 / name :op1 "β-catenin") :ARG1-of (r / resemble-01 :ARG2 (p2 / protein :name (n3 / name :op1 "LEF-1") :xref (x / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002"))) :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :mod (a / also)) # ::id pmid_1563_0473.31 # ::date 2015-03-21T03:39:27 # ::file pmid_1563_0473_31.txt # ::snt At sites of cell-cell contact, however, E-cadherin-β-catenin complexes recruit α-catenin, which in turn coordinates the associated actin polymerization dynamics necessary to stabilize nascent AJs and integrate the cytoskeleton across an epithelial sheet [6,7,8]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (h / have-concession-91 :ARG2 (r / recruit-01 :ARG0 (m2 / macro-molecular-complex :part (p7 / protein :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :part (p8 / protein :name (n9 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG1 (p / protein :name (n3 / name :op1 "α-catenin") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :location (s / site :location-of (c3 / contact-01 :ARG1 (a5 / and :op1 (c5 / cell) :op2 (c6 / cell)))) :ARG0-of (c / coordinate-01 :ARG1 (a / associate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "actin") :ARG1-of (p2 / polymerize-01) :mod (d / dynamic) :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")) :ARG1-of (n5 / need-01 :ARG0 (a2 / and :op1 (s2 / stabilize-01 :ARG1 (p4 / protein :name (n6 / name :op1 "AJ") :mod (n7 / nascent))) :op2 (i2 / integrate-01 :ARG1 (c4 / cytoskeleton :xref (x4 / xref :value "GO:0005856" :prob "0.8")) :ARG2 (a3 / across :op1 (s3 / sheet :consist-of (e / epithelium))))))) :mod (i / in-turn))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 "6" :op2 "7" :op3 "8"))))) # ::id pmid_1563_0473.32 # ::date 2015-03-21T04:53:14 # ::file pmid_1563_0473_32.txt # ::snt α-Catenin also binds to the class III Lin-1, Isl-1, Mec-3 (LIM) protein Ajuba (a member of the zyxin family of proteins), which appears to function dually in both adhesion and in activation of the Ras-mitogen-activated protein kinase (MAPK) pathway [9,10]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (b / bind-01 :ARG0 (p2 / protein :name (n2 / name :op1 "α-Catenin") :xref (x / xref :value "UNIPROT:PLAK_HUMAN" :prob "0.283")) :ARG1 (p5 / protein :name (n5 / name :op1 "Ajuba") :ARG1-of (m3 / mean-01 :ARG2 (m / member :ARG1-of (i / include-91 :ARG2 (p8 / protein-family :name (n7 / name :op1 "zyxin"))))) :ARG0-of (f2 / function-01 :ARG1 (a4 / and :op1 (a5 / adhere-01) :op2 (a6 / activate-01 :ARG1 (p / pathway :name (n / name :op1 "Ras-mitogen-activated" :op2 "protein" :op3 "kinase")))) :ARG1-of (a2 / appear-02) :manner (d / dual)) :xref (x4 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :ARG2 (a / and :op1 (p3 / protein :name (n3 / name :op1 "Lin-1") :xref (x1 / xref :value "UNIPROT:LIN7A_HUMAN" :prob "0.232")) :op2 (p4 / protein :name (n4 / name :op1 "Isl-1") :xref (x3 / xref :value "UNIPROT:ISL1_HUMAN" :prob "0.592")) :op3 (p6 / protein :name (n6 / name :op1 "Mec-3") :xref (x2 / xref :value "UNIPROT:CCL28_HUMAN" :prob "0.202")) :ARG1-of (m2 / mean-01 :ARG2 (n10 / name :op1 "LIM")) :part-of (c2 / class :ord (o / ordinal-entity :value "3"))) :mod (a3 / also) :ARG1-of (d2 / describe-01 :ARG0 (p10 / publication :ARG1-of (c / cite-01 :ARG2 (a9 / and :op1 "9" :op2 "10"))))) # ::id pmid_1563_0473.33 # ::date 2015-03-21T04:55:21 # ::file pmid_1563_0473_33.txt # ::snt Through these links, AJs appear able to couple adhesion with cytoskeletal dynamics as well as with nuclear and cytoplasmic signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (h / have-condition-91 :ARG1 (l / link-01 :mod (t / this)) :ARG2 (p2 / possible-01 :ARG1 (c / couple-01 :ARG0 (p3 / protein :name (n / name :op1 "AJ")) :ARG1 (a / adhere-01) :ARG2 (a2 / and :op1 (d / dynamic :mod (c3 / cytoskeleton :xref (x / xref :value "GO:0005856" :prob "0.8"))) :op2 (s / signal-07 :ARG0 (a3 / and :op1 (n3 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :op2 (c2 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8"))))) :ARG1-of (a4 / appear-02)))) # ::id pmid_1563_0473.34 # ::date 2015-03-21T04:56:44 # ::file pmid_1563_0473_34.txt # ::snt This provides a framework for conceptualizing why E-cadherin levels appear to impact upon a plethora of developmental processes (reviewed in [11]). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p / provide-01 :ARG0 (t / this) :ARG1 (f / framework) :ARG2 (c / conceptualize-00 :ARG1 (t2 / thing :ARG0-of (c3 / cause-01 :ARG1 (a / appear-02 :ARG1 (l / level :quant-of (p5 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG0-of (i / impact-01 :ARG1 (p2 / process-02 :ARG1 (g2 / growth) :quant (p3 / plethora)))))))) :ARG1-of (r / review-02 :ARG2 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "11")))) # ::id pmid_1563_0473.35 # ::date 2015-03-21T04:56:59 # ::file pmid_1563_0473_35.txt # ::snt As we probed more deeply into the underlying mechanisms governing E-cadherin promoter activity, we were intrigued by the close proximity of the LEF-1/β-catenin binding site to a site known to bind the Snail/Slug family of zinc finger transcriptional repressor proteins [12,13,14,15]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / cause-01 :ARG0 (p2 / probe-01 :ARG0 "w2" :ARG1 (m / mechanism :ARG0-of (u / underlie-01) :ARG0-of (g / govern-01 :ARG1 (a / activity-06 :ARG0 (m3 / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (g2 / gene :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))))) :ARG1-of (d / deep-02 :degree (m2 / more))) :ARG1 (i2 / intrigue-01 :ARG0 (c / close-10 :ARG1 (s / site :location-of (b / bind-01 :ARG1 (p4 / protein :name (n2 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :ARG2 (p5 / protein :name (n3 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :ARG2 (s2 / site :location-of (b2 / bind-01 :ARG1 (p6 / protein :ARG0-of (r2 / repress-01 :ARG1 (t / transcribe-01 :ARG1 (p8 / protein :name (n6 / name :op1 "zinc" :op2 "finger") :xref (x3 / xref :value "UNIPROT:CHD3_HUMAN" :prob "0.302")))) :part-of (s3 / slash :op1 (p9 / protein-family :name (n4 / name :op1 "Snail")) :op2 (p10 / protein-family :name (n5 / name :op1 "Slug")))) :ARG1-of (k / know-01)))) :ARG1 (w2 / we)) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 "12" :op2 "13" :op3 "14" :op4 "15"))))) # ::id pmid_1563_0473.36 # ::date 2015-03-21T10:06:54 # ::file pmid_1563_0473_36.txt # ::snt Both activity of Snail and down-regulation of E-cadherin play pivotal roles in epithelial to mesenchymal transitions (EMTs), typified by the transformation of polarized, adhering epithelial cells into motile mesenchymal cells [16,17]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / play-02 :ARG0 (a / and :op1 (a2 / activity-06 :ARG0 (p6 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :op2 (d / downregulate-01 :ARG1 (p5 / protein :name (n2 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG1 (r / role :mod (p2 / pivotal) :topic (t / transition-01 :ARG1 (e / epithelium) :ARG2 (m / mesenchyme) :ARG1-of (t2 / typify-01 :ARG0 (t3 / transform-01 :ARG1 (c / cell :mod (e2 / epithelium) :ARG1-of (p3 / polarize-01) :ARG1-of (a4 / adhere-01)) :ARG2 (c4 / cell :mod (m3 / motile) :part-of m))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 (a5 / and :op1 "16" :op2 "17"))))) # ::id pmid_1563_0473.37 # ::date 2015-03-21T10:07:09 # ::file pmid_1563_0473_37.txt # ::snt Bud formation differs from an EMT in that E-cadherin activity needs to be down-regulated but not prevented, so that adhesive junctions are remodeled rather than quantitatively impaired. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (d / differ-02 :ARG1 (f / form-01 :ARG1 (b / bud)) :ARG2 (t / transition-01 :ARG2 (c3 / cell :mod (m / mesenchymal)) :ARG3 (c2 / cell :mod (e / epithelial))) :ARG3 (n2 / need-01 :ARG1 (d2 / downregulate-01 :ARG1 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG1-of (c / contrast-01 :ARG2 (p2 / prevent-01 :polarity "-" :ARG1 a)) :purpose (r / remodel-01 :ARG1 (p3 / protein :name (n3 / name :op1 "adhesive" :op2 "junctions") :xref (x / xref :value "UNIPROT:AJAP1_HUMAN" :prob "0.222")) :ARG1-of (i / instead-of-91 :ARG2 (i2 / impair-01 :ARG1 p3 :manner (q / quantitative))))))) # ::id pmid_1563_0473.38 # ::date 2015-03-21T10:07:28 # ::file pmid_1563_0473_38.txt # ::snt Supportive of an underlying ability to fine-tune cadherin expression at the transcriptional level, Snail seems to have an additive effect with LEF-1/β-catenin in negatively modulating E-cadherin promoter activity [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c2 / cause-01 :ARG0 (s / support-01 :ARG1 (c3 / capable-01 :ARG2 (f / finetune-01 :ARG1 (e / express-03 :ARG2 (p7 / protein :name (n / name :op1 "cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "0.353")) :ARG3 (l / level :mod (t / transcribe-01)))) :ARG0-of (u / underlie-01)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication-91 :ARG0-of (c / cite-01 :ARG2 "4")))) :ARG1 (s2 / seem-01 :ARG1 (a2 / affect-01 :ARG0 (a3 / and :op1 (p6 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op2 (a4 / and :op1 (p / protein :name (n3 / name :op1 "LEF-1") :xref (x4 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n4 / name :op1 "β-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :ARG2 (m / modulate-01 :ARG1 (a / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (g / gene :name (n5 / name :op1 "E-cadherin") :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :ARG1-of (n6 / negative-02)) :mod (a5 / additive)))) # ::id pmid_1563_0473.39 # ::date 2015-03-21T10:07:43 # ::file pmid_1563_0473_39.txt # ::snt In the present study, we discovered that Snail is expressed briefly at an early stage of hair bud formation, when E-cadherin down-regulation and activation of proliferation take place. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d / discover-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :duration (b / brief) :time (e2 / early :op1 (s / stage :part-of (f / form-01 :ARG1 (b2 / bud :mod (h2 / hair)))))) :medium (s2 / study-01 :time (p / present)) :time (a / and :op1 (d2 / downregulate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :op2 (a2 / activate-01 :ARG1 (p3 / proliferate-01)))) # ::id pmid_1563_0473.40 # ::date 2015-03-21T10:07:59 # ::file pmid_1563_0473_40.txt # ::snt Thereafter, Snail disappears and remains absent during subsequent follicle down-growth and maturation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (a / and :op1 (d / disappear-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :op2 (r / remain-01 :ARG1 p :ARG3 (a2 / absent-01 :ARG1 p) :time (a3 / and :op1 (g2 / grow-01 :ARG1 (f / follicle) :ARG1-of (d2 / down-03)) :op2 (m / maturate-03 :ARG1 f) :mod (s / subsequent))) :time (t / thereafter)) # ::id pmid_1563_0473.41 # ::date 2015-03-21T10:08:12 # ::file pmid_1563_0473_41.txt # ::snt This exquisite pattern appears to be functionally relevant since altering it in vivo correspondingly affects features associated with hair bud formation, including down-regulation of E-cadherin, increased proliferation, and repressed terminal differentiation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (c2 / cause-01 :ARG0 (a2 / alter-01 :ARG1 "p" :manner (i / in-vivo) :ARG1-of (c / correspond-02) :ARG0-of (a3 / affect-01 :ARG1 (f2 / feature :ARG1-of (a4 / associate-01 :ARG2 (f3 / form-01 :ARG1 (b / bud :mod (h / hair)))) :ARG1-of (i2 / include-01 :ARG2 (a5 / and :op1 (d / downregulate-01 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :op2 (p3 / proliferate-01 :ARG1-of (i3 / increase-01)) :op3 (d2 / differentiate-01 :ARG1 (t2 / terminus) :ARG1-of (r2 / repress-01))))))) :ARG1 (a / appear-02 :ARG1 (r / relevant-01 :ARG1 (p / pattern :mod (t / this) :mod (e / exquisite)) :ARG2 (f / function-01)))) # ::id pmid_1563_0473.42 # ::date 2015-03-19T10:03:48 # ::file pmid_1563_0473_42.txt # ::snt Although the temporal spike of Snail in the hair bud is reflected at the mRNA level and seems to follow Wnt signaling and BMP inhibition, LEF-1/β-catenin activation does not appear to induce Snail gene expression in embryonic skin keratinocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (r / reflect-01 :ARG1 (l / level :mod (n8 / nucleic-acid :name (n7 / name :op1 "mRNA"))) :ARG2 (s / spike-04 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :mod (t / time) :location (b / bud :mod (h / hair)))) :op2 (s2 / seem-01 :ARG1 (f / follow-01 :ARG1 s :ARG2 (a2 / and :op1 (s3 / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "Wnt"))) :op2 (i / inhibit-01 :ARG1 (p2 / protein :name (n3 / name :op1 "BMP") :xref (x / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263")))))) :concession-of (a5 / appear-02 :polarity "-" :ARG1 (i2 / induce-01 :ARG0 (a3 / activate-01 :ARG1 (a4 / and :op1 (p3 / protein :name (n4 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n5 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :ARG2 (e / express-03 :ARG1 g) :location (c / cell :name (n6 / name :op1 "keratinocyte") :mod (e2 / embryo) :part-of (s4 / skin))))) # ::id pmid_1563_0473.43 # ::date 2015-03-19T10:03:16 # ::file pmid_1563_0473_43.txt # ::snt In contrast, we provide in vitro, transgenic (Tg), and gene targeting evidence to show that TGF-β2 and small phenotype– and mothers against decapentaplegic–related protein 2 (SMAD2) signaling are upstream inducers of Snail gene expression in skin epithelium. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (p / provide-01 :ARG0 (w / we) :ARG1 (a / and :op1 (e / evidence :ARG1-of (t / target-01 :mod (t2 / transgenic :ARG1-of (m / mean-01 :ARG2 (n5 / name :op1 "Tg"))))) :op2 (e2 / evidence :ARG1-of (t3 / target-01 :ARG0 (g / gene)))) :manner (i / in-vitro) :ARG2-of (c / contrast-01) :purpose (s / show-01 :ARG0 a :ARG1 (a2 / and :op1 (p2 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :op2 (p5 / protein :name (n3 / name :op1 "protein" :op2 "2") :ARG1-of (r / relate-01 :ARG2 (p4 / phenotype :mod (s2 / small))) :xref (x3 / xref :value "UNIPROT:PRC2A_HUMAN" :prob "0.362")) :op3 (p6 / protein :name (n2 / name :op1 "mothers" :op2 "against" :op3 "decapentaplegic" :op4 "protein" :op5 "2") :xref (x2 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "0.382")) :ARG0-of (s3 / signal-07 :ARG0-of (i2 / induce-01 :ARG2 (e3 / express-03 :ARG1 (g2 / gene :name (n4 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :direction (u / upstream) :location (e4 / epithelium :mod (s4 / skin))))))) # ::id pmid_1563_0473.44 # ::date 2015-03-19T10:02:54 # ::file pmid_1563_0473_44.txt # ::snt In the absence of TGF-β2 signaling and Snail gene expression, hair placodes can form, but further follicle down-growth is blocked. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / absent-01 :ARG1 (a2 / and :op1 (s / signal-07 :ARG0 (p / protein :name (n / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :op2 (e / express-03 :ARG1 (g / gene :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :condition-of (p2 / possible-01 :ARG1 (f / form-01 :ARG1 (p3 / placode :mod (h2 / hair))) :ARG1-of (c / contrast-01 :ARG2 (b / block-01 :ARG1 (g2 / grow-01 :ARG1 (f2 / follicle) :ARG1-of (d / down-03) :degree (f3 / further)))))) # ::id pmid_1563_0473.45 # ::date 2015-03-19T10:02:28 # ::file pmid_1563_0473_45.txt # ::snt Our studies point to the view that Snail likely functions downstream of cell fate specification, at a stage where the bud begins to exhibit enhanced proliferation and migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p / point-01 :ARG0 (s / study-01 :ARG0 (w / we)) :ARG1 (v / view-01 :ARG1 (l / likely-01 :ARG1 (f / function-01 :ARG0 (p3 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :location (r / relative-position :op1 (s2 / specify-01 :ARG1 (f2 / fate :mod (c / cell))) :direction (d2 / downstream))))) :time (s3 / stage :time-of (b / begin-01 :ARG0 (b2 / bud) :ARG1 (e / exhibit-01 :ARG0 b2 :ARG1 (a / and :op1 (p2 / proliferate-01) :op2 (m / migrate-01) :ARG1-of (e2 / enhance-01)))))) # ::id pmid_1563_0473.46 # ::date 2015-03-23T06:44:15 # ::file pmid_1563_0473_46.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 26, 2015 (t / thing :ARG2-of (r2 / result-01)) # ::id pmid_1563_0473.47 # ::date 2015-03-23T06:54:40 # ::file pmid_1563_0473_47.txt # ::snt Snail mRNA and Protein Are Expressed Transiently at the Hair Bud Stage of Follicle Morphogenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (e / express-03 :ARG2 (a / and :op1 (n3 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n4 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :op2 (p / protein :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (t / transient-02) :time (s / stage :subevent-of (m / morphogenesis :mod (f / follicle)) :mod (b / bud :mod (h / hair)))) # ::id pmid_1563_0473.48 # ::date 2015-03-23T07:28:59 # ::file pmid_1563_0473_48.txt # ::snt Although Snail family members are most frequently associated with EMTs, they also participate in many malignant processes involving a down-regulation but not a quantitative abrogation of intercellular junctions [18]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / participate-01 :ARG0 (m3 / member :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n / name :op1 "Snail")))) :ARG1 (p3 / process-02 :ARG2-of (m / malignant-02) :quant (m2 / many) :ARG2-of (i2 / involve-01 :ARG1 (d / downregulate-01 :ARG1 "j" :ARG1-of (c2 / contrast-01 :ARG2 (i4 / involve-01 :polarity "-" :ARG1 (a2 / abrogate-01 :ARG1 (j / junction :mod (i3 / intercellular)) :mod (q / quantity))))))) :concession (a / associate-01 :ARG1 m3 :ARG2 (t / transition-01 :ARG2 (c3 / cell :mod (m5 / mesenchymal)) :ARG3 (c4 / cell :mod (e / epithelial))) :ARG1-of (f2 / frequent-02 :degree (m4 / most))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "18"))) :mod (a3 / also)) # ::id pmid_1563_0473.49 # ::date 2015-03-23T07:55:07 # ::file pmid_1563_0473_49.txt # ::snt The range of developmental processes in which Snail family members have been implicated thus includes the type of epithelial remodeling that is observed in hair follicle bud formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (i4 / infer-01 :ARG1 (i / include-01 :ARG1 (r / remodel-01 :ARG1 (e / epithelium) :ARG1-of (o / observe-01 :time (f2 / form-01 :ARG1 (b / bud :part-of (f3 / follicle :mod (h / hair))))) :ARG1-of (t / type-03)) :ARG2 (r2 / range-01 :ARG1 (p / process-02 :ARG1 (g / growth) :ARG2-of (i2 / implicate-01 :ARG1 (m / member :ARG1-of (i3 / include-91 :ARG2 (p2 / protein-family :name (n / name :op1 "Snail"))))))))) # ::id pmid_1563_0473.50 # ::date 2015-03-24T06:15:25 # ::file pmid_1563_0473_50.txt # ::snt Given our prior observation that exogenously added Snail can participate with LEF-1/β-catenin in down-regulating E-cadherin expression in keratinocytes [4], coupled with the established requirement for LEF-1/β-catenin in hair follicle morphogenesis [4,19], we turned to addressing whether Snail/Slug family members might also participate in the process. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / address-02 :ARG0 (w / we) :ARG1 (p2 / participate-01 :mode "interrogative" :ARG0 (m / member :ARG1-of (i / include-91 :ARG2 (a2 / and :op1 (p3 / protein-family :name (n / name :op1 "Snail")) :op2 (p4 / protein-family :name (n2 / name :op1 "Slug"))))) :ARG1 (p5 / process-02) :mod (a6 / also)) :ARG1-of (c / cause-01 :ARG0 (a4 / and :op1 (o / observe-01 :ARG0 (w2 / we) :ARG1 (p / possible-01 :ARG1 (p7 / participate-01 :ARG0 (p8 / protein-family :name (n3 / name :op1 "Snail") :ARG1-of (a3 / add-02 :manner (e / exogenous)) :accompanier (m2 / macro-molecular-complex :part (p12 / protein :name (n6 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :part (p13 / protein :name (n7 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :ARG1 (d / downregulate-01 :ARG1 (e2 / express-03 :ARG1 (g / gene :name (n5 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG3 (k / keratinocyte))))) :time (p6 / prior) :ARG1-of (d2 / describe-01 :ARG0 (p10 / publication :ARG1-of (c2 / cite-01 :ARG2 "4")))) :op2 (r / require-01 :ARG0 (m3 / morphogenesis :mod (f2 / follicle :mod (h / hair))) :ARG1 m2 :ARG1-of (d3 / describe-01 :ARG0 (p11 / publication :ARG1-of (c3 / cite-01 :ARG2 (a5 / and :op1 "4" :op2 "19")))) :ARG1-of (e3 / establish-01))))) # ::id pmid_1563_0473.51 # ::date 2015-03-23T08:18:54 # ::file pmid_1563_0473_51.txt # ::snt PCR analyses identified transient Snail mRNA expression during a period of skin embryogenesis when waves of hair follicles are forming (unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / identify-01 :ARG0 (a2 / analyze-01 :instrument (r / react-01 :ARG0 (p3 / polymerase) :ARG1-of (c / chain-01))) :ARG1 (e / express-03 :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA") :mod (g / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (t / transient-02) :time (p2 / period :time-of (e2 / embryogenesis :mod (s / skin)) :time-of (f2 / form-01 :ARG1 (w / wave-04 :ARG1 (f / follicle :mod (h / hair)))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (p / publish-01 :polarity "-")))) # ::id pmid_1563_0473.52 # ::date 2015-03-23T08:33:46 # ::file pmid_1563_0473_52.txt # ::snt To pinpoint specifically where Snail mRNA is expressed in the developing skin, we conducted in situ hybridization using a cRNA probe unique to the Snail 3′ untranslated region (UTR). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (h / hybridize-01 :ARG0 (w / we) :purpose (p / pinpoint-01 :ARG0 w :ARG1 (l / location :ARG3-of (e / express-03 :ARG1 (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 "g2"))) :part-of (s2 / skin :ARG1-of (d / develop-02))) :ARG1-of (s / specific-02)) :ARG2-of (u / use-01 :ARG0 w :ARG1 (p2 / probe :mod (n6 / nucleic-acid :name (n2 / name :op1 "complementary" :op2 "RNA")) :mod (u2 / unique :topic (d2 / dna-sequence :name (n3 / name :op1 "3′" :op2 "untranslated" :op3 "region") :part-of (g2 / gene :name (n4 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))))) :manner (i / in-situ)) # ::id pmid_1563_0473.53 # ::date 2015-03-23T09:00:34 # ::file pmid_1563_0473_53.txt # ::snt Embryonic day 17.5 (E17.5) was chosen, since the multiple waves of follicle morphogenesis occurring at this time enabled us to evaluate Snail expression at different stages of the process. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / choose-01 :ARG0 "w2" :ARG1 (t / temporal-quantity :quant "17.5" :unit (d2 / day) :age-of (e / embryo)) :ARG1-of (c2 / cause-01 :ARG0 (e2 / enable-01 :ARG0 (w / wave-04 :ARG1 (m2 / morphogenesis :mod (f / follicle)) :quant (m / multiple) :time (a / age-01 :ARG1 e :ARG2 t)) :ARG1 (e3 / evaluate-101 :ARG0 (w2 / we) :ARG2 (e4 / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :time (s / stage :subevent-of m2 :ARG1-of (d3 / differ-02)))) :ARG2 w2))) # ::id pmid_1563_0473.54 # ::date 2015-03-23T09:48:36 # ::file pmid_1563_0473_54.txt # ::snt As shown in Figure 1A, specific hybridization was detected within the epithelium of nascent hair buds. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (d / detect-01 :ARG1 (h / hybridize-01 :ARG1-of (s / specific-02)) :location (e / epithelium :part-of (b / bud :mod (h2 / hair) :mod (n / nascent))) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1563_0473.55 # ::date 2015-03-23T09:52:54 # ::file pmid_1563_0473_55.txt # ::snt By contrast, as follicles progressed further through their development (e.g., germ and peg stages), they exhibited no signs of hybridization (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG2 (e / exhibit-01 :polarity "-" :ARG0 "f" :ARG1 (s3 / signal-07 :ARG1 (h / hybridize-01)) :time (d / develop-02 :ARG1 (f / follicle) :example (a / and :op1 (s / stage :mod (g / germ)) :op2 (s2 / stage :mod (p / peg))) :degree (f3 / further))) :ARG1-of (d2 / describe-01 :ARG2 (f2 / figure :mod "1A"))) # ::id pmid_1563_0473.56 # ::date 2015-03-23T10:13:04 # ::file pmid_1563_0473_56.txt # ::snt The transient nature of Snail mRNA expression during follicle development was most apparent in hybridized skin sections containing follicles from two different waves of morphogenesis (as shown in Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (a / apparent :degree (m / most) :domain (e / express-03 :ARG1 (n2 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1-of (t / transient-02) :time (d / develop-02 :ARG1 (f / follicle))) :location (s / section :part-of (s2 / skin :ARG1-of (h / hybridize-01)) :ARG0-of (c / contain-01 :ARG1 (f2 / follicle :source (w / wave-04 :quant "2" :ARG1 (m2 / morphogenesis) :ARG1-of (d2 / differ-02))))) :ARG1-of (s3 / show-01 :ARG0 (f3 / figure :mod "1"))) # ::id pmid_1563_0473.57 # ::date 2015-03-24T02:06:17 # ::file pmid_1563_0473_57.txt # ::snt Hybridizing hair buds from a later wave appeared juxtaposed with nonhybridizing follicles from an earlier wave. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / appear-01 :ARG1 (j / juxtapose-01 :ARG1 (b / bud :ARG1-of (h / hybridize-01) :mod (h2 / hair) :time (w / wave-01 :mod (l / late :degree (m / more)))) :ARG2 (f / follicle :ARG1-of (h3 / hybridize-01 :polarity "-") :source (w2 / wave-04 :time (e / early :degree (m2 / more)))))) # ::id pmid_1563_0473.58 # ::date 2015-03-24T02:18:39 # ::file pmid_1563_0473_58.txt # ::snt To determine whether this transient nature of Snail mRNA expression is reflected at the protein level, we generated an antibody against the N-terminal sequence that resides upstream of the more conserved zinc finger domains. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (g / generate-01 :ARG0 (w / we) :ARG1 (a / antibody :ARG0-of (o / oppose-01 :ARG1 (s / sequence :mod (p2 / protein-segment :name (n2 / name :op1 "N" :op2 "terminus") :ARG0-of (r3 / reside-01 :ARG1 (r4 / relative-position :op1 (p3 / protein-segment :name (n3 / name :op1 "zinc" :op2 "finger" :op3 "domain") :ARG1-of (c / conserve-01 :degree (m / more))) :direction (u / upstream))))))) :purpose (d / determine-01 :ARG0 w :ARG1 (r / reflect-01 :mode "interrogative" :ARG1 (l / level :mod (p / protein)) :ARG2 (n4 / nature :mod (t2 / this) :ARG1-of (t / transient-02 :manner-of (e / express-03 :ARG1 (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (g2 / gene :name (n6 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))))))))) # ::id pmid_1563_0473.59 # ::date 2015-03-24T02:42:37 # ::file pmid_1563_0473_59.txt # ::snt As judged by Western blot analysis, the antibody did not detect endogenous proteins from cultured keratinocytes, but it did yield a band of the expected size from keratinocytes transiently expressing a hemagglutinin (HA)-tagged Snail protein (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (c / contrast-01 :ARG1 (d / detect-01 :polarity "-" :ARG0 (a2 / antibody) :ARG1 (p / protein :mod (e / endogenous)) :ARG2 (k / keratinocyte :ARG1-of (c2 / culture-01))) :ARG2 (y / yield-01 :ARG0 a2 :ARG1 (b / band :mod (s2 / size :ARG1-of (e3 / expect-01))) :source (k2 / keratinocyte :ARG3-of (e2 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "Snail") :ARG1-of (t2 / tag-01 :ARG2 (s / small-molecule :name (n4 / name :op1 "hemagglutinin") :xref (x1 / xref :value "PUBCHEM:10235423" :prob "9.286493"))) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (t / transient-02)))) :ARG2-of (j / judge-01 :ARG3 (i / immunoblot-01) :ARG1-of (d3 / describe-01 :ARG2 (f / figure :mod "1B")))) # ::id pmid_1563_0473.60 # ::date 2015-03-24T03:09:37 # ::file pmid_1563_0473_60.txt # ::snt The antibody also recognized a band corresponding to the size of endogenous Snail (approximately 28 kDa) in lysates from embryonic mouse skin, the temporal appearance of which corresponded to the waves of hair follicle morphogenesis from E15.5 to newborn when over 90% of the hair on the mouse is formed (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (r / recognize-02 :ARG0 (a3 / antibody) :ARG1 (b / band :ARG1-of (c / correspond-02 :ARG2 (s / size :poss (p2 / protein :name (n / name :op1 "Snail") :mod (e / endogenous) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (e2 / equal-01 :ARG2 (a4 / approximately :op1 (m / mass-quantity :quant "28" :unit (k / kilodalton)))))) :ARG1-of (a5 / appear-01 :ARG1-of (c2 / correspond-02 :ARG2 (w / wave-04 :ARG1 (m3 / morphogenesis :mod (f / follicle :mod (h / hair))) :time (d / date-interval :op1 (a2 / age-01 :ARG1 (e4 / embryo) :ARG2 (t2 / temporal-quantity :quant "15.5" :unit (d2 / day))) :op2 (b2 / bear-02 :ARG1 (m5 / mouse) :time (n2 / new-01)) :time-of (f2 / form-01 :ARG1 (h2 / hair :mod (p / percentage-entity :value (o2 / over :op1 "90")) :part-of (m4 / mouse)))))) :mod (t / time))) :location (l / lysate :source (s2 / skin :mod (e3 / embryo) :mod (m2 / mouse))) :mod (a / also)) # ::id pmid_1563_0473.61 # ::date 2015-03-24T05:04:57 # ::file pmid_1563_0473_61.txt # ::snt Consistent with the Western blot data, immunohistochemical analysis did not detect Snail in single-layered E13.5 epidermis (Figure 1C) nor in the placode, which is the earliest morphological sign of the commitment of multipotent cells of the embryonic ectoderm to a hair cell fate (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / detect-01 :polarity "-" :ARG0 (a2 / analyze-01 :mod (i / immunohistochemistry)) :ARG1 (p / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (c / consistent-01 :ARG2 (d2 / data :ARG2-of (r / result-01 :ARG1 (i2 / immunoblot-01)))) :location (a3 / and :op1 (e / epidermis :mod (l / layer :ARG1-of (s / single-02)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "1C")) :part-of (e2 / embryo :age (t / temporal-quantity :quant "13.5" :unit (d3 / day)))) :op2 (p2 / placode :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure :mod "1D")) :ARG0-of (s3 / signal-07 :ARG1 (c2 / commit-01 :ARG1 (c3 / cell :mod (m3 / multipotent) :part-of (e4 / ectoderm :mod (e5 / embryo))) :ARG2 (f3 / fate :mod (c4 / cell :mod (h / hair)))) :mod (e3 / early :degree (m / most)) :mod (m2 / morphology))))) # ::id pmid_1563_0473.62 # ::date 2015-03-24T03:13:30 # ::file pmid_1563_0473_62.txt # ::snt Consistent with the in situ hybridization results, anti-Snail antibody labeled only hair buds and not follicles at more mature stages of development (Figure 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 5, 2015 (a2 / and :op1 (l / label-01 :ARG0 (a / antibody :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1 (b / bud :mod (h2 / hair) :mod (o / only)) :ARG1-of (c / consistent-01 :ARG2 (t / thing :ARG2-of (r / result-01 :ARG1 (h / hybridize-01 :manner (i / in-situ)))))) :op2 (l2 / label-01 :polarity "-" :ARG0 a :ARG1 (f / follicle) :time (s / stage :subevent-of (d / develop-02) :ARG1-of (m / mature-02 :degree (m2 / more)))) :ARG1-of (d2 / describe-01 :ARG2 (f2 / figure :mod "1E"))) # ::id pmid_1563_0473.63 # ::date 2015-03-24T03:31:23 # ::file pmid_1563_0473_63.txt # ::snt Taken together, the anti-Snail antibody appeared to be specific for its target protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a2 / appear-01 :ARG1 (s / specific-02 :ARG1 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG2 (p2 / protein :ARG1-of (t / target-01 :ARG0 a))) :ARG1-of (c2 / cause-01 :ARG0 (t2 / take-01 :mod (t3 / together)))) # ::id pmid_1563_0473.64 # ::date 2015-03-24T03:40:24 # ::file pmid_1563_0473_64.txt # ::snt It did not detect other Snail family members known to be expressed in keratinocytes and/or skin (unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (d / detect-01 :polarity "-" :ARG0 (i / it) :ARG1 (m / member :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n / name :op1 "Snail") :ARG2-of (e / express-03 :ARG3 (a / and-or :op1 (k2 / keratinocyte) :op2 (s / skin)) :ARG1-of (k / know-01)))) :mod (o / other)) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (p2 / publish-01 :polarity "-")))) # ::id pmid_1563_0473.65 # ::date 2015-03-24T03:48:50 # ::file pmid_1563_0473_65.txt # ::snt Furthermore, the immunohistochemical data paralleled our Snail in situ hybridization data revealing transient Snail expression at the hair bud stage (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (a / and :op2 (p / parallel-01 :ARG0 (d / data :mod (i / immunohistochemistry)) :ARG1 (d2 / data :topic (h / hybridize-01 :ARG0 (w / we) :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :manner (i2 / in-situ)) :ARG0-of (r / reveal-01 :ARG1 (e / express-03 :ARG2 g :ARG1-of (t / transient-02) :time (s / stage :mod (b / bud :mod (h2 / hair))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1A"))))))) # ::id pmid_1563_0473.66 # ::date 2015-03-19T00:29:08 # ::file pmid_1563_0473_66.txt # ::snt As judged by immunohistochemistry, Snail protein was localized to the nuclei of the hair bud cells (Figure 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 28, 2015 (j / judge-01 :ARG0 (i / immunohistochemistry) :ARG1 (b2 / be-located-at-91 :ARG1 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (n / nucleus :poss (c2 / cell :part-of (b / bud :part-of (h2 / hair))) :xref (x1 / xref :value "GO:0005634" :prob "0.8"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1E"))) # ::id pmid_1563_0473.67 # ::date 2015-03-19T00:48:44 # ::file pmid_1563_0473_67.txt # ::snt This feature was consistent with Snail's known function as a transcriptional repressor [12,13]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (c / consistent-01 :ARG1 (f / feature :mod (t / this)) :ARG2 (f2 / function-01 :ARG0 (p2 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1 (r2 / repress-01 :ARG1 (t2 / transcribe-01)) :ARG1-of (k / know-01)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "12" :op2 "13"))))) # ::id pmid_1563_0473.68 # ::date 2015-03-19T01:31:27 # ::file pmid_1563_0473_68.txt # ::snt Additionally, anti-Snail labeling was detected in only three of the four major waves of follicle morphogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op2 (d / detect-01 :ARG1 (l / label-01 :ARG0-of (o / oppose-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :location (t / thing :quant "3" :ARG1-of (i / include-91 :ARG2 (w2 / wave-04 :quant "4" :ARG1 (m2 / morphogenesis :mod (f / follicle)) :ARG1-of (m / major-02))) :mod (o2 / only)))) # ::id pmid_1563_0473.69 # ::date 2015-03-19T01:48:11 # ::file pmid_1563_0473_69.txt # ::snt Snail was not found in the buds of guard hairs that are the earliest of all hairs to form (at E13.5), and which constitute less than 5% of the mouse coat (unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (f4 / find-01 :polarity "-" :ARG1 (p2 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :location (b / bud :poss (h / hair :mod (g / guard) :ARG1-of (f2 / form-01 :time (e / early :mod (m / most) :compared-to (h2 / hair :mod (a / all))) :op1-of (a2 / and :op2 (c / constitute-01 :ARG0 h)) :time (a3 / age-01 :ARG1 (e2 / embryo) :ARG2 (t / temporal-quantity :quant "13.5" :unit (d / day)))) :ARG1-of (i / include-91 :ARG2 (c2 / coat :poss (m2 / mouse)) :ARG3 (l2 / less-than :op1 (p3 / percentage-entity :value "5")) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (p4 / publish-01 :polarity "-"))))))) # ::id pmid_1563_0473.70 # ::date 2015-03-19T02:21:51 # ::file pmid_1563_0473_70.txt # ::snt As judged by immunofluorescence with antibodies against the proliferating nuclear antigen Ki67, the timing of Snail expression coincided with the stage at which the developing follicle enhanced its proliferation and down-growth (Figure 1F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (j / judge-01 :ARG0 (i / immunofluoresce-01 :ARG2 (a / antibody :ARG0-of (o / oppose-01 :ARG1 (p5 / protein :name (n4 / name :op1 "Ki67") :mod (n5 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :ARG0-of (p / proliferate-01) :mod (a2 / antigen) :xref (x1 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))))) :ARG1 (c / coincide-01 :ARG1 (t / time-02 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG2 (s / stage :time-of (e2 / enhance-01 :ARG0 (f / follicle :ARG1-of (d / develop-02)) :ARG1 (a5 / and :op1 (p3 / proliferate-01 :ARG0 f) :op2 (g / grow-01 :ARG1 f :ARG1-of (d2 / down-03)))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "1F"))) # ::id pmid_1563_0473.71 # ::date 2015-03-21T04:50:41 # ::file pmid_1563_0473_71.txt # ::snt Immunohistochemistry with antibodies against the active (phosphorylated) form of MAPK (pMAPK) marked a subset of the proliferating (Ki67-positive) cells, and pMAPK-positive cells were enriched in the hair bud (Figure 1G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (a3 / and :op1 (m / mark-02 :ARG0 (i / immunohistochemistry :mod (a / antibody) :ARG0-of (o2 / oppose-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MAPK") :ARG0-of (a2 / activity-06) :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :ARG2 (s / subset :quant-of (c2 / cell :ARG0-of (p4 / proliferate-01) :part (p5 / protein :name (n3 / name :op1 "Ki67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))))) :op2 (e / enrich-01 :ARG1 (c3 / cell :location (b / bud :mod (h2 / hair)) :part e2)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1G"))) # ::id pmid_1563_0473.72 # ::date 2015-03-22T02:43:10 # ::file pmid_1563_0473_72.txt # ::snt The timing of Snail induction and Ki67 and pMAPK enrichment in the hair bud appeared to follow closely the induction of LEF-1/β-catenin activity, known to initiate in the hair placode stage [20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (a / appear-02 :ARG1 (f / follow-01 :ARG1 (t / time-02 :ARG1 (a5 / and :op1 (i / induce-01 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x4 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :op2 (e / enrich-01 :ARG1 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "Ki67") :xref (x1 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653")) :op2 (e2 / enzyme :name (n3 / name :op1 "MAPK") :ARG3-of (p7 / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :location (b / bud :poss (h / hair))))) :ARG2 (i2 / induce-01 :ARG2 (a2 / activity-06 :ARG0 (m / macro-molecular-complex :part (p4 / protein :name (n4 / name :op1 "LEF-1") :xref (x3 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :part (p3 / protein :name (n5 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG1-of (i3 / initiate-01 :time (s / stage :mod (p5 / placode) :mod (h2 / hair)) :ARG1-of (k / know-01)))) :ARG1-of (c2 / close-10)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 "20")))) # ::id pmid_1563_0473.73 # ::date 2015-03-22T05:00:06 # ::file pmid_1563_0473_73.txt # ::snt However, like placodes, hair buds exhibited down-regulation in E-cadherin expression (Figure 1H; see also [4]). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / contrast-01 :ARG2 (e / exhibit-01 :ARG0 (b / bud :poss (h / hair) :ARG1-of (r2 / resemble-01 :ARG2 (p3 / placode))) :ARG1 (d / downregulate-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1H") :op2 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "4") :ARG1-of (s / see-01 :mode "imperative" :ARG0 (y / you) :mod (a2 / also)))))) # ::id pmid_1563_0473.74 # ::date 2015-03-22T05:16:34 # ::file pmid_1563_0473_74.txt # ::snt Sustained Expression of Snail Results in Epidermal Hyperproliferation and Differentiation Defects in Tg Mouse Skin # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 28, 2015 (r / result-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (s / sustain-01)) :ARG2 (a / and :op1 (p2 / proliferate-01 :ARG0 (e2 / epidermis) :degree (h / hyper)) :op2 (d / defect :location (s2 / skin :part-of (m / mouse :mod (t / transgenic))) :mod (d2 / differentiate-01)))) # ::id pmid_1563_0473.75 # ::date 2015-03-22T05:30:29 # ::file pmid_1563_0473_75.txt # ::snt The striking spike of Snail expression coincident with hair bud formation and enhanced proliferation prompted us to examine the consequences of ectopically expressing Snail elsewhere in mouse skin epidermis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (p / prompt-02 :ARG0 (c2 / coincide-01 :ARG1 (s3 / spike-04 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (s / strike-04)) :ARG2 (a2 / and :op1 (f / form-01 :ARG1 (b / bud :poss (h / hair))) :op2 (p3 / proliferate-01 :ARG1-of (e2 / enhance-01)))) :ARG1 (w / we) :ARG2 (e3 / examine-01 :ARG0 w :ARG1 (c3 / consequence :poss (e4 / express-03 :ARG2 p2 :ARG3 (e6 / epidermis :part-of (s2 / skin :part-of (m / mouse)) :mod (e7 / elsewhere)) :manner (e5 / ectopic))))) # ::id pmid_1563_0473.76 # ::date 2015-03-22T05:50:04 # ::file pmid_1563_0473_76.txt # ::snt To distinguish Tg from endogenous Snail, we used the HA-epitope, shown previously not to alter Snail's transcriptional activity [12]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (d / dna-sequence :name (n / name :op1 "HA-epitope") :ARG0-of (a / alter-01 :polarity "-" :ARG1 (a2 / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1 (t / transcribe-01)) :ARG1-of (s / show-01 :time (p / previous)))) :purpose (d2 / distinguish-01 :ARG0 w :ARG1 (p5 / protein :name (n4 / name :op1 "Snail") :mod (t2 / transgenic) :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (p3 / protein :name (n3 / name :op1 "Snail") :mod (e / endogenous) :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "12")))) # ::id pmid_1563_0473.77 # ::date 2015-03-22T06:15:03 # ::file pmid_1563_0473_77.txt # ::snt Of 20 K14-Snail[HA] Tg animals generated, three expressed the transgene and all exhibited analogous phenotypes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 25, 2015 (g / generate-01 :ARG1 (a / animal :quant "20" :mod (t / transgene) :part (p / protein :name (n / name :op1 "K14-Snail") :part (p2 / protein :name (n2 / name :op1 "HA") :xref (x / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :ARG2-of (i / include-91 :ARG1 (a2 / animal :quant "3" :ARG1-of (e / express-03 :ARG2 t))) :ARG0-of (e2 / exhibit-01 :ARG1 (p3 / phenotype :mod (a3 / analogue))))) # ::id pmid_1563_0473.78 # ::date 2015-03-22T06:45:22 # ::file pmid_1563_0473_78.txt # ::snt Mice that integrated the transgene at the single-cell stage died at or shortly after birth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / die-01 :ARG1 (m / mouse :ARG0-of (i / integrate-01 :ARG1 (t / transgene) :time (s / stage :mod (c / cell :ARG1-of (s2 / single-02))))) :time (o / or :op1 (b / bear-02) :op2 (a / after :op1 b :quant (s3 / short-07)))) # ::id pmid_1563_0473.79 # ::date 2015-03-22T06:50:07 # ::file pmid_1563_0473_79.txt # ::snt The three surviving full-Tg founder mice harbored transgene integrations that gave stable transmission of mosaic Snail gene expression through the germline. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (h / harbor-01 :ARG0 (m / mouse :quant "3" :ARG0-of (f / found-01) :ARG0-of (s / survive-01) :mod (t / transgene :ARG1-of (f2 / full-09))) :ARG1 (i / integrate-01 :ARG1 (t3 / transgene) :ARG0-of (g / give-01 :ARG1 (t2 / transmit-01 :ARG1 (e / express-03 :ARG1 (g3 / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :mod (m2 / mosaic)) :instrument (g2 / germline) :ARG1-of (s2 / stable-03))))) # ::id pmid_1563_0473.80 # ::date 2015-03-22T06:59:12 # ::file pmid_1563_0473_80.txt # ::snt Progressively poor health necessitated our sacrificing most offspring from these lines within a year of birth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (n / necessitate-01 :ARG0 (h / healthy :polarity "-" :ARG1-of (p / progress-01)) :ARG1 (s / sacrifice-01 :ARG0 (w / we) :ARG1 (o / offspring :mod (m / most) :source (l / line :mod (t2 / this))) :time (a / after :op1 (b / bear-02) :quant (u / up-to :op1 (t3 / temporal-quantity :quant "1" :unit (y2 / year)))))) # ::id pmid_1563_0473.81 # ::date 2015-03-22T07:11:11 # ::file pmid_1563_0473_81.txt # ::snt As Snail Tg animals grew, they became distinguished by their small size, short tails, and flaky skin (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (d / distinguish-01 :ARG0 (a2 / and :op1 (s / size :mod (s4 / small) :poss "a") :op2 (t2 / tail :ARG1-of (s2 / short-07) :poss "a") :op3 (s3 / skin :mod (f / flake) :poss "a")) :ARG1 (a / animal :mod (g3 / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :mod (t / transgene)) :time (g / grow-01 :ARG1 a) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2A"))) # ::id pmid_1563_0473.82 # ::date 2015-03-22T07:58:30 # ::file pmid_1563_0473_82.txt # ::snt Histological analyses of 3-d old (P3) mice revealed mosaic patches marked by epidermal thickening (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (m / mouse :age (t / temporal-quantity :quant "3" :unit (d / day))) :mod (h / histology)) :ARG1 (p / patch :mod (m2 / mosaic) :ARG1-of (m3 / mark-02 :ARG3 (t2 / thicken-01 :ARG1 (e / epidermis)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id pmid_1563_0473.83 # ::date 2015-03-22T08:08:44 # ::file pmid_1563_0473_83.txt # ::snt The mosaic morphology was reflected at the level of Tg Snail protein, with only the hyperthickened regions expressing nuclear HA-tagged Snail (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (r / reflect-01 :ARG1 (l / level :poss (p / protein :name (n / name :op1 "Snail") :mod (t3 / transgene) :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG2 (m / morphology :mod (m2 / mosaic)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2C"))) :op2 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "Snail") :ARG1-of (t2 / tag-01 :ARG2 (p3 / protein :name (n4 / name :op1 "HA") :xref (x1 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :mod (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (r2 / region :ARG1-of (t / thicken-01 :degree (h2 / hyper)) :mod (o / only)))) # ::id pmid_1563_0473.84 # ::date 2015-03-22T08:24:20 # ::file pmid_1563_0473_84.txt # ::snt These hyperthickened areas were marked by excessive proliferation, as revealed by antibodies against the proliferating nuclear antigen Ki67 (Figure 2D and 2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (m / mark-02 :ARG1 (a / area :ARG1-of (t / thicken-01 :degree (h / hyper)) :mod (t2 / this)) :ARG3 (p / proliferate-01 :ARG1-of (e / excessive-02)) :ARG1-of (r / reveal-01 :ARG0 (a2 / antibody :ARG0-of (o / oppose-01 :ARG1 (p2 / protein :name (n / name :op1 "Ki67") :ARG0-of (p3 / proliferate-01) :mod (n2 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :mod (a3 / antigen) :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2D") :op2 (f2 / figure :mod "2E")))) # ::id pmid_1563_0473.85 # ::date 2015-03-22T08:31:56 # ::file pmid_1563_0473_85.txt # ::snt Activated, pMAPK-positive cells were also prevalent in these areas (Figure 2F and 2G), as were cells expressing keratin 6, a keratin induced in the suprabasal layers of hyperproliferative skin (Figure 2H and 2I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (p5 / prevail-02 :ARG1 (a4 / and :op1 (c / cell :part (e2 / enzyme :name (n / name :op1 "MAPK") :ARG1-of (a / activate-01) :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :op2 (c2 / cell :ARG3-of (e / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "keratin-6") :ARG2-of (i / induce-01 :location (l / layer :mod (s3 / suprabasal) :part-of (s2 / skin :ARG0-of (p4 / proliferate-01 :degree (h / hyper))))) :xref (x1 / xref :value "UNIPROT:K1C16_HUMAN" :prob "0.362"))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f3 / figure :mod "2H") :op2 (f4 / figure :mod "2I"))))) :location (a2 / area :mod (t / this) :mod (a8 / also)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "2F") :op2 (f2 / figure :mod "2G")))) # ::id pmid_1563_0473.86 # ::date 2015-03-22T08:51:10 # ::file pmid_1563_0473_86.txt # ::snt Expression of the Snail transgene did not block terminal differentiation in the hyperproliferative epidermis, but it distorted it markedly (Figure 3A–3H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / contrast-01 :ARG1 (b / block-01 :polarity "-" :ARG0 (e / express-03 :ARG1 (t2 / transgene :mod (g / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1 (d / differentiate-01 :ARG1 (e2 / epidermis :ARG0-of (p2 / proliferate-01 :degree (h / hyper))) :mod (t / terminus))) :ARG2 (d2 / distort-01 :ARG0 e :ARG1 d :manner (m / marked)) :ARG1-of (d3 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B") :op3 (f3 / figure :mod "3C") :op4 (f4 / figure :mod "3D") :op5 (f5 / figure :mod "3E") :op6 (f6 / figure :mod "3F") :op7 (f7 / figure :mod "3G") :op8 (f8 / figure :mod "3H")))) # ::id pmid_1563_0473.87 # ::date 2015-03-22T09:02:18 # ::file pmid_1563_0473_87.txt # ::snt Typical of most hyperproliferating conditions, Snail expression led to a large expansion in layers with spinous and granular morphology. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (l / lead-03 :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG2 (e2 / expand-01 :location (l2 / layer :mod (m / morphology :mod (s / spine) :mod (g / granule))) :degree (l3 / large)) :ARG1-of (t / typical-02) :condition (p2 / proliferate-01 :degree (h / hyper) :mod (m2 / most))) # ::id pmid_1563_0473.88 # ::date 2015-03-22T09:12:12 # ::file pmid_1563_0473_88.txt # ::snt Additionally, however, was a marked and variable expansion of keratin 5 (K5), normally restricted to the innermost basal layer (see Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a2 / and :op2 (c / contrast-01 :ARG2 (e / expand-01 :ARG1 (p / protein :name (n / name :op1 "keratin-5") :xref (x / xref :value "UNIPROT:K2C5_HUMAN" :prob "0.702")) :ARG1-of (r / restrict-01 :ARG2 (l / layer :mod (b / basal) :mod (i / inner :degree (m2 / most))) :ARG1-of (n2 / normal-02)) :ARG1-of (m / mark-01) :ARG1-of (v / vary-01))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3" :ARG1-of (s / see-01 :mode "imperative" :ARG0 (y / you))))) # ::id pmid_1563_0473.89 # ::date 2015-03-23T07:16:25 # ::file pmid_1563_0473_89.txt # ::snt Although the failure of Snail-null mice to develop past gastrulation [21] precluded our ability to study the loss of Snail function in skin development, a good correlation emerged between the expression of Snail protein and the extension of K5, Ki67, and pMAPK suprabasally (compare data in Figures 2 and 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / multi-sentence :snt1 (h / have-concession-91 :ARG1 (e / emerge-02 :ARG0 (c / correlate-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x4 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG2 (e3 / extend-01 :ARG1 (a / and :op1 (p7 / protein :mod "7" :name (n2 / name :op1 "K5") :xref (x2 / xref :value "UNIPROT:K2C5_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n3 / name :op1 "Ki67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653")) :op3 (e4 / enzyme :name (n4 / name :op1 "MAPK") :ARG3-of (p8 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :manner (s / suprabasal)) :ARG1-of (g / good-02))) :ARG2 (p4 / preclude-01 :ARG0 (f / fail-01 :ARG1 (m2 / mouse :mod (p9 / protein :name (n5 / name :op1 "Snail") :ARG2-of (m3 / mutate-01 :mod "−/−") :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG2 (d / develop-02 :ARG1 m2 :time (a2 / after :op1 (g2 / gastrulate-00))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "21")))) :ARG1 (p6 / possible-01 :ARG1 (s2 / study-01 :ARG0 (w / we) :ARG1 (l / lose-02 :ARG1 (f2 / function :mod p) :location (d2 / develop-01 :ARG2 (s3 / skin))))))) :snt2 (c3 / compare-01 :ARG1 (d3 / data :ARG1-of (d4 / describe-01 :ARG0 (a3 / and :op1 (f3 / figure :mod "2") :op2 (f4 / figure :mod "3")))))) # ::id pmid_1563_0473.90 # ::date 2015-03-23T07:54:23 # ::file pmid_1563_0473_90.txt # ::snt The changes in hyperproliferation and differentiation were not initially accompanied by gross signs of epithelial invaginations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / accompany-01 :polarity "-" :ARG0 (c / change-01 :ARG1 (a2 / and :op1 (p / proliferate-01 :degree (h / hyper)) :op2 (d / differentiate-01))) :ARG1 (s / signal-07 :ARG1 (e / epithelium :ARG1-of (i2 / invaginate-01)) :ARG1-of (g / gross-04)) :time (i / initial)) # ::id pmid_1563_0473.91 # ::date 2015-03-23T08:17:02 # ::file pmid_1563_0473_91.txt # ::snt With age, however, epidermal folds and undulations developed in areas where Snail was expressed, and proliferative markers persisted in these regions (Figure 3I and 3J; anti-cyclin D staining). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / have-concession-91 :ARG1 (a2 / and :op1 (c / cause-01 :ARG0 (a / age-01) :ARG1 (a5 / and :op1 (d / develop-02 :ARG1 (a3 / and :op1 (f / fold-03 :ARG1 (e / epidermis)) :op2 (u / undulate-01 :ARG1 e)) :location (a4 / area :location-of (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :op2 (p2 / persist-01 :ARG0 (m / marker :ARG0-of (p3 / proliferate-01)) :location a4)))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (f2 / figure :mod "3I") :op2 (f3 / figure :mod "3J")) :ARG2 (s / stain-01 :ARG2 (m2 / molecular-physical-entity :ARG0-of (c3 / counter-01 :ARG1 (p4 / protein :name (n4 / name :op1 "cyclin" :op2 "D") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.371"))))))) # ::id pmid_1563_0473.92 # ::date 2015-04-13T13:46:04 # ::file pmid_1563_0473_92.txt # ::snt The undulations were accompanied by partial dissolution of the underlying basement membrane (Figure 3K and 3L). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / accompany-01 :ARG0 (d / dissolute-00 :ARG1 (m / membrane :mod (b / basement) :ARG1-of (u / underlie-01) :xref (x / xref :value "GO:0016020" :prob "0.8")) :degree (p / part)) :ARG1 (u2 / undulate-01) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3K") :op2 (f2 / figure :mod "3L")))) # ::id pmid_1563_0473.93 # ::date 2015-03-23T10:59:36 # ::file pmid_1563_0473_93.txt # ::snt Aberrant staining was also observed with antibodies against components of the hemidesmosomes, which provide strong adhesion of basal epidermal cells to the underlying basal lamina (Figure 3M and 3N). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (o / observe-01 :ARG1 (s / stain-01 :ARG2 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (c2 / component :part-of (h / hemidesmosome :ARG0-of (p / provide-01 :ARG1 (a4 / adhere-01 :ARG1 (c3 / cell :mod (e / epidermis :mod (b / basal))) :ARG2 (l2 / lamina :mod (b2 / basal) :ARG1-of (u / underlie-01)) :ARG1-of (s2 / strong-02))))))) :manner (a / aberrant)) :mod (a3 / also) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "3M") :op2 (f2 / figure :mod "3N")))) # ::id pmid_1563_0473.94 # ::date 2015-03-23T11:10:16 # ::file pmid_1563_0473_94.txt # ::snt Interestingly, similar types of alterations occur in the basement membrane in the hair bud of embryonic and newborn mice when Snail is normally expressed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / alter-01 :location (m / membrane :mod (b / basement) :part-of (b2 / bud :mod (h / hair) :poss (a2 / and :op1 (e / embryo :mod (m2 / mouse)) :op2 (m3 / mouse :ARG1-of (b3 / bear-02 :time (n / new-01))))) :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :time (e2 / express-03 :ARG2 (p / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (n3 / normal-02)) :ARG2-of (t / type-03 :ARG1-of (r / resemble-01)) :ARG2-of (i2 / interest-01)) # ::id pmid_1563_0473.95 # ::date 2015-03-23T11:16:49 # ::file pmid_1563_0473_95.txt # ::snt The fact that the basement membrane separating the epidermis from the dermis is altered only in the adult Tg animals suggests the involvement of intermediary factors not as readily available in the epidermis as they are in the follicle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (s / suggest-01 :ARG0 (a / alter-01 :ARG1 (m / membrane :mod (b / basement) :ARG0-of (s2 / separate-01 :ARG1 (e / epidermis) :ARG2 (d / dermis)) :xref (x / xref :value "GO:0016020" :prob "0.8")) :location (a2 / animal :mod (a3 / adult) :mod (t / transgenic)) :mod (o / only)) :ARG1 (i / involve-01 :ARG1 (f2 / factor :mod (i2 / intermediary) :ARG2-of (a4 / available-02 :polarity "-" :manner (r / ready) :location (e2 / epidermis) :compared-to (f3 / follicle))))) # ::id pmid_1563_0473.96 # ::date 2015-03-23T13:15:15 # ::file pmid_1563_0473_96.txt # ::snt Possible Links between Epidermal Hyperproliferation and Down-regulation of AJ Proteins in Snail Tg Mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p / possible-01 :ARG1 (l / link-01 :ARG1 (p4 / proliferate-01 :ARG0 (e / epidermis) :degree (h / hyper)) :ARG2 (d / downregulate-01 :ARG1 (p3 / protein :name (n / name :op1 "AJ"))) :location (m / mouse :mod (g / gene :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :mod (t / transgenic)))) # ::id pmid_1563_0473.97 # ::date 2015-03-24T02:26:54 # ::file pmid_1563_0473_97.txt # ::snt Given that the E-cadherin promoter is a direct target for Snail-mediated repression in vitro [4,12,13], and that E-cadherin was down-regulated in Snail-expressing hair buds, we examined the status of E-cadherin and other AJ proteins within regions of hyperproliferative epidermis where Tg Snail was present (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c2 / cause-01 :ARG0 (a / and :op1 (t / target-01 :ARG0 (r / repress-01 :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :manner (i / in-vitro)) :ARG1 (m2 / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :ARG1-of (d3 / direct-02) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "4" :op2 "12" :op3 "13"))))) :op2 (d / downregulate-01 :ARG1 p :location (b / bud :mod (h / hair) :ARG3-of (e / express-03 :ARG2 p2)))) :ARG1 (e2 / examine-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (s / status :poss p) :op2 (s2 / status :poss (p3 / protein :name (n3 / name :op1 "AJ") :mod (o / other))) :location (r2 / region :poss (e3 / epidermis :ARG0-of (p8 / proliferate-01 :degree (h2 / hyper))) :ARG2-of (p7 / present-02 :ARG1 (p6 / protein :name (n4 / name :op1 "Snail") :mod (t2 / transgenic) :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A")))) # ::id pmid_1563_0473.98 # ::date 2015-03-24T09:44:53 # ::file pmid_1563_0473_98.txt # ::snt In these regions, immunofluorescence staining of E-cadherin and α-catenin were markedly diminished. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (d / diminish-01 :ARG1 (s / stain-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG2 (i / immunofluoresce-01)) :degree (m / marked) :location (r / region :mod (t / this))) # ::id pmid_1563_0473.99 # ::date 2015-03-24T09:51:15 # ::file pmid_1563_0473_99.txt # ::snt In contrast, the intensity of antibody staining for two other AJ proteins, β-catenin and Ajuba, was still strong. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (c / contrast-01 :ARG2 (i / intensity :degree-of (s / stain-01 :ARG1 (p / protein :quant "2" :name (n / name :op1 "AJ") :example (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "β-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op2 (p3 / protein :name (n3 / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))) :mod (o / other)) :ARG2 (a / antibody)) :ARG1-of (s2 / strong-02 :mod (s3 / still)))) # ::id pmid_1563_0473.100 # ::date 2015-03-24T09:59:38 # ::file pmid_1563_0473_100.txt # ::snt Interestingly, however, despite appreciable immunofluorescence, localization of β-catenin and Ajuba appeared to be largely cytoplasmic rather than at cell-cell borders (Figure 4A insets). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (h / have-concession-91 :ARG1 (a / appear-02 :ARG1 (c / cytoplasmic :location-of (a2 / and :op1 (p / protein :name (n / name :op1 "β-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op2 (p2 / protein :name (n2 / name :op1 "Ajuba") :xref (x / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))) :ARG1-of (i / instead-of-91 :ARG2 (b / border-01 :ARG1 (c2 / cell) :ARG2 (c3 / cell)))) :degree (l2 / large)) :ARG2 (i2 / immunofluoresce-01 :ARG1-of (a3 / appreciate-03 :ARG1-of (p3 / possible-01))) :ARG1-of (d / describe-01 :ARG2 (f / figure :mod "4A" :mod (i4 / inset))) :ARG2-of (i3 / interest-01)) # ::id pmid_1563_0473.101 # ::date 2015-03-24T10:05:56 # ::file pmid_1563_0473_101.txt # ::snt Architectural differences in the epidermis made Western blot analyses somewhat difficult to gauge. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / make-02 :ARG0 (d3 / differ-02 :ARG3 (a2 / architecture) :location (e / epidermis)) :ARG1 (d / difficult :domain (g / gauge-01 :ARG1 (a / analyze-01 :manner (i / immunoblot-01))) :degree (s / somewhat))) # ::id pmid_1563_0473.102 # ::date 2015-03-25T03:59:46 # ::file pmid_1563_0473_102.txt # ::snt However, in regions such as ear skin, where the highest levels of Snail protein were expressed, the effects were accentuated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (h / have-concession-91 :ARG1 (a / accentuate-01 :ARG1 (a2 / affect-01) :location (r / region :example (s / skin :mod (e / ear)) :location-of (l / level :ARG1-of (h2 / high-02 :degree (m2 / most)) :quant-of (p / protein :name (n / name :op1 "Snail") :ARG2-of (e2 / express-03) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))))) # ::id pmid_1563_0473.103 # ::date 2015-03-25T04:05:07 # ::file pmid_1563_0473_103.txt # ::snt In both back skin and ear skin, overall levels of E-cadherin and α-catenin were reduced, under conditions where β-catenin and Ajuba levels remained unchanged relative to controls (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 31, 2015 (r / reduce-01 :ARG1 (a4 / and :op1 (l / level :quant-of (p / protein :name (n / name :op1 "E-cadherin") :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :op2 (l3 / level :quant-of (p2 / protein :name (n2 / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :degree (o / overall)) :location (a2 / and :op1 (s / skin :mod (b / back)) :op2 (s2 / skin :mod (e / ear))) :condition (r2 / remain-01 :ARG1 (c / change-01 :polarity "-" :ARG1 (a / and :op1 (l2 / level :quant-of (p3 / protein :name (n3 / name :op1 "β-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :op2 (l4 / level :quant-of (p4 / protein :name (n4 / name :op1 "Ajuba") :xref (x2 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))))) :ARG1-of (r3 / relate-01 :ARG2 (c2 / control-01))) :ARG1-of (d / describe-01 :ARG2 (f / figure :mod "4B"))) # ::id pmid_1563_0473.104 # ::date 2015-03-25T04:14:43 # ::file pmid_1563_0473_104.txt # ::snt Taken together, these data were consistent with our results obtained from immunofluorescence microscopy. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (h / have-condition-91 :ARG1 (d / data :ARG1-of (c / consistent-01 :ARG2 (t3 / thing :ARG2-of (r / result-01 :ARG1-of (o / obtain-01 :ARG0 "w" :ARG2 (m / microscopy :mod (i / immunofluoresce-01)))) :poss (w / we))) :mod (t4 / this)) :ARG2 (t / take-01 :mod (t5 / together))) # ::id pmid_1563_0473.105 # ::date 2015-03-25T04:18:56 # ::file pmid_1563_0473_105.txt # ::snt A priori, the decrease in α-catenin levels could be due to either direct transcriptional repression by Snail or perturbations in AJ formation caused by the decrease in E-cadherin gene expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (d / decrease-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG1-of (c / cause-01 :ARG0 (o / or :op1 (r / repress-01 :ARG0 (p3 / protein :name (n2 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (t / transcribe-01 :ARG1-of (d2 / direct-02))) :op2 (p4 / perturb-01 :ARG1 (f / form-01 :ARG1 (p5 / protein :name (n3 / name :op1 "AJ"))) :ARG1-of (c2 / cause-01 :ARG0 (d3 / decrease-01 :ARG1 (e / express-03 :ARG1 (g2 / gene :name (n4 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))))))) :time (a / a-priori)) # ::id pmid_1563_0473.106 # ::date 2015-03-25T04:29:19 # ::file pmid_1563_0473_106.txt # ::snt To distinguish between these possibilities, we tested whether α-catenin levels could be restored by exogenous expression of E-cadherin in Snail-expressing keratinocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 31, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (r / restore-01 :mode "interrogative" :ARG0 w :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :manner (e / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :mod (e2 / exogenous) :location (c / cell :name (n3 / name :op1 "keratinocyte") :ARG3-of (e3 / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))))) :purpose (d / distinguish-01 :ARG0 w :ARG1 (p5 / possible-01 :mod (t2 / this)))) # ::id pmid_1563_0473.107 # ::date 2015-03-25T04:37:46 # ::file pmid_1563_0473_107.txt # ::snt As shown in Figure 4C, transiently transfected keratinocytes expressing HA-tagged Snail displayed a loss of E-cadherin and α-catenin at cell-cell borders. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / display-01 :ARG0 (c / cell :name (n / name :op1 "keratinocyte") :ARG1-of (t / transfect-01 :ARG1-of (t2 / transient-02)) :ARG3-of (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "Snail") :ARG1-of (t3 / tag-01 :ARG2 (p4 / protein :name (n6 / name :op1 "HA") :xref (x2 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1 (l / lose-02 :ARG0 c :ARG1 (a / and :op1 (p2 / protein :name (n4 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n5 / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :location (b / border-01 :ARG1 (c2 / cell) :ARG2 (c3 / cell))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "4C"))) # ::id pmid_1563_0473.108 # ::date 2015-03-25T04:47:07 # ::file pmid_1563_0473_108.txt # ::snt Coexpression of exogenous HA-tagged E-cadherin not only enabled cell-cell border localization of E-cadherin protein, but also rescued the cell-cell border staining of α-catenin (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (e / enable-01 :ARG0 (c / coexpress-01 :ARG2 (p / protein :name (n / name :op1 "E-cadherin") :ARG1-of (t / tag-01 :ARG2 (p4 / protein :name (n5 / name :op1 "HA") :xref (x1 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :mod (e3 / exogenous) :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG1 (a / and :op1 (b2 / be-located-at-91 :ARG1 p :mod (b / border-01 :ARG1 (c2 / cell) :ARG2 (c3 / cell))) :op2 (r / rescue-01 :ARG1 (s / stain-01 :ARG1 (p3 / protein :name (n4 / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :mod b) :mod (a2 / also))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id pmid_1563_0473.109 # ::date 2015-03-25T07:19:55 # ::file pmid_1563_0473_109.txt # ::snt The ability to restore α-catenin expression and localization under these conditions argues against the notion that Snail transcriptionally represses α-catenin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (a3 / argue-01 :ARG1 (p / possible-01 :ARG1 (r / restore-01 :ARG1 (a / and :op1 (e / express-03 :ARG2 "p4") :op2 (l / localize-01 :ARG1 "p4")) :condition (t / this))) :ARG0-of (c / counter-01 :ARG1 (n2 / notion :topic (r2 / repress-01 :ARG0 (p3 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1 (p4 / protein :name (n4 / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :ARG2 (t2 / transcribe-01))))) # ::id pmid_1563_0473.110 # ::date 2015-03-17T05:47:58 # ::file pmid_1563_0473_110.txt # ::snt Rather, the findings are consistent with a previous report that E-cadherin is required for the translation of α-catenin mRNA [22]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (c / consistent-01 :ARG1 (t / thing :ARG1-of (f / find-01)) :ARG2 (r2 / report-01 :ARG1 (r3 / require-01 :ARG0 (t2 / translate-02 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p3 / protein :name (n3 / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))))) :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :time (p / previous)) :mod (r / rather) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "22")))) # ::id pmid_1563_0473.111 # ::date 2015-03-18T08:31:32 # ::file pmid_1563_0473_111.txt # ::snt Despite the reductions in AJ markers, Tg skin still displayed sealed membranes and intercellular junctions that were largely intact, as judged by ultrastructural analyses (unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 30, 2015 (d / display-01 :ARG0 (s / skin :mod (t / transgenic)) :ARG1 (a / and :op1 (m / membrane :ARG1-of (s3 / seal-01) :xref (x / xref :value "GO:0016020" :prob "0.8")) :op2 (j / junction :mod (i2 / intercellular)) :mod (i / intact :degree (l / large) :ARG1-of (j2 / judge-01 :ARG3 (a2 / analyze-01 :mod (u / ultrastructural))))) :mod (s2 / still) :concession (r / reduce-01 :ARG1 (m2 / marker :mod (p2 / protein :name (n2 / name :op1 "AJ")))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (p / publish-01 :polarity "-")))) # ::id pmid_1563_0473.112 # ::date 2015-03-19T01:30:29 # ::file pmid_1563_0473_112.txt # ::snt In this respect, the skin epithelium resembled that of the hair bud, where the down-regulation in junction proteins is permissive for cell-cell remodeling without abrogating intercellular adhesion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (r / resemble-01 :ARG1 (e / epithelium :part-of (s / skin)) :ARG2 (e2 / epithelium :poss (b / bud :mod (h / hair)) :location-of (p / permissive-02 :ARG0 (d / downregulate-01 :location (p2 / protein :mod (j / junction))) :ARG1 (r3 / remodel-01 :ARG0 d :ARG1 (a / and :op1 (c / cell) :op2 (c2 / cell))) :ARG0-of (a2 / abrogate-01 :polarity "-" :ARG1 (a3 / adhere-01 :mod (i / intercellular))))) :mod (i2 / in-respect :mod (t / this))) # ::id pmid_1563_0473.113 # ::date 2015-03-18T12:02:19 # ::file pmid_1563_0473_113.txt # ::snt The similarities between Snail Tg epidermis and hair buds extended to the hyperproliferative state, leading us to wonder whether the down-regulation of AJ proteins might contribute to this condition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (e3 / extend-01 :ARG0 (t2 / thing :ARG1-of (r2 / resemble-01 :ARG2 (a / and :op1 (e2 / epidermis :mod (g / gene :name (n2 / name :op1 "Snail") :mod (t3 / transgenic) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :op2 (b / bud :mod (h / hair))))) :ARG4 (s / state :mod (p2 / proliferate-01 :degree (h2 / hyper))) :ARG0-of (l / lead-03 :ARG1 (w / we) :ARG2 (w2 / wonder-01 :ARG0 w :ARG1 (p / possible-01 :mode "interrogative" :ARG1 (c2 / contribute-01 :ARG0 (d / downregulate-01 :ARG1 (p3 / protein :name (n / name :op1 "AJ"))) :ARG2 (c3 / condition :mod (t / this))))))) # ::id pmid_1563_0473.114 # ::date 2015-03-18T12:40:19 # ::file pmid_1563_0473_114.txt # ::snt Given the increase in pMAPK staining in Snail Tg epidermis (see Figure 2G), we used pMAPK levels as our assay to test whether the loss of E-cadherin contributed to the Snail-mediated increase in proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / cause-01 :ARG0 (i / increase-01 :ARG1 (s / stain-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MAPK") :location (e / epidermis :mod (g / gene :name (n / name :op1 "Snail") :mod (t2 / transgenic) :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG1-of (s2 / see-01 :ARG2 (f / figure :mod "2G"))) :ARG1 (u / use-01 :ARG0 (w / we) :ARG1 (l / level :quant-of e2) :ARG2 (a / assay-01 :ARG0 w :purpose (t / test-01 :ARG0 w :ARG1 l :ARG2 (c2 / contribute-01 :mode "interrogative" :ARG0 (l2 / lose-02 :ARG1 (p4 / protein :name (n3 / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG2 (i2 / increase-01 :ARG1 (p5 / proliferate-01) :ARG1-of (m / mediate-01 :ARG0 g))))))) # ::id pmid_1563_0473.115 # ::date 2015-03-18T09:02:36 # ::file pmid_1563_0473_115.txt # ::snt Consistent with our in vivo observations, transfected keratinocytes expressing Snail exhibited a substantial increase in pMAPK levels relative to control cells (Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (e / exhibit-01 :ARG0 (k / keratinocyte :ARG1-of (t / transfect-01) :ARG3-of (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (e3 / enzyme :name (n2 / name :op1 "MAPK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1-of (r / relative-05 :ARG3 (c / cell :ARG0-of (c2 / control-01)))) :mod (s / substantial)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4D")) :ARG1-of (c3 / consistent-01 :ARG2 (t2 / thing :ARG1-of (o / observe-01 :ARG0 (w / we) :manner (i2 / in-vivo))))) # ::id pmid_1563_0473.116 # ::date 2015-03-17T08:16:55 # ::file pmid_1563_0473_116.txt # ::snt Coexpression of E-cadherin with Snail appeared to abrogate this effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / appear-02 :ARG1 (a2 / abrogate-01 :ARG0 (e2 / express-03 :ARG2 (a3 / and :op1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1 (a4 / affect-01 :mod (t / this)))) # ::id pmid_1563_0473.117 # ::date 2015-03-17T09:08:20 # ::file pmid_1563_0473_117.txt # ::snt Together, these findings raised the possibility that an AJ-associated protein that is normally sequestered at the plasma membrane may participate in a proliferation signaling pathway when AJs are deconstructed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (r / raise-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (p6 / possible-01 :ARG1 (p2 / possible-01 :ARG1 (p3 / participate-01 :ARG0 (p7 / protein :ARG1-of (a / associate-01 :ARG2 (p8 / protein :name (n2 / name :op1 "AJ"))) :ARG1-of (s2 / sequester-01 :ARG1-of (n / normal-02) :location (m / membrane :part-of (p9 / plasma) :xref (x / xref :value "GO:0016020" :prob "0.8")))) :ARG1 (p4 / proliferate-01 :ARG0 (p5 / pathway :ARG0-of (s / signal-07))) :time (c / construct-01 :polarity "-" :ARG1 p8)))) :mod (t3 / together)) # ::id pmid_1563_0473.118 # ::date 2015-03-18T13:48:01 # ::file pmid_1563_0473_118.txt # ::snt Numerous studies have correlated a down-regulation of E-cadherin with a translocation of β-catenin to the nucleus and a transactivation of genes that are regulated by the LEF-1/T cell factor (TCF) family of DNA binding proteins [23,24,25]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / correlate-01 :ARG0 (s / study-01 :quant (n / numerous)) :ARG1 (d3 / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG2 (a / and :op1 (t / translocate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "β-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :ARG2 (n4 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8"))) :op2 (t2 / transactivate-01 :ARG1 (g / gene :ARG1-of (r2 / regulate-01 :ARG0 (p5 / protein-family :name (n9 / name :op1 "LEF-1/T" :op2 "cell" :op3 "factor") :poss (p3 / protein :ARG1-of (b / bind-01 :ARG2 (n7 / nucleic-acid :wiki "DNA" :name (n8 / name :op1 "DNA"))))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 "23" :op2 "24" :op3 "25"))))) # ::id pmid_1563_0473.119 # ::date 2015-03-18T11:29:58 # ::file pmid_1563_0473_119.txt # ::snt The presence of nuclear cyclin D in hyperproliferative Snail Tg epidermis was particularly intriguing since prior studies have reported cyclin D gene as a direct target of TCF/β-catenin transcription [26]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / intrigue-01 :ARG0 (p8 / present-02 :ARG1 (p9 / protein :name (n7 / name :op1 "cyclin" :op2 "D") :mod (n2 / nucleus :xref (x5 / xref :value "GO:0005634" :prob "0.8")) :xref (x4 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.371")) :ARG2 (e / epidermis :mod (g2 / gene :name (n3 / name :op1 "Snail") :mod (t3 / transgenic) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG0-of (p / proliferate-01 :degree (h / hyper)))) :manner (p3 / particular) :ARG1-of (c5 / cause-01 :ARG0 (r / report-01 :ARG0 (s / study-01 :time (p4 / prior)) :ARG1 (t / target-01 :ARG0 (t2 / transcribe-01 :ARG1 (s2 / slash :op1 (p7 / protein :name (n6 / name :op1 "TCF") :xref (x2 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.263")) :op2 (p5 / protein :name (n5 / name :op1 "β-catenin") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :ARG1 (g / gene :name (n4 / name :op1 "cyclin" :op2 "D") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.371")) :ARG1-of (d / direct-02)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "26")))) # ::id pmid_1563_0473.120 # ::date 2015-03-18T12:01:19 # ::file pmid_1563_0473_120.txt # ::snt This said, we did not detect nuclear β-catenin in our Tg epidermis, and mating the Snail Tg mice against the TOPGal reporter mouse [20] gave no signs of ectopic LEF-1/Tcf/β-catenin activity (unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / cause-01 :ARG0 (s2 / say-01 :ARG1 (t2 / this)) :ARG1 (a3 / and :op1 (d / detect-01 :polarity "-" :ARG0 (w / we) :ARG1 (p2 / protein :name (n / name :op1 "β-catenin") :mod (n7 / nucleus :xref (x5 / xref :value "GO:0005634" :prob "0.8")) :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :location (e / epidermis :mod (t3 / transgenic) :poss w)) :op2 (g / give-01 :polarity "-" :ARG0 (m / mate-02 :ARG0 w :ARG1 (m2 / mouse :mod (p4 / protein :name (n3 / name :op1 "Snail") :mod (t / transgenic) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG2 (m5 / mouse :name (n9 / name :op1 "TopGal") :ARG0-of (r / report-01) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG0-of (c / cite-01 :ARG2 "20"))))) :ARG1 (s / signal-07 :ARG1 (a / activity-06 :ARG0 (m4 / macro-molecular-complex :part (p7 / protein :name (n4 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :part (p5 / protein :name (n5 / name :op1 "Tcf") :xref (x3 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.203")) :part (p8 / protein :name (n6 / name :op1 "β-catenin") :xref (x4 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :mod (e2 / ectopic))))) :ARG1-of (d4 / describe-01 :ARG0 (d5 / data :ARG1-of (p6 / publish-01 :polarity "-"))))) # ::id pmid_1563_0473.121 # ::date 2015-03-17T09:49:36 # ::file pmid_1563_0473_121.txt # ::snt We next turned to the presence of cytoplasmic Ajuba for a possible mechanistic link to the proliferative increase in our Snail Tg epidermis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (t / turn-01 :ARG1 (w / we) :direction (p / present-02 :ARG1 (p4 / protein :name (n / name :op1 "Ajuba") :mod (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))) :purpose (l / link-01 :ARG1 p4 :ARG2 (i / increase-01 :ARG1 (e / epidermis :mod (g / gene :name (n2 / name :op1 "Snail") :mod (t2 / transgenic) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG0-of (p3 / proliferate-01)) :ARG1-of (p2 / possible-01) :mod (m / mechanistic)) :time (n3 / next)) # ::id pmid_1563_0473.122 # ::date 2015-03-18T05:27:34 # ::file pmid_1563_0473_122.txt # ::snt In addition to its documented ability to bind α-catenin [10], Ajuba can also associate with growth factor receptor-bound protein-2 (Grb-2)/son of sevenless (Sos), the nucleotide exchange factor for Ras, which is upstream from activation of MAPK [9]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a / and :op1 (c3 / capable-01 :ARG1 "p3" :ARG2 (b2 / bind-01 :ARG1 "p3" :ARG2 (p8 / protein :name (n / name :op1 "α-catenin") :xref (x6 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG1-of (d2 / document-01) :ARG1-of (d3 / describe-01 :ARG0 (p9 / publication :ARG0-of (c4 / cite-01 :ARG2 "10")))) :op2 (p2 / possible-01 :ARG1 (a2 / associate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "Ajuba") :xref (x4 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :ARG1 (s / slash :op1 (p12 / protein :name (n10 / name :op1 "protein-2") :ARG1-of (b / bind-01 :ARG2 (r2 / receptor :mod (g / growth-factor))) :ARG1-of (m / mean-01 :ARG2 (p5 / protein :name (n5 / name :op1 "Grb-2") :xref (x5 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593"))) :xref (x3 / xref :value "UNIPROT:NCOA1_HUMAN" :prob "0.372")) :op2 (p4 / protein :name (n9 / name :op1 "son" :op2 "of" :op3 "sevenless") :ARG1-of (m2 / mean-01 :ARG2 (p11 / protein :name (n2 / name :op1 "Sos") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))) :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.333"))) :ARG2 (f / factor :mod (e / exchange-01 :ARG1 (n7 / nucleotide)) :purpose (e2 / enzyme :name (n8 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :location (r / relative-position :op1 (a4 / activate-01 :ARG1 (p / pathway :name (n3 / name :op1 "MAPK"))) :direction (u / upstream))) :mod (a3 / also)) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG0-of (c2 / cite-01 :ARG2 "9"))))) # ::id pmid_1563_0473.123 # ::date 2015-03-18T05:28:28 # ::file pmid_1563_0473_123.txt # ::snt Given the increase in pMAPK staining in Tg skin, we examined the possibility that Ajuba might have changed its binding partner in Snail-expressing epidermis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / cause-01 :ARG0 (i / increase-01 :ARG1 (s2 / stain-01 :ARG1 (e / enzyme :name (n3 / name :op1 "MAPK") :location (s / skin :mod (t / transgenic)) :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :ARG1 (e4 / examine-01 :ARG0 (w / we) :ARG1 (p2 / possible-01 :ARG1 (p3 / possible-01 :ARG1 (c / change-01 :ARG0 (p7 / protein :name (n / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :ARG1 (p4 / partner :ARG2-of (b / bind-01 :ARG1 p4) :location (e2 / epidermis :ARG1-of (e3 / express-03 :ARG2 (p5 / protein :name (n2 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))))))))) # ::id pmid_1563_0473.124 # ::date 2015-03-18T06:35:46 # ::file pmid_1563_0473_124.txt # ::snt Interestingly, Ajuba was readily detected in anti-Grb-2 immunoprecipitates of protein lysates from skins of Snail Tg mice but not from the corresponding wild-type (WT) animals (Figure 4E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / contrast-01 :ARG1 (d / detect-01 :ARG1 (p5 / protein :name (n / name :op1 "Ajuba") :xref (x2 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :manner (r / ready) :location (m2 / molecular-physical-entity :ARG1-of (i / immunoprecipitate-01 :ARG2 (l / lysate :mod (p / protein) :source (s / skin :part-of (m / mice :mod (g / gene :name (n4 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :mod (t / transgenic)))) :ARG0-of (c3 / counter-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))))) :ARG2 (d3 / detect-01 :polarity "-" :ARG1 p5 :location (m4 / molecular-physical-entity :source (a / animal :mod (w / wild-type :ARG1-of (m3 / mean-01 :ARG2 (n2 / name :op1 "WT"))) :ARG1-of (c2 / correspond-02)) :ARG1-of i :ARG0-of c3)) :manner (i2 / interesting) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4E"))) # ::id pmid_1563_0473.125 # ::date 2015-03-18T07:34:56 # ::file pmid_1563_0473_125.txt # ::snt When these experiments were repeated with α-catenin-null epidermis, a similar Grb-2-Ajuba association was detected, and again, this interaction was not detected in the protein extracts from control littermate skin (Figure 4E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 24, 2015 (a / and :op1 (d / detect-01 :ARG1 (a3 / associate-01 :ARG1 (m / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :part (p3 / protein :name (n2 / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))) :ARG1-of (r2 / resemble-01))) :op2 (d2 / detect-01 :polarity "-" :ARG1 (i / interact-01 :ARG0 "e2" :ARG1 p3 :mod (t3 / this)) :location (e3 / extract-01 :ARG1 (p4 / protein) :ARG2 (s / skin :mod (l / littermate) :ARG0-of (c / control-01))) :mod (a2 / again)) :time (r / repeat-01 :ARG1 (t / thing :ARG1-of (e / experiment-01 :ARG2 (e2 / epidermis :polarity "-" :mod (p / protein :name (n / name :op1 "α-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :mod (n4 / null))) :mod (t2 / this))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4E"))) # ::id pmid_1563_0473.126 # ::date 2015-03-18T09:02:01 # ::file pmid_1563_0473_126.txt # ::snt Together, these data demonstrate that the reduction in α-catenin levels, either by Snail-mediated down-regulation of E-cadherin or by α-catenin conditional targeting, allows Ajuba to interact with Grb-2/Sos. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (d / demonstrate-01 :ARG0 (d2 / data :mod (t / this)) :ARG1 (a / allow-02 :ARG0 (r / reduce-01 :ARG0 (o / or :op1 (d3 / downregulate-01 :ARG1 (g2 / gene :name (n6 / name :op1 "E-cadherin") :ARG1-of (m2 / mediate-01 :ARG0 (p5 / protein :name (n5 / name :op1 "Snail") :xref (x4 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :op2 (t2 / target-01 :ARG1 "g" :mod (c2 / conditional))) :ARG1 (l / level :degree-of (g / gene :name (n4 / name :op1 "α-catenin") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :ARG1 (p / protein :name (n / name :op1 "Ajuba") :xref (x5 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :ARG2 (i / interact-01 :ARG0 p :ARG1 (m / macro-molecular-complex :part (p2 / protein :name (n2 / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :part (p3 / protein :name (n3 / name :op1 "Sos") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))))) :mod (t3 / together)) # ::id pmid_1563_0473.127 # ::date 2015-03-19T00:03:50 # ::file pmid_1563_0473_127.txt # ::snt If the competition between Grb-2/Sos and α-catenin for Ajuba is functionally relevant to the hyperproliferative state of a keratinocyte, then overexpression of Ajuba would be expected to bypass the competition and promote activation of the Ras-MAPK pathway in WT keratinocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (e / expect-01 :ARG1 (a / and :op1 (b / bypass-01 :ARG0 (o / overexpress-01 :ARG1 "p2") :ARG1 "c") :op2 (p / promote-01 :ARG0 o :ARG1 (a2 / activate-01 :ARG1 (p8 / pathway :name (n5 / name :op1 "Ras-MAPK")) :location (k2 / keratinocyte :mod (w / wild-type))))) :condition (r / relevant-01 :ARG1 (c / compete-01 :ARG0 (m / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "Grb-2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :part (p5 / protein :name (n3 / name :op1 "Sos") :xref (x3 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))) :ARG1 (p3 / protein :name (n4 / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :ARG2 (p2 / protein :name (n / name :op1 "Ajuba") :xref (x / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))) :ARG2 (s / state :mod (p6 / proliferate-01 :degree (h / hyper)) :mod (k / keratinocyte)) :manner (f / functional))) # ::id pmid_1563_0473.128 # ::date 2015-03-18T13:51:34 # ::file pmid_1563_0473_128.txt # ::snt Indeed, when serum-starved keratinocytes were transiently transfected with an Ajuba expression vector, the levels of pMAPK were not only elevated but also comparable to those transfected with the K14-HASnail transgene (Figure 4F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (e / elevate-01 :ARG1 (l / level :quant-of (e3 / enzyme :name (n / name :op1 "MAPK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :mod (o / only)) :op2 (c / comparable-03 :ARG1 l :ARG2 (l2 / level :location (k2 / keratinocyte :ARG1-of (t4 / transfect-01 :ARG2 (t5 / transgene :name (n3 / name :op1 "K14-HASnail")))) :quant-of e3)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4F")) :mod (i / indeed) :time (t / transfect-01 :ARG1 (k / keratinocyte :ARG1-of (s / starve-01 :ARG2 (s2 / serum))) :ARG2 (v / vector :ARG1-of (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")))) :ARG1-of (t2 / transient-02))) # ::id pmid_1563_0473.129 # ::date 2015-03-17T09:09:39 # ::file pmid_1563_0473_129.txt # ::snt This activation was abolished when cells were treated with a small peptide inhibitor that specifically interrupts the Grb-2/Sos interaction (Figure 4F; see lanes marked “inh”) [27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / abolish-01 :ARG1 (a2 / activate-01 :mod (t3 / this)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4F") :op2 (s3 / see-01 :ARG1 (l / lane :ARG1-of (m / mark-01 :ARG0 (s4 / string-entity :value "inh")))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG0-of (c3 / cite-01 :ARG2 "27"))) :time (t2 / treat-04 :ARG1 (c2 / cell) :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / peptide)) :mod (s / small) :ARG0-of (i2 / interrupt-01 :ARG1 (i3 / interact-01 :ARG0 (p2 / protein :name (n / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :ARG1 (p3 / protein :name (n2 / name :op1 "Sos") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))) :ARG1-of (s2 / specific-02))))) # ::id pmid_1563_0473.130 # ::date 2015-03-18T07:45:18 # ::file pmid_1563_0473_130.txt # ::snt Ajuba's pre-LIM domain is the segment that associates with Grb-2's Src-homology 3 domain [9]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (s / segment :ARG1-of (a / associate-01 :ARG2 (p5 / protein-segment :name (n / name :op1 "Src-homology" :op2 "3" :op3 "domain") :part-of (p2 / protein :name (n2 / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "9"))) :domain (d3 / domain :part-of (p3 / protein :name (n3 / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :mod (p4 / protein-segment :name (n4 / name :op1 "pre-LIM")))) # ::id pmid_1563_0473.131 # ::date 2015-03-19T06:20:35 # ::file pmid_1563_0473_131.txt # ::snt When this domain was overexpressed in serum-starved keratinocytes, a comparable elevation in pMAPK was observed (Figure 4F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (o / observe-01 :ARG1 (e / elevate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1-of (c / comparable-03)) :time (o2 / overexpress-01 :ARG1 (d / domain :mod (t / this)) :location (c2 / cell :name (n2 / name :op1 "keratinocyte") :ARG1-of (s / starve-01 :ARG2 (s2 / serum)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4F"))) # ::id pmid_1563_0473.132 # ::date 2015-03-19T08:33:20 # ::file pmid_1563_0473_132.txt # ::snt As expected, the small peptide inhibitor that interrupts the Grb-2/Sos association blocked the effects. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 24, 2015 (b / block-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / peptide :mod (s / small))) :ARG0-of (i2 / interrupt-01 :ARG1 (a / associate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :ARG2 (p3 / protein :name (n3 / name :op1 "Sos") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))))) :ARG1 (e / effect) :ARG1-of (e2 / expect-01)) # ::id pmid_1563_0473.133 # ::date 2015-03-19T09:08:38 # ::file pmid_1563_0473_133.txt # ::snt These data suggested that by elevating cytosolic Ajuba levels, Ajuba's pre-LIM domain may associate with Grb-2/Sos in a manner that stimulates its nucleotide exchange activity and leads to activation of the Ras-MAPK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (a / associate-01 :ARG1 (p2 / protein-segment :name (n / name :op1 "pre-LIM") :part-of (p3 / protein :name (n2 / name :op1 "Ajuba") :location (c / cytosol :xref (x3 / xref :value "GO:0005829" :prob "0.8")) :xref (x / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))) :ARG2 (m / macro-molecular-complex :part (p4 / protein :name (n3 / name :op1 "Grb-2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :part (p5 / protein :name (n4 / name :op1 "Sos") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))) :manner (a2 / and :op1 (s2 / stimulate-01 :ARG0 a :ARG1 (a3 / activity-06 :ARG0 p2 :ARG1 (e / exchange-01 :ARG1 (n5 / nucleotide)))) :op2 (l / lead-03 :ARG0 a :ARG2 (a4 / activate-01 :ARG1 (p6 / pathway :name (n6 / name :op1 "Ras-MAPK"))))) :manner-of (e2 / elevate-01 :ARG1 (l2 / level :degree-of p3))))) # ::id pmid_1563_0473.134 # ::date 2015-03-19T10:43:40 # ::file pmid_1563_0473_134.txt # ::snt Although this pathway provides one mechanism by which Snail expression and proliferation may be coupled in skin epithelium, proliferative circuitries involving AJs are known to be complex and often interwoven. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 26, 2015 (k / know-01 :ARG1 (a / and :op1 (c / complex :domain (c2 / circuitry :ARG0-of (p / proliferate-01) :ARG2-of (i / involve-01 :ARG1 (p2 / protein :name (n / name :op1 "AJ"))))) :op2 (i2 / interweave-01 :ARG1 c2 :frequency (o / often))) :concession (p3 / provide-01 :ARG0 (p4 / pathway :mod (t / this)) :ARG1 (p5 / possible-01 :ARG1 (c3 / couple-01 :ARG1 (e / express-03 :ARG2 (p6 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG2 (p7 / proliferate-01 :ARG0 p6) :location (e2 / epithelium :part-of (s / skin)) :instrument (m / mechanism :quant "1"))))) # ::id pmid_1563_0473.135 # ::date 2015-03-19T12:06:51 # ::file pmid_1563_0473_135.txt # ::snt Future studies will be needed to systematically dissect these putative intricacies at a molecular level. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 24, 2015 (n / need-01 :ARG1 (s / study-01 :time (f / future)) :purpose (d / dissect-01 :ARG1 (i / intricacy :mod (t / this) :ARG2-of (t2 / think-01)) :manner (s2 / systematic) :location (l / level :mod (m / molecule)))) # ::id pmid_1563_0473.136 # ::date 2015-03-19T12:28:00 # ::file pmid_1563_0473_136.txt # ::snt Probing the Regulation of Snail Gene Expression Reveals an Essential Link to TGF-β2 Signaling in the Developing Hair Bud # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 19, 2015 (r / reveal-01 :ARG0 (p / probe-01 :ARG1 (r2 / regulate-01 :ARG1 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG1 (l / link-01 :ARG2 (s / signal-07 :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :location (b / bud :ARG1-of (d / develop-02) :mod (h / hair))) :mod (e2 / essential))) # ::id pmid_1563_0473.137 # ::date 2015-03-19T13:56:00 # ::file pmid_1563_0473_137.txt # ::snt The temporal spike of Snail mRNA expression in the hair bud prompted us to consider what factor(s) may be regulating the Snail gene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p / prompt-01 :ARG0 (s / spike-04 :ARG1 (e / express-03 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :location (b / bud :mod (h / hair))) :time (t / temporal)) :ARG1 (c / consider-02 :ARG0 (w / we) :ARG1 (f / factor :mode "interrogative" :ARG0-of (r2 / regulate-01 :ARG1 g :ARG1-of (p2 / possible-01))))) # ::id pmid_1563_0473.138 # ::date 2015-03-20T03:55:03 # ::file pmid_1563_0473_138.txt # ::snt A variety of extracellular signals have an impact on the cell type-specific expression of different Snail family members, and many of them, including Wnts, BMPs, FGFs, and TGF-βs, also affect hair bud development [2,16,28]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (i / impact-01 :ARG0 (s / signal-07 :location (e / extracellular) :mod (v / variety)) :ARG1 (e2 / express-03 :ARG2 (m3 / member :ARG1-of (d / differ-02) :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n / name :op1 "Snail")))) :ARG1-of (s2 / specific-02 :ARG2 (t / type-03 :ARG1 (c / cell))))) :op2 (a2 / affect-01 :ARG0 (s3 / signal-07 :quant (m2 / many) :ARG1-of (i3 / include-91 :ARG2 s) :ARG2-of (i4 / include-91 :ARG1 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "Wnt") :xref (x / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")) :op2 (p3 / protein :name (n3 / name :op1 "BMP") :xref (x1 / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263")) :op3 (p4 / protein :name (n4 / name :op1 "FGF") :xref (x2 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001")) :op4 (p5 / protein :name (n5 / name :op1 "TGF-β") :xref (x3 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233"))))) :ARG1 (d2 / develop-02 :ARG1 (b / bud :mod (h / hair))) :mod (a4 / also)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 "2" :op2 "16" :op3 "28"))))) # ::id pmid_1563_0473.139 # ::date 2015-03-20T06:25:42 # ::file pmid_1563_0473_139.txt # ::snt Since Snail is not expressed in cultured skin keratinocytes that secrete active BMPs and FGFs (see Figure 1B), we focused our attention on Wnt and TGF-β signaling as more likely candidates for Snail induction in this cell type. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / cause-01 :ARG0 (e / express-03 :polarity "-" :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x4 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (k / keratinocyte :mod (s / skin) :ARG1-of (c2 / culture-01) :ARG0-of (s2 / secrete-01 :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "BMP") :xref (x / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263")) :op2 (p3 / protein :name (n3 / name :op1 "FGF") :xref (x1 / xref :value "UNIPROT:A0A087WUF6_HUMAN" :prob "1.001")) :ARG0-of (a2 / activity-06)))) :ARG1-of (s3 / see-01 :ARG2 (f / figure :mod "1B"))) :ARG1 (f2 / focus-01 :ARG0 (w / we) :ARG1 (a3 / attend-02 :ARG0 w :ARG1 "s4") :ARG2 (s4 / signal-07 :ARG0 (a4 / and :op1 (p4 / protein :name (n4 / name :op1 "Wnt") :xref (x2 / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")) :op2 (p5 / protein :name (n5 / name :op1 "TGF-β") :xref (x3 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233"))) :ARG0-of (a5 / act-01 :ARG1 (l / likely-01 :ARG1 (c3 / candidate :purpose (i / induce-01 :ARG2 p :location (c4 / cell :ARG1-of (t / type-03) :mod (t2 / this)))) :degree (m / more)))))) # ::id pmid_1563_0473.140 # ::date 2015-03-20T07:06:15 # ::file pmid_1563_0473_140.txt # ::snt Previously, we showed that effective transmission of a Wnt-3a signal in cultured keratinocytes can be achieved through their exposure to the BMP inhibitor noggin, which induces LEF-1 expression [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (a / achieve-01 :ARG1 (t / transmit-01 :ARG1 (s2 / signal-07 :ARG0 (p2 / protein :name (n / name :op1 "Wnt-3a") :xref (x / xref :value "UNIPROT:WNT3A_HUMAN" :prob "0.592")) :location (c / cell :name (n2 / name :op1 "keratinocyte") :ARG1-of (c2 / culture-01))) :ARG1-of (e / effective-04)) :manner (e2 / expose-01 :ARG1 c :ARG2 (p3 / protein :name (n3 / name :op1 "noggin") :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein :name (n4 / name :op1 "BMP") :ARG0-of (i2 / induce-01 :ARG2 (e3 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "LEF-1") :xref (x3 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")))) :xref (x2 / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263"))) :xref (x1 / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702"))))) :time (p6 / previous) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 "4")))) # ::id pmid_1563_0473.141 # ::date 2015-03-21T08:57:36 # ::file pmid_1563_0473_141.txt # ::snt In vitro, these conditions down-regulated the E-cadherin promoter and induced a LEF-1/β-catenin-sensitive reporter gene, TOPFLASH [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (a / and :op1 (d / downregulate-01 :ARG0 (c / condition :mod (t / this)) :ARG1 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :op2 (i / induce-01 :ARG0 c :ARG2 (g / gene :name (n2 / name :op1 "TOPFLASH") :ARG0-of (r / report-01) :ARG0-of (s / sensitive-03 :ARG1 (m2 / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "LEF-1") :xref (x2 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :part (p4 / protein :name (n4 / name :op1 "β-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))))) :manner (i2 / in-vitro) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "4")))) # ::id pmid_1563_0473.142 # ::date 2015-03-21T09:31:40 # ::file pmid_1563_0473_142.txt # ::snt In contrast, Snail expression was not induced by these conditions (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (c / contrast-01 :ARG2 (i / induce-01 :polarity "-" :ARG0 (c2 / condition :mod (t / this)) :ARG2 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A")))) # ::id pmid_1563_0473.143 # ::date 2015-03-21T09:38:48 # ::file pmid_1563_0473_143.txt # ::snt Thus, despite essential roles for Wnts and noggin in hair follicle specification [4,29,30], our studies did not support an essential role for these signals in governing Snail expression in keratinocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / cause-01 :ARG1 (s / support-01 :polarity "-" :ARG0 (s2 / study-01 :ARG0 (w / we)) :ARG1 (r / role :mod (e / essential) :beneficiary (s3 / signal-07 :mod (t / this)) :topic (g / govern-01 :ARG1 (e2 / express-03 :ARG1 (g2 / gene :wiki "-" :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (c2 / cell :wiki "Keratinocyte" :name (n / name :op1 "keratinocyte"))))) :concession (r2 / role :mod (e3 / essential) :beneficiary (a / and :op1 (p / protein :wiki "-" :name (n3 / name :op1 "Wnt") :xref (x2 / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")) :op2 (p2 / protein :wiki "Noggin_(protein)" :name (n4 / name :op1 "noggin") :xref (x / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702"))) :topic (s4 / specify-01 :ARG1 (f / follicle :mod (h / hair))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 "4" :op2 "29" :op3 "30"))))))) # ::id pmid_1563_0473.144 # ::date 2015-03-21T10:31:17 # ::file pmid_1563_0473_144.txt # ::snt TGF-β1 has been shown to induce Snail family members in hepatocytes and heart [15, 31]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (s / show-01 :ARG1 (i / induce-01 :ARG0 (p / protein :name (n / name :op1 "TGF-β1") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.283")) :ARG2 (m / member :ARG1-of (i2 / include-91 :ARG2 (p2 / protein-family :name (n2 / name :op1 "Snail")))) :location (a / and :op1 (c / cell :name (n3 / name :op1 "hepatocyte")) :op2 (h / heart))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "15" :op2 "31"))))) # ::id pmid_1563_0473.145 # ::date 2015-03-21T11:03:12 # ::file pmid_1563_0473_145.txt # ::snt In keratinocytes, however, TGF-β1 inhibits keratinocyte growth and seems to be involved in triggering the destructive phase of the cycling hair follicle [32]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (h / have-concession-91 :ARG2 (a / and :op1 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "TGF-β1") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.283")) :ARG1 (g / grow-01 :ARG1 (c / cell :name (n2 / name :op1 "keratinocyte")))) :op2 (s / seem-01 :ARG1 (i2 / involve-01 :ARG1 p :ARG2 (t / trigger-01 :ARG0 p :ARG1 (p2 / phase :ARG0-of (d / destroy-01) :part-of (f / follicle :mod (h2 / hair) :ARG1-of (c2 / cycle-02)))))) :location c) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "32")))) # ::id pmid_1563_0473.146 # ::date 2015-03-21T11:42:53 # ::file pmid_1563_0473_146.txt # ::snt Of the loss-of-function mutations generated in each of the TGF-β genes, only the TGF-β2 null state blocked follicle development at the hair bud stage [32]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 24, 2015 (b / block-01 :ARG0 (s / state :mod (n / null) :poss (g / gene :name (n2 / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :mod (o / only) :ARG1-of (i / include-91 :ARG2 (m / mutate-01 :ARG2 (l / lose-02 :ARG1 (f2 / function-01)) :ARG1-of (g2 / generate-01 :ARG3 (g3 / gene :name (n3 / name :op1 "TGF-β") :mod (e / each) :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233")))))) :ARG1 (f / follicle :ARG1-of (d / develop-02)) :time (s2 / stage :mod (b2 / bud :mod (h / hair))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "32")))) # ::id pmid_1563_0473.147 # ::date 2015-03-21T12:38:11 # ::file pmid_1563_0473_147.txt # ::snt Thus, we turned towards addressing whether TGF-β2 might be involved in regulating Snail expression in keratinocytes isolated from the basal layer of the epidermis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / cause-01 :ARG1 (t / turn-01 :ARG0 (w / we) :location (a / address-02 :ARG0 w :ARG1 (p / possible-01 :mode "interrogative" :ARG1 (i / involve-01 :ARG1 (p2 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG2 (r / regulate-01 :ARG0 p2 :ARG1 (e / express-03 :ARG1 (g / gene :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :location (c2 / cell :name (n3 / name :op1 "keratinocyte") :ARG1-of (i2 / isolate-01 :ARG2 (l / layer :mod (b / basal) :part-of (e2 / epidermis)))))))))) # ::id pmid_1563_0473.148 # ::date 2015-03-21T13:32:50 # ::file pmid_1563_0473_148.txt # ::snt Though there is no cell culture system available to specifically study placodal cells, these keratinocytes are their progenitors and are the closest approximation available to study the behavior of epithelial cells of the placode. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (h / have-rel-role-91 :ARG0 (c / cell :name (n / name :op1 "keratinocyte") :mod (t / this)) :ARG1 (c2 / cell :location (p2 / placode)) :ARG2 (p / progenitor :poss c)) :op2 (a2 / available-02 :ARG2 (a3 / approximate-01 :ARG0 c :ARG1-of (c3 / close-11 :degree (m / most)) :purpose (s / study-01 :ARG1 (b / behave-01 :ARG0 (c4 / cell :location (e / epithelium) :part-of p2))))) :concession (a4 / available-02 :polarity "-" :ARG2 (s2 / system :mod (c5 / culture-01 :ARG1 (c6 / cell))) :purpose (s3 / study-01 :ARG1 c2 :ARG1-of (s4 / specific-02)))) # ::id pmid_1563_0473.149 # ::date 2015-03-22T02:46:07 # ::file pmid_1563_0473_149.txt # ::snt Interestingly, treatment of cultured keratinocytes with as little as 5 ng/ml of TGF-β2 caused a rapid and transient induction of Snail (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (c / cause-01 :ARG0 (t / treat-04 :ARG1 (c2 / cell :name (n / name :op1 "keratinocyte") :ARG1-of (c3 / culture-01)) :ARG2 (p / protein :name (n2 / name :op1 "TGF-β2") :quant (c4 / concentration-quantity :quant "5" :mod (l / little) :unit (n4 / nanogram-per-milliliter)) :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG1 (i / induce-01 :ARG0 t :ARG2 (p2 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :mod (r / rapid) :ARG1-of (t2 / transient-02)) :manner (i2 / interesting) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id pmid_1563_0473.150 # ::date 2015-03-22T03:31:14 # ::file pmid_1563_0473_150.txt # ::snt Following this treatment, Snail protein was detected within 30 min, peaked at 2 h, and then declined thereafter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 27, 2015 (f / follow-01 :ARG1 (a / and :op1 (d / detect-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :time (a2 / after :op1 (t / treat-04 :mod (t2 / this)) :quant (u / up-to :op1 (t3 / temporal-quantity :quant "30" :unit (m / minute))))) :op2 (p2 / peak-01 :ARG1 p :time (a4 / after :op1 (t4 / temporal-quantity :quant "2" :unit (h / hour)))) :op3 (d2 / decline-01 :ARG1 p :time (a3 / after :op1 p2)))) # ::id pmid_1563_0473.151 # ::date 2015-03-22T04:26:07 # ::file pmid_1563_0473_151.txt # ::snt The induction of Snail appeared to be specific for the active form of the growth factor, as pretreatment of TGF-β2 for 10 min at 100 °C obliterated the response [Figure 5B, lanes marked (–)]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (c / cause-01 :ARG0 (o / obliterate-01 :ARG0 (p / pretreat-01 :ARG1 (p2 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG3 (t / temperature-quantity :quant "100" :scale (c2 / celsius)) :duration (t2 / temporal-quantity :quant "10" :unit (m / minute))) :ARG1 (r / respond-01)) :ARG1 (a / appear-02 :ARG1 (i / induce-01 :ARG2 (p3 / protein :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (s / specific-02 :ARG2 (f / form :ARG0-of (a2 / activity-06) :mod (g / growth-factor))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5B") :ARG2-of (m2 / mark-02 :ARG1 (l / lane)))) # ::id pmid_1563_0473.152 # ::date 2015-03-22T05:32:46 # ::file pmid_1563_0473_152.txt # ::snt By contrast, although TGF-β receptor activation remained elevated during the duration of the experiment (as measured by the sustained phosphorylation of the downstream effector SMAD2) Snail expression could not be maintained (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 12, 2015 (c / contrast-01 :ARG2 (p / possible-01 :polarity "-" :ARG1 (m / maintain-01 :ARG1 (e / express-03 :ARG2 (g / gene :wiki "-" :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :concession (r / remain-01 :ARG1 (a / activate-01 :ARG1 (r2 / receptor :wiki "TGF_beta_receptors" :name (n2 / name :op1 "TGF-β")) :ARG1-of (m2 / measure-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (e2 / effector :mod (p3 / protein :wiki "Mothers_against_decapentaplegic_homolog_2" :name (n3 / name :op1 "SMAD2") :xref (x1 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :mod (d / downstream)) :ARG1-of (s / sustain-01)) :ARG3 (e3 / elevate-01))) :ARG3 e3 :time (e4 / experiment-01)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id pmid_1563_0473.153 # ::date 2015-03-22T07:36:33 # ::file pmid_1563_0473_153.txt # ::snt Thus, although Snail expression correlated with phosphorylated SMAD2 (pSMAD2) induction, its decline seemed to rely on secondary downstream events. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / cause-01 :ARG1 (s / seem-01 :ARG1 (r / rely-01 :ARG0 (d / decline-01 :ARG1 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1 (e2 / event :direction (d2 / downstream) :mod (s2 / secondary))) :concession (c2 / correlate-01 :ARG1 e :ARG2 (i / induce-01 :ARG2 (p / protein :name (n2 / name :op1 "SMAD2") :ARG1-of (p2 / phosphorylate-01) :ARG1-of (d3 / describe-01 :ARG0 (p3 / protein :name (n3 / name :op1 "pSMAD2") :xref (x / xref :value "UNIPROT:PSA2_HUMAN" :prob "0.302"))) :xref (x2 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")))))) # ::id pmid_1563_0473.154 # ::date 2015-03-21T14:59:41 # ::file pmid_1563_0473_154.txt # ::snt The rapid kinetics of Snail expression were reflected at the mRNA level, suggesting that Snail promoter activity in keratinocytes might be sensitive to TGF-β2 signaling (Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (r / reflect-01 :ARG1 (l / level :mod (n4 / nucleic-acid :name (n2 / name :op1 "mRNA"))) :ARG2 (k / kinetics :mod (r2 / rapid) :poss (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG0-of (s / suggest-01 :ARG1 (p / possible-01 :ARG1 (s2 / sensitive-03 :ARG0 (a / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 g)) :location (k2 / keratinocyte)) :ARG1 (s3 / signal-07 :ARG0 (p3 / protein :name (n3 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id pmid_1563_0473.155 # ::date 2015-03-22T00:28:57 # ::file pmid_1563_0473_155.txt # ::snt To test this possibility, we engineered a transgene driving the β-galactosidase reporter under the control of approximately 2.2 kb of promoter sequence located 5′ from the transcription initiation site of the mouse Snail gene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (e / engineer-01 :ARG0 (w / we) :ARG1 (t3 / transgene) :purpose (t / test-01 :ARG0 w :ARG1 (t2 / this :ARG1-of (p / possible-01))) :manner (d / drive-02 :ARG0 w :ARG1 (e2 / enzyme :name (n / name :op1 "β-galactosidase") :ARG0-of (r / report-01) :xref (x1 / xref :value "UNIPROT:GALK1_HUMAN" :prob "0.302")) :ARG2 (c / control-01 :ARG0 (s / sequence :quant (a / approximately :op1 (d2 / distance-quantity :quant "2.2" :unit (k / kilo-base-pair))) :location (r2 / relative-position :op1 (p3 / protein-segment :location-of (i / initiate-01 :ARG1 (t4 / transcribe-01)) :part-of (g / gene :name (n2 / name :op1 "Snail") :mod (m2 / mouse) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :direction (d3 / dna-sequence :name (n3 / name :op1 "5'"))) :mod (m / molecular-physical-entity :ARG0-of (p2 / promote-02))) :ARG1 e2))) # ::id pmid_1563_0473.156 # ::date 2015-03-22T01:19:41 # ::file pmid_1563_0473_156.txt # ::snt At 2 d after transient transfection, keratinocytes were treated with TGF-β2 (t = 0) and then assayed for transgene activity over the same time course in which we had observed Snail protein induction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (t2 / treat-04 :ARG1 (k / keratinocyte) :ARG2 (p / protein :name (n / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :time (a3 / after :op1 (t3 / transfect-01 :ARG1-of (t4 / transient-02)) :quant (t5 / temporal-quantity :quant "2" :unit (d / day))) :condition (e / equal-01 :ARG1 (t8 / time) :ARG2 "0")) :op2 (a2 / assay-01 :ARG1 (a4 / activity-06 :ARG0 k :ARG1 (t7 / transgene)) :time (t6 / then) :duration (c2 / course :ARG1-of (s / same-01 :ARG2 (c / course :time-of (o2 / observe-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :mod "t")) :mod (t / time)))) # ::id pmid_1563_0473.157 # ::date 2015-03-22T12:33:25 # ::file pmid_1563_0473_157.txt # ::snt The results of this experiment are presented in Figure 5D. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 22, 2015 (p / present-01 :ARG0 (f / figure :mod "5") :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (e / experiment-01 :mod (t2 / this))))) # ::id pmid_1563_0473.158 # ::date 2015-03-22T12:52:36 # ::file pmid_1563_0473_158.txt # ::snt Within 0.5 h of TGF-β2 treatment, Snail promoter activity had increased 3-fold, and by 2 h, it peaked to approximately 10-fold over control levels (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a / and :op1 (i / increase-01 :ARG1 (a2 / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p6 / promote-01 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG4 (p4 / product-of :op1 "3" :op2 (l / level :mod (c / control))) :time (a3 / after :op1 (t / treat-04 :ARG2 (p2 / protein :name (n2 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :quant (u / up-to :op1 (t2 / temporal-quantity :quant "0.5" :unit (h / hour))))) :op2 (p3 / peak-01 :ARG1 (a4 / approximately :op1 (p5 / product-of :op1 "10" :op2 l)) :time (a5 / after :op1 t :quant (u2 / up-to :op1 (t3 / temporal-quantity :quant "2" :unit h)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id pmid_1563_0473.159 # ::date 2015-03-22T13:33:03 # ::file pmid_1563_0473_159.txt # ::snt Thereafter, Snail promoter activity rapidly returned to the basal levels seen in unstimulated keratinocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (r / return-01 :ARG1 (a / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG4 (l / level :ARG1-of (s / see-01 :location (k / keratinocyte :ARG1-of (s2 / stimulate-01 :polarity "-"))) :mod (b / basal)) :manner (r2 / rapid) :time (t / thereafter)) # ::id pmid_1563_0473.160 # ::date 2015-03-22T13:40:11 # ::file pmid_1563_0473_160.txt # ::snt The kinetics of Snail promoter activity closely paralleled those observed for Snail protein induction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / parallel-01 :ARG0 (k / kinetics :mod (a / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))))) :ARG1 (k2 / kinetics :ARG1-of (o / observe-01 :topic (i / induce-01 :ARG2 (p3 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG1-of (c / close-10)) # ::id pmid_1563_0473.161 # ::date 2015-03-22T13:59:01 # ::file pmid_1563_0473_161.txt # ::snt Moreover, the stimulatory effects appeared to be specific to TGF-β2, since they were abrogated either by heat inactivation of the TGF-β2 protein or by mutation of a putative SMAD binding element located about 1.8 kb 5′ from the Snail transcription start site (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (a2 / appear-02 :ARG1 (s / specific-02 :ARG1 (e / effect-03 :ARG1 (s2 / stimulate-01)) :ARG2 (p / protein :name (n / name :op1 "TGF-β2") :xref (x2 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG1-of (c / cause-01 :ARG0 (a3 / abrogate-01 :ARG1 e :ARG2 (o / or :op1 (a4 / activate-01 :polarity "-" :ARG1 p :mod (h / heat)) :op2 (m / mutate-01 :ARG1 (e2 / element :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n2 / name :op1 "SMAD") :xref (x / xref :value "UNIPROT:SMAD1_HUMAN" :prob "0.312")) :ARG1-of (t / think-01)) :ARG1-of (l / locate-01 :location (r / relative-position :op1 (p3 / protein-segment :location-of (s3 / start-01 :ARG1 (t2 / transcribe-01 :ARG1 (g / gene :name (n3 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :quant (d / distance-quantity :quant "1.8" :unit (k / kilo-base-pair)) :direction (d3 / dna-sequence :name (n4 / name :op1 "5'")))))))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id pmid_1563_0473.162 # ::date 2015-03-22T15:16:26 # ::file pmid_1563_0473_162.txt # ::snt Taken together, these results suggested that in keratinocytes, TGF-β2 signaling results in a pSMAD2-dependent transient activation of the Snail gene, and that maintenance of Snail protein relies, in part, upon sustained promoter activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s / suggest-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01) :ARG1-of (t3 / take-01 :mod (t4 / together))) :ARG1 (a / and :op1 (r2 / result-01 :ARG1 (s2 / signal-07 :ARG0 (p / protein :name (n / name :op1 "TGF-β2") :xref (x3 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG2 (a2 / activate-01 :ARG1 (g / gene :name (n2 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (t5 / transient-02) :ARG0-of (d / depend-01 :ARG1 (p2 / protein :name (n3 / name :op1 "SMAD2") :ARG1-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")))) :location (k / keratinocyte)) :op2 (r3 / rely-01 :ARG0 (m / maintain-01 :ARG1 (p4 / protein :name (n4 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1 (a3 / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (p5 / promote-01)) :ARG1-of (s3 / sustain-01)) :degree (p6 / part)))) # ::id pmid_1563_0473.163 # ::date 2015-03-22T15:29:22 # ::file pmid_1563_0473_163.txt # ::snt The brevity of Snail gene and protein induction in TGF-β2 treated cultured keratinocytes resembled the temporal appearance of Snail mRNA and protein at the initiation of hair follicle morphogenesis in embryonic mouse skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (r / resemble-01 :ARG1 (a / and :op1 (b / brevity :poss (g / gene :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :op2 (i / induce-01 :ARG2 (p / protein) :location (k / keratinocyte :ARG1-of (c / culture-01) :ARG1-of (t / treat-04 :ARG2 (p2 / protein :name (n2 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))))) :ARG2 (a2 / appear-01 :ARG1 (a3 / and :op1 (n3 / nucleic-acid :name (n4 / name :op1 "mRNA") :part-of g) :op2 (p3 / protein)) :mod (t2 / time) :time (i2 / initiate-01 :ARG1 (m2 / morphogenesis :mod (f / follicle :mod (h / hair))) :location (s / skin :part-of (e / embryo :mod (m3 / mouse)))))) # ::id pmid_1563_0473.164 # ::date 2015-03-22T15:49:36 # ::file pmid_1563_0473_164.txt # ::snt To test whether TGF-β2 might be required for Snail induction in hair bud formation in vivo, we first analyzed whether TGF-β2 was expressed in or around the hair bud. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (e / express-03 :mode "interrogative" :ARG2 (p / protein :name (n / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG3 (o / or :op1 (b / bud :mod (h / hair)) :op2 (a2 / around :op1 h))) :mod (f / first) :purpose (t / test-01 :ARG0 w :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (r / require-01 :ARG0 (i / induce-01 :ARG2 (g / gene :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :subevent-of (f2 / form-01 :ARG1 b :manner (i2 / in-vivo))) :ARG1 p)))) # ::id pmid_1563_0473.165 # ::date 2015-03-22T15:59:07 # ::file pmid_1563_0473_165.txt # ::snt Consistent with previous observations [33], an anti-TGF-β2 antibody labeled developing hair buds (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (l / label-01 :ARG0 (a / antibody :ARG0-of (c3 / counter-01 :ARG1 (p3 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG1 (b / bud :mod (h / hair) :ARG1-of (d / develop-01)) :ARG1-of (c / consistent-01 :ARG2 (t / thing :ARG1-of (o / observe-01 :time (p / previous)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "33"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_1563_0473.166 # ::date 2015-03-22T16:15:56 # ::file pmid_1563_0473_166.txt # ::snt This labeling appeared to be specific as judged by the lack of staining in follicle buds from mice homozygous for a TGF-β2 null mutation (Figure 6A; [34]). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / appear-02 :ARG1 (s / specific-02 :ARG1 (l / label-01 :mod (t / this))) :ARG2-of (j / judge-01 :ARG3 (s2 / stain-01 :polarity "-" :location (b2 / bud :mod (f / follicle :mod (m2 / mouse) :mod (h / homozygous :topic (m / mutate-01 :ARG2 (p / protein :name (n2 / name :op1 "TGF-β2") :mod (n / null) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "6A") :op2 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "34"))))) # ::id pmid_1563_0473.167 # ::date 2015-03-22T16:25:45 # ::file pmid_1563_0473_167.txt # ::snt Moreover, the downstream effector of TGF-β2 signaling, pSMAD2, was also expressed in WT, but not TGF-β2-null, hair buds (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (a / and :op2 (e / express-03 :ARG2 (e2 / effector :location (d / downstream) :mod (s / signal-07 :ARG0 (p / protein :name (n / name :op1 "TGF-β2") :xref (x2 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n2 / name :op1 "SMAD2") :ARG1-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")))) :ARG3 (b / bud :mod (h / hair) :mod (w / wild-type)) :mod (a2 / also) :ARG1-of (c / contrast-01 :ARG2 (e3 / express-03 :polarity "-" :ARG2 p2 :ARG3 (b2 / bud :mod (p5 / protein :name (n4 / name :op1 "TGF-β2") :ARG2-of (m2 / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :mod (h2 / hair))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id pmid_1563_0473.168 # ::date 2015-03-22T16:38:31 # ::file pmid_1563_0473_168.txt # ::snt Together, these data underscore the importance of the TGF-β2 isoform despite expression of both TGF-β1 and TGF-β2 in developing hair buds at this stage. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (u / underscore-01 :ARG0 (d / data :mod (t / this) :mod (t2 / together)) :ARG1 (i / important :domain (i2 / isoform :mod (p / protein :name (n / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :concession (e / express-03 :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "TGF-β1") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.283")) :op2 p) :ARG3 (b / bud :mod (h / hair) :ARG2-of (d2 / develop-01)) :time (s / stage :mod (t3 / this))))) # ::id pmid_1563_0473.169 # ::date 2015-03-22T16:45:53 # ::file pmid_1563_0473_169.txt # ::snt To further explore the possible relation between Snail and TGF-β2, we examined the status of Snail expression in TGF-β2-null hair buds. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (s / status :mod (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (b / bud :mod (h / hair) :mod (p2 / protein :name (n3 / name :op1 "TGF-β2") :mod (n2 / null) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))))) :purpose (e3 / explore-01 :ARG0 w :ARG1 (r / relation-03 :ARG0 p :ARG2 p2 :ARG1-of (p3 / possible-01)) :degree (f / further))) # ::id pmid_1563_0473.170 # ::date 2015-03-22T16:50:48 # ::file pmid_1563_0473_170.txt # ::snt As judged by immunohistochemistry, Snail protein was absent from E17.5 skin of TGF-β2-null embryos but not from that of control littermates (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 31, 2015 (a / absent-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (s / skin :part-of (e2 / embryo :mod (n2 / null :mod (p2 / protein :name (n3 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :age (t / temporal-quantity :quant "17.5" :unit (d2 / day)))) :ARG1-of (c / contrast-01 :ARG2 (a2 / absent-01 :polarity "-" :ARG1 p :ARG2 (s2 / skin :part-of (l / littermate :mod (c2 / control))))) :ARG2-of (j / judge-01 :ARG0 (i / immunohistochemistry)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id pmid_1563_0473.171 # ::date 2015-03-22T17:01:04 # ::file pmid_1563_0473_171.txt # ::snt This effect appeared to be exerted at the transcriptional level, since Snail mRNAs were also not found in TGF-β2 null hair buds under conditions in which the signal was readily detected in the hair buds of littermate skin (Figure 6D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (a / appear-02 :ARG1 (e2 / exert-01 :ARG1 (e / effect-03 :mod (t / this)) :location (l / level :mod (t2 / transcribe-01))) :ARG1-of (c / cause-01 :ARG0 (f / find-01 :polarity "-" :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA") :mod (g / gene :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :mod (a2 / also) :location (b / bud :mod (h / hair) :mod (p2 / protein :name (n3 / name :op1 "TGF-β2") :mod (n2 / null) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :condition (d / detect-01 :ARG1 (s / signal-07) :manner (r / ready) :location (b2 / bud :mod h :part-of (s2 / skin :part-of (l2 / littermate)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6D"))) # ::id pmid_1563_0473.172 # ::date 2015-03-22T17:09:49 # ::file pmid_1563_0473_172.txt # ::snt Conversely, in 2-wk-old K14-Smad2 Tg mice, which display elevated TGF-β signaling in skin [35], Snail protein was readily detected by Western blot analyses, where it was not found in postnatal skin (Figure 6E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (c / contrast-01 :ARG2 (d / detect-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (a / analyze-01 :manner (i / immunoblot-01)) :manner (r / ready) :location (f / find-01 :polarity "-" :ARG1 p :location (s / skin :mod (p2 / postnatal))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6A")) :location (m / mouse :age (t / temporal-quantity :quant "2" :unit (w2 / week)) :mod (t2 / transgenic) :mod (m2 / macro-molecular-complex :part (p3 / protein :name (n2 / name :op1 "K14") :xref (x / xref :value "UNIPROT:K1C14_HUMAN" :prob "1.002")) :part (p4 / protein :name (n3 / name :op1 "Smad2") :xref (x1 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003"))) :ARG0-of (d3 / display-01 :ARG1 (s2 / signal-07 :ARG0 (p5 / protein :name (n4 / name :op1 "TGF-β") :xref (x2 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233")) :ARG1-of (e / elevate-01)) :ARG2 (s3 / skin) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "35"))))))) # ::id pmid_1563_0473.173 # ::date 2015-03-22T18:10:35 # ::file pmid_1563_0473_173.txt # ::snt Taken together, these results provide compelling evidence that TGF-β2 is functionally important for inducing Snail gene expression in a pSMAD-dependent manner in developing hair buds. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (p / provide-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01) :ARG1-of (t3 / take-01 :mod (t4 / together))) :ARG1 (e / evidence-01 :ARG1 (i / important :domain (p2 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :mod (f / function-01) :purpose (i2 / induce-01 :ARG2 (e2 / express-03 :ARG1 (g / gene :name (n2 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (b / bud :mod (h / hair) :ARG2-of (d / develop-01))) :ARG0-of (d2 / depend-01 :ARG1 (p3 / protein :name (n3 / name :op1 "SMAD") :ARG1-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:SMAD1_HUMAN" :prob "0.312"))))) :ARG0-of (c / compel-01))) # ::id pmid_1563_0473.174 # ::date 2015-03-22T18:27:49 # ::file pmid_1563_0473_174.txt # ::snt Whether pMARK activity also contributes to Snail induction was not addressed in the present study [15]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / address-02 :polarity "-" :ARG1 (c / contribute-01 :mode "interrogative" :ARG0 (a3 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "MAPK") :ARG1-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG2 (i / induce-01 :ARG2 (p3 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :mod (a2 / also)) :medium (s / study :time (p / present)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "15")))) # ::id pmid_1563_0473.175 # ::date 2015-03-22T18:36:33 # ::file pmid_1563_0473_175.txt # ::snt Although some hair buds still formed in TGF-β2 null skin, their number was reduced by approximately 50% [32]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (h / have-concession-91 :ARG1 (r / reduce-01 :ARG1 (n3 / number :quant-of "b") :ARG2 (a / approximately :op1 (p2 / percentage-entity :value "50"))) :ARG2 (f / form-01 :ARG1 (b / bud :mod (h2 / hair) :mod (s2 / some)) :mod (s / still) :location (s3 / skin :mod (p / protein :name (n2 / name :op1 "TGF-β2") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "32")))) # ::id pmid_1563_0473.176 # ::date 2015-03-22T21:50:33 # ::file pmid_1563_0473_176.txt # ::snt Thus, although the pathway mediated by TGF-β2 signaling impacts the earliest step of epithelial invagination, it does not appear to be essential for bud morphogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / infer-01 :ARG1 (h / have-concession-91 :ARG1 (a / appear-02 :polarity "-" :ARG1 (e3 / essential :domain "p" :purpose (m3 / morphogenesis :mod (b / bud)))) :ARG2 (i2 / impact-01 :ARG0 (p / pathway :ARG1-of (m / mediate-01 :ARG0 (s / signal-07 :ARG0 (p2 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))))) :ARG1 (s2 / step-01 :ARG1 (i3 / invaginate-01 :ARG1 (e2 / epithelium)) :mod (e / early :degree (m2 / most)))))) # ::id pmid_1563_0473.177 # ::date 2015-03-22T22:06:45 # ::file pmid_1563_0473_177.txt # ::snt Consistent with this notion, basement membrane remodeling still took place in the TGF-β2-null buds, as judged by immunofluorescence with antibodies against β4 integrin, an integral component of keratinocyte-mediated adhesion to its underlying basement membrane (Figure 6F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / consistent-01 :ARG1 (r / remodel-01 :ARG1 (m / membrane :mod (b / basement) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :location (b2 / bud :mod (p / protein :name (n2 / name :op1 "TGF-β2") :mod (n / null) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :mod (s / still) :ARG1-of (j / judge-01 :ARG3 (i / immunofluoresce-01 :ARG2 (a / antibody :ARG0-of (c3 / counter-01 :ARG1 (p2 / protein :name (n4 / name :op1 "β4" :op2 "integrin") :ARG1-of (m2 / mean-01 :ARG2 (c2 / component :mod (i2 / integral) :mod (a2 / adhere-01 :ARG2 (m4 / membrane :mod (b3 / basement) :ARG1-of (u / underlie-01) :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (m3 / mediate-01 :ARG0 (k / keratinocyte)))))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6F"))) :ARG2 (n3 / notion :mod (t / this))) # ::id pmid_1563_0473.178 # ::date 2015-03-22T22:26:32 # ::file pmid_1563_0473_178.txt # ::snt In contrast, TGF-β2 signaling appeared to be an important factor for the early proliferation that occurs in the developing hair buds, as judged by anti-Ki67 and anti-pMAPK immunofluorescence (Figure 6F and 6G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / contrast-01 :ARG2 (a / appear-02 :ARG1 (f / factor :mod (i / important) :mod (p / proliferate-01 :mod (e / early) :location (b / bud :mod (h / hair) :ARG2-of (d / develop-01))) :domain (s / signal-07 :ARG0 (p2 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG1-of (j / judge-01 :ARG3 (i2 / immunofluoresce-01 :ARG0-of (c2 / counter-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Ki67") :xref (x2 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))) :ARG0-of (c3 / counter-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MAPK") :ARG3-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f2 / figure :mod "6F") :op2 (f3 / figure :mod "6G")))) # ::id pmid_1563_0473.179 # ::date 2015-03-22T22:33:21 # ::file pmid_1563_0473_179.txt # ::snt If TGF-β2 stimulates Snail expression in developing buds, loss of this morphogen would be expected to affect the expression of genes that are typically repressed by Snail. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (e / expect-01 :ARG1 (a / affect-01 :ARG0 (l / lose-02 :ARG1 "m2") :ARG1 (e3 / express-03 :ARG1 (g / gene :ARG1-of (r / repress-01 :ARG0 "g2" :ARG1-of (t / typical-02))))) :condition (s / stimulate-01 :ARG0 (m2 / morphogen :name (n / name :op1 "TGF-β2")) :ARG1 (e2 / express-03 :ARG1 (g2 / gene :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (b / bud :ARG2-of (d / develop-01))))) # ::id pmid_1563_0473.180 # ::date 2015-03-22T22:41:26 # ::file pmid_1563_0473_180.txt # ::snt Since a major target for Snail-mediated repression is the E-cadherin gene [12,13], we investigated the status of E-cadherin in TGF-β2-null buds. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 31, 2015 (i / investigate-01 :ARG0 (w / we) :ARG1 (s / status :mod (g / gene :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :location (b / bud :mod (p2 / protein :name (n3 / name :op1 "TGF-β2") :ARG2-of (m3 / mutate-01 :mod "−/−") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG1-of (c / cause-01 :ARG0 (t / target-01 :ARG0 (r / repress-01 :ARG1-of (m2 / mediate-01 :ARG0 (p / protein :name (n4 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1 g :ARG1-of (m / major-02) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "12" :op2 "13"))))))) # ::id pmid_1563_0473.181 # ::date 2015-03-22T22:51:49 # ::file pmid_1563_0473_181.txt # ::snt As shown in Figure 6H, hair buds in TGF-β2 null skin displayed elevated immunofluorescence staining relative to their WT counterparts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (d / display-01 :ARG0 (b / bud :mod (h / hair) :location (s / skin :mod (p / protein :name (n2 / name :op1 "TGF-β2") :mod (n / null) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG1 (s2 / stain-01 :ARG1 b :mod (i / immunofluoresce-01) :ARG1-of (e / elevate-01 :compared-to (c / counterpart :poss b :mod (w / wild-type)))) :ARG1-of (s3 / show-01 :ARG0 (f / figure :mod "6H"))) # ::id pmid_1563_0473.182 # ::date 2015-03-22T22:56:07 # ::file pmid_1563_0473_182.txt # ::snt Previously we demonstrated that the concerted action of the extracellular signals Wnt and noggin are required for the generation of a LEF-1/β-catenin transcription complex to repress E-cadherin transcription at the onset of hair fate specification. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (r / require-01 :ARG0 (r2 / repress-01 :ARG0 (g / generate-01 :ARG1 (m / macro-molecular-complex :ARG0-of (t / transcribe-01) :part (p3 / protein :name (n3 / name :op1 "LEF-1") :xref (x2 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :part (p4 / protein :name (n4 / name :op1 "β-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :ARG1 (t2 / transcribe-01 :ARG1 (g2 / gene :name (n5 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :time (o / onset :poss (s / specify-01 :ARG1 (f / fate :poss (h / hair)))))) :ARG1 (a / act-01 :ARG0 (a2 / and :op1 (p / pathway :name (n6 / name :op1 "Wnt") :mod (e / extracellular)) :op2 (p2 / pathway :name (n / name :op1 "noggin") :mod e) :ARG0-of (s2 / signal-07)) :mod (c / concerted))) :time (p5 / previous)) # ::id pmid_1563_0473.183 # ::date 2015-03-22T23:31:27 # ::file pmid_1563_0473_183.txt # ::snt As shown in Figure 6I and 6J, both WT and TGF-β2 null buds exhibited nuclear LEF-1 and β-catenin localization, signs that the Wnt-noggin signaling pathway was intact. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 26, 2015 (e / exhibit-01 :ARG0 (a / and :op1 (b / bud :mod (w / wild-type)) :op2 (b2 / bud :mod (p / protein :name (n2 / name :op1 "TGF-β2") :mod (n / null) :xref (x2 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG1 (b3 / be-located-at-91 :ARG1 (a3 / and :op1 (p2 / protein :name (n3 / name :op1 "LEF-1") :xref (x / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n6 / name :op1 "β-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG2 (n4 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8"))) :ARG1-of (s / show-01 :ARG0 (a2 / and :op1 (f / figure :mod "6I") :op2 (f2 / figure :mod "6J"))) :ARG0-of (s2 / signal-07 :ARG1 (i / intact :domain (p3 / pathway :name (n5 / name :op1 "Wnt-noggin") :ARG0-of (s3 / signal-07))))) # ::id pmid_1563_0473.184 # ::date 2015-03-22T23:41:39 # ::file pmid_1563_0473_184.txt # ::snt These data suggest that during hair follicle morphogenesis, TGF-β2 functions subsequently to Wnt/noggin-mediated determination of hair fate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 23, 2015 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (f / function-01 :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :time (m / morphogenesis :mod (f2 / follicle :mod (h / hair))) :time (s2 / subsequent :op1 (d2 / determine-01 :ARG1 (f3 / fate :poss (h2 / hair)) :ARG1-of (m2 / mediate-01 :ARG0 (p / pathway :name (n / name :op1 "Wnt/noggin"))))))) # ::id pmid_1563_0473.185 # ::date 2015-03-22T23:49:06 # ::file pmid_1563_0473_185.txt # ::snt Moreover, through activation of Snail gene expression, TGF-β2 appears to work in tandem with these other morphogens to down-regulate E-cadherin levels, which contributes to the activation of proliferative circuitries. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Mar 26, 2015 (a / and :op2 (a2 / appear-02 :ARG2 (w / work-01 :ARG0 (p / protein :name (n / name :op1 "TGF-β2") :xref (x2 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG1 (d / downregulate-01 :ARG0 (a4 / and :op1 p :op2 "m") :ARG1 (l / level :quant-of (g2 / gene :name (n3 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG0-of (c2 / contribute-01 :ARG2 (a5 / activate-01 :ARG1 (c3 / circuitry :ARG0-of (p3 / proliferate-01))))) :ARG3 (m / morphogen :mod (o / other) :mod (t2 / this)) :mod (t / tandem)) :ARG1-of (c / cause-01 :ARG0 (a3 / activate-01 :ARG1 (e / express-03 :ARG1 (g / gene :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))))) # ::id pmid_1563_0473.186 # ::date 2015-03-23T02:46:24 # ::file pmid_1563_0473_186.txt # ::snt Discussion # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 25, 2015 (d / discuss-01) # ::id pmid_1563_0473.187 # ::date 2015-03-23T02:47:25 # ::file pmid_1563_0473_187.txt # ::snt During budding morphogenesis, intersecting signaling networks from the epithelium and mesenchyme govern transcriptional, adhesive, polarity, and motility programs in these select groups of cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (g / govern-01 :ARG0 (n2 / network :ARG0-of (s / signal-07) :ARG0-of (i / intersect-01) :source (a / and :op1 (e / epithelium) :op2 (m / mesenchyme))) :ARG1 (a4 / and :op1 (p3 / program :topic (t3 / transcribe-01)) :op2 (p4 / program :topic (a3 / adhere-01)) :op3 (p5 / program :topic (p2 / polarize-01)) :op4 (p6 / program :topic (m2 / motility))) :location (g2 / group :consist-of (c / cell) :mod (t4 / this) :mod (s2 / select)) :time (m3 / morphogenesis :ARG1-of (b / bud-01))) # ::id pmid_1563_0473.188 # ::date 2015-03-23T02:56:23 # ::file pmid_1563_0473_188.txt # ::snt The dynamic nuclear and cytosolic changes that take place during this time form the cornerstone for organ morphogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 30, 2015 (f / form-01 :ARG0 (c4 / change-01 :ARG0 (a2 / and :op1 (n / nucleus :xref (x / xref :value "GO:0005634" :prob "0.8")) :op2 (c2 / cytosol :xref (x1 / xref :value "GO:0005829" :prob "0.8"))) :mod (d / dynamic) :time (t / this)) :ARG1 (c3 / cornerstone) :purpose (m / morphogenesis :mod (o / organ))) # ::id pmid_1563_0473.189 # ::date 2015-03-23T03:03:05 # ::file pmid_1563_0473_189.txt # ::snt Two major challenges in understanding the mechanisms underlying a particular budding process are to order the temporal sequence of external cues involved and then to dissect how the cells of the developing bud translate these signals into the downstream events of cellular remodeling, proliferation, and differentiation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (a / and :op1 (o / order-03 :ARG1 (s / sequence :mod (t / time) :consist-of (c / cue :source (e / external) :ARG1-of (i / involve-01)))) :op2 (d / dissect-01 :ARG1 (t3 / thing :manner-of (t4 / translate-01 :ARG0 (c2 / cell :part-of (b / bud :ARG1-of (d2 / develop-02))) :ARG1 (t5 / thing :ARG0-of (s2 / signal-07) :mod (t6 / this)) :ARG2 (a2 / and :op1 (e3 / event :mod (r / remodel-01 :ARG1 c2)) :op2 (e4 / event :mod (d4 / differentiate-01 :ARG1 c2)) :op3 (e5 / event :mod (p / proliferate-01 :ARG0 c2)) :location (d3 / downstream)))) :time (t2 / then)) :domain (c3 / challenge-01 :quant "2" :ARG2 (u / understand-01 :ARG1 (m2 / mechanism :ARG0-of (u2 / underlie-01 :ARG1 (p2 / process-02 :ARG1 (b2 / bud-01) :mod (p3 / particular))))) :ARG1-of (m / major-02))) # ::id pmid_1563_0473.190 # ::date 2015-03-23T03:16:56 # ::file pmid_1563_0473_190.txt # ::snt Our studies here provide some insights into how these events are orchestrated during hair bud formation in developing skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 30, 2015 (p / provide-01 :ARG0 (s / study-01 :ARG0 (w / we) :mod (h / here)) :ARG1 (i / insight :quant (s2 / some) :topic (t / thing :manner-of (o / orchestrate-01 :ARG1 (e / event :mod (t2 / this)) :time (f / form-01 :ARG1 (b / bud :mod (h2 / hair)) :location (s3 / skin :ARG1-of (d / develop-02))))))) # ::id pmid_1563_0473.191 # ::date 2015-03-23T03:22:39 # ::file pmid_1563_0473_191.txt # ::snt Signaling during Early Hair Follicle Morphogenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 23, 2015 (s / signal-07 :time (e / early :op1 (m / morphogenesis :mod (f / follicle :mod (h / hair))))) # ::id pmid_1563_0473.192 # ::date 2015-03-23T03:52:20 # ::file pmid_1563_0473_192.txt # ::snt Recent studies on hair bud morphogenesis suggest that Wnt signals likely from the epithelium and BMP inhibitory signals from the underlying mesenchyme converge to produce an active transcription factor complex involving β-catenin and LEF-1, which in turn plays a key role in specifying the hair follicle fate [4,29,30,36,37]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (s / suggest-01 :ARG0 (s2 / study-01 :ARG1 (m / morphogenesis :mod (b / bud :mod (h / hair))) :time (r / recent)) :ARG1 (c / converge-01 :ARG0 (s6 / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Wnt")) :source (l / likely-01 :ARG1 (e / epithelium))) :ARG1 (s3 / signal-07 :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein :name (n2 / name :op1 "BMP") :xref (x / xref :value "UNIPROT:BMP1_HUMAN" :prob "0.263"))) :source (m2 / mesenchyme :ARG0-of (u / underlie-01))) :purpose (p3 / produce-01 :ARG0 (a / and :op1 s6 :op2 s3) :ARG1 (m3 / macro-molecular-complex :part (f / factor :ARG0-of (t3 / transcribe-01)) :ARG0-of (i2 / involve-01 :ARG1 (a3 / and :op1 (p4 / protein :name (n4 / name :op1 "β-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op2 (p5 / protein :name (n5 / name :op1 "LEF-1") :xref (x2 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")))) :ARG0-of (a2 / activity-06) :ARG0-of (p6 / play-02 :ARG1 (r2 / role :ARG1-of (k / key-02 :ARG2 (s5 / specify-01 :ARG1 (f2 / fate-01 :ARG1 (f3 / follicle :mod (h2 / hair)))))) :mod (i3 / in-turn))))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 "4" :op2 "29" :op3 "30" :op4 "36" :op5 "37"))))) # ::id pmid_1563_0473.193 # ::date 2015-03-23T04:20:25 # ::file pmid_1563_0473_193.txt # ::snt Sonic hedgehog (Shh) and TGF-β2 signaling also play essential roles in follicle morphogenesis, but in contrast to β-catenin null skin, in which follicle invaginations are absent [30], some hair buds still form in the absence of LEF-1, Shh, or TGF-β2 [32,38]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / play-08 :ARG0 (a / and :op1 (s2 / signal-07 :ARG0 (p2 / protein :name (n / name :op1 "Sonic" :op2 "hedgehog") :ARG1-of (d3 / describe-01 :ARG2 (n5 / name :op1 "Shh")) :xref (x / xref :value "UNIPROT:SHH_HUMAN" :prob "0.352"))) :op2 (s3 / signal-07 :ARG0 (p7 / protein :name (n2 / name :op1 "TGF-β2") :xref (x2 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG1 (m / morphogenesis :mod (f / follicle)) :mod (a2 / also) :concession (f2 / form-01 :ARG1 (b / bud :mod (h2 / hair) :quant (s4 / some)) :mod (s5 / still) :condition (a5 / absent-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :op2 p2 :op3 p7) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 "32" :op2 "38"))))) :ARG1-of (c / contrast-01 :ARG2 (s7 / skin :ARG2-of (a6 / absent-01 :ARG1 (i / invaginate-01 :ARG1 (f3 / follicle))) :ARG0-of (c4 / contain-01 :ARG1 (p4 / protein :name (n4 / name :op1 "β-catenin") :ARG2-of (m2 / mutate-01 :mod "−/−") :xref (x3 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "30")))))) :mod (e / essential)) # ::id pmid_1563_0473.194 # ::date 2015-03-23T05:17:32 # ::file pmid_1563_0473_194.txt # ::snt These likely reflect the first wave of follicle (i.e., guard hair) morphogenesis, which accounts for a small number (fewer than 5%) of hairs and is under distinct regulatory control. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (l / likely-01 :ARG1 (r / reflect-01 :ARG1 (t / this) :ARG2 (w / wave-04 :ARG1 (m / morphogenesis :mod (f / follicle)) :ord (o / ordinal-entity :value "1") :ARG0-of (a / account-01 :ARG1 (h3 / hair :quant (n / number :mod (s / small) :ARG0-of (m3 / mean-01 :ARG1 (l2 / less-than :op1 (p / percentage-entity :value "5")))))) :ARG1-of (c / control-01 :mod (d / distinct) :ARG0-of (r2 / regulate-01)) :ARG0-of (m2 / mean-01 :ARG1 (h2 / hair :mod (g / guard)))))) # ::id pmid_1563_0473.195 # ::date 2015-03-23T05:30:06 # ::file pmid_1563_0473_195.txt # ::snt Guard hairs form in the absence of LEF-1 and TGF-β2, and we have found that they also fail to express Snail at the budding stage of development (unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (f / form-01 :ARG1 (h / hair :mod (g / guard)) :condition (a4 / absent-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "LEF-1") :xref (x2 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n2 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))))) :op2 (f2 / find-01 :ARG0 (w / we) :ARG1 (f3 / fail-01 :ARG1 h :ARG2 (e / express-03 :ARG1 h :ARG2 (p4 / protein :name (n3 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :mod (a3 / also) :time (s2 / stage :subevent-of (d / develop-02) :mod (b2 / bud-01)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (p2 / publish-01 :polarity "-")))) # ::id pmid_1563_0473.196 # ::date 2015-03-23T05:58:02 # ::file pmid_1563_0473_196.txt # ::snt How E-cadherin is regulated in guard hairs remains to be determined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 23, 2015 (r / remain-01 :ARG1 (d / determine-01 :ARG1 (t / thing :manner-of (r2 / regulate-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :location (h / hair :mod (g / guard)))))) # ::id pmid_1563_0473.197 # ::date 2015-03-23T05:59:56 # ::file pmid_1563_0473_197.txt # ::snt Several candidates include other Snail family members such as Slug or twist, or alternatively, transcription factors involving β-catenin and a different member of the LEF-1/TCF/Sry-type HMG box (commonly known as SOX) family [39,40]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i / include-01 :ARG1 (o3 / or :op1 (m / member :mod (o / other) :example (o2 / or :op1 (p8 / protein :name (n2 / name :op1 "Slug") :xref (x / xref :value "UNIPROT:SNAI2_HUMAN" :prob "0.602")) :op2 (p9 / protein :name (n3 / name :op1 "twist") :xref (x1 / xref :value "UNIPROT:TWST1_HUMAN" :prob "0.602"))) :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family :name (n / name :op1 "Snail")))) :op2 (f2 / factor :ARG0-of (t / transcribe-01) :ARG2-of (i2 / involve-01 :ARG1 (a2 / and :op1 (p / protein :name (n4 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op2 (m2 / member :ARG1-of (d / differ-02) :ARG1-of (i4 / include-91 :ARG2 (s2 / slash :op1 (p2 / protein-family :name (n6 / name :op1 "LEF-1")) :op2 (p5 / protein-family :name (n7 / name :op1 "TCF")) :op3 (p6 / protein-family :name (n8 / name :op1 "Sry-type" :op2 "HMG" :op3 "box") :ARG1-of (k / know-02 :ARG2 (n5 / name :op1 "SOX") :manner (c2 / common))))))))) :manner (a / alternative)) :ARG2 (c / candidate :quant (s / several)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 "39" :op2 "40"))))) # ::id pmid_1563_0473.198 # ::date 2015-03-23T06:31:38 # ::file pmid_1563_0473_198.txt # ::snt Further investigation will be required to determine whether the signaling pathway we have elucidated here is a theme with multiple variations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (r / require-01 :ARG1 (i / investigate-01 :degree (f / further)) :purpose (d / determine-01 :ARG0 "w" :ARG1 (t / theme :mode "interrogative" :domain (p / pathway :ARG0-of (s / signal-07) :ARG1-of (e / elucidate-01 :ARG0 (w / we) :location (h / here))) :ARG0-of (v / vary-01 :mod (m / multiple))))) # ::id pmid_1563_0473.199 # ::date 2015-03-23T06:43:10 # ::file pmid_1563_0473_199.txt # ::snt TGF-βs are known to promote withdrawal of keratinocytes from the cell cycle [41]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (k / know-01 :ARG1 (p / promote-02 :ARG0 (p3 / protein :name (n / name :op1 "TGF-β") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233")) :ARG1 (w / withdraw-01 :ARG1 (c / cell :name (n2 / name :op1 "keratinocyte")) :ARG2 (c2 / cycle-02 :ARG1 (c3 / cell)))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 "41")))) # ::id pmid_1563_0473.200 # ::date 2015-03-23T06:46:50 # ::file pmid_1563_0473_200.txt # ::snt Hence, when TGF-β2 protein was detected at the transition between the growing and destructive phases of the adult hair cycle, research initially and naturally focused on a role for this family member in cessation of growth and/or triggering apoptosis ([42] and references therein). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (i2 / infer-01 :ARG1 (f / focus-01 :ARG1 (r / research-01) :ARG2 (r2 / role :poss (m / member :part-of (p5 / protein-family :mod (t / this))) :purpose (a4 / and-or :op1 (c / cease-01 :ARG1 (g / grow-01)) :op2 (t2 / trigger-01 :ARG1 (a / apoptosis)))) :time (i / initial) :ARG1-of (n / natural-03) :time (d / detect-01 :ARG1 (p / protein :name (n2 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :time (t3 / transition-01 :ARG2 (p3 / phase :mod (d2 / destroy-01) :subevent-of (c2 / cycle-02 :ARG1 (h / hair :mod (a2 / adult)))) :ARG3 (p2 / phase :mod (g2 / grow-01) :subevent-of c2))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 "42" :op2 (r3 / reference :location (h2 / herein))))))) # ::id pmid_1563_0473.201 # ::date 2015-03-23T07:01:44 # ::file pmid_1563_0473_201.txt # ::snt However, in contrast to TGF-β1-null skin, which exhibits an extended growing phase of postnatal hair follicles, TGF-β2-null skin displays an embryonic block in follicle bud progression [32]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 30, 2015 (h2 / have-concession-91 :ARG2 (d / display-01 :ARG0 (s / skin :ARG0-of (c / contain-01 :ARG1 (p6 / protein :name (n / name :op1 "TGF-β2") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG1 (b / block :mod (e / embryo) :time (p2 / progress-01 :ARG1 (b2 / bud :mod (f / follicle)))) :ARG1-of (c2 / contrast-01 :ARG2 (s2 / skin :ARG0-of (e2 / exhibit-01 :ARG1 (p4 / phase :mod (g / grow-01 :ARG1 (f2 / follicle :mod (h / hair) :mod (p5 / postnatal))) :ARG1-of (e3 / extend-01))) :ARG0-of (c3 / contain-01 :ARG1 (p3 / protein :name (n2 / name :op1 "TGF-β1") :ARG2-of m :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.283")))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c4 / cite-01 :ARG2 "32")))) # ::id pmid_1563_0473.202 # ::date 2015-03-23T07:17:53 # ::file pmid_1563_0473_202.txt # ::snt Although this phenotype is consistent with TGF-β2's embryonic expression patterns [33], about 50% of TGF-β2 null buds appear unable to progress to the down-growth phase, a feature that cannot be explained readily on the basis of previously established effects of TGF-βs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / appear-02 :ARG1 (i / include-91 :ARG2 (b / bud :ARG0-of (c4 / contain-01 :ARG1 (p3 / protein :name (n / name :op1 "TGF-β2") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG3 (a4 / about :op1 (p4 / percentage-entity :value "50")) :ARG1-of (c / capable-01 :polarity "-" :ARG2 (p5 / progress-01 :ARG4 (p6 / phase :mod (g / grow-01 :ARG1-of (d / down-03)))) :ARG0-of (m2 / mean-01 :ARG1 (f / feature :ARG1-of (p2 / possible-01 :polarity "-") :ARG1-of (e / explain-01 :ARG0 (a3 / affect-01 :ARG0 (p10 / protein :name (n2 / name :op1 "TGF-β") :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233")) :ARG1-of (e2 / establish-01 :time (p7 / previous))) :manner (r / ready)))))) :concession (c2 / consistent-01 :ARG1 (p / phenotype :mod (t / this)) :ARG2 (p9 / pattern :path-of (e3 / express-03 :ARG2 p3 :ARG3 (e4 / embryo))) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 "33"))))) # ::id pmid_1563_0473.203 # ::date 2015-03-23T07:18:42 # ::file pmid_1563_0473_203.txt # ::snt Our finding that TGF-β2 is upstream from Ki67 expression and MAPK activation lends further support to the notion that hair follicle keratinocytes at this early stage of development react to TGF-β2 signaling in a fashion opposite to that typically expected for TGF-β factors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (l / lend-01 :ARG0 (f5 / find-01 :ARG0 (w / we) :ARG1 (p2 / protein :name (n2 / name :op1 "TGF-β2") :location (r / relative-position :op1 (a / and :op1 (e / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "Ki67") :xref (x1 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))) :op2 (a2 / activate-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")))) :direction (u / upstream)) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG1 (s / support-01 :ARG0 f5 :degree (f2 / further)) :ARG2 (n4 / notion :ARG0-of (m2 / mean-01 :ARG1 (r2 / react-01 :ARG0 (c / cell :name (n5 / name :op1 "keratinocyte") :part-of (f3 / follicle :mod (h / hair))) :ARG1 (s3 / signal-07 :ARG0 p2) :ARG2 (f4 / fashion :ARG1-of (o / opposite-01 :ARG2 (f / fashion :ARG1-of (e2 / expect-01 :ARG1-of (t / typical-02) :topic (p4 / protein :name (n6 / name :op1 "TGF-β" :op2 "factor")))))) :time (e3 / early :op1 (s2 / stage :subevent-of (d / develop-02) :mod (t4 / this))))))) # ::id pmid_1563_0473.204 # ::date 2015-03-23T07:22:07 # ::file pmid_1563_0473_204.txt # ::snt This said, based upon pSMAD2 immunohistochemistry, the immediate steps of downstream signaling appeared to be intact. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / appear-02 :ARG1 (i2 / intact :domain (s / step-01 :ARG1 (s2 / signal-07 :location (d / downstream)) :mod (i / immediate))) :time (a2 / after :op1 (s3 / say-01 :ARG1 (t / this))) :ARG1-of (b / base-02 :ARG2 (i3 / immunohistochemistry :instrument (p2 / protein :name (n2 / name :op1 "SMAD2") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003"))))) # ::id pmid_1563_0473.205 # ::date 2015-03-23T07:29:46 # ::file pmid_1563_0473_205.txt # ::snt Thus, we surmise that the proliferative outcome is likely to be rooted in differences in the repertoire of activated SMAD target genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 30, 2015 (i / infer-01 :ARG1 (s / surmise-01 :ARG0 (w / we) :ARG1 (l / likely-01 :ARG1 (r / root-02 :ARG1 (o / outcome :ARG1-of (c / cause-01 :ARG0 (p / proliferate-01))) :ARG2 (d / differ-02 :ARG1 (r2 / repertoire :consist-of (g / gene :ARG1-of (a / activate-01) :ARG1-of (t / target-01 :ARG0 (p2 / protein :name (n / name :op1 "SMAD") :xref (x / xref :value "UNIPROT:SMAD1_HUMAN" :prob "0.312")))))))))) # ::id pmid_1563_0473.206 # ::date 2015-03-23T07:37:51 # ::file pmid_1563_0473_206.txt # ::snt In this regard, the positive effects of TGF-β2 on proliferation within the hair bud may be more analogous to what has been seen in progression of squamous cell carcinoma to metastatic carcinoma [43] rather than that typically observed for keratinocytes [44,45,46]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a4 / analogous :domain (a / affect-01 :ARG0 (p3 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG1 (p4 / proliferate-01) :mod (p2 / positive) :location (b / bud :mod (h / hair))) :purpose (t4 / this) :degree (m / more) :prep-to (t / thing :ARG1-of (s / see-01 :ARG2 (p5 / progress-01 :ARG1 (c / carcinoma :mod (c6 / cell :mod (s2 / squamous))) :ARG4 (c2 / carcinoma :ARG1-of (m2 / metastasize-101)))) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c5 / cite-01 :ARG2 "43"))) :ARG1-of (i / instead-of-91 :ARG2 (t2 / that :ARG1-of (o / observe-01 :ARG1-of (t3 / typical-02) :location (c3 / cell :name (n2 / name :op1 "keratinocyte")))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 (a3 / and :op1 "44" :op2 "45" :op3 "46")))))) :ARG1-of (p / possible-01)) # ::id pmid_1563_0473.207 # ::date 2015-03-23T07:56:26 # ::file pmid_1563_0473_207.txt # ::snt The prior identification of the Snail gene as a potential target of TGF-β signaling [15] was intriguing, given the temporal wave of Snail gene expression that occurs in the developing hair bud. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / intrigue-01 :ARG0 (i2 / identify-01 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (t / target-01 :ARG1-of (s / signal-07 :ARG0 (p4 / protein :name (n2 / name :op1 "TGF-β") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233"))) :mod (p3 / potential)) :time (p / prior) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "15")))) :ARG1-of (c2 / cause-01 :ARG0 (w / wave-04 :ARG1 (e / express-03 :ARG1 g :location (b / bud :mod (h / hair) :ARG1-of (d2 / develop-02))) :mod (t2 / time)))) # ::id pmid_1563_0473.208 # ::date 2015-03-23T08:06:57 # ::file pmid_1563_0473_208.txt # ::snt The additional correlation between epithelial hyperproliferation and Snail transgene expression further fostered our interest in a possible link between TGF-β2 and Snail. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (f / foster-01 :ARG0 (c / correlate-01 :ARG1 (p / proliferate-01 :ARG0 (e / epithelium) :degree (h / hyper)) :ARG2 (e2 / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail") :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (a / add-02)) :ARG1 (i / interest-01 :ARG0 (w / we) :ARG2 (l / link-01 :ARG1 (p4 / protein :name (n2 / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG2 (p3 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (p2 / possible-01))) :degree (f2 / further)) # ::id pmid_1563_0473.209 # ::date 2015-03-23T08:12:25 # ::file pmid_1563_0473_209.txt # ::snt Our functional studies demonstrate that without TGF-β2, Snail expression is abolished in the mutant hair buds, and conversely, in K14-Smad2 skin, Snail is ectopically activated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (d / demonstrate-01 :ARG0 (s / study-01 :ARG0 (w / we) :mod (f / function-01)) :ARG1 (a / and :op1 (a2 / abolish-01 :ARG1 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :location (b / bud :ARG1-of (m / mutate-01) :mod (h / hair))) :op2 (a3 / activate-01 :ARG1 g :manner (e2 / ectopic) :location (s2 / skin :ARG0-of (c2 / contain-01 :ARG1 (g2 / gene :name (n3 / name :op1 "K14-Smad2")))) :ARG2-of (c / contrast-01 :ARG1 a2))) :condition (b2 / be-located-at-91 :polarity "-" :ARG1 (p / protein :name (n2 / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) # ::id pmid_1563_0473.210 # ::date 2015-03-23T08:23:04 # ::file pmid_1563_0473_210.txt # ::snt Moreover, our in vitro studies indicate that even sustained TGF-β2 exposure may cause only a transient induction of Snail, offering a possible explanation as to why Snail is so briefly expressed during hair follicle morphogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / and :op2 (i / indicate-01 :ARG0 (s / study-01 :ARG0 (w / we) :manner (i2 / in-vitro)) :ARG1 (p / possible-01 :ARG1 (c / cause-01 :ARG0 (e / expose-01 :ARG1 (p4 / protein :name (n / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG1-of (s3 / sustain-01) :mod (e2 / even)) :ARG1 (i3 / induce-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (t / transient-02) :mod (o / only)))) :ARG0-of (o2 / offer-01 :ARG1 (e3 / explain-01 :ARG1 (t2 / thing :ARG0-of (c2 / cause-01 :ARG1 (e4 / express-03 :ARG2 p2 :manner (b / brief :degree (s4 / so)) :time (m / morphogenesis :mod (f / follicle :mod (h / hair)))))) :ARG1-of (p3 / possible-01))))) # ::id pmid_1563_0473.211 # ::date 2015-03-24T01:41:47 # ::file pmid_1563_0473_211.txt # ::snt An additional point worth mentioning is that prolonged expression of Tg Snail in postnatal skin resulted in morphological and biochemical signs of epithelial to mesenchymal transitions (unpublished data), underscoring why transient Snail expression may be so important during normal hair follicle morphogenesis [18]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (w / worth-02 :ARG2 (m / mention-01 :ARG1 (p / point :ARG1-of (a / add-02) :ARG0-of (m2 / mean-01 :ARG1 (r / result-01 :ARG1 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail") :mod (t4 / transgenic) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (s / skin :mod (p3 / postnatal)) :ARG1-of (p2 / prolong-01)) :ARG2 (a2 / and :op1 (s4 / signal-07 :ARG1 (t / transition-01 :ARG2 (m5 / mesenchyme) :ARG3 (e2 / epithelium)) :mod (m3 / morphological)) :op2 (s5 / signal-07 :ARG1 t :mod (b / biochemical))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (p4 / publish-01 :polarity "-"))) :ARG0-of (u / underscore-01 :ARG1 (t3 / thing :ARG0-of (c2 / cause-01 :ARG1 (p5 / possible-01 :ARG1 (i / important :degree (s3 / so) :domain (e3 / express-03 :ARG1 g :ARG1-of (t2 / transient-02)) :time (m6 / morphogenesis :ARG1-of (n2 / normal-02) :mod (f / follicle :mod (h / hair))))))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 "18"))))))))) # ::id pmid_1563_0473.212 # ::date 2015-03-27T09:33:16 # ::file pmid_1563_0473_212.txt # ::snt At first glance, the sparsity in hair coat of K14-Snail Tg mice seemed indicative of a defect in follicle formation (see Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (s / seem-01 :ARG1 (i / indicate-01 :ARG0 (s2 / sparse :domain (c / coat :mod (h / hair) :part-of (m / mouse :mod (t / transgenic) :mod (p2 / protein :name (n2 / name :op1 "Snail") :ARG2-of (m3 / mutate-01 :value "K14") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG1 (d / defect-01 :ARG1 (f / form-01 :ARG1 (f2 / follicle)))) :time (g / glance-01 :mod (o / ordinal-entity :value "1")) :ARG1-of (s3 / see-01 :ARG2 (f3 / figure :mod "2A"))) # ::id pmid_1563_0473.213 # ::date 2015-03-28T12:21:52 # ::file pmid_1563_0473_213.txt # ::snt Closer inspection, however, revealed that not all hairs penetrated the hyperthickened Tg epidermis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Apr 6, 2015 (h3 / have-concession-91 :ARG1 (r / reveal-01 :ARG0 (i / inspect-01 :ARG1-of (c / close-10 :degree (m / more))) :ARG1 (p / penetrate-01 :polarity "-" :ARG0 (h / hair :mod (a / all)) :ARG1 (e / epidermis :mod (t / transgenic) :ARG1-of (t2 / thicken-01 :degree (h2 / hyper)))))) # ::id pmid_1563_0473.214 # ::date 2015-03-29T07:16:48 # ::file pmid_1563_0473_214.txt # ::snt Several factors may contribute to the seemingly normal follicle development in these mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (p / possible-01 :ARG1 (c / contribute-01 :ARG0 (f / factor :quant (s / several)) :ARG2 (d2 / develop-02 :ARG1 (f2 / follicle :ARG1-of (n / normal-02 :ARG1-of (s2 / seem-01))) :location (m / mouse :mod (t / this))))) # ::id pmid_1563_0473.215 # ::date 2015-03-29T07:22:37 # ::file pmid_1563_0473_215.txt # ::snt One obvious factor is the K14 promoter, which is elevated in the basal layer of the epidermis and the outer root sheath (ORS) of the hair follicle, but is markedly down-regulated in developing embryonic hair buds as well as in the postnatal hair progenitor cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (c / contrast-01 :ARG1 (f / factor :quant "1" :domain (m3 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n / name :op1 "K14") :xref (x / xref :value "UNIPROT:K1C14_HUMAN" :prob "1.002")))) :ARG1-of (o / obvious-01) :ARG1-of (e / elevate-01 :location (a / and :op1 (l / layer :mod (b / basal) :part-of (e2 / epidermis)) :op2 (s / sheath :part-of (r / root) :mod (o2 / outer) :part-of (f2 / follicle :mod (h / hair)))))) :ARG2 (d / downregulate-01 :ARG1 f :manner (m2 / marked) :location (a2 / and :op1 (b2 / bud :mod (h2 / hair) :ARG1-of (d2 / develop-02) :mod (e3 / embryo)) :op2 (c2 / cell :mod (p3 / progenitor) :part-of (h3 / hair) :time (p4 / postnatal))))) # ::id pmid_1563_0473.216 # ::date 2015-03-30T03:47:01 # ::file pmid_1563_0473_216.txt # ::snt The K14 promoter is also less active in the ORS than epidermis and hence this might also account for the lack of apparent response of the ORS to ectopic Snail. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / cause-01 :ARG0 (a / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n / name :op1 "K14") :xref (x / xref :value "UNIPROT:K1C14_HUMAN" :prob "1.002")))) :degree (l / less) :location (s / sheath :part-of (r2 / root :mod (o / outer))) :compared-to (e / epidermis)) :ARG1 (p4 / possible-01 :ARG1 (a2 / account-01 :ARG0 a :ARG1 (l2 / lack-01 :ARG1 (r / respond-01 :ARG0 s :ARG1 (p5 / protein :name (n3 / name :op1 "Snail") :mod (e2 / ectopic) :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (a4 / appear-02))) :mod (a3 / also)))) # ::id pmid_1563_0473.217 # ::date 2015-03-30T02:56:21 # ::file pmid_1563_0473_217.txt # ::snt Additional contributing factors could be the multiplicity of Snail family members and their differential expression, the saturation, and/or diversity of regulatory mechanisms that govern AJ formation, migration, and proliferation in the follicle ORS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p / possible-01 :ARG1 (f / factor :domain (a / and :op1 (m / multiply-01 :ARG1 (a3 / and :op1 (m2 / member :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n / name :op1 "Snail")))))) :op2 (e / express-03 :ARG1 m2 :ARG1-of (d2 / differ-02)) :op3 (a5 / and-or :op1 (s / saturate-01 :ARG1 "m3") :op2 (d / diversity :domain (m3 / mechanism :ARG0-of (r / regulate-01) :ARG0-of (g / govern-01 :ARG1 (a4 / and :op1 (f3 / form-01 :ARG1 (p4 / protein :name (n2 / name :op1 "AJ"))) :op2 (m4 / migrate-01 :ARG0 p4) :op3 (p3 / proliferate-01 :ARG0 p4 :location (f4 / follicle :name (n3 / name :op1 "ORS"))))))))) :ARG1-of (a2 / add-02) :ARG0-of (c / contribute-01))) # ::id pmid_1563_0473.218 # ::date 2015-03-29T09:06:50 # ::file pmid_1563_0473_218.txt # ::snt Distinguishing between these possibilities must await the generation of mice harboring skin-specific loss-of-function Snail mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (o2 / obligate-01 :ARG2 (a / await-01 :ARG1 (d / distinguish-01 :ARG1 (t / thing :ARG1-of (p / possible-01) :mod (t2 / this))) :ARG2 (g / generation :mod (m / mouse :ARG0-of (h / harbor-01 :ARG1 (m3 / mutate-01 :ARG1 (g2 / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG0-of (l / lose-02 :ARG1 (f / function)) :ARG1-of (s2 / specific-02 :ARG2 (s / skin)))))))) # ::id pmid_1563_0473.219 # ::date 2015-03-29T07:23:27 # ::file pmid_1563_0473_219.txt # ::snt Links between Signaling, Transcriptional Cascades, Epithelial Remodeling, and Proliferation in the Hair Bud # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (l / link-01 :ARG1 (s / signal-07) :ARG2 (a / and :op1 (c / cascade :ARG0-of (t / transcribe-01)) :op2 (r / remodel-01 :ARG1 (e / epithelium)) :op2 (p / proliferate-01) :location (b / bud :mod (h / hair)))) # ::id pmid_1563_0473.220 # ::date 2015-03-29T07:27:35 # ::file pmid_1563_0473_220.txt # ::snt Previously, we discovered that early during hair follicle morphogenesis, E-cadherin gene expression is down-regulated concomitantly with the invagination of developing bud cells into the skin [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (d / discover-01 :ARG0 (w / we) :ARG1 (d2 / downregulate-01 :ARG1 (e / express-03 :ARG2 (g / gene :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :time (i / invaginate-01 :ARG1 (c / cell :part-of (b / bud) :ARG1-of (d3 / develop-02)) :ARG2 (s / skin)) :time (e2 / early :op1 (m / morphogenesis :mod (f / follicle :mod (h / hair)))) :manner (c3 / concomitant)) :time (p / previous) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "4")))) # ::id pmid_1563_0473.221 # ::date 2015-03-29T07:46:39 # ::file pmid_1563_0473_221.txt # ::snt Because the timing of this event correlated with the activation of a LEF-1/β-catenin transcription factor complex [20], we were intrigued by the presence of a putative LEF-1/TCF binding site in the E-cadherin promoter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (c2 / correlate-01 :ARG1 (t2 / time-02 :ARG1 (e / event :mod (t3 / this))) :ARG2 (a / activate-01 :ARG1 (m2 / macro-molecular-complex :part "p7" :part (p5 / protein :name (n4 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :mod (f / factor :ARG0-of (t4 / transcribe-01))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "20"))))) :ARG1 (i / intrigue-01 :ARG0 (p3 / protein-segment :ARG1-of (p4 / present-02 :ARG2 (m4 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :ARG1-of (b2 / bind-01 :ARG2 (m / macro-molecular-complex :part (p7 / protein :name (n2 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :part (p8 / protein :name (n3 / name :op1 "TCF") :xref (x3 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.263")))) :ARG1-of (t5 / think-01)) :ARG1 (w / we))) # ::id pmid_1563_0473.222 # ::date 2015-03-29T09:50:43 # ::file pmid_1563_0473_222.txt # ::snt This prompted an investigation that subsequently led to our discovery that LEF-1/β-catenin can contribute to repression of E-cadherin gene expression in skin keratinocytes [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / prompt-01 :ARG0 (t / this) :ARG1 (i / investigate-01 :ARG0-of (l / lead-03 :ARG2 (d / discover-01 :ARG0 (w / we) :ARG1 (p5 / possible-01 :ARG1 (c / contribute-01 :ARG0 (m / macro-molecular-complex :part (p3 / protein :name (n / name :op1 "LEF-1") :xref (x2 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :part (p2 / protein :name (n2 / name :op1 "β-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG2 (r / repress-01 :ARG0 m :ARG1 (e / express-03 :ARG1 (g2 / gene :name (n3 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG3 (k / keratinocyte :part-of (s2 / skin))))))) :time (s / subsequent))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "4")))) # ::id pmid_1563_0473.223 # ::date 2015-03-29T12:32:44 # ::file pmid_1563_0473_223.txt # ::snt In the course of these studies, we also noted that Snail can also contribute to this process in keratinocytes in vitro, and our present studies revealed that Snail is expressed at the right place and time to be physiologically relevant in the process. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (n / note-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (c / contribute-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (p3 / process-02 :mod "t") :mod (a2 / also) :location (k / keratinocyte) :manner (i / in-vitro))) :time (s / study-01 :mod (t / this)) :mod (a3 / also)) :op2 (r / reveal-01 :ARG0 (s2 / study-01 :ARG0 w :time (p4 / present)) :ARG1 (e / express-03 :ARG2 p2 :ARG3 (p5 / place :ARG1-of (r2 / right-03)) :purpose (r3 / relevant-01 :ARG1 p2 :ARG2 p3 :manner (p6 / physiological)) :time (t2 / time :ARG1-of r2)))) # ::id pmid_1563_0473.224 # ::date 2015-03-29T12:35:07 # ::file pmid_1563_0473_224.txt # ::snt In noggin-null embryonic skin, LEF-1 expression and subsequent activation of the LEF-1/β-catenin reporter gene is abrogated in the developing placodes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a4 / abrogate-01 :ARG1 (a2 / and :op1 (e / express-03 :ARG2 (p4 / protein :name (n3 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002"))) :op2 (a3 / activate-01 :ARG1 (g2 / gene :ARG0-of (r / report-01 :ARG1 (m / macro-molecular-complex :part p4 :part (p / protein :name (n4 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))))) :time (s2 / subsequent))) :location (p2 / placode :ARG1-of (d / develop-02)) :location (s / skin :mod (e2 / embryo) :mod (p3 / protein :name (n / name :op1 "noggin") :mod (n2 / null) :xref (x / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702")))) # ::id pmid_1563_0473.225 # ::date 2015-03-29T12:51:03 # ::file pmid_1563_0473_225.txt # ::snt The corresponding failure of E-cadherin down-regulation underscores the importance of Wnt/noggin signaling in regulating this event in follicle morphogenesis [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Apr 6, 2015 (u2 / underscore-01 :ARG0 (f / fail-01 :ARG1 (d / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG1-of (c2 / correspond-02)) :ARG1 (i / important :domain (s / signal-07 :ARG0 (s2 / slash :op1 (p4 / protein :name (n5 / name :op1 "noggin") :xref (x / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702")) :op2 (p2 / pathway :name (n2 / name :op1 "Wnt")))) :purpose (r / regulate-01 :ARG1 (e / event :mod (t / this)) :location (m / morphogenesis :mod (f2 / follicle)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "4")))) # ::id pmid_1563_0473.226 # ::date 2015-03-29T13:09:27 # ::file pmid_1563_0473_226.txt # ::snt Conditional gene targeting studies will be necessary to establish whether Snail family members also contribute to the down-regulation in E-cadherin gene expression that occurs during follicle formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (n / need-01 :ARG1 (s / study-01 :ARG1 (t / target-01 :ARG1 (g / gene) :mod (c / conditional))) :purpose (e / establish-01 :ARG1 (c2 / contribute-01 :mode "interrogative" :ARG0 (m / member :ARG1-of (i / include-91 :ARG2 (p / protein-family :name (n2 / name :op1 "Snail")))) :ARG2 (d / downregulate-01 :ARG1 (e2 / express-03 :ARG2 (g2 / gene :name (n3 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :time (f2 / form-01 :ARG1 (f3 / follicle)))) :mod (a / also)))) # ::id pmid_1563_0473.227 # ::date 2015-03-29T09:21:11 # ::file pmid_1563_0473_227.txt # ::snt However, it is intriguing that K14-Snail Tg epidermis displayed a marked down-regulation in E-cadherin expression, thereby demonstrating its potential to do so in skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 25, 2016 (h / have-concession-91 :ARG1 (c2 / cause-01 :ARG0 (d2 / display-01 :ARG0 (e / epidermis :mod (t / transgenic) :mod (g / gene :name (n2 / name :op1 "Snail") :ARG2-of (m / mutate-01 :value "K14") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1 (d3 / downregulate-01 :ARG1 (e2 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG1-of (m2 / mark-01)) :ARG0-of (i / intrigue-01)) :ARG1 (d / demonstrate-01 :ARG0 e :ARG1 (p4 / potential :topic d3 :location (s / skin))))) # ::id pmid_1563_0473.228 # ::date 2015-03-29T08:26:35 # ::file pmid_1563_0473_228.txt # ::snt Our prior findings showed that by elevating E-cadherin levels or by conditionally ablating α-catenin, hair follicle morphogenesis can be impaired [4,7]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 3, 2015 (s2 / show-01 :ARG0 (t / thing :ARG1-of (f2 / find-01 :ARG0 (w / we))) :ARG1 (p7 / possible-01 :ARG1 (i / impair-01 :ARG0 (o / or :op1 (e / elevate-01 :ARG1 (l / level :quant-of (p3 / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :op2 (a / ablate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :manner (c / conditional)) :ARG1-of (s / show-01)) :ARG1 (m / morphogenesis :mod (f / follicle :mod (h / hair))))) :time (p2 / prior) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "4")) :op2 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "7"))))) # ::id pmid_1563_0473.229 # ::date 2015-03-29T08:52:25 # ::file pmid_1563_0473_229.txt # ::snt The marked epidermal hyperproliferation seen in the K14-Snail Tg skin, coupled with the converse suppression of proliferation and Snail in TGF-β2-null hair buds led us to wonder whether the down-regulation of E-cadherin during follicle morphogenesis might have a direct impact on elevating the proliferative state of these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (l / lead-03 :ARG0 (p8 / proliferate-01 :ARG0 (e / epidermis) :ARG1-of (m / mark-01) :ARG1-of (s / see-01 :location (s2 / skin :mod (t / transgenic) :mod (p2 / protein :name (n2 / name :op1 "Snail") :ARG2-of (m4 / mutate-01 :value "K14") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1-of (c / couple-01 :ARG2 (a / and :op1 (s3 / suppress-01 :ARG1 (p3 / proliferate-01) :mod (c2 / converse)) :op2 p2 :location (b2 / bud :mod (h2 / hair) :mod (p7 / protein :name (n4 / name :op1 "TGF-β2") :mod (n5 / null) :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))))) :ARG1 (w / we) :ARG2 (w2 / wonder-01 :ARG0 w :ARG1 (p6 / possible-01 :ARG1 (i / impact-01 :mode "interrogative" :ARG0 (d2 / downregulate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :time (m3 / morphogenesis :mod (f / follicle))) :ARG1 (e2 / elevate-01 :ARG0 d2 :ARG1 (p5 / proliferate-01 :ARG0 (c3 / cell :mod (t2 / this)))) :ARG1-of (d / direct-02))))) # ::id pmid_1563_0473.230 # ::date 2015-03-29T15:58:57 # ::file pmid_1563_0473_230.txt # ::snt Our Tg studies suggested that, at least in part through its regulation of E-cadherin, Snail is able to influence the subcellular localization of a variety of AJ-associated proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (s / suggest-01 :ARG0 (s2 / study-01 :ARG0 (w / we) :ARG1 (t / transgenic)) :ARG1 (p2 / possible-01 :ARG1 (i / influence-01 :ARG0 (p3 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1 (l / localize-01 :ARG1 (p / protein :ARG1-of (a / associate-01 :ARG2 (p6 / protein :name (n3 / name :op1 "AJ"))) :mod (v2 / variety)) :mod (s3 / subcellular)) :ARG1-of (c / cause-01 :ARG0 (r / regulate-01 :ARG0 p3 :ARG1 (g / gene :name (n2 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :degree (a2 / at-least :op1 (p4 / part))))) # ::id pmid_1563_0473.231 # ::date 2015-03-29T07:47:09 # ::file pmid_1563_0473_231.txt # ::snt One of these appears to be Ajuba, which was previously shown to have the dual capacity to bind Grb-2 as well as α-catenin [9,10]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Apr 6, 2015 (a / appear-02 :ARG1 (p / protein :quant "1" :name (n / name :op1 "Ajuba") :ARG1-of (i / include-91 :ARG2 (t2 / this)) :ARG1-of (c / capable-01 :ARG2 (b / bind-01 :ARG1 p :ARG2 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :op2 (p4 / protein :name (n3 / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :time (p2 / previous) :ARG1-of (s / show-01) :mod (d / dual)) :xref (x2 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 "9" :op2 "10")))))) # ::id pmid_1563_0473.232 # ::date 2015-03-29T08:25:47 # ::file pmid_1563_0473_232.txt # ::snt Our studies revealed that in skin keratinocytes that either harbor a conditional null mutation in α-catenin or that overexpress Snail, Ajuba develops an interaction with Grb-2 that is otherwise not observed in WT keratinocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (r / reveal-01 :ARG0 (s / study-01 :ARG0 (w2 / we)) :ARG1 (d / develop-02 :ARG0 (p / protein :name (n / name :op1 "Ajuba") :xref (x3 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :ARG1 (i / interact-01 :ARG0 p :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :ARG1-of (o / observe-01 :polarity "-" :mod (o2 / otherwise) :location (k2 / keratinocyte :mod (w / wild-type)))) :location (o3 / or :op1 (k / keratinocyte :ARG0-of (h / harbor-01 :ARG1 (m / mutate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :mod (n3 / null) :mod (c / conditional))) :mod (s2 / skin)) :op2 (k3 / keratinocyte :location-of (o4 / overexpress-01 :ARG1 (p4 / protein :name (n5 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))))) # ::id pmid_1563_0473.233 # ::date 2015-03-29T15:57:50 # ::file pmid_1563_0473_233.txt # ::snt The corresponding abilities of either Snail-transfected or Ajuba-transfected keratinocytes to exhibit elevated activation of the Ras-MAPK pathway suggest that the Grb-2 association of Ajuba under conditions of reduced levels of AJ proteins may be directly relevant to the parallel in hyperproliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (s / suggest-01 :ARG0 (c / capable-01 :ARG1 (o / or :op1 (k / keratinocyte :ARG1-of (t / transfect-01 :ARG2 (g / gene :name (n4 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :op2 (k2 / keratinocyte :ARG1-of (t2 / transfect-01 :ARG2 (g2 / gene :name (n5 / name :op1 "Ajuba") :xref (x / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))))) :ARG2 (e / exhibit-01 :ARG0 (a3 / and :op1 k :op2 k2) :ARG1 (a2 / activate-01 :ARG1 (p8 / pathway :name (n6 / name :op1 "Ras-MAPK")) :ARG1-of (e2 / elevate-01))) :ARG1-of (c2 / correspond-02)) :ARG1 (p / possible-01 :ARG1 (r / relevant-01 :ARG1 (a / associate-01 :ARG1 g2 :ARG2 (p3 / protein :name (n2 / name :op1 "Grb-2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593"))) :ARG2 (p5 / parallel :location (p2 / proliferate-01 :degree (h / hyper))) :ARG1-of (d / direct-02)) :condition (l / level :quant-of (p4 / protein :name (n3 / name :op1 "AJ")) :ARG1-of (r2 / reduce-01)))) # ::id pmid_1563_0473.234 # ::date 2015-03-30T02:00:28 # ::file pmid_1563_0473_234.txt # ::snt In stable epithelial (i.e., Madin-Darby canine kidney, or MDCK) cell lines, Snail has been shown to block cell cycle progression and promote motility and shape changes for invasion [47]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (s / show-01 :ARG1 (a2 / and :op1 (b / block-01 :ARG0 (p2 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1 (p3 / progress-01 :ARG1 (c2 / cycle-02 :ARG1 (c / cell)))) :op2 (p / promote-01 :ARG0 p2 :ARG1 (m2 / motility)) :op3 (s3 / shape-01 :ARG1 (c3 / change-01) :purpose (i / invade-01))) :location (c6 / cell-line :mod (e / epithelium) :ARG1-of (s2 / stable-03) :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :name (n2 / name :op1 "Madin-Darby" :op2 "canine" :op3 "kidney")))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "47")))) # ::id pmid_1563_0473.235 # ::date 2015-03-29T13:45:17 # ::file pmid_1563_0473_235.txt # ::snt While our in vivo studies are consistent with a role for Snail in motility and epithelial remodeling, they differ with respect to Snail's apparent proliferative effects. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (h / have-concession-91 :ARG1 (d2 / differ-01 :ARG0 "s" :ARG2 (a3 / affect-01 :ARG0 (p2 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (p / proliferate-01) :ARG1-of (a / appear-01))) :ARG2 (c / consistent-01 :ARG1 (s / study-01 :ARG0 (w / we) :manner (i / in-vivo)) :ARG2 (r / role :topic (a2 / and :op1 (m / motility) :op2 (r2 / remodel-01 :ARG1 (e2 / epithelium))) :purpose p2))) # ::id pmid_1563_0473.236 # ::date 2015-03-27T05:26:33 # ::file pmid_1563_0473_236.txt # ::snt A priori, this could be simply due to variations in the response of different cell types to Snail expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / infer-01 :ARG1 (p / possible-01 :ARG1 (c / cause-01 :ARG0 (v / vary-01 :ARG1 (r / respond-01 :ARG0 (c2 / cell :ARG1-of (t / type-03) :ARG1-of (d / differ-02)) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG1 (t2 / this) :ARG1-of (s / simple-02))) :mod (a / a-priori)) # ::id pmid_1563_0473.237 # ::date 2015-03-27T12:59:47 # ::file pmid_1563_0473_237.txt # ::snt Alternatively, these differences may be relevant to the benefit of using mouse models to reveal functions not always recapitulated in stable cell line models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 9, 2015 (p / possible-01 :manner (a / alternative) :ARG1 (r / relevant-01 :ARG1 (t / thing :ARG1-of (d / differ-02) :mod (t2 / this)) :ARG2 (b / benefit-01 :ARG0 (u / use-01 :ARG1 (m / model :mod (m2 / mouse)) :ARG2 (r2 / reveal-01 :ARG1 (f / function-01 :ARG1-of (r3 / recapitulate-01 :time (a2 / always :polarity "-") :location (m3 / model :mod (c / cell-line) :ARG1-of (s / stable-03))))))))) # ::id pmid_1563_0473.238 # ::date 2015-03-27T13:32:30 # ::file pmid_1563_0473_238.txt # ::snt Future studies should highlight the underlying reasons for these opposing results. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Apr 4, 2015 (r / recommend-01 :ARG1 (h / highlight-01 :ARG0 (s / study-01 :time (f / future)) :ARG1 (t / thing :ARG0-of (c / cause-01 :ARG1 (t2 / thing :ARG2-of (r2 / result-01) :mod (t3 / this) :ARG0-of (o / oppose-01))) :ARG0-of (u / underlie-01)))) # ::id pmid_1563_0473.239 # ::date 2015-03-27T13:50:09 # ::file pmid_1563_0473_239.txt # ::snt Irrespective of these differences, our in vivo studies do not stand alone, as there are many situations in which a down-regulation in AJ proteins correlate with enhanced proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (s / stand-01 :polarity "-" :ARG1 (s2 / study-01 :ARG0 (w / we) :manner (i / in-vivo)) :manner (a / alone) :ARG1-of (c / cause-01 :ARG0 (s3 / situation :quant (m / many) :mod (c2 / correlate-01 :ARG1 (d2 / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "AJ"))) :ARG2 (p2 / proliferate-01 :ARG1-of (e / enhance-01))))) :ARG1-of (r / regardless-91 :ARG2 (t / thing :ARG1-of (d / differ-02) :mod (t2 / this)))) # ::id pmid_1563_0473.240 # ::date 2015-03-27T14:45:01 # ::file pmid_1563_0473_240.txt # ::snt In fact, a myriad of diverse mechanisms have been implicated in activating epithelial proliferation upon down-regulation of AJ proteins [7,23,24,48]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (i / implicate-01 :ARG1 (m / mechanism :mod (d / diverse) :quant (m2 / myriad)) :ARG2 (a / activate-01 :ARG1 (p / proliferate-01 :ARG0 (e / epithelium)) :time (d2 / downregulate-01 :ARG1 (p2 / protein :name (n / name :op1 "AJ")))) :mod (i2 / in-fact) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 "7" :op2 "23" :op3 "24" :op4 "48"))))) # ::id pmid_1563_0473.241 # ::date 2015-03-27T15:16:41 # ::file pmid_1563_0473_241.txt # ::snt Sifting through these converging pathways is likely to be a difficult and painstaking process. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (l / likely-01 :ARG1 (p / process-02 :ARG1 (s / sift-01 :ARG1 (p3 / pathway :ARG0-of (c / converge-01) :mod (t / this))) :mod (d / difficult) :mod (p2 / painstaking))) # ::id pmid_1563_0473.242 # ::date 2015-03-27T15:45:36 # ::file pmid_1563_0473_242.txt # ::snt This said, by identifying the status of different players involved in specific cell types and at specific stages in development, our mechanistic understanding of how intercellular remodeling is linked to proliferation in epithelial morphogenesis should begin to surface in the future. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (r / recommend-01 :ARG1 (b / begin-01 :ARG1 (s / surface-01 :ARG1 (u / understand-01 :ARG0 (w / we) :ARG1 (l / link-01 :ARG1 (r2 / remodel-01 :mod (i / intercellular)) :ARG2 (p / proliferate-01 :ARG0 (m / morphogenesis :mod (e / epithelium))) :manner (a2 / amr-unknown)) :mod (m2 / mechanism)) :time (f / future)) :manner (i2 / identify-01 :ARG1 (s2 / status :poss (t / thing :ARG1-of (d / differ-02) :ARG1-of (i3 / involve-01 :ARG2 (c / cell :ARG2-of (t2 / type-03) :ARG1-of (s3 / specific-02)) :time (s4 / stage :ARG1-of s3 :subevent-of (d2 / develop-02))) :ARG0-of (p2 / play-08))))) :time (a3 / after :op1 (s5 / say-01 :ARG1 (t3 / this)))) # ::id pmid_1563_0473.243 # ::date 2015-03-28T11:07:10 # ::file pmid_1563_0473_243.txt # ::snt Elucidating the molecular mechanisms through which these networks converge is also a prerequisite for understanding how these processes go awry during tumorigenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (r / require-01 :ARG0 (u / understand-01 :ARG1 (g / go-08 :ARG1 (p / process-02 :mod (t / this)) :ARG2 (a / awry) :time (c / create-01 :ARG1 (t2 / tumor)) :manner (a2 / amr-unknown))) :ARG1 (e / elucidate-01 :ARG1 (m / mechanism :mod (m2 / molecule) :manner-of (c2 / converge-01 :ARG0 (n / network :mod (t3 / this))))) :mod (a3 / also)) # ::id pmid_1563_0473.244 # ::date 2015-03-28T11:07:50 # ::file pmid_1563_0473_244.txt # ::snt Materials and Methods # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 28, 2015 (a / and :op1 (m / material) :op2 (m2 / method)) # ::id pmid_1563_0473.245 # ::date 2015-03-28T11:43:16 # ::file pmid_1563_0473_245.txt # ::snt Reagents # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 28, 2015 (r / reagent) # ::id pmid_1563_0473.246 # ::date 2015-03-28T11:44:50 # ::file pmid_1563_0473_246.txt # ::snt Primary antibodies used were against: E-cadherin (M. Takeichi, Kyoto University, Japan); α-catenin, β-catenin, pMAPK, tubulin (Sigma, St. Louis, Missouri, United States), Ajuba (G. Longmore, Washington University, St. Louis, Missouri, United States); β4 integrin/CD104 (BD Pharmingen, San Diego, California, United States), laminin 5 (R. Burgeson, Harvard University, Cambridge, Massachusetts, United States), K5, K1, loricrin (Fuchs Lab), involucrin, fillagrin (Covance, Berkeley, California, United States), MAPK, pSMAD2 (Cell Signaling, Beverly, Massachusetts, United States); Grb-2 (Santa Cruz Biotech, Santa Cruz, California, United States); P-cadherin (Zymed Laboratories, South San Francisco, California, United States); HA (Roche Biochemicals), vimentin (Chemicon, Temecula, California, United States), Ki67 (Novo Castra, Newcastle Upon Tyne, United Kingdom), keratin 6 (P. Coulombe, John Hopkins University, Baltimore, Maryland, United States), cyclin D (Oncogene, San Diego, California, United States), and TGF-β2 (L. Gold, New York University, New York, New York, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 11, 2016 (u / use-01 :ARG1 (a / and :op1 (a2 / antibody :mod (p / primary) :ARG0-of (o / oppose-01 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin") :source (p3 / person :name (n2 / name :op1 "M." :op2 "Takeichi") :location (u2 / university :wiki "Kyoto_University" :name (n3 / name :op1 "Kyoto" :op2 "University") :location (c / country :wiki "Japan" :name (n4 / name :op1 "Japan")))) :xref (x15 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :op2 (a7 / antibody :mod p :ARG0-of (o2 / oppose-01 :ARG1 (a3 / and :op1 (p4 / protein :name (n5 / name :op1 "α-catenin") :xref (x17 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op2 (p5 / protein :name (n6 / name :op1 "β-catenin") :xref (x18 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op3 (e / enzyme :name (n7 / name :op1 "MAPK") :ARG1-of (p6 / phosphorylate-01) :xref (x20 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op4 (p7 / protein :name (n8 / name :op1 "tubulin") :xref (x16 / xref :value "UNIPROT:TBB4A_HUMAN" :prob "0.282")) :source (c2 / company :name (n9 / name :op1 "Sigma") :location (c3 / city :wiki "St._Louis" :name (n10 / name :op1 "St." :op2 "Louis") :location (s / state :wiki "Missouri" :name (n11 / name :op1 "Missouri") :location (c4 / country :wiki "United_States" :name (n12 / name :op1 "United" :op2 "States")))))))) :op3 (a8 / antibody :mod p :ARG0-of (o3 / oppose-01 :ARG1 (p8 / protein :name (n13 / name :op1 "Ajuba") :source (p9 / person :name (n14 / name :op1 "G." :op2 "Longmore") :location (u3 / university :wiki "Washington_University_in_St._Louis" :name (n15 / name :op1 "Washington" :op2 "University") :location c3)) :xref (x19 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")))) :op4 (a9 / antibody :mod p :ARG0-of (o4 / oppose-01 :ARG1 (p10 / protein :name (n16 / name :op1 "β4-integrin/CD104") :source (c5 / company :name (n17 / name :op1 "BD" :op2 "Pharmingen") :location (c6 / city :wiki "San_Diego" :name (n18 / name :op1 "San" :op2 "Diego") :location (s2 / state :wiki "California" :name (n19 / name :op1 "California") :location c4)))))) :op5 (a10 / antibody :mod p :ARG0-of (o5 / oppose-01 :ARG1 (p11 / protein :name (n20 / name :op1 "laminin-5") :source (p12 / person :name (n21 / name :op1 "R." :op2 "Burgeson") :location (u4 / university :wiki "Harvard_University" :name (n22 / name :op1 "Harvard" :op2 "University") :location (c7 / city :wiki "Cambridge,_Massachusetts" :name (n23 / name :op1 "Cambridge") :location (s3 / state :wiki "Massachusetts" :name (n24 / name :op1 "Massachusetts") :location c4)))) :xref (x / xref :value "UNIPROT:LM-111_HUMAN_COMPLEX" :prob "0.33")))) :op6 (a11 / antibody :mod p :ARG0-of (o6 / oppose-01 :ARG1 (a4 / and :op1 (p13 / protein :name (n25 / name :op1 "K5") :xref (x1 / xref :value "UNIPROT:K2C5_HUMAN" :prob "1.002")) :op2 (p14 / protein :name (n26 / name :op1 "K1") :xref (x2 / xref :value "UNIPROT:K2C1_HUMAN" :prob "1.002")) :op3 (p15 / protein :name (n27 / name :op1 "loricrin") :xref (x3 / xref :value "UNIPROT:LORI_HUMAN" :prob "0.702")) :location (r / research-institute :name (n28 / name :op1 "Fuchs" :op2 "Lab"))))) :op7 (a12 / antibody :mod p :ARG0-of (o7 / oppose-01 :ARG1 (a5 / and :op1 (p16 / protein :name (n29 / name :op1 "involucrin") :xref (x4 / xref :value "UNIPROT:INVO_HUMAN" :prob "0.702")) :op2 (p17 / protein :name (n30 / name :op1 "fillagrin") :xref (x5 / xref :value "UNIPROT:FILA_HUMAN" :prob "0.362")) :source (c8 / company :wiki "Covance" :name (n31 / name :op1 "Covance") :location (c9 / city :wiki "Berkeley,_California" :name (n32 / name :op1 "Berkeley") :location s2))))) :op8 (a13 / antibody :mod p :ARG0-of (o8 / oppose-01 :ARG1 (a6 / and :op1 e :op2 (p18 / protein :name (n33 / name :op1 "SMAD2") :ARG1-of p6 :xref (x6 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :source (c10 / company :name (n34 / name :op1 "Cell" :op2 "Signaling") :location (c11 / city :wiki "Beverly,_Massachusetts" :name (n35 / name :op1 "Beverly") :location s3))))) :op9 (a14 / antibody :mod p :ARG0-of (o9 / oppose-01 :ARG1 (p19 / protein :name (n36 / name :op1 "Grb-2") :source (c12 / company :name (n37 / name :op1 "Santa" :op2 "Cruz" :op3 "Biotech") :location (c13 / city :wiki "Santa_Cruz,_California" :name (n38 / name :op1 "Santa" :op2 "Cruz") :location s2)) :xref (x7 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")))) :op10 (a15 / antibody :mod p :ARG0-of (o10 / oppose-01 :ARG1 (p20 / protein :name (n39 / name :op1 "P-cadherin") :source (c14 / company :name (n40 / name :op1 "Zymed" :op2 "Laboratories") :location (c15 / city :wiki "South_San_Francisco,_California" :name (n41 / name :op1 "South" :op2 "San" :op3 "Francisco") :location s2)) :xref (x12 / xref :value "UNIPROT:CADH3_HUMAN" :prob "1.002")))) :op11 (a16 / antibody :mod p :ARG0-of (o11 / oppose-01 :ARG1 (p21 / protein :name (n42 / name :op1 "HA") :source (c16 / company :name (n43 / name :op1 "Roche" :op2 "Biochemicals")) :xref (x11 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002")))) :op12 (a17 / antibody :mod p :ARG0-of (o12 / oppose-01 :ARG1 (p22 / protein :name (n44 / name :op1 "vimentin") :source (c17 / company :name (n45 / name :op1 "Chemicon") :location (c18 / city :wiki "Temecula,_California" :name (n46 / name :op1 "Temecula") :location s2)) :xref (x14 / xref :value "UNIPROT:VIME_HUMAN" :prob "0.702")))) :op13 (a18 / antibody :mod p :ARG0-of (o13 / oppose-01 :ARG1 (p23 / protein :name (n47 / name :op1 "Ki67") :source (c19 / company :name (n48 / name :op1 "Novo" :op2 "Castra") :location (c20 / city :wiki "Newcastle_upon_Tyne" :name (n49 / name :op1 "Newcastle" :op2 "Upon" :op3 "Tyne") :location (c21 / country :wiki "United_Kingdom" :name (n50 / name :op1 "United" :op2 "Kingdom")))) :xref (x13 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653")))) :op14 (a19 / antibody :mod p :ARG0-of (o14 / oppose-01 :ARG1 (p24 / protein :name (n51 / name :op1 "keratin-6") :source (p25 / person :name (n52 / name :op1 "P." :op2 "Coulombe") :location (u5 / university :wiki "Johns_Hopkins_University" :name (n53 / name :op1 "John" :op2 "Hopkins" :op3 "University") :location (c22 / city :wiki "Baltimore" :name (n54 / name :op1 "Baltimore") :location (s4 / state :wiki "Maryland" :name (n55 / name :op1 "Maryland") :location c4)))) :xref (x8 / xref :value "UNIPROT:K1C16_HUMAN" :prob "0.362")))) :op15 (a20 / antibody :mod p :ARG0-of (o15 / oppose-01 :ARG1 (p26 / protein :name (n56 / name :op1 "cyclin-D") :source (c23 / company :name (n57 / name :op1 "Oncogene") :location c6) :xref (x10 / xref :value "UNIPROT:CCNY_HUMAN" :prob "0.342")))) :op16 (a21 / antibody :mod p :ARG0-of (o16 / oppose-01 :ARG1 (p27 / protein :name (n58 / name :op1 "TGF-β2") :source (p28 / person :name (n59 / name :op1 "L." :op2 "Gold") :location (u6 / university :wiki "New_York_University" :name (n60 / name :op1 "New" :op2 "York" :op3 "University") :location (c24 / city :wiki "New_York" :name (n61 / name :op1 "New" :op2 "York") :location (s5 / state :name n61 :location c4)))) :xref (x9 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))))) # ::id pmid_1563_0473.247 # ::date 2015-03-28T15:44:45 # ::file pmid_1563_0473_247.txt # ::snt FITC-, Texas Red-, or HRP-conjugated secondary antibodies were from Jackson ImmunoResearch (West Grove, Pennsylvania, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / antibody :mod (s / secondary) :ARG1-of (c / conjugate-02 :ARG2 (o / or :op1 (p / product :name (n / name :op1 "FITC")) :op2 (p2 / product :name (n2 / name :op1 "Texas" :op2 "Red")) :op3 (e / enzyme :name (n3 / name :op1 "HRP") :xref (x / xref :value "UNIPROT:UBP6_HUMAN" :prob "0.262")))) :source (c2 / company :name (n4 / name :op1 "Jackson" :op2 "ImmunoResearch") :location (c3 / city :name (n5 / name :op1 "West" :op2 "Grove") :location (s2 / state :wiki "Pennsylvania" :name (n6 / name :op1 "Pennsylvania") :location (c4 / country :wiki "United_States" :name (n7 / name :op1 "United" :op2 "States")))))) # ::id pmid_1563_0473.248 # ::date 2015-03-28T16:06:14 # ::file pmid_1563_0473_248.txt # ::snt Biotinylated secondary antibodies were from Vector Labs (Burlingame, California, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 11, 2016 (a / antibody :mod (s / secondary) :ARG1-of (b / biotinylate-01) :source (c / company :name (n / name :op1 "Vector" :op2 "Labs") :location (c2 / city :wiki "Burlingame,_California" :name (n2 / name :op1 "Burlingame") :location (s2 / state :wiki "California" :name (n3 / name :op1 "California") :location (c3 / country :wiki "United_States" :name (n4 / name :op1 "United" :op2 "States")))))) # ::id pmid_1563_0473.249 # ::date 2015-03-28T16:19:15 # ::file pmid_1563_0473_249.txt # ::snt Dilutions were according to the manufacturer's recommendation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 15, 2015 (c / conform-01 :ARG1 (d / dilute-01) :ARG2 (r / recommend-01 :ARG0 (c2 / company :ARG0-of (m / manufacture-01)) :ARG4 d)) # ::id pmid_1563_0473.250 # ::date 2015-03-28T16:26:28 # ::file pmid_1563_0473_250.txt # ::snt The Snail antibody was generated in Guinea pigs by inoculating them with the N-terminal sequence of murine Snail fused to GST (Covance, Princeton, New Jersey, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 11, 2016 (g / generate-01 :ARG1 (a / antibody :ARG0-of (c4 / counter-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :location (o2 / organism :name (n2 / name :op1 "Guinea" :op2 "pig")) :manner (i / inoculate-01 :ARG1 o2 :ARG3 (p2 / protein-segment :name (n3 / name :op1 "N" :op2 "terminus") :part-of (p3 / protein :name (n4 / name :op1 "Snail") :mod (m / mouse) :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG1-of (f / fuse-01 :ARG3 (e / enzyme :name (n6 / name :op1 "GST") :source (c / company :wiki "Covance" :name (n7 / name :op1 "Covance") :location (c2 / city :wiki "Princeton,_New_Jersey" :name (n8 / name :op1 "Princeton") :location (s / state :wiki "New_Jersey" :name (n9 / name :op1 "New" :op2 "Jersey") :location (c3 / country :wiki "United_States" :name (n10 / name :op1 "United" :op2 "States"))))) :xref (x2 / xref :value "UNIPROT:SO6A1_HUMAN" :prob "1.002")))))) # ::id pmid_1563_0473.251 # ::date 2015-03-29T08:20:56 # ::file pmid_1563_0473_251.txt # ::snt Recombinant human TGF-β2 was purchased from R&D (Minneapolis, Minnesota, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (p / purchase-01 :ARG1 (p2 / protein :name (n / name :op1 "TGF-β2") :mod (h / human) :ARG3-of (r / recombine-01) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG2 (c / company :name (n2 / name :op1 "R&D") :location (c2 / city :wiki "Minneapolis" :name (n3 / name :op1 "Minneapolis") :location (s / state :wiki "Minnesota" :name (n4 / name :op1 "Minnesota") :location (c3 / country :wiki "United_States" :name (n5 / name :op1 "United" :op2 "States")))))) # ::id pmid_1563_0473.252 # ::date 2015-03-29T08:36:13 # ::file pmid_1563_0473_252.txt # ::snt Heat inactivated TGF-β2 was generated by heating the recombinant protein at 100 °C for 10 min. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (g / generate-01 :ARG1 (p / protein :name (n / name :op1 "TGF-β2") :ARG1-of (a / activate-01 :polarity "-" :ARG0 (h / heat-01)) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :manner (h2 / heat-01 :ARG1 (p2 / protein :ARG3-of (r / recombine-01)) :destination (t / temperature-quantity :quant "100" :scale (c / celsius)) :duration (t2 / temporal-quantity :quant "10" :unit (m / minute)))) # ::id pmid_1563_0473.253 # ::date 2015-03-29T09:03:55 # ::file pmid_1563_0473_253.txt # ::snt Mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (m / mouse) # ::id pmid_1563_0473.254 # ::date 2015-03-29T09:05:28 # ::file pmid_1563_0473_254.txt # ::snt The K14-Snail Tg mouse was generated by digesting the pcDNA3-mm Snail-HA plasmid (G. de Herreros, Universitat Pompeu, Fabra, Barcelona, Spain) with BamHI and NotI and subcloned into the K14 vector [49]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (g / generate-01 :ARG1 (m / mouse :mod (t / transgenic) :mod (p2 / protein :name (n2 / name :op1 "Snail") :ARG1-of (m5 / mutate-01 :value "K14") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :manner (d / digest-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "plasmid") :mod (m3 / macro-molecular-complex :part (s3 / small-molecule :name (n4 / name :op1 "pcDNA3-mm")) :part p2 :part (p3 / protein :name (n5 / name :op1 "HA") :xref (x2 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :source (p4 / person :name (n6 / name :op1 "G." :op2 "de" :op3 "Herreros") :location (u / university :wiki "Pompeu_Fabra_University" :name (n7 / name :op1 "Universitat" :op2 "Pompeu" :op3 "Fabra") :location (c / city :wiki "Barcelona" :name (n8 / name :op1 "Barcelona") :location (c2 / country :wiki "Spain" :name (n9 / name :op1 "Spain")))))) :instrument (a2 / and :op1 (e / enzyme :name (n10 / name :op1 "BamHI") :xref (x3 / xref :value "UNIPROT:BAMBI_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n11 / name :op1 "NotI") :xref (x / xref :value "UNIPROT:ALG3_HUMAN" :prob "0.202"))))) :op2 (s2 / subclone-01 :ARG1 m :ARG3 (v / vector :mod (p / protein))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "49")))) # ::id pmid_1563_0473.255 # ::date 2015-03-29T10:28:13 # ::file pmid_1563_0473_255.txt # ::snt The linearized construct was injected into the nucleus of embryos from CD1 mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (i / inject-01 :ARG1 (c / construct :ARG1-of (l / linearize-00)) :ARG2 (n / nucleus :part-of (e / embryo :source (o / organism :name (n2 / name :op1 "CD1" :op2 "mouse"))) :xref (x / xref :value "GO:0005634" :prob "0.8"))) # ::id pmid_1563_0473.256 # ::date 2015-03-29T10:52:51 # ::file pmid_1563_0473_256.txt # ::snt The K14-Smad 2 Tg mouse was reported in Ito et al., 2001. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (r / report-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Ito")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2001")) :ARG1 (m / mouse :mod (t / transgenic) :mod (m2 / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "K14") :xref (x / xref :value "UNIPROT:K1C14_HUMAN" :prob "1.002")) :part (p5 / protein :name (n3 / name :op1 "SMAD2") :xref (x1 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003"))))) # ::id pmid_1563_0473.257 # ::date 2015-03-29T11:11:44 # ::file pmid_1563_0473_257.txt # ::snt The TGF-β2 knockout (KO) mouse was described in [34]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (d / describe-01 :ARG0 (p / publication-91 :ARG1-of (c / cite-01 :ARG2 "34")) :ARG1 (m / mouse :location-of (k / knock-out-03 :ARG1 (g / gene :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))))) # ::id pmid_1563_0473.258 # ::date 2015-03-29T11:32:51 # ::file pmid_1563_0473_258.txt # ::snt The shh KO mouse [38] and TOPGal mouse [20] have previously been reported. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (r / report-01 :ARG1 (a / and :op1 (m / mouse :location-of (k / knock-out-03 :ARG1 (g / gene :name (n / name :op1 "shh") :xref (x / xref :value "UNIPROT:SHH_HUMAN" :prob "0.603"))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "38")))) :op2 (m4 / mouse :name (n3 / name :op1 "TOPGal") :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "20"))))) :time (p3 / previous)) # ::id pmid_1563_0473.259 # ::date 2015-03-29T11:33:10 # ::file pmid_1563_0473_259.txt # ::snt Western blot and immunoprecipitation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (a / and :op1 (i2 / immunoblot-01) :op2 (i / immunoprecipitate-01)) # ::id pmid_1563_0473.260 # ::date 2015-03-29T11:57:59 # ::file pmid_1563_0473_260.txt # ::snt Protein extracts from primary keratinocytes were generated either by lysing cells in lysis buffer (1% NP-40, 1% sodium deoxycholate, 20 mM Tris-Cl [pH 7.4], 140 mM NaCl containing 1 mM sodium vanadate, 2 mM phenylmethylsulfonyl fluoride, and protease inhibitors) or directly in Laemmli bβuffer and boiled. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (g / generate-01 :ARG1 (e / extract-01 :ARG1 (p / protein) :ARG2 (k / keratinocyte :mod (p2 / primary))) :ARG2 (o / or :op1 (l / lyse-01 :ARG1 (c / cell) :location (b / buffer :ARG2-of (l2 / lyse-01) :consist-of (a2 / and :op1 (s / small-molecule :name (n / name :op1 "NP-40") :quant (p3 / percentage-entity :value "1") :xref (x5 / xref :value "PUBCHEM:24775" :prob "13.209696")) :op2 (s2 / small-molecule :name (n2 / name :op1 "sodium" :op2 "deoxycholate") :quant p3 :xref (x2 / xref :value "PUBCHEM:23668196" :prob "11.799748")) :op3 (s5 / small-molecule :name (n3 / name :op1 "Tris-Cl") :quant (c2 / concentration-quantity :quant "20" :unit (m4 / millimolar)) :mod (a3 / acidity-quantity :quant "7.4" :scale (p4 / ph))) :op4 (s3 / small-molecule :name (n4 / name :op1 "NaCl") :quant (c3 / concentration-quantity :quant "140" :unit m4) :ARG0-of (c4 / contain-01 :ARG1 (a4 / and :op1 (s6 / small-molecule :name (n5 / name :op1 "sodium" :op2 "vanadate") :quant (c5 / concentration-quantity :quant "1" :unit m4) :xref (x3 / xref :value "PUBCHEM:61671" :prob "8.721997")) :op2 (s4 / small-molecule :name (n6 / name :op1 "phenylmethylsulfonyl" :op2 "fluoride") :quant (c6 / concentration-quantity :quant "2" :unit m4) :xref (x4 / xref :value "PUBCHEM:4784" :prob "13.388928")) :op3 (m8 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "protease") :xref (x / xref :value "UNIPROT:VP113_HUMAN" :prob "0.702")))))) :xref (x1 / xref :value "PUBCHEM:5234" :prob "16.963549"))))) :op2 (l3 / lyse-01 :ARG1 c :location (t / thing :name (n8 / name :op1 "Laemmli" :op2 "buffer")) :ARG1-of (d / direct-02)))) :op2 (b2 / boil-01 :ARG1 e)) # ::id pmid_1563_0473.261 # ::date 2015-03-29T13:50:27 # ::file pmid_1563_0473_261.txt # ::snt For skin tissue: Frozen tissue was pulverized in a liquid nitrogen-cooled Gevebesmascher and the powder scraped into a chilled microcentrifuge tube. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (p / pulverize-01 :ARG1 (t / tissue :ARG1-of (f / freeze-01)) :location (s3 / small-molecule :name (n / name :op1 "Gevebesmascher") :ARG1-of (c / cool-01 :instrument (n2 / nitrogen)) :mod (l / liquid))) :op2 (s / scrape-02 :ARG1 (p2 / powder) :ARG3 (t2 / tube :mod (m2 / microcentrifuge) :ARG1-of (c2 / chill-01))) :topic (t3 / tissue :part-of (s2 / skin))) # ::id pmid_1563_0473.262 # ::date 2015-03-29T14:24:10 # ::file pmid_1563_0473_262.txt # ::snt RIPA buffer (1% Triton X-100 in PBS with 10 mM EDTA, 150 mN NaCl, 1% sodium deoxycholate, and 0.1% SDS) and protease inhibitors or Laemmli buffer was added. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / add-02 :ARG1 (a2 / and :op1 (t / thing :name (n / name :op1 "RIPA" :op2 "buffer") :consist-of (a3 / and :op1 (i / include-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "Triton" :op2 "X-100") :quant (p / percentage-entity :value "1") :xref (x6 / xref :value "PUBCHEM:5590" :prob "13.502792")) :ARG2 (s5 / small-molecule :name (n3 / name :op1 "PBS") :xref (x3 / xref :value "PUBCHEM:14819" :prob "11.035435")) :accompanier (s4 / small-molecule :name (n4 / name :op1 "EDTA") :quant (c / concentration-quantity :quant "10" :unit (m5 / millimolar)) :xref (x4 / xref :value "PUBCHEM:6049" :prob "14.194091"))) :op2 (m6 / molecular-physical-entity :name (n5 / name :op1 "NaCl") :quant (c2 / concentration-quantity :quant "150" :unit m5) :xref (x5 / xref :value "PUBCHEM:5234" :prob "16.963549")) :op3 (s3 / small-molecule :name (n6 / name :op1 "sodium" :op2 "deoxycholate") :quant p :xref (x1 / xref :value "PUBCHEM:23668196" :prob "11.799748")) :op4 (s2 / small-molecule :name (n7 / name :op1 "SDS") :quant (p2 / percentage-entity :value "0.1") :xref (x2 / xref :value "PUBCHEM:3423265" :prob "17.656696")))) :op2 (o / or :op1 (m9 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e / enzyme :name (n8 / name :op1 "protease") :xref (x / xref :value "UNIPROT:VP113_HUMAN" :prob "0.702")))) :op2 (t2 / thing :name (n9 / name :op1 "Laemmli" :op2 "buffer"))))) # ::id pmid_1563_0473.263 # ::date 2015-03-29T14:56:33 # ::file pmid_1563_0473_263.txt # ::snt The cell suspension was sonicated three times for 15 s and centrifuged at 14,000 rpm at 4 °C. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (a / and :op1 (s / sonicate-00 :frequency "3" :ARG1 (s2 / suspend-02 :ARG1 (c / cell)) :duration (t / temporal-quantity :quant "15" :unit (s3 / second))) :op2 (c2 / centrifuge-00 :ARG1 s2 :ARG2 (t2 / temperature-quantity :quant "4" :scale (c3 / celsius)) :frequency (s4 / speed-quantity :quant "14000" :unit (r / rotation-per-minute)))) # ::id pmid_1563_0473.264 # ::date 2015-03-27T19:20:18 # ::file pmid_1563_0473_264.txt # ::snt The supernatant was separated from the pellet and used in the experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 28, 2015 (a / and :op1 (s / separate-01 :ARG1 (s2 / supernatant) :ARG2 (p / pellet)) :op2 (u / use-01 :ARG1 s2 :ARG2 (e / experiment-01))) # ::id pmid_1563_0473.265 # ::date 2015-03-27T19:20:35 # ::file pmid_1563_0473_265.txt # ::snt Extracts subjected to immunoprecipitation were precleared with Protein G Sepharose (Amersham, Piscataway, New York, United States) and incubated with antibody with rocking overnight at 4 °C. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (a / and :op1 (p / preclear-00 :ARG1 (e / extract-01 :ARG1-of (s2 / subject-01 :ARG2 (i / immunoprecipitate-01))) :ARG2 (p3 / product :name (n6 / name :op1 "Protein" :op2 "G" :op3 "Sepharose") :source (c3 / company :name (n5 / name :op1 "Amersham") :location (c5 / city :name (n4 / name :op1 "Piscataway") :location (s / state :wiki "New_York" :name (n2 / name :op1 "New" :op2 "York") :location (c2 / country :wiki "United_States" :name (n3 / name :op1 "United" :op2 "States"))))))) :op2 (i2 / incubate-01 :ARG1 e :ARG2 (a2 / and :op1 (a3 / antibody) :op2 (r / rock-01 :ARG1 e)) :time (o / overnight) :mod (t / temperature-quantity :quant "4" :scale (c4 / celsius)))) # ::id pmid_1563_0473.266 # ::date 2015-03-27T19:21:06 # ::file pmid_1563_0473_266.txt # ::snt Protein G Sepharose was added and samples were incubated for 1 h at 4 °C with rocking. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (a2 / add-02 :ARG1 (p2 / product :wiki "-" :name (n2 / name :op1 "Protein" :op2 "G" :op3 "Sepharose"))) :op2 (i / incubate-01 :ARG1 (t3 / thing :ARG1-of (s / sample-01)) :ARG2 (r / rock-01 :ARG1 t3) :duration (t / temporal-quantity :quant "1" :unit (h / hour)) :mod (t2 / temperature-quantity :quant "4" :scale (c / celsius)))) # ::id pmid_1563_0473.267 # ::date 2015-03-27T19:21:23 # ::file pmid_1563_0473_267.txt # ::snt Samples were washed three times for 5 min each in lysis buffer, and the Protein G Sepharose-antibody-antigen pellet was resuspended in Laemmli buffer and boiled for 10 min. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (w / wash-01 :frequency "3" :ARG1 (t3 / thing :mod (e / each) :ARG1-of (s / sample-01)) :ARG2 (b / buffer :ARG2-of (l / lyse-01)) :duration (t / temporal-quantity :quant "5" :unit (m / minute))) :op2 (a4 / and :op1 (s2 / suspend-02 :ARG1 (p / pellet :mod (a2 / antigen) :mod (a3 / antibody) :mod (p3 / product :name (n4 / name :op1 "Protein" :op2 "G" :op3 "Sepharose"))) :location (b2 / buffer :name (n2 / name :op1 "Laemmli")) :mod (a5 / again)) :op2 (b3 / boil-01 :ARG1 p :duration (t2 / temporal-quantity :quant "10" :unit (m2 / minute))))) # ::id pmid_1563_0473.268 # ::date 2015-03-27T19:21:44 # ::file pmid_1563_0473_268.txt # ::snt Samples were run on SDS-PAGE and transferred to nitrocellulose membrane (Schleicher and Schuell Bioscience, Keene, New Hampshire, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (r / run-01 :ARG1 (t2 / thing :ARG1-of (s2 / sample-01)) :manner (t3 / thing :name (n7 / name :op1 "SDS-PAGE"))) :op2 (t / transfer-01 :ARG1 t2 :ARG2 (m / membrane :mod (n4 / nitrocellulose) :source (c2 / company :name (n5 / name :op1 "Schleicher" :op2 "and" :op3 "Schuell" :op4 "Bioscience") :location (c4 / city :name (n6 / name :op1 "Keene") :location (s / state :wiki "New_Hampshire" :name (n / name :op1 "New" :op2 "Hampshire") :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States"))))) :xref (x / xref :value "GO:0016020" :prob "0.8")))) # ::id pmid_1563_0473.269 # ::date 2015-03-27T19:22:09 # ::file pmid_1563_0473_269.txt # ::snt Western blot signals were developed using the enhanced chemiluminescence kit from Amersham # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (d / develop-02 :ARG1 (s / signal-07 :ARG0 (i / immunoblot-01)) :ARG2-of (u / use-01 :ARG1 (k / kit :ARG1-of (e / enhance-01) :mod (c / chemiluminescence) :source (c2 / company :wiki "Amersham_plc" :name (n2 / name :op1 "Amersham"))))) # ::id pmid_1563_0473.270 # ::date 2015-03-27T19:22:25 # ::file pmid_1563_0473_270.txt # ::snt Cell culture # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (c / culture :mod (c2 / cell)) # ::id pmid_1563_0473.271 # ::date 2015-03-27T19:22:43 # ::file pmid_1563_0473_271.txt # ::snt Primary keratinocytes were culture in low-calcium medium as previously described [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 23, 2015 (c / culture-01 :ARG1 (k / keratinocyte :mod (p / primary)) :location (m / medium :ARG1-of (l / low-04 :ARG2 (c2 / calcium))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "4")) :time (p2 / previous))) # ::id pmid_1563_0473.272 # ::date 2015-03-27T19:22:59 # ::file pmid_1563_0473_272.txt # ::snt Transient transfections were carried out with FuGENE6 reagent (Roche, Indianapolis, Indiana, United States) according to the manufacturer's protocol. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (c4 / carry-out-03 :ARG1 (t / transfect-01 :ARG1-of (t2 / transient-02)) :ARG1-of (s2 / say-01 :ARG0 (p / protocol :poss "c5")) :instrument (r / reagent :name (n5 / name :op1 "FuGENE6") :source (c5 / company :name (n4 / name :op1 "Roche") :location (c / city :wiki "Indianapolis" :name (n / name :op1 "Indianapolis") :location (s / state :wiki "Indiana" :name (n2 / name :op1 "Indiana") :location (c2 / country :wiki "United_States" :name (n3 / name :op1 "United" :op2 "States")))) :ARG0-of (m / manufacture-01)))) # ::id pmid_1563_0473.273 # ::date 2015-03-27T19:23:25 # ::file pmid_1563_0473_273.txt # ::snt Measurement of β-galactosidase or luciferase levels in promoter activity studies were carried out with the Galacto-Lite assay kit (TROPIX, Bedford, Massachusetts, United States) and the Dual luciferase (Promega, Madison, Wisconsin, United States), respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c6 / carry-out-03 :ARG1 (m / measure-01 :ARG1 (o / or :op1 (l3 / level :quant-of (e / enzyme :name (n4 / name :op1 "β-galactosidase") :xref (x / xref :value "UNIPROT:GALK1_HUMAN" :prob "0.302"))) :op2 (l / level :quant-of (l2 / luciferase))) :subevent-of (s3 / study-01 :ARG1 (a2 / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (p / promote-01))))) :mod (r / respective) :instrument (a3 / and :op1 (p3 / product :name (n7 / name :op1 "Galacto-Lite") :mod (k2 / kit :instrument-of (a / assay-01)) :source (c3 / company :name (n5 / name :op1 "TROPIX") :location (c4 / city :name (n6 / name :op1 "Bedford") :location (s / state :wiki "Massachusetts" :name (n / name :op1 "Massachusetts") :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States")))))) :op2 (p2 / product :name (n8 / name :op1 "Dual" :op2 "luciferase") :source (c2 / company :name (n9 / name :op1 "Promega") :location (c5 / city :name (n10 / name :op1 "Madison") :location (s2 / state :wiki "Wisconsin" :name (n3 / name :op1 "Wisconsin") :location c)))))) # ::id pmid_1563_0473.274 # ::date 2015-03-27T19:23:58 # ::file pmid_1563_0473_274.txt # ::snt Runella luciferase was cotransfected into cells to correct for transfection efficiency. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (c / cotransfect-01 :ARG1 (c2 / cell) :ARG2 (l / luciferase :name (n / name :op1 "Runella")) :ARG0-of (c3 / correct-01 :ARG1 (e / efficient-01 :ARG1 (t / transfect-01)))) # ::id pmid_1563_0473.275 # ::date 2015-03-27T19:24:14 # ::file pmid_1563_0473_275.txt # ::snt Experiments were done in triplicate and repeated at least three times. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (e2 / experiment-01 :quant (t / triplicate) :ARG1-of (r / repeat-01 :frequency "3" :mod (a / at-least))) # ::id pmid_1563_0473.276 # ::date 2015-03-28T04:57:30 # ::file pmid_1563_0473_276.txt # ::snt Measurements were done on a luminometer (MGM Instruments, Hamden, Connecticut, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (m2 / measure-01 :instrument (l / luminometer :source (c2 / company :name (n3 / name :op1 "MGM" :op2 "Instruments") :location (c3 / city :name (n4 / name :op1 "Hamden") :location (s / state :wiki "Connecticut" :name (n / name :op1 "Connecticut") :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States"))))))) # ::id pmid_1563_0473.277 # ::date 2015-03-28T11:38:29 # ::file pmid_1563_0473_277.txt # ::snt For experiments measuring phosphorylation of MAPK, keratinocytes were serum starved for 3 h prior to harvesting of cells by incubation in medium lacking serum. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (h / have-purpose-91 :ARG1 (s / starve-01 :ARG1 (k / keratinocyte) :ARG2 (s2 / serum) :duration (t / temporal-quantity :quant "3" :unit (h2 / hour)) :time (p3 / prior :op1 (h3 / harvest-01 :ARG1 (c / cell))) :manner (i / incubate-01 :ARG1 k :location (m / medium :ARG0-of (l / lack-01 :ARG1 s2)))) :ARG2 (m2 / measure-01 :ARG0 (e / experiment-01) :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))))) # ::id pmid_1563_0473.278 # ::date 2015-03-28T14:25:45 # ::file pmid_1563_0473_278.txt # ::snt Treatment of cells with Wnt- and noggin-conditioned medium was previously described [4]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 2, 2015 (t / treat-04 :ARG1 (c / cell) :ARG2 (m / medium :ARG1-of (c2 / condition-01 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "Wnt") :xref (x1 / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")) :op2 (p2 / protein :name (n2 / name :op1 "noggin") :xref (x / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702"))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "4")) :time (p3 / previous))) # ::id pmid_1563_0473.279 # ::date 2015-03-28T14:38:17 # ::file pmid_1563_0473_279.txt # ::snt Constructs # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 28, 2015 (c / construct-01) # ::id pmid_1563_0473.280 # ::date 2015-03-28T14:39:39 # ::file pmid_1563_0473_280.txt # ::snt The 2.2-kb murine Snail promoter was generated by PCR using a forward primer with an XbaI linker sequence, 5′-TCTAGAATTGTTTGCTGCTGTATGGTCTTC-3′, along with a reverse primer with a BglII linker sequence, 5′-AGATCTGTTGGCCAGAGCGACCTAG-GTAG-3′, and mouse genomic DNA as a template. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (g / generate-01 :ARG0 (r2 / react-01 :ARG0 (p / polymerase) :ARG1-of (c / chain-01)) :ARG1 (m2 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (g2 / gene :name (n2 / name :op1 "Snail") :quant (d / distance-quantity :quant "2.2" :unit (k / kilo-base-pair)) :mod (o / organism :name (n7 / name :op1 "Murinae")) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG2-of (u / use-01 :ARG1 (a / and :op1 (p3 / primer :value "5′-TCTAGAATTGTTTGCTGCTGTATGGTCTTC-3′" :ARG1-of (f / forward-01) :part (p5 / protein-segment :name (n8 / name :op1 "XbaI") :ARG0-of (l / link-01))) :op2 (p4 / primer :value "5′-AGATCTGTTGGCCAGAGCGACCTAGGTAG-3′" :ARG1-of (r / reverse-01) :part (p6 / protein-segment :name (n3 / name :op1 "BglII") :ARG0-of (l2 / link-01))) :op3 (t / template :mod (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA") :mod (g3 / genome) :mod (m4 / mouse)))))) # ::id pmid_1563_0473.281 # ::date 2015-03-28T16:07:59 # ::file pmid_1563_0473_281.txt # ::snt The PCR product was purified with the Gel Extraction Kit (Qiagen, Valencia, California, United States) and ligated into pCRII-TOPO TA vector (Invitrogen, Carlsbad, California, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (p / purify-01 :ARG1 (r / react-01 :ARG0 (p5 / polymerase) :ARG1-of (c6 / chain-01)) :instrument (p3 / product :name (n4 / name :op1 "Gel" :op2 "Extraction" :op3 "Kit") :source (c2 / company :name (n5 / name :op1 "Qiagen") :location (c3 / city :name (n6 / name :op1 "Valencia") :location (s / state :wiki "California" :name (n / name :op1 "California") :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States"))))))) :op2 (l / ligate-01 :ARG1 (p2 / product) :ARG2 (p4 / product :name (n7 / name :op1 "pCRII-TOPO" :op2 "TA") :mod (v / vector) :source (c4 / company :name (n8 / name :op1 "Invitrogen") :location (c5 / city :name (n9 / name :op1 "Carlsbad") :location s))))) # ::id pmid_1563_0473.282 # ::date 2015-03-29T03:52:29 # ::file pmid_1563_0473_282.txt # ::snt The promoter was verified by sequencing and digested with XbaI and BglII and subcloned into the pβ-gal BASIC vector (BD Biosciences Clontech, Palo Alto, California, United States). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (v / verify-01 :ARG1 (m / molecular-physical-entity :ARG0-of (p / promote-01)) :manner (s2 / sequence-01 :ARG1 m)) :op2 (d / digest-01 :ARG1 m :instrument (a2 / and :op1 (p2 / protein-segment :name (n3 / name :op1 "XbaI")) :op2 (p3 / protein-segment :name (n4 / name :op1 "BglII")))) :op3 (s3 / subclone-01 :ARG1 m :ARG3 (p4 / product :name (n5 / name :op1 "pβ-gal" :op2 "BASIC") :mod (v2 / vector) :source (c2 / company :name (n6 / name :op1 "BD" :op2 "Biosciences" :op3 "Clontech") :location (c3 / city :name (n7 / name :op1 "Palo" :op2 "Alto") :location (s / state :wiki "California" :name (n / name :op1 "California") :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States")))))))) # ::id pmid_1563_0473.283 # ::date 2015-03-29T04:18:52 # ::file pmid_1563_0473_283.txt # ::snt The point mutations in the SMAD binding element was generated with the Quik-Change Kit (Stratagene, La Jolla, California, United States) using the forward primer 5′-GGGCGGGCTTAGGTGTTTTCATTTACTCTTGAGGAAAAGCTTGGC-3′ and the reverse primer 5′-GCTTTT-CCTCAAGAGTAAATGAAAACACCTAAGCCCGCCCTGCCC-3′. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (g / generate-01 :ARG1 (m / mutate-01 :mod (p / point) :location (e / element :ARG0-of (b / bind-01 :ARG1 (p2 / protein :name (n3 / name :op1 "SMAD") :xref (x / xref :value "UNIPROT:SMAD1_HUMAN" :prob "0.312"))))) :instrument (p3 / product :name (n4 / name :op1 "Quik-Change" :op2 "Kit") :source (c2 / company :name (n5 / name :op1 "Stratagene") :location (c3 / city :name (n6 / name :op1 "La" :op2 "Jolla") :location (s / state :wiki "California" :name (n / name :op1 "California") :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States")))))) :ARG2-of (u / use-01 :ARG1 (a / and :op1 (p4 / primer :value "5′-GGGCGGGCTTAGGTGTTTTCATTTACTCTTGAGGAAAAGCTTGGC-3′" :ARG1-of (f / forward-01)) :op2 (p5 / primer :value "5′-GCTTTTCCTCAAGAGTAAATGAAAACACCTAAGCCCGCCCTGCCC-3′" :ARG1-of (r / reverse-01))))) # ::id pmid_1563_0473.284 # ::date 2015-03-29T04:41:26 # ::file pmid_1563_0473_284.txt # ::snt The probes for the Snail in situ hybridization were generated against the 3′ UTR by PCR using the forward primer 5′-ACCTTCTCCCGCATGTCCTTGCTCC-3′ and the reverse primer 5′-CTGCTGAGGCATGGTTACAGCTGG-3′, and genomic DNA as a template. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (g4 / generate-01 :ARG0 (r3 / react-01 :ARG0 (p5 / polymerase) :ARG1-of (c / chain-01)) :ARG1 (p / probe-01 :ARG2 (h / hybridize-01 :ARG1 (g2 / gene :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :manner (i2 / in-situ))) :prep-against (r2 / region :value "3" :wiki "Three_prime_untranslated_region" :ARG1-of (t2 / translate-02 :polarity "-") :ARG0-of (t3 / trail-01)) :ARG2-of (u / use-01 :ARG1 (a / and :op1 (p3 / primer :value "5′-ACCTTCTCCCGCATGTCCTTGCTCC-3′" :ARG1-of (f / forward-01)) :op2 (p4 / primer :value "5′-CTGCTGAGGCATGGTTACAGCTGG-3′" :ARG1-of (r / reverse-01)) :op3 (t / template :mod (n3 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :mod (g3 / genomic)))))) # ::id pmid_1563_0473.285 # ::date 2015-03-29T05:24:23 # ::file pmid_1563_0473_285.txt # ::snt The PCR product was gel purified and ligated into pCRII-TOPO TA vector. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (p / purify-01 :ARG1 (r / react-01 :ARG0 (p4 / polymerase) :ARG1-of (c / chain-01)) :mod (g / gel)) :op2 (l / ligate-01 :ARG1 (p2 / product) :ARG3 (p3 / product :name (n2 / name :op1 "pCRII-TOPO" :op2 "TA") :mod (v / vector)))) # ::id pmid_1563_0473.286 # ::date 2015-03-29T05:31:33 # ::file pmid_1563_0473_286.txt # ::snt The pre-LIM domain of Ajuba was generated essentially as described [9], but was fused to GFP by subcloning from the pEGFP-N1 20 vector (BD Biosciences Clontech) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c3 / contrast-01 :ARG1 (g / generate-01 :ARG1 (p5 / protein-segment :name (n6 / name :op1 "pre-LIM") :part-of (p / protein :name (n / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "9")) :mod (e / essential))) :ARG2 (f / fuse-01 :ARG0 (s / subclone-01 :ARG2 (v2 / vector :name (n5 / name :op1 "pEGFP-N1" :op2 "20") :source (c2 / company :name (n4 / name :op1 "BD" :op2 "Biosciences" :op3 "Clontech")))) :ARG1 p5 :ARG2 (p3 / protein :name (n2 / name :op1 "GFP") :xref (x / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342")))) # ::id pmid_1563_0473.287 # ::date 2015-03-29T05:40:34 # ::file pmid_1563_0473_287.txt # ::snt In situ hybridization # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 3, 2015 (h / hybridize-01 :manner (i / in-situ)) # ::id pmid_1563_0473.288 # ::date 2015-03-29T05:40:48 # ::file pmid_1563_0473_288.txt # ::snt The pCRII-TOPO TA vector containing a region of the 3′ UTR of Snail was used as a template to generate digoxigenin-labeled sense and antisense riboprobes (Roche). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (u / use-01 :ARG1 (p / product :name (n / name :op1 "pCRII-TOPO" :op2 "TA") :mod (v / vector) :ARG0-of (c / contain-01 :ARG1 (d2 / dna-sequence :name (n4 / name :op1 "3′" :op2 "untranslated" :op3 "region") :part-of (g / gene :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG2 (t / template) :purpose (g2 / generate-01 :ARG1 (a / and :op1 (r2 / riboprobe :mod (s / sense) :ARG1-of (l / label-01 :ARG2 (d / digoxigenin))) :op2 (r3 / riboprobe :ARG1-of l :mod (a3 / antisense)) :source (c2 / company :name (n3 / name :op1 "Roche"))))) # ::id pmid_1563_0473.289 # ::date 2015-03-29T06:26:44 # ::file pmid_1563_0473_289.txt # ::snt The respective probes were obtained by XhoI and BamH1 digestions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (o / obtain-01 :ARG1 (p / probe-01 :mod (r / respective)) :ARG2 (d / digest-01 :ARG1 (a / and :op1 (p2 / product :name (n / name :op1 "XhoI")) :op2 (p3 / product :name (n2 / name :op1 "BamH1"))))) # ::id pmid_1563_0473.290 # ::date 2015-03-29T06:30:27 # ::file pmid_1563_0473_290.txt # ::snt In situ hybridizations were performed on 10-μm thick sections of E17.5 mouse embryos. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (p / perform-02 :ARG1 (h / hybridize-01 :manner (i / in-situ)) :location (s / section-01 :ARG2 (a / area-quantity :quant "10" :unit (m4 / micrometer)) :ARG3 (e / embryo :mod (m3 / mouse) :age (t2 / temporal-quantity :quant "17.5" :unit (d / day))) :ARG1-of (t / thick-03))) # ::id pmid_1563_0473.291 # ::date 2015-03-29T06:30:42 # ::file pmid_1563_0473_291.txt # ::snt The sections were fixed with 4% PFA for 10 min at room temperature, prehybridized at room temperature for 4.5 h, hybridized with the probe (2 μg/ml) at 55 °C for 12–14 h, blocked with 10% NGS, and treated with anti-dig Fab-AP antibody (Roche #1093274) at a 1:2,500 dilution for 3 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (f / fix-02 :ARG1 (s2 / section-01) :instrument (p3 / product :name (n / name :op1 "PFA") :quant (p / percentage-entity :value "4")) :duration (t / temporal-quantity :quant "10" :unit (m / minute)) :mod (t2 / temperature :mod (r / room))) :op2 (p4 / prehybridize-00 :ARG1 s2 :mod t2 :duration (t3 / temporal-quantity :quant "4.5" :unit (h / hour))) :op3 (h2 / hybridize-01 :ARG1 s2 :ARG2 (p5 / probe-01 :quant (c / concentration-quantity :quant "2" :unit (m2 / microgram-per-milliliter))) :manner (t4 / temperature-quantity :quant "55" :scale (c2 / celsius)) :duration (b2 / between :op1 (t6 / temporal-quantity :quant "12" :unit (h3 / hour)) :op2 (t7 / temporal-quantity :quant "14" :unit (h4 / hour)))) :op4 (b / block-01 :ARG1 s2 :ARG3 (p6 / product :name (n2 / name :op1 "NGS") :quant (p2 / percentage-entity :value "10"))) :op5 (t8 / treat-04 :ARG1 s2 :ARG2 (a2 / antibody :name (n3 / name :op1 "anti-dig" :op2 "Fab-AP") :source (c3 / company :name (n4 / name :op1 "Roche")) :ARG1-of (d2 / describe-01 :ARG2 (s3 / string-entity :value "1093274"))) :manner (d / dilute-01 :ARG1-of (e / equal-01 :ARG2 "1/2500")) :duration (t9 / temporal-quantity :quant "3" :unit (h5 / hour)))) # ::id pmid_1563_0473.292 # ::date 2015-03-28T05:23:09 # ::file pmid_1563_0473_292.txt # ::snt The sections were incubated with NBT and BCIP until adequate signal was detected. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 3, 2015 (i / incubate-01 :ARG1 (s / section-01) :ARG2 (a / and :op1 (p / product :name (n / name :op1 "NBT")) :op2 (p2 / product :name (n2 / name :op1 "BCIP"))) :time (u / until :op1 (d / detect-01 :ARG1 (s2 / signal-07 :mod (a2 / adequate))))) # ::id pmid_1563_0473.293 # ::date 2015-03-28T14:24:01 # ::file pmid_1563_0473_293.txt # ::snt Immunofluorescence and immunohistochemistry # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (i / immunofluoresce-01) :op2 (i2 / immunohistochemistry)) # ::id pmid_1563_0473.294 # ::date 2015-03-28T14:30:59 # ::file pmid_1563_0473_294.txt # ::snt Tissue samples for immunofluorescence were frozen in OCT and sectioned 10 μm thick on a cryostat. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (f / freeze-01 :ARG1 (t / tissue :ARG1-of (s2 / sample-01 :purpose (i / immunofluoresce-01))) :instrument (t3 / thing :name (n / name :op1 "Optimal" :op2 "Cutting" :op3 "Temperature"))) :op2 (s / section-01 :ARG1 t :ARG2 (t2 / thick-03 :mod (d / distance-quantity :quant "10" :unit (m / micrometer))) :location (c / cryostat))) # ::id pmid_1563_0473.295 # ::date 2015-03-28T15:37:20 # ::file pmid_1563_0473_295.txt # ::snt Sections were fixed in 4% paraformaldehyde for 10 min at room temperature, blocked, and stained with antibodies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (f / fix-00 :ARG1 (t / thing :ARG2-of (s2 / section-01)) :ARG2 (s3 / small-molecule :name (n / name :op1 "paraformaldehyde") :mod (p / percentage-entity :value "4") :xref (x / xref :value "PUBCHEM:712" :prob "16.525295")) :duration (t2 / temporal-quantity :quant "10" :unit (m2 / minute)) :mod (t3 / temperature :poss (r / room))) :op2 (b / block-01 :ARG1 t) :op2 (s / stain-01 :ARG1 t :ARG2 (a2 / antibody))) # ::id pmid_1563_0473.296 # ::date 2015-03-29T01:58:17 # ::file pmid_1563_0473_296.txt # ::snt Tissue samples for immunohistochemistry were fixed in 4% paraformaldehyde, dehydrated, and embedded in paraffin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (f / fix-03 :ARG1 (t / tissue :ARG1-of (s / sample-01 :purpose (i / immunohistochemistry))) :ARG2 (s2 / small-molecule :name (n / name :op1 "paraformaldehyde") :mod (p / percentage-entity :value "4") :xref (x / xref :value "PUBCHEM:712" :prob "16.525295"))) :op2 (d / dehydrate-01 :ARG1 t) :op3 (e / embed-01 :ARG1 t :ARG2 (p2 / paraffin))) # ::id pmid_1563_0473.297 # ::date 2015-03-29T02:09:33 # ::file pmid_1563_0473_297.txt # ::snt Samples were sectioned on a microtome (10 μm thick) and rehydrated prior to staining with antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (s / section-01 :ARG1 (t2 / thing :ARG1-of (s2 / sample-01) :ARG1-of (t / thick-03 :mod (d / distance-quantity :quant "10" :unit (m2 / micrometer)))) :instrument (m / microtome)) :op2 (h / hydrate-01 :ARG1 t2 :mod (a3 / again)) :time (p / prior :op1 (s3 / stain-01 :ARG1 t2 :ARG2 (a2 / antibody)))) # ::id pmid_1563_0473.298 # ::date 2015-03-29T03:04:21 # ::file pmid_1563_0473_298.txt # ::snt Samples stained with Snail, pMAPK, pSmad2, and cyclin D were antigen unmasked with 10 mM sodium citrate (pH 6) in an Antigen Retriever 2100 (Pickcell Laboratories, Leiden, Netherlands). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (u / unmask-01 :ARG1 (t / thing :ARG1-of (s / sample-01) :ARG1-of (s2 / stain-01 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "Snail") :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op2 (e / enzyme :name (n2 / name :op1 "MAPK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op3 (p3 / protein :name (n3 / name :op1 "Smad2") :ARG1-of p2 :xref (x / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :op4 (p4 / protein :name (n4 / name :op1 "cyclin" :op2 "D") :xref (x2 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.371"))))) :topic (a2 / antigen) :instrument (s3 / small-molecule :name (n5 / name :op1 "sodium" :op2 "citrate") :mod (c / concentration-quantity :quant "10" :unit (m2 / micromolar)) :mod (a3 / acidity-quantity :quant "6" :scale (p6 / ph)) :xref (x4 / xref :value "PUBCHEM:6224" :prob "9.450866")) :location (p5 / product :name (n6 / name :op1 "Antigen" :op2 "Retriever" :op3 "2100") :ARG1-of (m3 / manufacture-01 :ARG0 (c2 / company :name (n7 / name :op1 "Pickcell" :op2 "Laboratories") :location (c3 / city :name (n8 / name :op1 "Leiden") :location (c4 / country :wiki "Netherlands" :name (n9 / name :op1 "Netherlands"))))))) # ::id pmid_1563_0473.299 # ::date 2015-03-29T03:52:50 # ::file pmid_1563_0473_299.txt # ::snt The DAB substrate kit (Vector Labs) was used according to manufacturer's instructions to develop the signal. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Apr 20, 2015 (u / use-01 :ARG1 (k2 / kit :name (n2 / name :op1 "DAB") :ARG1-of (m2 / manufacture-01 :ARG0 (c2 / company :name (n / name :op1 "Vector" :op2 "Labs"))) :mod (s / substrate)) :ARG2-of (i / instruct-01 :ARG0 c2) :purpose (d / develop-02 :ARG1 (s2 / signal-07))) # ::id pmid_1563_0473.300 # ::date 2015-03-29T04:19:39 # ::file pmid_1563_0473_300.txt # ::snt RT-PCR # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (r2 / react-01 :ARG0 (p / polymerase) :ARG1-of (c / chain-01) :mod (t / transcribe-01 :ARG1-of (r3 / reverse-01))) # ::id pmid_1563_0473.301 # ::date 2015-03-29T04:31:43 # ::file pmid_1563_0473_301.txt # ::snt RNA was extracted from keratinocytes or skin tissue with Trizol (Invitrogen) according to the manufacturer's protocol. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / extract-01 :ARG1 (n / nucleic-acid :name (n4 / name :op1 "RNA")) :ARG2 (o / or :op1 (k / keratinocyte) :op2 (t / tissue :part-of (s / skin))) :instrument (s2 / small-molecule :name (n2 / name :op1 "Trizol") :mod (c2 / company :name (n3 / name :op1 "Invitrogen")) :xref (x / xref :value "PUBCHEM:6484282" :prob "4.240887")) :ARG1-of (s4 / say-01 :ARG0 (p / protocol :poss (c / company :ARG0-of (m2 / manufacture-01))))) # ::id pmid_1563_0473.302 # ::date 2015-03-29T10:38:56 # ::file pmid_1563_0473_302.txt # ::snt cDNA was generated using oligo-dT primers and the Superscript II kit (Invitrogen). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (g / generate-01 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA") :ARG1-of (c / complement-01)) :ARG2 (u / use-01 :ARG1 (a / and :op1 (d / dna-sequence :name (n3 / name :op1 "oligo-dT" :op2 "primer")) :op2 (k / kit :mod (e / enzyme :name (n / name :op1 "Superscript" :op2 "II"))) :source (c2 / company :name (n2 / name :op1 "Invitrogen"))))) # ::id pmid_1563_0473.303 # ::date 2015-03-29T10:57:10 # ::file pmid_1563_0473_303.txt # ::snt The primers used for PCR were Snail forward: 5′-CAGCTGGCCAGGCTCTCGGT-3′; Snail reverse: 5′-GCGAGGGCCTCCGGAGCA-3′; GAPDH forward 5′-CGTAGACAAAATGGTGAAGGTCGG-3′; and GAPDH reverse: 5′-AAGCAGTTGGTGGTGCAGGATG-3′. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (u / use-01 :ARG1 (a / and :op1 (p / primer :value "5′-CAGCTGGCCAGGCTCTCGGT-3′" :ARG1-of (f / forward-01) :part-of (g / gene :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :op2 (p2 / primer :value "5′-GCGAGGGCCTCCGGAGCA-3′" :ARG1-of (r / reverse-01) :part-of g) :op3 (p3 / primer :value "5′-CGTAGACAAAATGGTGAAGGTCGG-3′" :mod (g2 / gene :name (n3 / name :op1 "GAPDH") :xref (x / xref :value "UNIPROT:G3P_HUMAN" :prob "1.002")) :ARG1-of f) :op4 (p4 / primer :value "5′-AAGCAGTTGGTGGTGCAGGATG-3′" :ARG1-of r :part-of g2)) :ARG2 (r2 / react-01 :ARG0 (p5 / polymerase) :ARG1-of (c / chain-01))) # ::id pmid_1563_0473.304 # ::date 2015-03-29T11:53:22 # ::file pmid_1563_0473_304.txt # ::snt Figure 1 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (f / figure :mod "1") # ::id pmid_1563_0473.305 # ::date 2015-03-29T11:54:06 # ::file pmid_1563_0473_305.txt # ::snt Embryos were either frozen in OCT embedding compound (A, F, and H) or embedded in paraffin (C, D, E, and G), and then sectioned (8 μm). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (o / or :op1 (f / freeze-01 :ARG1 (e2 / embryo) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "A") :op2 (f3 / figure :mod "F") :op3 (f4 / figure :mod "H"))) :instrument (c3 / compound :name (n / name :op1 "OCT") :ARG2-of (e4 / embed-01))) :op2 (e / embed-01 :ARG1 e2 :ARG2 (p / paraffin) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f5 / figure :mod "C") :op2 (f6 / figure :mod "D") :op3 (f7 / figure :mod "E") :op4 (f8 / figure :mod "G"))))) :op2 (s / section-01 :ARG1 e2 :ARG2 (d3 / distance-quantity :quant "8" :unit (m / micrometer)) :time (t / then))) # ::id pmid_1563_0473.306 # ::date 2015-03-29T12:09:54 # ::file pmid_1563_0473_306.txt # ::snt (A) In situ hybridizations with Snail sense or antisense cRNA probes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (h / hybridize-01 :ARG2 (o / or :op1 (p / probe-01 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "cRNA")) :ARG2 (g / gene :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :mod (s / sense)) :op2 (p3 / probe-01 :ARG1 n3 :ARG2 g :mod (a / antisense))) :manner (i / in-situ) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"))) # ::id pmid_1563_0473.307 # ::date 2015-03-29T12:26:43 # ::file pmid_1563_0473_307.txt # ::snt Black dotted lines demarcate the basement membrane that separates the epidermis (epi) from dermis (der). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 28, 2015 (d / demarcate-01 :ARG0 (l / line :ARG1-of (b / black-04) :ARG1-of (d2 / dot-01)) :ARG1 (m / membrane :mod (b2 / basement) :ARG0-of (s / separate-01 :ARG1 (e / epidermis :ARG1-of (d5 / describe-01 :ARG2 (s2 / string-entity :value "epi"))) :ARG2 (d3 / dermis :ARG1-of (d6 / describe-01 :ARG2 (s3 / string-entity :value "der")))) :xref (x / xref :value "GO:0016020" :prob "0.8"))) # ::id pmid_1563_0473.308 # ::date 2015-03-29T12:30:42 # ::file pmid_1563_0473_308.txt # ::snt Arrows point to Snail RNA expression, restricted to the hair bud stage of follicle morphogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p / point-01 :ARG0 (a / arrow) :ARG1 (e / express-03 :ARG2 (n3 / nucleic-acid :name (n / name :op1 "RNA") :mod (g / gene :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (r2 / restrict-01 :ARG2 (s / stage :mod (b / bud :mod (h / hair)) :subevent-of (m / morphogenesis :mod (f / follicle)))))) # ::id pmid_1563_0473.309 # ::date 2015-03-29T12:44:32 # ::file pmid_1563_0473_309.txt # ::snt It was not seen in later hair germ or peg stages. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Apr 20, 2015 (s / see-01 :polarity "-" :ARG1 (i / it) :topic (o / or :op1 (g / germ :mod (h / hair) :time (l / late :degree (m / more))) :op2 (s2 / stage :mod (p / peg) :time l))) # ::id pmid_1563_0473.310 # ::date 2015-03-29T12:53:17 # ::file pmid_1563_0473_310.txt # ::snt (B) Expression of Snail protein coincides with hair development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (c / coincide-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG2 (d / develop-01 :ARG2 (h / hair)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "B"))) # ::id pmid_1563_0473.311 # ::date 2015-03-29T12:56:42 # ::file pmid_1563_0473_311.txt # ::snt Protein extracts were prepared from keratinocytes transfected with empty expression vector (K14), containing the K14 promoter or with the vector driving HA-tagged Snail (K14-Snail); or from whole skin from E13.5 to P5 animals, including newborn (nb). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p / prepare-01 :ARG1 (e / extract-01 :ARG1 (p2 / protein)) :ARG2 (o / or :op1 (k / keratinocyte :ARG1-of (t / transfect-01 :ARG2 (o3 / or :op1 (v / vector :mod (e2 / express-03) :ARG1-of (e3 / empty-02) :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n / name :op1 "K14") :xref (x1 / xref :value "UNIPROT:K1C14_HUMAN" :prob "1.002"))) :ARG0-of (c / contain-01 :ARG1 (m4 / molecular-physical-entity :ARG0-of (p8 / promote-01 :ARG1 p3)))) :op2 (v2 / vector :ARG0-of (d / drive-02 :ARG1 (p5 / protein :name (n2 / name :op1 "Snail") :ARG1-of (t2 / tag-01 :ARG2 (p6 / protein :name (n3 / name :op1 "HA") :xref (x / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (m2 / mean-01 :ARG2 (g / gene :name (n4 / name :op1 "Snail") :ARG1-of (m5 / mutate-01 :value "K14") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))))) :op2 (s / skin :mod (w / whole) :part-of (o2 / or :op1 (e4 / embryo :age (a4 / at-least :op1 (t3 / temporal-quantity :quant "13.5" :unit (d3 / day)))) :op2 (a / animal :ARG2-of (i / include-91 :ARG1 (a2 / animal :ARG1-of (b / bear-02 :time (n5 / new-01)))) :age (a5 / at-most :op1 (t4 / temporal-quantity :quant "5" :unit (d4 / day)))))))) # ::id pmid_1563_0473.312 # ::date 2015-03-29T13:47:16 # ::file pmid_1563_0473_312.txt # ::snt Equal amounts of proteins were then resolved by SDS-PAGE through 12% gels and subjected to Western blotting using either an affinity-purified Snail polyclonal antiserum, which we generated, or anti-tubulin (loading control). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 31, 2016 (a / and :op1 (r / resolve-03 :ARG1 (p / protein :quant (a2 / amount :ARG1-of (e / equal-01))) :ARG3 (t2 / thing :name (n / name :op1 "SDS-PAGE") :instrument (g / gel :mod (p2 / percentage-entity :value "12"))) :time (t / then)) :op2 (s / subject-01 :ARG1 p :ARG2 (i / immunoblot-01 :ARG3 (o / or :op1 (s2 / serum :ARG0-of (c / counter-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :mod (p4 / polyclonal) :ARG1-of (p5 / purify-01 :ARG2 (a4 / affinity)) :ARG1-of (g2 / generate-01 :ARG0 (w / we))) :op2 (m / molecular-physical-entity :ARG0-of (c2 / counter-01 :ARG1 (p6 / protein :name (n4 / name :op1 "tubulin") :xref (x1 / xref :value "UNIPROT:TBB4A_HUMAN" :prob "0.282"))) :ARG0-of (c3 / control-01 :ARG1 (l / load-01))))))) # ::id pmid_1563_0473.313 # ::date 2015-03-29T14:06:54 # ::file pmid_1563_0473_313.txt # ::snt (C–E) Immunohistochemistry shows expression of Snail protein in the nuclei of cells within the hair and skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (s / show-01 :ARG0 (i / immunohistochemistry) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (n2 / nucleus :part-of (c / cell :part-of (a / and :op1 (h / hair) :op2 (s2 / skin))) :xref (x1 / xref :value "GO:0005634" :prob "0.8"))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "C") :op2 (f2 / figure :mod "D") :op3 (f3 / figure :mod "E")))) # ::id pmid_1563_0473.314 # ::date 2015-03-29T14:12:09 # ::file pmid_1563_0473_314.txt # ::snt (C) E13.5 skin with a single layered epidermis (epi) shows no Snail expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (s2 / skin :part (e2 / epidermis :mod (l / layer :ARG1-of (s3 / single-02))) :time (d2 / day :mod "13.5" :mod (e3 / embryo))) :ARG1 (e / express-03 :polarity "-" :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"))) # ::id pmid_1563_0473.315 # ::date 2015-03-29T14:17:06 # ::file pmid_1563_0473_315.txt # ::snt (D) The first morphological sign that cells have adopted a hair follicle fate is a cluster of cells called a placode in E16.5 skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (s / signal-07 :ARG0 (c / cluster-01 :ARG1 (c2 / cell) :ARG1-of (c3 / call-01 :ARG2 (p / placode)) :location (s2 / skin :part-of (e / embryo :age (t / temporal-quantity :quant "16.5" :unit (d2 / day))))) :ARG1 (a / adopt-01 :ARG0 c2 :ARG1 (f / fate :poss (f2 / follicle :mod (h / hair)))) :ord (o / ordinal-entity :value "1") :mod (m / morphological) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "D"))) # ::id pmid_1563_0473.316 # ::date 2015-03-29T14:27:35 # ::file pmid_1563_0473_316.txt # ::snt Snail is not expressed at this stage of development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (e / express-03 :polarity "-" :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :time (s / stage :mod (t / this) :subevent-of (d / develop-01))) # ::id pmid_1563_0473.317 # ::date 2015-03-29T14:28:51 # ::file pmid_1563_0473_317.txt # ::snt (E) Snail is expressed in the hair bud of E17.5 skin but not in later stages of development such as the germ or peg. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (b / bud :mod (h / hair) :part-of (s / skin :part-of (e4 / embryo :age (t / temporal-quantity :quant "17.5" :unit (d4 / day))))) :ARG1-of (c / contrast-01 :ARG2 (e2 / express-03 :polarity "-" :ARG2 p :ARG3 (s2 / stage :time (l / late :degree (m / more)) :subevent-of (d / develop-01) :example (o2 / or :op1 (g / germ) :op2 (p2 / peg))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "E"))) # ::id pmid_1563_0473.318 # ::date 2015-03-29T14:32:14 # ::file pmid_1563_0473_318.txt # ::snt (F) Immunofluorescence with anti-Ki67 (green) identifies the proliferating cells of the skin, restricted to the basal layer of the epidermis and developing hair follicles. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / identify-01 :ARG0 (i2 / immunofluoresce-01 :ARG2 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "Ki67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))) :ARG1-of (g / green-02))) :ARG1 (c2 / cell :part-of (s / skin) :ARG0-of (p2 / proliferate-01) :ARG1-of (r / restrict-01 :ARG2 (l / layer :mod (b / basal) :part-of (a2 / and :op1 (e / epidermis) :op2 (f / follicle :mod (h / hair) :ARG2-of (d / develop-01)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "F"))) # ::id pmid_1563_0473.319 # ::date 2015-03-29T14:37:51 # ::file pmid_1563_0473_319.txt # ::snt Anti-β4 int labeling reveals the presence of the hemidesmosomal integrin β4, restricted to the base of cells adhering to the underlying basement membrane. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (r / reveal-01 :ARG0 (l / label-01 :ARG0 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p2 / protein :name (n / name :op1 "β4" :op2 "integrin"))))) :ARG1 (p3 / present-02 :ARG1 (p / protein :name (n2 / name :op1 "β4" :op2 "integrin") :mod (h / hemidesmosome) :ARG1-of (r2 / restrict-01 :ARG2 (b2 / base :part-of (c2 / cell :ARG1-of (a / adhere-01 :ARG2 (m3 / membrane :mod (b3 / basement) :ARG0-of (u / underlie-01) :xref (x / xref :value "GO:0016020" :prob "0.8"))))))))) # ::id pmid_1563_0473.320 # ::date 2015-03-29T14:48:56 # ::file pmid_1563_0473_320.txt # ::snt The white dotted line marks the outermost surface of the skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (m / mark-01 :ARG0 (l / line :ARG1-of (w / white-03) :ARG1-of (d / dot-01)) :ARG1 (s / surface :part-of (s2 / skin :mod (o / outer :degree (m2 / most))))) # ::id pmid_1563_0473.321 # ::date 2015-03-29T14:52:33 # ::file pmid_1563_0473_321.txt # ::snt (G) Immunohistochemistry with pMAPK marks a subset of proliferating cells within the epidermis and hair bud. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (m / mark-01 :ARG0 (i / immunohistochemistry :instrument (e / enzyme :name (n / name :op1 "MAPK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG1 (s / subset :ARG1-of (i2 / include-91 :ARG2 (c / cell :ARG0-of (p2 / proliferate-01) :location (a / and :op1 (e2 / epidermis) :op2 (b / bud :mod (h / hair)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "G"))) # ::id pmid_1563_0473.322 # ::date 2015-03-29T14:55:13 # ::file pmid_1563_0473_322.txt # ::snt Anti-pMAPK labeling was consistently robust within the hair bud. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (r / robust :manner (c / consistent-02) :domain (l / label-01 :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "MAPK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :location (b / bud :mod (h / hair)))) # ::id pmid_1563_0473.323 # ::date 2015-03-29T14:58:20 # ::file pmid_1563_0473_323.txt # ::snt (H) Immunofluorescence with anti-laminin 5 (lam5), which demarcates the basement membrane, and anti-E-cadherin (E-cad), a component of AJs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / immunofluoresce-01 :ARG2 (a / and :op1 (m / molecular-physical-entity :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "laminin" :op2 "5") :ARG0-of (d / demarcate-01 :ARG1 (m2 / membrane :mod (b / basement) :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :xref (x1 / xref :value "UNIPROT:LM-111_HUMAN_COMPLEX" :prob "0.3")))) :op1 (m3 / molecular-physical-entity :ARG0-of (c2 / counter-01 :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin") :part-of (m4 / macro-molecular-complex :name (n3 / name :op1 "adherens" :op2 "junction")) :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "H"))) # ::id pmid_1563_0473.324 # ::date 2015-03-29T15:09:34 # ::file pmid_1563_0473_324.txt # ::snt At the leading edge of the growing bud, cell-cell borders show markedly diminished anti-E-cadherin labeling (arrowheads). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun May 17, 2015 (s / show-01 :ARG0 (b / border-01 :ARG1 (c / cell) :ARG2 (c2 / cell)) :ARG1 (l2 / label-01 :ARG1-of (d / diminish-01 :manner (m / marked)) :ARG0-of (c3 / counter-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :location (e / edge :ARG0-of (l / lead-01) :part-of (b2 / bud :ARG1-of (g / grow-01))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / arrowhead))) # ::id pmid_1563_0473.325 # ::date 2015-03-29T15:15:20 # ::file pmid_1563_0473_325.txt # ::snt Figure 2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (f / figure :mod "2") # ::id pmid_1563_0473.326 # ::date 2015-03-29T15:15:49 # ::file pmid_1563_0473_326.txt # ::snt Three different surviving Tg founder mice harbored a K14-Snail transgene that was integrated into a locus that resulted in inheritable, mosaic expression of the transgene in skin epidermis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (h / harbor-01 :ARG0 (m / mouse :quant "3" :mod (t / transgenic) :ARG0-of (f / found-01) :ARG1-of (d / differ-02) :ARG0-of (s / survive-01)) :ARG1 (t2 / transgene :ARG1-of (i / integrate-01 :ARG2 (l / locus :ARG1-of (r / result-01 :ARG2 (e / express-03 :ARG1 (t3 / transgene) :ARG3 (e2 / epidermis :part-of (s2 / skin)) :ARG1-of (i2 / inherit-01 :ARG1-of (p3 / possible-01)) :mod (m3 / mosaic))))) :mod (g / gene :name (n2 / name :op1 "Snail") :ARG2-of (m4 / mutate-01 :value "K14") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) # ::id pmid_1563_0473.327 # ::date 2015-03-29T15:28:40 # ::file pmid_1563_0473_327.txt # ::snt All displayed similar abnormalities, as did their offspring. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (d / display-01 :ARG0 (a3 / and :op1 (a / all) :op2 (o / offspring :poss a)) :ARG1 (a2 / abnormality :ARG1-of (r / resemble-01))) # ::id pmid_1563_0473.328 # ::date 2015-03-29T15:33:38 # ::file pmid_1563_0473_328.txt # ::snt (A) P16 WT and K14-Snail Tg mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (m3 / mouse :mod (w / wild-type) :time (a3 / after :op1 (b / bear-02) :quant (t2 / temporal-quantity :quant "16" :unit (d3 / day)))) :op2 (m / mouse :mod (t / transgenic) :mod (g / gene :name (n3 / name :op1 "Snail") :ARG2-of (m2 / mutate-01 :value "K14") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"))) # ::id pmid_1563_0473.329 # ::date 2015-03-29T15:36:49 # ::file pmid_1563_0473_329.txt # ::snt Insets denote magnified tail segments, which displayed a mosaic, flaky appearance in Tg mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (d / denote-01 :ARG0 (i / inset) :ARG1 (s / segment :part-of (t / tail) :ARG1-of (m / magnify-01) :ARG0-of (d2 / display-01 :ARG1 (a / appear-02 :ARG1 s :mod (m2 / mosaic) :mod (f / flake) :location (m3 / mouse :mod (t2 / transgenic)))))) # ::id pmid_1563_0473.330 # ::date 2015-03-29T15:42:09 # ::file pmid_1563_0473_330.txt # ::snt Size differences appeared with age, and are likely due to K14-promoter activity in the tongue and oral epithelium, resulting in progressive defects and reduced food intake. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a / and :op1 (a2 / appear-01 :ARG1 (d / differ-02 :ARG3 (s / size)) :time (a3 / age)) :op2 (l / likely-01 :ARG1 (c / cause-01 :ARG0 (a4 / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (p / protein :name (n / name :op1 "K14") :xref (x / xref :value "UNIPROT:K1C14_HUMAN" :prob "1.002")))) :location (a5 / and :op1 (t / tongue) :op2 (e / epithelium :part-of (m / mouth))) :ARG1-of (r / result-01 :ARG2 (a6 / and :op1 (d2 / defect :ARG1-of (p3 / progress-01)) :op2 (i / intake :mod (f / food) :ARG1-of (r2 / reduce-01))))) :ARG1 d))) # ::id pmid_1563_0473.331 # ::date 2015-03-29T15:50:38 # ::file pmid_1563_0473_331.txt # ::snt Hence, skin sections from young (P3) mice were analyzed (B–I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / cause-01 :ARG1 (a / analyze-01 :ARG1 (t / thing :ARG2-of (s / section-01 :ARG1 (s2 / skin :source (m / mouse :mod (y / young) :ARG1-of (m2 / mean-01 :ARG2 (a2 / after :op1 (b / bear-02) :quant (t2 / temporal-quantity :quant "3" :unit (d3 / day)))))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "B") :op2 (f2 / figure :mod "C") :op3 (f3 / figure :mod "D") :op4 (f4 / figure :mod "E") :op5 (f5 / figure :mod "F") :op6 (f6 / figure :mod "G") :op7 (f7 / figure :mod "H") :op8 (f8 / figure :mod "I"))))) # ::id pmid_1563_0473.332 # ::date 2015-03-29T15:54:47 # ::file pmid_1563_0473_332.txt # ::snt (B) Hematoxylin- and eosin-stained Tg skin section. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (t / thing :ARG1-of (s3 / stain-01 :ARG2 (a / and :op1 (s4 / small-molecule :name (n / name :op1 "hematoxylin") :xref (x1 / xref :value "PUBCHEM:10603" :prob "16.740406")) :op2 (s5 / small-molecule :name (n2 / name :op1 "eosin") :xref (x / xref :value "PUBCHEM:11048" :prob "9.837358")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B")) :ARG2-of (s / section-01 :ARG1 (s2 / skin))) # ::id pmid_1563_0473.333 # ::date 2015-03-29T15:57:31 # ::file pmid_1563_0473_333.txt # ::snt Double arrows demarcate the border of mosaic histology, with seemingly normal epidermis (epi) and a mature hair follicle (hf) at left and hyperthickened epidermis at right. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (d / demarcate-01 :ARG0 (a / arrow :mod (d2 / double)) :ARG1 (b / border-01 :ARG1 (h / histology :mod (m / mosaic) :part (e / epidermis :ARG1-of (n / normal-02 :ARG1-of (s / seem-01))) :part (f / follicle :mod (h2 / hair) :ARG1-of (m2 / mature-02) :ARG1-of (l / left-20)) :part (e2 / epidermis :ARG1-of (t / thicken-01 :degree (h3 / hyper)) :ARG1-of (r / right-04))))) # ::id pmid_1563_0473.334 # ::date 2015-03-29T16:03:44 # ::file pmid_1563_0473_334.txt # ::snt (C) Immunofluorescence of Tg skin section labeled with antibodies as color-coded on frame. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / immunofluoresce-01 :ARG1 (t2 / thing :ARG1-of (l / label-01 :ARG2 (a / antibody) :ARG1-of (c / code-01 :ARG0 (c2 / color) :location (f / frame))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "C")) :ARG2-of (s / section-01 :ARG1 (s2 / skin :mod (t / transgenic))))) # ::id pmid_1563_0473.335 # ::date 2015-03-29T16:06:54 # ::file pmid_1563_0473_335.txt # ::snt Double arrows demarcate the border of mosaic anti-Snail (green), revealing Snail expression coincident with regions of hyperthickened epidermis (at left) and absent in regions of normal epidermis (at right). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (d / demarcate-01 :ARG0 (a / arrow :mod (d2 / double) :ARG1-of (g / green-02)) :ARG1 (b / border-01 :ARG1 (m / molecular-physical-entity :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :mod (m2 / mosaic))) :ARG0-of (r / reveal-01 :ARG1 (a2 / and :op1 (c2 / coincide-01 :ARG1 (e / express-03 :ARG2 p) :ARG2 (r2 / region :part-of (e2 / epidermis :ARG1-of (t / thicken-01 :degree (h / hyper))) :ARG1-of (l / left-20))) :op2 (a4 / absent-01 :ARG1 e :ARG2 (r3 / region :part-of (e3 / epidermis :ARG1-of (n2 / normal-02))) :ARG1-of (r4 / right-04))))) # ::id pmid_1563_0473.336 # ::date 2015-03-29T16:15:17 # ::file pmid_1563_0473_336.txt # ::snt (D–I) Sections of P3 WT or Tg skin (affected region) subjected to either immunofluorescence (D, E, H, and I) or immunohistochemistry (F and G) with antibodies as indicated on the panel. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / subject-01 :ARG1 (t2 / thing :ARG2-of (s2 / section-01 :ARG1 (o / or :op1 (s3 / skin :mod (w / wild-type) :time (a5 / after :op1 (b / bear-02) :quant (t3 / temporal-quantity :quant "3" :unit (d3 / day)))) :op2 (s4 / skin :mod (t / transgenic)) :ARG1-of (m / mean-01 :ARG2 (r / region :ARG1-of (a / affect-01)))))) :ARG2 (o3 / or :op1 (i / immunofluoresce-01 :ARG1 t2 :ARG2 "a2" :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f3 / figure :mod "D") :op2 (f4 / figure :mod "E") :op3 (f5 / figure :mod "H") :op4 (f6 / figure :mod "I")))) :op2 (i3 / immunohistochemistry :instrument (a2 / antibody :ARG1-of (i4 / indicate-01 :location (p / panel))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "F") :op2 (f7 / figure :mod "G"))))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 f3 :op2 f4 :op3 f :op4 f7 :op5 f5))) # ::id pmid_1563_0473.337 # ::date 2015-03-27T09:09:53 # ::file pmid_1563_0473_337.txt # ::snt Anti-keratin 5 indicates K5, normally restricted to the basal layer of the epidermis; anti-keratin 6 detects keratin 6, expressed in postnatal epidermis under conditions such as wounding, in which hyperproliferation occurs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (m / multi-sentence :snt1 (i / indicate-01 :ARG0 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "keratin" :op2 "5") :ARG1-of (r / restrict-01 :ARG2 (l / layer :part-of (e / epidermis) :mod (b / basal)) :ARG1-of (n2 / normal-02)) :xref (x1 / xref :value "UNIPROT:K2C5_HUMAN" :prob "0.672")))) :ARG1 p) :snt2 (d / detect-01 :ARG0 (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p2 / protein :name (n3 / name :op1 "keratin" :op2 "6") :ARG2-of (e2 / express-03 :ARG3 (e3 / epidermis :mod (p3 / postnatal)) :ARG1-of (c3 / condition-01 :example (w / wound-01 :time-of (p4 / proliferate-01 :degree (h / hyper))))) :xref (x / xref :value "UNIPROT:Q16195_HUMAN" :prob "0.361")))) :ARG1 p2)) # ::id pmid_1563_0473.338 # ::date 2015-03-27T09:42:17 # ::file pmid_1563_0473_338.txt # ::snt All other antibodies are as in the legend to Figure 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 3, 2015 (r / resemble-01 :ARG1 (a / antibody :mod (a2 / all) :mod (o / other)) :ARG2 (a3 / antibody :location (l / legend :mod (f / figure :mod "2")))) # ::id pmid_1563_0473.339 # ::date 2015-03-27T09:45:13 # ::file pmid_1563_0473_339.txt # ::snt Comparison of D and E provide representative examples that illustrate that pMAPK is found in only a subset of all proliferating (Ki67-positive) cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (p2 / provide-01 :ARG0 (c / compare-01 :ARG1 (f / figure :mod "D") :ARG2 (f2 / figure :mod "E")) :ARG1 (e / example :ARG0-of (r2 / represent-01) :ARG0-of (i / illustrate-01 :ARG1 (b / be-located-at-91 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2 (s / subset :mod (o / only) :ARG1-of (i2 / include-91 :ARG2 (c2 / cell :ARG0-of (p4 / proliferate-01) :mod (p5 / positive :mod (p6 / protein :name (n2 / name :op1 "Ki67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))) :mod (a / all)))))))) # ::id pmid_1563_0473.340 # ::date 2015-03-27T10:39:46 # ::file pmid_1563_0473_340.txt # ::snt Note also the presence of Ki67- (E) and pMAPK-positive (G) cells in some suprabasal areas; Ki67-positive cells colabeled with anti-Snail (E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (m / multi-sentence :snt1 (n / note-02 :mode "imperative" :ARG0 (y / you) :ARG1 (p8 / present-02 :ARG1 (a / and :op1 (c / cell :mod (p / positive :mod (p2 / protein :name (n2 / name :op1 "Ki67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "E"))) :op2 (c2 / cell :mod (p3 / positive :mod (e / enzyme :name (n3 / name :op1 "MAPK") :ARG3-of (p4 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "G")))) :ARG2 (a2 / area :quant (s / some) :mod (s2 / suprabasal))) :mod (a4 / also)) :snt2 (c3 / colabel-00 :ARG1 (c5 / cell :mod (p6 / positive :mod (p7 / protein :name (n5 / name :op1 "Ki67") :xref (x1 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653")))) :ARG2 (a3 / antibody :ARG0-of (c4 / counter-01 :ARG1 (p5 / protein :name (n4 / name :op1 "Snail") :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1-of (d3 / describe-01 :ARG0 f))) # ::id pmid_1563_0473.341 # ::date 2015-03-28T03:49:54 # ::file pmid_1563_0473_341.txt # ::snt Figure 3 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Mar 28, 2015 (f / figure :mod "3") # ::id pmid_1563_0473.342 # ::date 2015-03-28T03:53:43 # ::file pmid_1563_0473_342.txt # ::snt (A–H) Immunofluorescence of skin sections from P3 WT and Tg mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / immunofluoresce-01 :ARG1 (s2 / section-01 :ARG1 (s / skin :source (a / and :op1 (m / mouse :mod (w / wild-type)) :op2 (m2 / mouse :mod (t2 / transgenic)) :age (t / temporal-quantity :quant "3" :unit (d / day))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "A") :op2 (f2 / figure :mod "B") :op3 (f3 / figure :mod "C") :op4 (f4 / figure :mod "D") :op5 (f5 / figure :mod "E") :op6 (f6 / figure :mod "F") :op7 (f7 / figure :mod "G") :op8 (f8 / figure :mod "H")))) # ::id pmid_1563_0473.343 # ::date 2015-03-28T04:29:12 # ::file pmid_1563_0473_343.txt # ::snt Shown are affected areas of Tg skin; in areas where Snail protein was not expressed, stainings were normal. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG1 (a / area :mod (s2 / skin :mod (t / transgenic)) :ARG1-of (a2 / affect-01))) :snt2 (n / normal-02 :ARG1 (s3 / stain-01) :location (a3 / area :ARG3-of (e / express-03 :polarity "-" :ARG2 (p / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))))) # ::id pmid_1563_0473.344 # ::date 2015-03-28T04:38:05 # ::file pmid_1563_0473_344.txt # ::snt Sections were labeled with antibodies as indicated and color-coded on each frame. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (l / label-01 :ARG1 (t / thing :ARG1-of (s / section-01)) :ARG2 (a / antibody :ARG1-of (i / indicate-01 :location (f / frame :mod (e / each))) :ARG1-of (c / code-01 :ARG0 (c2 / color) :location f))) # ::id pmid_1563_0473.345 # ::date 2015-03-28T04:49:48 # ::file pmid_1563_0473_345.txt # ::snt Antibodies are against markers of normal epidermal differentiation, and include K5 (a basally expressed keratin), K1 (a suprabasal keratin, expressed in spinous layer cells), involucrin (Inv; a suprabasally expressed cornified envelope protein found in upper spinous and granular layer cells), loricrin (Lor; a cornified envelope protein expressed in the granular layer), and filaggrin (Fil; a protein that bundles keratin filaments in the granular layer and stratum corneum). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / antibody :ARG0-of (c / counter-01 :ARG1 (m / marker :ARG0-of (d / differentiate-101 :ARG1 (e / epidermis) :ARG1-of (n / normal-02)))) :ARG2-of (i / include-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "keratin" :op2 "5") :ARG1-of (m2 / mean-01 :ARG2 (k / keratin :ARG2-of (e2 / express-03 :manner (b / basal)))) :xref (x5 / xref :value "UNIPROT:K2C5_HUMAN" :prob "0.672")) :op2 (p2 / protein :name (n3 / name :op1 "keratin" :op2 "1") :ARG1-of (m3 / mean-01 :ARG2 (k2 / keratin :ARG2-of (e3 / express-03 :ARG3 (c2 / cell :part-of (l / layer :mod (s / spinous))) :manner (s2 / suprabasal)))) :xref (x1 / xref :value "UNIPROT:K2C1_HUMAN" :prob "0.672")) :op3 (p3 / protein :name (n4 / name :op1 "involucrin") :ARG1-of (m4 / mean-01 :ARG2 (p7 / protein :mod (e6 / envelope :ARG1-of (c6 / cornify-01)) :ARG2-of (e4 / express-03 :ARG3 (a3 / and :op1 (c3 / cell :part-of (l2 / layer :mod (g / granular))) :op2 (c4 / cell :part-of (l3 / layer :mod (s4 / spinous) :mod (u / upper)))) :manner (s3 / suprabasal)))) :xref (x2 / xref :value "UNIPROT:INVO_HUMAN" :prob "0.702")) :op4 (p4 / protein :name (n5 / name :op1 "loricrin") :ARG1-of (m5 / mean-01 :ARG2 (p8 / protein :mod (e7 / envelope :ARG1-of (c7 / cornify-01)) :ARG2-of (e5 / express-03 :ARG3 (c5 / cell :part-of l2)))) :xref (x / xref :value "UNIPROT:LORI_HUMAN" :prob "0.702")) :op5 (p5 / protein :name (n6 / name :op1 "filaggrin") :ARG1-of (m6 / mean-01 :ARG2 (p9 / protein :ARG0-of (b2 / bundle-01 :ARG2 (f / filament :mod (p6 / protein :name (n7 / name :op1 "keratin") :xref (x4 / xref :value "UNIPROT:Q16195_HUMAN" :prob "1.001"))) :location (a4 / and :op1 l2 :op2 (c8 / corneum :mod (s5 / stratum)))))) :xref (x3 / xref :value "UNIPROT:FILA_HUMAN" :prob "0.702"))))) # ::id pmid_1563_0473.346 # ::date 2015-03-28T05:33:32 # ::file pmid_1563_0473_346.txt # ::snt Note abnormal extension of anti-K5 suprabasally, often present in anti-K1 positive suprabasal Tg cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (n / note-02 :mode "imperative" :ARG0 (y / you) :ARG1 (e / extend-01 :ARG1 (a / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n3 / name :op1 "keratin" :op2 "5") :xref (x1 / xref :value "UNIPROT:K2C5_HUMAN" :prob "0.672")))) :ARG4 (s / suprabasal) :ARG1-of (n2 / normal-02 :polarity "-") :ARG1-of (p4 / present-02 :ARG2 (c2 / cell :mod (t / transgenic) :mod (s2 / suprabasal) :mod (p2 / positive :mod (a2 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p3 / protein :name (n4 / name :op1 "keratin" :op2 "1") :xref (x / xref :value "UNIPROT:K2C1_HUMAN" :prob "0.672")))))) :frequency (o / often)))) # ::id pmid_1563_0473.347 # ::date 2015-03-28T05:57:44 # ::file pmid_1563_0473_347.txt # ::snt (I–N) Immunohistochemistry (I and J) or immunofluorescence (K–N) of sections of P30 Wt (I, K, and M) and Tg (J, L, and N) (affected areas) skins using the antibodies indicated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op1 (i / immunohistochemistry :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "I") :op2 (f6 / figure :mod "J"))) :manner (u / use-01 :ARG1 (a8 / antibody :ARG1-of (i3 / indicate-01))) :mod (t3 / thing :ARG2-of (s / section-01 :ARG1 (a3 / and :op1 (s2 / skin :mod (w / wild-type) :ARG1-of (d5 / describe-01 :ARG0 (a4 / and :op1 (f4 / figure :mod "I") :op2 (f7 / figure :mod "K") :op3 (f8 / figure :mod "M"))) :age (t2 / temporal-quantity :quant "30" :unit (d4 / day))) :op2 (s3 / skin :mod (t / transgenic) :ARG1-of (d6 / describe-01 :ARG0 (a5 / and :op1 (f5 / figure :mod "J") :op2 (f9 / figure :mod "L") :op3 (f10 / figure :mod "N"))) :age t2 :ARG1-of (d7 / describe-01 :ARG2 (a6 / area :ARG1-of (a7 / affect-01)))))))) :op2 (i2 / immunofluoresce-01 :ARG1 t3 :ARG2 a8 :ARG1-of (d3 / describe-01 :ARG0 (a11 / and :op1 f7 :op2 f9 :op3 f8 :op4 f10))) :ARG1-of (d / describe-01 :ARG0 (a12 / and :op1 f4 :op2 f5 :op3 f7 :op4 f9 :op5 f8 :op6 f10))) # ::id pmid_1563_0473.348 # ::date 2015-03-28T06:12:20 # ::file pmid_1563_0473_348.txt # ::snt Note that with age, affected areas of the Tg epidermis became increasingly undulating, often exhibiting papilloma-like invaginations (J). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (n / note-02 :mode "imperative" :ARG0 (y / you) :ARG1 (a5 / and :op1 (b / become-01 :ARG1 (a / area :part-of (e / epidermis :mod (t / transgenic)) :ARG1-of (a2 / affect-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "J"))) :ARG2 (u / undulate-01 :ARG1 a :degree (i / increase-01)) :ARG1-of (c / cause-01 :ARG0 (a3 / age-01))) :op2 (e2 / exhibit-01 :ARG0 a :ARG1 (i2 / invaginate-01 :ARG1-of (r / resemble-01 :ARG2 (p / papilloma))) :frequency (o / often)))) # ::id pmid_1563_0473.349 # ::date 2015-03-28T06:17:50 # ::file pmid_1563_0473_349.txt # ::snt Insets in I and J are magnified views of the boxed areas, illustrating the absence (Wt) or presence (Tg) of nuclear anti-cyclin D staining. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / inset :location (a / and :op1 (f / figure :mod "I") :op2 (f2 / figure :mod "J")) :domain (v / view-01 :ARG1 (a2 / area :ARG1-of (b / box-02)) :ARG1-of (m / magnify-01) :ARG0-of (i2 / illustrate-01 :ARG1 (o / or :op1 (a3 / absent-01 :ARG1 (s / stain-01 :ARG1 (n5 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :ARG2 (a4 / antibody :ARG0-of (c / counter-01 :ARG1 (p2 / protein :name (n6 / name :op1 "cyclin" :op2 "D") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "0.371"))))) :ARG1-of (d / describe-01 :ARG2 (n / name :op1 "Wt"))) :op2 (p / present-02 :ARG1 s :ARG1-of (d2 / describe-01 :ARG2 (n3 / name :op1 "Tg"))))))) # ::id pmid_1563_0473.350 # ::date 2015-03-28T06:34:28 # ::file pmid_1563_0473_350.txt # ::snt With age, affected areas of the Tg epidermis also displayed perturbations within the basement membrane, as judged by antibody labeling against either basement membrane (K and L) or hemidesmosomal (M and N) components. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 3, 2015 (d / display-01 :ARG0 (a / area :ARG1-of (a2 / affect-01) :part-of (e / epidermis :mod (t / transgenic))) :ARG1 (p / perturb-01 :ARG1 a) :ARG2 (m / membrane :mod (b / basement) :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :mod (a3 / also) :ARG2-of (j / judge-01 :ARG3 (l / label-01 :ARG1 (o / or :op1 (m2 / membrane :mod (b2 / basement) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (f / figure :mod "K") :op2 (f3 / figure :mod "L"))) :xref (x / xref :value "GO:0016020" :prob "0.8")) :op2 (c / component :mod (h / hemidesmosomal) :ARG1-of (d3 / describe-01 :ARG0 (a7 / and :op1 (f2 / figure :mod "M") :op2 (f4 / figure :mod "N"))))) :instrument (a5 / antibody))) :ARG1-of (c2 / cause-01 :ARG0 (a4 / age-01))) # ::id pmid_1563_0473.351 # ::date 2015-03-29T02:33:19 # ::file pmid_1563_0473_351.txt # ::snt Double arrows in L demarcate mosaic zones, revealing that perturbations were restricted to hyperthickened, i.e., Snail-positive zones (to left of double arrows). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (d2 / demarcate-01 :ARG0 (a / arrow :quant (d / double) :location (f / figure :mod "L") :ARG0-of (r / reveal-01 :ARG1 (r2 / restrict-01 :ARG1 (p / perturb-01) :ARG2 (z2 / zone :ARG1-of (t / thicken-01 :degree (h / hyper) :ARG1-of (m2 / mean-01 :ARG2 (p2 / positive :mod (p3 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :location (r3 / relative-position :op1 a :direction (l / left-20)))))) :ARG1 (z / zone :mod (m / mosaic))) # ::id pmid_1563_0473.352 # ::date 2015-03-29T02:43:10 # ::file pmid_1563_0473_352.txt # ::snt Other abbreviations are as noted in the legend to Figure 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (r / resemble-01 :ARG1 (t / thing :ARG1-of (a / abbreviate-01) :mod (o / other)) :ARG2 (n / note-01 :location (l / legend :mod (f / figure :mod "2")))) # ::id pmid_1563_0473.353 # ::date 2015-03-29T02:47:33 # ::file pmid_1563_0473_353.txt # ::snt Figure 4 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Mar 29, 2015 (f / figure :mod "4") # ::id pmid_1563_0473.354 # ::date 2015-03-29T02:47:53 # ::file pmid_1563_0473_354.txt # ::snt (A) Immunofluorescence of skin sections from P30 Wt and Tg mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / immunofluoresce-01 :ARG1 (t3 / thing :ARG2-of (s / section-01 :ARG1 (s2 / skin :source (a / and :op1 (m / mouse :mod (w / wild-type) :age (t2 / temporal-quantity :quant "30" :unit (d2 / day))) :op2 (m2 / mouse :mod (t / transgenic) :age t2))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"))) # ::id pmid_1563_0473.355 # ::date 2015-03-29T02:52:52 # ::file pmid_1563_0473_355.txt # ::snt Shown are affected areas of Tg skin; in areas where Snail protein was not expressed, stainings were normal. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (m / multi-sentence :snt1 (s / show-01 :ARG1 (a / area :ARG1-of (a2 / affect-01) :mod (s2 / skin :mod (t / transgenic)))) :snt2 (n / normal-02 :ARG1 (s3 / stain-01) :location (a3 / area :ARG3-of (e / express-03 :polarity "-" :ARG2 (p / protein :wiki "SNAI1" :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))))) # ::id pmid_1563_0473.356 # ::date 2015-03-29T02:56:40 # ::file pmid_1563_0473_356.txt # ::snt Antibodies used are against AJ proteins and include E-cadherin (E-cad), the transmembrane core protein; β-catenin (β-cat), which binds E-cadherin at AJs and which can also participate as a transcription cofactor when associated with LEF-1/TCF proteins in the nucleus; α-catenin (α-cat) which binds to both β-catenin and Ajuba, a close relative of zyxin; and Ajuba, which can associate with proteins that bind to the actin cytoskeleton, as well as with Grb-2, a mediator of the GTP nucleotide-exchange protein Sos, involved in activation of the Ras-MAPK signaling cascade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / antibody :ARG0-of (c / counter-01 :ARG1 (m / macro-molecular-complex :name (n10 / name :op1 "adherens" :op2 "junction"))) :ARG2-of (i / include-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "E-cadherin") :mod (t / transmembrane) :mod (c2 / core) :xref (x4 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "β-catenin") :ARG0-of (b / bind-01 :ARG1 p3 :ARG2 m) :ARG0-of (p7 / participate-01 :ARG1-of (p8 / possible-01) :mod (c3 / cofactor :ARG0-of (t2 / transcribe-01)) :condition (a3 / associate-01 :ARG1 p4 :ARG2 (p16 / protein :name (n14 / name :op1 "LEF-1" :op2 "TCF") :xref (x3 / xref :value "UNIPROT:LEF1_HUMAN" :prob "0.272")) :location (n8 / nucleus :xref (x9 / xref :value "GO:0005634" :prob "0.8"))) :mod (a8 / also)) :xref (x6 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op3 (p5 / protein :name (n5 / name :op1 "α-catenin") :ARG0-of (b2 / bind-01 :ARG2 (a4 / and :op1 p4 :op2 "p6")) :xref (x7 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op4 (p6 / protein :name (n6 / name :op1 "Ajuba") :ARG1-of (r / relate-01 :ARG2 (p10 / protein :name (n9 / name :op1 "zyxin") :xref (x2 / xref :value "UNIPROT:ZYX_HUMAN" :prob "0.702")) :ARG1-of (c4 / close-10)) :ARG1-of (a5 / associate-01 :ARG2 (a6 / and :op1 (p12 / protein :ARG1-of (b3 / bind-01 :ARG2 (c5 / cytoskeleton :mod (a9 / actin) :xref (x8 / xref :value "GO:0005856" :prob "0.8")))) :op2 (p13 / protein :name (n11 / name :op1 "Grb-2") :ARG0-of (m2 / mediate-01 :ARG1 (p / protein :name (n7 / name :op1 "Sos") :ARG1-of (i2 / involve-01 :ARG2 (a7 / activate-01 :ARG1 (p15 / pathway :name (n13 / name :op1 "Ras" :op2 "MAPK") :ARG0-of (s / signal-07)))) :mod (p9 / protein :name (n / name :op1 "GTP" :op2 "nucleotide" :op3 "exchange" :op4 "factor")) :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))) :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593"))) :ARG1-of (p11 / possible-01)) :xref (x5 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")))) :ARG1-of (u / use-01)) # ::id pmid_1563_0473.357 # ::date 2015-03-29T03:53:22 # ::file pmid_1563_0473_357.txt # ::snt In Snail-expressing Tg regions, there was a reduced staining with anti-E-cad and anti-α-cat and a more diffuse staining with anti-Ajuba. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 3, 2015 (a / and :op1 (s / stain-01 :ARG2 (a2 / and :op1 (a3 / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :op2 (a4 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p2 / protein :name (n2 / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))))) :ARG1-of (r2 / reduce-01)) :op2 (s2 / stain-01 :ARG2 (a5 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p4 / protein :name (n4 / name :op1 "Ajuba") :xref (x2 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")))) :mod (d / diffuse :degree (m / more))) :location (r / region :ARG3-of (e / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :mod (t / transgenic))) # ::id pmid_1563_0473.358 # ::date 2015-03-29T04:02:05 # ::file pmid_1563_0473_358.txt # ::snt Insets in the panels for β-catenin and Ajuba staining are magnified views of the boxed areas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / inset :location (a / and :op1 (p4 / panel :purpose (s / stain-01 :ARG1 (p2 / protein :name (n / name :op1 "β-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :op2 (p5 / panel :purpose (s2 / stain-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603"))))) :domain (v / view-01 :ARG1 (a2 / area :ARG1-of (b / box-02)) :ARG1-of (m / magnify-01))) # ::id pmid_1563_0473.359 # ::date 2015-03-29T04:09:08 # ::file pmid_1563_0473_359.txt # ::snt Arrows mark membrane localization of the protein and asterisks mark cells with elevated levels of cytoplasmic β-catenin or Ajuba. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 3, 2015 (a / and :op1 (m / mark-01 :ARG0 (a2 / arrow) :ARG1 (b / be-located-at-91 :ARG1 (p / protein) :ARG2 (m3 / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8")))) :op2 (m2 / mark-01 :ARG0 (a3 / asterisk) :ARG1 (c / cell :ARG0-of (h / have-03 :ARG1 (l / level :ARG1-of (e / elevate-01) :quant-of (o / or :op1 (p2 / protein :name (n / name :op1 "β-catenin") :mod (c2 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op2 (p3 / protein :name (n2 / name :op1 "Ajuba") :mod c2 :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")))))))) # ::id pmid_1563_0473.360 # ::date 2015-03-29T04:17:31 # ::file pmid_1563_0473_360.txt # ::snt (B) Western blot analyses of protein extracts from P30 Wt and Tg back and ear skins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / immunoblot-01 :ARG1 (p / protein :ARG1-of (e / extract-01 :ARG2 (a4 / and :op1 (s2 / skin :mod (w2 / wild-type) :part-of (a3 / and :op1 (b / back) :op2 (e2 / ear)) :age (t2 / temporal-quantity :quant "30" :unit (d2 / day))) :op2 (s3 / skin :mod (t / transgenic) :part-of a3 :age t2)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"))) # ::id pmid_1563_0473.361 # ::date 2015-03-29T04:24:07 # ::file pmid_1563_0473_361.txt # ::snt Antibodies are as in (A) except anti-P-cad, which detects P-cadherin, whose expression in the hair follicle was not affected, and anti-tubulin, which detects tubulin, a control for equal protein loadings. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Apr 3, 2015 (r / resemble-01 :ARG1 (a / antibody) :ARG2 (a6 / antibody :location (f / figure :mod "A")) :ARG2-of (e / except-01 :ARG1 (a2 / and :op1 (a3 / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :wiki "-" :name (n / name :op1 "P-cadherin") :ARG2-of (e2 / express-03 :ARG3 (f2 / follicle :mod (h / hair)) :ARG1-of (a5 / affect-01 :polarity "-")) :xref (x1 / xref :value "UNIPROT:CADH3_HUMAN" :prob "1.002"))) :ARG0-of (d / detect-01 :ARG1 p)) :op2 (a4 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p2 / protein :wiki "Tubulin" :name (n2 / name :op1 "tubulin") :ARG0-of (c3 / control-01 :ARG1 (l2 / load-01 :ARG1 (p3 / protein) :ARG1-of (e3 / equal-01))) :xref (x / xref :value "UNIPROT:TBB4A_HUMAN" :prob "0.282"))) :ARG0-of (d2 / detect-01 :ARG1 p2))))) # ::id pmid_1563_0473.362 # ::date 2015-03-29T04:36:43 # ::file pmid_1563_0473_362.txt # ::snt Note that the reductions seen in E-cadherin and α-catenin are likely to be underestimates of the actual differences in affected regions, since the Tg skin expressed Snail mosaically. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (n / note-02 :mode "imperative" :ARG0 (y / you) :ARG1 (l / likely-01 :ARG1 (u / underestimate-01 :ARG0 (r / reduce-01 :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n3 / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :ARG1-of (s2 / see-01)) :ARG1 (d / differ-02 :ARG1-of (a2 / actual-02) :location (r2 / region :ARG1-of (a3 / affect-01)))) :ARG1-of (c / cause-01 :ARG0 (e / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (s / skin :mod (t / transgenic)) :manner (m / mosaical))))) # ::id pmid_1563_0473.363 # ::date 2015-03-29T04:48:50 # ::file pmid_1563_0473_363.txt # ::snt (C) In the presence of elevated Snail, α-catenin levels can be restored by overexpression of E-cadherin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 14, 2015 (p / possible-01 :ARG1 (r / restore-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :manner (o / overexpress-01 :ARG1 (p3 / protein :name (n2 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :condition (p4 / present-02 :ARG1 (p5 / protein :name (n3 / name :op1 "Snail") :ARG1-of (e2 / elevate-01) :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"))) # ::id pmid_1563_0473.364 # ::date 2015-04-01T00:13:55 # ::file pmid_1563_0473_364.txt # ::snt Keratinocytes were transfected with either HA-tagged Snail (Snail[HA]; images on the left) or Snail(HA) and Ecad(HA) (images on the right). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (t / transfect-01 :ARG1 (c / cell :name (n / name :op1 "keratinocyte")) :ARG2 (o2 / or :op1 (p / protein :name (n2 / name :op1 "Snail") :ARG1-of (t2 / tag-01 :ARG2 (p2 / protein :name (n3 / name :op1 "HA") :xref (x / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002"))) :ARG1-of (d / describe-01 :ARG0 (i / image :ARG1-of (l / left-20))) :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op2 (a / and :op1 p :op2 (p4 / protein :name (n5 / name :op1 "E-cadherin") :ARG1-of (t4 / tag-01 :ARG2 p2) :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG1-of (d2 / describe-01 :ARG0 (i2 / image :ARG1-of (r / right-04)))))) # ::id pmid_1563_0473.365 # ::date 2015-04-01T00:35:54 # ::file pmid_1563_0473_365.txt # ::snt 2 d after transfection, cells were switched from low-calcium growth medium to high-calcium medium for 6 h to induce AJ formation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (s / switch-01 :ARG1 (c / cell) :ARG2 (m2 / medium :mod (g2 / grow-01) :mod (c3 / calcium :ARG1-of (h / high-02))) :ARG3 (m / medium :mod (g / grow-01) :ARG1-of (l / low-04 :ARG2 (c2 / calcium))) :duration (t / temporal-quantity :quant "6" :unit (h2 / hour)) :purpose (i / induce-01 :ARG2 (f / form-01 :ARG1 (p / protein :name (n / name :op1 "AJ")))) :time (a / after :op1 (t2 / transfect-01) :quant (t3 / temporal-quantity :quant "2" :unit (d / day)))) # ::id pmid_1563_0473.366 # ::date 2015-04-01T00:56:05 # ::file pmid_1563_0473_366.txt # ::snt Cells were stained with antibodies as indicated on the panels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 1, 2015 (s / stain-01 :ARG1 (c / cell) :ARG2 (a / antibody) :ARG1-of (i / indicate-01 :location (p / panel))) # ::id pmid_1563_0473.367 # ::date 2015-04-01T00:57:43 # ::file pmid_1563_0473_367.txt # ::snt Arrowheads point to sites of intercellular contact between a Snail-transfected keratinocyte and its neighboring untransfected cell. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (p / point-01 :ARG0 (a / arrowhead) :ARG2 (s / site :location-of (c / contact-01 :ARG0 (c2 / cell :name (n / name :op1 "keratinocyte") :ARG1-of (t / transfect-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG1 (c3 / cell :ARG1-of (t2 / transfect-01 :polarity "-") :ARG1-of (n3 / neighbor-01 :ARG2 c2)) :mod (i / intercellular)))) # ::id pmid_1563_0473.368 # ::date 2015-04-01T01:17:52 # ::file pmid_1563_0473_368.txt # ::snt (D) Reintroduction of E-cadherin in keratinocytes expressing Snail returns pMAPK to basal levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / return-04 :ARG0 (r3 / reintroduce-01 :ARG1 (g / gene :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG2 (c / cell :name (n2 / name :op1 "keratinocyte") :ARG1-of (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG1 (e2 / enzyme :name (n4 / name :op1 "MAPK") :ARG3-of (p4 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2 (l / level :mod (b / basal)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "D"))) # ::id pmid_1563_0473.369 # ::date 2015-04-01T01:25:01 # ::file pmid_1563_0473_369.txt # ::snt Keratinocytes were transfected with control vector (K14), or Snail(HA), or Snail(HA) + E-cad(HA). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (t / transfect-01 :ARG1 (c / cell :name (n / name :op1 "keratinocyte")) :ARG2 (o / or :op1 (v2 / vector :name (n2 / name :op1 "K14") :ARG0-of (c2 / control-01)) :op2 (g / gene :name (n3 / name :op1 "Snail(HA)")) :op3 (a / and :op1 g :op2 (g2 / gene :name (n4 / name :op1 "E-cad(HA)"))))) # ::id pmid_1563_0473.370 # ::date 2015-04-01T01:32:34 # ::file pmid_1563_0473_370.txt # ::snt After 2 d, cells were serum starved for 4 h and whole cell lysates were made and Western blotted with antibodies to pMAPK, HA to recognize the HA-tagged Snail and E-cadherin protein, 20or tubulin as a loading control. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (a / and :op1 (s / starve-01 :ARG1 (c / cell) :ARG2 (s2 / serum) :duration (t / temporal-quantity :quant "4" :unit (h / hour))) :op2 (m / make-01 :ARG1 (l / lysate :mod (w2 / whole) :mod (c2 / cell))) :op3 (i / immunoblot-01 :ARG2 l :ARG3 (a2 / and :op1 (a3 / antibody :ARG0-of (o / oppose-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MAPK") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :op2 (p6 / protein :name (n3 / name :op1 "HA") :purpose (r / recognize-02 :ARG1 (a4 / and :op1 (p3 / protein :name (n4 / name :op1 "Snail") :ARG1-of (t2 / tag-01 :ARG2 p6) :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op2 (p4 / protein :name (n5 / name :op1 "E-cadherin") :ARG1-of t2 :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :xref (x / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002")) :accompanier (p5 / protein :name (n6 / name :op1 "tubulin") :ARG0-of (c3 / control-01 :ARG0-of (l2 / load-01)) :xref (x4 / xref :value "UNIPROT:TBB4A_HUMAN" :prob "0.282")))) :time (a5 / after :quant (t3 / temporal-quantity :quant "2" :unit (d2 / day)))) # ::id pmid_1563_0473.371 # ::date 2015-04-01T02:15:38 # ::file pmid_1563_0473_371.txt # ::snt (E) Ajuba interacts with Grb-2 under conditions where α-catenin levels are reduced. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 15, 2015 (i / interact-01 :ARG0 (p3 / protein :name (n / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :ARG1 (p / protein :name (n2 / name :op1 "Grb-2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :condition (r / reduce-01 :ARG1 (l / level :quant-of (p2 / protein :name (n3 / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "E"))) # ::id pmid_1563_0473.372 # ::date 2015-04-02T06:04:11 # ::file pmid_1563_0473_372.txt # ::snt Protein extracts were made from skins of P30 Wt and K14-Snail Tg P30 mice (blots on the left) and of newborn Wt and K14-Cre/α-catenin (fl/fl) conditionally null animals (blots on the right) [7]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (e / extract-01 :ARG1 (p / protein) :ARG2 (a2 / and :op1 (a6 / and :op1 (s / skin :part-of (m / mouse :mod (w / wild-type) :age (t / temporal-quantity :quant "30" :unit (d / day)))) :op2 (s2 / skin :part-of (m2 / mouse :mod (t2 / transgenic) :mod (g / gene :name (n / name :op1 "Snail") :ARG2-of (m5 / mutate-01 :value "K14") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :age (t3 / temporal-quantity :quant "30" :unit (d2 / day)))) :ARG1-of (d4 / describe-01 :ARG0 (b2 / blot :ARG1-of (l / left-20)))) :op2 (a7 / and :op1 (s3 / skin :part-of (a4 / animal :mod (w2 / wild-type) :ARG1-of (b / bear-02 :time (n4 / new-01)))) :op2 (s4 / skin :part-of (a5 / animal :mod (m3 / macro-molecular-complex :part (p3 / protein :name (n2 / name :op1 "K14-Cre") :xref (x1 / xref :value "UNIPROT:K1C14_HUMAN" :prob "0.202")) :part (p4 / protein :name (n3 / name :op1 "α-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :ARG2-of (m4 / mutate-01 :mod "−/−" :mod (c2 / conditional))))) :ARG1-of (d5 / describe-01 :ARG0 (b3 / blot :ARG1-of (r / right-04))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "7")))) # ::id pmid_1563_0473.373 # ::date 2015-04-02T06:11:30 # ::file pmid_1563_0473_373.txt # ::snt Equal amounts of protein extracts were treated with anti-Grb-2 antibody (+) or control isotype antibody (–), and following centrifugation, immunoprecipitates were subjected to SDS-PAGE and Western blot analysis with anti-Ajuba and anti-Grb-2 antibodies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a4 / and :op1 (t / treat-04 :ARG1 (a / amount :ARG1-of (e2 / equal-01) :quant-of (t2 / thing :ARG1-of (e / extract-01 :ARG2 (p4 / protein)))) :ARG2 (o2 / or :op1 (a2 / antibody :ARG0-of (o / oppose-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")))) :op2 (a3 / antibody :mod (i / isotype :ARG1-of (c / control-01))))) :op2 (s / subject-01 :ARG1 (m / molecular-physical-entity :ARG1-of (i2 / immunoprecipitate-01)) :ARG2 (a9 / and :op1 (a5 / analyze-01 :ARG1 m :mod (t5 / thing :name (n / name :op1 "SDS-PAGE"))) :op2 (a8 / analyze-01 :ARG1 m :manner (i3 / immunoblot-01 :ARG1 m :ARG3 (a10 / and :op1 (a6 / antibody :ARG0-of (o3 / oppose-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Ajuba") :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")))) :op2 (a7 / antibody :ARG0-of (o4 / oppose-01 :ARG1 p2)))))) :ARG1-of (f / follow-01 :ARG2 (c2 / centrifugate)))) # ::id pmid_1563_0473.374 # ::date 2015-04-02T06:27:02 # ::file pmid_1563_0473_374.txt # ::snt Note the presence of Ajuba only under conditions where levels of α-catenin and other AJ proteins were aberrantly low or absent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 14, 2015 (n / note-02 :ARG0 (y / you) :ARG1 (p / present-02 :ARG1 (p2 / protein :name (n2 / name :op1 "Ajuba") :xref (x / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :condition (o / or :op1 (l / low-04 :ARG1 (a4 / and :op1 (l2 / level :quant-of (p3 / protein :name (n3 / name :op1 "α-catenin") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :op2 (l3 / level :quant-of (p4 / protein :name (n4 / name :op1 "AJ") :mod (o2 / other)))) :mod (a2 / aberrant)) :op2 (a / absent-01 :ARG1 a4)) :mod (o3 / only))) # ::id pmid_1563_0473.375 # ::date 2015-04-02T06:36:49 # ::file pmid_1563_0473_375.txt # ::snt (F) Transgene expression of excess Ajuba or the Grb-2-interacting domain (pre-LIM) of Ajuba in keratinocytes results in the activation of the Ras-MAPK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (r / result-01 :ARG1 (e / express-03 :ARG2 (o / or :op1 (p / protein :name (n / name :op1 "Ajuba") :ARG0-of (e3 / exceed-01) :xref (x1 / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :op2 (p5 / protein-segment :name (n6 / name :op1 "pre-LIM") :ARG0-of (i2 / interact-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593"))) :location (c / cell :name (n3 / name :op1 "keratinocyte")) :part-of p)) :mod (t / transgene)) :ARG2 (a / activate-01 :ARG1 (p3 / pathway :name (n4 / name :op1 "Ras-MAPK"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "F"))) # ::id pmid_1563_0473.376 # ::date 2015-04-02T07:14:46 # ::file pmid_1563_0473_376.txt # ::snt Primary newborn mouse keratinocytes were transfected with either the empty K14 expression vector (K14), or the expression vector driving Snail, full length Ajuba, or the pre-LIM domain of Ajuba in the absence or presence of a peptide inhibitor (inh) that disrupts the interaction between Grb-2 and Sos. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t2 / transfect-01 :ARG1 (c / cell :name (n / name :op1 "keratinocyte") :part-of (m / mouse :mod (p / primary) :ARG1-of (b / bear-02 :time (n2 / new-01)))) :ARG2 (o / or :op1 (v / vector :ARG1-of (e / express-03 :ARG2 (p8 / protein :name (n3 / name :op1 "K14") :xref (x4 / xref :value "UNIPROT:K1C14_HUMAN" :prob "1.002"))) :ARG1-of (e3 / empty-02)) :op2 (v2 / vector :ARG1-of (e4 / express-03) :ARG0-of (d / drive-02 :ARG1 (p2 / protein :name (n4 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :op3 (p7 / protein :name (n5 / name :op1 "Ajuba") :ARG1-of (l / long-03 :degree (f2 / full)) :xref (x / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :op4 (p6 / protein-segment :name (n10 / name :op1 "pre-LIM") :part-of p7)) :condition (o2 / or :op1 (a / absence :domain (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (s / small-molecule :name (n7 / name :op1 "peptide") :xref (x5 / xref :value "PUBCHEM:3362" :prob "8.018239")) :ARG0-of (d3 / disrupt-01 :ARG1 (i3 / interact-01 :ARG0 (p4 / protein :name (n8 / name :op1 "Grb-2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.593")) :ARG1 (p5 / protein :name (n9 / name :op1 "Sos") :xref (x3 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))))))) :op2 (p3 / present-02 :ARG1 m2))) # ::id pmid_1563_0473.377 # ::date 2015-04-05T00:51:37 # ::file pmid_1563_0473_377.txt # ::snt 48 h posttransfection, protein extracts were prepared and subjected to SDS-PAGE and Western blot analyses with antibodies against pMAPK, total MAPK, Ajuba (also recognizing the smaller, pre-LIM domain), and Snail. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (p2 / prepare-02 :ARG1 (t4 / thing :ARG1-of (e2 / extract-01 :ARG2 (p8 / protein)))) :op2 (s / subject-01 :ARG1 t4 :ARG2 (a2 / and :op1 (a3 / analyze-01 :ARG1 t4 :mod (t5 / thing :name (n / name :op1 "SDS-PAGE"))) :op2 (a4 / analyze-01 :ARG1 t4 :manner (i / immunoblot-01 :ARG1 t4 :ARG3 (a5 / antibody :ARG0-of (o / oppose-01 :ARG1 (a6 / and :op1 (e / enzyme :name (n2 / name :op1 "MAPK") :ARG3-of (p4 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK") :mod (t / total) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op3 (p6 / protein :name (n6 / name :op1 "Ajuba") :xref (x / xref :value "UNIPROT:AJUBA_HUMAN" :prob "0.603")) :op4 (p7 / protein :name (n7 / name :op1 "Snail") :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :ARG0-of (r / recognize-02 :ARG1 (p9 / protein-segment :name (n9 / name :op1 "pre-LIM") :mod (s2 / small :degree (m / more))) :mod (a8 / also))))))) :time (a7 / after :op1 (t2 / transfect-01) :quant (t3 / temporal-quantity :quant "48" :unit (h / hour)))) # ::id pmid_1563_0473.378 # ::date 2015-04-05T01:28:06 # ::file pmid_1563_0473_378.txt # ::snt Figure 5 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Apr 5, 2015 (f / figure :mod "5") # ::id pmid_1563_0473.379 # ::date 2015-04-05T01:29:31 # ::file pmid_1563_0473_379.txt # ::snt (A) Failure of Wnt and noggin signaling to induce Snail in cultured keratinocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (f / fail-01 :ARG1 (a / and :op1 (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Wnt"))) :op2 (s2 / signal-07 :ARG0 (p2 / protein :name (n2 / name :op1 "noggin") :xref (x / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702")))) :ARG2 (i / induce-01 :ARG0 a :ARG2 (p3 / protein :name (n3 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :location (c / cell :name (n4 / name :op1 "keratinocyte") :ARG1-of (c2 / culture-01))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "A"))) # ::id pmid_1563_0473.380 # ::date 2015-04-05T01:34:24 # ::file pmid_1563_0473_380.txt # ::snt Primary mouse keratinocytes were treated with Wnt- and/or noggin-conditioned medium (+) or the corresponding control medium (–). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 16, 2015 (t / treat-04 :ARG1 (c / cell :name (n / name :op1 "keratinocyte") :part-of (m / mouse) :mod (p / primary)) :ARG2 (o3 / or :op1 (m2 / medium :ARG1-of (c2 / condition-02 :ARG2 (a2 / and-or :op1 (p2 / pathway :name (n2 / name :op1 "Wnt")) :op2 (p3 / protein :name (n3 / name :op1 "noggin") :xref (x / xref :value "UNIPROT:NOGG_HUMAN" :prob "0.702"))))) :op2 (m3 / medium :ARG2-of (c3 / correspond-02) :ARG0-of (c4 / control-01)))) # ::id pmid_1563_0473.381 # ::date 2015-04-05T02:08:44 # ::file pmid_1563_0473_381.txt # ::snt These conditions are known to activate the LEF-1/β-catenin reporter TOPGal and down-regulate the E-cadherin promoter (see [4] for details). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (k / know-01 :ARG1 (a2 / and :op1 (a / activate-01 :ARG0 (c / condition :mod (t / this)) :ARG1 (t2 / thing :name (n3 / name :op1 "TOPGal") :ARG0-of (r2 / report-01 :ARG1 (m3 / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "LEF-1") :xref (x / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :part (p3 / protein :name (n2 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))))) :op2 (d4 / downregulate-01 :ARG1 (m / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (g / gene :name (n4 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))))) :ARG1-of (s2 / see-01 :ARG0 (y / you) :purpose (d / detail-01) :location (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "4")))) # ::id pmid_1563_0473.382 # ::date 2015-04-05T02:26:25 # ::file pmid_1563_0473_382.txt # ::snt Using Western blot analyses, cellular proteins were then analyzed for Snail, LEF-1, β-catenin, and tubulin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (a / analyze-01 :ARG1 (p / protein :mod (c / cell)) :purpose (f / find-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op2 (p3 / protein :name (n3 / name :op1 "LEF-1") :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :op3 (p4 / protein :name (n4 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :op4 (p5 / protein :name (n5 / name :op1 "tubulin") :xref (x3 / xref :value "UNIPROT:TBB4A_HUMAN" :prob "0.282")))) :ARG0-of (u / use-01 :ARG1 (i / immunoblot-01))) # ::id pmid_1563_0473.383 # ::date 2015-04-05T03:57:22 # ::file pmid_1563_0473_383.txt # ::snt Proteins from keratinocytes transfected with K14-Snail were used as a positive control for Snail expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (u / use-01 :ARG1 (p / protein :source (c / cell :name (n / name :op1 "keratinocyte") :ARG1-of (t / transfect-01 :ARG2 (g / gene :name (n2 / name :op1 "Snail") :ARG2-of (m / mutate-01 :value "K14") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG2 (c2 / control-01 :ARG0 p :ARG1 (e2 / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :mod (p3 / positive))) # ::id pmid_1563_0473.384 # ::date 2015-04-05T05:05:55 # ::file pmid_1563_0473_384.txt # ::snt (B) TGF-β2 can induce Snail protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 3, 2015 (p / possible-01 :ARG1 (i / induce-01 :ARG0 (p2 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG2 (p3 / protein :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"))) # ::id pmid_1563_0473.385 # ::date 2015-04-05T05:09:20 # ::file pmid_1563_0473_385.txt # ::snt Primary keratinocytes were treated for the indicated times with recombinant TGF-β2 (+) or heat inactivated TGF-β2 (–). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (t / treat-04 :ARG1 (c / cell :name (n / name :op1 "keratinocyte") :mod (p / primary)) :ARG2 (o / or :op1 (p2 / protein :name (n2 / name :op1 "TGF-β2") :ARG1-of (r / recombine-01) :ARG1-of (d / describe-01 :ARG2 (s / string-entity :value "+")) :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :op2 (p3 / protein :name (n3 / name :op1 "TGF-β2") :ARG1-of (a2 / activate-01 :polarity "-" :ARG0 (h / heat)) :ARG1-of (d2 / describe-01 :ARG2 (s2 / string-entity :value "-")) :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :time (t2 / time :ARG1-of (i / indicate-01))) # ::id pmid_1563_0473.386 # ::date 2015-04-05T05:15:47 # ::file pmid_1563_0473_386.txt # ::snt Total cellular proteins were then isolated and analyzed by Western blot for Snail, pSMAD2 (reflective of activated TGF- signaling), and tubulin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i / isolate-01 :ARG1 (p / protein :mod (c / cell) :mod (t / total))) :op2 (a2 / analyze-01 :ARG1 p :manner (i2 / immunoblot-01 :ARG1 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op2 (p5 / protein :name (n3 / name :op1 "SMAD2") :ARG3-of (p3 / phosphorylate-01) :ARG1-of (r / reflect-01 :ARG2 (s / signal-07 :ARG1 (p6 / protein :name (n4 / name :op1 "TGF") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.263")) :ARG1-of (a5 / activate-01))) :xref (x3 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n5 / name :op1 "tubulin") :xref (x2 / xref :value "UNIPROT:TBB4A_HUMAN" :prob "0.282"))) :ARG2 p)) :time (t2 / then)) # ::id pmid_1563_0473.387 # ::date 2015-04-05T05:25:57 # ::file pmid_1563_0473_387.txt # ::snt Note the activation of Snail expression, peaking at 2 h post-TGF-β2 treatment and then disappearing thereafter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Apr 25, 2015 (n2 / note-02 :ARG0 (y / you) :ARG1 (a / and :op1 (p / peak-01 :ARG1 (a2 / activate-01 :ARG1 (e / express-03 :ARG1 (p2 / protein :name (n / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")))) :time (a3 / after :op1 (t / treat-04 :ARG2 (p3 / protein :name (n3 / name :op1 "TGF-β2") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :quant (t3 / temporal-quantity :quant "2" :unit (h / hour)))) :op2 (d / disappear-01 :ARG1 a2 :time (t2 / then)))) # ::id pmid_1563_0473.388 # ::date 2015-04-05T05:45:41 # ::file pmid_1563_0473_388.txt # ::snt (C) Snail mRNA expression is transiently induced by TGF-β2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / induce-01 :ARG0 (p2 / protein :name (n3 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :ARG2 (e / express-03 :ARG2 (n4 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))))) :ARG1-of (t / transient-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"))) # ::id pmid_1563_0473.389 # ::date 2015-04-05T05:50:37 # ::file pmid_1563_0473_389.txt # ::snt The experiment in (B) was repeated, and this time, total RNAs were isolated from keratinocytes treated with TGF-β2 for the indicated times. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Apr 16, 2015 (a / and :op1 (r / repeat-01 :ARG1 (e / experiment-01 :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B")))) :op2 (i / isolate-01 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "RNA") :mod (t / total)) :ARG2 (c / cell :name (n2 / name :op1 "keratinocyte") :ARG1-of (t2 / treat-04 :ARG2 (p / protein :name (n3 / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")) :duration (t3 / time :ARG1-of (i2 / indicate-01)))) :time (t4 / time :mod (t5 / this)))) # ::id pmid_1563_0473.390 # ::date 2015-04-05T05:58:33 # ::file pmid_1563_0473_390.txt # ::snt RT-PCR was then used with (+) or without (–) reverse transcriptase (RT) and with primer sets specific for Snail and GAPDH mRNAs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / use-01 :ARG1 (t2 / thing :name (n / name :op1 "RT-PCR") :manner (a6 / and :op1 (o / or :op1 (a / accompany-01 :ARG0 (e / enzyme :name (n2 / name :op1 "transcriptase") :ARG1-of (r / reverse-01) :xref (x1 / xref :value "UNIPROT:CEBPB_HUMAN" :prob "0.263"))) :op2 (a2 / accompany-01 :polarity "-" :ARG0 e)) :op2 (a3 / accompany-01 :ARG0 (s / set :mod (d / dna-sequence :name (n3 / name :op1 "primer")) :ARG1-of (s2 / specific-02 :ARG2 (a4 / and :op1 (g / gene :name (n4 / name :op1 "Snail") :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op2 (n7 / nucleic-acid :name (n5 / name :op1 "mRNA") :part-of (e2 / enzyme :name (n6 / name :op1 "GAPDH") :xref (x / xref :value "UNIPROT:G3P_HUMAN" :prob "1.002"))))))))) :time (t / then)) # ::id pmid_1563_0473.391 # ::date 2015-04-05T06:11:53 # ::file pmid_1563_0473_391.txt # ::snt Note that Snail mRNA expression also peaked at 2 h, paralleling Snail protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Apr 18, 2015 (n3 / note-02 :ARG0 (y / you) :ARG1 (p / peak-01 :ARG1 (e / express-03 :ARG2 (n4 / nucleic-acid :name (n / name :op1 "mRNA") :part (p2 / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG0-of (p3 / parallel-01 :ARG1 (e2 / express-03 :ARG2 p2))) :mod (a / also)) :time (a2 / after :op1 (t / temporal-quantity :quant "2" :unit (h / hour)))) # ::id pmid_1563_0473.392 # ::date 2015-04-05T06:21:50 # ::file pmid_1563_0473_392.txt # ::snt (D) TGF-β2 treatment results in enhanced activity of a Snail promoter-β-galactosidase reporter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (r2 / result-01 :ARG1 (t / treat-04 :ARG2 (p2 / protein :name (n / name :op1 "TGF-β2") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG2 (a / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (g / gene :name (n2 / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG0-of (r3 / report-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "β-galactosidase") :ARG0-of p3 :xref (x2 / xref :value "UNIPROT:GALK1_HUMAN" :prob "0.302")))) :ARG1-of (e / enhance-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "D"))) # ::id pmid_1563_0473.393 # ::date 2015-04-05T06:27:46 # ::file pmid_1563_0473_393.txt # ::snt Keratinocytes were transfected with a β-galactosidase reporter driven by a Snail promoter that is either WT (wt prom) or harbors a mutation in a putative pSMAD2/pSMAD4 binding site (mt prom). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (t / transfect-01 :ARG1 (c / cell :wiki "Keratinocyte" :name (n / name :op1 "keratinocyte")) :ARG2 (m2 / molecular-physical-entity :ARG0-of (r2 / report-01 :ARG1 (e / enzyme :wiki "Beta-galactosidase" :name (n2 / name :op1 "β-galactosidase") :xref (x2 / xref :value "UNIPROT:GALK1_HUMAN" :prob "0.302"))) :ARG1-of (d / drive-02 :ARG0 (o / or :op1 (m3 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (g / gene :wiki "-" :name (n3 / name :op1 "Snail") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :ARG0-of (h / harbor-01 :ARG1 (m / mutate-01 :ARG2 (p6 / protein-segment :ARG1-of (b / bind-01 :ARG2 (p8 / protein :wiki "Mothers_against_decapentaplegic_homolog_4" :name (n5 / name :op1 "SMAD4") :ARG1-of (p5 / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:SMAD4_HUMAN" :prob "1.003"))) :part-of (p7 / protein :wiki "Mothers_against_decapentaplegic_homolog_2" :name (n6 / name :op1 "SMAD2") :ARG1-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :ARG1-of (t2 / think-01))))) :op2 (m4 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 g) :ARG0-of h))))) # ::id pmid_1563_0473.394 # ::date 2015-04-05T07:33:55 # ::file pmid_1563_0473_394.txt # ::snt At 2 d posttransfection, cells were treated with either TGF-β or heat-inactivated TGF-β2 (inact) for the times indicated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (t / treat-04 :ARG1 (c / cell) :ARG2 (o / or :op1 (p / protein :name (n / name :op1 "TGF-β") :xref (x1 / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233")) :op2 (p2 / protein :name (n2 / name :op1 "TGF-β") :ARG1-of (a3 / activate-01 :polarity "-" :ARG0 (h / heat)) :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233"))) :duration (t2 / temporal-quantity :ARG1-of (i / indicate-01)) :time (a2 / after :op1 (t3 / transfect-01) :quant (t4 / temporal-quantity :quant "2" :unit (d / day)))) # ::id pmid_1563_0473.395 # ::date 2015-04-05T07:40:18 # ::file pmid_1563_0473_395.txt # ::snt β-galactosidase assays were then conducted, and results are reported as fold increase over a basal level of activity of 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a / and :op1 (c / conduct-01 :ARG1 (a2 / assay-01 :ARG1 (e / enzyme :name (n / name :op1 "β-galactosidase") :xref (x / xref :value "UNIPROT:GALK1_HUMAN" :prob "0.302"))) :time (t / then)) :op2 (r / report-01 :ARG1 (t2 / thing :ARG2-of (r2 / result-01)) :manner (i / increase-01 :ARG3 (l / level :mod (b / basal) :degree-of (a3 / activity-06) :ARG1-of (e2 / equal-01 :ARG2 "1")) :mod (f / fold)))) # ::id pmid_1563_0473.396 # ::date 2015-04-05T07:51:52 # ::file pmid_1563_0473_396.txt # ::snt The experiment was repeated three times in triplicate, and error bars reflect variations in the results. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon May 18, 2015 (a / and :op1 (r / repeat-01 :ARG1 (e / experiment-01 :quant "3") :ARG3 "3") :op2 (r2 / reflect-01 :ARG1 (b / bar :mod (e2 / error)) :ARG2 (v / vary-01 :ARG1 (t / thing :ARG2-of (r3 / result-01))))) # ::id pmid_1563_0473.397 # ::date 2015-04-05T07:55:35 # ::file pmid_1563_0473_397.txt # ::snt Figure 6 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Apr 5, 2015 (f / figure :mod "6") # ::id pmid_1563_0473.398 # ::date 2015-04-05T07:56:04 # ::file pmid_1563_0473_398.txt # ::snt (A–D) Skins from TGF-β2 WT or KO E17.5 embryos were analyzed for expression of TGF-β2 protein (A), which is present in the epidermis and dermis as previously described [33] and in the hair bud, pSMAD2 (B), Snail (C), and Snail mRNA (D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 31, 2015 (a3 / and :op1 (a / analyze-01 :ARG1 (o2 / or :op1 (s / skin :source (e / embryo :mod (p / protein :name (n / name :op1 "TGF-β2") :mod (w / wild-type) :xref (x3 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :op2 (s3 / skin :source (e5 / embryo :mod (e3 / enzyme :name (n2 / name :op1 "KO")) :age (t / temporal-quantity :quant "17.5" :unit (d4 / day))))) :purpose (f / find-01 :ARG1 (e4 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "TGF-β2") :ARG1-of (p8 / present-02 :ARG2 (a2 / and :op1 (a5 / and :op1 (e2 / epidermis) :op2 (d / dermis) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "33")) :time (p3 / previous))) :op2 (a6 / and :op1 (b / bud :mod (h / hair)) :op2 (p7 / protein :name (n4 / name :op1 "SMAD2") :ARG1-of (p5 / phosphorylate-01) :ARG1-of (d6 / describe-01 :ARG0 (f4 / figure :mod "B")) :xref (x / xref :value "UNIPROT:SMAD2_HUMAN" :prob "1.003")) :op3 (p6 / protein :name (n5 / name :op1 "Snail") :ARG1-of (d7 / describe-01 :ARG0 (f5 / figure :mod "C")) :xref (x2 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op4 (n7 / nucleic-acid :name (n6 / name :op1 "mRNA") :part p6 :ARG1-of (d8 / describe-01 :ARG0 (f6 / figure :mod "D")))))) :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283")))) :ARG1-of (d5 / describe-01 :ARG0 (f3 / figure :mod "A"))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 f3 :op2 f4 :op3 f5 :op4 f6))) # ::id pmid_1563_0473.399 # ::date 2015-04-05T08:15:28 # ::file pmid_1563_0473_399.txt # ::snt Arrows point to the hair buds. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Apr 21, 2015 (p / point-01 :ARG0 (a / arrow) :ARG2 (b / bud :mod (h / hair))) # ::id pmid_1563_0473.400 # ::date 2015-04-05T08:16:37 # ::file pmid_1563_0473_400.txt # ::snt (E) Western blot analyses of Snail expression in the skins of 2-wk-old K14-Smad2 transgenic (SMAD2 TG) and WT littermate (WT) mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / immunoblot-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG3 (a / and :op1 (s / skin :mod (m / mouse :mod (g / gene :name (n3 / name :op1 "K14-Smad2")) :age (t / temporal-quantity :quant "2" :unit (w2 / week)) :mod (t2 / transgenic))) :op2 (s2 / skin :mod (m2 / mouse :mod (l / littermate) :mod (w / wild-type))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "E"))) # ::id pmid_1563_0473.401 # ::date 2015-04-05T08:24:24 # ::file pmid_1563_0473_401.txt # ::snt Antibody to tubulin was used as a control for equal protein loadings. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Apr 21, 2015 (u / use-01 :ARG1 (a / antibody :ARG0-of (o / oppose-01 :ARG1 (p / protein :name (n / name :op1 "tubulin") :xref (x / xref :value "UNIPROT:TBB4A_HUMAN" :prob "0.282")))) :ARG2 (c / control-01 :ARG1 (l / load-01 :ARG1 (p2 / protein) :ARG1-of (e / equal-01)) :ARG2 a)) # ::id pmid_1563_0473.402 # ::date 2015-04-05T08:30:14 # ::file pmid_1563_0473_402.txt # ::snt The K14-Smad2 Tg mouse was previously shown to possess activated TGF-β signaling [35]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat May 23, 2015 (s / show-01 :ARG1 (p / possess-01 :ARG0 (m / mouse :mod (e / enzyme :name (n2 / name :op1 "K14-Smad2")) :mod (t / transgenic)) :ARG1 (s2 / signal-07 :ARG0 (p2 / protein :name (n3 / name :op1 "TGF-β") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:TGFB1_HUMAN" :prob "0.233")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "35"))) :time (p4 / previous)) # ::id pmid_1563_0473.403 # ::date 2015-04-05T08:36:00 # ::file pmid_1563_0473_403.txt # ::snt (F–G) Proliferation markers Ki67 (F) and pMAPK (G) are diminished in TGF-β2-null hair relative to its WT counterpart. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 31, 2015 (d / diminish-01 :ARG1 (a2 / and :op1 (p / protein :name (n5 / name :op1 "Ki67") :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "F")) :xref (x2 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653")) :op2 (e / enzyme :name (n6 / name :op1 "MAPK") :ARG3-of (p4 / phosphorylate-01) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "G")) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG0-of (m4 / mark-01 :ARG1 (p2 / proliferate-01))) :location (h / hair :mod (p5 / protein :name (n3 / name :op1 "TGF-β2") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG1-of (c / compare-01 :ARG2 (c2 / counterpart :mod (w / wild-type))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 f2 :op2 f3))) # ::id pmid_1563_0473.404 # ::date 2015-04-05T08:43:21 # ::file pmid_1563_0473_404.txt # ::snt (H–J) TGF-β2-null hair fails to down-regulate E-cadherin (H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 31, 2015 (d3 / downregulate-01 :polarity "-" :ARG0 (h / hair :mod (p / protein :name (n / name :op1 "TGF-β2") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x1 / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "H") :op2 (f3 / figure :mod "I") :op3 (f4 / figure :mod "J")))) # ::id pmid_1563_0473.405 # ::date 2015-04-05T08:45:45 # ::file pmid_1563_0473_405.txt # ::snt Wnt and noggin signaling pathways are still intact in the TGF-β2 null hair as nuclear LEF-1 (I) and nuclear β-catenin (J) are still expressed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 5, 2015 (i / intact :location (h / hair :mod (p2 / protein :name (n / name :op1 "TGF-β2") :ARG2-of (m / mutate-01 :mod "−/−") :xref (x / xref :value "UNIPROT:TGFB2_HUMAN" :prob "0.283"))) :ARG1-of (c / cause-01 :ARG0 (e / express-03 :ARG2 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "LEF-1") :mod (n3 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "I")) :xref (x1 / xref :value "UNIPROT:LEF1_HUMAN" :prob "1.002")) :op2 (p4 / protein :name (n4 / name :op1 "β-catenin") :mod (n5 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "J")) :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :mod "s2")) :domain (a3 / and :op1 (p5 / pathway :name (n7 / name :op1 "Wnt") :ARG0-of (s3 / signal-07)) :op2 (p6 / pathway :name (n8 / name :op1 "noggin") :ARG0-of s3) :mod (s2 / still))) # ::id pmid_1627_1139.1 # ::date 2015-08-11T01:04:58 # ::file pmid_1627_1139_1.txt # ::snt Transformation of human bronchial epithelial cells alters responsiveness to inflammatory cytokines (PMID:16271139) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (a / alter-01 :ARG0 (t / transform-01 :ARG1 (c / cell :mod (h / human) :mod (b / bronchus) :mod (e / epithelium))) :ARG1 (r / responsive-02 :ARG1 (c2 / cytokine :ARG0-of (i / inflame-01))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID16271139"))) # ::id pmid_1627_1139.11 # ::date 2015-08-11T07:51:06 # ::file pmid_1627_1139_11.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1627_1139.12 # ::date 2015-08-11T11:54:58 # ::file pmid_1627_1139_12.txt # ::snt Normal epithelial cells respond strongly to OSM, IFNγ and EGF, and respond moderately to IL-6, and do not exhibit a detectable response to LIF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (r / respond-01 :ARG0 (c / cell :mod (n / normal) :source (e / epithelium)) :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "OSM") :xref (x4 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n3 / name :op1 "IFNγ") :xref (x1 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.252")) :op3 (p6 / protein :name (n4 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG1-of (s / strong-02)) :op2 (r2 / respond-01 :ARG0 c :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :manner (m / moderate)) :op3 (e2 / exhibit-01 :polarity "-" :ARG0 c :ARG1 (r3 / respond-01 :ARG0 c :ARG1 (p5 / protein :name (n6 / name :op1 "LIF") :xref (x3 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :ARG1-of (d / detect-01 :ARG1-of (p4 / possible-01))))) # ::id pmid_1627_1139.13 # ::date 2015-08-11T12:26:12 # ::file pmid_1627_1139_13.txt # ::snt In preneoplastic cells, the aberrant signaling that was detected most frequently was an elevated activation of ERK, a reduced or increased IL-6 and EGF response, and an increased LIF response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (e / elevate-01)) :op2 (a3 / and :op1 (o / or :op1 (r2 / respond-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (r / reduce-01)) :op2 (r3 / respond-01 :ARG1 p2 :ARG1-of (i / increase-01))) :op2 (o2 / or :op1 (r4 / respond-01 :ARG1 (p / protein :name (n4 / name :op1 "EGF") :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1-of r) :op2 (r5 / respond-01 :ARG1 p :ARG1-of i))) :op3 (r6 / respond-01 :ARG1 (p3 / protein :name (n3 / name :op1 "LIF") :xref (x2 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :ARG1-of i) :domain (s2 / signal-07 :mod (a4 / aberrant) :ARG1-of (d / detect-01 :ARG1-of (f / frequent-02 :degree (m / most))) :location (c / cell :mod (p4 / preneoplasm)))) # ::id pmid_1627_1139.14 # ::date 2015-08-11T13:12:15 # ::file pmid_1627_1139_14.txt # ::snt Some of these changes in preneoplastic cell signaling approach those observed in established lung cancer cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / approach-02 :ARG0 (c / change-01 :ARG1-of (i / include-91 :ARG2 (c2 / change-01 :ARG1 (s / signal-07 :ARG0 (c3 / cell :mod (p / preneoplasm)))) :ARG3 (s2 / some)) :mod (t / this)) :ARG1 (c4 / change-01 :ARG1-of (o / observe-01 :location (c5 / cell-line :mod (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer") :ARG1-of (e / establish-01)))))) # ::id pmid_1627_1139.15 # ::date 2015-08-11T13:29:31 # ::file pmid_1627_1139_15.txt # ::snt Epigenetic control of LIF receptor expression by histone acetylation can account for the gain of LIF responsiveness. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (a / account-01 :ARG0 (c / control-01 :ARG1 (e2 / express-03 :ARG2 (r2 / receptor :mod "p2") :ARG3-of (a2 / acetylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "histone") :xref (x / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332")))) :mod (e / epigenetic)) :ARG1 (g / gain-02 :ARG1 (r / responsive-02 :ARG1 (p2 / protein :name (n / name :op1 "LIF") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")))))) # ::id pmid_1627_1139.16 # ::date 2015-08-11T13:51:10 # ::file pmid_1627_1139_16.txt # ::snt OSM and macrophage-derived cytokines suppressed proliferation of normal epithelial cells, but reduced inhibition or even stimulated proliferation was noted for preneoplastic cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (c / contrast-01 :ARG1 (s / suppress-01 :ARG0 (a / and :op1 (c6 / cytokine :name (n / name :op1 "OSM")) :op2 (c3 / cytokine :ARG1-of (d / derive-01 :ARG0 (m / macrophage)))) :ARG1 (p2 / proliferate-01 :ARG0 (c4 / cell :mod (n2 / normal) :source (e / epithelium)))) :ARG2 (n3 / note-01 :ARG1 (o / or :op1 (i / inhibit-01 :ARG1-of (r / reduce-01)) :op2 (p3 / proliferate-01 :ARG1-of (s2 / stimulate-01) :mod (e2 / even))) :location (c5 / cell :mod (p4 / preneoplasm)))) # ::id pmid_1627_1139.17 # ::date 2015-08-11T14:12:22 # ::file pmid_1627_1139_17.txt # ::snt These alterations likely contribute to the supporting effects that inflammation has on lung tumor progression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (c / contribute-01 :ARG0 (a / alter-01 :mod (t / this)) :ARG2 (a2 / affect-01 :ARG0 (i / inflame-01) :ARG1 (p / progress-01 :ARG1 (t2 / tumor :mod (l2 / lung))) :ARG0-of (s / support-01)) :ARG1-of (l / likely-01)) # ::id pmid_1627_1139.123 # ::date 2015-08-11T14:23:13 # ::file pmid_1627_1139_123.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1627_1139.124 # ::date 2015-08-11T14:28:30 # ::file pmid_1627_1139_124.txt # ::snt Transformed lung epithelial cell lines have grossly abnormal patterns of cytokine responsiveness # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (h / have-03 :ARG0 (c / cell-line :source (e / epithelium) :mod (l / lung) :ARG1-of (t / transform-01)) :ARG1 (p / pattern-01 :ARG1 (r / responsive-02 :ARG1 (c2 / cytokine)) :ARG1-of (n / normal-02 :polarity "-" :ARG1-of (g / gross-06)))) # ::id pmid_1627_1139.125 # ::date 2015-08-11T15:16:01 # ::file pmid_1627_1139_125.txt # ::snt We predicted that if oncogenic transformation of lung epithelial cells is associated with altered responsiveness to inflammation and reduced growth-inhibition, then the most prominent deviations from the regulatory phenotype should be seen in advanced lung cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (p / predict-01 :ARG0 (w / we) :ARG1 (r / recommend-01 :ARG1 (s / see-01 :ARG1 (d / deviate-01 :ARG1 (p3 / phenotype :ARG0-of (r2 / regulate-01)) :mod (p2 / prominent :degree (m / most))) :location (c / cell :mod (d2 / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer") :ARG1-of (a / advance-01)))) :condition (a2 / associate-01 :ARG1 (t / transform-01 :ARG1 (c3 / cell :mod (l2 / lung) :source (e / epithelium)) :ARG0-of (c4 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))) :ARG2 (a3 / and :op1 (r3 / responsive-02 :ARG1 (i / inflame-01) :ARG1-of (a4 / alter-01)) :op2 (i2 / inhibit-01 :ARG1 (g / grow-01) :ARG1-of (r4 / reduce-01)))))) # ::id pmid_1627_1139.126 # ::date 2015-08-11T15:44:07 # ::file pmid_1627_1139_126.txt # ::snt Therefore, as first step, we determined if responsiveness to members of the IL-6 family (IL-6, OSM and LIF) were detectable in established lines of malignant human non-small cell lung carcinoma cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / cause-01 :ARG1 (d / determine-01 :ARG0 (w / we) :ARG1 (d2 / detect-01 :ARG1 (r / responsive-02 :ARG1 (m / member :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n / name :op1 "IL-6"))) :example (a / and :op1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n3 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op3 (p5 / protein :name (n4 / name :op1 "LIF") :xref (x2 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003"))))) :ARG1-of (p / possible-01 :mode "interrogative") :location (c4 / cell-line :ARG1-of (e / establish-01) :mod (m3 / medical-condition :name (n5 / name :op1 "carcinoma") :mod (l2 / lung :mod (c3 / cell :mod (h / human) :mod (s2 / small :polarity "-") :ARG1-of (m2 / malignant-02)))))) :ARG4-of (s / step-01 :ord (o / ordinal-entity :value "1")))) # ::id pmid_1627_1139.127 # ::date 2015-08-11T16:17:32 # ::file pmid_1627_1139_127.txt # ::snt The responsiveness to the cytokines was defined by measurable phosphorylation of STAT and ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / define-01 :ARG0 (p / phosphorylate-01 :ARG1 (a / and :op1 (p3 / protein :name (n / name :op1 "STAT") :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")) :op2 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (m / measure-01 :ARG1-of (p2 / possible-01))) :ARG1 (r / responsive-02 :ARG1 (c / cytokine))) # ::id pmid_1627_1139.128 # ::date 2015-08-11T16:23:40 # ::file pmid_1627_1139_128.txt # ::snt This is a treatment reaction that is a measure for the level of active cytokine receptors and downstream signaling pathways in the target cells [14,16]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (r / react-01 :ARG1 (t2 / treat-04) :domain (t / this) :ARG0-of (m / measure-01 :ARG1 (a2 / and :op1 (l / level :degree-of (r2 / receptor :mod (c / cytokine) :ARG0-of (a / activity-06))) :op2 (l2 / level :degree-of (p / pathway :ARG0-of (s / signal-07 :source (d / downstream))))) :location (c2 / cell :ARG1-of (t3 / target-01))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 "14" :op2 "16"))))) # ::id pmid_1627_1139.129 # ::date 2015-08-12T05:01:57 # ::file pmid_1627_1139_129.txt # ::snt Normal type II epithelial cells and pulmonary fibroblasts were included in the analyses to gauge cell type-specific differences in signaling reactions (Fig. 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (i / include-01 :ARG1 (a / and :op1 (c / cell :source (e / epithelium) :mod (n / normal) :mod (t / type :name (n2 / name :op1 "II"))) :op2 (f / fibroblast :part-of (l / lung))) :ARG2 (a2 / analyze-01) :purpose (g / gauge-01 :ARG1 (d / differ-02 :ARG1 (c2 / cell) :ARG3 (r / react-01 :ARG0-of (s2 / signal-07)) :ARG1-of (s / specific-02 :ARG2 (t2 / type)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1"))) # ::id pmid_1627_1139.130 # ::date 2015-08-12T05:23:22 # ::file pmid_1627_1139_130.txt # ::snt Phosphorylation of STAT3 and ERK was sufficient for identifying responsiveness to cytokines in specific cell types (Fig. 1A shows representative immunoblots and Fig. 1B presents the quantitative data from independently performed experiments involving 5 separate matched cultures of type II epithelial cells and fibroblasts). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / suffice-01 :ARG0 (p / phosphorylate-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (i / identify-01 :ARG1 (r / responsive-02 :ARG1 (c / cytokine)) :location (c2 / cell :mod (t / type) :ARG1-of (s2 / specific-02))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1A" :ARG0-of (s3 / show-01 :ARG1 (i2 / immunoblot-01 :ARG0-of (r2 / represent-01)))) :op2 (f2 / figure :mod "1B" :ARG0-of (p4 / present-01 :ARG1 (d2 / data :mod (q / quantity) :source (e / experiment-01 :ARG1-of (p5 / perform-02 :ARG0-of (d3 / depend-01 :polarity "-")) :ARG2-of (i4 / involve-01 :ARG1 (c3 / culture :quant "5" :ARG1-of (s4 / separate-02) :ARG1-of (m / match-01) :consist-of (a3 / and :op1 (c4 / cell :source (e2 / epithelium) :mod (t2 / type :name (n3 / name :op1 "II"))) :op2 (f3 / fibroblast))))))))))) # ::id pmid_1627_1139.131 # ::date 2015-08-12T05:41:08 # ::file pmid_1627_1139_131.txt # ::snt In brief, normal type II epithelial cells showed the following features (Fig. 1A, top panel): OSM strongly activated phosphorylation of STAT3 and ERK, while IL-6 was less effective, and LIF did not produce any detectable response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / show-01 :ARG0 (c / cell :mod (t / type :name (n / name :op1 "II")) :source (e / epithelium) :ARG1-of (n2 / normal-02)) :ARG1 (f / feature :ARG1-of (f2 / follow-04) :example (c2 / contrast-01 :ARG1 (a2 / activate-01 :ARG0 (p / protein :name (n3 / name :op1 "OSM") :xref (x4 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n5 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1-of (s2 / strong-02)) :ARG2 (a4 / and :op1 (e3 / effective-04 :ARG0 (p5 / protein :name (n6 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :degree (l / less)) :op2 (p6 / produce-01 :polarity "-" :ARG0 (p7 / protein :name (n7 / name :op1 "LIF") :xref (x2 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :ARG1 (r / respond-01 :ARG1-of (d / detect-01 :ARG1-of (p8 / possible-01))))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "1A" :location (p9 / panel :mod (t2 / top)))) :ARG2-of (b / brief-01)) # ::id pmid_1627_1139.132 # ::date 2015-08-12T09:26:08 # ::file pmid_1627_1139_132.txt # ::snt EGF stimulated phosphorylation of ERK in the range of OSM, while insulin was minimally effective. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (s / stimulate-01 :ARG0 (p2 / protein :name (n / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :part-of (r / range-01 :ARG1 (p3 / protein :name (n3 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002"))))) :ARG2 (e / effective-04 :ARG0 (p4 / protein :name (n4 / name :op1 "insulin") :xref (x2 / xref :value "UNIPROT:INS_HUMAN" :prob "0.703")) :degree (m / minimal-02))) # ::id pmid_1627_1139.133 # ::date 2015-08-12T10:11:45 # ::file pmid_1627_1139_133.txt # ::snt Fibroblasts exhibited a prominent LIF response and a several-fold higher activation of ERK relative to STAT3 by IL-6 cytokines (Fig. 1A, bottom panel), in contrast to normal epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (f / fibroblast :ARG0-of (e / exhibit-01 :ARG1 (a / and :op1 (r / respond-01 :ARG0 f :ARG1 (p2 / protein :name (n / name :op1 "LIF") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :mod (p / prominent)) :op2 (a2 / activate-01 :ARG0 (c4 / cytokine :name (n5 / name :op1 "IL-6")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (h / high-02 :degree (m / more :quant (p4 / product-of :op1 (s / several))) :ARG1-of (r2 / relative-05 :ARG3 (p5 / protein :name (n6 / name :op1 "STAT3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1A") :location (p6 / panel :mod (b / bottom)))) :ARG2 (c2 / cell :ARG1-of (n4 / normal-02) :source (e3 / epithelium))) # ::id pmid_1627_1139.134 # ::date 2015-08-12T11:29:32 # ::file pmid_1627_1139_134.txt # ::snt The maximal level of receptor action in epithelial cells was reached after 15 min agonist treatment (Fig. 1D, example of OSM on normal type II epithelial cells). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (r / reach-01 :ARG1 (l / level :degree (m / maximal) :degree-of (a / act-02 :ARG0 (r2 / receptor)) :location (c / cell :source (e / epithelium))) :time (a2 / after :op1 (t / treat-04 :ARG2 (a3 / agonist) :duration (t2 / temporal-quantity :quant "15" :unit (m2 / minute)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1D" :example-of (p / protein :name (n / name :op1 "OSM") :location (c2 / cell :ARG1-of (n2 / normal-02) :mod (t3 / type :name (n3 / name :op1 "II")) :source (e3 / epithelium)) :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002"))))) # ::id pmid_1627_1139.135 # ::date 2015-08-12T11:59:37 # ::file pmid_1627_1139_135.txt # ::snt Deviations from the normal regulatory phenotype of epithelial cells were already evident in immortalized bronchial epithelial cells, HBE4 (Fig. 1A) and HBE137 (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (e / evidence-01 :ARG1 (d / deviate-01 :ARG1 (p / phenotype :ARG1-of (n / normal-02) :ARG0-of (r / regulate-01) :poss (c / cell :source (e2 / epithelium)))) :time (a / already) :location (c2 / cell :source (e3 / epithelium) :mod (b / bronchus) :ARG1-of (i / immortalize-03) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (c3 / cell-line :name (n2 / name :op1 "HBE4") :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1A"))) :op2 (c4 / cell-line :name (n3 / name :op1 "HBE137") :ARG1-of (s / show-01 :polarity "-")))))) # ::id pmid_1627_1139.136 # ::date 2015-08-12T12:28:08 # ::file pmid_1627_1139_136.txt # ::snt These cell lines responded to IL-6 cytokines like normal epithelial cells, but showed a detectable STAT3 signaling by LIF and a ~2-fold higher ERK activation by OSM and IL-6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (r / respond-01 :ARG0 (c2 / cell-line :mod (t / this)) :ARG1 (c3 / cytokine :name (n / name :op1 "IL-6")) :ARG1-of (r2 / resemble-01 :ARG2 (r3 / respond-01 :ARG0 (c4 / cell :ARG1-of (n2 / normal-02) :source (e / epithelium))))) :ARG2 (s / show-01 :ARG0 c2 :ARG1 (a / and :op1 (s2 / signal-07 :ARG0 (p / protein :name (n3 / name :op1 "STAT3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG2 (p3 / protein :name (n4 / name :op1 "LIF") :xref (x2 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :ARG1-of (d / detect-01 :ARG1-of (p2 / possible-01))) :op2 (a2 / activate-01 :ARG0 (a3 / and :op1 (p4 / protein :name (n5 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 c3) :ARG1 (e2 / enzyme :name (n7 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (h / high-02 :degree (m / more :quant (a4 / approximately :op1 (p6 / product-of :op1 "2")))))))) # ::id pmid_1627_1139.137 # ::date 2015-08-12T13:08:41 # ::file pmid_1627_1139_137.txt # ::snt More profound differences were detected in carcinoma lines (Fig. 1A and not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / detect-01 :ARG1 (d2 / differ-02 :mod (p / profound :degree (m / more))) :location (l / line :source (m2 / medical-condition :name (n / name :op1 "carcinoma"))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1A") :op2 (d5 / data :ARG1-of (s / show-01 :polarity "-"))))) # ::id pmid_1627_1139.138 # ::date 2015-08-12T13:21:10 # ::file pmid_1627_1139_138.txt # ::snt In carcinoma cell lines, the major trends included a strong STAT3 activation by LIF (ADLC, H125), an increased (ADLC, H23) or decreased STAT3 activation by IL-6 (H125, H324), a decreased ERK activation by EGF (H522), and a treatment-independent, constitutive activation of the ERK pathway (H23). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / include-91 :ARG1 (a / and :op1 (a2 / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "LIF") :location (a3 / and :op1 (c3 / cell-line :name (n4 / name :op1 "ADLC")) :op2 (c8 / cell-line :name (n5 / name :op1 "H125"))) :xref (x4 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :ARG1 (p2 / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (s / strong-02)) :op2 (o2 / or :op1 (a4 / activate-01 :ARG0 (p5 / protein :name (n6 / name :op1 "IL-6") :location (a7 / and :op1 c3 :op2 (c4 / cell-line :name (n11 / name :op1 "H23"))) :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 p2 :ARG1-of (i2 / increase-01)) :op2 (a5 / activate-01 :ARG0 (p3 / protein :name (n18 / name :op1 "IL-6") :location (a6 / and :op1 c8 :op2 (c5 / cell-line :name (n8 / name :op1 "H324"))) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 p2 :ARG1-of (d2 / decrease-01))) :op3 (a8 / activate-01 :ARG0 (p4 / protein :name (n14 / name :op1 "EGF") :location (c7 / cell-line :name (n15 / name :op1 "H522")) :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p12 / pathway :name (n13 / name :op1 "ERK")) :ARG1-of d2) :op4 (a9 / activate-01 :ARG1 (p13 / pathway :name (n16 / name :op1 "ERK") :location c4) :mod (c2 / constitutive) :ARG0-of (d4 / depend-01 :polarity "-" :ARG1 (t2 / treat-04)))) :ARG2 (t / trend-01 :ARG1-of (m / major-02)) :location (c / cell-line :source (m2 / medical-condition :name (n / name :op1 "carcinoma")))) # ::id pmid_1627_1139.139 # ::date 2015-08-12T14:17:12 # ::file pmid_1627_1139_139.txt # ::snt Despite the substantial changes in response patterns, STAT and ERK signaling in response to OSM was consistently high in all analyzed lung cancer cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (h / high-02 :ARG1 (s / signal-07 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "STAT") :xref (x2 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")) :op2 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG0-of (r / respond-01 :ARG1 (p3 / protein :name (n3 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")))) :manner (c / consistent-02) :location (c2 / cell-line :mod (a2 / all) :ARG1-of (a3 / analyze-01) :mod (d / disease :wiki "Lung_cancer" :name (n4 / name :op1 "lung" :op2 "cancer"))) :concession (c4 / change-01 :ARG1 (p4 / pattern :ARG1-of (r2 / respond-01)) :degree (s2 / substantial))) # ::id pmid_1627_1139.140 # ::date 2015-08-12T14:36:10 # ::file pmid_1627_1139_140.txt # ::snt Moreover, the cell-type and line specific differences in STAT3 and ERK signaling were not due different expression of the signaling proteins as demonstrated by the comparable expression level of total STAT3 and ERK proteins among the cell types (Fig. 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a4 / and :op2 (c / cause-01 :polarity "-" :ARG0 (e / express-03 :ARG2 (p3 / protein :ARG0-of (s3 / signal-07)) :ARG1-of (d3 / differ-02)) :ARG1 (a2 / and :op1 (d / differ-02 :ARG1 (t / type :mod (c2 / cell)) :ARG3 (s2 / signal-07 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "STAT3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :op2 (d2 / differ-02 :ARG3 s2 :ARG1-of (s / specific-02 :ARG2 (l / line)))) :ARG1-of (d4 / demonstrate-01 :ARG0 (l2 / level :degree-of (e2 / express-03 :ARG2 (a3 / and :op1 (p4 / protein :name (n3 / name :op1 "STAT3") :mod (t2 / total) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK") :mod t2 :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1-of (c3 / comparable-03) :location t))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id pmid_1627_1139.141 # ::date 2015-08-12T15:31:09 # ::file pmid_1627_1139_141.txt # ::snt Cell line-specific effect of cytokines on proliferation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (a / affect-01 :ARG0 (c / cytokine) :ARG1 (p / proliferate-01) :ARG1-of (s2 / specific-02 :ARG2 (c2 / cell-line))) # ::id pmid_1627_1139.142 # ::date 2015-08-12T15:35:09 # ::file pmid_1627_1139_142.txt # ::snt To relate cytokine signaling with effects on cell proliferation, representative lung cell types were cultured for 6 days in growth medium containing in addition increasing concentrations of OSM, IL-6 or LIF (Fig. 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (c / culture-01 :ARG1 (t / type :mod (c2 / cell :mod (l / lung)) :ARG0-of (r / represent-01)) :duration (t2 / temporal-quantity :quant "6" :unit (d / day)) :location (m / medium :mod (g / grow-01) :ARG0-of (c3 / contain-01 :ARG1 (c4 / concentrate-02 :ARG1 (o / or :op1 (p / protein :name (n / name :op1 "OSM") :xref (x2 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "LIF") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003"))) :ARG1-of (i / increase-01) :ARG1-of (a / add-02)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2")) :purpose (r2 / relate-01 :ARG1 (s / signal-07 :ARG0 (c5 / cytokine)) :ARG2 (a2 / affect-01 :ARG0 s :ARG1 (p4 / proliferate-01 :ARG0 (c6 / cell))))) # ::id pmid_1627_1139.143 # ::date 2015-08-12T15:53:57 # ::file pmid_1627_1139_143.txt # ::snt In all cell types, OSM reduced in a dose-dependent manner proliferation, with maximal effect at a concentration of 20 to 100 ng/ml. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (r / reduce-01 :ARG0 (p / protein :name (n / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (p2 / proliferate-01) :location (t / type :mod (c / cell) :mod (a / all)) :manner (d / depend-01 :ARG1 (d2 / dose)) :ARG1-of (a2 / affect-01 :degree (m / maximal :quant (c2 / concentration-quantity :unit (n2 / nanogram-per-milliliter) :quant (v / value-interval :op1 "20" :op2 "100"))))) # ::id pmid_1627_1139.144 # ::date 2015-08-12T16:22:34 # ::file pmid_1627_1139_144.txt # ::snt Maximal inhibition varied among the cell types and ranged from >80% (normal primary epithelial cells) to ~40% (HBE137, A549, fibroblasts) and ~20% (H23). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (a / and :op1 (v / vary-01 :ARG1 (i / inhibit-01 :degree (m / maximal)) :ARG5 (t / type :mod (c / cell))) :op2 (r / range-01 :ARG1 i :ARG3 (m2 / more-than :op1 (p / percentage-entity :value "80" :location (c2 / cell :ARG1-of (n / normal-02) :mod (p2 / primary) :source (e / epithelium)))) :ARG4 (a2 / and :op1 (a3 / approximately :op1 (p3 / percentage-entity :value "40" :location (a4 / and :op1 (c3 / cell-line :name (n2 / name :op1 "HBE137")) :op2 (c4 / cell-line :name (n3 / name :op1 "A549")) :op3 (f / fibroblast)))) :op2 (a5 / approximately :op1 (p4 / percentage-entity :value "20" :location (c5 / cell-line :name (n4 / name :op1 "H23"))))))) # ::id pmid_1627_1139.145 # ::date 2015-08-10T12:32:26 # ::file pmid_1627_1139_145.txt # ::snt IL-6 and LIF did not appreciably alter proliferation of epithelial or fibroblastic cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (a / alter-01 :polarity "-" :ARG0 (a2 / and :op1 (p / protein :wiki "Interleukin_6" :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p2 / protein :wiki "Leukemia_inhibitory_factor" :name (n2 / name :op1 "LIF") :xref (x / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003"))) :ARG1 (p3 / proliferate-01 :ARG0 (o / or :op1 (c / cell :mod (e / epithelium)) :op2 (c2 / cell :mod (f / fibroblast)))) :ARG1-of (a4 / appreciate-03 :ARG1-of (p4 / possible-01))) # ::id pmid_1627_1139.146 # ::date 2015-08-10T19:49:01 # ::file pmid_1627_1139_146.txt # ::snt The comparative analyses also indicated that immortalization of epithelial cells with the E6E7 gene (HBE4 or HBE137) or constitutive activation of ERK pathway (H23) correlated with a lower growth inhibition by OSM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (i / indicate-01 :ARG0 (a / analyze-01 :ARG0-of (c / compare-01)) :ARG1 (o / or :op1 (i2 / immortalize-03 :ARG1 (c3 / cell :mod (e / epithelium) :ARG1-of (m2 / mean-01 :ARG2 (o2 / or :op1 (c5 / cell-line :name (n4 / name :op1 "HBE4")) :op2 (c6 / cell-line :name (n5 / name :op1 "HBE137"))))) :ARG2 (g / gene :name (n / name :op1 "E6E7"))) :op2 (a4 / activate-01 :ARG1 (p / pathway :name (n3 / name :op1 "ERK")) :ARG0-of (c4 / constitute-01) :location (c7 / cell-line :name (n6 / name :op1 "H23"))) :ARG1-of (c2 / correlate-01 :ARG2 (i3 / inhibit-01 :ARG0 (p2 / protein :name (n2 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1-of (g2 / grow-01) :ARG1-of (l2 / low-04 :degree (m / more))))) :mod (a2 / also)) # ::id pmid_1627_1139.147 # ::date 2015-08-10T20:12:21 # ::file pmid_1627_1139_147.txt # ::snt The same cells were tested for growth in the presence of conditioned medium from lipopolysaccaride (LPS) activated macrophages. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (t / test-01 :ARG1 (c / cell :ARG1-of (s / same-01)) :ARG2 (g / grow-01 :condition (p / present-02 :ARG1 (m / medium :source (m2 / macrophage :ARG1-of (a / activate-01 :ARG0 (m4 / molecular-physical-entity :name (n / name :op1 "lipopolysaccaride")))) :ARG1-of (c2 / condition-02))))) # ::id pmid_1627_1139.148 # ::date 2015-08-10T20:27:48 # ::file pmid_1627_1139_148.txt # ::snt Such medium is considered to contain a physiologically relevant mixture of inflammatory mediators (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (c / consider-01 :ARG1 (c2 / contain-01 :ARG0 (m / medium :mod (s / such)) :ARG1 (m2 / mix-01 :ARG1 (m4 / molecular-physical-entity :ARG1-of (i / inflame-01) :ARG0-of (m3 / mediate-01)) :ARG1-of (r2 / relevant-01 :mod (p / physiological)))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "1"))) # ::id pmid_1627_1139.149 # ::date 2015-08-10T20:37:37 # ::file pmid_1627_1139_149.txt # ::snt The LPS macrophage medium suppressed the proliferation of epithelial cells in a dose-dependent fashion (Fig. 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (s / suppress-01 :ARG0 (m / medium :mod (m2 / molecular-physical-entity :name (n / name :op1 "LPS") :mod (m3 / macrophage) :xref (x / xref :value "PUBCHEM:53481794" :prob "9.905254"))) :ARG1 (p / proliferate-01 :ARG0 (c / cell :mod (e / epithelium)) :manner (f / fashion :ARG0-of (d / depend-01 :ARG1 (d2 / dose)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2"))) # ::id pmid_1627_1139.150 # ::date 2015-08-10T20:52:14 # ::file pmid_1627_1139_150.txt # ::snt Suppression ranged from >80% (primary epithelial cells and A549) to <20% in HBE137 and H23. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (r / range-01 :ARG1 (s / suppress-01) :ARG3 (m2 / more-than :op1 (p / percentage-entity :value "80" :location (a / and :op1 (c / cell :mod (e / epithelium :mod (p3 / primary))) :op2 (c2 / cell-line :name (n / name :op1 "A549"))))) :ARG4 (l2 / less-than :op1 (p2 / percentage-entity :value "20" :location (a2 / and :op1 (c3 / cell-line :name (n2 / name :op1 "HBE137")) :op2 (c4 / cell-line :name (n3 / name :op1 "H23")))))) # ::id pmid_1627_1139.151 # ::date 2015-08-10T21:08:13 # ::file pmid_1627_1139_151.txt # ::snt In contrast, the same treatment led to enhanced proliferation of fibroblasts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (c / contrast-01 :ARG2 (l / lead-03 :ARG0 (t / treat-04 :ARG1-of (s / same-01)) :ARG2 (p / proliferate-01 :ARG0 (f / fibroblast) :ARG1-of (e / enhance-01)))) # ::id pmid_1627_1139.152 # ::date 2015-08-10T21:15:29 # ::file pmid_1627_1139_152.txt # ::snt Taken together, these data indicated that cytokine responsiveness and growth regulation by OSM and inflammatory mediators are indeed subject to alterations in lung epithelial cells in part as a function of immortalization and transformation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (i / indicate-01 :ARG0 (d / data :mod (t / this) :ARG1-of (t2 / take-01 :mod (t3 / together))) :ARG1 (s / subject-02 :ARG1 (a2 / and :op1 (r / responsive-02 :ARG1 (c2 / cytokine)) :op2 (r2 / regulate-01 :ARG0 (a3 / and :op1 (p3 / protein :name (n2 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (m3 / molecular-physical-entity :ARG0-of (m / mediate-01) :ARG0-of (i3 / inflame-01))) :ARG1 (g / grow-01))) :ARG2 (a / alter-01 :location (c / cell :mod (e2 / epithelium) :mod (l / lung))) :mod (i2 / indeed) :ARG1-of (f / function-01 :ARG0 (a4 / and :op1 (i4 / immortalize-03) :op2 (t5 / transform-01)) :mod (p2 / part)))) # ::id pmid_1627_1139.153 # ::date 2015-08-10T21:43:03 # ::file pmid_1627_1139_153.txt # ::snt Characteristic changes in the cellular response patterns may serve as markers for the transformation process or may even contribute functionally to tumorigenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (p / possible-01 :ARG1 (o / or :op1 (s / serve-01 :ARG0 (c / change-01 :ARG1 (p2 / pattern-01 :ARG1 (r / respond-01 :ARG0 (c3 / cell))) :ARG1-of (c2 / characteristic-02)) :ARG1 (m2 / marker :purpose (p3 / process-02 :ARG1 (t3 / transform-01)))) :op2 (c4 / contribute-01 :ARG0 c :ARG2 (c5 / create-01 :ARG1 (t / tumor)) :manner (f / function-01) :mod (e / even)))) # ::id pmid_1627_1139.154 # ::date 2015-08-10T22:06:09 # ::file pmid_1627_1139_154.txt # ::snt One of the key questions is at what stage in the transformation of lung epithelial cells are these changes established. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (q / question-01 :quant "1" :ARG1 (s / stage-02 :time (a / amr-unknown) :subevent-of (t / transform-01 :ARG1 (c / cell :mod (l / lung) :mod (e / epithelium))) :time-of (c2 / change-01 :mod (t2 / this) :ARG1-of (e2 / establish-01))) :ARG1-of (i / include-91 :ARG2 (q2 / question :ARG2-of (k / key-02)))) # ::id pmid_1627_1139.155 # ::date 2015-08-10T22:31:32 # ::file pmid_1627_1139_155.txt # ::snt To address this question, we used short-term primary cultures of non-immortalized epithelial cells derived from normal and pathologically distinct stages of premalignant lesions sampled by brushing during bronchoscopy of patients. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (c / culture-01 :ARG1 (c2 / cell :mod (e / epithelium) :ARG1-of (d / derive-01 :ARG2 (a2 / and :op1 (s2 / stage :ARG1-of (n / normal-02)) :op2 (s3 / stage) :mod (d2 / distinct :mod (p3 / pathology)) :topic (l / lesion :mod (p2 / premalignant) :ARG1-of (s4 / sample-01 :time (b2 / bronchoscopy :beneficiary (p5 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)))) :manner (b / brush-01))))) :ARG1-of (i / immortalize-03 :polarity "-")) :mod (p / primary) :mod (t2 / term :ARG1-of (s / short-07))) :purpose (a / address-01 :ARG0 w :ARG1 (q / question-01 :mod (t / this)))) # ::id pmid_1627_1139.156 # ::date 2015-08-10T23:25:53 # ::file pmid_1627_1139_156.txt # ::snt The experimental approach also allowed us to establish the more basic information of what is the cytokine responsiveness of normal epithelial cells and what is the range among individuals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / allow-01 :ARG0 (a2 / approach-02 :ARG1-of (e / experiment-01)) :ARG1 (e2 / establish-01 :ARG0 (w / we) :ARG1 (i / information :mod (b / basic :degree (m / more)) :topic (a4 / and :op1 (r / responsive-02 :ARG0 (c / cell :mod (e3 / epithelium) :ARG1-of (n2 / normal-02)) :ARG1 (c2 / cytokine) :degree (a5 / amr-unknown)) :op2 (r2 / range-01 :ARG2 (a6 / amr-unknown) :ARG5 (i2 / individual :ARG1-of (i3 / include-91 :ARG2 (i4 / individual))))))) :mod (a3 / also)) # ::id pmid_1627_1139.157 # ::date 2015-08-10T23:41:17 # ::file pmid_1627_1139_157.txt # ::snt Application of primary epithelial cells derived from bronchial brushing # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (a2 / apply-02 :ARG1 (c / cell :mod (p / primary) :mod (e / epithelium) :ARG1-of (d / derive-01 :ARG2 (b / brush-01 :mod (b2 / bronchus))))) # ::id pmid_1627_1139.158 # ::date 2015-08-10T23:46:55 # ::file pmid_1627_1139_158.txt # ::snt Epithelial cell cultures were established from the brushed bronchial epithelium. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (e / establish-01 :ARG1 (c / culture-01 :ARG1 (c2 / cell :mod (e2 / epithelium))) :source (e3 / epithelium :mod (b / bronchus) :ARG1-of (b2 / brush-01))) # ::id pmid_1627_1139.159 # ::date 2015-08-10T23:50:34 # ::file pmid_1627_1139_159.txt # ::snt Biopsies of the same sites were processed for pathological and cytological evaluation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (p / process-01 :ARG1 (b / biopsy-101 :ARG1 (s / site :ARG1-of (s2 / same-01))) :purpose (a / and :op1 (e / evaluate-01 :mod (p2 / pathology)) :op2 (e2 / evaluate-01 :mod (c / cytology)))) # ::id pmid_1627_1139.160 # ::date 2015-08-10T23:55:26 # ::file pmid_1627_1139_160.txt # ::snt The pathological findings (normal, metaplasia, dysplasia or non-invasive carcinoma in situ) were subsequently applied in the interpretation of the signaling data (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (a / apply-02 :ARG1 (t2 / thing :ARG1-of (f / find-01) :mod (p / pathology) :example (o / or :op1 (n / normal-02) :op2 (m / metaplasia) :op3 (d / dysplasia) :op4 (c / carcinoma :ARG0-of (i / invade-01 :polarity "-" :ARG1 (s / situ))))) :ARG2 (i2 / interpret-01 :ARG1 (d2 / data :ARG0-of (s3 / signal-07))) :manner (s2 / subsequent) :ARG1-of (d3 / describe-01 :ARG0 (t / table :mod "2"))) # ::id pmid_1627_1139.161 # ::date 2015-08-11T00:03:03 # ::file pmid_1627_1139_161.txt # ::snt No cases of invasive carcinoma or advanced lung cancer were included. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / include-01 :ARG1 (o2 / or :op1 (c / case-04 :polarity "-" :ARG1 (c2 / carcinoma :ARG0-of (i3 / invade-01))) :op2 (c3 / case-04 :polarity "-" :ARG1 (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer") :ARG1-of (a / advance-01))))) # ::id pmid_1627_1139.162 # ::date 2015-08-11T00:11:17 # ::file pmid_1627_1139_162.txt # ::snt From May 2000 to March 2005, 192 separate brushings were taken from 96 patients (EC-1 to EC-96). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (t / take-01 :ARG1 (b / brush-01 :quant "192" :ARG1-of (s / separate-02)) :ARG2 (p / person :quant "96" :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient))) :time (d / date-interval :op1 (d2 / date-entity :month "5" :year "2000") :op2 (d3 / date-entity :month "3" :year "2005")) :mod (v / value-interval :op1 (c / cell-line :name (n / name :op1 "EC-1")) :op2 (c2 / cell-line :name (n2 / name :op1 "EC-96")))) # ::id pmid_1627_1139.163 # ::date 2015-08-11T00:42:33 # ::file pmid_1627_1139_163.txt # ::snt From these, 113 brushings (59%) yielded sufficient epithelial cells that expanded to cultures suitable for functional analyses. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (y / yield-01 :ARG0 (b / brush-01 :quant "113" :ARG1-of (i / include-91 :ARG2 (b2 / brush-01 :mod (t / this)) :ARG3 (p / percentage-entity :value "59"))) :ARG1 (c / cell :mod (e / epithelium) :ARG0-of (s / suffice-01) :ARG1-of (e2 / expand-01 :ARG4 (c2 / culture :ARG1-of (s2 / suitable-04 :ARG2 (a / analyze-01 :ARG1-of (f2 / function-01))))))) # ::id pmid_1627_1139.164 # ::date 2015-08-11T01:04:40 # ::file pmid_1627_1139_164.txt # ::snt Approximately 50% of sites initially judged to be abnormal by bronchoscopy proved to be normal by histology. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (p2 / prove-01 :ARG0 (h / histology) :ARG1 (n2 / normal-02 :ARG1 (s / site :ARG1-of (i / include-91 :ARG2 (s2 / site :ARG1-of (j / judge-01 :ARG0 (b / bronchoscopy) :ARG2 (n / normal-02 :polarity "-" :ARG1 s2) :time (i2 / initial))) :ARG3 (a2 / approximately :op1 (p / percentage-entity :value "50")))))) # ::id pmid_1627_1139.165 # ::date 2015-08-11T01:25:52 # ::file pmid_1627_1139_165.txt # ::snt Based on immunostaining, every cell preparation consisted of >95% cytokeratin-positive epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / consist-01 :ARG1 (p / prepare-01 :ARG1 (c2 / cell) :mod (e / every)) :ARG2 (c3 / cell :mod (e2 / epithelium) :mod (p3 / positive :topic (p4 / protein :name (n / name :op1 "cytokeratin") :xref (x / xref :value "UNIPROT:K2C1_HUMAN" :prob "0.382"))) :quant (m2 / more-than :op1 (p2 / percentage-entity :value "95"))) :ARG1-of (b / base-02 :ARG0 (i / immunostain-01))) # ::id pmid_1627_1139.166 # ::date 2015-08-11T01:40:31 # ::file pmid_1627_1139_166.txt # ::snt All cultures derived from normal and abnormal sites showed essentially the same epithelial cell morphology. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (s / show-01 :ARG0 (c / culture :mod (a / all) :ARG1-of (d / derive-01 :ARG2 (a2 / and :op1 (s2 / site :ARG1-of (n / normal-02)) :op2 (s3 / site :ARG1-of (n2 / normal-02 :polarity "-"))))) :ARG1 (m / morphology :poss (c2 / cell :mod (e2 / epithelium)) :ARG1-of (s4 / same-01)) :manner (e / essential)) # ::id pmid_1627_1139.167 # ::date 2015-08-11T01:48:45 # ::file pmid_1627_1139_167.txt # ::snt To determine whether or not the primary cultures demonstrated any gross chromosomal abnormalities, cells were analyzed by SKY. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / analyze-01 :ARG1 (c / cell) :manner (k / karyotype :mod (s / spectrum)) :purpose (d / determine-01 :ARG1 (d2 / demonstrate-01 :mode "interrogative" :ARG0 (c2 / culture :mod (p / primary)) :ARG1 (n2 / normal-02 :polarity "-" :ARG1 (c3 / chromosome :xref (x / xref :value "GO:0005694" :prob "0.8")) :ARG1-of (g2 / gross-06))))) # ::id pmid_1627_1139.168 # ::date 2015-08-11T02:25:52 # ::file pmid_1627_1139_168.txt # ::snt With the exception of one carcinoma, the cells showed normal karyotypes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (s / show-01 :ARG0 (c / cell) :ARG1 (k / karyotype :ARG1-of (n / normal-02)) :ARG2-of (e / except-01 :ARG1 (c2 / carcinoma :quant "1"))) # ::id pmid_1627_1139.169 # ::date 2015-08-11T02:39:08 # ::file pmid_1627_1139_169.txt # ::snt The carcinoma cell culture carried a chromosome 10 deletion (q11.2-q22) in all metaphase spreads. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (c / carry-01 :ARG0 (c2 / culture :mod (c3 / cell :mod (c4 / carcinoma))) :ARG1 (d / delete-01 :ARG1 (c5 / chromosome :mod "10" :ARG1-of (m2 / mean-01 :ARG2 (v / value-interval :op1 (d2 / dna-sequence :name (n / name :op1 "q11.2")) :op2 (d3 / dna-sequence :name (n2 / name :op1 "q22")))) :xref (x / xref :value "GO:0005694" :prob "0.8")) :location (s / spread-02 :mod (a / all) :mod (m / metaphase)))) # ::id pmid_1627_1139.170 # ::date 2015-08-11T02:44:45 # ::file pmid_1627_1139_170.txt # ::snt Paired epithelial cell cultures indicate the occurrence of altered cytokine responsiveness at early stage of transformation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (i / indicate-01 :ARG0 (c / culture :mod (c2 / cell :mod (e / epithelium) :mod (p / paired) :ARG1-of (p2 / pair-01))) :ARG1 (r / responsive-02 :ARG1 (c3 / cytokine :ARG1-of (a / alter-01)) :time (s / stage :mod (e2 / early) :poss (t / transform-01)))) # ::id pmid_1627_1139.171 # ::date 2015-08-11T23:42:06 # ::file pmid_1627_1139_171.txt # ::snt The cytokine responsiveness of the epithelial cells was determined by the activation of signaling and by the effect on DNA synthesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (d / determine-01 :ARG0 (a2 / and :op1 (a / activate-01 :ARG1 (s2 / signal-07)) :op2 (a3 / affect-01 :ARG1 (s / synthesize-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"))))) :ARG1 (r / responsive-02 :ARG0 (c2 / cell :mod (e / epithelium)) :ARG1 (c / cytokine))) # ::id pmid_1627_1139.172 # ::date 2015-08-11T23:51:29 # ::file pmid_1627_1139_172.txt # ::snt Signaling was measured in first passage subcultures by treatment with cytokines and growth factors for 15 min followed by immunodetection of the phosphorylated signaling proteins (representative example in Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (m / measure-01 :ARG1 (s / signal-07) :ARG2 (t / treat-04 :ARG2 (a / and :op1 (c / cytokine) :op2 (s4 / small-molecule :name (n / name :op1 "growth_factor"))) :duration (t2 / temporal-quantity :quant "15" :unit (m2 / min)) :ARG2-of (f2 / follow-01 :ARG1 (i / immunodetect-01 :ARG1 (s3 / signal-07 :ARG0 (p2 / protein :ARG3-of (p3 / phosphorylate-01)))))) :location (p / pass-03 :ARG1 (s2 / subculture) :mod (o / ordinal-entity :value "1")) :ARG1-of (d / describe-01 :ARG0 (e / example :ARG0-of (r / represent-01) :mod (f3 / figure :mod "3")))) # ::id pmid_1627_1139.173 # ::date 2015-08-12T00:21:31 # ::file pmid_1627_1139_173.txt # ::snt The level of phosphorylated STAT1, STAT3 and ERK1/2 were quantified and expressed relative to the level of these proteins in OSM-treated normal cultures in each pair (Fig. 4A–F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a3 / and :op1 (q / quantify-01 :ARG1 (a / and :op1 (l3 / level :quant-of (p / protein :name (n / name :op1 "STAT1") :ARG3-of (p3 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))) :op2 (l4 / level :quant-of (p2 / protein :name (n2 / name :op1 "STAT3") :ARG3-of p3 :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :op3 (l5 / level :quant-of (e4 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of p3)))) :op2 (e2 / express-01 :ARG2 a) :ARG1-of (r / relative-05 :ARG3 (a4 / and :op1 l3 :op2 l4 :op3 l5 :location (c / culture :ARG1-of (n4 / normal-02) :ARG1-of (t / treat-04 :ARG2 (p4 / protein :name (n5 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :location (p5 / pair :mod (e / each)))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B") :op3 (f3 / figure :mod "4C") :op4 (f4 / figure :mod "4D") :op5 (f5 / figure :mod "4E") :op6 (f6 / figure :mod "4F")))) # ::id pmid_1627_1139.174 # ::date 2015-08-12T00:43:33 # ::file pmid_1627_1139_174.txt # ::snt The analyses of normal bronchial epithelial cells defined the following response pattern. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (d / define-01 :ARG0 (a / analyze-01 :ARG1 (c / cell :mod (b / bronchus) :mod (e / epithelium) :ARG1-of (n / normal-02))) :ARG1 (p / pattern-01 :ARG1 (r / respond-01 :ARG1-of (f / follow-04)))) # ::id pmid_1627_1139.175 # ::date 2015-08-10T15:13:54 # ::file pmid_1627_1139_175.txt # ::snt The reaction to cytokine treatment (Fig. 3) was comparable to that of type II epithelial cells (Fig. 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / comparable-03 :ARG1 (r / react-01 :ARG1 (t / treat-04 :ARG2 (c3 / cytokine)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3"))) :ARG2 (r2 / react-01 :ARG0 (c2 / cell-line :mod (e / epithelium) :mod (t2 / type :mod "II")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1A")))) # ::id pmid_1627_1139.176 # ::date 2015-08-10T15:14:09 # ::file pmid_1627_1139_176.txt # ::snt Data from 63 separate preparations of normal bronchial epithelial cell cultures indicated that basal level of phosphorylated ERK was consistently low (7.5 ± 5.6 % of OSM level; mean ± SD) and the basal levels of phosphorylated STAT3 and STAT1 were generally low to non-detectable. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (i / indicate-01 :ARG0 (d / data :source (p / prepare-01 :quant "63" :ARG1 (c / culture-01 :ARG1 (c2 / cell :mod (e / epithelium) :mod (b / bronchus) :ARG1-of (n / normal-02))) :ARG1-of (s3 / separate-01))) :ARG1 (a / and :op1 (l / low-04 :ARG1 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :mod (b2 / basal) :ARG1-of (e3 / equal-01 :ARG2 (v2 / value-interval :op1 (p3 / product-of :op1 (p4 / percentage-entity :value "7.5" :ARG2-of (a2 / add-02 :ARG1 (p5 / percentage-entity :value "5.6"))) :op2 (l3 / level :quant-of (p6 / protein :name (n3 / name :op1 "OSM") :xref (x2 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")))) :op2 (p8 / product-of :op1 (p11 / percentage-entity :value "7.5" :ARG2-of (s / subtract-01 :ARG1 p5)) :op2 l3) :condition (d3 / deviate-01 :mod (m / mean) :ARG1-of (s2 / standard-02))))) :manner (c3 / consistent-02)) :op2 (v / value-interval :op1 (l5 / low-04) :op2 (d2 / detect-01 :ARG1-of (p10 / possible-01 :polarity "-")) :domain (l4 / level :quant-of (a3 / and :op1 (p7 / protein :name (n4 / name :op1 "STAT3") :ARG3-of p2 :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (p9 / protein :name (n5 / name :op1 "STAT1") :ARG3-of p2 :xref (x3 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))) :mod b2) :ARG1-of (g / general-02)))) # ::id pmid_1627_1139.177 # ::date 2015-08-10T15:33:45 # ::file pmid_1627_1139_177.txt # ::snt OSM prominently activated ERK (Fig. 4A &4B) and STAT3 (Fig. 4C &4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (a2 / activate-01 :ARG0 (p / protein :name (n / name :op1 "OSM") :xref (x2 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B")))) :op2 (a4 / activate-01 :ARG0 p :ARG1 (p4 / protein :name (n3 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f3 / figure :mod "4C") :op2 (f4 / figure :mod "4D")))) :manner (p2 / prominent)) # ::id pmid_1627_1139.178 # ::date 2015-08-10T15:37:57 # ::file pmid_1627_1139_178.txt # ::snt The response was uniformly high among cultures from different individuals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (h / high-02 :ARG1 (r / respond-01) :manner (u / uniform) :location (c / culture-01 :source (i / individual :ARG1-of (d / differ-02)))) # ::id pmid_1627_1139.179 # ::date 2015-08-10T15:43:31 # ::file pmid_1627_1139_179.txt # ::snt IL-6 response, although quite variable among individuals, was consistently below that of OSM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (h / have-concession-91 :ARG1 (r / respond-01 :ARG0 (p / protein :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (e / equal-01 :ARG2 (b / below :op1 (r2 / respond-01 :ARG0 (p2 / protein :name (n2 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002"))) :manner (c / consistent-02)))) :ARG2 (v / vary-01 :ARG1 r :location (i / individual) :degree (q / quite))) # ::id pmid_1627_1139.180 # ::date 2015-08-10T15:49:14 # ::file pmid_1627_1139_180.txt # ::snt The level of activated ERK was 37 ± 18% of OSM (Fig. 4A &4B) and activated STAT3 was 63 ± + 27% (Fig. 4C &4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK") :ARG1-of (a2 / activate-01) :ARG1-of (e2 / equal-01 :ARG2 (v / value-interval :op1 (p / product-of :op1 (p2 / percentage-entity :value "37" :ARG2-of (a3 / add-02 :ARG1 (p3 / percentage-entity :value "18"))) :op2 (p4 / protein :name (n3 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002"))) :op2 (p6 / product-of :op1 (p7 / percentage-entity :value "37" :ARG2-of (s / subtract-01 :ARG1 p3)) :op2 p4))) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B")))) :op2 (p5 / protein :name (n2 / name :op1 "STAT3") :ARG1-of a2 :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (f3 / figure :mod "4C") :op2 (f4 / figure :mod "4D"))) :ARG1-of (e3 / equal-01 :ARG2 (v2 / value-interval :op1 (p10 / product-of :op1 (p8 / percentage-entity :value "63" :ARG2-of (a5 / add-02 :ARG1 (p9 / percentage-entity :value "27"))) :op2 p4) :op2 (p11 / product-of :op1 (p12 / percentage-entity :value "63" :ARG2-of (s2 / subtract-01 :ARG1 p9)) :op2 p4))) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) # ::id pmid_1627_1139.181 # ::date 2015-08-10T22:24:02 # ::file pmid_1627_1139_181.txt # ::snt The two-fold lower activation of ERK relative to STAT3 by IL-6 is due to the difference in signaling by the IL-6 and OSM receptor [16,22]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / cause-01 :ARG0 (d / differ-02 :ARG1 (s / signal-07 :ARG0 (r2 / receptor :mod "p")) :ARG2 (s2 / signal-07 :ARG0 (r3 / receptor :mod (p4 / protein :name (n4 / name :op1 "OSM") :xref (x2 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002"))))) :ARG1 (a / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (l / low-04 :degree (m / more) :ARG2-of (r / relative-05 :ARG3 (p2 / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :degree (p3 / product-of :op1 "2")) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "16" :op2 "22"))))) # ::id pmid_1627_1139.182 # ::date 2015-08-10T22:37:47 # ::file pmid_1627_1139_182.txt # ::snt LIF did not elicit a measurable ERK and STAT3 signaling in any of normal epithelial cell culture. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / elicit-01 :polarity "-" :ARG0 (p / protein :name (n / name :op1 "LIF") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")) :ARG1 (s / signal-07 :ARG0 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :ARG1-of (m / measure-01 :ARG1-of (p2 / possible-01))) :location (c / culture-01 :ARG1 (c2 / cell :mod (e3 / epithelium) :ARG1-of (n4 / normal-02) :mod (a2 / any)))) # ::id pmid_1627_1139.183 # ::date 2015-08-10T22:44:35 # ::file pmid_1627_1139_183.txt # ::snt EGF activated ERK to 90 ± 29% of OSM level (Fig. 4A &4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :ARG1-of (e2 / equal-01 :ARG2 (v / value-interval :op1 (p2 / product-of :op1 (p3 / percentage-entity :value "90" :ARG2-of (a3 / add-02 :ARG1 (p4 / percentage-entity :value "29"))) :op2 (l / level :quant-of (p5 / protein :name (n3 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")))) :op2 (p6 / product-of :op1 (p7 / percentage-entity :value "90" :ARG2-of (s / subtract-01 :ARG1 p4)) :op2 l))) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B")))) # ::id pmid_1627_1139.184 # ::date 2015-08-11T21:30:12 # ::file pmid_1627_1139_184.txt # ::snt EGF generally had no measurable effect on STAT3 even when the cells were treated with EGF for longer than 15 minutes (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (a / affect-01 :polarity "-" :ARG0 (p / protein :name (n / name :op1 "EGF") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p2 / protein :name (n2 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (m / measure-01 :ARG1-of (p3 / possible-01)) :ARG1-of (g / general-02) :concession (e / even-when :op1 (t / treat-04 :ARG1 (c / cell) :ARG2 p :duration (m2 / more-than :op1 (t2 / temporal-quantity :quant "15" :unit (m3 / minute))))) :ARG1-of (s / show-01 :polarity "-")) # ::id pmid_1627_1139.185 # ::date 2015-08-11T21:50:18 # ::file pmid_1627_1139_185.txt # ::snt In all cases, IFNγ did not appreciably activate ERK and STAT3, but yielded highest level of STAT1 phosphorylation (2441 ± 2073% of OSM level (Fig. 4E &4F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (a / activate-01 :polarity "-" :ARG0 (p / protein :name (n / name :op1 "IFNγ") :xref (x4 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.252")) :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :degree (a3 / appreciate-03 :ARG1-of (p3 / possible-01))) :ARG2 (y / yield-01 :ARG0 p :ARG1 (l / level :ARG1-of (h / high-02 :degree (m / most)) :degree-of (p4 / phosphorylate-01 :ARG1 (p5 / protein :name (n4 / name :op1 "STAT1") :xref (x2 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))) :ARG1-of (e2 / equal-01 :ARG2 (v / value-interval :op1 (p6 / product-of :op1 (p7 / percentage-entity :value "2441" :ARG2-of (a4 / add-02 :ARG1 (p8 / percentage-entity :value "2073"))) :op2 (l2 / level :quant-of (p9 / protein :name (n5 / name :op1 "OSM") :xref (x3 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")))) :op2 (p10 / product-of :op1 (p11 / percentage-entity :value "2441" :ARG2-of (s / subtract-01 :ARG1 p8)) :op2 l2))))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "4E") :op2 (f2 / figure :mod "4F"))) :mod (c2 / case-04 :mod (a6 / all))) # ::id pmid_1627_1139.186 # ::date 2015-08-11T22:09:11 # ::file pmid_1627_1139_186.txt # ::snt The IFNγ response from patient to patient showed the highest variability among the cytokine responses, even though paired cultures from individual patients exhibited highly consistent levels of STAT1 activation by IFNγ. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (s / show-01 :ARG0 (r / respond-01 :ARG0 (p / protein :name (n / name :op1 "IFNγ") :xref (x1 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.252")) :source (p7 / person :ARG0-of (h5 / have-org-role-91 :ARG2 (p5 / patient)))) :ARG1 (h / high-02 :ARG1 (v / vary-01 :ARG1 (r2 / respond-01 :ARG0 p :ARG1-of (i / include-91 :ARG2 (r3 / respond-01 :ARG1 (c3 / cytokine))))) :degree (m / most)) :concession (e / exhibit-01 :ARG0 (c / culture-01 :ARG1-of (p3 / pair-01) :source (p4 / person :mod (i2 / individual) :ARG0-of h5)) :ARG1 (l / level :degree-of (a / activate-01 :ARG0 p :ARG1 (p6 / protein :name (n3 / name :op1 "STAT1") :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))) :ARG1-of (c2 / consistent-02 :ARG1-of (h4 / high-02))))) # ::id pmid_1627_1139.187 # ::date 2015-08-11T22:27:25 # ::file pmid_1627_1139_187.txt # ::snt The reproducibility of detecting comparable patterns in independently derived cell cultures was assessed in those paired cultures in which the samples were initially classified as "abnormal" (or "suspicious") by autofluorescence bronchoscopy but proved normal by subsequent pathological analysis (Fig. 4A,C &4E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / assess-01 :ARG1 (r / reproduce-01 :ARG0 (d / detect-01 :ARG1 (p2 / pattern :ARG1-of (c / comparable-03))) :ARG1-of (p / possible-01) :location (c2 / culture-01 :ARG1 (c3 / cell) :ARG1-of (d2 / derive-01 :ARG1-of (d4 / depend-01 :polarity "-")))) :location (c4 / culture-01 :ARG1-of (p3 / pair-01) :location-of (c5 / classify-01 :ARG0 (b / bronchoscopy :mod (a3 / autofluorescence)) :ARG1 (t / thing :ARG1-of (s / sample-01)) :ARG2 (o / or :op1 (n / normal-02 :polarity "-" :ARG1 c4) :op2 (s2 / suspicious)) :ARG1-of (c6 / contrast-01 :ARG2 (p5 / prove-01 :ARG0 (a4 / analyze-01 :mod (p6 / pathology) :mod (s3 / subsequent)) :ARG2 (n2 / normal-02 :ARG1 c4))) :time (i / initial)) :mod (t2 / that)) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4C") :op3 (f3 / figure :mod "4E")))) # ::id pmid_1627_1139.188 # ::date 2015-08-12T10:40:38 # ::file pmid_1627_1139_188.txt # ::snt When cell cultures were derived from histologically normal areas with abnormal fluorescence, the level and range of signaling reactions elicited by the treatments were essentially identical to those with normal histology and normal fluorescence. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (h / have-condition-91 :ARG1 (i / identical-01 :ARG1 (a2 / and :op1 (l / level :degree-of (r2 / react-01 :ARG0 "c" :ARG2 (s / signal-07))) :op2 (r / range-01 :ARG1 r2) :ARG1-of (e / elicit-01 :ARG0 (t / treat-04))) :ARG2 (c3 / culture-01 :ARG1 "c2" :ARG0-of (h4 / have-03 :ARG1 (a3 / and :op1 (h5 / histology :ARG1-of (n / normal-02)) :op2 (f2 / fluorescence :ARG1-of n)))) :mod (e2 / essential)) :ARG2 (d / derive-01 :ARG1 (c / culture-01 :ARG1 (c2 / cell)) :ARG2 (a / area :ARG0-of (h3 / have-03 :ARG1 (f / fluorescence :ARG1-of (n2 / normal-02 :polarity "-"))) :poss h5))) # ::id pmid_1627_1139.189 # ::date 2015-08-12T11:10:22 # ::file pmid_1627_1139_189.txt # ::snt ERK activation by OSM was 108 ± 35%, by IL-6 was 31 ± 15%, and by EGF was 85 ± 40%. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (a2 / activate-01 :ARG0 (p / protein :name (n / name :op1 "OSM") :xref (x3 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (e2 / equal-01 :ARG2 (v3 / value-interval :op1 (p2 / percentage-entity :value "108" :ARG2-of (a4 / add-02 :ARG1 (p3 / percentage-entity :value "35"))) :op2 (p4 / percentage-entity :value "108" :ARG2-of (s / subtract-01 :ARG1 p3))))) :op2 (a3 / activate-01 :ARG0 (p5 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 p :ARG1-of (e3 / equal-01 :ARG2 (v2 / value-interval :op1 (p6 / percentage-entity :value "31" :ARG2-of (a5 / add-02 :ARG1 (p7 / percentage-entity :value "15"))) :op2 (p8 / percentage-entity :ARG2-of (s2 / subtract-01 :ARG1 p7))))) :op3 (a6 / activate-01 :ARG0 (p9 / protein :name (n4 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 p :ARG1-of (e4 / equal-01 :ARG2 (v / value-interval :op1 (p10 / percentage-entity :value "85" :ARG2-of (a7 / add-02 :ARG1 (p11 / percentage-entity :value "40"))) :op2 (p12 / percentage-entity :value "85" :ARG2-of (s3 / subtract-01 :ARG1 p11)))))) # ::id pmid_1627_1139.190 # ::date 2015-08-12T11:26:55 # ::file pmid_1627_1139_190.txt # ::snt STAT3 activation by OSM was 97 ± 31% and by IL-6 was 63 ± 27%. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (a / and :op1 (a2 / activate-01 :ARG0 (p / protein :name (n / name :op1 "OSM") :xref (x2 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1 (p2 / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (e / equal-01 :ARG2 (v / value-interval :op1 (p3 / percentage-entity :value "97" :ARG2-of (a3 / add-02 :ARG1 (p4 / percentage-entity :value "31"))) :op2 (p5 / percentage-entity :value "97" :ARG2-of (s / subtract-01 :ARG1 p4))))) :op2 (a4 / activate-01 :ARG0 (p6 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1 p2 :ARG1-of (e2 / equal-01 :ARG2 (v2 / value-interval :op1 (p7 / percentage-entity :value "63" :ARG2-of (a5 / add-02 :ARG1 (p8 / percentage-entity :value "27"))) :op2 (p9 / percentage-entity :value "63" :ARG2-of (s2 / subtract-01 :ARG1 p8)))))) # ::id pmid_1627_1139.191 # ::date 2015-08-12T11:35:53 # ::file pmid_1627_1139_191.txt # ::snt The cytokine-induced activation of ERK and STAT3 in paired cultures indicated highly consistent response patterns (Fig. 4G and 4H, left side panels). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (i / indicate-01 :ARG0 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (p / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :ARG2-of (i2 / induce-01 :ARG0 (c3 / cytokine)) :location (c / culture :ARG1-of (p3 / pair-01))) :ARG1 (p4 / pattern-01 :ARG1 (r / respond-01) :ARG1-of (c2 / consistent-02 :ARG1-of (h / high-02))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4G") :op2 (f2 / figure :mod "4H") :location (p5 / panel :location (s / side :ARG1-of (l / left-20)))))) # ::id pmid_1627_1139.192 # ::date 2015-08-12T11:59:30 # ::file pmid_1627_1139_192.txt # ::snt Confirmed premalignant epithelial cells (metaplasia, dysplasia and carcinoma) exhibited two recurring aberrant phenotypes when compared with normal cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (e / exhibit-01 :ARG0 (c / cell :mod (e2 / epithelium) :mod (p / premalignant) :ARG1-of (c2 / confirm-01) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (m / metaplasia) :op2 (d / dysplasia) :op3 (c3 / carcinoma)))) :ARG1 (p2 / phenotype :quant "2" :ARG0-of (r / recur-01) :mod (a2 / aberrant)) :condition (c4 / compare-01 :ARG1 c :ARG2 (c5 / cell :ARG1-of (n / normal-02)))) # ::id pmid_1627_1139.193 # ::date 2015-08-12T12:16:54 # ::file pmid_1627_1139_193.txt # ::snt The first aberrancy was the elevated basal or cytokine-stimulated level of phosphorylated ERK (Fig. 4B and 4G, right panel) and the second was the reactivation of LIFR function (Fig. 4D and 4H, right panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (a2 / aberrancy :ord (o / ordinal-entity :value "1") :domain (o2 / or :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (e2 / elevate-01) :mod (b / basal)) :op2 (l2 / level :ARG1-of (s / stimulate-01 :ARG0 (c / cytokine)) :quant-of e :ARG1-of e2)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4B") :op2 (f2 / figure :mod "4G") :location (p3 / panel :ARG1-of (r / right-04))))) :op2 (a4 / aberrancy :ord (o3 / ordinal-entity :value "2") :domain (r2 / reactivate-01 :ARG1 (f3 / function-01 :ARG0 (p4 / protein :name (n3 / name :op1 "LIFR") :xref (x / xref :value "UNIPROT:LIFR_HUMAN" :prob "1.003")))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f4 / figure :mod "4D") :op2 (f5 / figure :mod "4H") :location p3)))) # ::id pmid_1627_1139.194 # ::date 2015-08-12T12:43:16 # ::file pmid_1627_1139_194.txt # ::snt In the 23 preneoplastic cell cultures, the basal level of phosphorylated ERK was increased to 22 ± 27% of the OSM value (p = 0.07). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / increase-01 :ARG1 (l / level :mod (b / basal) :quant-of (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG4 (v2 / value-interval :op1 (p2 / product-of :op1 (p3 / percentage-entity :value "22" :ARG2-of (a / add-02 :ARG1 (p4 / percentage-entity :value "27"))) :op2 (v / value :quant-of (p5 / protein :name (n2 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")))) :op2 (p8 / product-of :op1 (p9 / percentage-entity :value "22" :ARG2-of (s / subtract-01 :ARG1 p4)) :op2 v)) :location (c / culture-01 :quant "23" :ARG1 (c2 / cell) :mod (p7 / preneoplastic)) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.07")) # ::id pmid_1627_1139.195 # ::date 2015-08-12T12:57:23 # ::file pmid_1627_1139_195.txt # ::snt Based on two-sample Kolmogorov-Smirnov test, two cases that were cultured from metaplastic foci were above the 95% confidence interval. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / above :op1 (p / percentage-entity :value "95" :quant-of (i / interval :mod (c / confidence))) :domain (c2 / case-04 :quant "2" :ARG1-of (c3 / culture-01 :source (f / focus :mod (m / metaplastic)))) :ARG1-of (b / base-02 :ARG2 (t / test :mod (t2 / thing :quant "2" :ARG1-of (s / sample-01)) :mod (t3 / thing :name (n / name :op1 "Kolmogorov-Smirnov"))))) # ::id pmid_1627_1139.196 # ::date 2015-08-12T13:15:45 # ::file pmid_1627_1139_196.txt # ::snt Preneoplastic cells showed also an overall trend of increased ERK signaling when treated with OSM (133 ± 66%; p = 0.17) or IL-6 (53 ± 38%; p = 0.01) but not with EGF (85 ± 67%; p = 0.46). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / show-01 :ARG0 (c / cell :mod (p / preneoplastic)) :ARG1 (t / trend-01 :ARG1 (o4 / or :op1 (i / increase-01 :ARG1 (s2 / signal-07 :ARG0 (e / enzyme :name (n5 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2 (v3 / value-interval :op1 (p3 / percentage-entity :value "133" :ARG2-of (a2 / add-02 :ARG1 (p4 / percentage-entity :value "66"))) :op2 (p5 / percentage-entity :value "133" :ARG2-of (s3 / subtract-01 :ARG1 p4))) :condition (t2 / treat-04 :ARG1 c :ARG2 (p2 / protein :name (n2 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002"))) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.17")) :op2 (i2 / increase-01 :ARG1 s2 :ARG2 (v / value-interval :op1 (p6 / percentage-entity :value "53" :ARG2-of (a / add-02 :ARG1 (p7 / percentage-entity :value "38"))) :op2 (p8 / percentage-entity :value "53" :ARG2-of (s4 / subtract-01 :ARG1 p7))) :condition (t3 / treat-04 :ARG1 c :ARG2 (p9 / protein :name (n3 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (s7 / statistical-test-91 :ARG2 "0.01")) :ARG1-of (c2 / contrast-01 :ARG2 (i3 / increase-01 :ARG1 s2 :ARG2 (v2 / value-interval :op1 (p13 / percentage-entity :value "85" :ARG2-of (a3 / add-02 :ARG1 (p14 / percentage-entity :value "67"))) :op2 (p15 / percentage-entity :value "85" :ARG2-of (s5 / subtract-01 :ARG1 p14))) :condition (t4 / treat-04 :ARG1 c :ARG2 (p12 / protein :name (n4 / name :op1 "EGF") :ARG1-of (e4 / equal-01) :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG1-of (s8 / statistical-test-91 :ARG2 "0.46"))))) :mod (o / overall) :mod (a4 / also)) # ::id pmid_1627_1139.197 # ::date 2015-08-12T13:54:15 # ::file pmid_1627_1139_197.txt # ::snt The ERK signaling by IL-6 and EGF included several cases that lie outside of the 95% confidence interval. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / include-01 :ARG1 (c / case-04 :quant (s2 / several) :ARG1-of (l / lie-07 :ARG2 (o / outside :op1 (p3 / percentage-entity :value "95" :quant-of (i2 / interval :mod (c2 / confidence)))))) :ARG2 (s / signal-07 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG1 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) # ::id pmid_1627_1139.198 # ::date 2015-08-12T14:01:44 # ::file pmid_1627_1139_198.txt # ::snt For the IL-6 response, 3/23 cases were above and 5/23 cases below the 95% confidence interval, and for EGF response, 4/23 cases were above and 3/23 cases below. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (r / respond-01 :ARG0 (p / protein :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (a2 / above :op1 (p2 / percentage-entity :value "95" :quant-of (i / interval :mod (c / confidence)))) :location (c2 / case-04 :quant "3" :ARG1-of (i2 / include-91 :ARG2 (c3 / case-04 :quant "23")))) :op2 (r2 / respond-01 :ARG0 p :ARG2 (b / below :op1 p2) :location (c4 / case-04 :quant "5" :ARG1-of i2)) :op3 (r3 / respond-01 :ARG0 (p3 / protein :name (n2 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG2 a2 :location (c5 / case-04 :quant "4" :ARG1-of i2)) :op4 (r4 / respond-01 :ARG0 p3 :ARG2 b :location c2)) # ::id pmid_1627_1139.199 # ::date 2015-08-12T14:21:44 # ::file pmid_1627_1139_199.txt # ::snt STAT3 phosphorylation by OSM and IL-6, and STAT1 phosphorylation by OSM, IL-6 and IFNγ did not show significant differences among the cases tested (Fig. 4C–F), in contrast to ERK phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (s / show-01 :polarity "-" :ARG0 (a / and :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG2 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op3 (p4 / protein :name (n3 / name :op1 "IL-6") :xref (x4 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :op2 (p5 / phosphorylate-01 :ARG1 (p6 / protein :name (n4 / name :op1 "STAT1") :xref (x2 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG2 (a3 / and :op1 p3 :op2 p4 :op3 (p7 / protein :name (n5 / name :op1 "IFNγ") :xref (x3 / xref :value "UNIPROT:IFNB_HUMAN" :prob "0.252")))) :ARG1-of (c2 / contrast-01 :ARG2 (p8 / phosphorylate-01 :ARG1 (e / enzyme :name (n6 / name :op1 "ERK") :xref (x5 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :ARG1 (d / differ-01 :ARG1-of (s2 / significant-02)) :location (c / case-04 :ARG1-of (t / test-01) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "4C") :op2 (f2 / figure :mod "4D") :op3 (f3 / figure :mod "4E") :op4 (f4 / figure :mod "4F"))))) # ::id pmid_1627_1139.200 # ::date 2015-08-12T14:34:20 # ::file pmid_1627_1139_200.txt # ::snt Among the abnormal epithelial cells with elevated basal ERK phosphorylation (Fig. 4B), the two cell cultures from metaplastic foci in the airway were distinct because the basal ERK phosphorylation that was equivalent to the OSM-treated control culture (Fig. 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / include-91 :ARG1 (c2 / culture-01 :quant "2" :ARG1 (c3 / cell) :source (f2 / focus :mod (m / metaplastic)) :location (a / airway) :mod (d3 / distinct :ARG0-of (c4 / cause-01 :ARG1 (e4 / equal-01 :ARG1 (p2 / phosphorylate-01 :ARG1 "e2" :mod "b") :ARG2 (c5 / culture :mod (c6 / control) :ARG1-of (t / treat-04 :ARG2 (p3 / protein :name (n3 / name :op1 "OSM") :xref (x1 / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002"))))))) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "5A"))) :ARG2 (c / cell :mod (e / epithelium) :ARG1-of (n / normal-02 :polarity "-") :ARG0-of (h / have-03 :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (e3 / elevate-01) :mod (b / basal))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B")))) # ::id pmid_1627_1139.201 # ::date 2015-08-12T14:54:06 # ::file pmid_1627_1139_201.txt # ::snt The increased phosphorylation of ERK, but not of STATs in these metaplastic cells was similar to the regulatory phenotype of NCI H23 tumor cell line (Fig. 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / resemble-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (i / increase-01) :location (c / cell :mod (m / metaplastic) :mod (t2 / this)) :ARG1-of (c3 / contrast-01 :ARG2 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "STAT") :xref (x1 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))))) :ARG2 (p2 / phenotype :poss (c2 / cell-line :name (n2 / name :op1 "NCI" :op2 "H23") :mod (t / tumor)) :ARG0-of (r2 / regulate-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1627_1139.202 # ::date 2015-08-12T15:08:56 # ::file pmid_1627_1139_202.txt # ::snt Due to the elevated ERK phosphorylation, the response to EGF was obscured, even though a normal or even enhanced level of EGFR could be demonstrated (Fig. 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (o / obscure-02 :ARG1 (r / respond-01 :ARG1 (p / protein :name (n / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG1-of (c / cause-01 :ARG0 (e / elevate-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :concession (p3 / possible-01 :ARG1 (d / demonstrate-01 :ARG1 (o2 / or :op1 (l / level :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (n4 / normal-02)) :op2 (l2 / level :quant-of e3 :ARG1-of (e4 / enhance-01 :mod (e5 / even)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id pmid_1627_1139.203 # ::date 2015-08-12T15:23:26 # ::file pmid_1627_1139_203.txt # ::snt The high basal level phosphorylation of ERK was abrogated by treatment with U0126, an inhibitor for MEK1 (Fig. 5C), suggesting a constitutive activation of the MAPK pathway upstream of ERK in these metaplastic cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / abrogate-01 :ARG1 (l / level :degree-of (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :mod (b / basal) :ARG1-of (h / high-02)) :ARG2 (t / treat-04 :ARG1 l :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126") :ARG1-of (m / mean-01 :ARG2 (s2 / small-molecule :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))))) :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C")) :ARG0-of (s3 / suggest-01 :ARG1 (a2 / activate-01 :ARG1 (p2 / pathway :name (n4 / name :op1 "MAPK")) :mod (c / constitutive) :location (u / upstream :op1 e) :location (c2 / cell :mod (m2 / metaplastic))))) # ::id pmid_1627_1139.204 # ::date 2015-08-12T15:33:03 # ::file pmid_1627_1139_204.txt # ::snt The pair-wise comparison also revealed that 5/23 of the abnormal cases (4 metaplasia and 1 carcinoma) had a LIF response detectable by the activation of ERK and STAT3 (Fig. 3, Fig. 4B,D,G and 4H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (r / reveal-01 :ARG0 (c / compare-01 :mod (p / pairwise)) :ARG1 (h / have-03 :ARG0 (c2 / case-04 :quant "5" :ARG1-of (i / include-91 :ARG2 (c3 / case-04 :quant "23" :ARG1-of (n4 / normal-02 :polarity "-"))) :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (m2 / metaplasia :quant "4") :op2 (c4 / carcinoma :quant "1")))) :ARG1 (r2 / respond-01 :ARG0 (p2 / protein :name (n / name :op1 "LIF") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")))) :mod (a / also) :ARG1-of (d / detect-01 :ARG2 (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :ARG1-of (p3 / possible-01)) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "3") :op2 (f2 / figure :mod "4B") :op3 (f3 / figure :mod "4D") :op4 (f4 / figure :mod "4G") :op5 (f5 / figure :mod "4H")))) # ::id pmid_1627_1139.205 # ::date 2015-08-18T06:49:36 # ::file pmid_1627_1139_205.txt # ::snt Three cases (2 metaplasia and 1 carcinoma) produced a signaling that lied outside of the 95% confidence interval. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (p / produce-01 :ARG0 (c / case-04 :quant "3" :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (m2 / metaplasia :quant "2") :op2 (m3 / medical-condition :name (n / name :op1 "carcinoma"))))) :ARG1 (s / signal-07 :ARG1-of (l / lay-01 :ARG2 (o / outside :op1 (i / interval :mod (c2 / confidence) :mod (p2 / percentage-entity :value "95")))))) # ::id pmid_1627_1139.206 # ::date 2015-08-18T09:43:53 # ::file pmid_1627_1139_206.txt # ::snt The carcinoma case also included a prominent reduction of IL-6 receptor function (Fig. 6), which resulted in an overall cytokine response pattern comparable to that of the NCI H125 tumor cell line (Fig. 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / include-01 :ARG1 (r / reduce-01 :ARG1 (f / function-01 :ARG0 (r2 / receptor :name (n2 / name :op1 "IL-6"))) :mod (p / prominent) :ARG1-of (r3 / result-01 :ARG2 (p2 / pattern :ARG1-of (r4 / respond-01 :ARG0 (c2 / cytokine) :mod (o / overall)) :ARG1-of (c3 / comparable-03 :ARG2 (p3 / pattern :ARG1-of (r5 / respond-01 :ARG0 (c4 / cell-line :name (n3 / name :op1 "NCI" :op2 "H125") :mod (t / tumor)))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "1A")))) :ARG2 (c / case-04 :ARG1 (m / medical-condition :name (n / name :op1 "carcinoma"))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6")) :mod (a / also)) # ::id pmid_1627_1139.207 # ::date 2015-08-18T10:10:39 # ::file pmid_1627_1139_207.txt # ::snt The changes in signaling reactions correlated with receptor expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (c / correlate-01 :ARG1 (c2 / change-01 :ARG1 (r / react-01 :ARG1 (s / signal-07))) :ARG2 (e / express-03 :ARG2 (r2 / receptor))) # ::id pmid_1627_1139.208 # ::date 2015-08-18T10:16:50 # ::file pmid_1627_1139_208.txt # ::snt The expression of LIFRα in normal cells was undetectable by immunoblotting whereas expression was observed in the 5 cultures of abnormal cells with LIF response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / contrast-01 :ARG1 (d / detect-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "LIFRα") :xref (x / xref :value "UNIPROT:LIFR_HUMAN" :prob "0.672")) :ARG3 (c2 / cell :ARG1-of (n3 / normal-02))) :ARG2 (i / immunoblot-01) :ARG1-of (p / possible-01 :polarity "-")) :ARG2 (o / observe-01 :ARG1 (e2 / express-03 :ARG2 p2 :ARG3 (c3 / culture-01 :quant "5" :ARG1 (c4 / cell :ARG1-of (n2 / normal-02 :polarity "-") :ARG0-of (r / respond-01 :ARG1 (p3 / protein :name (n4 / name :op1 "LIF") :xref (x1 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")))))))) # ::id pmid_1627_1139.209 # ::date 2015-08-18T10:37:15 # ::file pmid_1627_1139_209.txt # ::snt The re-expression of LIFR in various cell types is controlled by an epigenetic process that depends on histone acetylation within CpG islands of the LIFR promoter region [22]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / control-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "LIFR") :xref (x1 / xref :value "UNIPROT:LIFR_HUMAN" :prob "1.003")) :ARG3 (t / type :mod (c2 / cell :mod (v / various))) :mod (a / again)) :ARG2 (p2 / process :mod (e2 / epigenetic) :ARG0-of (d / depend-01 :ARG1 (a2 / acetylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "histone") :xref (x / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332")) :location (i / island :mod (d2 / dna-sequence :name (n3 / name :op1 "CpG")) :location (r / region :ARG1-of (p4 / promote-01 :ARG0 p)))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "22")))) # ::id pmid_1627_1139.210 # ::date 2015-08-18T11:07:47 # ::file pmid_1627_1139_210.txt # ::snt To determine whether altered protein acetylation could account for the switch in LIF responsiveness from normal to carcinoma cells, the normal epithelial cells were treated for 6 h with the histone deacetylase inhibitor FR901228. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (t / treat-04 :ARG1 (c / cell :source (e / epithelium) :ARG1-of (n / normal-02)) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "FR901228") :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein :name (n4 / name :op1 "histone") :ARG1-of (d3 / deacetylate-01) :xref (x1 / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332"))) :xref (x2 / xref :value "PUBCHEM:5352062" :prob "19.266134")) :duration (t2 / temporal-quantity :quant "6" :unit (h / hour)) :purpose (d / determine-01 :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (a4 / account-01 :ARG0 (a2 / acetylate-01 :ARG1 (p / protein :ARG1-of (a3 / alter-01))) :ARG1 (s / switch-01 :ARG1 (r / responsive-02 :ARG1 (p3 / protein :name (n3 / name :op1 "LIF") :xref (x / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003"))) :ARG2 (c3 / cell :mod (m / medical-condition :name (n5 / name :op1 "carcinoma"))) :ARG3 (c2 / cell :ARG1-of n)))))) # ::id pmid_1627_1139.211 # ::date 2015-08-18T11:17:24 # ::file pmid_1627_1139_211.txt # ::snt The treatment induced the expression of LIFRα and established a LIF-dependent STAT3 and ERK signaling that was comparable to the level observed in the carcinoma cells (Fig. 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (i / induce-01 :ARG0 (t / treat-04) :ARG2 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "LIFRα") :xref (x3 / xref :value "UNIPROT:LIFR_HUMAN" :prob "0.672")))) :op2 (e2 / establish-01 :ARG0 t :ARG1 (a2 / and :op1 (s / signal-07 :ARG0 (p2 / protein :name (n3 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n4 / name :op1 "LIF") :xref (x2 / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003")))) :op2 (s2 / signal-07 :ARG0 (e3 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG0-of d) :ARG1-of (c2 / comparable-03 :ARG2 (l / level :ARG1-of (o / observe-01 :location (c / cell :mod (m / medical-condition :name (n5 / name :op1 "carcinoma")))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "6"))) # ::id pmid_1627_1139.212 # ::date 2015-08-18T12:36:25 # ::file pmid_1627_1139_212.txt # ::snt A similar FR901228 treatment of the carcinoma cells further enhanced LIFR expression and LIF-dependent signaling (Fig. 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / enhance-01 :ARG1 (a / and :op1 (e2 / express-03 :ARG2 (p / protein :name (n3 / name :op1 "LIFR") :xref (x1 / xref :value "UNIPROT:LIFR_HUMAN" :prob "1.003"))) :op2 (s2 / signal-07 :ARG0-of (d2 / depend-01 :ARG1 (p2 / protein :name (n4 / name :op1 "LIF") :xref (x / xref :value "UNIPROT:LIF_HUMAN" :prob "1.003"))))) :ARG2 (t / treat-04 :ARG1 (c / cell :mod (m / medical-condition :name (n2 / name :op1 "carcinoma"))) :ARG2 (s / small-molecule :name (n / name :op1 "FR901228") :xref (x2 / xref :value "PUBCHEM:5352062" :prob "19.266134")) :ARG1-of (r / resemble-01)) :mod (f / further) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "6"))) # ::id pmid_1627_1139.213 # ::date 2015-08-19T03:40:52 # ::file pmid_1627_1139_213.txt # ::snt Interestingly, the same treatment reduced he expression of IL-6R in normal cells resulting in a response pattern as found in the corresponding carcinoma cells from the same patient (Fig. 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / reduce-01 :ARG0 (t / treat-04 :ARG1-of (s / same-01)) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "IL-6R") :xref (x / xref :value "UNIPROT:IL6RA_HUMAN" :prob "0.673")) :ARG3 (c / cell :ARG1-of (n2 / normal-02))) :ARG1-of (r2 / result-01 :ARG2 (p2 / pattern :ARG1-of (r3 / respond-01) :ARG1-of (r4 / resemble-01 :ARG2 (p3 / pattern :ARG1-of (f / find-01 :location (c2 / cell :mod (m / medical-condition :name (n3 / name :op1 "carcinoma")) :ARG2-of (c3 / correspond-02 :ARG1 c) :source (p4 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient)) :ARG1-of s))))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6")) :ARG2-of (i2 / interest-01)) # ::id pmid_1627_1139.214 # ::date 2015-08-19T08:34:57 # ::file pmid_1627_1139_214.txt # ::snt OSM and secreted macrophage factors attenuate proliferation of bronchial epithelial cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (a / attenuate-01 :ARG0 (a2 / and :op1 (p / protein :name (n / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (f / factor :mod (m / macrophage) :ARG1-of (s / secrete-01))) :ARG1 (p2 / proliferate-01 :ARG0 (c / cell :source (e / epithelium) :mod (b / bronchus)))) # ::id pmid_1627_1139.215 # ::date 2015-08-19T10:33:45 # ::file pmid_1627_1139_215.txt # ::snt DNA synthesis of the epithelial cells was inhibited by OSM and LPS conditioned medium from of activated macrophages in a dose-dependent fashion (Fig. 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (i / inhibit-01 :ARG0 (m / medium :ARG1-of (c2 / condition-01 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS") :xref (x1 / xref :value "PUBCHEM:53481794" :prob "9.905254")))) :source (m3 / macrophage :ARG1-of (a2 / activate-01))) :ARG1 (s / synthesize-01 :ARG0 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")) :ARG1 (c / cell :source (e / epithelium))) :manner (d2 / depend-01 :ARG1 (d3 / dose)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "7"))) # ::id pmid_1627_1139.216 # ::date 2015-08-19T10:51:22 # ::file pmid_1627_1139_216.txt # ::snt The data for all cultures identified as normal cells (Fig. 7A) indicated that low concentrations of OSM (≤ 0.1 ng/ml) or LPS conditioned macrophage medium (<10-3 dilution) had no appreciable modulating effects. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (i / indicate-01 :ARG0 (d / data :topic (c / culture :mod (a / all) :ARG1-of (i2 / identify-01 :ARG2 (c2 / cell :ARG1-of (n / normal-02)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7A"))))) :ARG1 (h / have-03 :polarity "-" :ARG0 (c3 / concentrate-02 :ARG1 (m / medium :mod (m2 / macrophage) :ARG1-of (c4 / condition-01 :ARG2 (o / or :op1 (p / protein :name (n2 / name :op1 "OSM") :quant (c5 / concentration-quantity :quant (o2 / or :op1 "0.1" :op2 (l2 / less-than :op1 "0.1")) :unit (n4 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :op2 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS") :xref (x1 / xref :value "PUBCHEM:53481794" :prob "9.905254"))))) :ARG1-of (l / low-04) :ARG1-of (d4 / dilute-01 :ARG2 (l4 / less-than :op1 "0.001"))) :ARG1 (a2 / affect-01 :ARG0-of (m4 / modulate-01) :ARG1-of (a3 / appreciate-02 :ARG1-of (p2 / possible-01))))) # ::id pmid_1627_1139.217 # ::date 2015-08-19T11:38:35 # ::file pmid_1627_1139_217.txt # ::snt Only at higher concentrations, suppression of DNA synthesis became evident (p < 0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-condition-91 :ARG1 (e / evidence-01 :ARG1 (s / suppress-01 :ARG1 (s2 / synthesize-01 :ARG0 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA")))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) :ARG2 (c / concentrate-02 :ARG1-of (h2 / high-02 :degree (m / more :mod (o / only))))) # ::id pmid_1627_1139.218 # ::date 2015-08-19T11:51:35 # ::file pmid_1627_1139_218.txt # ::snt In contrast, several cultures of metaplastic and dysplastic cells exhibited the trend, in which the cells responded to low doses of OSM or conditioned medium from macrophages by a stimulation of DNA synthesis (Fig. 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / contrast-01 :ARG2 (e / exhibit-01 :ARG0 (c2 / culture-01 :ARG1 (a / and :op1 (c3 / cell :mod (m / metaplasia)) :op2 (c4 / cell :mod (d / dysplasia))) :quant (s / several)) :ARG1 (t / trend-01 :ARG2 (r / respond-01 :ARG0 a :ARG1 (o / or :op1 (d2 / dose-01 :ARG1 (c5 / cell) :ARG2 (p / protein :name (n / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1-of (l / low-04)) :op2 (m2 / medium :ARG1-of (c6 / condition-01) :source (m3 / macrophage))) :ARG2 (s2 / stimulate-01 :ARG1 (s3 / synthesize-01 :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "7B")))) # ::id pmid_1627_1139.219 # ::date 2015-08-19T12:22:44 # ::file pmid_1627_1139_219.txt # ::snt The exact sign test using the paired samples (normal and abnormal) indicated a significant increase of DNA synthesis by low dose (10-3 dilution) of macrophage medium (p = 0.016). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (i / indicate-01 :ARG0 (t2 / test-01 :ARG0-of (u / use-01 :ARG1 (a / and :op1 (t / thing :ARG1-of (n2 / normal-02) :ARG1-of (s / sample-01)) :op2 (t3 / thing :ARG1-of (n3 / normal-02 :polarity "-") :ARG1-of s) :ARG1-of (p / pair-01))) :mod (s6 / sign) :mod (e / exact)) :ARG1 (i2 / increase-01 :ARG0 (d2 / dose-01 :ARG1 "s3" :ARG2 (m / medium :mod (m2 / macrophage)) :ARG1-of (l / low-04) :ARG1-of (d4 / dilute-01 :ARG2 (l2 / less-than :op1 "0.001"))) :ARG1 (s3 / synthesize-01 :ARG0 (n / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))) :ARG1-of (s4 / significant-02) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.016"))) # ::id pmid_1627_1139.220 # ::date 2015-08-19T12:47:38 # ::file pmid_1627_1139_220.txt # ::snt The comparison of the data from paired cultures by the Wilcoxon two-sample test also indicated that DNA synthesis in the abnormal epithelial cells was significantly increased at lowest concentration of OSM (p = 0.02) and macrophage medium (p = 0.005) relative to the normal cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (i / indicate-01 :ARG0 (c / compare-01 :ARG0 (t2 / test-01 :mod (t3 / thing :quant "2" :ARG1-of (s3 / sample-01)) :mod (p5 / person :name (n / name :op1 "Wilcoxon"))) :ARG1 (d / data :source (c2 / culture :ARG1-of (p / pair-01)))) :ARG1 (a / and :op1 (i2 / increase-01 :ARG0 (c4 / concentrate-02 :ARG1 (p2 / protein :name (n3 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1-of (l / low-04 :degree (m / most))) :ARG1 (s / synthesize-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.02")) :op2 (i3 / increase-01 :ARG0 (c6 / concentrate-02 :ARG1 (m2 / medium :mod (m3 / macrophage))) :ARG1 s :ARG1-of (s5 / statistical-test-91 :ARG2 "0.005")) :ARG1-of (s2 / significant-02 :ARG1-of (r / relative-05 :ARG3 (c5 / cell :ARG1-of (n4 / normal-02)))) :location (c3 / cell :source (e / epithelium) :ARG1-of (n2 / normal-02 :polarity "-"))) :mod (a2 / also)) # ::id pmid_1627_1139.221 # ::date 2015-08-19T13:14:30 # ::file pmid_1627_1139_221.txt # ::snt The reduced sensitivity for inhibited DNA synthesis in all cases could be correlated with metaplasia which shows enhanced ERK phosphorylation in response to cytokine treatment (example of dysplastic cells in Fig. 7C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (p3 / possible-01 :ARG1 (c / correlate-01 :ARG1 (s / sensitive-03 :ARG0 (s2 / synthesize-01 :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA") :ARG1-of (i / inhibit-01))) :ARG1-of (r / reduce-01) :condition (c2 / case-04 :mod (a / all))) :ARG2 (m / metaplasia :ARG0-of (s3 / show-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (e2 / enhance-01) :ARG2-of (r2 / respond-01 :ARG1 (t / treat-04 :ARG2 (c3 / cytokine)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7C") :ARG2 (c4 / cell :mod (d3 / dysplasia))))) # ::id pmid_1627_1139.222 # ::date 2015-08-19T13:50:09 # ::file pmid_1627_1139_222.txt # ::snt In addition, we noted that in premalignant cells the basal ERK phosphorylation approached the level of OSM-treated cells or EGF-treated cells (Fig. 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (n / note-01 :ARG0 (w / we) :ARG1 (a2 / approach-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :mod (b / basal)) :ARG2 (l / level :quant-of (o / or :op1 (c / cell :ARG1-of (t / treat-04 :ARG2 (p2 / protein :name (n3 / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")))) :op2 (c2 / cell :ARG1-of (t2 / treat-04 :ARG2 (p4 / protein :name (n4 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))))) :location (c3 / cell :mod (p3 / premalignant))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B")))) # ::id pmid_1627_1139.223 # ::date 2015-08-19T14:01:02 # ::file pmid_1627_1139_223.txt # ::snt In addition, the thymidine incorporation by premalignant cells maintained in growth medium was close to two-fold higher than in the corresponding normal cultures (Fig. 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op2 (c / close-06 :ARG1 (i / incorporate-02 :ARG0 (c2 / cell :mod (p / premalignant)) :ARG1 (s / small-molecule :name (n / name :op1 "thymidine") :xref (x / xref :value "PUBCHEM:5789" :prob "12.207807")) :ARG1-of (m2 / maintain-01 :location (m3 / medium :mod (g / grow-01)))) :ARG2 (h / high-02 :degree (m4 / more) :degree (p2 / product-of :op1 "2") :compared-to (c3 / culture :ARG1-of (n2 / normal-02) :ARG1-of (c4 / correspond-02 :ARG2 m3)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id pmid_1627_1139.224 # ::date 2015-08-19T14:35:17 # ::file pmid_1627_1139_224.txt # ::snt As expected, the ERK activity was reduced by treatment in both normal and carcinoma cells with U0126 which correlates with the suppression of DNA synthesis observed (Fig. 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / reduce-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :instrument (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :location (a2 / and :op1 (c / cell :ARG1-of (n3 / normal-02)) :op2 (c2 / cell :mod (m / medical-condition :name (n4 / name :op1 "carcinoma")))) :ARG1-of (e2 / expect-01) :ARG1-of (c3 / correlate-01 :ARG2 (s2 / suppress-01 :ARG1 (s3 / synthesize-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))) :ARG1-of (o / observe-01))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id pmid_1627_1139.225 # ::date 2015-08-19T14:46:32 # ::file pmid_1627_1139_225.txt # ::snt High concentrations of OSM or macrophage factors were effective to reduce this intrinsically stimulated DNA synthesis in both normal and premalignant epithelial cell cultures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (e / effective-04 :ARG0 (o / or :op1 (c / concentrate-02 :ARG1 (p / protein :name (n / name :op1 "OSM") :xref (x / xref :value "UNIPROT:ONCM_HUMAN" :prob "1.002")) :ARG1-of (h / high-02)) :op2 (f / factor :mod (m / macrophage))) :ARG1 (r / reduce-01 :ARG0 o :ARG1 (s / synthesize-01 :ARG0 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")) :ARG1-of (s2 / stimulate-01 :manner (i / intrinsic)) :mod (t / this)) :location (c2 / culture-01 :ARG1 (a / and :op1 (c3 / cell :source (e2 / epithelium) :ARG1-of (n2 / normal-02)) :op2 (c4 / cell :mod (p2 / premalignant) :source e2))))) # ::id pmid_1859_7688.1 # ::date 2015-07-06T08:26:01 # ::file pmid_1859_7688_1.txt # ::snt TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation (PMID:18597688) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / oppose-01 :ARG0 (p / protein :name (n / name :op1 "TDAG51") :ARG1-of (t / target-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG0-of (s / signal-07) :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG1 (t2 / transform-01 :ARG1 (c / cell-line :name (n4 / name :op1 "HME16C") :mod (e3 / epithelium :mod (m2 / mammary))) :ARG1-of (m / mediate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID18597688"))) # ::id pmid_1859_7688.10 # ::date 2015-07-06T08:29:23 # ::file pmid_1859_7688_10.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1859_7688.11 # ::date 2015-07-06T08:31:19 # ::file pmid_1859_7688_11.txt # ::snt Activation of both the ERK and PI3K signaling pathways was sufficient to induce cellular transformation, which was accompanied by up-regulation of EGFR ligands, suggesting autocrine EGFR stimulation during the transformation process. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (s / suggest-01 :ARG0 (a / activate-01 :ARG1 (a2 / and :op1 (p / pathway :name (n / name :op1 "ERK")) :op2 (p2 / pathway :name (n2 / name :op1 "PI3K")) :mod (b / both) :ARG0-of (s2 / signal-07)) :ARG0-of (s3 / suffice-01 :ARG1 (i / induce-01 :ARG0 a :ARG2 (t / transform-01 :ARG1 (c / cell) :ARG1-of (a3 / accompany-01 :ARG0 (u / upregulate-01 :ARG1 (l / ligand :mod (e / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))))))) :ARG1 (s4 / stimulate-01 :ARG1 e :mod (a4 / autocrine) :time (p3 / process-02 :ARG1 (t2 / transform-01)))) # ::id pmid_1859_7688.12 # ::date 2015-07-06T08:47:03 # ::file pmid_1859_7688_12.txt # ::snt Only activation of the ERK pathway was sufficient to transform cells in the presence of EGFR inhibition and was sufficient for tumorigenesis in xenografts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (s / suffice-01 :ARG0 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "ERK")) :mod (o / only)) :ARG1 (a2 / and :op1 (t / transform-01 :ARG1 (c / cell :condition (b / be-located-at-91 :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR") :ARG1-of (i / inhibit-01) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) :op2 (c2 / create-01 :ARG1 (t2 / tumor) :location (x / xenograft)))) # ::id pmid_1859_7688.13 # ::date 2015-07-06T08:53:45 # ::file pmid_1859_7688_13.txt # ::snt Up-regulation of the PHLDA1 gene product, TDAG51, was found to correlate with persistent ERK activation and anchorage-independent growth in the absence or presence of EGFR inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (c / correlate-01 :ARG1 (u / upregulate-01 :ARG1 (p / produce-01 :ARG0 (g / gene :name (n / name :op1 "PHLDA1") :xref (x3 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG1 (p3 / protein :name (n2 / name :op1 "TDAG51") :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")))) :ARG2 (a / and :op1 (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (p2 / persist-01)) :op2 (g3 / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a3 / anchorage)))) :condition (o / or :op1 (a4 / absent-01 :ARG1 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :op2 (p4 / present-02 :ARG1 i)))) # ::id pmid_1859_7688.14 # ::date 2015-07-06T09:11:58 # ::file pmid_1859_7688_14.txt # ::snt Knockdown of this putative breast cancer tumor-suppressor gene resulted in increased ERK pathway activation and enhanced matrix-detached cellular proliferation of Ras/Raf transformed cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (r / result-01 :ARG1 (k / knock-down-02 :ARG1 (g / gene :ARG1-of (t3 / think-01 :ARG2 (s / suppress-01 :ARG0 g :ARG1 (t / tumor :source (d2 / disease :wiki "Breast_cancer" :name (n4 / name :op1 "breast" :op2 "cancer"))))) :mod (t4 / this))) :ARG2 (a / and :op1 (i / increase-01 :ARG1 (a2 / activate-01 :ARG1 (p2 / pathway :name (n / name :op1 "ERK")))) :op2 (e / enhance-01 :ARG1 (p3 / proliferate-01 :ARG0 (c2 / cell :ARG1-of (t2 / transform-01 :ARG0 (s2 / slash :op1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n3 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :ARG1-of (d / detach-01 :ARG2 (m / matrix))))))) # ::id pmid_1859_7688.114 # ::date 2015-07-07T05:44:35 # ::file pmid_1859_7688_114.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 7, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1859_7688.115 # ::date 2015-07-07T05:45:14 # ::file pmid_1859_7688_115.txt # ::snt Generation of H-Ras- and Rlf-CAAX-expressing HME16C cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 8, 2015 (g / generate-01 :ARG1 (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e3 / enzyme :name (n2 / name :op1 "Rlf-CAAX"))) :ARG3 (c / cell-line :name (n3 / name :op1 "HME16C")))) # ::id pmid_1859_7688.116 # ::date 2015-07-07T06:36:18 # ::file pmid_1859_7688_116.txt # ::snt Retroviral vectors coding for amino terminal HA-tagged activated H-RasV12, the H-RasV12 effector domain mutants (EDM) H-RasV12G37, H-RasV12S35, and H-RasV12C40, and the constitutively activated version of a RalGEF, Rlf-CAAX, were used to infect telomerase immortalized HME16C human mammary epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (u2 / use-01 :ARG1 (a4 / and :op1 (v / vector :mod (r / retrovirus) :ARG0-of (c / code-01 :ARG1 (p4 / protein-segment :name (n12 / name :op1 "amino-terminus") :part-of (e / enzyme :name (n2 / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :value "V12") :ARG1-of (t2 / tag-01 :ARG2 (p3 / protein :name (n10 / name :op1 "haemagglutinin" :op2 "A"))) :ARG1-of (a / activate-01) :xref (x4 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :op2 (d / domain :mod (e9 / effector) :mod (e3 / enzyme :name (n3 / name :op1 "H-Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x3 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG1-of (m7 / mean-01 :ARG2 (a6 / and :op1 (e4 / enzyme :name (n4 / name :op1 "H-Ras") :ARG2-of (m3 / mutate-01 :value "V12G37") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e5 / enzyme :name (n5 / name :op1 "H-Ras") :ARG2-of (m4 / mutate-01 :value "V12S35") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op3 (e6 / enzyme :name (n6 / name :op1 "H-Ras") :ARG2-of (m5 / mutate-01 :value "V12C40") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))) :op3 (p2 / pathway :name (n7 / name :op1 "RalGEF") :ARG1-of (a5 / activate-01 :mod (c2 / constitutive) :ARG1-of (m6 / mean-01 :ARG2 (e7 / enzyme :name (n8 / name :op1 "Rlf-CAAX")))))) :ARG2 (i / infect-01 :ARG0 a4 :ARG1 (c3 / cell-line :name (n9 / name :op1 "HME16C") :mod (e2 / epithelium :mod (m8 / mammary :mod (h / human))) :ARG1-of (i2 / immortalize-03 :ARG2 (t / telomerase))))) # ::id pmid_1859_7688.117 # ::date 2015-07-07T06:40:35 # ::file pmid_1859_7688_117.txt # ::snt Anti-Ras and anti-HA western blotting demonstrated approximately equal levels of ectopic Ras expression among Ras-infected cells, with slightly lower levels in HME16C RasV12-infected cells relative to EDM-infected cells (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / demonstrate-01 :ARG0 (a / and :op1 (i4 / immunoblot-01 :ARG3 (a3 / antibody :ARG0-of (c3 / counter-01 :ARG1 "e5"))) :op2 (i5 / immunoblot-01 :ARG3 (a4 / antibody :ARG0-of (c5 / counter-01 :ARG1 (p / protein :name (n2 / name :op1 "HA") :xref (x4 / xref :value "UNIPROT:MORN_HUMAN" :prob "1.002")))))) :ARG1 (l / level :ARG1-of (e / equal-01 :ARG0-of (a2 / approximate-01)) :degree-of (e2 / express-03 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras") :mod (e3 / ectopic) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG3 (c / cell :ARG1-of (i / infect-01 :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :prep-with (l2 / level :ARG1-of (l3 / low-04 :degree (m / more :degree (s / slight))) :ARG1-of (r / relative-05 :ARG2 (l4 / level :mod (c4 / cell :ARG1-of (i3 / infect-01 :ARG2 (e7 / enzyme :name (n8 / name :op1 "EDM") :xref (x2 / xref :value "UNIPROT:EMD_HUMAN" :prob "0.262")))))) :location (c2 / cell-line :name (n / name :op1 "HME16C") :ARG1-of (i2 / infect-01 :ARG2 (e6 / enzyme :name (n7 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1859_7688.118 # ::date 2015-07-07T07:11:12 # ::file pmid_1859_7688_118.txt # ::snt Analysis of activated, GTP-bound Ral A demonstrated highly elevated levels of activated Ral A only in Rlf-CAAX-expressing cells and not in Ras-infected cells grown under standard culture conditions (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / demonstrate-01 :ARG0 (a / analyze-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ral" :op2 "A") :ARG1-of (a2 / activate-01) :ARG2-of (b / bind-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x1 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.593"))) :ARG1 (a4 / and :op1 (e3 / elevate-01 :ARG1 (l / level :mod (a3 / activate-01 :ARG1 e2)) :ARG1-of (h / high-02) :location (c / cell :ARG3-of (e4 / express-03 :ARG2 (e5 / enzyme :name (n3 / name :op1 "Rlf-CAAX")))) :mod (o / only)) :op2 (e6 / elevate-01 :polarity "-" :ARG1 l :location (c2 / cell :ARG1-of (i / infect-01 :ARG2 (e7 / enzyme :name (n4 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (g / grow-03 :condition (c5 / culture-01 :mod (s2 / standard)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id pmid_1859_7688.119 # ::date 2015-07-07T07:28:50 # ::file pmid_1859_7688_119.txt # ::snt To assess activation of the ERK pathway, anti-phospho Erk western blotting was performed and showed significantly elevated Erk phosphoprotein in RasV12- and RasV12S35-infected HME16C cells relative to control pLRT-infected cells (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (p / perform-01 :ARG1 (i3 / immunoblot-01 :ARG0-of (c / counter-01 :ARG1 (e4 / enzyme :name (n2 / name :op1 "Erk") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")))) :purpose (a2 / assess-01 :ARG1 (a3 / activate-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "ERK"))))) :op2 (s / show-01 :ARG0 i3 :ARG1 (e2 / elevate-01 :ARG1 e4 :location (c3 / cell-line :name (n4 / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (a4 / and :op1 (e / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1-of (r / relative-05 :ARG2 (c2 / cell :ARG1-of (i2 / infect-01 :ARG2 (p4 / protein :name (n7 / name :op1 "LRT") :ARG3-of (p5 / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:LRC51_HUMAN" :prob "0.292"))) :ARG0-of (c4 / control-01))) :ARG1-of (s2 / significant-02))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1859_7688.120 # ::date 2015-07-07T07:48:46 # ::file pmid_1859_7688_120.txt # ::snt Elevated levels of phosphorylated Erk were also observed in RasV12G37- and RasV12C40-infected cells, although at a much lower level than that found in RasV12- and RasV12S35-infected cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (o / observe-01 :ARG1 (e / elevate-01 :ARG1 (l / level :quant-of (e6 / enzyme :name (n / name :op1 "Erk") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :location (c / cell :ARG1-of (i / infect-01 :ARG2 (a / and :op1 (e5 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e4 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) :mod (a2 / also)) :ARG2 (l3 / low-04 :ARG1 l :degree (m3 / more) :ARG1-of (c2 / compare-01 :ARG2 (l2 / level :ARG1-of (f2 / find-01) :location (c3 / cell :ARG1-of (i2 / infect-01 :ARG2 (a3 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12S35") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) :degree (m6 / much))) # ::id pmid_1859_7688.121 # ::date 2015-07-07T10:44:20 # ::file pmid_1859_7688_121.txt # ::snt To assess activation of the PI3K signaling pathway, anti-phosphoAkt (Ser473) western blotting was performed to detect activated, phosphorylated Akt. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (p / perform-01 :ARG1 (i / immunoblot-01 :ARG1 (a / amino-acid :mod "473" :name (n3 / name :op1 "Serine") :part-of (e / enzyme :name (n2 / name :op1 "Akt") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :purpose (d / detect-01 :ARG1 (a2 / and :op1 (a3 / activate-01 :ARG1 e) :op2 e)) :purpose (a4 / assess-01 :ARG1 (a5 / activate-01 :ARG1 (p3 / pathway :name (n4 / name :op1 "PI3K") :ARG0-of (s / signal-07))))) # ::id pmid_1859_7688.122 # ::date 2015-07-07T10:49:40 # ::file pmid_1859_7688_122.txt # ::snt In cells that were serum starved for 24 hours and matrix detached for 6 hours, elevated levels of phosphorylated Akt were observed in RasV12-, RasV12C40-, and RasV12G37-infected HME16C, with highest levels present in RasV12-infected cells (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (o / observe-01 :ARG1 (e / elevate-01 :ARG1 (l / level :quant-of (e2 / enzyme :name (n / name :op1 "Akt") :ARG3-of (p / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :location (c2 / cell-line :name (n2 / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e4 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12C40") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op3 (e5 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12G37") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1-of (h / high-02 :degree (m5 / most) :location (c3 / cell :ARG1-of (i2 / infect-01 :ARG2 e3))))) :location (c / cell :ARG1-of (s / starve-01 :ARG2 (s2 / serum) :duration (t / temporal-quantity :quant "24" :unit (h4 / hour))) :ARG1-of (d / detach-01 :ARG2 (m / matrix) :duration (t2 / temporal-quantity :quant "6" :unit h4))) :ARG1-of (d2 / describe-01 :ARG2 (f / figure :mod "1C"))) # ::id pmid_1859_7688.123 # ::date 2015-07-07T11:24:43 # ::file pmid_1859_7688_123.txt # ::snt Anchorage-independent growth of mammary epithelial cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 8, 2015 (g / grow-01 :ARG1 (c / cell-line :mod (e / epithelium :mod (m / mammary))) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a / anchorage))) # ::id pmid_1859_7688.124 # ::date 2015-07-07T11:28:43 # ::file pmid_1859_7688_124.txt # ::snt To assess transformation by different Ras signaling pathways, anchorage-independent growth assays were performed in soft agar and in ultra-low attachment tissue culture plates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / perform-01 :ARG1 (a / assay-01 :ARG1 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :mod (a2 / anchorage)))) :ARG2 (p2 / plate :mod (c / culture-01 :ARG1 (t / tissue :ARG3-of (a5 / attach-01 :ARG1-of (l / low-04 :degree (u / ultra)))) :instrument (a4 / agar :ARG1-of (s / soft-02)))) :purpose (a6 / assess-01 :ARG1 (t2 / transform-01 :ARG0 (p3 / pathway :name (n / name :op1 "Ras") :ARG0-of (s2 / signal-07) :ARG1-of (d2 / differ-02))))) # ::id pmid_1859_7688.125 # ::date 2015-07-07T14:19:43 # ::file pmid_1859_7688_125.txt # ::snt Ras- and Ras EDM-infected HME16C cells formed significantly more soft agar colonies >100 μm in diameter than pLRT vector-infected cells (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (f / form-01 :ARG0 (c / cell-line :name (n / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (a / and :op1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras" :op2 "EDM") :xref (x / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212"))))) :ARG1 (c2 / colony :mod (a2 / agar :ARG1-of (s / soft-02)) :mod (d / diameter :mod (m2 / more-than :op1 (d2 / distance-quantity :quant "100" :unit (m / micrometer)))) :quant (m3 / more :ARG1-of (s2 / significant-02) :ARG1-of (c3 / compare-01 :ARG2 (c4 / cell :ARG1-of (i2 / infect-01 :ARG2 (v / vector :name (n4 / name :op1 "LRT") :ARG3-of (p2 / phosphorylate-01))))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2A"))) # ::id pmid_1859_7688.126 # ::date 2015-07-07T14:36:07 # ::file pmid_1859_7688_126.txt # ::snt The RasV12-infected cells formed large colonies, many exceeding 1000 μm, although the total number exceeding 100 μm was typically less than that for the Ras EDM (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (f / form-01 :ARG0 (c / cell :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1 (c2 / colony :mod (l / large) :quant (m2 / many) :ARG0-of (e4 / exceed-01 :ARG1 (d / distance-quantity :quant "1000" :unit (m3 / micrometer)))) :concession (n2 / number :mod (t / total) :ARG0-of (e2 / exceed-01 :ARG1 (d2 / distance-quantity :quant "100" :unit m3)) :quant (l2 / less :ARG1-of (t2 / typical-02)) :ARG1-of (c3 / compare-01 :ARG2 (n4 / number :condition (e3 / enzyme :name (n3 / name :op1 "Ras" :op2 "EDM") :xref (x / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212"))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2B"))) # ::id pmid_1859_7688.127 # ::date 2015-07-07T14:52:55 # ::file pmid_1859_7688_127.txt # ::snt Among the Ras EDM-infected cells, the RasV12S35-infected cells formed the largest colonies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 8, 2015 (f / form-01 :ARG0 (c / cell :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (i2 / include-91 :ARG2 (c2 / cell :ARG1-of (i3 / infect-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM") :xref (x1 / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212")))))) :ARG1 (c3 / colony :mod (l / large :degree (m2 / most)))) # ::id pmid_1859_7688.128 # ::date 2015-07-07T14:56:41 # ::file pmid_1859_7688_128.txt # ::snt These were similar to, but smaller than, the RasV12-infected cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 8, 2015 (c3 / contrast-01 :ARG1 (r / resemble-01 :ARG1 (t / this) :ARG2 (c / cell :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG2 (s / small :domain t :degree (m2 / more) :ARG1-of (c2 / compare-01 :ARG2 c))) # ::id pmid_1859_7688.129 # ::date 2015-07-07T15:04:54 # ::file pmid_1859_7688_129.txt # ::snt For colonies above 100 μm in diameter, RasV12C40-infected cells were the most efficient at colony formation, despite the smaller mean size of colonies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (h / have-concession-91 :ARG1 (e / efficient-01 :ARG1 (c / cell :ARG1-of (i / infect-01 :ARG2 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12C40") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (f / form-01 :ARG1 (c2 / colony)) :degree (m2 / most)) :ARG2 (s / size-01 :ARG1 c2 :ARG2 (s2 / small :degree (m4 / more)) :mod (m3 / mean)) :condition (c3 / colony :mod (d2 / diameter :mod (a / above :op1 (d / distance-quantity :quant "100" :unit (m5 / micrometer)))))) # ::id pmid_1859_7688.130 # ::date 2015-07-07T23:27:10 # ::file pmid_1859_7688_130.txt # ::snt Rlf-CAAX-infected cells formed slightly more colonies above 100 μm than vector-transfected control cells, but these were significantly smaller than those formed by Ras- and Ras EDM-infected cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (c / contrast-01 :ARG1 (f / form-01 :ARG0 (c2 / cell :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Rlf-CAAX")))) :ARG1 (c3 / colony :quant (m2 / more :degree (s3 / slight)) :compared-to (c4 / cell :ARG0-of (c5 / control-01) :ARG1-of (t / transfect-01 :ARG2 (v / vector))) :mod (a / above :op1 (d / distance-quantity :quant "100" :unit (m / micrometer))))) :ARG2 (s / small :degree (m3 / more) :ARG1-of (s2 / significant-02) :domain c2 :compared-to (c7 / colony :ARG1-of (f2 / form-01 :ARG0 (c6 / cell :ARG1-of (i2 / infect-01 :ARG2 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n3 / name :op1 "Ras" :op2 "EDM") :xref (x / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212"))))))))) # ::id pmid_1859_7688.131 # ::date 2015-07-07T23:42:02 # ::file pmid_1859_7688_131.txt # ::snt When grown under anchorage-independent conditions in ultra-low attachment plates, the accumulation of cells for the various infected cell lines roughly paralleled the total cell masses seen in soft agar growth assays (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / parallel-01 :ARG0 (a / accumulate-01 :ARG1 (c / cell) :mod (c2 / cell-line :ARG1-of (i / infect-01) :mod (v / various))) :ARG1 (m / mass-01 :ARG0 (c3 / cell :mod (t / total)) :ARG1-of (s / see-01 :location (a2 / assay-01 :ARG1 (g / grow-01 :condition (a3 / agar :ARG1-of (s2 / soft-02)))))) :degree (r / rough) :condition (g2 / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a4 / anchorage)) :location (p2 / plate :ARG3-of (a5 / attach-01 :ARG1-of (l / low-04 :degree (u / ultra))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2C"))) # ::id pmid_1859_7688.132 # ::date 2015-07-07T23:55:16 # ::file pmid_1859_7688_132.txt # ::snt The RasV12- and RasV12 EDM-expressing cells grew well, while the growth of the Rlf-CAAX-expressing cells was significantly less. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 8, 2015 (c / contrast-01 :ARG1 (g / grow-01 :ARG1 (c2 / cell :ARG3-of (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212"))))) :ARG1-of (w / well-09)) :ARG2 (g2 / grow-01 :ARG1 (c3 / cell :ARG3-of (e4 / express-03 :ARG2 (e5 / enzyme :name (n3 / name :op1 "Rlf-CAAX")))) :mod (l / less :ARG1-of (s / significant-02)) :compared-to g)) # ::id pmid_1859_7688.133 # ::date 2015-07-08T00:03:31 # ::file pmid_1859_7688_133.txt # ::snt The HME16C cells maintained viability but did not increase in number. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 8, 2015 (c / contrast-01 :ARG1 (m / maintain-01 :ARG0 (c2 / cell-line :name (n / name :op1 "HME16C")) :ARG1 (v / viability)) :ARG2 (i / increase-01 :polarity "-" :ARG1 c2 :mod (n2 / number))) # ::id pmid_1859_7688.134 # ::date 2015-07-08T00:06:34 # ::file pmid_1859_7688_134.txt # ::snt To compare our results to others, we verified the function of pLRT vector driven Ras EDM mutants and Rlf-CAAX in HEK-HT cells, which previously have been reported to form colonies in soft agar upon expression of H-RasV12G37 and Rlf-CAAX [27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (v / verify-01 :ARG0 (w / we) :ARG1 (f / function-01 :ARG0 (a / and :op1 (e / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212")) :op2 (e2 / enzyme :name (n3 / name :op1 "Rlf-CAAX")) :ARG1-of (d / drive-02 :ARG0 (v2 / vector :name (n / name :op1 "LRT") :ARG3-of (p4 / phosphorylate-01)))) :location (c / cell-line :name (n4 / name :op1 "HEK-HT") :ARG0-of (f2 / form-01 :ARG1 (c2 / colony) :location (a2 / agar :ARG1-of (s / soft-02)) :condition (e3 / express-03 :ARG2 (a3 / and :op1 (e4 / enzyme :name (n5 / name :op1 "H-Ras") :ARG2-of (m2 / mutate-01 :value "V12G37") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 e2)) :ARG1-of (r / report-01 :time (p2 / previous))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "27"))) :purpose (c4 / compare-01 :ARG0 w :ARG1 (t2 / thing :ARG2-of (r2 / result-01) :poss w) :ARG2 (t / thing :ARG2-of r2 :poss (p5 / person) :mod (o / other)))) # ::id pmid_1859_7688.135 # ::date 2015-07-08T00:07:46 # ::file pmid_1859_7688_135.txt # ::snt In our hands, expression of H-RasV12, H-RasV12G37, and Rlf-CAAX from the pLRT vector induced efficient soft agar colony growth, and H-RasV12S35 and H-RasV12C40 did not (not shown), identical to previously reported results [27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i / induce-01 :ARG0 (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x3 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e3 / enzyme :name (n3 / name :op1 "H-Ras") :ARG2-of (m2 / mutate-01 :value "V12G37") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op3 (e4 / enzyme :name (n4 / name :op1 "Rlf-CAAX")) :source (v / vector :name (n / name :op1 "LRT") :ARG3-of (p4 / phosphorylate-01)))) :ARG2 (g / grow-01 :ARG2 (c2 / colony :location (a2 / agar :ARG1-of (s / soft-02))) :ARG1-of (e5 / efficient-01))) :ARG2 (i3 / induce-01 :polarity "-" :ARG0 (a3 / and :op1 (e6 / enzyme :name (n5 / name :op1 "H-ras") :ARG2-of (m3 / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.601")) :op2 (e7 / enzyme :name (n6 / name :op1 "H-ras") :ARG2-of (m4 / mutate-01 :value "V12C40") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.601"))) :ARG2 g :ARG1-of (s2 / show-01 :polarity "-")) :location (h / hand :part-of (w / we)) :ARG1-of (i2 / identical-01 :ARG2 (t / thing :ARG2-of (r / result-01 :ARG1-of (r2 / report-01 :time (p2 / previous))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "27")))) # ::id pmid_1859_7688.136 # ::date 2015-07-08T00:26:16 # ::file pmid_1859_7688_136.txt # ::snt Expression of exogenous H-Ras and Rlf-CAAX, and activation of endogenous RalA, in this cell line was similar to that observed in HME16C cells (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / resemble-01 :ARG1 (a / and :op1 (e / express-03 :ARG2 (a3 / and :op1 (e2 / enzyme :name (n / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e3 / enzyme :name (n2 / name :op1 "Rlf-CAAX")) :mod (e4 / exogene)) :ARG3 (c / cell-line :mod (t / this))) :op2 (a2 / activate-01 :ARG1 (p / protein :name (n3 / name :op1 "RalA") :mod (e6 / endogene) :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604")) :location c)) :ARG2 (o / observe-01 :ARG1 (a4 / and :op1 e :op2 a2) :location (c2 / cell-line :name (n4 / name :op1 "HME16C") :ARG1-of (s / show-01 :polarity "-")))) # ::id pmid_1859_7688.137 # ::date 2015-07-08T01:00:01 # ::file pmid_1859_7688_137.txt # ::snt Therefore, expression of Rlf-CAAX and subsequent RalA activation did not appear to be sufficient to induce anchorage-independent growth in the HME16C mammary epithelial cell line in contrast to HEK-HT and various other immortalized human cell types [27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (i / infer-01 :ARG1 (a / appear-01 :polarity "-" :ARG1 (a2 / and :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "Rlf-CAAX"))) :op1 (a3 / activate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "RalA") :xref (x / xref :value "UNIPROT:RALA_HUMAN" :prob "0.604")) :mod (s / subsequent))) :ARG0-of (s2 / suffice-01 :ARG1 (i2 / induce-01 :ARG0 a2 :ARG2 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a4 / anchorage))) :location (c / cell-line :name (n3 / name :op1 "HME16C") :mod (e4 / epithelium :mod (m / mammary)))) :ARG1-of (c2 / contrast-01 :ARG2 (a5 / and :op1 (c3 / cell-line :name (n4 / name :op1 "HEK-HT")) :op2 (t / type-03 :ARG1 (c4 / cell :mod (h / human) :ARG1-of (i3 / immortalize-03)) :mod (o / other) :mod (v / various)))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 "27")))) # ::id pmid_1859_7688.138 # ::date 2015-07-08T01:15:29 # ::file pmid_1859_7688_138.txt # ::snt Tumorigenesis of HME16C cell lines in nude mice # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (c / create-01 :ARG1 (t / tumor) :mod (c2 / cell-line :name (n / name :op1 "HME16C")) :location (m / mouse :mod (n2 / nude))) # ::id pmid_1859_7688.139 # ::date 2015-07-08T01:20:45 # ::file pmid_1859_7688_139.txt # ::snt Anchorage-independent growth often predicts the ability of cells to grow as xenografted tumors in immuno-compromised mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / predict-01 :ARG0 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a / anchorage))) :ARG1 (c / capable-01 :ARG1 (c2 / cell) :ARG2 (g2 / grow-01 :ARG1 c2 :manner (t / tumor :mod (x / xenograft) :location (m / mouse :ARG1-of (i / immune-02 :ARG1-of (c3 / compromise-02)))))) :frequency (o / often)) # ::id pmid_1859_7688.140 # ::date 2015-07-08T01:57:32 # ::file pmid_1859_7688_140.txt # ::snt Tumor formation was assessed following subcutaneous inoculation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a / assess-01 :ARG1 (f / form-01 :ARG1 (t / tumor)) :ARG1-of (f2 / follow-01 :ARG2 (i / inoculate-01 :mod (s / subcutaneous)))) # ::id pmid_1859_7688.141 # ::date 2015-07-08T02:02:10 # ::file pmid_1859_7688_141.txt # ::snt The RasV12-infected HME16C cells formed rapidly growing, fluid-filled tumors with an average latency of 4 weeks and a mean tumor volume of 808.8 mm3 at 6 weeks (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (f / form-01 :ARG0 (c / cell-line :name (n / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1 (t / tumor :ARG1-of (g / grow-01 :manner (r2 / rapid)) :ARG1-of (f2 / fill-01 :ARG2 (f3 / fluid)) :mod (l / latency :ARG1-of (a / average-01 :ARG2 (t2 / temporal-quantity :quant "4" :unit (w / week)))) :mod (v / volume-quantity :quant "808.8" :mod (t3 / tumor :mod (m2 / mean)) :unit (c2 / cubic-millimeter) :time (a2 / after :op1 (t4 / temporal-quantity :quant "6" :unit w)))) :ARG1-of (d / describe-01 :ARG0 (t5 / table :mod "1"))) # ::id pmid_1859_7688.142 # ::date 2015-07-08T02:16:14 # ::file pmid_1859_7688_142.txt # ::snt Approximately one-half of the tumors were aspirated prior to sacrifice, and a sero-sanguinous fluid was observed, on average accounting for roughly one-third of the measured tumor volume. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (a / and :op1 (a2 / aspirate-101 :ARG1 (t / tumor :quant (h / half :ARG1-of (a3 / approximate-01))) :time (p / prior :op1 (s / sacrifice-01))) :op2 (o2 / observe-01 :ARG1 (f / fluid :mod (s2 / sero-sanguine) :ARG0-of (a4 / account-01 :ARG1 (v / volume :mod (t2 / tumor) :ARG1-of (m / measure-01) :quant (r2 / roughly :op1 "1/3")) :ARG1-of (a5 / average-01))))) # ::id pmid_1859_7688.143 # ::date 2015-07-08T08:07:08 # ::file pmid_1859_7688_143.txt # ::snt Histological analysis of H&E stained tumor sections revealed poorly differentiated spindle-shaped tumor cells with prominent squamous cell differentiation and extracellular keratin deposition (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (s / section-01 :ARG1 (t / tumor) :ARG1-of (s2 / stain-01 :ARG2 (a2 / and :op1 (s7 / small-molecule :name (n / name :op1 "hematoxylin") :xref (x1 / xref :value "PUBCHEM:10603" :prob "16.740406")) :op2 (s8 / small-molecule :name (n2 / name :op1 "eosin") :xref (x / xref :value "PUBCHEM:11048" :prob "9.837358"))))) :mod (h / histology)) :ARG1 (c / cell :mod t :ARG1-of (s3 / shape-01 :ARG2 (s4 / spindle)) :ARG1-of (d / differentiate-101 :degree (p / poor)) :ARG0-of (h2 / have-03 :ARG1 (a3 / and :op1 (d2 / differentiate-101 :ARG1 (c2 / cell :mod (s5 / squamous)) :degree (p2 / prominent)) :op2 (d3 / deposit-01 :ARG1 (k / keratin) :mod (e / extracellular))))) :ARG1-of (s6 / show-01 :polarity "-")) # ::id pmid_1859_7688.144 # ::date 2015-07-08T10:29:13 # ::file pmid_1859_7688_144.txt # ::snt Tumors also contained a strong inflammatory component. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 8, 2015 (c / contain-01 :ARG0 (t / tumor) :ARG1 (c2 / component :ARG0-of (i / inflame-01) :ARG1-of (s / strong-02)) :mod (a / also)) # ::id pmid_1859_7688.145 # ::date 2015-07-08T10:40:39 # ::file pmid_1859_7688_145.txt # ::snt Of the other cell lines tested, only the RasV12S35-infected HME16C cells formed palpable tumors in 50% of injected animals with an average latency of approximately 12 weeks and a mean tumor volume of 109.0 mm3 at 16 weeks, considerably smaller than RasV12-expressing tumors (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / form-01 :ARG1 (t / tumor :mod (p / palpable) :ARG0-of (h / have-03 :ARG1 (a3 / and :op1 (l / latency :duration (a4 / approximately :op1 (t3 / temporal-quantity :quant "12" :unit (w / week)))) :op2 (v / volume :mod t :ARG1-of (a5 / average-01 :ARG2 "109.0" :ARG3 (c3 / cubic-millimeter)) :time (a6 / after :quant (t4 / temporal-quantity :quant "16" :unit w)) :degree (s / small :degree (m2 / more) :mod (c4 / considerable) :compared-to (t5 / tumor :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))))) :ARG2 (c / cell-line :name (n / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (i2 / include-01 :ARG2 (c2 / cell-line :ARG1-of (t2 / test-01) :mod (o / other))) :mod (o2 / only)) :location (a / animal :ARG1-of (i3 / include-91 :ARG2 (a2 / animal :ARG2-of (i4 / inject-01)) :ARG3 (p2 / percentage-entity :value "50"))) :ARG1-of (d / describe-01 :ARG0 (t6 / table :mod "1"))) # ::id pmid_1859_7688.146 # ::date 2015-07-08T21:54:15 # ::file pmid_1859_7688_146.txt # ::snt Cells within RasV12S35-infected tumors resembled the histology of RasV12 tumor cells but with less keratin deposition and without the formation of fluid-filled spaces (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (r / resemble-01 :ARG1 (c / cell :location (t / tumor :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG2 (h / histology :poss (c2 / cell :mod (t2 / tumor :ARG1-of (i2 / infect-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :ARG1-of (c3 / contrast-01 :ARG2 (a / and :op1 (h2 / have-03 :ARG0 c :ARG1 (d / deposit-01 :ARG1 (k / keratin) :quant (l / less))) :op2 (f / form-01 :polarity "-" :ARG1 (s / space :ARG1-of (f2 / fill-01 :ARG2 (f3 / fluid))) :ARG2 c))) :ARG1-of (s2 / show-01 :polarity "-")) # ::id pmid_1859_7688.147 # ::date 2015-07-08T22:06:57 # ::file pmid_1859_7688_147.txt # ::snt Empty vector-, RasV12G37-, RasV12C40-, and Rlf-CAAX-infected cells failed to form palpable tumors four months after injection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (f / fail-01 :ARG1 (a / and :op1 (c / cell :ARG1-of (i / infect-01 :ARG2 (v / vector :ARG2-of (e / empty-01)))) :op2 (c2 / cell :ARG1-of (i2 / infect-01 :ARG2 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op3 (c3 / cell :ARG1-of (i3 / infect-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op4 (c4 / cell :ARG1-of (i4 / infect-01 :ARG2 (e4 / enzyme :name (n3 / name :op1 "Rlf-CAAX"))))) :ARG2 (f2 / form-01 :ARG0 c :ARG1 (t / tumor :mod (p2 / palpable))) :time (a2 / after :op1 (i5 / inject-01) :quant (t2 / temporal-quantity :quant "4" :unit (m3 / month)))) # ::id pmid_1859_7688.148 # ::date 2015-07-08T22:27:50 # ::file pmid_1859_7688_148.txt # ::snt The metastatic potential of RasV12- and RasV12G37-expressing cell lines was tested by tail-vein injection in nude mice, but no metastatic lesions were observed by histological analysis in lungs, liver, spleen, or kidneys at 16 weeks post injection (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (c / contrast-01 :ARG1 (t / test-01 :ARG1 (p / potential :mod (m / metastasize-101 :ARG2 (a / and :op1 (c2 / cell-line :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c3 / cell-line :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12G37") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) :manner (i / inject-01 :ARG2 (v / vein :part-of (t2 / tail :part-of (m4 / mouse :mod (n3 / nude)))))) :ARG2 (o / observe-01 :polarity "-" :ARG1 (l / lesion :mod m) :manner (a2 / analyze-01 :mod (h / histology)) :location (o2 / or :op1 (l2 / lung) :op2 (l3 / liver) :op3 (s / spleen) :op4 (k / kidney)) :time (a3 / after :op1 (i2 / inject-01) :quant (t3 / temporal-quantity :quant "16" :unit (w / week)))) :ARG1-of (s2 / show-01 :polarity "-")) # ::id pmid_1859_7688.149 # ::date 2015-07-08T22:44:22 # ::file pmid_1859_7688_149.txt # ::snt Autocrine EGFR signaling is required for RasV12G37- and RasV12C40-mediated, but not RasV12S35-mediated, HME16C cell anchorage- independent growth # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / require-01 :ARG0 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a / anchor-01 :ARG1 (c / cell-line :name (n / name :op1 "HME16C")))) :ARG1-of (m / mediate-01 :ARG0 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12G37") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12C40") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1 (s / signal-07 :ARG0 (a3 / autocrine) :ARG1 (e4 / enzyme :name (n4 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1-of (c2 / contrast-01 :ARG2 (r2 / require-01 :polarity "-" :ARG0 (g2 / grow-01 :ARG0-of d :ARG1-of (m4 / mediate-01 :ARG0 (e3 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1 s))) # ::id pmid_1859_7688.150 # ::date 2015-07-08T23:06:02 # ::file pmid_1859_7688_150.txt # ::snt EGFR signaling is frequently altered in breast cancer, where EGFR and ErbB2 over-expression are common events. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / alter-01 :ARG1 (s / signal-07 :ARG1 (e2 / enzyme :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1-of (f / frequent-02) :location (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer") :location-of (e / event :mod (c2 / common) :domain (o / overexpress-01 :ARG1 (a2 / and :op1 e2 :op2 (p / protein :name (n3 / name :op1 "ErbB2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.634"))))))) # ::id pmid_1859_7688.151 # ::date 2015-07-08T23:15:36 # ::file pmid_1859_7688_151.txt # ::snt cDNA microarray and real-time RT-PCR analysis of HME16C RasV12- and Ras EDM-infected cells (Additional file 1) revealed increased levels of mRNAs for EGFR ligands, including epiregulin, amphiregulin, and TGFa (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reveal-01 :ARG0 (a / and :op1 (a2 / analyze-01 :ARG1 (a3 / and :op1 (c / cell-line :name (n / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c2 / cell-line :name (n3 / name :op1 "HME16C") :ARG1-of (i2 / infect-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras" :op2 "EDM") :xref (x / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212"))))) :instrument (m2 / microarray :consist-of (n5 / nucleic-acid :name (n13 / name :op1 "cDNA")))) :op2 (a4 / analyze-01 :ARG1 a3 :mod (r3 / react-01 :ARG0 (p / polymerase) :mod (c3 / chain) :subevent (t / transcribe-01 :ARG1-of (r4 / reverse-01)) :mod (r2 / real-time))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "1" :ARG1-of (a5 / add-02)))) :ARG1 (l / level :quant-of (n12 / nucleic-acid :name (n7 / name :op1 "mRNA")) :ARG1-of (i3 / increase-01)) :location (l2 / ligand :name (n8 / name :op1 "EGFR") :ARG2-of (i4 / include-91 :ARG1 (a6 / and :op1 (l3 / ligand :name (n9 / name :op1 "epiregulin")) :op2 (l4 / ligand :name (n10 / name :op1 "amphiregulin")) :op3 (l5 / ligand :name (n11 / name :op1 "TGFa"))))) :ARG1-of (d2 / describe-01 :ARG0 (t3 / table :mod "2"))) # ::id pmid_1859_7688.152 # ::date 2015-07-08T23:42:09 # ::file pmid_1859_7688_152.txt # ::snt In addition, increased levels of phospho-Erk were unexpectedly seen in RasV12G37- and RasV12C40-infected cells, possibly the result of autocrine activation of endogenous EGFR by secreted EGFR ligands. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op2 (s / see-01 :ARG1 (l / level :quant-of (e4 / enzyme :name (n / name :op1 "Erk") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :ARG1-of (i / increase-01)) :ARG1-of (e2 / expect-01 :polarity "-") :location (a2 / and :op1 (c / cell :ARG1-of (i2 / infect-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c2 / cell :ARG1-of (i3 / infect-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG2-of (r / result-01 :ARG1 (a3 / activate-01 :ARG0 (l2 / ligand :name (n4 / name :op1 "EGFR") :ARG1-of (s2 / secrete-01)) :ARG1 (e5 / enzyme :name (n5 / name :op1 "EGFR") :mod (e6 / endogenous) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :mod (a4 / autocrine)) :ARG1-of (p2 / possible-01)))) # ::id pmid_1859_7688.153 # ::date 2015-07-08T23:58:31 # ::file pmid_1859_7688_153.txt # ::snt The presence of EGFR was established using Western blots (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (e / establish-01 :ARG1 (b / be-located-at-91 :ARG1 (e2 / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG2-of (u / use-01 :ARG1 (i / immunoblot-01)) :ARG1-of (s / show-01 :polarity "-")) # ::id pmid_1859_7688.154 # ::date 2015-07-09T00:03:47 # ::file pmid_1859_7688_154.txt # ::snt Therefore, we sought to determine if autocrine signaling by the EGFR was required for the anchorage-independent growth of Ras- or Ras EDM-infected cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (c / cause-01 :ARG1 (s / seek-01 :ARG0 (w / we) :ARG1 (d / determine-01 :ARG0 w :ARG1 (r / require-01 :mode "interrogative" :ARG0 (g / grow-01 :ARG1 (o / or :op1 (c2 / cell :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c3 / cell :ARG1-of (i2 / infect-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM") :xref (x2 / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212"))))) :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 (a / anchor-01))) :ARG1 (s2 / signal-07 :ARG0 (e3 / enzyme :name (n3 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :mod (a2 / autocrine)))))) # ::id pmid_1859_7688.155 # ::date 2015-07-09T00:18:43 # ::file pmid_1859_7688_155.txt # ::snt RasV12- and Ras EDM-infected HME16C cells were grown in soft agar in the presence or absence of the EGFR-specific inhibitors, PD153035 and PD168393. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (g / grow-01 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c2 / cell-line :name (n3 / name :op1 "HME16C") :ARG1-of (i2 / infect-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras" :op2 "EDM") :xref (x1 / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212"))))) :location (a2 / agar :ARG1-of (s / soft-02)) :manner (o / or :op1 (b / be-located-at-91 :ARG1 (a3 / and :op1 (s2 / small-molecule :name (n5 / name :op1 "PD153035") :xref (x4 / xref :value "PUBCHEM:4705" :prob "15.816147")) :op2 (s3 / small-molecule :name (n6 / name :op1 "PD168393") :xref (x3 / xref :value "PUBCHEM:4708" :prob "19.266134")) :ARG0-of (i3 / inhibit-01) :ARG1-of (s4 / specific-02 :ARG2 (e3 / enzyme :name (n7 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) :op2 (a4 / absent-01 :ARG1 a3))) # ::id pmid_1859_7688.156 # ::date 2015-07-09T00:58:21 # ::file pmid_1859_7688_156.txt # ::snt Complete inhibition of colony formation for RasV12G37-infected and RasV12C40-infected cells was observed at 0.25 μM PD153035, a concentration that specifically inhibits EGFR [28], whereas both the RasV12- and RasV12S35-infected cells formed colonies efficiently at this same concentration of inhibitor (Figure 3A and 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG1 (o / observe-01 :ARG1 (i / inhibit-01 :ARG1 (f / form-01 :ARG0 (a / and :op1 (c2 / cell :ARG1-of (i2 / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c3 / cell :ARG1-of (i3 / infect-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1 (c4 / colony)) :degree (c5 / complete-01)) :manner (s / small-molecule :name (n3 / name :op1 "PD153035") :quant (c6 / concentration-quantity :quant "0.25" :unit (m3 / micromolar) :ARG0-of (i4 / inhibit-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (s2 / specific-02))) :xref (x5 / xref :value "PUBCHEM:4705" :prob "15.816147")) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c7 / cite-01 :ARG2 "28")))) :ARG2 (f2 / form-01 :ARG0 (a2 / and :op1 (c8 / cell :ARG1-of (i5 / infect-01 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c9 / cell :ARG1-of (i6 / infect-01 :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12S35") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1 c4 :ARG2-of (e6 / efficient-01) :manner s) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f3 / figure :mod "3A") :op2 (f4 / figure :mod "3B")))) # ::id pmid_1859_7688.157 # ::date 2015-07-09T01:54:35 # ::file pmid_1859_7688_157.txt # ::snt Identical results were found for the EGFR-specific inhibitor PD168393 used at 0.1 μM, a concentration that specifically inhibits EGFR and Her-2 receptors [29](not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG2-of (i / identical-01)) :ARG2 (s / small-molecule :name (n / name :op1 "PD168393") :ARG0-of (i2 / inhibit-01) :ARG1-of (s2 / specific-02 :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1-of (u / use-01 :manner (c / concentration-quantity :quant "0.1" :unit (m / micromolar) :ARG0-of (i3 / inhibit-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n3 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (r3 / receptor :name (n4 / name :op1 "Her-2"))) :ARG1-of (s3 / specific-02)))) :xref (x2 / xref :value "PUBCHEM:4708" :prob "19.266134")) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "29"))) :ARG1-of (s4 / show-01 :polarity "-")) # ::id pmid_1859_7688.158 # ::date 2015-07-09T02:12:45 # ::file pmid_1859_7688_158.txt # ::snt Similarly, treatment of cells grown in ultra-low-attachment plates also demonstrated that EGFR inhibition substantially inhibited growth of RasV12G37-and RasV12C40-expressing cells relative to that of RasV12- and RasV12S35-expressing HME16C (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / demonstrate-01 :ARG0 (t / treat-04 :ARG1 (c / cell :ARG1-of (g / grow-01 :location (p / plate :ARG2-of (a / attach-01 :ARG1-of (l / low-04 :degree (u / ultra))))))) :ARG1 (i / inhibit-01 :ARG0 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x4 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1 (g2 / grow-01 :ARG1 (c2 / cell :ARG3-of (e2 / express-03 :ARG2 (a2 / and :op1 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e4 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :degree (s / substantial) :ARG1-of (r / relative-05 :ARG3 (g3 / grow-01 :ARG1 (c3 / cell-line :name (n4 / name :op1 "HME16C") :ARG3-of (e5 / express-03 :ARG2 (a3 / and :op1 (e6 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e7 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))))) :mod (a4 / also) :ARG1-of (r2 / resemble-01) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2C"))) # ::id pmid_1859_7688.159 # ::date 2015-07-09T02:45:18 # ::file pmid_1859_7688_159.txt # ::snt Western blotting of cellular lysates from cells treated with 0.25 μM PD153035 showed that high levels of phosphorylated Erk were maintained only in RasV12- and RasV12S35-infected cells, but were significantly reduced in RasV12G37- or RasV12C40-infected cells treated with the inhibitor (Figure 3C), while phoshorylated Akt was minimally affected (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (i6 / immunoblot-01 :ARG1 (l / lysate :mod (c2 / cell) :source (c3 / cell :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "PD153035") :quant (c4 / concentration-quantity :quant "0.25" :unit (m / micromolar)) :ARG0-of (i / inhibit-01) :xref (x6 / xref :value "PUBCHEM:4705" :prob "15.816147")))))) :ARG1 (c5 / contrast-01 :ARG1 (m2 / maintain-01 :ARG1 (l2 / level :quant-of (e / enzyme :name (n3 / name :op1 "Erk") :ARG3-of (p / phosphorylate-01) :xref (x5 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :ARG1-of (h / high-02)) :location (a2 / and :op1 (c6 / cell :ARG1-of (i2 / infect-01 :ARG2 (e5 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c7 / cell :ARG1-of (i3 / infect-01 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12S35") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :mod (o / only))) :ARG2 (r / reduce-01 :ARG1 l2 :ARG2 (s3 / significant-02) :location (o2 / or :op1 (c8 / cell :ARG1-of (i4 / infect-01 :ARG2 (e2 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12G37") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c9 / cell :ARG1-of (i5 / infect-01 :ARG2 (e3 / enzyme :name (n7 / name :op1 "Ras") :ARG2-of (m6 / mutate-01 :value "V12C40") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1-of (t3 / treat-04 :ARG2 s2)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3C"))) :ARG2 (a3 / affect-01 :ARG1 (e6 / enzyme :name (n8 / name :op1 "Akt") :ARG3-of p :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of (m7 / minimal-02) :ARG1-of (s4 / show-01 :polarity "-"))) # ::id pmid_1859_7688.160 # ::date 2015-07-09T03:12:41 # ::file pmid_1859_7688_160.txt # ::snt Anchorage-independent growth therefore correlated with maintenance of high Erk activity in HME16C cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (c2 / correlate-01 :ARG1 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a / anchor-01))) :ARG2 (m / maintain-01 :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "Erk") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :ARG1-of (h / high-02)) :location (c3 / cell-line :name (n2 / name :op1 "HME16C"))))) # ::id pmid_1859_7688.161 # ::date 2015-07-09T03:16:46 # ::file pmid_1859_7688_161.txt # ::snt Consistent with this observation, inhibition of MEK, and therefore ERK signaling, using the MEK-specific inhibitor PD98059 at 10 μM, significantly inhibited soft agar colony formation by all cell lines (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / inhibit-01 :ARG0 (a / and :op1 (i2 / inhibit-01 :ARG1 (s / signal-07 :ARG0 (e / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :op2 (i3 / inhibit-01 :ARG1 (s2 / signal-07 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Erk") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))) :ARG1-of (c / cause-01 :ARG0 i2)) :ARG2-of (u / use-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "PD98059") :ARG0-of (i4 / inhibit-01 :ARG1 e) :ARG1-of (s4 / specific-02 :ARG2 e) :quant (c2 / concentration-quantity :quant "10" :unit (m / micromolar)) :xref (x2 / xref :value "PUBCHEM:4713" :prob "18.349844")))) :ARG1 (f / form-01 :ARG1 (c3 / colony :mod (a2 / agar :ARG1-of (s5 / soft-02))) :ARG2 (c4 / cell-line :mod (a3 / all))) :ARG1-of (s6 / significant-02) :ARG1-of (c5 / consistent-01 :ARG2 (o / observe-01 :mod (t / this))) :ARG1-of (s7 / show-01 :polarity "-")) # ::id pmid_1859_7688.162 # ::date 2015-07-09T03:39:35 # ::file pmid_1859_7688_162.txt # ::snt Microarray analysis of gene expression changes in RasV12-, RasV12G37-, RasV12S35-, and RasV12C40-infected HME16C cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (a / analyze-01 :ARG1 (c / change-01 :ARG1 (e / express-03 :ARG1 (g / gene))) :mod (m / microarray) :location (a2 / and :op1 (c2 / cell-line :wiki "-" :name (n / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (e2 / enzyme :wiki "Ras_subfamily" :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c3 / cell-line :wiki "-" :name (n3 / name :op1 "HME16C") :ARG1-of (i2 / infect-01 :ARG2 (e3 / enzyme :wiki "Ras_subfamily" :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12G37") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op3 (c4 / cell-line :wiki "-" :name (n5 / name :op1 "HME16C") :ARG1-of (i3 / infect-01 :ARG2 (e4 / enzyme :wiki "Ras_subfamily" :name (n6 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12S35") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op4 (c5 / cell-line :wiki "-" :name (n7 / name :op1 "HME16C") :ARG1-of (i4 / infect-01 :ARG2 (e5 / enzyme :wiki "Ras_subfamily" :name (n8 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12C40") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) # ::id pmid_1859_7688.163 # ::date 2015-07-09T03:44:45 # ::file pmid_1859_7688_163.txt # ::snt Activation of the Ras oncogene is accompanied by the stimulation of multiple signal transduction pathways leading to the activation or repression of numerous transcription factors as well as changes in mRNA translation and stability, and thus, the modulation of gene expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / accompany-01 :ARG0 (s / stimulate-01 :ARG1 (p / pathway :ARG2-of (t / transduce-01 :ARG1 (s2 / signal-07)) :quant (m / multiple))) :ARG1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Ras") :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG0-of (l / lead-03 :ARG2 (a3 / and :op1 (a4 / and :op1 (o2 / or :op1 (a5 / activate-01 :ARG1 (f / factor :ARG0-of (t2 / transcribe-01) :quant (n2 / numerous))) :op2 (r / repress-01 :ARG1 f)) :op2 (c / change-01 :ARG1 (a6 / and :op1 (t3 / translate-02 :ARG1 (n4 / nucleic-acid :name (n3 / name :op1 "mRNA"))) :op2 (s3 / stable-03 :ARG1 n4)))) :op2 (c2 / cause-01 :ARG0 a4 :ARG1 (m2 / modulate-01 :ARG1 (e / express-03 :ARG1 (g / gene))))))) # ::id pmid_1859_7688.164 # ::date 2015-07-09T04:17:05 # ::file pmid_1859_7688_164.txt # ::snt To determine which gene expression changes accompany the transformation of HME16C human epithelial cells by activated Ras, we examined our transformed HME16C cells by cDNA microarray analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / examine-01 :ARG0 (w / we) :ARG1 (c / cell-line :name (n / name :op1 "HME16C") :ARG1-of (t / transform-01) :ARG1-of (a / analyze-01 :instrument (m / microarray :consist-of (n2 / nucleic-acid :name (n5 / name :op1 "cDNA")))) :poss w) :purpose (d / determine-01 :ARG0 w :ARG1 (a2 / accompany-01 :ARG0 (c2 / change-01 :ARG1 (e2 / express-03 :ARG1 (g / gene))) :ARG1 (t3 / transform-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG1-of (a3 / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (c3 / cell-line :name (n4 / name :op1 "HME16C") :mod (e4 / epithelium :part-of (h / human))))))) # ::id pmid_1859_7688.165 # ::date 2015-07-09T04:37:52 # ::file pmid_1859_7688_165.txt # ::snt To do this, RNA was isolated from H-RasV12 and H-RasV12 EDM expressing cells after treatment with doxycycline to fully induce gene expression and compared to RNA from identically treated pLRT vector-infected control cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / and :op1 (i / isolate-01 :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "RNA")) :ARG2 (a2 / and :op1 (c / cell :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))) :op2 (c2 / cell :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n2 / name :op1 "H-Ras" :op2 "EDM") :ARG2-of m :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "0.243"))))) :time (a3 / after :op1 (t / treat-04 :ARG1 a2 :ARG2 (d / doxycycline))) :purpose (i2 / induce-01 :ARG0 n4 :ARG2 (e5 / express-03 :ARG1 (g / gene)) :degree (f / full))) :op2 (c3 / compare-01 :ARG1 i :ARG2 (i3 / isolate-01 :ARG1 n4 :ARG2 (c4 / cell :ARG2-of (c5 / control-01) :ARG1-of (i4 / infect-01 :ARG2 (v / vector :name (n3 / name :op1 "LRT") :ARG3-of (p / phosphorylate-01))) :ARG1-of (t2 / treat-04 :ARG2 d :ARG2-of (i5 / identical-01))))) :purpose (d2 / do-02 :ARG1 (t3 / this))) # ::id pmid_1859_7688.166 # ::date 2015-07-09T05:01:44 # ::file pmid_1859_7688_166.txt # ::snt Statistical analysis of microarray (SAM) data analysis was performed for the datasets, and a delta value of 0.4 was chosen for each dataset, which maintains the estimated false discovery rate (FDR) below 1% for each. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 10, 2015 (a / and :op1 (p / perform-01 :ARG1 (a2 / analyze-01 :ARG1 (d5 / data :topic (m2 / microarray)) :purpose (d / dataset) :mod (s / statistics))) :op2 (c / choose-01 :ARG1 (v / value :quant "0.4" :mod (d2 / delta)) :ARG3 (d3 / dataset :mod (e / each)) :ARG0-of (m / maintain-01 :ARG1 (r / rate :mod (d4 / discover-01) :mod (f / false) :ARG1-of (e2 / estimate-01)) :ARG2 (b / below :quant (p2 / percentage-entity :value "1"))) :beneficiary d3)) # ::id pmid_1859_7688.167 # ::date 2015-07-09T05:19:32 # ::file pmid_1859_7688_167.txt # ::snt A summary of the genes up- or down-regulated greater than 2-fold in the H-RasV12- and Ras effector domain mutant-infected HME16C cell lines is presented in Additional file 1, organized according to broad categories of gene function. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / present-01 :ARG1 (s / summarize-01 :ARG1 (o / or :op1 (g / gene :ARG1-of (u / upregulate-01)) :op2 (g2 / gene :ARG1-of (d / downregulate-01)) :quant (m2 / more-than :op1 (p2 / product-of :quant "2")) :location (a / and :op1 (c / cell-line :name (n / name :op1 "HME16C") :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n2 / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))) :op2 (c2 / cell-line :name (n3 / name :op1 "HME16C") :ARG1-of (i2 / infect-01 :ARG2 (d2 / domain :part-of (e2 / effector :mod (p3 / protein-family :name (n4 / name :op1 "Ras"))) :ARG2-of (m3 / mutate-01)))))) :ARG1-of (o2 / organize-01 :ARG1-of (c3 / consistent-01 :ARG2 (c4 / categorize-01 :ARG1 (f / function :mod (g4 / gene)) :ARG1-of (b / broad-02))))) :location (f2 / file :mod "1" :ARG1-of (a2 / add-02))) # ::id pmid_1859_7688.168 # ::date 2015-07-09T05:57:59 # ::file pmid_1859_7688_168.txt # ::snt To validate gene expression changes identified by cDNA microarray analysis, quantitative RT-PCR was performed using RNA from the same samples used in microarray analysis, and is presented in Additional file 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (p / perform-01 :ARG1 (r / react-01 :ARG0 (p3 / polymerase) :mod (q / quantitative) :mod (c2 / chain) :subevent (t / transcribe-01 :ARG1-of (r2 / reverse-01))) :ARG2-of (u / use-01 :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "RNA") :source (t2 / thing :ARG1-of (s / sample-01) :ARG1-of (s2 / same-01 :ARG2 (t3 / thing :ARG1-of (s3 / sample-01) :ARG1-of (u2 / use-01 :ARG2 (a2 / analyze-01 :mod (m / microarray :consist-of (n5 / nucleic-acid :name (n6 / name :op1 "cDNA"))))))))))) :op2 (p2 / present-01 :ARG1 r :location (f / file :mod "2" :ARG1-of (a3 / add-02))) :purpose (v / validate-01 :ARG1 (c / change-01 :ARG1 (e / express-03 :ARG1 (g / gene)) :ARG1-of (i / identify-01 :ARG0 a2)))) # ::id pmid_1859_7688.169 # ::date 2015-07-09T06:10:53 # ::file pmid_1859_7688_169.txt # ::snt Results for 22 of 26 genes chosen to reflect genes up- or down-regulated both strongly or weakly showed strong agreement with microarray data, demonstrating that the microarray dataset represents a reliable quantification of gene expression changes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01 :ARG1 (g / gene :quant "22" :ARG1-of (i / include-91 :ARG2 (g2 / gene :quant "26" :ARG2-of (c / choose-01 :ARG1 g :ARG4 (r2 / reflect-01 :ARG1 g :ARG2 (o / or :op1 (g3 / gene :ARG1-of (u / upregulate-01 :degree (o2 / or :op1 (s2 / strong-02) :op2 (w / weak-02)))) :op2 (g4 / gene :ARG1-of (d / downregulate-01 :degree o2)))))))))) :ARG1 (a / agree-01 :ARG0 t :ARG1 (d2 / data :mod (m / microarray)) :degree s2) :ARG0-of (d3 / demonstrate-01 :ARG1 (r3 / represent-01 :ARG0 (d4 / dataset :mod m) :ARG1 (q / quantify-01 :ARG1 (c2 / change-01 :ARG1 (e / express-03 :ARG1 o)) :ARG1-of (r4 / rely-01 :ARG1-of (p / possible-01)))))) # ::id pmid_1859_7688.170 # ::date 2015-07-09T06:27:48 # ::file pmid_1859_7688_170.txt # ::snt To evaluate the effect of EGFR inhibition on gene expression, RasV12-, RasV12S35-, and RasV12G37-infected cells were induced with doxycycline and subsequently incubated either in the presence or absence of 0.25 μM PD153035, and microarray analysis comparisons were made to vehicle-treated pLRT-infected cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / and :op1 (i / induce-01 :ARG0 (d / doxycycline) :ARG2 (a3 / and :op1 (c / cell :ARG1-of (i2 / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c2 / cell :ARG1-of (i3 / infect-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12S35") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op3 (c3 / cell :ARG1-of (i4 / infect-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12G37") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :op2 (i5 / incubate-01 :ARG1 a3 :ARG2 (o / or :op1 (b / be-located-at-91 :ARG1 (s / small-molecule :name (n4 / name :op1 "PD153035") :ARG0-of (i6 / inhibit-01) :quant (c4 / concentration-quantity :quant "0.25" :unit (m4 / micromolar)) :xref (x5 / xref :value "PUBCHEM:4705" :prob "15.816147"))) :op2 (a4 / absent-01 :ARG1 s) :mod (e4 / either)) :time (s2 / subsequent))) :op2 (m5 / make-01 :ARG1 (c5 / compare-01 :ARG1 a3 :ARG2 (c6 / cell :ARG1-of (i7 / infect-01 :ARG2 (p2 / protein :name (n5 / name :op1 "LRT") :ARG3-of (p / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:LRC51_HUMAN" :prob "0.292"))) :ARG1-of (t / treat-04 :ARG2 (v / vehicle))) :mod (m7 / microarray))) :purpose (e5 / evaluate-01 :ARG1 (a5 / affect-01 :ARG0 (i8 / inhibit-01 :ARG1 (e7 / enzyme :name (n6 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1 (e6 / express-03 :ARG1 (g / gene))))) # ::id pmid_1859_7688.171 # ::date 2015-07-09T06:56:08 # ::file pmid_1859_7688_171.txt # ::snt Almost all Ras and Ras EDM-induced upregulated transcriptional responses were blocked by pharmacological inhibition of EGFR, consistent with previous reports for inhibition of Raf-regulated transcription [30]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 15, 2016 (b / block-01 :ARG0 (i / inhibit-01 :ARG1 (e4 / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :mod (p2 / pharmacology)) :ARG1 (t / thing :ARG2-of (r / respond-01) :ARG1-of (t2 / transcribe-01) :ARG1-of (u / upregulate-01) :ARG2-of (i2 / induce-01 :ARG0 (a / and :op1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras" :op2 "EDM") :xref (x2 / xref :value "UNIPROT:RASE_HUMAN" :prob "0.212")))) :mod (a2 / all :degree (a3 / almost))) :ARG1-of (c / consistent-01 :ARG2 (r2 / report-01 :ARG1 (i3 / inhibit-01 :ARG1 (t3 / transcribe-01 :ARG1-of (r3 / regulate-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))) :time (p3 / previous))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "30")))) # ::id pmid_1859_7688.172 # ::date 2015-07-09T15:10:23 # ::file pmid_1859_7688_172.txt # ::snt Our analysis identified PHLDA1 as an up-regulated gene in both vehicle-treated and PD153035-treated RasV12 and RasV12S35 cells, although the relative fold increase was reduced following EGFR inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (h / have-concession-91 :ARG1 (i / identify-01 :ARG0 (a / analyze-01 :ARG0 (w / we)) :ARG1 (g2 / gene :wiki "-" :name (n2 / name :op1 "PHLDA1") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG2 (g3 / gene :ARG1-of (u / upregulate-01)) :location (a2 / and :op1 (c2 / cell :ARG1-of (t2 / treat-04 :ARG2 (s / small-molecule :wiki "-" :name (n3 / name :op1 "PD153035") :xref (x4 / xref :value "PUBCHEM:4705" :prob "15.816147"))) :mod (e / enzyme :wiki "Ras_subfamily" :name (n4 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (c3 / cell :ARG1-of (t / treat-04 :ARG0 (v / vehicle)) :mod (e2 / enzyme :wiki "Ras_subfamily" :name (n5 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12S35") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG2 (r / reduce-01 :ARG1 (i2 / increase-01 :ARG2 (p / product-of) :ARG1-of (r2 / relative-05)) :ARG1-of (f2 / follow-01 :ARG2 (i3 / inhibit-01 :ARG1 (e3 / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))))) # ::id pmid_1859_7688.173 # ::date 2015-07-10T06:05:56 # ::file pmid_1859_7688_173.txt # ::snt By comparison, PHLDA1 was down-regulated in PD153035-treated RasV12G37 relative to vehicle-treated cells (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (d / downregulate-01 :ARG1 (g / gene :name (n / name :op1 "PHLDA1") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG1-of (c / compare-01) :location (c3 / cell :mod (e / enzyme :ARG2-of (m / mutate-01 :value "V12G37") :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD153035") :xref (x1 / xref :value "PUBCHEM:4705" :prob "15.816147")))) :ARG1-of (r / relative-05 :ARG3 (c2 / cell :ARG1-of (t2 / treat-04 :ARG0 (v / vehicle))))) :ARG1-of (s / show-01 :polarity "-")) # ::id pmid_1859_7688.174 # ::date 2015-07-10T06:22:26 # ::file pmid_1859_7688_174.txt # ::snt Therefore, PHLDA1 represents a Raf/ERK-responsive gene whose expression parallels EGFR-independent HME16C mammary epithelial cell transformation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / cause-01 :ARG1 (r / represent-01 :ARG0 (g / gene :name (n / name :op1 "PHLDA1") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG1 (p2 / pathway :name (n2 / name :op1 "Raf/ERK") :ARG0-of (r2 / responsive-02) :ARG1-of (e / express-01 :ARG0-of (p / parallel-01 :ARG1 (t / transform-01 :ARG1 (c / cell-line :name (n3 / name :op1 "HME16C") :location (e2 / epithelium) :mod (m / mammary) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))))))))) # ::id pmid_1859_7688.175 # ::date 2015-07-10T03:22:41 # ::file pmid_1859_7688_175.txt # ::snt TDAG51 expression is up-regulated by Ras signaling in a ERK-dependent manner, and is associated with EGFR-independent transformation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (u2 / upregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG2 (s / signal-07 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (d / depend-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :op2 (a2 / associate-01 :ARG1 e :ARG2 (t / transform-01 :ARG0-of (d2 / depend-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))))) # ::id pmid_1859_7688.176 # ::date 2015-07-10T03:49:59 # ::file pmid_1859_7688_176.txt # ::snt The PHLDA1 gene is of interest as it has been suggested to be a tumor suppressor in breast adenocarcinoma and melanoma [17,18]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / cause-01 :ARG0 (s / suggest-01 :ARG1 (s2 / suppress-01 :ARG0 "g" :ARG1 (t / tumor) :location (a / and :op1 (m2 / medical-condition :name (n2 / name :op1 "adenocarcinoma")) :op2 (m / medical-condition :name (n3 / name :op1 "melanoma")) :mod (b / breast)))) :ARG1 (i / interest-01 :ARG0 (g / gene :name (n / name :op1 "PHLDA1") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "17" :op2 "18"))))) # ::id pmid_1859_7688.177 # ::date 2015-07-10T04:15:47 # ::file pmid_1859_7688_177.txt # ::snt We further analyzed the signal dependent expression of the PHLDA1 gene and its protein product, TDAG51. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (e / express-03 :ARG1 (g / gene :name (n2 / name :op1 "PHLDA1") :ARG0-of (d / depend-01 :ARG1 (s / signal)) :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :op2 (p2 / protein :name (n / name :op1 "TDAG51") :ARG1-of (p / produce-01 :ARG0 g) :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :degree (f / further)) # ::id pmid_1859_7688.178 # ::date 2015-07-10T04:23:06 # ::file pmid_1859_7688_178.txt # ::snt Microarray analysis identified the PHLDA1 gene as being dramatically up-regulated in RasV12- and Ras EDM-infected cells to levels that correlated with the level of ERK activation and the extent of anchorage-independent growth (Additional file 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / identify-01 :ARG0 (a2 / analyze-01 :ARG1 (m / microarray)) :ARG1 (u / upregulate-01 :ARG1 (g / gene :name (n / name :op1 "PHLDA1") :xref (x3 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :location (a3 / and :op1 (c / cell :ARG1-of (i2 / infect-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c2 / cell :ARG1-of (i3 / infect-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "EDM") :xref (x1 / xref :value "UNIPROT:EMD_HUMAN" :prob "0.262"))))) :manner (d2 / dramatic) :degree (l / level :ARG1-of (c3 / correlate-01 :ARG2 (a5 / and :op1 (l2 / level :degree-of (a4 / activate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :op2 (e4 / extent :degree-of (g2 / grow-01 :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 (a6 / anchorage)))))))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "1" :mod (a / additional)))) # ::id pmid_1859_7688.179 # ::date 2015-07-10T16:37:38 # ::file pmid_1859_7688_179.txt # ::snt Western blotting confirmed that TDAG51 was also upregulated in a similar manner (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / confirm-01 :ARG0 (i / immunoblot-01) :ARG1 (u / upregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :mod (a2 / also) :ARG1-of (r / resemble-01 :ARG2 (m / manner))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id pmid_1859_7688.180 # ::date 2015-07-10T16:44:18 # ::file pmid_1859_7688_180.txt # ::snt The PHLDA1 gene was elevated in PD153035-treated RasV12- and RasV12S35-infected cells but was significantly dependent upon EGFR tyrosine kinase activity for upregulation in RasV12G37- and RasV12C40-infected cells (not shown), and the expression of the encoded TDAG51 protein approximately paralleled PHLDA1 RNA expression (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (c / contrast-01 :ARG1 (e4 / elevate-01 :ARG1 (g2 / gene :wiki "-" :name (n7 / name :op1 "PHLDA1") :xref (x2 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :location (a3 / and :op1 (c2 / cell :ARG1-of (i / infect-01 :ARG2 (e6 / enzyme :wiki "Ras_subfamily" :name (n4 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c3 / cell :ARG1-of (i2 / infect-01 :ARG2 (e7 / enzyme :wiki "Ras_subfamily" :name (n5 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12S35") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :wiki "-" :name (n6 / name :op1 "PD153035") :xref (x8 / xref :value "PUBCHEM:4705" :prob "15.816147"))))) :ARG2 (d2 / depend-01 :ARG0 g2 :ARG1 (a4 / activity-06 :ARG0 (k / kinase :mod (e10 / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n11 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :mod (t2 / tyrosine)) :ARG1 (u / upregulate-01 :ARG1 (a5 / and :op1 (c4 / cell :ARG1-of (i3 / infect-01 :ARG2 (e8 / enzyme :wiki "Ras_subfamily" :name (n9 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12G37") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c5 / cell :ARG1-of (i4 / infect-01 :ARG2 (e9 / enzyme :wiki "Ras_subfamily" :name (n10 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12C40") :xref (x7 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1-of (s3 / show-01 :polarity "-"))) :ARG1-of (s2 / significant-02))) :op2 (p / parallel-01 :ARG0 (e3 / express-03 :ARG2 (p2 / protein :wiki "PHLDA1" :name (n / name :op1 "TDAG51") :ARG1-of (e2 / encode-01) :xref (x5 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG1 (e / express-03 :ARG1 (n8 / nucleic-acid :wiki "RNA" :name (n3 / name :op1 "RNA") :ARG0-of (e5 / encode-01 :ARG1 (g / gene :wiki "-" :name (n2 / name :op1 "PHLDA1") :xref (x6 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))))) :degree (a2 / approximate)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id pmid_1859_7688.181 # ::date 2015-07-11T04:11:30 # ::file pmid_1859_7688_181.txt # ::snt As shown in Figure 3C, EGFR inhibition significantly reduced ERK signaling in RasV12G37- and RasV12C40-infected cells without affecting RasV12- and RasV12S35-infected cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / reduce-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x5 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1 (s3 / signal-07 :ARG0 (e6 / enzyme :name (n2 / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :location (a / and :op1 (c2 / cell :ARG1-of (i2 / infect-01 :ARG2 (e4 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c / cell :ARG1-of (i5 / infect-01 :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :ARG2 (s2 / significant-02) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "3C")) :ARG0-of (a2 / affect-01 :polarity "-" :ARG1 (a3 / and :op1 (c3 / cell :ARG1-of (i3 / infect-01 :ARG2 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12") :xref (x4 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c4 / cell :ARG1-of (i4 / infect-01 :ARG2 (e2 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12S35") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) # ::id pmid_1859_7688.182 # ::date 2015-07-10T16:46:21 # ::file pmid_1859_7688_182.txt # ::snt To confirm that TDAG51 up-regulation was induced specifically by ERK activation, we treated pLRT-, RasV12-, and RasV12S35-infected cells with the MEK-specific inhibitor PD98059. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t / treat-04 :ARG0 "w" :ARG1 (a2 / and :op1 (c2 / cell :mod (p4 / protein :name (n5 / name :op1 "LRT") :ARG1-of (p2 / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:LRC51_HUMAN" :prob "0.292"))) :op2 (c3 / cell :ARG1-of (i4 / infect-01 :ARG2 (e / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op3 (c4 / cell :ARG1-of (i5 / infect-01 :ARG2 (e5 / enzyme :name (n7 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD98059") :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK"))) :ARG1-of (s / specific-02) :xref (x5 / xref :value "PUBCHEM:4713" :prob "18.349844")) :purpose (c / confirm-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG0 (a / activate-01 :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2 (u / upregulate-01 :ARG1 (p / protein :name (n / name :op1 "TDAG51") :xref (x4 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG1-of s))) # ::id pmid_1859_7688.183 # ::date 2015-07-10T17:01:48 # ::file pmid_1859_7688_183.txt # ::snt PD98059 used at 20 μM appears to be specific for MEK1 as it does not nonspecifically inhibit a variety of other protein kinases that have been assayed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a3 / appear-02 :ARG1 (s / specific-02 :ARG1 (s3 / small-molecule :name (n / name :op1 "PD98059") :ARG1-of (u / use-01 :ARG2 (c2 / concentration-quantity :quant "20" :unit (n2 / nanomolar))) :xref (x1 / xref :value "PUBCHEM:4713" :prob "18.349844")) :ARG2 (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG1-of (c3 / cause-01 :ARG0 (i / inhibit-01 :polarity "-" :ARG0 s3 :ARG1 (k / kinase :mod (o / other) :ARG1-of (a2 / assay-01) :mod (v / variety) :mod (p / protein)) :ARG1-of (s2 / specific-02 :polarity "-")))) # ::id pmid_1859_7688.184 # ::date 2015-07-10T17:41:09 # ::file pmid_1859_7688_184.txt # ::snt [31]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (p / publication :ARG1-of (c / cite-01 :ARG2 "31")) # ::id pmid_1859_7688.185 # ::date 2015-07-10T09:26:08 # ::file pmid_1859_7688_185.txt # ::snt TDAG51 up-regulation was attenuated by MEK inhibition (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (a / attenuate-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1 (u / upregulate-01 :ARG1 (p / protein :name (n / name :op1 "TDAG51") :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5"))) # ::id pmid_1859_7688.186 # ::date 2015-07-10T09:28:20 # ::file pmid_1859_7688_186.txt # ::snt TDAG51 therefore represents an ERK-inducible gene whose up-regulation in HME16C is correlated with an EGFR-independent, ERK-mediated transformation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / cause-01 :ARG1 (r2 / represent-01 :ARG0 (g2 / gene :name (n / name :op1 "TDAG51") :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG1 (g / gene :ARG2-of (i / induce-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (p / possible-01)) :ARG1-of (u / upregulate-01 :location (c3 / cell-line :name (n3 / name :op1 "HME16C")) :ARG1-of (c / correlate-01 :ARG2 (t / transform-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (e2 / enzyme :name (n4 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1-of (m2 / mediate-01 :ARG0 e))))))) # ::id pmid_1859_7688.187 # ::date 2015-07-10T13:15:43 # ::file pmid_1859_7688_187.txt # ::snt TDAG51 up-regulation opposes ERK-mediated HME16C transformation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / oppose-01 :ARG0 (u / upregulate-01 :ARG1 (p / protein :name (n / name :op1 "TDAG51") :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG1 (t / transform-01 :ARG1 (c / cell-line :name (n2 / name :op1 "HME16C") :ARG1-of (m2 / mediate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))) # ::id pmid_1859_7688.188 # ::date 2015-07-10T14:41:07 # ::file pmid_1859_7688_188.txt # ::snt To analyze the role of TDAG51 in ERK-dependent growth, we reduced TDAG51 expression in RasV12- and RasV12S35-infected cells to a level comparable to that in non-transformed vector-infected control cells using stably expressed TDAG51-specific shRNA (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / reduce-01 :ARG0 "w" :ARG1 (e2 / express-03 :ARG2 "p" :ARG3 (a2 / and :op1 (c / cell :ARG1-of (i3 / infect-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c2 / cell) :ARG1-of (i / infect-01 :ARG2 (e4 / enzyme :name n3 :ARG2-of (m2 / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG4 (l / level :ARG1-of (c3 / comparable-03 :ARG2 (l2 / level :location (c4 / cell :ARG1-of (i2 / infect-01 :ARG2 (v / vector)) :ARG0-of (c5 / control-01) :ARG1-of (t / transform-01 :polarity "-"))))) :manner (u / use-01 :ARG0 "w" :ARG1 (n5 / nucleic-acid :name (n4 / name :op1 "shRNA") :ARG1-of (s / specific-02 :ARG2 "p") :ARG2-of (e5 / express-03 :ARG1-of (s2 / stable-03)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A")) :purpose (a / analyze-01 :ARG0 (w / we) :ARG1 (r2 / role :poss (p / protein :name (n / name :op1 "TDAG51") :xref (x3 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :topic (g / grow-01 :ARG0-of (d2 / depend-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))))) # ::id pmid_1859_7688.189 # ::date 2015-07-11T06:00:17 # ::file pmid_1859_7688_189.txt # ::snt Cell proliferation of attached cells grown on tissue culture plastic was unaffected by lowered TDAG51 protein levels (not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (a / affect-01 :polarity "-" :ARG0 (l / level :quant-of (p3 / protein :name (n / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG1-of (l2 / low-04)) :ARG1 (p / proliferate-01 :ARG0 (c / cell :ARG1-of (a2 / attach-01) :ARG1-of (g / grow-01 :location (p2 / plastic :mod (c3 / culture :source (t / tissue)))))) :ARG1-of (s / show-01 :polarity "-")) # ::id pmid_1859_7688.190 # ::date 2015-07-11T05:27:41 # ::file pmid_1859_7688_190.txt # ::snt However, cell growth under anchorage-independent conditions in ultra-low attachment plates was significantly enhanced by TDAG51 knock-down in RasV12S35-infected cells (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / contrast-01 :ARG2 (e / enhance-01 :ARG1 (g / grow-01 :ARG1 (c3 / cell) :location (p / plate :ARG3-of (a2 / attach-01) :ARG1-of (l / low-04 :degree (u / ultra))) :condition (d2 / depend-01 :polarity "-" :ARG1 (a / anchorage))) :ARG2 (k / knock-down-02 :ARG1 (p2 / protein :name (n / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG1-of (s / significant-02) :location (c5 / cell :ARG1-of (i / infect-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id pmid_1859_7688.191 # ::date 2015-07-11T05:37:30 # ::file pmid_1859_7688_191.txt # ::snt Likewise, results with RasV12-infected cells stably infected with TDAG51-targeting shRNA also showed enhanced growth relative to vector-infected control cells, although to a lesser extent than that seen with RasV12S35-infected cells (Figure 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (t / thing :ARG2-of (r2 / result-01 :ARG1 (c4 / cell :ARG1-of (i2 / infect-01 :ARG2 (e2 / enzyme :wiki "Ras_subfamily" :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (i3 / infect-01 :ARG2 (n5 / nucleic-acid :wiki "Small_hairpin_RNA" :name (n2 / name :op1 "shRNA") :ARG0-of (t2 / target-01 :ARG1 (p / protein :wiki "PHLDA1" :name (n3 / name :op1 "TDAG51") :xref (x2 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")))) :ARG1-of (s3 / stable-03))))) :ARG1 (g / grow-01 :ARG1-of (e / enhance-01) :ARG1-of (r3 / relative-05 :ARG2 (c2 / cell :ARG0-of (c3 / control-01) :ARG1-of (i / infect-01 :ARG0 (v / vector))))) :mod (a / also)) :ARG2 (s2 / show-01 :ARG0 t :ARG1 (g2 / grow-01 :degree (l / less :degree (m2 / more)) :compared-to (g3 / grow-01 :ARG1-of (s4 / see-01 :location (c5 / cell :ARG1-of (i4 / infect-01 :ARG2 (e3 / enzyme :wiki "Ras_subfamily" :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12S35") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))))) :ARG1-of (r / resemble-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id pmid_1859_7688.192 # ::date 2015-07-10T16:45:12 # ::file pmid_1859_7688_192.txt # ::snt This suggests that Ras signaling pathways other than ERK compensate partially for the negative growth effects of TDAG51, or that RasV12-infected cells are already close to maximally transformed under anchorage-independent growth conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / suggest-01 :ARG0 (t / this) :ARG1 (o / or :op1 (c / compensate-01 :ARG0 (p2 / pathway :name (n / name :op1 "Ras") :ARG0-of (s2 / signal-07) :ARG2-of (e2 / except-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "ERK")))) :ARG1 (a2 / affect-01 :ARG0 (g / grow-01 :ARG1 (p4 / protein :name (n4 / name :op1 "TDAG51") :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG2-of (n3 / negative-05)) :degree (p / part)) :op2 (c2 / close-10 :ARG1 (c4 / cell :ARG1-of (i / infect-01 :ARG2 (e / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (t2 / transform-01 :ARG1 c4 :degree (m / maximal)) :time (a3 / already) :condition (g2 / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a / anchorage)))))) # ::id pmid_1859_7688.193 # ::date 2015-07-10T14:42:06 # ::file pmid_1859_7688_193.txt # ::snt Loss of TDAG51 expression in transformed cells stimulates both cell cycle progression and apoptosis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / stimulate-01 :ARG0 (l / lose-02 :ARG1 (e / express-03 :ARG1 (p / protein :name (n / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG3 (c / cell :ARG1-of (t / transform-01)))) :ARG1 (a / and :op1 (p2 / progress-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell))) :op2 (a2 / apoptosis :mod c3))) # ::id pmid_1859_7688.194 # ::date 2015-07-10T15:11:06 # ::file pmid_1859_7688_194.txt # ::snt To characterize the effect of TDAG51 on cell proliferation under anchorage-independent conditions, cell cycle analysis and cell proliferation assays for RasV12S35- and RasV12-infected cells were performed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / perform-01 :ARG1 (a / and :op1 (a2 / analyze-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell))) :op2 (a3 / assay-01 :ARG1 (p2 / proliferate-01 :ARG0 c3)) :purpose (a4 / and :op1 (c4 / cell :ARG1-of (i2 / infect-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (c5 / cell :ARG1-of (i / infect-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :purpose (c / characterize-01 :ARG1 (a5 / affect-01 :ARG0 (p3 / protein :name (n3 / name :op1 "TDAG51") :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :ARG1 (p4 / proliferate-01 :ARG0 c3 :condition (d / depend-01 :ARG1 (a6 / anchorage)))))) # ::id pmid_1859_7688.195 # ::date 2015-07-10T16:03:42 # ::file pmid_1859_7688_195.txt # ::snt Both RasV12S35- and RasV12- TDAG51 shRNA-expressing cells demonstrated an increased S-phase fraction versus pLVTHM vector control cells at various time points during anchorage-independent growth (Figure 7A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (d / demonstrate-01 :ARG0 (a / and :op1 (c / cell :ARG3-of (e / express-03 :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA") :ARG0-of (e5 / encode-01 :ARG1 (p4 / protein :name (n5 / name :op1 "TDAG51") :ARG1-of (i2 / infect-01 :ARG2 (e3 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x2 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")))))) :op2 (c2 / cell :ARG3-of (e2 / express-03 :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 n4))) :ARG1 (f2 / fraction :ARG1-of (i / increase-01) :part-of (p / phase :mod (s / synthesize-01))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "7A")) :compared-to (c3 / cell :ARG0-of (c4 / control-01) :mod (v / vector :name (n3 / name :op1 "LVTHM") :ARG3-of (p2 / phosphorylate-01))) :time (p3 / point :mod (t / time) :ARG1-of (v2 / vary-01)) :time (g / grow-01 :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 (a2 / anchorage)))) # ::id pmid_1859_7688.196 # ::date 2015-07-11T09:32:12 # ::file pmid_1859_7688_196.txt # ::snt In concordance with these results, RasV12S35 and RasV12 cells expressing the TDAG51-specific shRNA showed enhanced incorporation of 5-ethynyl-2'-deoxyuridine (EdU) in cell proliferation assays, indicating a higher rate of DNA synthesis in cells with reduced TDAG51 protein (Figure 7C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / show-01 :ARG0 (a / and :op1 (c2 / cell :mod (e / enzyme :wiki "Ras_subfamily" :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (c3 / cell :mod (e5 / enzyme :wiki "Ras_subfamily" :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG3-of (e3 / express-03 :ARG1 (n7 / nucleic-acid :wiki "Small_hairpin_RNA" :name (n2 / name :op1 "shRNA") :ARG1-of (s2 / specific-02 :ARG2 (p / protein :wiki "PHLDA1" :name (n3 / name :op1 "TDAG51") :xref (x3 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")))))) :ARG1 (i2 / incorporate-01 :ARG0 n7 :ARG1 (s4 / small-molecule :wiki "5-Ethynyl-2'-deoxyuridine" :name (n4 / name :op1 "5-ethynyl-2'-deoxyuridine") :xref (x4 / xref :value "PUBCHEM:122879" :prob "13.794952")) :ARG1-of (e4 / enhance-01) :location (a2 / assay-01 :ARG1 (p2 / proliferate-01 :ARG0 (c4 / cell)))) :ARG0-of (i / indicate-01 :ARG1 (r3 / rate-entity-91 :ARG4 (s3 / synthesize-01 :ARG1 (n8 / nucleic-acid :wiki "DNA" :name (n9 / name :op1 "DNA"))) :ARG1-of (h / high-02 :degree (m4 / more))) :location (c5 / cell :ARG0-of (h2 / have-03 :ARG1 (p4 / protein :wiki "PHLDA1" :name (n5 / name :op1 "TDAG51") :ARG1-of (r4 / reduce-01) :xref (x2 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7C")) :ARG1-of (r5 / resemble-01 :ARG2 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)))) # ::id pmid_1859_7688.197 # ::date 2015-07-10T15:19:46 # ::file pmid_1859_7688_197.txt # ::snt Since cell growth under anchorage-independent conditions is a balance between cell proliferation and cell death, we sought to evaluate the effect upon cellular death of TDAG51 knock-down. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (c / cause-01 :ARG0 (b / balance-01 :ARG0 (g / grow-01 :ARG1 (c3 / cell) :condition (d3 / depend-01 :polarity "-" :ARG1 (a2 / anchorage))) :ARG1 (a3 / and :op1 (p2 / proliferate-01 :ARG0 (c5 / cell)) :op2 (d2 / die-01 :ARG1 c5))) :ARG1 (s / seek-01 :ARG0 (w / we) :ARG1 (e / evaluate-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :ARG1 (d / die-01 :ARG1 (c2 / cell)))))) # ::id pmid_1859_7688.198 # ::date 2015-07-10T04:38:09 # ::file pmid_1859_7688_198.txt # ::snt We used an assay of cellular cytotoxicity that measures the release of the lactose deydrogenase enzyme, LDH. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (a / assay-01 :ARG1 (c / cytotoxicity :mod (c2 / cell)) :ARG0-of (m / measure-01 :ARG1 (r / release-01 :ARG1 (e / enzyme :name (n / name :op1 "lactose" :op2 "deydrogenase") :xref (x / xref :value "UNIPROT:LDHD_HUMAN" :prob "0.312")))))) # ::id pmid_1859_7688.199 # ::date 2015-07-10T04:43:14 # ::file pmid_1859_7688_199.txt # ::snt LDH release was increased by TDAG51 shRNA-expressing RasV12S35 cells relative to pLVTHM-infected cells at various time points after the initiation of matrix-detached growth (Figure 8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (i / increase-01 :ARG0 (c / cell :ARG3-of (e2 / express-03 :ARG2 (n6 / nucleic-acid :name (n5 / name :op1 "shRNA") :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "TDAG51") :xref (x2 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))))) :mod (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (r / release-01 :ARG1 (e / enzyme :name (n / name :op1 "LDH") :xref (x1 / xref :value "UNIPROT:LDHB_HUMAN" :prob "0.342"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8")) :ARG1-of (r2 / relative-05 :ARG3 (c2 / cell :ARG1-of (i2 / infect-01 :ARG2 (v2 / vector :name (n4 / name :op1 "LVTHM") :ARG3-of (p2 / phosphorylate-01))))) :time (p3 / point :mod (t / time) :ARG1-of (v / vary-01)) :time (a / after :op1 (i3 / initiate-01 :ARG1 (g / grow-01 :ARG1-of (d2 / detach-01 :ARG2 (m3 / matrix)))))) # ::id pmid_1859_7688.200 # ::date 2015-07-10T07:22:49 # ::file pmid_1859_7688_200.txt # ::snt The difference in LDH release for TDAG51 shRNA-expressing RasV12 cells was minimal and rarely approached statistical significance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (m / minimal-02 :ARG1 (d / differ-02 :ARG1 (r2 / release-01 :ARG0 (c / cell :ARG3-of (e2 / express-03 :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "shRNA") :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "TDAG51") :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))))) :mod (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (e / enzyme :name (n / name :op1 "LDH") :xref (x / xref :value "UNIPROT:LDHB_HUMAN" :prob "0.342"))))) :op2 (a2 / approach-01 :ARG1 d :ARG2 (s / significant-02 :ARG1 d :mod (s2 / statistics)) :ARG1-of (r / rare-02))) # ::id pmid_1859_7688.201 # ::date 2015-07-10T05:34:16 # ::file pmid_1859_7688_201.txt # ::snt Sub-G1 peaks indicative of dead cells were sometimes seen with cell cycle analysis at late time points, but varied from experiment to experiment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / see-01 :ARG1 (p / peak :ARG0-of (i / indicate-01 :ARG1 (c / cell :ARG1-of (d / die-01))) :mod (s4 / sub :op1 (p2 / phase :mod "1" :mod (g / grow-01)))) :frequency (s2 / sometimes) :instrument (a / analyze-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell))) :time (p3 / point :mod (t / time :time (l / late))) :ARG1-of (c4 / contrast-01 :ARG2 (v / vary-01 :ARG1 p :ARG3 (e / experiment-01) :ARG4 e))) # ::id pmid_1859_7688.202 # ::date 2015-07-10T05:25:14 # ::file pmid_1859_7688_202.txt # ::snt Therefore, for RasV12S35-infected cells, the differences in cell growth after TDAG51 reduction under anchorage-independent conditions resulted from an enhanced rate of cellular proliferation that exceeded a concomitant increase in cell death. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (c7 / cause-01 :ARG1 (r / result-01 :ARG1 (r2 / rate :ARG1-of (e / enhance-01) :ARG0-of (e2 / exceed-01 :ARG1 (i / increase-01 :ARG1 (d / die-01 :ARG1 (c3 / cell)) :time (c2 / concomitant))) :degree-of (p / proliferate-01 :ARG0 (c / cell))) :ARG2 (d2 / differ-02 :ARG1 (c6 / cell) :ARG3 (g / grow-01 :ARG1 (c4 / cell :ARG1-of (i2 / infect-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :time (a / after :op1 (r3 / reduce-01 :ARG1 (p2 / protein :name (n / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :condition (d3 / depend-01 :polarity "-" :ARG1 (a2 / anchorage)))))))) # ::id pmid_1859_7688.203 # ::date 2015-07-10T04:43:41 # ::file pmid_1859_7688_203.txt # ::snt Reduction of TDAG51 in transformed cells enhances proximal ERK signaling # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / enhance-01 :ARG0 (r / reduce-01 :ARG1 (p2 / protein :name (n / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")) :location (c / cell :ARG1-of (t / transform-01))) :ARG1 (s / signal-07 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :mod (p / proximal) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) # ::id pmid_1859_7688.204 # ::date 2015-07-10T04:46:15 # ::file pmid_1859_7688_204.txt # ::snt Reducing TDAG51 protein levels in ERK-driven cellular transformation enhanced cell growth under anchorage-independent, but not attached, conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / enhance-01 :ARG0 (r / reduce-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :time (t / transform-01 :ARG1 (c / cell) :ARG1-of (d / drive-02 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :ARG1 (g / grow-01 :ARG1 c) :condition (d2 / depend-01 :polarity "-" :ARG1 (a / anchorage) :ARG1-of (c2 / contrast-01 :ARG2 (a2 / attach-01 :polarity "-")))) # ::id pmid_1859_7688.205 # ::date 2015-07-10T04:49:46 # ::file pmid_1859_7688_205.txt # ::snt To test whether TDAG51 might affect proximal ERK signaling, we examined the activation status of Erk in cells expressing TDAG51-specific shRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / examine-01 :ARG0 (w / we) :ARG1 (s / status :mod (a / activate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Erk") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :location (c / cell :ARG3-of (e3 / express-03 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA") :ARG1-of (s2 / specific-02 :ARG2 (p / protein :name (n3 / name :op1 "TDAG51") :xref (x / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")))))))) :purpose (t / test-01 :ARG0 w :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (a2 / affect-01 :ARG0 p :ARG1 (s3 / signal-07 :ARG1 e2 :mod (p3 / proximal)))))) # ::id pmid_1859_7688.206 # ::date 2015-07-10T05:12:06 # ::file pmid_1859_7688_206.txt # ::snt Interestingly, the levels of phosphorylated Erk were enhanced when TDAG51 protein levels were reduced in RasV12S35 and RasV12 cells grown under anchorage-independent, but not attached, conditions (Figure 9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / enhance-01 :ARG1 (l / level :quant-of (e2 / enzyme :name (n / name :op1 "Erk") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))) :time (r / reduce-01 :ARG1 (l2 / level :quant-of (p2 / protein :name (n2 / name :op1 "TDAG51") :xref (x3 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002"))) :location (a / and :op1 (c4 / cell :mod (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12S35") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (c5 / cell :mod (e4 / enzyme :name n3 :ARG2-of (m / mutate-01 :value "V12") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (g / grow-01 :condition (d / depend-01 :polarity "-" :ARG1 (a2 / anchorage) :ARG1-of (c / contrast-01 :ARG2 (a3 / attach-01 :polarity "-")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "9")) :ARG0-of (i / interest-01)) # ::id pmid_1859_7688.207 # ::date 2015-07-10T08:10:38 # ::file pmid_1859_7688_207.txt # ::snt The fact that the activation status of Erk was unchanged in cells grown under attached conditions suggests that reducing TDAG51 expression had no selective effect with regard to ERK activation in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / suggest-01 :ARG0 (c2 / change-01 :polarity "-" :ARG1 (s3 / status :mod (a3 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")))) :location (c3 / cell :ARG1-of (g / grow-01) :condition (a4 / attach-01))) :ARG1 (a / affect-01 :polarity "-" :ARG0 (r / reduce-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "TDAG51") :xref (x1 / xref :value "UNIPROT:PHLA1_HUMAN" :prob "1.002")))) :manner (s2 / selective) :topic (a2 / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK") :location c3 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) # ::id pmid_1859_7688.208 # ::date 2015-07-10T05:51:12 # ::file pmid_1859_7688_208.txt # ::snt Rather, the enhanced activation of Erk was specific to anchorage-independent growth conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / instead-of-91 :ARG1 (s / specific-02 :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Erk") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :ARG1-of (e / enhance-01)) :ARG2 (c / condition :mod (g / grow-01) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a2 / anchorage))))) # ::id pmid_1901_4680.1 # ::date 2015-06-16T04:05:04 # ::file pmid_1901_4680_1.txt # ::snt Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors (PMID:19014680) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (s / suffice-01 :ARG0 (a / activate-01 :ARG1 (o / or :op1 (i / isoform :mod (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (i2 / isoform :mod (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG1 (a2 / and :op1 (t / transform-01 :ARG0 a :ARG1 (c / cell :part-of (e3 / epithelium :part-of (i3 / intestine))) :degree (f / full)) :op2 (i4 / induce-01 :ARG0 a :ARG2 (f2 / form-01 :ARG2 (t2 / tumor :mod (m / metastasis))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID19014680"))) # ::id pmid_1901_4680.10 # ::date 2015-06-16T04:07:04 # ::file pmid_1901_4680_10.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1901_4680.11 # ::date 2015-06-16T04:07:52 # ::file pmid_1901_4680_11.txt # ::snt We found that expression of activated MEK1 or MEK2 is sufficient to morphologically transform intestinal epithelial cells, dysregulate cell proliferation and induce the formation of high-grade adenocarcinomas after orthotopic transplantation in mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (s / suffice-01 :ARG0 (e / express-03 :ARG2 (o / or :op1 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG1-of (a / activate-01))) :ARG1 (a2 / and :op1 (t / transform-01 :ARG0 e :ARG1 (c / cell :part-of (e4 / epithelium :part-of (i / intestine))) :manner (m / morphological)) :op2 (d / dysregulate-01 :ARG0 e :ARG1 (p / proliferate-01 :ARG0 (c2 / cell))) :op3 (i2 / induce-01 :ARG0 e :ARG2 (f2 / form-01 :ARG1 (m3 / medical-condition :name (n3 / name :op1 "adenocarcinoma") :mod (g / grade :ARG1-of (h / high-02)))))) :condition (t2 / transplant-01 :ARG2 (m2 / mouse) :mod (o2 / orthotopic)))) # ::id pmid_1901_4680.12 # ::date 2015-06-16T04:22:43 # ::file pmid_1901_4680_12.txt # ::snt A large proportion of these intestinal tumors metastasize to the liver and lung. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (m / metastasize-101 :ARG1 (t / tumor :mod (i / intestine) :quant (p / proportion :mod (l / large)) :mod (t2 / this)) :ARG2 (a / and :op1 (l2 / liver) :op2 (l3 / lung))) # ::id pmid_1901_4680.13 # ::date 2015-06-16T04:24:45 # ::file pmid_1901_4680_13.txt # ::snt Mechanistically, activation of MEK1 or MEK2 up-regulates the expression of matrix metalloproteinases, promotes invasiveness and protects cells from undergoing anoikis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / and :op1 (u / upregulate-01 :ARG1 (e3 / express-03 :ARG2 (e4 / enzyme :name (n3 / name :op1 "matrix" :op2 "metalloproteinase") :xref (x1 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.393"))) :ARG2 (a2 / activate-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :op2 (p / promote-01 :ARG0 a2 :ARG1 (i / invade-01)) :op3 (p2 / protect-01 :ARG0 a2 :ARG1 (c / cell) :ARG2 (u2 / undergo-28 :ARG1 c :ARG2 (a3 / anoikis))) :manner (m / mechanistic)) # ::id pmid_1901_4680.14 # ::date 2015-06-16T04:32:55 # ::file pmid_1901_4680_14.txt # ::snt Importantly, we show that silencing of MEK2 expression completely suppresses the proliferation of human colon carcinoma cell lines, whereas inactivation of MEK1 has a much weaker effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (s2 / suppress-01 :ARG0 (s3 / silence-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (p / proliferate-01 :ARG0 (c3 / cell-line :mod (m3 / medical-condition :name (n2 / name :op1 "carcinoma") :mod (c4 / colon)) :mod (h / human))) :degree (c2 / complete)) :ARG2 (a / affect-01 :ARG0 (a2 / activate-01 :polarity "-" :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG1 p :ARG1-of (w2 / weak-02 :degree (m / more :degree (m2 / much))))) :mod (i / important)) # ::id pmid_1901_4680.126 # ::date 2015-06-16T04:39:05 # ::file pmid_1901_4680_126.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1901_4680.127 # ::date 2015-06-16T04:39:57 # ::file pmid_1901_4680_127.txt # ::snt Constitutive activation of MEK1 or MEK2 is sufficient for transformation of intestinal epithelial cells and formation of tumors in vivo # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (s / suffice-01 :ARG0 (a / activate-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (c / constitutive)) :ARG1 (a2 / and :op1 (t / transform-01 :ARG1 (c2 / cell :part-of (e3 / epithelium :part-of (i / intestine)))) :op2 (f / form-01 :ARG1 (t2 / tumor) :manner (i2 / in-vivo)))) # ::id pmid_1901_4680.128 # ::date 2015-06-16T04:45:50 # ::file pmid_1901_4680_128.txt # ::snt Immunohistochemistry analysis of a colorectal cancer tissue microarray containing over 400 colorectal cancer and 50 normal colon tissue biopsies revealed that 44% of colorectal cancers display high cytoplasmic expression of phosphorylated MEK1/MEK2 as compared to 10% of normal tissues (analysis to be published elsewhere). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (m / microarray :mod (t2 / tissue :mod (d6 / disease :wiki "Colorectal_cancer" :name (n10 / name :op1 "colorectal" :op2 "cancer"))) :ARG0-of (c2 / contain-01 :ARG1 (a2 / and :op1 (b / biopsy :mod t2 :quant (o / over :op1 "400")) :op2 (b2 / biopsy :quant "50" :mod (t3 / tissue :part-of (c3 / colon) :ARG1-of (n2 / normal-02)))))) :instrument (i3 / immunohistochemistry) :ARG1-of (s / suppose-02 :ARG2 (p4 / publish-01 :ARG1 a :location (e4 / elsewhere)))) :ARG1 (d2 / display-01 :ARG0 (d5 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer") :ARG1-of (i / include-91 :ARG2 d6 :ARG3 (p / percentage-entity :value "44")) :compared-to (t / tissue :ARG0-of (d4 / display-01 :ARG1 "e") :ARG1-of (i2 / include-91 :ARG2 (t4 / tissue :ARG1-of n2) :ARG3 (p3 / percentage-entity :value "10")))) :ARG1 (e / express-03 :ARG2 (a4 / and :op1 (e2 / enzyme :name (n5 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n6 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG3-of (p2 / phosphorylate-01)) :ARG3 (c5 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (h / high-02)))) # ::id pmid_1901_4680.129 # ::date 2015-06-16T05:00:35 # ::file pmid_1901_4680_129.txt # ::snt To assess the functional significance of MEK1/MEK2 activation in colorectal cancer, we ectopically expressed wild type and constitutively active (DD mutant) versions of MEK1 and MEK2 by retroviral gene transfer in the normal undifferentiated intestinal epithelial cell line IEC-6 [27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / express-03 :ARG2 (a / and :op1 (e3 / enzyme :name (n / name :op1 "MEK1") :mod (w2 / wild-type) :xref (x4 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n2 / name :op1 "MEK1") :ARG1-of (a5 / activate-01 :manner (c4 / constitutive) :ARG1-of (m / mean-01 :ARG2 (p2 / protein-segment :name (n10 / name :op1 "DD") :ARG2-of (m2 / mutate-01)))) :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op3 (e5 / enzyme :name (n3 / name :op1 "MEK2") :mod (w3 / wild-type) :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :op4 (e6 / enzyme :name (n4 / name :op1 "MEK2") :ARG0-of a5 :xref (x3 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :manner (e2 / ectopic) :purpose (a2 / assess-01 :ARG0 "w" :ARG1 (s / significant-02 :ARG1 (a3 / activate-01 :ARG1 (a4 / and :op1 (e7 / enzyme :name (n5 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e8 / enzyme :name (n6 / name :op1 "MEK2") :xref (x5 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :prep-in (d4 / disease :wiki "Colorectal_cancer" :name (n11 / name :op1 "colorectal" :op2 "cancer"))) :ARG0-of (f / function-01))) :manner (t / transfer-01 :ARG1 (g / gene) :mod (r / retroviral) :location (c2 / cell-line :name (n8 / name :op1 "IEC-6") :part-of (e9 / epithelium :part-of (i / intestine)) :ARG1-of (n7 / normal-02) :ARG1-of (d2 / differentiate-01 :polarity "-"))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 "27"))) :ARG1-of (c5 / cause-01 :ARG0 (w / we))) # ::id pmid_1901_4680.130 # ::date 2015-06-16T05:09:27 # ::file pmid_1901_4680_130.txt # ::snt Polyclonal populations of infected clones were selected in puromycin and used for subsequent experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (a / and :op1 (s / select-01 :ARG1 (p / population :mod (c / clone :ARG1-of (i / infect-01)) :mod (p2 / polyclonal)) :location (s2 / small-molecule :name (n / name :op1 "puromycin") :xref (x / xref :value "PUBCHEM:4984" :prob "16.295719"))) :op2 (u / use-01 :ARG1 p :purpose (e / experiment-01 :time (s3 / subsequent)))) # ::id pmid_1901_4680.131 # ::date 2015-06-17T10:31:44 # ::file pmid_1901_4680_131.txt # ::snt Immunoblot analysis confirmed that ectopic MEK isoforms are expressed at comparable levels in IEC-6 transduced populations (Fig. 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / confirm-01 :ARG0 (a2 / analyze-01 :manner (i2 / immunoblot-01)) :ARG1 (p / possible-01 :ARG1 (c2 / compare-01 :ARG1 (l / level :quant-of (e2 / express-03 :ARG2 (i / isoform :mod (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :mod (e3 / ectopic)) :ARG3 (p2 / population :ARG1-of (t / transduce-01 :ARG2 (c3 / cell-line :name (n3 / name :op1 "IEC-6")))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1901_4680.132 # ::date 2015-06-17T10:44:10 # ::file pmid_1901_4680_132.txt # ::snt Overexpression of wild type MEK1 or MEK2 did not affect the expression of endogenous MEK isoforms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (a / affect-01 :polarity "-" :ARG0 (o / overexpress-01 :ARG1 (o2 / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :mod (w / wild-type))) :ARG1 (e3 / express-03 :ARG2 (i / isoform :mod (e4 / enzyme :name (n3 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :mod (e5 / endogenous)))) # ::id pmid_1901_4680.133 # ::date 2015-06-17T11:12:36 # ::file pmid_1901_4680_133.txt # ::snt However, ectopic expression or MEK2DD slightly increased the steady-state levels of endogenous MEK1, while overexpression of MEK1DD had a similar effect on MEK2 levels (Fig. 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (c2 / contrast-01 :ARG2 (c / contrast-01 :ARG1 (i / increase-01 :ARG0 (e / express-03 :ARG2 (e3 / enzyme :name (n / name :op1 "MEK2DD") :xref (x3 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283")) :mod (e2 / ectopic)) :ARG1 (l / level :quant-of (e4 / enzyme :name (n2 / name :op1 "MEK1") :mod (e5 / endogenous) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :mod (s / state :mod (s2 / steady))) :ARG2 (s3 / slight)) :ARG2 (r / resemble-01 :ARG1 (a / affect-01 :ARG0 (o / overexpress-01 :ARG1 (e6 / enzyme :name (n3 / name :op1 "MEK1DD") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283"))) :ARG1 (l2 / level :quant-of (e7 / enzyme :name (n4 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG2 i) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B")))) # ::id pmid_1901_4680.134 # ::date 2015-06-17T11:21:40 # ::file pmid_1901_4680_134.txt # ::snt As expected, substitution of the activation loop Ser phosphorylation sites by Asp residues strongly potentiated the enzymatic activity of MEK1 and MEK2, but no reproducible difference in activity was observed between the two isoforms (Fig. 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG1 (p2 / potentiate-01 :ARG1 (a / activity-06 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :mod (e3 / enzyme))) :ARG2 (s / substitute-01 :ARG1 (r / residue :mod (a6 / amino-acid :name (n3 / name :op1 "aspartic" :op2 "acid") :xref (x3 / xref :value "PUBCHEM:424" :prob "7.741247"))) :ARG2 (s4 / site :location-of (p / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :mod (l / loop :mod (a4 / activate-01)))) :manner (s2 / strong) :ARG1-of (e4 / expect-01)) :ARG2 (o / observe-01 :polarity "-" :ARG1 (d / differ-02 :ARG1 e :ARG2 e2 :ARG3 (a5 / activity-06) :ARG1-of (r2 / reproduce-01 :ARG1-of (p3 / possible-01)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id pmid_1901_4680.135 # ::date 2015-06-17T11:35:49 # ::file pmid_1901_4680_135.txt # ::snt IEC-6 cells grow as a monolayer and display a typical epithelial morphology with organized cell-cell adhesions (Fig. 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (g / grow-01 :ARG1 (c / cell-line :name (n / name :op1 "IEC-6")) :manner (m / monolayer)) :op2 (d / display-01 :ARG0 c :ARG1 (m2 / morphology :ARG1-of (t / typical-02) :mod (e / epithelium) :accompanier (a2 / adhere-01 :ARG1 (c2 / cell) :ARG2 (c3 / cell) :ARG1-of (o / organize-01)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1D"))) # ::id pmid_1901_4680.136 # ::date 2015-06-17T11:40:38 # ::file pmid_1901_4680_136.txt # ::snt Overexpression of wild type MEK isoforms had no noticeable effect on the morphology of IEC-6 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (p / possible-01 :polarity "-" :ARG1 (n3 / notice-01 :ARG1 (a / affect-01 :ARG0 (o / overexpress-01 :ARG1 (i / isoform :mod (e / enzyme :name (n / name :op1 "MEK") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG1 (m / morphology :mod (c / cell-line :name (n2 / name :op1 "IEC-6")))))) # ::id pmid_1901_4680.137 # ::date 2015-06-17T11:42:38 # ::file pmid_1901_4680_137.txt # ::snt In contrast, expression of activated MEK1 or MEK2 led to drastic morphological changes accompanied by loss of cell-cell contacts; the cells adopted a spindle-like fibroblast morphology, were more refractile and formed multilayers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (m / multi-sentence :snt1 (c / contrast-01 :ARG2 (l / lead-03 :ARG0 (e / express-03 :ARG2 (o / or :op1 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG1-of (a / activate-01))) :ARG2 (c2 / change-01 :ARG1 (m2 / morphology) :mod (d / drastic) :ARG1-of (a2 / accompany-01 :ARG0 (l2 / lose-02 :ARG1 (c3 / contact-01 :ARG0 (c4 / cell) :ARG1 (c5 / cell))))))) :snt2 (a3 / and :op1 (a4 / adopt-01 :ARG0 (c6 / cell) :ARG1 (m3 / morphology :mod (f / fibroblast) :ARG1-of (r / resemble-01 :ARG2 (s / spindle)))) :op2 (r2 / refractile :domain c6 :degree (m4 / more)) :op3 (f2 / form-01 :ARG0 c6 :ARG1 (m5 / multilayer)))) # ::id pmid_1901_4680.138 # ::date 2015-06-18T01:25:38 # ::file pmid_1901_4680_138.txt # ::snt These changes are characteristic of epithelial-mesenchymal transitions (EMT) that play an important role in tumor progression [39]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c / characteristic-02 :ARG1 (e / event :name (n / name :op1 "epithelial-mesenchymal" :op2 "transition") :ARG0-of (p / play-02 :ARG1 (r / role :prep-in (p2 / progress-01 :ARG1 (t2 / tumor)) :mod (i / important)))) :ARG2 (c2 / change-01 :mod (t / this)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "39")))) # ::id pmid_1901_4680.139 # ::date 2015-06-18T01:29:24 # ::file pmid_1901_4680_139.txt # ::snt To determine whether MEK1DD- and MEK2DD-expressing cells undergo an EMT, we examined the localization and measured the expression levels of various epithelial and mesenchymal markers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / and :op1 (e / examine-01 :ARG0 (w / we) :ARG1 (b / be-located-at-91 :ARG1 "a3")) :op2 (m / measure-01 :ARG0 w :ARG1 (l2 / level :quant-of (e7 / express-03 :ARG2 (a3 / and :op1 (m2 / marker :mod (e8 / epithelium)) :op2 (m3 / marker :mod (m4 / mesenchymal)) :mod (v / various))))) :purpose (d / determine-01 :ARG0 w :ARG1 (u / undergo-28 :mode "interrogative" :ARG1 (a2 / and :op1 (c / cell :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")))) :op2 (c2 / cell :ARG3-of (e4 / express-03 :ARG2 (e5 / enzyme :name (n2 / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283"))))) :ARG2 (e6 / event :name (n3 / name :op1 "epithelial-mesenchymal" :op2 "transition"))))) # ::id pmid_1901_4680.140 # ::date 2015-06-18T01:34:20 # ::file pmid_1901_4680_140.txt # ::snt Parental and vector-infected IEC-6 cells showed a polarized basolateral membrane distribution of the epithelial marker E-cadherin, with basal expression of the fibroblast marker vimentin (Fig. 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "IEC-6") :mod (p / parent)) :op2 (c2 / cell-line :name (n2 / name :op1 "IEC-6") :ARG1-of (i / infect-01 :ARG2 (v / vector)))) :ARG1 (d / distribute-01 :ARG1 (m4 / marker :name (n3 / name :op1 "E-cadherin") :mod (e / epithelium)) :ARG2 (m / membrane :mod (b / basolateral) :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (p2 / polarize-01) :accompanier (e2 / express-03 :ARG2 (m3 / marker :mod (f / fibroblast) :mod (p4 / protein :name (n4 / name :op1 "vimentin") :xref (x / xref :value "UNIPROT:VIME_HUMAN" :prob "0.702"))) :mod (b2 / basal))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1E"))) # ::id pmid_1901_4680.141 # ::date 2015-06-18T01:43:10 # ::file pmid_1901_4680_141.txt # ::snt Ectopic expression of MEK1DD or MEK2DD resulted in the loss of E-cadherin staining at the plasma membrane (Fig. 1E), concomitant with a marked reduction of E-cadherin protein and mRNA levels (Fig. 1F and 1G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (r / result-01 :ARG1 (e / express-03 :ARG2 (o / or :op1 (e3 / enzyme :name (n / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")) :op2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283"))) :mod (e2 / ectopic)) :ARG2 (l / lose-02 :ARG1 (s / stain-01 :ARG1 (p / protein :name (n3 / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :location (m / membrane :mod (p2 / plasma) :xref (x3 / xref :value "GO:0016020" :prob "0.8"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1E")) :time (r2 / reduce-01 :ARG1 (a / and :op1 (l2 / level :quant-of p) :op2 (l3 / level :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")))) :ARG2 (m2 / mark-01) :manner (c / concomitant) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1F") :op2 (f3 / figure :mod "1G")))))) # ::id pmid_1901_4680.142 # ::date 2015-06-18T01:54:31 # ::file pmid_1901_4680_142.txt # ::snt No significant change in the expression of keratins and no induction of the mesenchymal proteins vimentin and smooth muscle α-actin (we instead observed a decreased expression) were observed in these cells (Fig. 1F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (o / observe-01 :ARG1 (a / and :op1 (c / change-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "keratin") :xref (x2 / xref :value "UNIPROT:Q16195_HUMAN" :prob "1.001"))) :ARG1-of (s / significant-02)) :op2 (i / induce-01 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "vimentin") :xref (x / xref :value "UNIPROT:VIME_HUMAN" :prob "0.702")) :op2 (p3 / protein :name (n3 / name :op1 "smooth" :op2 "muscle" :op3 "α-actin") :xref (x1 / xref :value "UNIPROT:ACTH_HUMAN" :prob "0.382")) :mod (m / mesenchymal)))) :location (c2 / cell :mod (t / this)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1F")) :ARG2-of (i2 / instead-of-91 :ARG1 (o2 / observe-01 :ARG0 (w / we) :ARG1 (e2 / express-03 :ARG1-of (d2 / decrease-01))))) # ::id pmid_1901_4680.143 # ::date 2015-06-18T02:01:30 # ::file pmid_1901_4680_143.txt # ::snt These results indicate that constitutive activation of MEK1 or MEK2, while disrupting normal epithelial morphology and polarization, is not sufficient to induce a full EMT in intestinal epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (c3 / contrast-01 :ARG1 (d / disrupt-01 :ARG0 "a" :ARG1 (a2 / and :op1 (m / morphology :ARG1-of (n4 / normal-02) :mod (e5 / epithelium)) :op2 (p / polarize-01 :ARG1 e5))) :ARG2 (s / suffice-01 :polarity "-" :ARG0 (a / activate-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (c / constitutive)) :ARG1 (i2 / induce-01 :ARG0 a :ARG1 (c2 / cell :part-of (e4 / epithelium :part-of (i3 / intestine))) :ARG2 (e3 / event :name (n3 / name :op1 "epithelial-mesenchymal" :op2 "transition") :ARG1-of (f / full-09)))))) # ::id pmid_1901_4680.144 # ::date 2015-06-18T02:11:08 # ::file pmid_1901_4680_144.txt # ::snt This epithelial plasticity change has been referred to as scattering and is distinct from EMT [40]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / and :op1 (r / reference-04 :ARG1 (c / change-01 :ARG1 (p / plasticity :mod (e / epithelium)) :mod (t / this)) :ARG2 (s / scatter-01)) :op2 (d / distinct :domain c :compared-to (e3 / event :name (n2 / name :op1 "epithelial-mesenchymal" :op2 "transition"))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "40")))) # ::id pmid_1901_4680.145 # ::date 2015-06-18T02:15:33 # ::file pmid_1901_4680_145.txt # ::snt We examined whether constitutive activation of MEK1 or MEK2 was conferring some proliferation advantage to intestinal epithelial cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (c / confer-02 :mode "interrogative" :ARG0 (a / activate-01 :ARG1 (o / or :op1 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :mod (c2 / constitutive))) :ARG1 (a2 / advantage :mod (p / proliferate-01) :mod (s / some)) :ARG2 (c3 / cell :part-of (e4 / epithelium :part-of (i / intestine))))) # ::id pmid_1901_4680.146 # ::date 2015-06-18T02:17:42 # ::file pmid_1901_4680_146.txt # ::snt Ectopic expression of either activated MEK1 or MEK2 significantly increased the proliferation rate of IEC-6 cells grown in 10% serum containing-medium when compared to vector-infected cells or cells overexpressing wild type MEK isoforms (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (i / increase-01 :ARG0 (e2 / express-03 :ARG2 (o / or :op1 (e4 / enzyme :name (n2 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n3 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG1-of (a / activate-01)) :mod (e3 / ectopic)) :ARG1 (r / rate :mod (p2 / proliferate-01 :ARG0 (c / cell-line :name (n4 / name :op1 "IEC-6") :ARG1-of (g / grow-01 :location (m / medium :ARG0-of (c2 / contain-01 :ARG1 (s2 / serum :mod (p / percentage-entity :value "10"))))) :compared-to (o2 / or :op1 (c3 / cell :ARG1-of (i2 / infect-01 :ARG2 (v / vector))) :op2 (c4 / cell :location-of (o3 / overexpress-01 :ARG1 (i3 / isoform :mod (e / enzyme :name (n / name :op1 "MEK") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))))))) :ARG2 (s / significant-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_1901_4680.147 # ::date 2015-06-18T02:25:21 # ::file pmid_1901_4680_147.txt # ::snt This increase in proliferation was not observed in low serum (2%) containing-medium (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (o / observe-01 :polarity "-" :ARG1 (i / increase-01 :ARG1 (p2 / proliferate-01) :mod (t / this) :location (m / medium :ARG0-of (c / contain-01 :ARG1 (s / serum :mod (p / percentage-entity :value "2") :ARG1-of (l / low-04))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity "-")))) # ::id pmid_1901_4680.148 # ::date 2015-06-18T02:27:59 # ::file pmid_1901_4680_148.txt # ::snt Both activated MEK1 and MEK2 conferred anchorage-independence growth to IEC-6 cells (Fig. 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (c / confer-02 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG1-of (a2 / activate-01)) :ARG1 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a3 / anchorage))) :ARG2 (c2 / cell-line :name (n3 / name :op1 "IEC-6")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id pmid_1901_4680.149 # ::date 2015-06-18T02:30:47 # ::file pmid_1901_4680_149.txt # ::snt To test the tumorigenic potential of IEC-6 transduced cell populations in vivo, the cells were injected subcutaneously into athymic mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (i / inject-01 :ARG1 (c / cell) :ARG2 (m / mouse :mod (a / athymic)) :manner (s / subcutaneous) :purpose (t / test-01 :ARG1 (p / potential :mod (c2 / cause-01 :ARG0 (p2 / population :ARG1-of (t2 / transduce-01 :ARG2 (c3 / cell-line :name (n / name :op1 "IEC-6")))) :ARG1 (t3 / tumor)) :mod (i2 / in-vivo)))) # ::id pmid_1901_4680.150 # ::date 2015-06-18T02:35:18 # ::file pmid_1901_4680_150.txt # ::snt Cells infected with vector or wild type MEK isoforms never formed any tumor (Fig. 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (f / form-01 :polarity "-" :ARG0 (c / cell :ARG1-of (i / infect-01 :ARG2 (o / or :op1 (v / vector) :op2 (i2 / isoform :mod (e / enzyme :name (n / name :op1 "MEK") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))))) :ARG1 (t / tumor :mod (a / any)) :time (e2 / ever) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2C"))) # ::id pmid_1901_4680.151 # ::date 2015-06-18T02:37:28 # ::file pmid_1901_4680_151.txt # ::snt In contrast, both MEK1DD- and MEK2DD-expressing cells generated rapidly growing tumors in all injected mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c / contrast-01 :ARG2 (g / generate-01 :ARG0 (a / and :op1 (c2 / cell :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")))) :op2 (c3 / cell :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283"))))) :ARG1 (t / tumor :ARG1-of (g2 / grow-01 :manner (r / rapid))) :location (m / mouse :ARG2-of (i / inject-01) :mod (a2 / all)))) # ::id pmid_1901_4680.152 # ::date 2015-06-18T02:40:07 # ::file pmid_1901_4680_152.txt # ::snt Injection of as low as 3 × 104 cells produced tumors of ~1,000 mm3 after 2 weeks. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 1, 2016 (p / produce-01 :ARG0 (i / inject-01 :ARG1 (c / cell :quant "30000" :ARG3-of (l / low-04))) :ARG1 (t2 / tumor :mod (a / approximately :op1 (v / volume-quantity :quant "1000" :unit (c2 / cubic-millimeter)))) :time (a2 / after :op1 (t / temporal-quantity :quant "2" :unit (w / week)))) # ::id pmid_1901_4680.153 # ::date 2015-06-18T02:45:12 # ::file pmid_1901_4680_153.txt # ::snt No major difference was observed in the growth rate of tumors expressing activated MEK1 or MEK2 (Fig. 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (o / observe-01 :ARG1 (d / differ-02 :polarity "-" :ARG1 (r / rate :mod (g / grow-01 :ARG1 (t / tumor :ARG3-of (e / express-03 :ARG2 (o2 / or :op1 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG1-of (a / activate-01)))))) :ARG1-of (m / major-02)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2D"))) # ::id pmid_1901_4680.154 # ::date 2015-06-18T02:47:59 # ::file pmid_1901_4680_154.txt # ::snt To analyze the impact of active MEK isoforms on tumorigenesis in a more pathologically relevant model, IEC-6 transduced cells were orthotopically transplanted into the caecum of athymic mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (t / transplant-01 :ARG1 (c / cell :ARG1-of (t2 / transduce-01 :ARG2 (c4 / cell-line :name (n2 / name :op1 "IEC-6")))) :ARG2 (c2 / caecum :part-of (m / mouse :mod (a / athymic))) :manner (o / orthotopic) :purpose (a2 / analyze-01 :ARG1 (i / impact-01 :ARG0 (i2 / isoform :mod (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (a3 / activate-01)) :ARG1 (c3 / cause-01 :ARG1 (t3 / tumor))) :prep-in (m2 / model :ARG1-of (r / relevant-01 :ARG2 (p / pathology) :degree (m3 / more))))) # ::id pmid_1901_4680.155 # ::date 2015-06-16T09:31:40 # ::file pmid_1901_4680_155.txt # ::snt This model more closely recapitulates human colorectal cancer progression, in particular the spontaneous metastatic process that is highly dependent on the host environment [41]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / recapitulate-01 :ARG0 (m / model :mod (t / this)) :ARG1 (a / and :op1 (p / progress-01 :ARG1 (d3 / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer") :mod (h / human))) :op2 (p2 / process-02 :ARG1 (m3 / metastasize-101) :mod (s / spontaneous) :mod (p3 / particular) :ARG0-of (d / depend-01 :ARG1 (e / environment :ARG0-of (h3 / host-01)) :ARG1-of (h2 / high-02)))) :ARG1-of (c / close-10 :degree (m2 / more)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "41")))) # ::id pmid_1901_4680.156 # ::date 2015-06-16T10:00:03 # ::file pmid_1901_4680_156.txt # ::snt Strikingly, 100% of the mice transplanted with 105 IEC-6 cells expressing either MEK1DD or MEK2DD developed massive intestinal tumors, while the control group remained tumor-free (Fig. 2C and 2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (d / develop-02 :ARG0 (m / mouse :ARG1-of (i2 / include-91 :ARG2 (m3 / mouse :ARG2-of (t / transplant-01 :ARG1 (c2 / cell-line :quant "100000" :name (n / name :op1 "IEC-6") :ARG3-of (e / express-03 :ARG2 (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283"))))))) :ARG3 (p / percentage-entity :value "100"))) :ARG1 (t2 / tumor :mod (i / intestine) :mod (m2 / massive))) :ARG2 (r / remain-01 :ARG1 (g / group :mod (c3 / control)) :ARG3 (f / free-04 :ARG1 g :ARG2 t2)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "2C") :op2 (f3 / figure :mod "2E"))) :ARG1-of (s / strike-04)) # ::id pmid_1901_4680.157 # ::date 2015-06-16T10:40:42 # ::file pmid_1901_4680_157.txt # ::snt The mice were sacrificed when they became moribund or presented symptoms of weight loss, respiratory distress, or a palpable abdominal mass. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / sacrifice-01 :ARG1 (m / mouse) :time (o / or :op1 (b / become-01 :ARG1 m :ARG2 (m2 / moribund)) :op2 (p / present-102 :ARG0 m :ARG1 (o2 / or :op1 (s2 / symptom :mod (l / lose-02 :ARG1 (w / weight))) :op2 (s3 / symptom :mod (d / distress-01 :ARG1 (r / respiration))) :op3 (s4 / symptom :mod (m3 / mass :ARG1-of (p2 / palpate-00 :ARG1-of (p3 / possible-01)) :mod (a2 / abdomen))))))) # ::id pmid_1901_4680.158 # ::date 2015-06-16T11:20:56 # ::file pmid_1901_4680_158.txt # ::snt Microscopic examination of the tumors revealed a poorly differentiated morphology with occasional signet-ring cells (inset) corresponding to a high-grade adenocarcinoma (Fig. 2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / reveal-01 :ARG0 (e / examine-01 :ARG1 (t / tumor) :mod (m / microscopic)) :ARG1 (m2 / morphology :ARG1-of (d / differentiate-01 :manner (p / poor)) :consist-of (c / cell-line :name (n / name :op1 "signet-ring") :ARG1-of (m3 / mean-01 :ARG2 (i / inset)) :ARG1-of (c2 / correspond-02 :ARG2 (m4 / medical-condition :name (n2 / name :op1 "adenocarcinoma") :mod (g / grade :ARG1-of (h / high-02)))) :frequency (o / occasional))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2E"))) # ::id pmid_1901_4680.159 # ::date 2015-06-16T11:33:57 # ::file pmid_1901_4680_159.txt # ::snt The tumors are invasive and diffusely infiltrate the lamina propria and the underlying muscular layers (muscularis propria and muscularis mucosae). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / and :op1 (i / invade-01 :ARG0 (t / tumor)) :op2 (i2 / infiltrate-01 :ARG0 t :ARG1 (a2 / and :op1 (l / lamina-propria) :op2 (l2 / layer :mod (m / muscle) :ARG1-of (u / underlie-01) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (l3 / layer :name (n / name :op1 "muscularis" :op2 "propria")) :op2 (l4 / layer :name (n2 / name :op1 "muscularis" :op2 "mucosae")))))) :manner (d / diffuse))) # ::id pmid_1901_4680.160 # ::date 2015-06-16T11:48:25 # ::file pmid_1901_4680_160.txt # ::snt Together, these data demonstrate that constitutive activation of MEK1 or MEK2 is sufficient to transform intestinal epithelial cells and induce the formation of invasive colon adenocarcinomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / demonstrate-01 :ARG0 (d2 / data :mod (t / this) :mod (t2 / together)) :ARG1 (s / suffice-01 :ARG0 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (c3 / constitutive)) :ARG1 (a3 / and :op1 (t3 / transform-01 :ARG0 a :ARG1 (c / cell :mod (e3 / epithelium) :part-of (i2 / intestine))) :op2 (i / induce-01 :ARG0 a :ARG2 (f / form-01 :ARG1 (m / medical-condition :name (n3 / name :op1 "adenocarcinoma") :mod (c2 / colon) :ARG0-of (i3 / invade-01))))))) # ::id pmid_1901_4680.161 # ::date 2015-06-16T11:55:45 # ::file pmid_1901_4680_161.txt # ::snt Constitutive activation of MEK1 or MEK2 confers metastatic properties to transformed intestinal epithelial cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c / confer-02 :ARG0 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (c2 / constitutive)) :ARG1 (p / property :mod (m / metastasize-101)) :ARG2 (c3 / cell :mod (e3 / epithelium) :part-of (i / intestine) :ARG1-of (t / transform-01))) # ::id pmid_1901_4680.162 # ::date 2015-06-16T12:01:26 # ::file pmid_1901_4680_162.txt # ::snt Activation of the ERK1/2 MAP kinase pathway has been implicated in the regulation of cell motility and invasion [42]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (i / implicate-01 :ARG1 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "ERK1/2" :op2 "MAP-kinase"))) :ARG2 (r / regulate-01 :ARG0 a :ARG1 (a2 / and :op1 (m / motility :mod (c / cell)) :op2 (i2 / invade-01 :ARG0 c))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "42")))) # ::id pmid_1901_4680.163 # ::date 2015-06-16T12:10:00 # ::file pmid_1901_4680_163.txt # ::snt Notably, treatment of colon carcinoma cells with the MEK1/2 inhibitor PD184352 was shown to inhibit HGF-induced cell scattering and to reduce their invasive properties [20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG1 (a / and :op1 (i2 / inhibit-01 :ARG0 (t / treat-04 :ARG1 (c / cell :mod (m / medical-condition :name (n / name :op1 "carcinoma")) :part-of (c2 / colon)) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD184352") :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "MEK1/2"))) :xref (x1 / xref :value "PUBCHEM:6918454" :prob "18.013371"))) :ARG1 (s3 / scatter-01 :ARG1 (c3 / cell) :ARG2-of (i3 / induce-01 :ARG0 (p / protein :name (n4 / name :op1 "HGF") :xref (x / xref :value "UNIPROT:HGF_HUMAN" :prob "1.004"))))) :op2 (r / reduce-01 :ARG0 t :ARG1 (p2 / property :mod (i4 / invade-01 :ARG0 c3) :poss c3))) :ARG1-of (n5 / notable-04) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "20")))) # ::id pmid_1901_4680.164 # ::date 2015-06-16T12:34:13 # ::file pmid_1901_4680_164.txt # ::snt We examined the impact of MEK1 or MEK2 activation on the motility of IEC-6 cells using two different cell migration assays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (i / impact-01 :ARG0 (a / activate-01 :ARG1 (o / or :op1 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (m / motility :poss (c / cell-line :name (n3 / name :op1 "IEC-6")))) :ARG2-of (u / use-01 :ARG0 w :ARG1 (a2 / assay-01 :quant "2" :ARG1 (m2 / migrate-01 :ARG0 (c2 / cell)) :ARG1-of (d / differ-02)))) # ::id pmid_1901_4680.165 # ::date 2015-06-16T13:27:53 # ::file pmid_1901_4680_165.txt # ::snt No difference in the migration rate of the different IEC-6 transduced populations was observed in a standard chemotaxis assay with serum as chemoattractant (Fig. 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (o / observe-01 :ARG1 (d / differ-02 :polarity "-" :ARG1 (r / rate :mod (m / migrate-01 :ARG1 (p / population :ARG1-of (t / transduce-01 :ARG2 (c / cell-line :name (n / name :op1 "IEC-6"))))))) :location (a / assay-01 :ARG1 (c2 / chemotaxis) :mod (s / standard) :instrument (s2 / serum :purpose (c3 / chemoattractant))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_1901_4680.166 # ::date 2015-06-16T13:59:23 # ::file pmid_1901_4680_166.txt # ::snt Similar results were obtained using a wound-healing assay (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (o / obtain-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :ARG2-of (u / use-01 :ARG1 (a / assay-01 :ARG1 (h / heal-01 :ARG2 (w / wound)))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s / show-01 :polarity "-")))) # ::id pmid_1901_4680.167 # ::date 2015-06-16T14:08:51 # ::file pmid_1901_4680_167.txt # ::snt We next analyzed the ability of the cells to migrate through a Matrigel-coated membrane as a reflection of their invasive properties. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (c / capable-01 :ARG1 (c2 / cell) :ARG2 (m / migrate-01 :ARG0 c2 :ARG1 (m2 / membrane :ARG1-of (c3 / coat-01 :ARG2 (p3 / protein :name (n3 / name :op1 "Matrigel") :xref (x / xref :value "UNIPROT:MMP7_HUMAN" :prob "0.273"))) :xref (x1 / xref :value "GO:0016020" :prob "0.8"))) :ARG1-of (r / reflect-01 :ARG2 (p2 / property :mod (i / invade-01 :ARG0 c2) :poss c2))) :time (n2 / next)) # ::id pmid_1901_4680.168 # ::date 2015-06-16T14:16:12 # ::file pmid_1901_4680_168.txt # ::snt Ectopic expression of activated MEK1 or MEK2 significantly enhanced the invasive capacity of IEC-6 cells, while the wild type MEK isoforms had no effect (Fig. 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c / contrast-01 :ARG1 (e / enhance-01 :ARG0 (e2 / express-03 :ARG2 (o / or :op1 (e4 / enzyme :name (n / name :op1 "MEK1") :ARG1-of (a / activate-01) :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n2 / name :op1 "MEK2") :ARG1-of a :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (e3 / ectopic)) :ARG1 (c2 / capable-01 :ARG1 (c3 / cell-line :name (n3 / name :op1 "IEC-6")) :ARG2 (i / invade-01)) :ARG1-of (s / significant-02)) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 (i2 / isoform :mod (e6 / enzyme :name (n4 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :mod (w / wild-type))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_1901_4680.169 # ::date 2015-06-16T14:34:56 # ::file pmid_1901_4680_169.txt # ::snt Interestingly, the MEK2DD-transduced cells appeared more invasive than cells expressing MEK1DD in this assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / appear-02 :ARG1 (i / invade-01 :ARG0 (c / cell :ARG1-of (t / transduce-01 :ARG2 (e / enzyme :name (n / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283")))) :degree (m / more) :compared-to (c2 / cell :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283"))))) :mod (i2 / interesting) :location (a2 / assay-01 :mod (t2 / this))) # ::id pmid_1901_4680.170 # ::date 2015-06-16T14:44:00 # ::file pmid_1901_4680_170.txt # ::snt The invasive properties of the cells in vitro and the histology of the intestinal tumors suggest that MEK1DD- and MEK2DD-expressing IEC-6 cells may have metastatic properties in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (s / suggest-01 :ARG0 (a / and :op1 (p / property :mod (i / invade-01 :ARG0 (c / cell) :manner (i2 / in-vitro))) :op2 (h / histology :poss (t / tumor :location (i3 / intestine)))) :ARG1 (p2 / possible-01 :ARG1 (h2 / have-03 :ARG0 (c2 / cell-line :name (n / name :op1 "IEC-6") :ARG3-of (e / express-03 :ARG2 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283"))))) :ARG1 (p3 / property :mod (m / metastasize-101)) :manner (i4 / in-vivo)))) # ::id pmid_1901_4680.171 # ::date 2015-06-16T14:58:30 # ::file pmid_1901_4680_171.txt # ::snt Detailed histological examination of a subset of mice that develop orthotopic tumors revealed the presence of metastasis in the lymph nodes, the lungs and the liver in both the MEK1DD and MEK2DD groups (Fig. 3C and 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 26, 2015 (r / reveal-01 :ARG0 (e / examine-01 :ARG1 (s / subset :ARG1-of (i / include-91 :ARG2 (m / mouse :ARG1-of (d2 / develop-01 :ARG2 (t / tumor :mod (o / orthotopic)))))) :ARG1-of (d / detail-01) :mod (h / histology)) :ARG1 (m2 / metastasize-101 :ARG2 (a / and :op1 (n / node :mod (l / lymph)) :op2 (l2 / lung) :op3 (l3 / liver))) :location (a2 / and :op1 (g / group :mod (e2 / enzyme :name (n2 / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283"))) :op2 (g2 / group :mod (e3 / enzyme :name (n3 / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283")))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3C") :op2 (f2 / figure :mod "3D")))) # ::id pmid_1901_4680.172 # ::date 2015-06-16T15:12:30 # ::file pmid_1901_4680_172.txt # ::snt These observations indicate that constitutive activation of either MEK1 or MEK2 is sufficient to confer a metastatic phenotype to intestinal tumor cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (i / indicate-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (s / suffice-01 :ARG0 (a / activate-01 :ARG1 (o2 / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (c3 / constitutive)) :ARG1 (c / confer-02 :ARG0 a :ARG1 (p / phenotype :mod (m / metastasize-101)) :ARG2 (c2 / cell :mod (t2 / tumor) :part-of (i2 / intestine))))) # ::id pmid_1901_4680.173 # ::date 2015-06-17T10:28:20 # ::file pmid_1901_4680_173.txt # ::snt The acquisition of invasiveness does not result from changes in cellular motility. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (r / result-01 :polarity "-" :ARG1 (c / change-01 :ARG1 (m / motility :mod (c2 / cell))) :ARG2 (a / acquire-01 :ARG1 (i / invade-01))) # ::id pmid_1901_4680.174 # ::date 2015-06-17T10:41:39 # ::file pmid_1901_4680_174.txt # ::snt To identify downstream targets of MEK1/MEK2 involved in intestinal tumor progression, we analyzed the transcriptional profile of MEK1DD- and MEK2DD-expressing IEC-6 cells using Affymetrix GeneChip arrays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (p / profile-01 :ARG1 (c / cell-line :name (n / name :op1 "IEC-6") :ARG3-of (e / express-03 :ARG2 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283"))))) :mod (t4 / transcribe-01 :ARG0 c)) :ARG2-of (u / use-01 :ARG1 (a2 / array-01 :mod (t / thing :name (n4 / name :op1 "Affymetrix" :op2 "GeneChip")))) :purpose (i / identify-01 :ARG0 w :ARG1 (t2 / target-01 :ARG0 (s / slash :op1 (e4 / enzyme :name (n5 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n6 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :location (d / downstream) :ARG1-of (i2 / involve-01 :ARG2 (p2 / progress-01 :ARG1 (t3 / tumor :location (i3 / intestine))))))) # ::id pmid_1901_4680.175 # ::date 2015-06-17T11:17:24 # ::file pmid_1901_4680_175.txt # ::snt Analysis of the gene expression data identified several genes that were up-regulated or down-regulated in MEK1DD- and MEK2DD-expressing cells as compared to control IEC-6 cells (Additional files 1 and 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 26, 2015 (i / identify-01 :ARG0 (a / analyze-01 :ARG1 (d / data :topic (g / gene :ARG1-of (e / express-03)))) :ARG1 (o / or :op1 (g2 / gene :quant (s / several) :ARG1-of (u / upregulate-01)) :op2 (g3 / gene :quant s :ARG1-of (d2 / downregulate-01)) :location (c / cell :ARG3-of (e2 / express-03 :ARG2 (a2 / and :op1 (e3 / enzyme :name (n / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")) :op2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283")))) :ARG1-of (c2 / compare-01 :ARG2 (c3 / cell-line :name (n3 / name :op1 "IEC-6") :mod (c4 / control-01))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / file :mod "1" :ARG1-of (a4 / add-02)) :op2 (f2 / file :mod "2" :ARG1-of a4)))) # ::id pmid_1901_4680.176 # ::date 2015-06-17T11:47:33 # ::file pmid_1901_4680_176.txt # ::snt The list of modulated genes included growth factors, signaling molecules, drug metabolism enzymes and, interestingly, several proteases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (i / include-01 :ARG1 (a / and :op1 (g2 / growth-factor) :op2 (m2 / molecule :ARG0-of (s2 / signal-07)) :op3 (e / enzyme :ARG0-of (m3 / metabolize-01 :ARG1 (d / drug))) :op4 (p / protease :quant (s3 / several))) :ARG2 (l / list :consist-of (g / gene :ARG1-of (m / modulate-01))) :mod (i2 / interesting)) # ::id pmid_1901_4680.177 # ::date 2015-06-17T11:58:02 # ::file pmid_1901_4680_177.txt # ::snt The matrix metalloproteinases (MMPs) MMP-3 and MMP-13 were up-regulated in both MEK1DD- and MEK2DD-expressing cells, while up-regulation of MMP-10 reached significance only in MEK2DD cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (c / contrast-01 :ARG1 (u / upregulate-01 :ARG1 (a / and :op1 (e5 / enzyme :name (n / name :op1 "MMP-3") :xref (x / xref :value "UNIPROT:MMP3_HUMAN" :prob "1.003")) :op2 (e6 / enzyme :name (n2 / name :op1 "MMP-13") :xref (x3 / xref :value "UNIPROT:MMP13_HUMAN" :prob "1.002")) :ARG1-of (i / include-91 :ARG2 (e7 / enzyme :name (n7 / name :op1 "matrix" :op2 "metalloproteinase") :xref (x2 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.393")))) :location (c2 / cell :ARG3-of (e / express-03 :ARG2 (a2 / and :op1 (e2 / enzyme :name (n3 / name :op1 "MEK1DD") :xref (x5 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")) :op2 (e3 / enzyme :name (n4 / name :op1 "MEK2DD") :xref (x4 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283")))))) :ARG2 (r / reach-01 :ARG0 (u2 / upregulate-01 :ARG1 (e8 / enzyme :name (n5 / name :op1 "MMP-10") :xref (x1 / xref :value "UNIPROT:MMP10_HUMAN" :prob "1.002"))) :ARG1 (s / significant-02) :location (c3 / cell :mod e3) :mod (o / only))) # ::id pmid_1901_4680.178 # ::date 2015-06-17T12:14:42 # ::file pmid_1901_4680_178.txt # ::snt Expression of the urokinase receptor was also up-regulated in IEC-6 cells expressing activated MEK2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (u / upregulate-01 :ARG1 (e / express-03 :ARG2 (r / receptor :mod (e2 / enzyme :name (n / name :op1 "urokinase") :xref (x1 / xref :value "UNIPROT:HUTU_HUMAN" :prob "0.292")))) :mod (a / also) :location (c / cell-line :name (n2 / name :op1 "IEC-6") :ARG1-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MEK2") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) # ::id pmid_1901_4680.179 # ::date 2015-06-17T12:21:07 # ::file pmid_1901_4680_179.txt # ::snt Because of the importance of MMPs and urokinase receptor in tumor progression [43,44], we further validated the regulation of these genes by MEK1 and MEK2 signaling to confirm the data from the arrays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (v / validate-01 :ARG0 (w / we) :ARG1 (r / regulate-01 :ARG0 (s / signal-07 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (g / gene :mod (t / this))) :time (f / further) :purpose (c / confirm-01 :ARG0 w :ARG1 (d / data :source (a2 / array))) :ARG1-of (c2 / cause-01 :ARG0 (i / important :domain (a3 / and :op1 (e3 / enzyme :name (n3 / name :op1 "MMP") :xref (x1 / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263")) :op2 (r2 / receptor :mod (e4 / enzyme :name (n4 / name :op1 "urokinase") :xref (x / xref :value "UNIPROT:HUTU_HUMAN" :prob "0.292")))) :purpose (p / progress-01 :ARG1 (t2 / tumor))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 "43" :op2 "44")))))) # ::id pmid_1901_4680.180 # ::date 2015-06-17T13:29:33 # ::file pmid_1901_4680_180.txt # ::snt No expression or activity of MMPs could be detected in empty vector-infected IEC-6 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (d / detect-01 :ARG1 (o / or :op1 (e / express-03 :polarity "-" :ARG2 (e2 / enzyme :name (n / name :op1 "MMP") :xref (x / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263"))) :op2 (a / activity-06 :polarity "-" :ARG0 e2)) :location (c / cell-line :name (n2 / name :op1 "IEC-6") :ARG1-of (i / infect-01 :ARG2 (v / vector :ARG1-of (e3 / empty-01)))))) # ::id pmid_1901_4680.181 # ::date 2015-06-17T13:45:02 # ::file pmid_1901_4680_181.txt # ::snt However, activation of either MEK1 or MEK2 markedly up-regulated the expression of MMP-13 protein (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (u / upregulate-01 :ARG0 (a / activate-01 :ARG1 (o / or :op2 (e2 / enzyme :name (n2 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (e / express-03 :ARG2 (e4 / enzyme :name (n / name :op1 "MMP-13") :xref (x / xref :value "UNIPROT:MMP13_HUMAN" :prob "1.002"))) :manner (m / marked)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id pmid_1901_4680.182 # ::date 2015-06-17T14:13:17 # ::file pmid_1901_4680_182.txt # ::snt Notably, higher levels of MMP-13 protein were detected in IEC-6 cells expressing the activated MEK2 isoform. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / detect-01 :ARG1 (l / level :quant-of (e3 / enzyme :name (n / name :op1 "MMP-13") :xref (x / xref :value "UNIPROT:MMP13_HUMAN" :prob "1.002")) :ARG1-of (h / high-02 :degree (m / more))) :location (c / cell-line :name (n2 / name :op1 "IEC-6") :ARG3-of (e / express-03 :ARG2 (i / isoform :ARG1-of (a / activate-01) :mod (e2 / enzyme :name (n3 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG1-of (n4 / notable-04)) # ::id pmid_1901_4680.183 # ::date 2015-06-17T14:16:47 # ::file pmid_1901_4680_183.txt # ::snt The expression of MMP-3/10 was analyzed by measuring their activity by zymography in casein-containing gels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / analyze-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MMP-3/10"))) :manner (m / measure-01 :ARG1 (a2 / activity-06 :ARG0 e2) :ARG2 (z / zymography) :location (g / gel :ARG0-of (c / contain-01 :ARG1 (p / protein :name (n3 / name :op1 "casein")))))) # ::id pmid_1901_4680.184 # ::date 2015-06-17T14:29:24 # ::file pmid_1901_4680_184.txt # ::snt Again, we observed that MEK2DD increased MMP-3/10 enzymatic activity more robustly than MEK1DD (Fig. 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG0 (e / enzyme :name (n / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283")) :ARG1 (a / activity-06 :ARG0 (e2 / enzyme :name (n2 / name :op1 "MMP-3/10")) :mod (e3 / enzyme)) :manner (r / robust :degree (m / more) :compared-to (e4 / enzyme :name (n3 / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")))) :mod (a2 / again) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id pmid_1901_4680.185 # ::date 2015-06-17T14:48:02 # ::file pmid_1901_4680_185.txt # ::snt Quantitative PCR analysis confirmed that constitutive activation of MEK1 or MEK2 induces the expression of urokinase receptor mRNA (Fig. 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / confirm-01 :ARG0 (a / analyze-01 :manner (r2 / react-01 :ARG0 (p / polymerase :ARG1-of (c3 / chain-01)) :mod (q / quantitative))) :ARG1 (i / induce-01 :ARG0 (a2 / activate-01 :ARG1 (o / or :op1 (e / enzyme :name (n2 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (c2 / constitutive)) :ARG2 (e3 / express-03 :ARG2 (n6 / nucleic-acid :name (n5 / name :op1 "mRNA") :mod (r / receptor :mod (e4 / enzyme :name (n4 / name :op1 "urokinase") :xref (x / xref :value "UNIPROT:HUTU_HUMAN" :prob "0.292")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id pmid_1901_4680.186 # ::date 2015-06-17T15:04:12 # ::file pmid_1901_4680_186.txt # ::snt As observed for the MMPs, the extent of induction of the urokinase receptor gene was higher in MEK2DD-expressing cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / high-02 :ARG1 (e / extent :extent-of (i / induce-01 :ARG2 (g / gene :mod (r / receptor :mod (e2 / enzyme :name (n / name :op1 "urokinase") :xref (x2 / xref :value "UNIPROT:HUTU_HUMAN" :prob "0.292")))))) :degree (m / more) :location (c / cell :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283")))) :ARG1-of (o / observe-01 :topic (e5 / enzyme :name (n3 / name :op1 "MMP") :xref (x / xref :value "UNIPROT:MMP3_HUMAN" :prob "0.263")))) # ::id pmid_1901_4680.187 # ::date 2015-06-17T15:15:03 # ::file pmid_1901_4680_187.txt # ::snt In a previous study, Komatsu et al. [45] have used oligonucleotide microarrays to analyze the gene expression profile of intestinal epithelial cells expressing a conditional allele of activated MEK1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (u / use-01 :ARG0 (a / and :op1 (p / person :name (n / name :op1 "Komatsu")) :op2 (p2 / person :mod (o / other))) :ARG1 (m / microarray :mod (o2 / oligonucleotide)) :ARG2 (a4 / analyze-01 :ARG0 a :ARG1 (p3 / profile-01 :ARG1 (e3 / express-03 :ARG2 (a2 / allele :mod (c2 / conditional) :part-of (e4 / enzyme :name (n3 / name :op1 "MEK1") :ARG1-of (a3 / activate-01) :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG3 (c / cell :mod (e2 / epithelium) :part-of (i / intestine))) :mod (g / gene))) :location (t / thing :ARG1-of (s2 / study-01 :time (p4 / previous))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "45")))) # ::id pmid_1901_4680.188 # ::date 2015-06-17T15:34:03 # ::file pmid_1901_4680_188.txt # ::snt We have compared the results of our transcriptional profiling analysis with this study. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c / compare-01 :ARG0 (w / we) :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (a / analyze-01 :ARG0 w :ARG0-of (p / profile-01) :mod (t2 / transcribe-01)))) :ARG2 (s / study-01 :mod (t4 / this))) # ::id pmid_1901_4680.189 # ::date 2015-06-17T15:40:10 # ::file pmid_1901_4680_189.txt # ::snt Of the 69 gene transcripts that showed altered expression in the study of Komatsu, 18 (26%) were found to be modulated in IEC-6 cells expressing constitutively active MEK1 or MEK2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (f / find-01 :ARG1 (m / modulate-01 :ARG1 (t3 / transcribe-01 :quant "18" :ARG1 (g2 / gene) :ARG1-of (i / include-91 :ARG2 (t / transcribe-01 :quant "69" :ARG1 (g / gene) :ARG0-of (s / show-01 :ARG1 (e / express-03 :ARG1-of (a / alter-01)) :location (s2 / study-01 :ARG0 (p / person :name (n / name :op1 "Komatsu"))))) :ARG3 (p2 / percentage-entity :value "26"))) :location (c / cell-line :name (n2 / name :op1 "IEC-6") :ARG3-of (e2 / express-03 :ARG2 (o / or :op1 (e3 / enzyme :name (n3 / name :op1 "MEK1") :ARG1-of (a2 / activate-01 :manner (c2 / constitutive)) :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n4 / name :op1 "MEK2") :ARG1-of a2 :manner c2 :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))))) # ::id pmid_1901_4680.190 # ::date 2015-06-17T16:01:57 # ::file pmid_1901_4680_190.txt # ::snt Importantly, the two studies converge on a series of genes involved in cell proliferation, cell invasion, tumor suppression and drug metabolism. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c / converge-01 :ARG0 (s / study-01 :quant "2") :ARG2 (g / gene :quant (s2 / series) :ARG1-of (i / involve-01 :ARG2 (a / and :op1 (p / proliferate-01 :ARG0 (c2 / cell)) :op2 (i2 / invade-01 :ARG0 c2) :op3 (s3 / suppress-01 :ARG1 (t2 / tumor)) :op4 (m / metabolize-01 :ARG1 (d / drug))))) :mod (i3 / important)) # ::id pmid_1901_4680.191 # ::date 2015-06-17T16:09:56 # ::file pmid_1901_4680_191.txt # ::snt Constitutive activation of MEK1 or MEK2 protects intestinal epithelial cells against anoikis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (p / protect-01 :ARG0 (a / activate-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (c / constitutive)) :ARG1 (c2 / cell :mod (e3 / epithelium) :part-of (i / intestine)) :ARG2 (a2 / anoikis)) # ::id pmid_1901_4680.192 # ::date 2015-06-17T14:50:57 # ::file pmid_1901_4680_192.txt # ::snt Epithelial cancer progression and metastasis is associated with the acquisition of resistance to anoikis [46]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / associate-01 :ARG1 (a2 / and :op1 (p / progress-01 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod (e / epithelium))) :op2 (m / metastasize-101 :ARG1 d)) :ARG2 (a3 / acquire-01 :ARG1 (r / resist-01 :ARG1 (a4 / anoikis))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "46")))) # ::id pmid_1901_4680.193 # ::date 2015-06-17T15:07:19 # ::file pmid_1901_4680_193.txt # ::snt To further explore the mechanism by which MEK1 and MEK2 promote tumor metastasis, we asked whether activated MEK isoforms protect intestinal epithelial cells from cell death induced by loss of adhesion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / ask-01 :ARG0 (w / we) :ARG1 (p / protect-01 :mode "interrogative" :ARG0 (i / isoform :mod (e / enzyme :name (n / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (a2 / activate-01)) :ARG1 (c / cell :mod (e2 / epithelium :mod (i2 / intestine))) :ARG2 (d / die-01 :ARG1 c :ARG2-of (i3 / induce-01 :ARG0 (l / lose-02 :ARG1 (a3 / adhere-01))))) :purpose (e3 / explore-01 :ARG0 w :ARG1 (m / mechanism :instrument-of (p2 / promote-01 :ARG0 (a4 / and :op1 (e4 / enzyme :name (n2 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n3 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG1 (m2 / metastasize-101 :ARG1 (t / tumor)))) :mod (f / further))) # ::id pmid_1901_4680.194 # ::date 2015-06-17T15:22:14 # ::file pmid_1901_4680_194.txt # ::snt IEC-6-transduced populations were placed on poly-HEMA-coated plates in normal growth medium and the extent of apoptosis was measured at different times by TUNEL. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (p / place-01 :ARG1 (p2 / population :ARG1-of (t / transduce-01 :ARG2 (c / cell-line :name (n / name :op1 "IEC-6")))) :ARG2 (p3 / plate :ARG1-of (c2 / coat-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "poly-HEMA") :xref (x / xref :value "PUBCHEM:13360" :prob "16.884884")))) :location (m2 / medium :mod (g / grow-01) :ARG1-of (n3 / normal-02))) :op2 (m3 / measure-01 :ARG1 (e / extent :degree-of (a2 / apoptosis)) :frequency (t2 / time :ARG1-of (d / differ-02)) :instrument (t3 / thing :name (n4 / name :op1 "TUNEL")))) # ::id pmid_1901_4680.195 # ::date 2015-06-17T15:36:05 # ::file pmid_1901_4680_195.txt # ::snt Detachment from matrix induced high levels of apoptosis of control IEC-6 cells, which was already detectable at 6 h and increased up to 24 h (Fig. 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (d / detach-01 :ARG2 (m / matrix)) :ARG2 (l / level :quant-of (a / apoptosis :poss (c / cell-line :name (n / name :op1 "IEC-6") :ARG2-of (c2 / control-01))) :ARG1-of (h / high-02)) :ARG1-of (d2 / detect-01 :ARG1-of (p / possible-01) :time (a2 / after :quant (t / temporal-quantity :quant "6" :unit (h2 / hour))) :time (a3 / already)) :ARG1-of (i2 / increase-01 :time (a4 / after :quant (u / up-to :op1 (t2 / temporal-quantity :quant "24" :unit h2)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id pmid_1901_4680.196 # ::date 2015-06-17T16:05:13 # ::file pmid_1901_4680_196.txt # ::snt Strikingly, expression of either MEK1DD or MEK2DD almost completely protected IEC-6 cells from undergoing anoikis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / protect-01 :ARG0 (e / express-03 :ARG2 (o / or :op1 (e2 / enzyme :name (n / name :op1 "MEK1DD") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2DD") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283")))) :ARG1 (c / cell-line :name (n3 / name :op1 "IEC-6")) :ARG2 (u / undergo-28 :ARG1 c :ARG2 (a / anoikis)) :degree (c2 / complete-01 :degree (a2 / almost)) :ARG1-of (s / strike-04)) # ::id pmid_1901_4680.197 # ::date 2015-06-17T16:19:02 # ::file pmid_1901_4680_197.txt # ::snt As a step to understand the molecular mechanism by which activated MEK isoforms suppress anoikis, we monitored the expression of Bcl-2 anti-apoptotic and pro-apoptotic family proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (m / monitor-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "Bcl-2") :mod (f / family) :ARG0-of (c / counter-01 :ARG1 (a2 / apoptosis)) :xref (x2 / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.701")) :op2 (p2 / protein :name (n2 / name :op1 "Bcl-2") :mod f :ARG0-of (f2 / favor-01 :ARG1 a2) :xref (x / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.701")))) :ARG4-of (s / step-01 :ARG2 (u / understand-01 :ARG0 w :ARG1 (m2 / mechanism :mod (m3 / molecule) :instrument-of (s2 / suppress-01 :ARG0 (i / isoform :mod (e2 / enzyme :name (n3 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (a3 / activate-01)) :ARG1 (a4 / anoikis)))))) # ::id pmid_1901_4680.198 # ::date 2015-06-17T16:31:37 # ::file pmid_1901_4680_198.txt # ::snt Constitutive activation of MEK1 or MEK2 resulted in the up-regulation of the pro-survival proteins Mcl-1, Bcl-2 and, to a lesser extent, Bcl-xL in IEC-6 cells (Fig. 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (r / result-01 :ARG1 (a / activate-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :mod (c / constitutive)) :ARG2 (u / upregulate-01 :ARG1 (a2 / and :op1 (p / protein :name (n3 / name :op1 "Mcl-1") :xref (x4 / xref :value "UNIPROT:MCL1_HUMAN" :prob "0.592")) :op2 (p2 / protein :name (n4 / name :op1 "Bcl-2") :xref (x / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.701")) :op3 (p3 / protein :name (n5 / name :op1 "Bcl-xL") :degree (e3 / extent :quant (l / less :degree (m / more))) :xref (x2 / xref :value "UNIPROT:BCL9_HUMAN" :prob "0.232")) :ARG0-of (f / favor-01 :ARG1 (s / survive-01))) :location (c2 / cell-line :name (n6 / name :op1 "IEC-6"))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5B"))) # ::id pmid_1901_4680.199 # ::date 2015-06-17T16:42:31 # ::file pmid_1901_4680_199.txt # ::snt Our results confirm and extend previous observations [47,48] by demonstrating that both MEK1 and MEK2 isoforms share the property to induce the accumulation of Bcl-2 family pro-survival members. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (c / confirm-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (o / observe-01 :mod (p / previous))) :op2 (e / extend-01 :ARG0 t :ARG1 o) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "47" :op2 "48")))) :manner (d2 / demonstrate-01 :ARG0 t :ARG1 (s / share-01 :ARG0 (a3 / and :op1 (i / isoform :mod (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (i2 / isoform :mod (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (p3 / property :mod (i3 / induce-01 :ARG0 a3 :ARG2 (a4 / accumulate-01 :ARG1 (m / member :ARG1-of (i4 / include-91 :ARG2 (p4 / protein-family :name (n3 / name :op1 "Bcl-2"))) :ARG0-of (f2 / favor-01 :ARG1 (s2 / survive-01))))))))) # ::id pmid_1901_4680.200 # ::date 2015-06-17T16:56:10 # ::file pmid_1901_4680_200.txt # ::snt Reciprocally, induction of the BH3-only pro-apoptotic protein Bim was completely suppressed in cells expressing MEK1DD or MEK2DD (Fig. 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / suppress-01 :ARG1 (i / induce-01 :ARG2 (p / protein :name (n / name :op1 "BH3-only" :op2 "protein" :op3 "Bim") :ARG0-of (f / favor-01 :ARG1 (a / apoptosis)) :xref (x / xref :value "UNIPROT:BOP_HUMAN" :prob "0.382"))) :location (c / cell :ARG3-of (e / express-03 :ARG2 (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.283")) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.283"))))) :degree (c2 / complete-01) :manner (r / reciprocal) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5C"))) # ::id pmid_1901_4680.201 # ::date 2015-06-17T17:14:40 # ::file pmid_1901_4680_201.txt # ::snt This finding is consistent with previous reports documenting the role of the ERK1/2 MAP kinase pathway in promoting the degradation of Bim [49,50]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (c / consistent-01 :ARG1 (f / find-01 :mod (t / this)) :ARG2 (t2 / thing :ARG1-of (r / report-01) :mod (p / previous) :ARG0-of (d / document-01 :ARG1 (r2 / role :poss (p2 / pathway :name (n / name :op1 "ERK1/2" :op2 "MAP-kinase")) :topic (p3 / promote-01 :ARG0 p2 :ARG1 (d2 / degrade-01 :ARG1 (p4 / protein :name (n2 / name :op1 "Bim") :xref (x / xref :value "UNIPROT:BIM_HUMAN_PROMOTER_PROBE" :prob "0.671"))))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "49" :op2 "50"))))) # ::id pmid_1901_4680.202 # ::date 2015-06-17T17:25:00 # ::file pmid_1901_4680_202.txt # ::snt MEK1 or MEK2 activation had no significant effect on the expression of the pro-apoptotic proteins Bax and Bak in these cells (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / affect-01 :polarity "-" :ARG0 (a2 / activate-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x3 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (e3 / express-03 :ARG2 (a3 / and :op1 (p / protein :name (n3 / name :op1 "Bax") :xref (x2 / xref :value "UNIPROT:A0A0C4MVT1_HUMAN" :prob "1.001")) :op2 (p2 / protein :name (n4 / name :op1 "Bak") :xref (x / xref :value "UNIPROT:BAK_HUMAN" :prob "0.603")) :ARG0-of (f / favor-01 :ARG1 (a4 / apoptosis))) :ARG3 (c / cell :mod (t / this))) :ARG1-of (s / significant-02) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity "-")))) # ::id pmid_1901_4680.203 # ::date 2015-06-17T17:33:44 # ::file pmid_1901_4680_203.txt # ::snt Silencing of MEK2 expression markedly inhibits the proliferation of human colon cancer cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / inhibit-01 :ARG0 (s / silence-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (p / proliferate-01 :ARG0 (c / cell :mod (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer") :mod (h / human)))) :degree (m / marked)) # ::id pmid_1901_4680.204 # ::date 2015-06-17T17:39:47 # ::file pmid_1901_4680_204.txt # ::snt The results presented above clearly demonstrate that constitutive activation of either MEK isoform, MEK1 or MEK2, is sufficient to fully transform intestinal epithelial cells to the metastatic stage. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (d / demonstrate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :ARG1-of (p / present-01 :location (a / above))) :ARG1 (s / suffice-01 :ARG0 (a2 / activate-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG1-of (m / mean-01 :ARG2 (i / isoform :mod (e3 / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :mod (e4 / either)) :mod (c / constitutive)) :ARG1 (t2 / transform-01 :ARG0 a2 :ARG1 (c2 / cell :mod (e5 / epithelium :mod (i2 / intestine))) :ARG2 (s2 / stage-02 :ARG2 (m2 / metastasize-101)) :degree (f / full))) :ARG1-of (c3 / clear-06)) # ::id pmid_1901_4680.205 # ::date 2015-06-17T17:52:08 # ::file pmid_1901_4680_205.txt # ::snt We next wanted to determine if human colon cancer cells depend on the activity of MEK isoforms for cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (w / want-01 :ARG0 (w2 / we) :ARG1 (d / determine-01 :ARG0 w2 :ARG1 (d2 / depend-01 :mode "interrogative" :ARG0 (c / cell :mod (d4 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colon" :op2 "cancer") :mod (h / human))) :ARG1 (a / activity-06 :ARG0 (i / isoform :mod (e / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :purpose (p / proliferate-01 :ARG0 c))) :time (n3 / next)) # ::id pmid_1901_4680.206 # ::date 2015-06-17T18:09:15 # ::file pmid_1901_4680_206.txt # ::snt Several human colon carcinoma cell lines display constitutive phosphorylation of ERK1/ERK2 MAP kinases [20], likely resulting from activation of MEK1/MEK2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (d / display-01 :ARG0 (c / cell-line :mod (c2 / carcinoma :mod (c3 / colon :part-of (h / human))) :quant (s / several)) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/ERK2" :op2 "MAP-kinase")) :mod (c4 / constitutive)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "20"))) :ARG2-of (r / result-01 :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1/MEK2"))) :ARG1-of (l / likely-01))) # ::id pmid_1901_4680.207 # ::date 2015-06-17T18:16:31 # ::file pmid_1901_4680_207.txt # ::snt The HCT116 cell line, which represents one of the best studied model of colorectal cancer cells, display constitutive activation of the two MEK isoforms (Fig. 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (d / display-01 :ARG0 (c / cell-line :name (n / name :op1 "HCT116") :ARG0-of (r / represent-01 :ARG1 (m / model :quant "1" :ARG1-of (i / include-91 :ARG2 (m2 / model :ARG1-of (s / study-01 :ARG1-of (w / well-09)) :mod (c2 / cell :mod (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer")))))))) :ARG1 (a / activate-01 :ARG1 (i2 / isoform :quant "2" :mod (e / enzyme :name (n3 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (c4 / constitutive)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_1901_4680.208 # ::date 2015-06-17T18:35:21 # ::file pmid_1901_4680_208.txt # ::snt To assess the individual roles of MEK1 and MEK2, we expressed short-hairpin (sh) RNAs specifically targeting MEK1 or MEK2 gene in HCT116 cells using VSV-pseudotyped lentiviral vectors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / express-03 :ARG1 (n6 / nucleic-acid :name (n / name :op1 "short-hairpin" :op2 "RNA") :ARG0-of (t / target-01 :ARG1 (o / or :op1 (g / gene :name (n2 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n3 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG1-of (s / specific-02))) :ARG3 (c / cell-line :name (n4 / name :op1 "HCT116")) :manner (u / use-01 :ARG0 (w / we) :ARG1 (v / vector :name (n5 / name :op1 "VSV-pseudotyped" :op2 "lentiviral" :op3 "vector"))) :purpose (a / assess-01 :ARG0 w :ARG1 (r2 / role :poss (a2 / and :op1 g :op2 g2) :mod (i / individual)))) # ::id pmid_1901_4680.209 # ::date 2015-06-17T18:51:12 # ::file pmid_1901_4680_209.txt # ::snt We tested the effect of 5 distinct shRNAs for MEK1 and 3 shRNAs for MEK2, using as control a GFP-encoding vector. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (a / and :op1 (a2 / affect-01 :ARG0 (n6 / nucleic-acid :quant "5" :name (n / name :op1 "shRNA") :mod (d / distinct)) :ARG1 (g / gene :name (n2 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (a3 / affect-01 :ARG0 (n7 / nucleic-acid :quant "3" :name (n3 / name :op1 "shRNA")) :ARG1 (g2 / gene :name (n4 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :manner (u / use-01 :ARG0 w :ARG1 (v / vector :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n5 / name :op1 "GFP") :xref (x2 / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342"))) :ARG2-of (c / control-01)))) # ::id pmid_1901_4680.210 # ::date 2015-06-17T18:59:05 # ::file pmid_1901_4680_210.txt # ::snt We selected the two most efficient shRNAs to MEK1 and MEK2 genes (Additional file 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 17, 2015 (s / select-01 :ARG0 (w / we) :ARG1 (n4 / nucleic-acid :quant "2" :name (n / name :op1 "shRNA") :ARG1-of (e / efficient-01 :degree (m / most)) :ARG0-of (a / affect-01 :ARG1 (a2 / and :op1 (g / gene :name (n2 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n3 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "3" :ARG1-of (a3 / add-02)))) # ::id pmid_1901_4680.211 # ::date 2015-06-17T19:06:35 # ::file pmid_1901_4680_211.txt # ::snt A non-silencing inactive MEK1 shRNA was used as additional negative control in these experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (u / use-01 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "shRNA") :mod (g / gene :name (n2 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :ARG1-of (a / activate-01 :polarity "-") :ARG0-of (s / silence-01 :polarity "-") :ARG2-of (c / control-01 :ARG2-of (n3 / negative-01)) :ARG1-of (a2 / add-02)) :location (e / experiment-01 :mod (t / this))) # ::id pmid_1901_4680.212 # ::date 2015-06-17T19:14:46 # ::file pmid_1901_4680_212.txt # ::snt The efficiency of transduction estimated by GFP immunofluorescence was over 90%, and therefore the experiments were performed without cellular selection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / cause-01 :ARG0 (e / estimate-01 :ARG0 (i / immunofluoresce-01 :ARG2 (p / protein :name (n2 / name :op1 "GFP") :xref (x / xref :value "UNIPROT:FPGT_HUMAN" :prob "0.342"))) :ARG1 (e2 / efficient-01 :ARG1 (t / transduce-01)) :ARG2 (o / over :quant (p2 / percentage-entity :value "90"))) :ARG1 (p3 / perform-01 :ARG1 (e3 / experiment-01) :manner (s / select-01 :polarity "-" :ARG1 (c2 / cell)))) # ::id pmid_1901_4680.213 # ::date 2015-06-17T19:24:47 # ::file pmid_1901_4680_213.txt # ::snt As shown by immunoblot analysis, lentivirus-mediated delivery of MEK1 shRNAs resulted in complete silencing of MEK1 expression with no effect on MEK2, whereas the two MEK2 shRNAs markedly knocked-down MEK2 expression without affecting MEK1 isoform (Fig. 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / result-01 :ARG1 (d / deliver-01 :ARG1 (n8 / nucleic-acid :name (n / name :op1 "shRNA") :mod (g / gene :name (n2 / name :op1 "MEK1") :xref (x4 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG1-of (m / mediate-01 :ARG0 (l / lentivirus))) :ARG2 (s / silence-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :degree (c2 / complete-01) :ARG0-of (a / affect-01 :polarity "-" :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG2 (k / knock-down-02 :ARG0 (n9 / nucleic-acid :quant "2" :name (n5 / name :op1 "shRNA") :mod (g2 / gene :name (n6 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG1 (e4 / express-03 :ARG2 e3) :ARG0-of (a2 / affect-01 :polarity "-" :ARG1 (e5 / enzyme :name (n10 / name :op1 "MEK1") :mod (i / isoform) :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :degree (m2 / marked)) :ARG1-of (s2 / show-01 :ARG0 (a3 / analyze-01 :manner (i2 / immunoblot-01))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id pmid_1901_4680.214 # ::date 2015-06-17T19:47:42 # ::file pmid_1901_4680_214.txt # ::snt We then analyzed the functional consequence of MEK1 or MEK2 silencing on the proliferation rate of the cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (c / consequence :ARG1-of (c2 / cause-01 :ARG0 (s / silence-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :topic (r / rate :degree-of (p / proliferate-01 :ARG0 (c3 / cell))) :mod (f / function-01)) :mod (t / then)) # ::id pmid_1901_4680.215 # ::date 2015-06-17T19:57:10 # ::file pmid_1901_4680_215.txt # ::snt Strikingly, lowering of MEK2 expression with the two shRNAs completely suppressed the proliferation of HCT116 cells, whereas MEK1 shRNAs exerted a significant but much weaker effect (Fig. 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (s / suppress-01 :ARG0 (l / lower-05 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :instrument (n7 / nucleic-acid :quant "2" :name (n2 / name :op1 "shRNA")))) :ARG1 (p / proliferate-01 :ARG0 (c2 / cell-line :name (n3 / name :op1 "HCT116"))) :degree (c3 / complete)) :ARG2 (e3 / exert-01 :ARG0 (n6 / nucleic-acid :name (n4 / name :op1 "shRNA") :mod (g / gene :name (n5 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG1 (a / affect-01 :ARG1-of (s2 / significant-02 :ARG1-of (c4 / contrast-01 :ARG2 (w / weak-02 :degree (m / more :degree (m2 / much))))))) :manner (s3 / strike-04) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id pmid_1901_4680.216 # ::date 2015-06-17T20:07:52 # ::file pmid_1901_4680_216.txt # ::snt The extent of inhibition observed with MEK2 shRNAs was similar to that obtained by treating cells with the non-selective MEK1/2 inhibitor U0126. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / resemble-01 :ARG1 (e / extent :degree-of (i / inhibit-01) :ARG1-of (o / observe-01 :topic (n5 / nucleic-acid :name (n / name :op1 "shRNA") :mod (g / gene :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG2 (e2 / extent :degree-of i :ARG1-of (o2 / obtain-01 :manner (t / treat-04 :ARG1 (c / cell) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "U0126") :ARG0-of (i2 / inhibit-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK1/2"))) :ARG0-of (s / select-01 :polarity "-") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")))))) # ::id pmid_1901_4680.217 # ::date 2015-06-17T20:26:26 # ::file pmid_1901_4680_217.txt # ::snt We also showed that silencing of MEK1 or MEK2 expression significantly reduces the extent of ERK1 and ERK2 activating phosphorylation (Fig. 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (r / reduce-01 :ARG0 (s2 / silence-01 :ARG1 (e / express-03 :ARG2 (o / or :op1 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG1 (e4 / extent :degree-of (p / phosphorylate-01 :ARG0-of (a / activate-01 :ARG1 (a2 / and :op1 (e5 / enzyme :name (n3 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e6 / enzyme :name (n4 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))))) :ARG2 (s3 / significant-02)) :mod (a3 / also) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7"))) # ::id pmid_1901_4680.218 # ::date 2015-06-17T20:33:27 # ::file pmid_1901_4680_218.txt # ::snt To verify whether this differential contribution of MEK isoforms could be generalized to other colorectal cancer cells, we examined the impact of MEK1 or MEK2 silencing on the proliferation of two other human colon cancer cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (i / impact-01 :ARG0 (s / silence-01 :ARG1 (o / or :op1 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (p / proliferate-01 :ARG0 (c / cell-line :quant "2" :mod (o2 / other) :mod (d4 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colorectal" :op2 "cancer") :mod (h / human))))) :purpose (v / verify-01 :ARG0 w :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (g / generalize-01 :ARG1 (c3 / contribute-01 :ARG0 (i2 / isoform :mod (e4 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (d2 / differential) :mod (t / this)) :ARG2 (c4 / cell :mod d4))))) # ::id pmid_1901_4680.219 # ::date 2015-06-17T20:47:59 # ::file pmid_1901_4680_219.txt # ::snt We specifically chose the human colon carcinoma cell lines SW480 (which harbors a KRAS mutation like HCT116) and HT-29 (harboring a BRAF mutation). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / choose-01 :ARG0 (w / we) :ARG1 (a / and :op1 (c2 / cell-line :name (n / name :op1 "SW480") :ARG0-of (h / harbor-01 :ARG1 (m / mutate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG1-of (r / resemble-01 :ARG2 (c3 / cell-line :name (n3 / name :op1 "HCT116")))) :op2 (c4 / cell-line :name (n4 / name :op1 "HT-29") :ARG0-of (h2 / harbor-01 :ARG1 (m2 / mutate-01 :ARG2 (g / gene :name (n5 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :mod (c5 / carcinoma :mod (c6 / colon :part-of (h3 / human)))) :ARG1-of (s / specific-02)) # ::id pmid_1901_4680.220 # ::date 2015-06-17T20:56:49 # ::file pmid_1901_4680_220.txt # ::snt SW480 cells display a comparable expression pattern of MEK1 and MEK2 proteins as HCT116 cells (Fig. 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (d / display-01 :ARG0 (c / cell-line :name (n / name :op1 "SW480")) :ARG1 (p / pattern-01 :ARG1 (e3 / express-03 :ARG2 (a / and :op1 (e / enzyme :name (n2 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1-of (c2 / compare-01 :ARG2 (c3 / cell-line :name (n4 / name :op1 "HCT116")) :ARG1-of (p2 / possible-01))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_1901_4680.221 # ::date 2015-06-17T21:06:45 # ::file pmid_1901_4680_221.txt # ::snt Similar to HCT116 cells, knock-down of MEK2 expression dramatically suppressed the proliferation of SW480 cells, whereas MEK1 silencing induced a significant but much lower decrease of cell proliferation (Fig. 6C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c / contrast-01 :ARG1 (s / suppress-01 :ARG0 (k / knock-down-02 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (p / proliferate-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "SW480"))) :degree (d / dramatic)) :ARG2 (i / induce-01 :ARG0 (s2 / silence-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG2 (d2 / decrease-01 :ARG1 p :ARG1-of (s3 / significant-02 :ARG1-of (c3 / contrast-01 :ARG2 (l / low-04 :degree (m / more :quant (m2 / much))))))) :ARG1-of (r / resemble-01 :ARG2 (c4 / cell-line :name (n4 / name :op1 "HCT116"))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id pmid_1901_4680.222 # ::date 2015-06-17T21:18:32 # ::file pmid_1901_4680_222.txt # ::snt Similar results were obtained in HT-29 cells, except that the inhibitory effect of MEK1 shRNAs on proliferation was quantitatively more important than on HCT116 and SW480 cells (Fig. 6D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (o / obtain-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :location (c / cell-line :name (n / name :op1 "HT-29")) :ARG2-of (e / except-01 :ARG1 (a / affect-01 :ARG0 (n6 / nucleic-acid :name (n2 / name :op1 "shRNA") :mod (g / gene :name (n3 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG1 (p / proliferate-01) :ARG2 (i / inhibit-01) :mod (i2 / important :degree (m / more) :manner (q / quantitative)) :compared-to (a2 / affect-01 :ARG0 n6 :ARG1 (a3 / and :op1 (c2 / cell-line :name (n4 / name :op1 "HCT116")) :op2 (c3 / cell-line :name (n5 / name :op1 "SW480")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6D"))) # ::id pmid_1901_4680.223 # ::date 2015-06-18T00:09:55 # ::file pmid_1901_4680_223.txt # ::snt This observation could be explained by the much higher expression of MEK1 in the HT-29 cell line as compared to HCT116 or SW480 cells (Fig. 6A), which may have a more important contribution to total MEK1/2 signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (p / possible-01 :ARG1 (e / explain-01 :ARG1 (t / thing :ARG1-of (o / observe-01) :mod (t2 / this)) :manner (e2 / express-03 :ARG2 (e3 / enzyme :wiki "MAP2K1" :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :ARG3 (c / cell-line :wiki "-" :name (n2 / name :op1 "HT-29")) :compared-to (e4 / express-03 :ARG2 e3 :ARG3 (o2 / or :op1 (c2 / cell-line :wiki "-" :name (n3 / name :op1 "HCT116")) :op2 (c3 / cell-line :wiki "-" :name (n4 / name :op1 "SW480")))) :ARG0-of (c4 / contribute-01 :ARG2 (s / signal-07 :ARG0 (e5 / enzyme :wiki "Mitogen-activated_protein_kinase_kinase" :name (n5 / name :op1 "MEK1/2")) :mod (t3 / total-01)) :mod (i / important :degree (m / more)) :ARG1-of (p2 / possible-01)) :ARG1-of (h / high-02 :degree (m2 / more :quant (m3 / much))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_1901_4680.224 # ::date 2015-06-18T00:24:32 # ::file pmid_1901_4680_224.txt # ::snt However, the single inactivation of MEK2 was still capable of abolishing the proliferation of HT-29 cells even in the presence of high MEK1 levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG2 (c2 / capable-01 :ARG1 (a / activate-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :ARG1-of (s / single-02)) :ARG2 (a2 / abolish-01 :ARG0 a :ARG1 (p / proliferate-01 :ARG0 (c3 / cell-line :name (n2 / name :op1 "HT-29")))) :concession (l / level :quant-of (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :ARG1-of (h / high-02)) :mod (s2 / still))) # ::id pmid_1901_4680.225 # ::date 2015-06-18T00:32:27 # ::file pmid_1901_4680_225.txt # ::snt For all colorectal cancer cell lines tested, the inhibition of proliferation seen with MEK2 shRNAs was comparable to that achieved with the MEK1/2 inhibitor U0126. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (c / compare-01 :ARG1 (i / inhibit-01 :ARG0 (n6 / nucleic-acid :name (n / name :op1 "shRNA") :mod (g / gene :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG1 (p2 / proliferate-01) :ARG1-of (s / see-01)) :ARG2 (i2 / inhibit-01 :ARG1 p2 :ARG1-of (a / achieve-01 :instrument (s2 / small-molecule :name (n3 / name :op1 "U0126") :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "MEK1/2"))) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))))) :location (c2 / cell-line :ARG1-of (t / test-01) :mod (a2 / all) :mod (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal" :op2 "cancer")))) # ::id pmid_1901_4680.226 # ::date 2015-06-18T00:52:30 # ::file pmid_1901_4680_226.txt # ::snt To further extend our investigation to non-colorectal carcinomas, we tested the effect of MEK1 and MEK2 shRNAs on the human breast adenocarcinoma cell line MDA-MB-231, which exhibit strong constitutive activation of MEK1/MEK2 signaling (Fig. 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (n7 / nucleic-acid :name (n / name :op1 "shRNA") :mod (g / gene :name (n2 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA") :mod (g2 / gene :name (n4 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG1 (c / cell-line :name (n5 / name :op1 "MDA-MB-231") :mod (a3 / adenocarcinoma :mod (b / breast :part-of (h / human))) :ARG0-of (e / exhibit-01 :ARG1 (a4 / activate-01 :ARG1 (s / signal-07 :ARG0 (e2 / enzyme :name (n6 / name :op1 "MEK1/MEK2"))) :mod (c2 / constitutive) :degree (s2 / strong))))) :purpose (e3 / extend-01 :ARG0 w :ARG1 (i / investigate-01 :ARG0 w :ARG1 (c3 / carcinoma :mod (c4 / colorectal :polarity "-"))) :mod (f / further)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6A"))) # ::id pmid_1901_4680.227 # ::date 2015-06-18T01:00:44 # ::file pmid_1901_4680_227.txt # ::snt Interestingly, the MEK2 shRNA-06 completely inhibited the proliferation of MDA-MB-231 cells to the same extent as the drug inhibitor U0126 (Additional file 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG0 (n5 / nucleic-acid :name (n / name :op1 "shRNA-06") :mod (g / gene :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG1 (p / proliferate-01 :ARG0 (c / cell-line :name (n3 / name :op1 "MDA-MB-231"))) :degree (e / extent :ARG1-of (s / same-01 :ARG2 (e2 / extent :degree-of (i2 / inhibit-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "U0126") :ARG0-of (i3 / inhibit-01 :ARG1 (d / drug)) :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1 p)))) :degree (c2 / complete) :manner (i4 / interesting) :ARG1-of (d2 / describe-01 :ARG0 (f / file :mod "4" :ARG1-of (a / add-02)))) # ::id pmid_1901_4680.228 # ::date 2015-06-18T01:10:49 # ::file pmid_1901_4680_228.txt # ::snt The other MEK2 shRNA-08 also markedly but not completely inhibited cell proliferation, consistent with its lower silencing activity in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / inhibit-01 :ARG0 (n3 / nucleic-acid :name (n / name :op1 "shRNA-08") :mod (g / gene :name (n2 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")) :mod (o / other)) :ARG1 (p / proliferate-01 :ARG0 (c2 / cell)) :degree (m / marked :ARG1-of (c / contrast-01 :ARG2 (c3 / complete :polarity "-"))) :mod (a / also) :ARG1-of (c4 / consistent-01 :ARG2 (a2 / activity-06 :ARG0 n3 :ARG1 (s / silence-01) :ARG1-of (l / low-04 :degree (m2 / more)) :location (c5 / cell :mod (t / this))))) # ::id pmid_1901_4680.229 # ::date 2015-06-18T01:18:59 # ::file pmid_1901_4680_229.txt # ::snt Expression of MEK1 shRNAs suppressed cell proliferation by approximately 50%. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (s / suppress-01 :ARG0 (e / express-03 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "shRNA") :mod (g / gene :name (n2 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")))) :ARG1 (p / proliferate-01 :ARG0 (c / cell)) :quant (a / approximately :op1 (p2 / percentage-entity :value "50"))) # ::id pmid_1943_2991.1 # ::date 2015-08-16T01:00:09 # ::file pmid_1943_2991_1.txt # ::snt Identification of the B-Raf/Mek/Erk MAP kinase pathway as a target for all-trans retinoic acid during skin cancer promotion (PMID:19432991) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / identify-01 :ARG1 (p / pathway :name (n2 / name :op1 "B-Raf/Mek/Erk") :mod (k / kinase :name (n3 / name :op1 "MAP") :xref (x / xref :value "UNIPROT:MOTI_HUMAN" :prob "1.002"))) :ARG2 (t / target-01 :ARG0 (s3 / small-molecule :name (n5 / name :op1 "all-trans-retinoic-acid") :xref (x1 / xref :value "PUBCHEM:444795" :prob "20.529016")) :ARG1 p :time (p2 / promote-01 :ARG1 (d / disease :wiki "Skin_cancer" :name (n / name :op1 "skin" :op2 "cancer")))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID19432991"))) # ::id pmid_1943_2991.6 # ::date 2015-08-16T01:21:32 # ::file pmid_1943_2991_6.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 16, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1943_2991.7 # ::date 2015-08-16T01:22:05 # ::file pmid_1943_2991_7.txt # ::snt We have used the 2-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis model to investigate the chemopreventive effects of ATRA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (m / model :mod (c / carcinogenesis :mod (s / skin :poss (m2 / mouse))) :mod (s2 / slash :op1 (s4 / small-molecule :name (n / name :op1 "dimethylbenzanthracene") :mod (s3 / stage :quant "2") :xref (x2 / xref :value "PUBCHEM:6001" :prob "18.167522")) :op2 (s5 / small-molecule :name (n2 / name :op1 "12-O-tetradecanoylphorbol-13-acetate") :xref (x1 / xref :value "PUBCHEM:27924" :prob "19.779699")))) :ARG2 (i / investigate-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (s6 / small-molecule :name (n4 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG2 (p / prevent-01 :ARG1 (d / disease :wiki "Breast_cancer" :name (n3 / name :op1 "breast" :op2 "cancer")) :mod (c2 / chemistry))))) # ::id pmid_1943_2991.8 # ::date 2015-08-16T01:33:39 # ::file pmid_1943_2991_8.txt # ::snt We have compared the gene expression profiles of control skin to skin subjected to the 2-stage protocol, with or without ATRA, using Affymetrix 430 2.0 DNA microarrays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (c / compare-01 :ARG0 (w / we) :ARG1 (p / profile-01 :ARG1 (s / skin :ARG0-of (c2 / control-01)) :topic (e / express-03 :ARG2 (g / gene))) :ARG2 (p2 / profile-01 :ARG1 (s2 / skin :ARG1-of (s3 / subject-01 :ARG2 (o / or :op1 (p3 / protocol :mod (s4 / stage :quant "2") :accompanier (s5 / small-molecule :name (n / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232"))) :op2 p3))) :topic e) :instrument (m / microarray :mod "430" :mod "2.0" :mod (n2 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")) :mod (c3 / company :name (n3 / name :op1 "Affymetrix")))) # ::id pmid_1943_2991.9 # ::date 2015-08-16T01:54:47 # ::file pmid_1943_2991_9.txt # ::snt Approximately 49% of the genes showing altered expression with TPA treatment are conversely affected when ATRA is co-administered. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (a3 / affect-01 :ARG1 (g / gene :quant (p2 / percentage-entity :value "49" :ARG1-of (i / include-91 :ARG2 (g2 / gene :ARG0-of (s / show-01 :ARG1 (e / express-03 :ARG1-of (a2 / alter-01)) :condition (t / treat-04 :ARG2 (s3 / small-molecule :name (n / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082"))))) :ARG3 (a / approximate-01)))) :manner (c / converse) :condition (a4 / administer-01 :ARG1 (a5 / and :op1 s3 :op2 (s2 / small-molecule :name (n2 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232"))))) # ::id pmid_1943_2991.10 # ::date 2015-08-16T02:02:18 # ::file pmid_1943_2991_10.txt # ::snt The activity of these genes, which we refer to as 'counter-regulated', may contribute to chemoprevention by ATRA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (p / possible-01 :ARG1 (c / contribute-01 :ARG1 (a / activity-06 :ARG0 (g / gene :mod (t / this)) :ARG1-of (r / refer-01 :ARG0 (w / we) :ARG2 (r2 / regulate-01 :ARG1 a :ARG1-of (c2 / counter-01)))) :ARG2 (p2 / prevent-01 :ARG1 (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")) :ARG3 (s / small-molecule :name (n2 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")) :mod (c3 / chemistry)))) # ::id pmid_1943_2991.11 # ::date 2015-08-16T02:08:09 # ::file pmid_1943_2991_11.txt # ::snt The counter-regulated genes have been clustered into functional categories and bioinformatic analysis has identified the B-Raf/Mek/Erk branch of the MAP kinase pathway as one containing several genes whose upregulation by TPA is blocked by ATRA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (c / cluster-01 :ARG1 (g / gene :ARG1-of (r / regulate-01 :ARG1-of (c2 / counter-01))) :ARG2 (c3 / category :ARG0-of (f / function-01))) :op2 (i / identify-01 :ARG0 (a2 / analyze-01 :mod (b / bioinformatic)) :ARG1 (b2 / branch :mod (s / slash :op1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "Mek") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243")) :op3 (e3 / enzyme :name (n3 / name :op1 "Erk") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))) :part-of (p / pathway :name (n4 / name :op1 "MAP" :op2 "kinase"))) :ARG2 (c4 / contain-01 :ARG0 b2 :ARG1 (g2 / gene :quant (s2 / several) :ARG1-of (u / upregulate-01 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "TPA") :xref (x3 / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1-of (b3 / block-01 :ARG0 (s4 / small-molecule :name (n6 / name :op1 "ATRA") :xref (x4 / xref :value "PUBCHEM:444795" :prob "17.251232")))))))) # ::id pmid_1943_2991.12 # ::date 2015-08-16T03:18:18 # ::file pmid_1943_2991_12.txt # ::snt We also show that ATRA blocks signaling through this pathway, as revealed by immunohistochemistry and Western blotting. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (s / show-01 :ARG0 (w2 / we) :ARG1 (b / block-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1 (s2 / signal-07 :ARG0 (p / pathway :mod (t / this)))) :ARG1-of (r / reveal-01 :ARG0 (a2 / and :op1 (i / immunohistochemistry) :op2 (i2 / immunoblot-01))) :mod (a / also)) # ::id pmid_1943_2991.13 # ::date 2015-08-17T05:52:16 # ::file pmid_1943_2991_13.txt # ::snt Finally, we found that blocking the B-Raf/Mek/Erk pathway with a pharmacological inhibitor, Sorafenib (BAY43-9006), induces squamous differentiation of existing skin SCCs formed in the 2-stage model. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (f4 / find-01 :ARG0 (w / we) :ARG1 (i2 / induce-01 :ARG0 (b / block-01 :ARG1 (p / pathway :name (n / name :op1 "B-Raf/Mek/Erk")) :ARG3 (s5 / small-molecule :name (n2 / name :op1 "Sorafenib") :ARG0-of (i / inhibit-01) :mod (p2 / pharmacology) :ARG1-of (n4 / name-01 :ARG2 (n6 / name :op1 "BAY43-9006")) :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406"))) :ARG2 (d / differentiate-01 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "carcinoma") :mod (c / cell) :mod (s2 / squamous) :mod (s3 / skin) :ARG1-of (f3 / form-01 :location (m / model :ARG0-of (h / have-03 :ARG1 (s4 / stage :quant "2"))))) :mod (s / squamous))) :time (f5 / final)) # ::id pmid_1943_2991.49 # ::date 2015-08-17T06:08:21 # ::file pmid_1943_2991_49.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 17, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1943_2991.50 # ::date 2015-08-17T06:08:53 # ::file pmid_1943_2991_50.txt # ::snt ATRA reverses many of the gene expression changes caused by TPA in mouse skin: microarray-based analysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (m2 / multi-sentence :snt1 (r / reverse-01 :ARG0 (s2 / small-molecule :wiki "Tretinoin" :name (n / name :op1 "ATRA") :xref (x1 / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1 (c / change-01 :ARG1 (e / express-03 :ARG2 (g / gene)) :ARG1-of (c2 / cause-01 :ARG0 (s3 / small-molecule :wiki "12-O-Tetradecanoylphorbol-13-acetate" :name (n2 / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082")) :location (s / skin :mod (m / mouse))) :mod (m3 / many) :ARG1-of (i / include-91 :ARG2 (c3 / change-01 :ARG1 (e2 / express-03 :ARG2 (g3 / gene)))))) :snt2 (a2 / analyze-01 :ARG1-of (b / base-02 :ARG2 (m4 / microarray)))) # ::id pmid_1943_2991.51 # ::date 2015-08-17T06:33:06 # ::file pmid_1943_2991_51.txt # ::snt Our group and others have shown that ATRA can suppress tumor promotion by TPA in the 2-stage model, but only as long as it is being co-administered with TPA [9,20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (s / show-01 :ARG0 (a2 / and :op1 (g / group :poss (w / we)) :op2 (o / other)) :ARG1 (p / possible-01 :ARG1 (s2 / suppress-01 :ARG0 (s4 / small-molecule :name (n / name :op1 "ATRA") :xref (x1 / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1 (p2 / promote-01 :ARG0 (s5 / small-molecule :name (n2 / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1 (t / tumor)) :location (m / model :ARG0-of (h / have-03 :ARG1 (s3 / stage :quant "2"))) :condition (a / as-long-as :op1 (a4 / administer-01 :ARG1 (a5 / and :op1 s4 :op2 s5) :mod (o2 / only))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a6 / and :op1 "9" :op2 "20"))))) # ::id pmid_1943_2991.52 # ::date 2015-08-17T06:42:55 # ::file pmid_1943_2991_52.txt # ::snt If ATRA treatment is discontinued while TPA treatment is maintained, the mice showed a linear increase in tumor multiplicity with time after stopping the last treatment [20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (s / show-01 :ARG0 (m / mouse) :ARG1 (i / increase-01 :ARG1 (m2 / multiply-01 :ARG1 (t / tumor)) :mod (l / linear) :ARG0-of (h / have-03 :ARG1 (t2 / time :time (a / after :op1 (s2 / stop-01 :ARG1 (t3 / treat-04 :mod (l2 / last))))))) :condition (a2 / and :op1 (d / discontinue-01 :ARG1 (t4 / treat-04 :ARG2 (s3 / small-molecule :name (n / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")))) :op2 (m3 / maintain-01 :ARG1 (t5 / treat-04 :ARG2 (s4 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082"))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "20")))) # ::id pmid_1943_2991.53 # ::date 2015-08-17T06:50:45 # ::file pmid_1943_2991_53.txt # ::snt This suggests that ATRA may be primarily acting to suppress promotion by TPA, but has little apparent effect on initiation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (c / contrast-01 :ARG1 (s / suggest-01 :ARG0 (t / this) :ARG1 (p / possible-01 :ARG1 (a / act-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")) :purpose (s2 / suppress-01 :ARG0 s3 :ARG1 (p2 / promote-01 :ARG0 (s4 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :mod (p4 / primary)))) :ARG2 (a3 / affect-01 :ARG0 s3 :ARG1 (i / initiate-01 :ARG1 p2) :degree (l / little) :ARG1-of (a4 / appear-01))) # ::id pmid_1943_2991.54 # ::date 2015-08-17T06:57:15 # ::file pmid_1943_2991_54.txt # ::snt In order to explore the mechanism of the chemopreventive effect of ATRA at an early step during TPA-induced tumor promotion, we performed Affymetrix DNA microarray analyses for mouse skin subjected to the 2-stage protocol for 3 weeks, with and without co-administration of ATRA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (p / perform-01 :ARG0 (w2 / we) :ARG1 (o / or :op1 (a2 / and :op1 (a / analyze-01 :ARG1 (s / skin :mod (m / mouse) :ARG1-of (s2 / subject-01 :ARG2 (p2 / protocol :ARG0-of (h / have-03 :ARG1 (s3 / stage :quant "2"))) :duration (t2 / temporal-quantity :quant "3" :unit (w3 / week)))) :mod (m3 / microarray :mod (n / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")) :source (c / company :name (n2 / name :op1 "Affymetrix")))) :op2 (a3 / administer-01 :ARG1 (s5 / small-molecule :name (n3 / name :op1 "ATRA") :xref (x1 / xref :value "PUBCHEM:444795" :prob "17.251232")))) :op2 (a5 / and :op1 a :op2 (a6 / administer-01 :polarity "-" :ARG1 s5))) :purpose (e / explore-01 :ARG0 w2 :ARG1 (m2 / mechanism :poss (a7 / affect-01 :ARG0 s5 :ARG2 (p3 / prevent-01 :ARG1 (d / disease :wiki "Breast_cancer" :name (n7 / name :op1 "breast" :op2 "cancer")) :mod (c2 / chemistry)) :time (s4 / step :mod (e2 / early) :subevent-of (p4 / promote-01 :ARG1 (t / tumor) :ARG2-of (i / induce-01 :ARG0 (s6 / small-molecule :name (n5 / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082"))))))))) # ::id pmid_1943_2991.55 # ::date 2015-08-18T01:39:53 # ::file pmid_1943_2991_55.txt # ::snt We chose the 3 week time point because this precedes the appearance of tumors but is after the TPA treated skin exhibits pronounced hyperplasia (Fig. 1); and this time point proved to be advantageous for identifying genes regulated by TPA plus retinoid combinations in mouse skin in a previous study from our laboratory [20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (a3 / and :op1 (c / choose-01 :ARG0 (w2 / we) :ARG1 (p / point :mod (t2 / time :ARG1-of (e / equal-01 :ARG2 (t3 / temporal-quantity :quant "3" :unit (w3 / week))))) :ARG1-of (c2 / cause-01 :ARG0 (c3 / contrast-01 :ARG1 (p2 / precede-01 :ARG1 p :ARG2 (a / appear-01 :ARG1 (t4 / tumor))) :ARG2 (a2 / after :op1 (e2 / exhibit-01 :ARG0 (s / skin :ARG1-of (t5 / treat-04 :ARG2 (s5 / small-molecule :name (n / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG1 (m / medical-condition :name (n2 / name :op1 "hyperplasia") :ARG1-of (p4 / pronounced-02))) :domain p))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1"))) :op2 (p5 / prove-01 :ARG0 p :ARG1 (a4 / advantageous :purpose (i / identify-01 :ARG1 (g / gene :ARG1-of (r / regulate-01 :ARG0 (a5 / and :op1 s5 :op2 (c4 / combine-01 :ARG1 (s4 / small-molecule :name (n3 / name :op1 "retinoid") :xref (x1 / xref :value "PUBCHEM:5282375" :prob "16.868237")) :time (s2 / study-01 :mod (p6 / previous) :location (l / laboratory :poss (w4 / we))) :location (s3 / skin :mod (m2 / mouse)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c5 / cite-01 :ARG2 "20"))))) # ::id pmid_1943_2991.56 # ::date 2015-08-18T02:01:17 # ::file pmid_1943_2991_56.txt # ::snt We reason that at least a portion of important TPA-induced promotion events will have taken place by this time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (r / reason-01 :ARG0 (w / we) :ARG1 (p3 / portion :mod (a / at-least) :part-of (e / event :ARG0-of (p / promote-01) :ARG1-of (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082"))) :mod (i3 / important)) :time (u / up-to :op1 (t / time :mod (t2 / this))))) # ::id pmid_1943_2991.57 # ::date 2015-08-18T02:10:26 # ::file pmid_1943_2991_57.txt # ::snt Of the ~45,000 probe sets (representing ~39,000 transcripts and variants from over 34,000 characterized mouse genes) on the 430 2.0 GeneChip, expression of 3,948 were altered by TPA, upwards or downwards, relative to untreated controls (fold changes between treatment groups ≥ 1.5, with p ≤ 0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (m2 / multi-sentence :snt1 (a / alter-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1 (e / express-03 :ARG2 (s / set :quant "3948" :mod (p / probe) :ARG1-of (i / include-91 :ARG2 (s2 / set :mod (p2 / probe) :quant (a2 / approximately :op1 "45000") :ARG0-of (r / represent-01 :ARG1 (a3 / and :op1 (t / transcribe-01 :ARG1 (g / gene :mod (m / mouse) :ARG1-of (c / characterize-01) :quant (o / over :op1 "34000"))) :op2 (v / vary-01 :ARG1 g) :quant (a4 / approximately :op1 "39000"))) :location (t2 / thing :mod "2.0" :mod "430" :name (n / name :op1 "GeneChip")))))) :direction (o2 / or :op1 (u / upward) :op2 (d / downward)) :ARG1-of (r2 / relate-01 :ARG2 (c2 / control-01 :ARG1-of (t3 / treat-04 :polarity "-")))) :snt2 (c3 / change-01 :mod (f / fold) :location (b2 / between :op1 (g2 / group :mod (t4 / treat-04))) :ARG1-of (e2 / equal-01 :ARG2 (o3 / over :op1 "1.5")) :ARG1-of (s4 / statistical-test-91 :ARG2 (o4 / or :op1 "0.05" :op2 (l / less-than :op1 "0.05"))))) # ::id pmid_1943_2991.58 # ::date 2015-08-18T03:52:24 # ::file pmid_1943_2991_58.txt # ::snt This group of genes was divided into clusters as described in Materials and Methods. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (d / divide-02 :ARG1 (g / group :consist-of (g2 / gene) :mod (t / this)) :ARG2 (c / cluster) :ARG1-of (d2 / describe-01 :medium (a / and :op1 (m / material) :op2 (m2 / method)))) # ::id pmid_1943_2991.59 # ::date 2015-08-18T03:56:18 # ::file pmid_1943_2991_59.txt # ::snt The heatmap in figure 2 represents the genes that fall into each subcluster, with expression patterns produced by normalized raw scores for the subcluster indicated in the panels on the right. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 18, 2015 (r / represent-01 :ARG0 (h / heatmap :location (f / figure :mod "2")) :ARG1 (g / gene :ARG1-of (f2 / fall-01 :ARG4 (s / subcluster :mod (e / each))) :ARG0-of (h2 / have-03 :ARG1 (p / pattern :topic (e2 / express-03) :ARG1-of (p2 / produce-01 :ARG0 (s2 / score :mod (r2 / raw) :ARG1-of (n / normalize-01)) :ARG3 (s3 / subcluster :ARG1-of (i / indicate-01 :location (p3 / panel :ARG1-of (r3 / right-04))))))))) # ::id pmid_1943_2991.60 # ::date 2015-08-18T04:04:42 # ::file pmid_1943_2991_60.txt # ::snt Amongst the 3,948 total TPA regulated genes, 49.5% were found to be in the C1A and C2A subclusters. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (g / gene :ARG1-of (i / include-91 :ARG2 (g2 / gene :quant "3948" :mod (t / total) :ARG1-of (r / regulate-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "TPA") :xref (x2 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG3 (p / percentage-entity :value "49.5"))) :location (a / and :op1 (s / subcluster :part-of (g3 / gene :name (n2 / name :op1 "C1A") :xref (x1 / xref :value "UNIPROT:C1AS1_HUMAN" :prob "0.232"))) :op2 (s2 / subcluster :part-of (g4 / gene :name (n3 / name :op1 "C2A") :xref (x / xref :value "UNIPROT:C2AIL_HUMAN" :prob "0.232"))))) # ::id pmid_1943_2991.61 # ::date 2015-08-18T04:09:27 # ::file pmid_1943_2991_61.txt # ::snt We are calling these genes 'counter-regulated' because their direction of expression (increase or decrease) in TPA + ATRA treated skin compared to TPA treated skin is opposite to that of TPA treated skin compared to control skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (c / call-01 :ARG0 (w / we) :ARG1 (g / gene :mod (t / this)) :ARG2 (g2 / gene :ARG1-of (r / regulate-01 :ARG1-of (c2 / counter-01))) :ARG1-of (c3 / cause-01 :ARG0 (o / opposite-01 :ARG1 (d / direct-01 :ARG1 (e / express-03 :ARG2 g :ARG3 (s / skin :ARG1-of (t2 / treat-04 :ARG2 (a / and :op1 (s5 / small-molecule :name (n / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")) :op2 (s6 / small-molecule :name (n2 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")))) :compared-to (s2 / skin :ARG1-of (t3 / treat-04 :ARG2 s5)))) :ARG1-of (m / mean-01 :ARG2 (o2 / or :op1 (i / increase-01) :op2 (d2 / decrease-01)))) :ARG2 (s3 / skin :ARG1-of (t4 / treat-04 :ARG2 s5) :compared-to (s4 / skin :ARG0-of (c4 / control-01)))))) # ::id pmid_1943_2991.62 # ::date 2015-08-18T04:19:30 # ::file pmid_1943_2991_62.txt # ::snt This data can also be represented graphically as scatterplots (Fig. S1, additional file 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (p / possible-01 :ARG1 (r / represent-01 :ARG1 (d / data :mod (t / this)) :ARG2 (s / scatterplot) :mod (g / graphic) :mod (a3 / also)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "S1") :op2 (f2 / file :mod "1" :ARG1-of (a2 / add-02))))) # ::id pmid_1943_2991.63 # ::date 2015-08-18T04:23:14 # ::file pmid_1943_2991_63.txt # ::snt We note that when comparing control skin with TPA + ATRA skin, the majority of counter-regulated genes lie close the x = y diagonal, indicating that ATRA can suppress TPA effects on expression of these genes completely or near completely (Fig. S1C, additional file 1, see C1A and C2A subclusters). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m2 / multi-sentence :snt1 (n / note-01 :ARG0 (w / we) :ARG1 (l / lie-07 :ARG1 (g / gene :quant (m / majority) :ARG1-of (i / include-91 :ARG2 (g2 / gene :ARG1-of (r / regulate-01 :ARG1-of (c2 / counter-01))))) :ARG2 (c / close-10 :ARG1 g :ARG2 (d / diagonal :location-of (e2 / equal-01 :ARG1 (s10 / string-entity :value "x") :ARG2 (s11 / string-entity :value "y")))) :time (c3 / compare-01 :ARG0 w :ARG1 (s / skin :ARG0-of (c4 / control-01)) :ARG2 (s2 / skin :ARG1-of (t / treat-04 :ARG2 (a / and :op1 (s8 / small-molecule :name (n3 / name :op1 "TPA") :xref (x3 / xref :value "PUBCHEM:27924" :prob "16.198082")) :op2 (s9 / small-molecule :name (n4 / name :op1 "ATRA") :xref (x2 / xref :value "PUBCHEM:444795" :prob "17.251232")))))) :ARG0-of (i2 / indicate-01 :ARG1 (p / possible-01 :ARG1 (o / or :op1 (s3 / suppress-01 :ARG1 (a3 / affect-01 :ARG0 s8 :ARG1 (e / express-03 :ARG2 g)) :ARG1-of (c6 / complete-02)) :op2 (s4 / suppress-01 :ARG1 a3 :ARG1-of (c7 / complete-02 :degree (n5 / near))))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "S1C") :op2 (f2 / file :mod "1" :ARG1-of (a5 / add-02))))) :snt2 (s5 / see-01 :ARG0 (y / you) :ARG1 (a6 / and :op1 (s6 / subcluster :part-of (g3 / gene :name (n2 / name :op1 "C1A") :xref (x1 / xref :value "UNIPROT:C1AS1_HUMAN" :prob "0.232"))) :op2 (s7 / subcluster :part-of (g4 / gene :name (n6 / name :op1 "C2A") :xref (x / xref :value "UNIPROT:C2AIL_HUMAN" :prob "0.232")))))) # ::id pmid_1943_2991.64 # ::date 2015-08-18T04:36:59 # ::file pmid_1943_2991_64.txt # ::snt A subset of the C1A and C2A genes are listed in Table S1 in additional file 2, sorted according to their known function in cellular signaling pathways, using the GeneSifter program. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (l / list-01 :ARG1 (s / subset :consist-of (a / and :op1 (g / gene :name (n / name :op1 "C1A") :xref (x1 / xref :value "UNIPROT:C1AS1_HUMAN" :prob "0.232")) :op2 (g2 / gene :name (n2 / name :op1 "C2A") :xref (x / xref :value "UNIPROT:C2AIL_HUMAN" :prob "0.232"))) :ARG1-of (s2 / sort-01 :ARG2 (f2 / function-01 :ARG0 a :ARG1 (p / pathway :ARG0-of (s4 / signal-07 :mod (c / cell))) :ARG1-of (k / know-01)))) :ARG2 (t / table :mod "S1" :location (f / file :mod "2")) :manner (u / use-01 :ARG1 (p2 / program :name (n5 / name :op1 "GeneSifter")))) # ::id pmid_1943_2991.65 # ::date 2015-08-18T04:46:30 # ::file pmid_1943_2991_65.txt # ::snt The table lists genes in the major signaling pathways in epithelial cells that have the highest Z-scores. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (l / list-01 :ARG0 (t / table) :ARG1 (g / gene :location (p / pathway :ARG0-of (s / signal-07) :ARG1-of (m2 / major-02) :location (c / cell :mod (e / epithelium) :ARG0-of (h2 / have-03 :ARG1 (s2 / score :name (n / name :op1 "Z") :ARG1-of (h / high-02 :degree (m / most)))))))) # ::id pmid_1943_2991.66 # ::date 2015-08-18T04:58:58 # ::file pmid_1943_2991_66.txt # ::snt Z-score is a measure of the significance of over-representation for a particular gene list within an ontology group [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (m / measure-01 :ARG1 (s2 / significant-02 :ARG1 (r / represent-01 :ARG2 (l / list :topic (g / gene) :location (g2 / group :mod (o2 / ontology)) :mod (p2 / particular)) :degree (o / over))) :ARG2 (s / score :name (n / name :op1 "Z")) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "21")))) # ::id pmid_1943_2991.67 # ::date 2015-08-18T05:06:22 # ::file pmid_1943_2991_67.txt # ::snt We also identified several counter-regulated genes that were previously determined to be TPA regulated (Table S2, additional file 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (i / identify-01 :ARG0 (w / we) :ARG1 (g / gene :quant (s / several) :ARG1-of (r / regulate-01 :ARG1-of (c / counter-01)) :ARG1-of (d / determine-01 :ARG3 (r2 / regulate-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1 g) :time (p / previous))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (t / table :mod "S2") :op2 (f / file :mod "3" :ARG1-of (a3 / add-02))))) # ::id pmid_1943_2991.68 # ::date 2015-08-18T05:10:40 # ::file pmid_1943_2991_68.txt # ::snt This abrogation of TPA effect on gene expression by ATRA is consistent with the findings of numerous investigators who have shown that TPA activates the AP-1 transcription factor complex, and that AP-1 activity is inhibited by ATRA through the retinoid receptors [10] for review and [14,22]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (c / consistent-01 :ARG1 (a / abrogate-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ATRA") :xref (x2 / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1 (a2 / affect-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1 (e / express-03 :ARG2 (g / gene))) :mod (t / this)) :ARG2 (f / find-01 :ARG0 (p3 / person :ARG0-of (i / investigate-01) :quant (n4 / numerous) :ARG0-of (s / show-01 :ARG1 (a5 / and :op1 (a4 / activate-01 :ARG0 s3 :ARG1 (c2 / complex :mod (f2 / factor :ARG0-of (t2 / transcribe-01)) :ARG1-of (m / mean-01 :ARG2 (p4 / protein :name (n5 / name :op1 "AP-1") :xref (x / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))))) :op2 (i2 / inhibit-01 :ARG0 s2 :ARG1 (a3 / activity-06 :ARG0 p4) :instrument (r / receptor :mod (r2 / retinoid)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (a7 / and :op1 "10" :op2 "14" :op3 "22")))))))))) # ::id pmid_1943_2991.69 # ::date 2015-08-18T05:20:23 # ::file pmid_1943_2991_69.txt # ::snt ATRA suppresses B-Raf/Mek/Erk signaling in early and late tumor progression times in the 2-stage skin carcinogenesis model # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (s / suppress-01 :ARG0 (s5 / small-molecule :name (n / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1 (s2 / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "B-Raf/Mek/Erk"))) :time (a2 / and :op1 (p2 / progress-01 :ARG1 (t2 / tumor) :mod (e / early)) :op2 (p3 / progress-01 :ARG1 t2 :mod (l / late))) :location (m / model :ARG0-of (h / have-03 :ARG1 (s4 / stage :quant "2")) :mod (c / carcinogenesis :mod (s3 / skin)))) # ::id pmid_1943_2991.70 # ::date 2015-08-18T05:26:03 # ::file pmid_1943_2991_70.txt # ::snt Examination of the above microarray results revealed altered expression of a disproportionate number of genes involved in the MAP kinase signaling pathway, in particular the B-Raf/Mek/Erk pathway (Table S1, additional file 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reveal-01 :ARG0 (e / examine-01 :ARG1 (m / microarray :ARG1-of (r2 / result-01) :location (a / above))) :ARG1 (e2 / express-03 :ARG2 (n2 / number :quant-of (g / gene :ARG1-of (i / involve-01 :ARG2 (a3 / and :op1 (p4 / pathway :name (n / name :op1 "MAP" :op2 "kinase") :ARG0-of (s / signal-07)) :op2 (p2 / pathway :name (n4 / name :op1 "B-Raf/Mek/Erk") :mod (p3 / particular))))) :mod (d / disproportionate)) :ARG1-of (a2 / alter-01)) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (t2 / table :mod "S1") :op2 (f / file :mod "2" :ARG1-of (a5 / add-02))))) # ::id pmid_1943_2991.71 # ::date 2015-08-18T05:34:00 # ::file pmid_1943_2991_71.txt # ::snt We next performed a 2-stage skin carcinogenesis experiment as above, except that in this study the protocol was carried out for 30 weeks. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (c / contrast-01 :ARG1 (p / perform-02 :ARG0 (w2 / we) :ARG1 (e / experiment-01 :ARG1 (c3 / carginogenesis :mod (s / skin)) :ARG0-of (h / have-03 :ARG1 (s2 / stage :quant "2")) :ARG1-of (r / resemble-01 :ARG2 (a / above))) :time (n / next)) :ARG2 (c2 / carry-out-03 :ARG0 w2 :ARG1 (p2 / protocol) :duration (t2 / temporal-quantity :quant "30" :unit (w3 / week)) :location (s3 / study :mod (t3 / this)))) # ::id pmid_1943_2991.72 # ::date 2015-08-18T05:45:11 # ::file pmid_1943_2991_72.txt # ::snt Tumor counts were recorded each week and mice were sacrificed at multiple time points (6 hours, 3, 7, 10, and 30 weeks of treatment), for subsequent analysis of B-Raf/Mek/Erk pathway signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (a / and :op1 (r / record-01 :ARG1 (c / count-01 :ARG1 (t3 / tumor)) :time (w2 / week :mod (e / each))) :op2 (s / sacrifice-01 :ARG1 (m / mouse) :time (p / point :mod (t4 / time) :quant (m2 / multiple) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and :op1 (a4 / after :op1 (t7 / treat-04 :quant (t / temporal-quantity :quant "6" :unit (h / hour)))) :op2 (a5 / after :op1 (t8 / treat-04 :quant (t5 / temporal-quantity :quant "3" :unit (w3 / week)))) :op3 (a6 / after :op1 (t9 / treat-04 :quant (t6 / temporal-quantity :quant "7" :unit (w4 / week)))) :op4 (a7 / after :op1 (t10 / treat-04 :quant (t11 / temporal-quantity :quant "10" :unit (w5 / week)))) :op5 (a8 / after :op1 (t12 / treat-04 :quant (t13 / temporal-quantity :quant "30" :unit (w6 / week))))))) :purpose (a3 / analyze-01 :ARG1 (s2 / signal-07 :ARG0 (p2 / pathway :name (n / name :op1 "B-Raf/Mek/Erk"))) :time (s3 / subsequent)))) # ::id pmid_1943_2991.73 # ::date 2015-08-18T05:54:03 # ::file pmid_1943_2991_73.txt # ::snt The reduced tumor multiplicity and increased tumor latency for mice treated with TPA+ATRA, compared to mice treated with TPA alone, indicated the potent tumor suppressive activity of ATRA, in agreement with previous results (Fig. 3A, compare black line with blue line) [8,9]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m4 / multi-sentence :snt1 (i / indicate-01 :ARG0 (a / and :op1 (m / multiply-01 :ARG1 (t / tumor) :ARG1-of (r / reduce-01)) :op2 (l / latent :domain t :ARG1-of (i2 / increase-01)) :location (m2 / mouse :ARG1-of (t2 / treat-04 :ARG2 (a2 / and :op1 (s2 / small-molecule :name (n / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")) :op2 (s3 / small-molecule :name (n2 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232"))))) :compared-to (m3 / mouse :ARG1-of (t3 / treat-04 :ARG2 s2 :mod (a4 / alone)))) :ARG1 (a3 / activity-06 :ARG0 s3 :ARG1 (s / suppress-01 :ARG1 t) :mod (p2 / potent) :ARG0-of (a6 / agree-01 :ARG2 (t5 / thing :ARG2-of (r2 / result-01 :time (p3 / previous))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) :snt2 (c / compare-01 :ARG0 (y / you) :ARG1 (l2 / line :ARG1-of (b / black-04)) :ARG2 (l3 / line :mod (b2 / blue))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (a7 / and :op1 "8" :op2 "9"))))) # ::id pmid_1943_2991.74 # ::date 2015-08-18T06:11:42 # ::file pmid_1943_2991_74.txt # ::snt However a small number of tumors were observed in the mice treated with TPA+ATRA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (h / have-concession-91 :ARG1 (o / observe-01 :ARG1 (n / number :quant-of (t / tumor) :mod (s / small)) :location (m / mouse :ARG1-of (t2 / treat-04 :ARG2 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")) :op2 (s3 / small-molecule :name (n3 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232"))))))) # ::id pmid_1943_2991.75 # ::date 2015-08-18T06:15:36 # ::file pmid_1943_2991_75.txt # ::snt Interestingly, histological examination of these ATRA resistant tumors revealed a less differentiated phenotype than for the tumors that arose in the mice treated with TPA alone (Fig. 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (r / reveal-01 :ARG0 (e / examine-01 :ARG1 (t / tumor :ARG0-of (r2 / resist-01 :ARG1 (s / small-molecule :name (n / name :op1 "ATRA") :mod (t2 / this) :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")))) :mod (h / histology)) :ARG1 (p / phenotype :ARG1-of (d / differentiate-01 :degree (l / less) :compared-to (t3 / tumor :ARG1-of (a2 / arise-02 :location (m / mouse :ARG1-of (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA") :mod (a3 / alone) :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")))))))) :ARG2-of (i / interest-01) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_1943_2991.76 # ::date 2015-08-18T06:22:35 # ::file pmid_1943_2991_76.txt # ::snt These tumors closely resembled advanced SCC, while the tumors in the TPA mice were papillary, with a high degree of keratinization as confirmed by a immunohistochemical (IHC) staining for cytokeratin 10 (Fig. 3B, lower panels). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c3 / contrast-01 :ARG1 (r / resemble-01 :ARG1 (t / tumor :mod (t2 / this)) :ARG2 (m / medical-condition :name (n / name :op1 "carcinoma") :mod (c2 / cell) :mod (s / squamous) :ARG1-of (a / advance-01)) :ARG1-of (c / close-10)) :ARG2 (p / papilla :domain (t3 / tumor :location (m2 / mouse :ARG1-of (t4 / treat-04 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG0-of (h / have-03 :ARG1 (d2 / degree :degree-of (k / keratinize-00) :ARG1-of (h2 / high-02)) :ARG1-of (c4 / confirm-01 :ARG0 (s2 / stain-01 :mod (i / immunohistochemical) :purpose (p3 / protein :name (n3 / name :op1 "cytokeratin" :op2 "10") :xref (x / xref :value "UNIPROT:K1C10_HUMAN" :prob "0.692"))))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3B") :op2 (p4 / panel :ARG1-of (l / low-04 :degree (m3 / more)))))) # ::id pmid_1943_2991.77 # ::date 2015-08-18T06:45:31 # ::file pmid_1943_2991_77.txt # ::snt In order to investigate the effects of ATRA on TPA-induced activation of the B-Raf/Mek/Erk pathway, we performed IHC staining of paraffin sections from mouse skin treated with TPA, ATRA, TPA+ATRA, or acetone solvent, with phosphorylation site-specific antibodies to B-Raf (phospho-Ser 445), Mek1/2 (phospho-Ser 217/221), and Erk1/2 (phospho-Thr202/Tyr 204). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (p2 / perform-02 :ARG0 (w / we) :ARG1 (s / stain-01 :ARG1 (s2 / section :source (s3 / skin :mod (m / mouse) :ARG1-of (t2 / treat-04 :ARG2 (o / or :op1 (s11 / small-molecule :name (n4 / name :op1 "TPA") :xref (x10 / xref :value "PUBCHEM:27924" :prob "16.198082")) :op2 (s12 / small-molecule :name (n5 / name :op1 "ATRA") :xref (x9 / xref :value "PUBCHEM:444795" :prob "17.251232")) :op3 (a3 / and :op1 s11 :op2 s12) :op4 (s4 / solvent :mod (a / acetone))))) :mod (p3 / paraffin)) :ARG2 (a5 / and :op1 (a4 / antibody :ARG1-of (s5 / specific-02 :ARG2 (s6 / site :ARG1-of (p / phosphorylate-01) :ARG1-of (m2 / mean-01 :ARG2 (a7 / amino-acid :mod "445" :name (n8 / name :op1 "serine") :ARG3-of (p4 / phosphorylate-01) :xref (x11 / xref :value "PUBCHEM:5951" :prob "11.218784"))))) :ARG0-of (c / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x4 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :op2 (a6 / antibody :ARG0-of (c2 / counter-01 :ARG1 (s7 / slash :op1 (e3 / enzyme :name (n6 / name :op1 "Mek1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n7 / name :op1 "Mek2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.603")))) :ARG1-of (s13 / specific-02 :ARG2 (s14 / site :ARG1-of (m3 / mean-01 :ARG2 (s10 / slash :op1 (a12 / amino-acid :mod "217" :name (n9 / name :op1 "serine") :ARG3-of (p5 / phosphorylate-01) :xref (x8 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a13 / amino-acid :mod "221" :name (n14 / name :op1 "serine") :xref (x7 / xref :value "PUBCHEM:5951" :prob "11.218784"))))))) :op3 (a9 / antibody :ARG0-of (c3 / counter-01 :ARG1 (s8 / slash :op1 (e5 / enzyme :name (n10 / name :op1 "Erk1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e6 / enzyme :name (n11 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :ARG1-of (s15 / specific-02 :ARG2 (s16 / site :ARG1-of (m4 / mean-01 :ARG2 (s9 / slash :op1 (a10 / amino-acid :mod "202" :name (n12 / name :op1 "threonine") :xref (x6 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a11 / amino-acid :mod "204" :name (n13 / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")))))))) :mod (i / immunohistochemistry)) :purpose (i2 / investigate-01 :ARG0 w :ARG1 (a14 / affect-01 :ARG0 s12 :ARG1 (a15 / activate-01 :ARG1 (p6 / pathway :name (n15 / name :op1 "B-Raf/Mek/Erk")) :ARG2-of (i3 / induce-01 :ARG0 s11)) :ARG1-of p))) # ::id pmid_1943_2991.78 # ::date 2015-08-18T07:16:34 # ::file pmid_1943_2991_78.txt # ::snt The 6 h, 3, 7, 10 and 30 week time points were selected for sample isolation in order to obtain data prior to tumor formation (6 h and 3 weeks), just as tumors are beginning to be detectable (7 weeks), after the majority of mice have tumors (10 weeks), and after tumors had grown substantially (30 weeks). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (s / select-01 :ARG1 (a / and :op1 (p / point :mod (t5 / time :ARG1-of (e2 / equal-01 :ARG2 (t6 / temporal-quantity :quant "6" :unit (h / hour))))) :op2 (p2 / point :mod (t7 / time :ARG1-of (e3 / equal-01 :ARG2 (t2 / temporal-quantity :quant "3" :unit (w2 / week))))) :op3 (p3 / point :mod (t8 / time :ARG1-of (e4 / equal-01 :ARG2 (t3 / temporal-quantity :quant "7" :unit (w3 / week) :ARG1-of (e / equal-01))))) :op4 (p4 / point :mod (t9 / time :ARG1-of (e5 / equal-01 :ARG2 (t4 / temporal-quantity :quant "10" :unit (w4 / week))))) :op5 (p5 / point :mod (t10 / time :ARG1-of (e6 / equal-01 :ARG2 (t / temporal-quantity :quant "30" :unit (w / week)))))) :ARG3 (i / isolate-01 :ARG1 (t13 / thing :ARG1-of (s2 / sample-01)) :purpose (o / obtain-01 :ARG1 (a4 / and :op1 (d / data :time (p6 / prior :op1 (f / form-01 :ARG1 (t11 / tumor)) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 t6 :op2 t2)))) :op2 (d3 / data :time (b / begin-01 :ARG0 t11 :ARG1 (d2 / detect-01 :ARG1 t11) :ARG1-of (m5 / mean-01 :ARG2 t3))) :op3 (d4 / data :time (a5 / after :op1 (h3 / have-03 :ARG0 (m2 / mouse :quant (m3 / majority) :ARG1-of (i2 / include-91 :ARG2 (m7 / mouse))) :ARG1 t11) :ARG1-of (m6 / mean-01 :ARG2 t4))) :op4 (d5 / data :time (a3 / after :op1 (g / grow-01 :ARG1 t11 :degree (s3 / substantial)) :ARG1-of (m4 / mean-01 :ARG2 t))))))) # ::id pmid_1943_2991.79 # ::date 2015-08-18T07:43:21 # ::file pmid_1943_2991_79.txt # ::snt In the TPA treated skin, hyperproliferation was correlated with increased levels of activated (phosphorylated) B-Raf, Mek1/2, and Erk1/2, as detected by increased red fluorescence from the Alexa 546-coupled secondary antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / correlate-01 :ARG1 (h / hyperproliferate-01) :ARG2 (a / and :op1 (l / level :ARG1-of (i / increase-01) :quant-of (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG1-of (a2 / activate-01 :ARG1-of (m / mean-01 :ARG2 (p / phosphorylate-01))) :xref (x4 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :op2 (l2 / level :ARG1-of i :quant-of (s / slash :op1 (e4 / enzyme :name (n4 / name :op1 "Mek1") :ARG1-of a2 :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.603")) :op2 (e5 / enzyme :name (n5 / name :op1 "Mek2") :ARG1-of a2 :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.603")))) :op3 (l3 / level :ARG1-of i :quant-of (s2 / slash :op1 (e6 / enzyme :name (n6 / name :op1 "Erk1") :ARG1-of a2 :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e7 / enzyme :name (n7 / name :op1 "Erk2") :ARG1-of a2 :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))))) :ARG1-of (d / detect-01 :ARG0 (f / fluoresce-01 :ARG1 (a3 / antibody :mod (s3 / secondary) :ARG1-of (c2 / couple-01 :ARG2 (s6 / small-molecule :name (n8 / name :op1 "Alexa" :op2 "546") :xref (x5 / xref :value "PUBCHEM:644247" :prob "10.151108")))) :ARG1-of (r / red-02) :ARG1-of i)) :location (s4 / skin :ARG1-of (t2 / treat-04 :ARG2 (s5 / small-molecule :name (n9 / name :op1 "TPA") :xref (x6 / xref :value "PUBCHEM:27924" :prob "16.198082"))))) # ::id pmid_1943_2991.80 # ::date 2015-08-18T07:51:55 # ::file pmid_1943_2991_80.txt # ::snt Results are shown for a representative (3 week) time point (Fig. 4A; compare TPA panels to Control panels for all 3 rows). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (m2 / multi-sentence :snt1 (s / show-01 :ARG1 (t2 / thing :ARG2-of (r2 / result-01)) :purpose (p2 / point :mod (t3 / time) :ARG0-of (r3 / represent-01) :ARG1-of (m / mean-01 :ARG2 (a2 / after :op1 (t / temporal-quantity :quant "3" :unit (w / week))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) :snt2 (c / compare-01 :ARG0 (y / you) :ARG1 (p3 / panel :consist-of (s2 / small-molecule :name (n / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082"))) :ARG2 (p5 / panel :ARG0-of (c2 / control-01)) :purpose (r4 / row :quant "3" :mod (a / all)))) # ::id pmid_1943_2991.81 # ::date 2015-08-18T07:58:10 # ::file pmid_1943_2991_81.txt # ::snt Skin treated with a single application of TPA, ATRA or TPA+ATRA showed no notable changes in staining for any of the phosphoproteins (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (s5 / show-01 :ARG0 (s2 / skin :ARG1-of (t / treat-04 :ARG2 (o / or :op1 (a / apply-02 :ARG1 (s6 / small-molecule :name (n / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")) :ARG1-of (s3 / single-02)) :op2 (a2 / apply-02 :ARG1 (s7 / small-molecule :name (n2 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1-of s3) :op3 (a4 / apply-02 :ARG1 (a5 / and :op1 s6 :op2 s7) :ARG1-of s3)))) :ARG1 (c / change-01 :ARG1 (s4 / stain-01 :ARG1 (p2 / protein :mod (a6 / any) :ARG1-of (p3 / phosphorylate-01))) :ARG1-of (n3 / notable-04)) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s / show-01 :polarity "-")))) # ::id pmid_1943_2991.82 # ::date 2015-08-18T08:16:33 # ::file pmid_1943_2991_82.txt # ::snt pB-Raf was expressed predominantly in the cytoplasm in TPA treated skin at all time points, and this effect was blocked with co-administration of ATRA with TPA (Fig. 4A, upper rows and data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (a / and :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG3 (c / cytoplasm :location (s / skin :ARG1-of (t / treat-04 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "TPA") :xref (x2 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (p2 / predominate-01) :time (p4 / point :mod (t2 / time) :mod (a2 / all))) :op2 (b / block-01 :ARG1 (a4 / affect-01 :mod (t3 / this)) :ARG3 (a5 / administer-01 :ARG1 (a6 / and :op1 (s4 / small-molecule :name (n3 / name :op1 "ATRA") :xref (x3 / xref :value "PUBCHEM:444795" :prob "17.251232")) :op2 s3))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4A" :location (r / row)) :op2 (d2 / data :ARG1-of (s2 / show-01 :polarity "-"))))) # ::id pmid_1943_2991.83 # ::date 2015-08-18T10:55:59 # ::file pmid_1943_2991_83.txt # ::snt We did not observe any changes in phosphorylation of c-Raf (RAF1), the other Raf family member present in skin, with any of the treatments using an antibody to phospho-serine 338 (Fig. S2, additional file 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (o / observe-01 :polarity "-" :ARG0 (w / we) :ARG1 (c / change-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "c-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))) :mod (a6 / any)) :condition (p3 / present :location (s / skin) :domain (m2 / member :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n3 / name :op1 "Raf") :ARG1-of (m / mean-01 :ARG2 e))) :mod (o2 / other))) :condition (t / treat-04 :mod (a / any) :ARG0-of (u / use-01 :ARG1 (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 (a3 / amino-acid :mod "338" :name (n5 / name :op1 "serine") :ARG3-of (p4 / phosphorylate-01) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "S2") :op2 (f2 / file :mod "4" :ARG1-of (a5 / add-02))))) # ::id pmid_1943_2991.84 # ::date 2015-08-18T11:07:07 # ::file pmid_1943_2991_84.txt # ::snt pMek1/2 levels were increased and expression was localized predominantly to the inner surface of the cell membrane in TPA treated skin (Fig. 4A, middle rows). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (a / and :op1 (i / increase-01 :ARG1 (s / slash :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "Mek1") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.603"))) :op2 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "Mek2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "0.603")) :ARG3-of p))) :op2 (l3 / localize-01 :ARG1 (e3 / express-03) :ARG1-of (p2 / predominate-01) :location (s2 / surface :mod (i2 / inner) :part-of (m / membrane :mod (c / cell) :location (s3 / skin :ARG1-of (t / treat-04 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "TPA") :xref (x3 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :xref (x2 / xref :value "GO:0016020" :prob "0.8")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A" :part (r / row :location (m2 / middle))))) # ::id pmid_1943_2991.85 # ::date 2015-08-17T09:31:09 # ::file pmid_1943_2991_85.txt # ::snt This observation is notable since it has been shown that the translocation of pMek to the cell membrane results in lowering the threshold for activation of MAP kinase signal output [23]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / cause-01 :ARG0 (s / show-01 :ARG1 (r / result-01 :ARG1 (t / translocate-01 :ARG1 (e / enzyme :name (n / name :op1 "Mek") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243")) :ARG2 (m / membrane :mod (c2 / cell) :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :ARG2 (l / lower-05 :ARG1 (t2 / threshold :degree-of (a / activate-01 :ARG1 (o / output :mod (s2 / signal-07 :ARG0 (k / kinase :name (n2 / name :op1 "MAP") :xref (x1 / xref :value "UNIPROT:MOTI_HUMAN" :prob "1.002"))))))))) :ARG1 (n3 / notable-04 :ARG1 (t3 / thing :ARG1-of (o2 / observe-01) :mod (t4 / this))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "23")))) # ::id pmid_1943_2991.86 # ::date 2015-08-17T09:31:21 # ::file pmid_1943_2991_86.txt # ::snt As was observed for pB-Raf, the increased levels of pMek1/2 was blocked with co-administration of ATRA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (b / block-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "Mek1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (i / increase-01)) :ARG3 (c / coadminister-00 :ARG1 (s / small-molecule :name (n2 / name :op1 "ATRA") :xref (x1 / xref :value "PUBCHEM:444795" :prob "17.251232"))) :ARG2-of (r / resemble-01 :ARG1 (o / observe-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "B-Raf") :ARG3-of p :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) # ::id pmid_1943_2991.87 # ::date 2015-08-17T09:57:38 # ::file pmid_1943_2991_87.txt # ::snt Staining for pErk1/2 was observed in pairs of scattered nuclei in control skin, with an increase in staining intensity for TPA treated skin, as would be predicted accompanying hyperproliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (o / observe-01 :ARG1 (s / stain-01 :purpose (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n / name :op1 "Erk1/2") :ARG3-of (p / phosphorylate-01)) :ARG0-of (h3 / have-03 :ARG1 (i / intensity :ARG1-of (i2 / increase-01 :location (s4 / skin :ARG1-of (t / treat-04 :ARG2 (s5 / small-molecule :wiki "12-O-Tetradecanoylphorbol-13-acetate" :name (n3 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG1-of (c2 / cause-01 :ARG0 (p3 / predict-01 :ARG0 i2 :ARG1 (h2 / hyperproliferate-01 :ARG0-of (a / accompany-01)))))))) :location (p2 / pair-01 :ARG1 (n2 / nucleus :ARG1-of (s2 / scatter-01) :location (s3 / skin :mod (c / control)) :xref (x / xref :value "GO:0005634" :prob "0.8")))) # ::id pmid_1943_2991.88 # ::date 2015-08-17T10:38:00 # ::file pmid_1943_2991_88.txt # ::snt Fewer nuclei were stained for TPA+ATRA treated skin than for TPA treatment alone (Fig. 4A, bottom rows). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (s / stain-01 :ARG1 (n / nucleus :quant (f / few :degree (m / more) :compared-to (t2 / treat-04 :ARG2 "s3" :mod (a2 / alone))) :xref (x / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4A" :location (r / row :location (b / bottom)))) :purpose (s2 / skin :ARG1-of (t / treat-04 :ARG2 (a / and :op1 (s3 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")) :op2 (s4 / small-molecule :name (n3 / name :op1 "ATRA") :xref (x2 / xref :value "PUBCHEM:444795" :prob "17.251232")))))) # ::id pmid_1943_2991.89 # ::date 2015-08-17T10:42:24 # ::file pmid_1943_2991_89.txt # ::snt We attempted to quantitate pErk1/2 levels by determining the percent positive nuclei in the treated skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / attempt-01 :ARG0 (w / we) :ARG1 (q / quantitate-01 :ARG0 w :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "Erk1/2") :ARG3-of (p / phosphorylate-01)))) :instrument (d / determine-01 :ARG0 w :ARG1 (p2 / percent :quant-of (n2 / nucleus :mod (p3 / positive) :xref (x / xref :value "GO:0005634" :prob "0.8")) :location (s / skin :ARG1-of (t / treat-04))))) # ::id pmid_1943_2991.90 # ::date 2015-08-17T10:48:07 # ::file pmid_1943_2991_90.txt # ::snt At all time points except 30 weeks, the percent positive pErk staining nuclei actually decreased in TPA treated skin compared to controls and TPA+ATRA skin (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 11, 2016 (d / decrease-01 :ARG1 (p / percent :mod (p2 / positive) :quant-of (n / nucleus :ARG1-of (s6 / stain-01 :purpose (e / enzyme :name (n4 / name :op1 "Erk") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))) :xref (x1 / xref :value "GO:0005634" :prob "0.8"))) :ARG1-of (a / actual-02) :location (s / skin :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA") :xref (x2 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :time (p4 / point :mod (t2 / time) :mod (a3 / all) :ARG2-of (e2 / except-01 :ARG1 (t3 / temporal-quantity :quant "30" :unit (w / week)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s7 / show-01 :polarity "-"))) :compared-to (a2 / and :op1 (s3 / skin :mod (c / control)) :op2 (s4 / skin :mod (s5 / small-molecule :name (n3 / name :op1 "ATRA") :xref (x3 / xref :value "PUBCHEM:444795" :prob "17.251232")) :mod s2))) # ::id pmid_1943_2991.91 # ::date 2015-08-17T11:24:48 # ::file pmid_1943_2991_91.txt # ::snt This was due to the far greater number of total cells in the hyperplastic TPA treated skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / cause-01 :ARG0 (n / number :quant-of (c2 / cell :mod (t / total) :location (s / skin :mod (h / hyperplasia) :ARG1-of (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082"))))) :mod (g / great :degree (m / more :degree (f / far)))) :ARG1 (t3 / this)) # ::id pmid_1943_2991.92 # ::date 2015-08-17T12:14:24 # ::file pmid_1943_2991_92.txt # ::snt To more precisely measure the levels of phosphorylation of the MAP kinase signaling proteins in this model, we performed Western blot analysis on epidermal lysates pooled from 5 mice per treatment group for each time point, from skin adjacent to the tissue that was embedded for sectioning and IHC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG0 (w / we) :ARG1 (i / immunoblot-01 :ARG2 (l / lysate :mod (e / epidermis) :ARG1-of (p2 / pool-01 :source (m / mouse :quant "5" :ARG1-of (r / rate-entity-91 :ARG2 (g / group :ARG1-of (t2 / treat-04)))) :time (p3 / point :mod (t3 / time) :mod (e2 / each))) :source (s / skin :ARG2-of (b / border-01 :ARG1 (t4 / tissue :ARG1-of (e3 / embed-01 :purpose (a2 / and :op1 (s2 / section-01) :op2 (i2 / immunohistochemistry)))))))) :purpose (m2 / measure-01 :ARG0 w :ARG1 (l2 / level :degree-of (p4 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "MAP" :op2 "kinase") :ARG0-of (s3 / signal-07) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.383")))) :location (m3 / model :mod (t6 / this)) :manner (p6 / precise :degree (m4 / more)))) # ::id pmid_1943_2991.93 # ::date 2015-08-17T12:14:51 # ::file pmid_1943_2991_93.txt # ::snt Using 10 weeks as a representative time point, co-administration of ATRA with TPA resulted in a lower level of pB-Raf, pMek1/2 and pErk1/2, than with TPA treatment alone (Fig. 4B compare TPA and TPA+ATRA lanes). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / result-01 :ARG1 (c / coadminister-00 :ARG1 (a / and :op1 (s / small-molecule :name (n / name :op1 "ATRA") :xref (x3 / xref :value "PUBCHEM:444795" :prob "17.251232")) :op2 (s2 / small-molecule :name (n2 / name :op1 "TPA") :xref (x2 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG2 (l / low-04 :ARG1 (a2 / and :op1 (l2 / level :quant-of (e / enzyme :name (n3 / name :op1 "B-Raf") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :mod (s4 / small-molecule)) :op2 (l3 / level :quant-of (e2 / enzyme :name (n4 / name :op1 "Mek1/2") :ARG3-of p)) :op3 (l4 / level :quant-of (e3 / enzyme :name (n5 / name :op1 "Erk1/2") :ARG3-of p))) :degree (m / more) :compared-to (t / treat-04 :ARG2 (s3 / small-molecule :name (n6 / name :op1 "TPA") :mod (a3 / alone) :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG2-of (u / use-01 :ARG1 (t2 / temporal-quantity :quant "10" :unit (w / week) :ARG0-of (r2 / represent-01 :ARG1 (p2 / point :mod (t3 / time))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B" :ARG0-of (c2 / compare-01 :ARG1 (l5 / lane :mod s2) :ARG2 (l7 / lane :mod s :mod s2))))) # ::id pmid_1943_2991.94 # ::date 2015-08-18T14:02:26 # ::file pmid_1943_2991_94.txt # ::snt At the same time there is an increase in the protein levels of total Erk1/2 with TPA treatment that is suppressed by ATRA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (i / increase-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "Erk1/2") :mod (t3 / total))) :condition (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082"))) :time (t2 / time :ARG1-of (s4 / same-01)) :ARG1-of (s2 / suppress-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")))) # ::id pmid_1943_2991.95 # ::date 2015-08-18T14:10:30 # ::file pmid_1943_2991_95.txt # ::snt The results from both IHC and Western blot analysis indicate that suppression of pB-Raf, pMek1/2, and pErk1/2 levels by ATRA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :source (a / and :op1 (a3 / analyze-01 :mod (i3 / immunohistochemistry)) :op2 (a2 / analyze-01 :manner (i2 / immunoblot-01)))) :ARG1 (s / suppress-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ATRA") :xref (x1 / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1 (a4 / and :op1 (l / level :quant-of (e / enzyme :name (n4 / name :op1 "B-Raf") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :op2 (l2 / level :quant-of (e2 / enzyme :name (n5 / name :op1 "Mek1/2") :ARG3-of p)) :op3 (l3 / level :quant-of (e3 / enzyme :name (n6 / name :op1 "Erk1/2") :ARG3-of p))))) # ::id pmid_1943_2991.96 # ::date 2015-08-18T14:24:40 # ::file pmid_1943_2991_96.txt # ::snt P38 and JNK branches of the MAP Kinase cascade are not suppressed by ATRA treatment # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (s / suppress-01 :polarity "-" :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "ATRA") :xref (x2 / xref :value "PUBCHEM:444795" :prob "17.251232"))) :ARG1 (a / and :op1 (b / branch :mod (e / enzyme :name (n2 / name :op1 "P38") :xref (x / xref :value "UNIPROT:GRAP2_HUMAN" :prob "1.003"))) :op2 (b2 / branch-01 :mod (e2 / enzyme :name (n3 / name :op1 "JNK") :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :part-of (p / pathway :name (n4 / name :op1 "MAP" :op2 "Kinase")))) # ::id pmid_1943_2991.97 # ::date 2015-08-18T14:35:45 # ::file pmid_1943_2991_97.txt # ::snt The two other major MAP kinase signaling pathways besides the B-Raf/Mek/Erk pathway are the Jun N-terminal kinase (JNK) and p38 MAP kinase pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (p3 / pathway :quant "2" :name (n3 / name :op1 "MAP" :op2 "kinase") :ARG0-of (s / signal-07) :mod (o / other) :ARG1-of (m / major-02) :ARG2-of (e / except-01 :ARG1 (p4 / pathway :name (n4 / name :op1 "B-Raf/Mek/Erk"))) :domain (a / and :op1 (p / pathway :name (n / name :op1 "Jun" :op2 "N-terminal" :op3 "kinase")) :op2 (p2 / pathway :name (n2 / name :op1 "p38" :op2 "MAP" :op3 "kinase")))) # ::id pmid_1943_2991.98 # ::date 2015-08-18T14:49:15 # ::file pmid_1943_2991_98.txt # ::snt In order to confirm our previous microarray results, which suggested that these pathways were less important in regards to ATRA suppression of TPA induced tumor promotion, we performed IHC on tissue sections taken at the 7 week time point from the same 2-stage skin carcinogenesis experiment as above. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG0 (w / we) :ARG1 (i3 / immunohistochemistry) :location (s / section-01 :ARG1 (t2 / tissue) :ARG1-of (t3 / take-01 :ARG2 (e / experiment-01 :ARG1 (c / carcinogenesis :mod (s2 / skin)) :mod (s3 / stage :mod "2") :ARG1-of (r / resemble-01 :ARG2 (a / above)) :ARG1-of (s8 / same-01)) :time (p2 / point :mod (t4 / time) :mod (t5 / temporal-quantity :quant "7" :unit (w2 / week))))) :purpose (c2 / confirm-01 :ARG0 w :ARG1 (t6 / thing :ARG2-of (r2 / result-01) :time (p3 / previous) :mod (m / microarray) :poss w :ARG0-of (s4 / suggest-01 :ARG1 (i / important :degree (l / less) :domain (p4 / pathway :mod (t7 / this)) :topic (s5 / suppress-01 :ARG0 (s6 / small-molecule :name (n2 / name :op1 "ATRA") :xref (x1 / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1 (p5 / promote-01 :ARG1 (t8 / tumor :ARG2-of (i2 / induce-01 :ARG0 (s7 / small-molecule :name (n3 / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082"))))))))))) # ::id pmid_1943_2991.99 # ::date 2015-08-18T15:11:55 # ::file pmid_1943_2991_99.txt # ::snt Using antibodies to phosphorylated (activated) p38 (Thr180/Tyr182), and JNK (Thr183/Tyr185) we observed that, unlike the B-Raf, Mek1/2 and Erk1/2 proteins, neither p38 nor JNK were increased in phosphorylation upon TPA treatment (Fig. 5A, compare TPA panels to Control). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (i / increase-01 :polarity "-" :ARG1 (p / phosphorylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "p38") :xref (x4 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "JNK") :xref (x3 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))) :ARG1-of (r / resemble-01 :polarity "-" :ARG2 (a2 / and :op1 (e5 / enzyme :name (n4 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e6 / enzyme :name (n5 / name :op1 "Mek1/2")) :op3 (e7 / enzyme :name (n6 / name :op1 "Erk1/2"))))) :condition (t / treat-04 :ARG0 a3 :ARG2 (s / small-molecule :name (n3 / name :op1 "TPA") :xref (x9 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG2-of (u / use-01 :ARG1 (a / antibody :ARG0-of (c3 / counter-01 :ARG1 (a7 / and :op1 (e3 / enzyme :name (n7 / name :op1 "p38") :ARG3-of (p2 / phosphorylate-01 :ARG1 (s3 / slash :op1 (a5 / amino-acid :mod "180" :name (n8 / name :op1 "threonine") :xref (x7 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a6 / amino-acid :mod "182" :name (n9 / name :op1 "threonine") :xref (x8 / xref :value "PUBCHEM:205" :prob "11.848252"))) :ARG1-of (m / mean-01 :ARG2 (a11 / activate-01))) :xref (x2 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n10 / name :op1 "JNK") :ARG3-of (p6 / phosphorylate-01 :ARG1 (s2 / slash :op1 (a9 / amino-acid :mod "183" :name (n11 / name :op1 "threonine") :xref (x6 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a10 / amino-acid :mod "185" :name (n12 / name :op1 "threonine") :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")))) :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A" :ARG0-of (c / compare-01 :ARG1 (p7 / panel :mod s) :ARG2 (c2 / control))))) # ::id pmid_1943_2991.100 # ::date 2015-08-18T15:44:13 # ::file pmid_1943_2991_100.txt # ::snt Importantly, the phosphorylation levels of p38 and JNK were not suppressed by co-administration of ATRA with TPA (Fig. 5A, compare TPA and TPA+ATRA panels). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / suppress-01 :polarity "-" :ARG0 (c / coadminister-00 :ARG1 (a / and :op1 (s2 / small-molecule :name (n / name :op1 "ATRA") :xref (x3 / xref :value "PUBCHEM:444795" :prob "17.251232")) :op2 (s3 / small-molecule :name (n2 / name :op1 "TPA") :xref (x2 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG1 (l / level :degree-of (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "JNK") :xref (x / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A" :ARG0-of (c2 / compare-01 :ARG1 (p2 / panel :mod s3) :ARG2 (a3 / and :op1 (p3 / panel :mod s3) :op2 (p4 / panel :mod s2))))) :mod (i / important)) # ::id pmid_1943_2991.101 # ::date 2015-08-18T15:56:01 # ::file pmid_1943_2991_101.txt # ::snt This observation was confirmed by Western blotting using the same phospho-specific antibodies, as well as antibodies to total p38 and total JNK (Fig. 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c / confirm-01 :ARG0 (i / immunoblot-01) :ARG1 (o / observe-01 :mod (t / this)) :ARG2-of (u / use-01 :ARG1 (a / and :op1 (a2 / antibody :ARG1-of (s / specific-02 :ARG2 (p / phosphorylate-01)) :ARG1-of (s2 / same-01)) :op2 (a3 / antibody :ARG0-of (c2 / counter-01 :ARG1 (a4 / and :op1 (e / enzyme :name (n2 / name :op1 "p38") :mod (t3 / total) :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "JNK") :mod t3 :xref (x1 / xref :value "UNIPROT:MP2K4_HUMAN" :prob "0.343")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B")))))) # ::id pmid_1943_2991.102 # ::date 2015-08-18T16:08:38 # ::file pmid_1943_2991_102.txt # ::snt Interestingly we observed a modest increase in p38 phosphorylation in the skin treated with ATRA alone, suggesting that the p38 pathway could play a role in mediating retinoid effects in skin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 "p4") :ARG2 (m / modest) :location (s / skin :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "ATRA") :mod (a2 / alone) :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")))) :ARG0-of (s3 / suggest-01 :ARG1 (p2 / possible-01 :ARG1 (p3 / play-02 :ARG0 (p4 / pathway :name (n3 / name :op1 "p38")) :ARG1 (m2 / mediate-01 :ARG1 (a / affect-01 :ARG0 (s4 / small-molecule :name (n4 / name :op1 "retinoid") :xref (x1 / xref :value "PUBCHEM:5282375" :prob "16.868237")) :ARG1 (s5 / skin))))))) :ARG2-of (i2 / interest-01)) # ::id pmid_1943_2991.103 # ::date 2015-08-18T16:21:45 # ::file pmid_1943_2991_103.txt # ::snt Sorafenib suppresses cell growth in TPA-induced tumors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (s / suppress-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "Sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG1 (g / grow-01 :ARG1 (c / cell)) :location (t / tumor :ARG2-of (i / induce-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082"))))) # ::id pmid_1943_2991.104 # ::date 2015-08-18T16:24:08 # ::file pmid_1943_2991_104.txt # ::snt We hypothesize that ATRA exerts its tumor suppressive effect by blocking B-Raf/Mek/Erk signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (e / exert-01 :ARG0 (s / small-molecule :name (n / name :op1 "ATRA") :xref (x / xref :value "PUBCHEM:444795" :prob "17.251232")) :ARG1 (a / affect-01 :ARG0 s :ARG2 (s2 / suppress-01 :ARG0 s :ARG1 (t / tumor))) :instrument (b / block-01 :ARG1 (s3 / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "B-Raf/Mek/Erk"))) :ARG3 s))) # ::id pmid_1943_2991.105 # ::date 2015-08-18T16:35:19 # ::file pmid_1943_2991_105.txt # ::snt This predicts that blocking this pathway through another means should also suppress tumorigenesis and/or the growth of tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (p / predict-01 :ARG0 (t / this) :ARG1 (r / recommend-01 :ARG1 (s / suppress-01 :ARG0 (b / block-01 :ARG1 (p2 / pathway :mod t) :manner (m / mean :mod (a2 / another))) :ARG1 (a / and-or :op1 (c / create-01 :ARG1 (t2 / tumor)) :op2 (g / grow-01 :ARG1 (t3 / tumor))) :mod (a3 / also)))) # ::id pmid_1943_2991.106 # ::date 2015-08-18T16:43:33 # ::file pmid_1943_2991_106.txt # ::snt To test this prediction we have used a novel Raf inhibiting bi-aryl urea compound from Bayer Pharmaceuticals called BAY 43-9006, or Sorafenib [24]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (c / compound :mod (u2 / urea) :source (c2 / company :wiki "Bayer" :name (n2 / name :op1 "Bayer" :op2 "Pharmaceuticals")) :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :wiki "RAF_kinase" :name (n5 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :mod (b / biaryl) :ARG1-of (c3 / call-01 :ARG2 (o / or :op1 (s / small-molecule :wiki "-" :name (n / name :op1 "BAY" :op2 "43-9006") :xref (x2 / xref :value "PUBCHEM:216239" :prob "14.335617")) :op2 (s2 / small-molecule :wiki "Sorafenib" :name (n3 / name :op1 "Sorafenib") :xref (x1 / xref :value "PUBCHEM:216239" :prob "16.740406"))))) :ARG2 (t / test-01 :ARG0 w :ARG1 (p / predict-01 :mod (t2 / this))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG0-of (c4 / cite-01 :ARG2 "24")))) # ::id pmid_1943_2991.107 # ::date 2015-08-22T11:59:06 # ::file pmid_1943_2991_107.txt # ::snt This compound has been shown to inhibit MAP kinase signaling in colon, pancreatic and breast cancer cell lines, as well as inhibit tumor growth in colon, breast and non-small-cell lung cancer mouse xenograft models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (s / show-01 :ARG1 (a / and :op1 (i / inhibit-01 :ARG0 (c / compound :mod (t / this)) :ARG1 (s2 / signal-07 :ARG0 (k / kinase :name (n / name :op1 "MAP") :xref (x1 / xref :value "UNIPROT:MOTI_HUMAN" :prob "1.002"))) :location (a2 / and :op1 (c2 / cell-line :mod (d / disease :wiki "Pancreatic_cancer" :name (n2 / name :op1 "pancreatic" :op2 "cancer"))) :op2 (c4 / cell-line :mod (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer"))) :op3 (c7 / cell-line :mod (d3 / disease :wiki "Breast_cancer" :name (n4 / name :op1 "breast" :op2 "cancer"))))) :op2 (i2 / inhibit-01 :ARG0 c :ARG1 (g / grow-01 :ARG1 (t2 / tumor)) :location (a3 / and :op1 (m / model :mod (m2 / mouse) :mod (x / xenograft) :mod d2) :op2 (m3 / model :mod m2 :mod x :mod d3) :op3 (m4 / model :mod m2 :mod x :mod (d4 / disease :wiki "Lung_cancer" :name (n5 / name :op1 "lung" :op2 "cancer") :mod (c10 / cell :mod (s3 / small :polarity "-")))))))) # ::id pmid_1943_2991.108 # ::date 2015-08-18T23:04:15 # ::file pmid_1943_2991_108.txt # ::snt Tumor-bearing SENCAR mice that had been treated topically with TPA, twice weekly for 27 weeks, were treated with Sorafenib either topically or by gavage, as described in the Materials and Methods. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (t / treat-04 :ARG1 (m / mouse :ARG0-of (b / bear-01 :ARG1 (t3 / tumor)) :ARG1-of (t4 / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")) :duration (t5 / temporal-quantity :quant "27" :unit (w / week)) :frequency (r / rate-entity-91 :ARG1 "2" :ARG2 (t6 / temporal-quantity :quant "1" :unit w)) :manner (t7 / topic)) :ARG0-of (s3 / sensitive-03 :ARG1 (c / carcinogen))) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "Sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :manner (o / or :op1 t7 :op2 (g / gavage)) :ARG1-of (d / describe-01 :ARG0 (t9 / title-01 :ARG1 (a / and :op1 (m2 / material) :op2 (m3 / method))))) # ::id pmid_1943_2991.109 # ::date 2015-08-18T23:41:30 # ::file pmid_1943_2991_109.txt # ::snt Mice were photographed twice weekly to monitor tumor morphology and size. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (p / photograph-01 :ARG1 (m / mouse) :frequency (r / rate-entity-91 :ARG1 "2" :ARG2 (t / temporal-quantity :quant "1" :unit (w / week))) :purpose (m2 / monitor-01 :ARG1 (a / and :op1 (m3 / morphology :mod (t2 / tumor)) :op2 (s / size :mod t2)))) # ::id pmid_1943_2991.110 # ::date 2015-08-18T23:45:29 # ::file pmid_1943_2991_110.txt # ::snt Tumors that received only topical acetone solvent, along with the TPA treatment, displayed the exophytic papilloma morphology normally observed in TPA-treated mice in this model (Fig. 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (d / display-01 :ARG0 (t / tumor :ARG0-of (r / receive-01 :ARG1 (a / and :op1 (s / solvent :mod (t2 / topic) :mod (s3 / solvent)) :op2 (t3 / treat-04 :ARG1 t :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082")))) :mod (o / only))) :ARG1 (m / morphology :mod (p / papilloma) :mod (e / exophytic) :ARG1-of (o2 / observe-01 :location (m2 / mouse :ARG1-of (t4 / treat-04 :ARG2 s2)) :ARG1-of (n3 / normal-02) :location (m3 / model :mod (t5 / this)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_1943_2991.111 # ::date 2015-08-19T00:00:36 # ::file pmid_1943_2991_111.txt # ::snt The histological appearance of these tumors was also typical of TPA-induced papillomas (Fig. 6E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (t / typical-02 :ARG1 (a / appear-01 :ARG1 (t2 / tumor :mod (t3 / this)) :mod (h / histology)) :ARG2 (p / papilloma :ARG2-of (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082")))) :mod (a2 / also) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6E"))) # ::id pmid_1943_2991.112 # ::date 2015-08-19T00:05:57 # ::file pmid_1943_2991_112.txt # ::snt Tumors receiving topical Sorafenib at either concentration displayed a dried and darkened appearance that was reminiscent of human keratoacanthoma (Fig. 6, compare A to B and data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (d / display-01 :ARG0 (t / tumor :ARG0-of (r / receive-01 :ARG1 (s / small-molecule :name (n / name :op1 "Sorafenib") :ARG1-of (c / concentrate-02 :mod (e / either)) :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")))) :ARG1 (a2 / appear-01 :ARG1 t :ARG1-of (d2 / dry-08) :ARG1-of (d3 / dark-02) :ARG0-of (r2 / reminisce-01 :ARG1 (k / keratoacanthoma :mod (h / human)))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "6" :ARG0-of (c2 / compare-01 :ARG1 (f2 / figure :mod "6A") :ARG2 (f3 / figure :mod "6B"))) :op2 (d5 / data :ARG1-of (s2 / show-01 :polarity "-"))))) # ::id pmid_1943_2991.113 # ::date 2015-08-19T00:29:18 # ::file pmid_1943_2991_113.txt # ::snt Histological analysis of these tumors revealed that the bulk of the tumor mass was non-cellular keratin, indicating a greatly enhanced level of squamous differentiation compared to the control TPA-induced tumors (Fig. 6, compare E to F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 19, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (t / tumor :mod (t2 / this)) :mod (h / histology)) :ARG1 (p / protein :name (n / name :op1 "keratin") :mod (c / cell :polarity "-") :domain (m / mass :mod (t3 / tumor) :quant (b / bulk)) :ARG0-of (i / indicate-01 :ARG1 (l / level :degree-of (d / differentiate-101 :mod (s / squamous)) :ARG1-of (e / enhance-01 :compared-to (t4 / tumor :mod (c2 / control) :ARG2-of (i2 / induce-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :degree (g / great)))) :xref (x / xref :value "UNIPROT:Q16195_HUMAN" :prob "1.001")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6" :ARG0-of (c3 / compare-01 :ARG1 (f2 / figure :mod "6E") :ARG2 (f3 / figure :mod "6F"))))) # ::id pmid_1943_2991.114 # ::date 2015-08-19T00:46:34 # ::file pmid_1943_2991_114.txt # ::snt Interestingly, the tumors of mice treated with Sorafenib by oral gavage did not differ drastically in outward appearance from the control TPA-induced tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (d / differ-02 :polarity "-" :ARG1 (t / tumor :poss (m / mouse :ARG1-of (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "Sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :manner (g / gavage :mod (o / oral))))) :ARG2 (t3 / tumor :mod (c / control) :ARG2-of (i / induce-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA") :xref (x1 / xref :value "PUBCHEM:27924" :prob "16.198082")))) :ARG3 (a / appear-01 :mod (o2 / outward)) :mod (d2 / drastic) :ARG2-of (i2 / interest-01)) # ::id pmid_1943_2991.115 # ::date 2015-08-19T00:56:13 # ::file pmid_1943_2991_115.txt # ::snt However upon histological examination these tumors appear very similar to the tumors that received topical Sorafenib (Fig. 6C and 6G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (h2 / have-concession-91 :ARG2 (a / appear-02 :ARG1 (r / resemble-01 :ARG1 (t / tumor :mod (t2 / this)) :ARG2 (t3 / tumor :ARG0-of (r2 / receive-01 :ARG1 (s / small-molecule :name (n / name :op1 "Sorafenib") :mod (t4 / topic) :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")))) :degree (v / very)) :condition (e / examine-01 :mod (h / histology))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "6C") :op2 (f2 / figure :mod "6G")))) # ::id pmid_1943_2991.116 # ::date 2015-08-19T01:23:57 # ::file pmid_1943_2991_116.txt # ::snt It was previously shown in the breast and colon tumor xenograft models that inhibition of tumor growth was closely associated with suppression of Erk1/2 phosphorylation [24]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (s / show-01 :ARG0 (a / and :op1 (m / model :mod (x / xenograft) :mod (b / breast)) :op2 (m2 / model :mod x :mod (c / colon))) :ARG1 (a2 / associate-01 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor))) :ARG2 (s2 / suppress-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "Erk1/2")))) :ARG1-of (c2 / close-10)) :time (p / previous) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "24")))) # ::id pmid_1943_2991.117 # ::date 2015-08-19T01:32:42 # ::file pmid_1943_2991_117.txt # ::snt We therefore stained paraffin-embedded sections of the TPA-induced tumors, with and without Sorafenib treatment, with the pErk1/2 antibody. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / cause-01 :ARG1 (s / stain-01 :ARG0 (w / we) :ARG1 (s2 / section-01 :ARG1 (a2 / and :op1 (t / tumor :ARG2-of (i / induce-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "TPA") :xref (x / xref :value "PUBCHEM:27924" :prob "16.198082"))) :ARG1-of (t2 / treat-04 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "Sorafenib") :xref (x1 / xref :value "PUBCHEM:216239" :prob "16.740406")))) :op2 (t3 / tumor :ARG1-of (t4 / treat-04 :polarity "-" :ARG2 s4) :ARG2-of i)) :ARG1-of (e / embed-01 :ARG2 (p / paraffin))) :ARG2 (a / antibody :ARG0-of (c2 / counter-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Erk1/2") :ARG3-of (p2 / phosphorylate-01)))))) # ::id pmid_1943_2991.118 # ::date 2015-08-19T01:55:23 # ::file pmid_1943_2991_118.txt # ::snt The number of nuclei and intensity of staining was reduced for Sorafenib treated tumors compared to the TPA only-treated tumors (Fig. 6H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (r / reduce-01 :ARG1 (a / and :op1 (n / number :quant-of (n2 / nucleus :xref (x / xref :value "GO:0005634" :prob "0.8"))) :op2 (i / intensity :degree-of (s / stain-01))) :location (t / tumor :ARG1-of (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "Sorafenib") :xref (x1 / xref :value "PUBCHEM:216239" :prob "16.740406")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6H")) :compared-to (t3 / tumor :ARG1-of (t4 / treat-04 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "TPA") :xref (x2 / xref :value "PUBCHEM:27924" :prob "16.198082")) :mod (o / only)))) # ::id pmid_1965_4571.1 # ::date 2015-08-05T04:57:06 # ::file pmid_1965_4571_1.txt # ::snt Combination of cetuximab with chemoradiation, trastuzumab or MAPK inhibitors: mechanisms of sensitisation of cervical cancer cells (PMID:19654571) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / combine-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG2 (o / or :op1 (c4 / chemoradiate-00) :op2 (s3 / small-molecule :name (n5 / name :op1 "trastuzumab") :xref (x / xref :value "PUBCHEM:9903" :prob "12.041334")) :op3 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n6 / name :op1 "MAPK"))))) :ARG1-of (m2 / mean-01 :ARG2 (m3 / mechanism :instrument-of (s / sensitize-01 :ARG1 (c2 / cell :mod (d2 / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical" :op2 "cancer")))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID19654571"))) # ::id pmid_1965_4571.9 # ::date 2015-08-05T05:30:11 # ::file pmid_1965_4571_9.txt # ::snt Results: # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1965_4571.10 # ::date 2015-08-05T05:31:02 # ::file pmid_1965_4571_10.txt # ::snt Cetuximab with cisplatin and radiation achieved maximum cytotoxic effects for A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively) in CA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / achieve-01 :ARG0 (a6 / and :op1 (s / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :op2 (s2 / small-molecule :name (n4 / name :op1 "cisplatin") :xref (x1 / xref :value "PUBCHEM:441203" :prob "10.782021")) :op3 (r2 / radiate-01)) :ARG1 (a3 / affect-01 :ARG1 (a4 / and :op1 (c2 / cell-line :name (n5 / name :op1 "A431")) :op2 (c3 / cell-line :name (n6 / name :op1 "Caski")) :op3 (c4 / cell-line :name (n7 / name :op1 "C33A"))) :mod (c / cytotoxic) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (e2 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (h2 / high-02)) :op2 (e3 / express-03 :ARG2 e :degree (i / intermediate)) :op3 (e4 / express-03 :ARG2 e :ARG1-of (l2 / low-04)) :mod (r3 / respective))) :degree (m / maximum) :time (a2 / assay-01 :mod (c5 / clonogenic)))) # ::id pmid_1965_4571.11 # ::date 2015-08-06T00:09:49 # ::file pmid_1965_4571_11.txt # ::snt Cetuximab efficiently decreased MAPK and AKT phosphorylation in A431 cells but slightly less in Caski and C33A cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / contrast-01 :ARG1 (d / decrease-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a3 / and :op1 (e3 / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op2 (e2 / enzyme :name (n3 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :manner (e / efficient-01) :location (c / cell-line :name (n4 / name :op1 "A431"))) :ARG2 (d2 / decrease-01 :ARG0 s2 :ARG1 a3 :ARG2 (l / less :mod (s / slight)) :location (a2 / and :op1 (c3 / cell-line :name (n5 / name :op1 "Caski")) :op2 (c4 / cell-line :name (n6 / name :op1 "C33A"))) :compared-to d)) # ::id pmid_1965_4571.12 # ::date 2015-08-06T01:01:31 # ::file pmid_1965_4571_12.txt # ::snt To check whether further EGFR, HER2 or MAPK inhibition would improve cetuximab's cytotoxicity, we combined it with an EGFR tyrosine kinase inhibitor (TKI), trastuzumab or a MEK1/2 inhibitor (PD98059). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / combine-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG1 (o / or :op1 (e3 / enzyme :name (n4 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e4 / enzyme :name (n5 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :op3 (e / enzyme :name (n6 / name :op1 "MAPK") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :degree (f / further)) :ARG2 (o2 / or :op1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 e3)) :op2 (s / small-molecule :name (n8 / name :op1 "trastuzumab") :xref (x5 / xref :value "PUBCHEM:9903" :prob "12.041334")) :op3 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n9 / name :op1 "MEK1/2"))) :ARG1-of (m3 / mean-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "PD98059") :xref (x3 / xref :value "PUBCHEM:4713" :prob "18.349844"))))) :purpose (c2 / check-01 :ARG0 w :ARG1 (i4 / improve-01 :mode "interrogative" :ARG0 i :ARG1 (c3 / cytotoxic :domain (s2 / small-molecule :name (n10 / name :op1 "cetuximab") :xref (x4 / xref :value "PUBCHEM:56842117" :prob "9.083761")))))) # ::id pmid_1965_4571.13 # ::date 2015-08-06T01:20:05 # ::file pmid_1965_4571_13.txt # ::snt In Caski, but not in C33A cells, cetuximab cooperated with the TKI, reducing cell survival and AKT and MAPK phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (c / cooperate-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (k / kinase :mod (t / tyrosine)))) :ARG2 (r2 / reduce-01 :ARG0 s2 :ARG1 (a / and :op1 (s / survive-01 :ARG0 (c6 / cell)) :op2 (p2 / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n6 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op2 (e2 / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))))) :location (c2 / cell-line :name (n4 / name :op1 "Caski"))) :ARG2 (c4 / cooperate-01 :polarity "-" :ARG0 s2 :ARG1 m :location (c5 / cell-line :name (n5 / name :op1 "C33A")))) # ::id pmid_1965_4571.14 # ::date 2015-08-06T01:30:11 # ::file pmid_1965_4571_14.txt # ::snt However, cetuximab with trastuzumab or PD98059 reduced survival and MAPK phosphorylation of both cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG2 (r / reduce-01 :ARG0 (a2 / and :op1 (s3 / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :op2 (o / or :op1 (s4 / small-molecule :name (n3 / name :op1 "trastuzumab") :xref (x2 / xref :value "PUBCHEM:9903" :prob "12.041334")) :op2 (s / small-molecule :name (n4 / name :op1 "PD98059") :xref (x3 / xref :value "PUBCHEM:4713" :prob "18.349844")))) :ARG1 (a / and :op1 (s2 / survive-01 :ARG0 (c / cell-line :mod (b / both))) :op2 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :location c)))) # ::id pmid_1965_4571.85 # ::date 2015-08-06T01:41:19 # ::file pmid_1965_4571_85.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_1965_4571.86 # ::date 2015-08-06T01:41:54 # ::file pmid_1965_4571_86.txt # ::snt Differential effects of RxT, cisplatin and cetuximab on cell proliferation and cell-cycle kinetics # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (a / affect-01 :ARG0 (a2 / and :op1 (r2 / radiotherapy) :op2 (s / small-molecule :name (n2 / name :op1 "cisplatin") :xref (x1 / xref :value "PUBCHEM:441203" :prob "10.782021")) :op3 (s2 / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :ARG1 (a3 / and :op1 (p2 / proliferate-01 :ARG0 (c / cell)) :op2 (k / kinetics :mod (c2 / cycle-02 :ARG1 (c3 / cell)))) :mod (d / differential)) # ::id pmid_1965_4571.87 # ::date 2015-08-06T03:28:54 # ::file pmid_1965_4571_87.txt # ::snt We examined the antiproliferative effects of isolated RxT, cisplatin and cetuximab treatments on A431, Caski and C33A cells (Figures 1A–F), which express high to low EGFR levels, respectively (see Figures 3A and 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e2 / examine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (r3 / radiotherapy :ARG1-of (i / isolate-01)) :op2 (t3 / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "cisplatin") :xref (x2 / xref :value "PUBCHEM:441203" :prob "10.782021"))) :op3 (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :ARG1 (a3 / and :op1 (c / cell-line :name (n5 / name :op1 "A431")) :op2 (c2 / cell-line :name (n6 / name :op1 "Caski")) :op3 (c3 / cell-line :name (n7 / name :op1 "C33A")) :ARG3-of (e3 / express-03 :ARG2 (v2 / value-interval :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (h / high-02)) :op2 (l2 / level :quant-of e :ARG1-of (l3 / low-04))) :mod (r2 / respective) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f3 / figure :mod "3A") :op2 (f4 / figure :mod "5A") :ARG1-of (s / see-01 :ARG0 (y / you)))))) :ARG0-of (o / oppose-01 :ARG1 (p / proliferate-01))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "1A") :op2 (f2 / figure :mod "1F")))) # ::id pmid_1965_4571.88 # ::date 2015-08-06T03:47:03 # ::file pmid_1965_4571_88.txt # ::snt A431 growth is impaired by EGFR inhibitors (Janmaat et al, 2003), so we used this cell line for comparison with the CC cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i2 / impair-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG1 (g / grow-01 :ARG1 (c / cell-line :name (n3 / name :op1 "A431"))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n4 / name :op1 "Janmaat")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2003"))) :ARG0-of (c2 / cause-01 :ARG1 (u / use-01 :ARG0 (w / we) :ARG1 c :ARG2 (c4 / compare-01 :ARG1 c :ARG2 (c5 / cell-line :mod (d3 / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical" :op2 "cancer"))))))) # ::id pmid_1965_4571.89 # ::date 2015-08-06T04:21:11 # ::file pmid_1965_4571_89.txt # ::snt A431 and Caski cells showed similar resistance to RxT and low cisplatin concentrations (IC30) in CA and MTT assays (Figures 1A and B), but Caski cells showed increased resistance at higher cisplatin concentrations (IC50 and IC80; Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c4 / contrast-01 :ARG1 (s2 / show-01 :ARG0 (a / and :op1 (c / cell-line :name (n2 / name :op1 "A431")) :op2 (c2 / cell-line :name (n3 / name :op1 "Caski"))) :ARG1 (a2 / and :op1 (r2 / resist-01 :ARG0 a :ARG1 (r / radiotherapy) :ARG1-of (r3 / resemble-01)) :op2 (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (s / small-molecule :name (n5 / name :op1 "cisplatin") :xref (x1 / xref :value "PUBCHEM:441203" :prob "10.782021")) :ARG2 "30" :ARG1-of (l / low-04) :time (a3 / and :op1 (a4 / assay-01 :mod (c5 / clonogenic)) :op2 (a5 / assay-01 :instrument (s4 / small-molecule :name (n / name :op1 "MTT") :xref (x / xref :value "PUBCHEM:64965" :prob "17.320225")))) :ARG1-of (m4 / mean-01 :ARG2 (c7 / concentrate-02 :mod (i2 / inhibit-01 :degree (p / percentage-entity :value "30")))))) :ARG1-of (d / describe-01 :ARG0 (a6 / and :op1 (f / figure :mod "1A") :op2 (f2 / figure :mod "1B")))) :ARG2 (s3 / show-01 :ARG0 c2 :ARG1 (r4 / resist-01 :ARG0 c2 :ARG1-of (i / increase-01)) :condition (c6 / concentrate-02 :ARG1 s :ARG1-of (m / mean-01 :ARG2 (a7 / and :op1 (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s :ARG2 "50") :op2 (h4 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s :ARG2 "80"))) :ARG1-of (h / high-02 :degree (m2 / more))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "1B")))) # ::id pmid_1965_4571.90 # ::date 2015-08-06T04:39:14 # ::file pmid_1965_4571_90.txt # ::snt C33A cells were, in turn, quite sensitive to both treatments (Figures 1A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / sensitive-03 :ARG0 (c / cell-line :name (n / name :op1 "C33A")) :ARG1 (t / treat-04 :mod (b / both)) :degree (q / quite) :mod (i / in-turn) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1A") :op2 (f2 / figure :mod "1B")))) # ::id pmid_1965_4571.91 # ::date 2015-08-06T05:32:04 # ::file pmid_1965_4571_91.txt # ::snt Cetuximab treatment decreased the viability of all cell lines in CA and MTT experiments at all concentrations tested (Figures 1C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (d / decrease-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :ARG1 (v / viable :mod (c / cell-line :mod (a2 / all) :time (e / experiment-01 :ARG1 (a3 / and :op1 (a4 / assay-01 :mod (c3 / clonogenic)) :op2 (a5 / assay-01 :instrument (s2 / small-molecule :name (n / name :op1 "MTT") :xref (x / xref :value "PUBCHEM:64965" :prob "17.320225"))))))) :condition (c2 / concentrate-02 :ARG1-of (t2 / test-01) :mod (a6 / all)) :ARG1-of (d2 / describe-01 :ARG0 (a7 / and :op1 (f / figure :mod "1C") :op2 (f2 / figure :mod "1D")))) # ::id pmid_1965_4571.92 # ::date 2015-08-06T05:40:15 # ::file pmid_1965_4571_92.txt # ::snt These effects were related to an increase of 14.1, 12.6 and 6.5% in cell number at G0/G1 for A431, Caski and C33A cells on cetuximab treatment, respectively (Figure 1E) and a decrease in the population of cells at S and G2/M phases when compared to controls (CT; Figure 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / relate-01 :ARG1 (a5 / affect-01 :mod (t / this)) :ARG2 (a3 / and :op1 (i / increase-01 :ARG1 (n / number :quant-of (c2 / cell-line :name (n2 / name :op1 "A431"))) :ARG2 (a / and :op1 (p / percentage-entity :value "14.1")) :time (s / slash :op1 (e / event :name (n8 / name :op1 "G0")) :op2 (e2 / event :name (n9 / name :op1 "G1"))) :condition (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :op2 (i2 / increase-01 :ARG1 (n6 / number :quant-of (c3 / cell-line :name (n3 / name :op1 "Caski"))) :ARG2 (p2 / percentage-entity :value "12.6") :time s :condition t2) :op3 (i3 / increase-01 :ARG1 (n7 / number :quant-of (c4 / cell-line :name (n4 / name :op1 "C33A"))) :ARG2 (p3 / percentage-entity :value "6.5") :time s :condition t2) :op4 (d2 / decrease-01 :ARG1 (p5 / population :mod (c5 / cell)) :time (a4 / and :op1 (p7 / phase :mod (s4 / synthesize-01)) :op2 (t3 / time :mod (s2 / slash :op1 (e3 / event :name (n10 / name :op1 "G2" :op2 "phase")) :op2 (e4 / event :name (n11 / name :op1 "M" :op2 "phase"))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "1E")) :condition (c / compare-01 :ARG1 (c6 / control)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1E"))) # ::id pmid_1965_4571.93 # ::date 2015-08-07T03:22:02 # ::file pmid_1965_4571_93.txt # ::snt Apoptotic cells are usually found in the sub-G1 phases and, accordingly, 24-h cetuximab treatment increased this cell population by 4.6, 3.9 and 2.9% in A431, Caski and C33A cells, respectively (Figure 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (f / find-01 :ARG1 (c / cell :mod (a / apoptotic)) :time (u / usual) :location (e / event :name (n / name :op1 "sub-G1" :op2 "phase"))) :op2 (a5 / and :op1 (i / increase-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour))) :ARG1 (p2 / population :mod (c3 / cell-line :name (n3 / name :op1 "A431"))) :ARG2 (p3 / percentage-entity :value "4.6")) :op2 (i2 / increase-01 :ARG0 t :ARG1 (p6 / population :mod (c4 / cell-line :name (n4 / name :op1 "Caski"))) :ARG2 (p4 / percentage-entity :value "3.9")) :op3 (i3 / increase-01 :ARG0 t :ARG1 (p7 / population :mod (c2 / cell-line :name (n5 / name :op1 "C33A"))) :ARG2 (p5 / percentage-entity :value "2.9"))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1E"))) # ::id pmid_1965_4571.94 # ::date 2015-08-07T03:29:29 # ::file pmid_1965_4571_94.txt # ::snt Additionally, apoptotic cells were also observed by Hoechst staining in all cell lines after cetuximab treatment (Figure 1F) and, even in C33A cells, which express low EGFR levels, a reduction of 21% in cell proliferation was obtained, especially at high MAb concentration (100 μg ml−1; Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a6 / and :op2 (a7 / and :op1 (a / add-01 :ARG1 (o / observe-01 :ARG1 (c / cell :mod (a2 / apoptotic)) :instrument (s / stain-01 :ARG2 (p3 / product :name (n5 / name :op1 "Hoechst"))) :time (a4 / after :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1F")) :location (c2 / cell-line :mod (a3 / all)) :mod (a8 / also))) :op2 (o2 / obtain-01 :ARG1 (r2 / reduce-01 :ARG1 (p2 / proliferate-01 :ARG0 (c4 / cell)) :ARG2 (p / percentage-entity :value "21")) :location (c3 / cell-line :name (n3 / name :op1 "C33A") :ARG1-of (e2 / express-03 :ARG2 (l / level :quant-of (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (l3 / low-04))) :mod (e5 / even)) :condition (c5 / concentrate-02 :ARG1 (a5 / antibody :mod (m2 / monoclone)) :degree (e3 / especially) :ARG1-of (e4 / equal-01 :ARG2 (c6 / concentration-quantity :quant "100" :unit (m / microgram-per-milliliter))) :ARG1-of (h2 / high-02)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1D"))))) # ::id pmid_1965_4571.95 # ::date 2015-08-07T03:45:53 # ::file pmid_1965_4571_95.txt # ::snt Cetuximab induces chemo/radiosensitisation of CC cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / induce-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (s / slash :op1 (c / chemosensitize-00 :ARG1 (c2 / cell-line :mod (d / disease :wiki "Cervical_cancer" :name (n2 / name :op1 "cervical" :op2 "cancer")))) :op2 (r / radiosensitize-00 :ARG1 c2))) # ::id pmid_1965_4571.96 # ::date 2015-08-07T03:48:58 # ::file pmid_1965_4571_96.txt # ::snt We evaluated whether the combination of cetuximab (100 μg ml−1) with RxT and/or cisplatin could enhance the cytotoxic effects observed in CA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 16, 2015 (e / evaluate-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (e2 / enhance-01 :mode "interrogative" :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab") :quant (c2 / concentration-quantity :quant "100" :unit (m / microgram-per-milliliter)) :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG2 (a / and-or :op1 (r / radiotherapy) :op2 (s2 / small-molecule :name (n4 / name :op1 "cisplatin") :xref (x / xref :value "PUBCHEM:441203" :prob "10.782021")))) :ARG1 (a2 / affect-01 :ARG2 (c3 / cytotoxic) :ARG1-of (o / observe-01 :time (a3 / assay-01 :mod (c4 / clonogenic))))))) # ::id pmid_1965_4571.97 # ::date 2015-08-07T03:56:06 # ::file pmid_1965_4571_97.txt # ::snt Isolated cetuximab, cisplatin and RxT treatments decreased the survival of all cell lines (Figures 2A–D) but the combination of cetuximab with either RxT or cisplatin enhanced these effects (P<0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c2 / contrast-01 :ARG1 (d / decrease-01 :ARG0 (a / and :op1 (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "cetuximab") :ARG1-of (i / isolate-01) :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :op2 (t3 / treat-04 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "cisplatin") :xref (x / xref :value "PUBCHEM:441203" :prob "10.782021"))) :op3 (t4 / treat-04 :ARG2 (r / radiotherapy))) :ARG1 (s / survive-01 :ARG0 (c / cell-line :mod (a2 / all))) :ARG1-of (d2 / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2D")))) :ARG2 (e / enhance-01 :ARG0 (c3 / combine-01 :ARG1 s2 :ARG2 (o / or :op1 r :op2 s3)) :ARG1 (a3 / affect-01 :mod (t5 / this)) :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.05")))) # ::id pmid_1965_4571.98 # ::date 2015-08-07T04:15:06 # ::file pmid_1965_4571_98.txt # ::snt Furthermore, the triple combination of cetuximab, cisplatin and RxT achieved maximum effects for all cell lines in CA (demonstrative pictures of A431 cells are shown in Figure 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m2 / multi-sentence :snt1 (a / and :op2 (a2 / achieve-01 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG2 (a3 / and :op1 (s2 / small-molecule :name (n3 / name :op1 "cisplatin") :xref (x / xref :value "PUBCHEM:441203" :prob "10.782021")) :op2 (r / radiotherapy)) :mod (t / triple)) :ARG1 (a4 / affect-01 :degree (m / maximum)) :location (c2 / cell-line :mod (a5 / all)) :ARG1-of (d / describe-01) :time (a6 / assay-01 :mod (c4 / clonogenic)))) :snt2 (s3 / show-01 :ARG1 (p / picture :ARG0-of (d2 / demonstrate-01 :ARG1 (c3 / cell-line :name (n6 / name :op1 "A431")))) :location (f / figure :mod "2D"))) # ::id pmid_1965_4571.99 # ::date 2015-08-07T04:20:31 # ::file pmid_1965_4571_99.txt # ::snt Caski cells are HPV-positive and express intermediate levels of EGFR and HER2, resembling typical CC tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (p / positive :topic (d / disease :name (n3 / name :op1 "HPV")) :domain (c / cell-line :name (n4 / name :op1 "Caski") :ARG1-of (r / resemble-01 :ARG2 (t / tumor :ARG0-of (t2 / typify-01) :mod (d2 / disease :wiki "Cervical_cancer" :name (n5 / name :op1 "cervical" :op2 "cancer")))))) :op2 (e3 / express-03 :ARG2 (a2 / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :degree (i / intermediate)) :op2 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :degree i)) :ARG3 c)) # ::id pmid_1965_4571.100 # ::date 2015-08-07T04:25:51 # ::file pmid_1965_4571_100.txt # ::snt In this cell line, the triple combination reached up to 70% inhibition in CA (Figure 2B) whereas in C33A cells, an inhibition of 60% was observed (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (r / reach-01 :ARG0 (c2 / combine-01 :mod (t2 / triple)) :ARG1 (i / inhibit-01 :degree (p / percentage-entity :value "70")) :location (c / cell-line :mod (t / this)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B")) :time (a / assay-01 :mod (c4 / clonogenic))) :ARG2 (o / observe-01 :ARG1 (i2 / inhibit-01 :degree (p2 / percentage-entity :value "60")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2C")) :location (c5 / cell-line :name (n / name :op1 "C33A")))) # ::id pmid_1965_4571.101 # ::date 2015-08-07T04:51:09 # ::file pmid_1965_4571_101.txt # ::snt The CC cell lines express different basal levels of total and phosphorylated EGFR, HER-2, AKT and ERK1/2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (e2 / express-03 :ARG2 (a2 / and :op1 (a / and :op1 (l / level :ARG0-of (d / differ-01) :quant-of (e / enzyme :name (n / name :op1 "EGFR") :mod (t / total) :xref (x7 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :mod (b / basal)) :op2 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR") :ARG3-of (p / phosphorylate-01) :xref (x6 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :mod b :ARG0-of d)) :op2 (a3 / and :op1 (l3 / level :quant-of (e4 / enzyme :name (n4 / name :op1 "HER-2") :mod t :xref (x3 / xref :value "UNIPROT:Q9UK79_HUMAN" :prob "1.001")) :mod b :ARG0-of d) :op2 (l4 / level :quant-of (e5 / enzyme :name (n5 / name :op1 "HER-2") :ARG3-of p :xref (x2 / xref :value "UNIPROT:Q9UK79_HUMAN" :prob "1.001")) :mod b)) :op3 (a4 / and :op1 (l5 / level :quant-of (e6 / enzyme :name (n6 / name :op1 "AKT") :mod t :xref (x5 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :mod b :ARG0-of d) :op2 (l6 / level :quant-of (e7 / enzyme :name (n7 / name :op1 "AKT") :ARG3-of p :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :mod b :ARG0-of d)) :op4 (a5 / and :op1 (l7 / level :quant-of (s / slash :op1 (e8 / enzyme :name (n8 / name :op1 "ERK1") :mod t :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e9 / enzyme :name (n9 / name :op1 "ERK2") :mod t :xref (x9 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :mod b :ARG0-of d) :op2 (l8 / level :quant-of (s2 / slash :op1 (e10 / enzyme :name (n10 / name :op1 "ERK1") :ARG3-of p :xref (x8 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e11 / enzyme :name (n11 / name :op1 "ERK2") :ARG3-of p :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :mod b :ARG0-of d))) :ARG3 (c / cell-line :mod (d2 / disease :wiki "Cervical_cancer" :name (n2 / name :op1 "cervical" :op2 "cancer")))) # ::id pmid_1965_4571.102 # ::date 2015-08-07T05:16:37 # ::file pmid_1965_4571_102.txt # ::snt A431 cells strongly express EGFR (Janmaat et al, 2003) whereas Caski and C33A cells show moderate and low expression levels, respectively (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / contrast-01 :ARG1 (e2 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG3 (c / cell-line :name (n2 / name :op1 "A431")) :manner (s / strong) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n3 / name :op1 "Janmaat")) :op2 (p3 / person :mod (o / other))) :time (d3 / date-entity :year "2003")))) :ARG2 (s2 / show-01 :ARG0 (a2 / and :op1 (c3 / cell-line :name (n4 / name :op1 "Caski")) :op2 (c4 / cell-line :name (n5 / name :op1 "C33A"))) :ARG1 (a3 / and :op1 (l / level :degree-of (e3 / express-03 :ARG1-of (m / moderate-03))) :op2 (l2 / level :degree-of (e4 / express-03 :ARG1-of (l3 / low-04)))) :mod (r / respective) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "3A")))) # ::id pmid_1965_4571.103 # ::date 2015-08-07T05:23:28 # ::file pmid_1965_4571_103.txt # ::snt Additionally, we confirmed EGFR expression by real-time RT-PCR and by FACS analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 2, 2016 (a / and :op2 (c / confirm-01 :ARG0 (w / we) :ARG1 (e2 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :instrument (a3 / and :op1 (a2 / analyze-01 :manner (r / real-time) :mod (r3 / react-01 :ARG0 (p / polymerase) :mod (c2 / chain) :subevent (t / transcribe-01 :ARG1-of (r2 / reverse-01)))) :op2 (a4 / analyze-01 :mod r :mod (s / sort-01 :ARG1 (c3 / cell) :ARG1-of (a5 / activate-01 :ARG0 (f / fluorescence))))))) # ::id pmid_1965_4571.104 # ::date 2015-08-07T05:27:44 # ::file pmid_1965_4571_104.txt # ::snt The relative EGFR mRNA level of A431 is high and Caski cells express two times more EGFR than C33A (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 26, 2016 (a / and :op1 (h / high-02 :ARG1 (l / level :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :quant-of (c / cell-line :name (n3 / name :op1 "A431")) :ARG1-of (r2 / relative-05))) :op2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n5 / name :op1 "EGFR") :quant (p / product-of :op1 "2" :op2 (m / mass-quantity :quant-of (e5 / enzyme :name (n8 / name :op1 "EGFR") :ARG2-of (e6 / express-03 :ARG3 (c3 / cell-line :name (n6 / name :op1 "C33A"))) :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG3 (c2 / cell-line :name (n4 / name :op1 "Caski"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id pmid_1965_4571.105 # ::date 2015-08-07T05:34:56 # ::file pmid_1965_4571_105.txt # ::snt Moreover, FACS analysis showed that both a murine anti-EGFR MAb and cetuximab could detect high EGFR expression on the surface of A431 cells and intermediate and low levels in Caski and C33A cells, respectively (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (s / show-01 :ARG0 (a2 / analyze-01 :mod (s4 / sort-01 :ARG1 (c4 / cell) :ARG1-of (a4 / activate-01 :ARG0 (f2 / fluorescence)))) :ARG1 (p / possible-01 :ARG1 (d / detect-01 :ARG0 (a3 / and :op1 (a7 / antibody :ARG0-of (o / oppose-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :mod (m / mouse)) :op2 (s3 / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :ARG1 (a5 / and :op1 (e2 / express-03 :ARG2 e :ARG3 (s2 / surface :poss (c / cell-line :name (n4 / name :op1 "A431"))) :ARG1-of (h2 / high-02)) :op2 (a6 / and :op1 (l / level :degree (i / intermediate) :location (c2 / cell-line :name (n5 / name :op1 "Caski"))) :op2 (l2 / level :ARG1-of (l3 / low-04) :location (c3 / cell-line :name (n6 / name :op1 "C33A"))) :mod (r2 / respective)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5B")) :mod (m2 / monoclone)) # ::id pmid_1965_4571.106 # ::date 2015-08-07T05:42:00 # ::file pmid_1965_4571_106.txt # ::snt HER2 expression was more homogenous among the cell lines with Caski and C33A cells expressing 20 and 40% more HER2 than A431 cells, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / homogenous :domain (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "HER2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :degree (m / more) :location (a / and :op1 (c / cell-line :name (n3 / name :op1 "Caski") :ARG3-of (e4 / express-03 :ARG2 (e5 / enzyme :name (n5 / name :op1 "HER2") :quant (p2 / percentage-entity :value "20" :mod (m2 / more) :compared-to (c3 / cell-line :name (n6 / name :op1 "A431"))) :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :op2 (c2 / cell-line :name (n4 / name :op1 "C33A") :ARG3-of (e6 / express-03 :ARG2 (e7 / enzyme :name (n7 / name :op1 "HER2") :quant (p3 / percentage-entity :value "40" :mod (m3 / more) :compared-to c3) :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))))) # ::id pmid_1965_4571.107 # ::date 2015-08-07T05:48:13 # ::file pmid_1965_4571_107.txt # ::snt The basal phosphorylation status of EGFR and HER2 was inversely correlated, with higher levels of p-EGFR in A431 cells and higher levels of p-HER2 in C33A and Caski cells (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / correlate-01 :ARG1 (s / status :topic (p / phosphorylate-01) :mod (b / basal) :poss (e / enzyme :name (n / name :op1 "EGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG2 (s2 / status :topic p :mod b :poss (e2 / enzyme :name (n2 / name :op1 "HER2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :manner (i / inverse) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A")) :ARG0-of (h2 / have-03 :ARG1 (a / and :op1 (l / level :ARG1-of (h / high-02 :degree (m / more)) :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR") :ARG3-of p :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :location (c2 / cell-line :name (n4 / name :op1 "A431"))) :op2 (l2 / level :ARG1-of h :quant-of (e4 / enzyme :name (n5 / name :op1 "HER2") :ARG3-of p :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :location (a3 / and :op1 (c3 / cell-line :name (n6 / name :op1 "C33A")) :op2 (c4 / cell-line :name (n7 / name :op1 "Caski"))))))) # ::id pmid_1965_4571.108 # ::date 2015-08-07T05:53:45 # ::file pmid_1965_4571_108.txt # ::snt On EGF binding, the major signalling pathways activated are the MAPK and AKT cascades (Citri and Yarden, 2006). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / pathway :ARG0-of (s / signal-07) :ARG1-of (a / activate-01 :condition (b / bind-01 :ARG1 (p4 / protein :name (n2 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n5 / name :op1 "Citri")) :op2 (p7 / person :name (n6 / name :op1 "Yarden"))) :time (d3 / date-entity :year "2006")))) :mod (m / major) :domain (a2 / and :op1 (p2 / pathway :name (n / name :op1 "MAPK")) :op2 (p3 / pathway :name (n3 / name :op1 "AKT")))) # ::id pmid_1965_4571.109 # ::date 2015-08-07T05:58:36 # ::file pmid_1965_4571_109.txt # ::snt A431 and Caski cells show low basal levels of p-AKT whereas C33A cells have a much higher level. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (s / show-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "A431")) :op2 (c2 / cell-line :name (n2 / name :op1 "Caski"))) :ARG1 (l / level :ARG1-of (l2 / low-04) :mod (b / basal) :quant-of (e / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :ARG2 (h2 / have-03 :ARG0 (c4 / cell-line :name (n4 / name :op1 "C33A")) :ARG1 (l3 / level :ARG1-of (h / high-02 :degree (m / more :mod (m2 / much)))))) # ::id pmid_1965_4571.110 # ::date 2015-08-07T06:01:28 # ::file pmid_1965_4571_110.txt # ::snt A431 and C33A cells had higher levels of activated ERK1/2 (p-p44/42 MAPK) but no significant differences in total MAPK were observed among the cell lines (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (h2 / have-03 :ARG0 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "A431")) :op2 (c3 / cell-line :name (n3 / name :op1 "C33A"))) :ARG1 (l / level :ARG1-of (h / high-02 :degree (m / more)) :quant-of (s / slash :op1 (e / enzyme :name (n4 / name :op1 "ERK1") :ARG1-of (a2 / activate-01) :xref (x4 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2") :ARG1-of a2 :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1-of (m2 / mean-01 :ARG2 (s2 / slash :op1 (e3 / enzyme :name (n8 / name :op1 "p44" :op2 "MAPK") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.683")) :op2 (e4 / enzyme :name (n / name :op1 "p42" :op2 "MAPK") :ARG3-of p2 :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.683")))))) :ARG2 (o / observe-01 :polarity "-" :ARG1 (d / differ-02 :ARG1 (e5 / enzyme :name (n7 / name :op1 "MAPK") :mod (t / total) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1-of (s3 / significant-02)) :location (c4 / cell-line)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_1965_4571.111 # ::date 2015-08-07T06:09:06 # ::file pmid_1965_4571_111.txt # ::snt Cetuximab inhibits EGFR and HER2 phosphorylation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n2 / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))))) # ::id pmid_1965_4571.112 # ::date 2015-08-07T06:10:35 # ::file pmid_1965_4571_112.txt # ::snt To investigate the molecular determinants for cetuximab's effects in MTT and CA, we analysed EGFR phosphorylation by WB in cells treated with cetuximab (100 μg ml−1) alone or in the presence of EGF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :location (c / cell :ARG1-of (t / treat-04 :ARG2 (o / or :op1 (s / small-molecule :name (n3 / name :op1 "cetuximab") :quant (c2 / concentration-quantity :quant "100" :unit (m / microgram-per-milliliter)) :mod (a2 / alone) :xref (x4 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :op2 (s2 / small-molecule :name (n4 / name :op1 "cetuximab") :quant c2 :condition (p2 / present-02 :ARG1 (p3 / protein :name (n5 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :xref (x3 / xref :value "PUBCHEM:56842117" :prob "9.083761"))))) :purpose (i / investigate-01 :ARG0 w :ARG1 (t2 / thing :ARG0-of (d / determine-01 :ARG1 (a3 / affect-01 :ARG0 s :time (a4 / and :op1 (a5 / assay-01 :instrument (s3 / small-molecule :name (n / name :op1 "MTT") :xref (x2 / xref :value "PUBCHEM:64965" :prob "17.320225"))) :op2 (a6 / assay-01 :mod (c3 / clonogenic))))) :mod (m2 / molecule))) :manner (i2 / immunoblot-01 :ARG0 w)) # ::id pmid_1965_4571.113 # ::date 2015-08-07T06:18:13 # ::file pmid_1965_4571_113.txt # ::snt Receptor phosphorylation was increased by EGF in A431 and Caski cells, whereas cetuximab reduced it (Figures 3B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (i / increase-01 :ARG0 (p2 / protein :name (n / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :ARG1 (p / phosphorylate-01 :ARG1 (r / receptor)) :location (a / and :op1 (c / cell-line :name (n2 / name :op1 "A431")) :op2 (c2 / cell-line :name (n3 / name :op1 "Caski")))) :ARG2 (r2 / reduce-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 p) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3B") :op2 (f2 / figure :mod "3C")))) # ::id pmid_1965_4571.114 # ::date 2015-08-07T06:20:52 # ::file pmid_1965_4571_114.txt # ::snt Epidermal growth factor and cetuximab also induced a slight decrease in the total amount of EGFR in these cells (Figures 3B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / induce-01 :ARG0 (a / and :op1 (p / protein :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x1 / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703")) :op2 (s / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :ARG2 (d / decrease-01 :ARG1 (a3 / amount :mod (t / total) :quant-of (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :degree (s2 / slight) :location (c / cell :mod (t2 / this))) :mod (a2 / also) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "3B") :op2 (f2 / figure :mod "3C")))) # ::id pmid_1965_4571.115 # ::date 2015-08-04T07:50:24 # ::file pmid_1965_4571_115.txt # ::snt Epidermal growth factor receptor can interact with another member of the ErbB family, HER2, to form heterodimers that are very potent in activating signal transduction pathways (Citri and Yarden, 2006). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n3 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.703")) :ARG1 (m / member :mod (a / another) :ARG1-of (i2 / include-91 :ARG2 (p2 / protein-family :name (n4 / name :op1 "ErbB"))) :ARG1-of (m2 / mean-01 :ARG2 (e3 / enzyme :name (n5 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :purpose (f2 / form-01 :ARG0 e :ARG1 (h / heterodimer :ARG1-of (c / capable-01 :ARG2 (a2 / activate-01 :ARG1 (p3 / pathway :ARG2-of (t / transduce-01 :ARG1 (s2 / signal-07)))) :degree (v / very))) :ARG2 (a4 / and :op1 e :op2 m))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n7 / name :op1 "Citri")) :op2 (p6 / person :name (n8 / name :op1 "Yarden")) :time (d / date-entity :year "2006"))))) # ::id pmid_1965_4571.116 # ::date 2015-08-04T08:49:30 # ::file pmid_1965_4571_116.txt # ::snt On cetuximab treatment there were no changes in total HER2 in the CC cell lines, whereas EGF-induced HER2 phosphorylation was inhibited in A431 and Caski cells (Figures 3B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (h / have-condition-91 :ARG1 (c2 / change-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "HER2") :mod (t2 / total) :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :location (c3 / cell-line :mod (d / disease :wiki "Cervical_cancer" :name (n3 / name :op1 "cervical" :op2 "cancer")))) :ARG2 (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :ARG2 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 e :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n4 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :location (a / and :op1 (c4 / cell-line :name (n5 / name :op1 "A431")) :op2 (c5 / cell-line :name (n6 / name :op1 "Caski")))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3B") :op2 (f2 / figure :mod "3C")))) # ::id pmid_1965_4571.117 # ::date 2015-08-04T09:24:51 # ::file pmid_1965_4571_117.txt # ::snt Interestingly, in C33A cells, which express more HER2 than EGFR (Fig 3A), cetuximab markedly reduced EGF-induced HER2 phosphorylation (Figure 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reduce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x3 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "HER2") :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :ARG2-of (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :manner (m / marked) :location (c / cell-line :name (n4 / name :op1 "C33A") :ARG3-of (e3 / express-03 :ARG2 e :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A")) :degree (m2 / more) :compared-to (e2 / enzyme :name (n5 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3D")) :mod (i2 / interesting)) # ::id pmid_1965_4571.118 # ::date 2015-08-04T09:45:20 # ::file pmid_1965_4571_118.txt # ::snt There were no changes in total AKT and MAPK proteins in all cell lines on cetuximab treatment (Figures 3B–D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / change-01 :polarity "-" :ARG1 (a / and :op1 (p2 / protein-family :name (n2 / name :op1 "AKT")) :op2 (p / protein-family :name (n / name :op1 "MAPK")) :mod (t2 / total)) :location (c2 / cell-line :mod (a2 / all) :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "3B") :op2 (f2 / figure :mod "3D")))) # ::id pmid_1965_4571.119 # ::date 2015-08-04T10:32:43 # ::file pmid_1965_4571_119.txt # ::snt Epidermal growth factor increased AKT and ERK1/2 phosphorylation in A431 and Caski cells but in C33A cells there was only a slight increase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i / increase-01 :ARG0 (p2 / protein :name (n2 / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703")) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op1 (p3 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")))) :location (a2 / and :op1 (c2 / cell-line :name (n5 / name :op1 "A431")) :op2 (c3 / cell-line :name (n6 / name :op1 "Caski")))) :ARG2 (i2 / increase-01 :ARG0 p2 :ARG1 a :location (c4 / cell-line :name (n7 / name :op1 "C33A")) :mod (o / only) :degree (s2 / slight))) # ::id pmid_1965_4571.120 # ::date 2015-08-04T10:54:11 # ::file pmid_1965_4571_120.txt # ::snt This was not unexpected, because both pathways are activated in this cell line (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (c / cause-01 :ARG0 (a / activate-01 :ARG1 (p / pathway :mod (b / both)) :location (c2 / cell-line :mod (t / this))) :ARG1 (e / expect-01 :polarity "-" :ARG1 (t2 / this)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_1965_4571.121 # ::date 2015-08-04T11:10:51 # ::file pmid_1965_4571_121.txt # ::snt Cetuximab inhibited EGF-induced AKT phosphorylation more strongly in A431 cells and less so in Caski and C33A cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n3 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :ARG1-of (s2 / strong-02 :degree (m / more)) :location (c / cell-line :name (n4 / name :op1 "A431"))) :op2 (i3 / inhibit-01 :ARG0 s :ARG1 p :degree (l / less) :location (a / and :op1 (c2 / cell-line :name (n5 / name :op1 "Caski")) :op2 (c3 / cell-line :name (n6 / name :op1 "C33A"))))) # ::id pmid_1965_4571.122 # ::date 2015-08-04T11:17:17 # ::file pmid_1965_4571_122.txt # ::snt Indeed, it markedly reduced EGF-induced ERK1/2 phosphorylation in A431 cells, but in Caski and C33A cells the reduction was more modest (60 and 20% inhibition, respectively; Figures 3B–D), suggesting that persistent signalling through these pathways led to increased survival of Caski and C33A cells, when compared to A431 cells in the presence of cetuximab. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (i / it) :ARG1 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n2 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :location (c2 / cell-line :name (n3 / name :op1 "A431")) :manner (m4 / marked)) :ARG2 (r3 / reduce-01 :ARG1 p2 :mod (m / modest :degree (m2 / more)) :location (a / and :op1 (c3 / cell-line :name (n4 / name :op1 "Caski")) :op2 (c4 / cell-line :name (n5 / name :op1 "C33A"))) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and :op1 (i3 / inhibit-01 :quant (p4 / percentage-entity :value "60") :location c3) :op2 (i4 / inhibit-01 :quant (p / percentage-entity :value "20") :location c4) :mod (r2 / respective)))) :ARG0-of (s / suggest-01 :ARG1 (l / lead-03 :ARG0 (s2 / signal-07 :ARG0 (p6 / pathway :mod (t / this)) :ARG1-of (p5 / persist-01)) :ARG2 (s3 / survive-01 :ARG1 (a3 / and :op1 c3 :op2 c4) :ARG1-of (i5 / increase-01)) :time (c5 / compare-01 :ARG2 (c6 / cell-line :name (n6 / name :op1 "A431") :ARG2-of (p7 / present-02 :ARG1 (s4 / small-molecule :name (n7 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761"))))))) :mod (i6 / indeed) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "3B") :op2 (f2 / figure :mod "3D")))) # ::id pmid_1965_4571.123 # ::date 2015-08-04T11:34:42 # ::file pmid_1965_4571_123.txt # ::snt Cetuximab combined with trastuzumab synergistically reduces cell proliferation and activation of downstream signalling pathways in CC cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (r / reduce-01 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab") :ARG1-of (c / combine-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "trastuzumab") :xref (x / xref :value "PUBCHEM:9903" :prob "12.041334"))) :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (a / and :op1 (p / proliferate-01 :ARG0 (c2 / cell)) :op2 (a2 / activate-01 :ARG1 (p2 / pathway :ARG0-of (s3 / signal-07 :location (d / downstream))))) :location (c3 / cell-line :mod (d2 / disease :wiki "Cervical_cancer" :name (n3 / name :op1 "cervical" :op2 "cancer"))) :manner (s4 / synergize-01)) # ::id pmid_1965_4571.124 # ::date 2015-08-04T11:41:50 # ::file pmid_1965_4571_124.txt # ::snt We speculated that cells expressing higher EGFR/HER2 ratios, such as A431 cells, rely more on EGFR signalling for MAPK pathway activation and cell proliferation, whereas cells with a lower EGFR/HER2 ratio, such as C33A cells, depend more on EGFR/HER2 heterodimer signalling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (s / speculate-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (r / rely-01 :ARG0 (c2 / cell-line :ARG3-of (e2 / express-03 :ARG2 (r2 / ratio-of :op1 (m3 / macro-molecular-complex :part (e3 / enzyme :name (n3 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :part (e4 / enzyme :name (n4 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :ARG1-of (h2 / high-02 :degree (m4 / more)) :part e3)) :example (c3 / cell-line :name (n5 / name :op1 "A431"))) :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (p2 / pathway :name (n6 / name :op1 "MAPK") :ARG0-of (s2 / signal-07 :ARG1 e3))) :op2 (p3 / proliferate-01 :ARG0 (c4 / cell))) :degree m4) :ARG2 (d / depend-01 :ARG0 (c5 / cell-line :ARG0-of (h3 / have-03 :ARG1 (r3 / ratio-of :op1 m3 :ARG1-of (l2 / low-04 :degree m4) :part e4)) :example (c6 / cell-line :name (n7 / name :op1 "C33A"))) :ARG1 (s3 / signal-07 :ARG1 (h / heterodimer :mod m3)) :degree m4))) # ::id pmid_1965_4571.125 # ::date 2015-08-04T11:51:49 # ::file pmid_1965_4571_125.txt # ::snt Based on this assumption, the inhibition of the EGFR/HER2 heterodimer by anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) MAbs should interfere with C33A cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p / possible-01 :ARG1 (i / interfere-01 :ARG0 (i2 / inhibit-01 :ARG0 (a3 / antibody :mod (m3 / monoclone) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (s / small-molecule :name (n / name :op1 "cetuximab") :ARG0-of (c / counter-01 :ARG1 "e") :xref (x3 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :op2 (s2 / small-molecule :name (n5 / name :op1 "trastuzumab") :ARG0-of (c2 / counter-01 :ARG1 "e2") :xref (x2 / xref :value "PUBCHEM:9903" :prob "12.041334"))))) :ARG1 (h / heterodimer :part (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :part (e2 / enzyme :name (n3 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))) :ARG1 (p2 / proliferate-01 :ARG0 (c3 / cell-line :name (n7 / name :op1 "C33A")))) :ARG1-of (b / base-02 :ARG2 (a2 / assume-02 :mod (t / this)))) # ::id pmid_1965_4571.126 # ::date 2015-08-04T13:29:57 # ::file pmid_1965_4571_126.txt # ::snt As expected, this combination markedly reduced C33A cell colony formation leading to a synergistic interaction (R=0.58; Figures 4A and B), with concomitant reduction of MAPK and AKT phosphorylation (Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (r / reduce-01 :ARG0 (c / combine-01 :mod (t / this)) :ARG1 (f / form-01 :ARG1 (c2 / colony :mod (c3 / cell-line :name (n2 / name :op1 "C33A")))) :manner (m / marked) :ARG0-of (l / lead-03 :ARG2 (i / interact-01 :ARG0-of (s / synergize-01) :ARG0-of (h / have-03 :ARG1 (r3 / reduce-01 :ARG1 (a3 / and :op1 (p2 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :op2 (p3 / phosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :mod (c4 / concomitant) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure :mod "4D")))) :ARG1-of (m2 / mean-01 :ARG2 (s2 / string-entity :value "R" :ARG1-of (e3 / equal-01 :ARG2 "0.58"))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "4A") :op2 (f3 / figure :mod "4B"))) :ARG1-of (e2 / expect-01)) # ::id pmid_1965_4571.127 # ::date 2015-08-04T13:47:05 # ::file pmid_1965_4571_127.txt # ::snt Indeed, an additive effect (R=0.84) was also noted for Caski cells, that express intermediate levels of EGFR and HER2 (Figure 3A), with a decrease of almost 60% in cell survival (Figures 4A and B) and inhibition of downstream signalling pathways (MAPK and AKT; Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (n4 / note-02 :ARG1 (a / affect-01 :ARG1-of (a2 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (s3 / string-entity :value "R" :ARG1-of (e4 / equal-01 :ARG2 "0.84")))) :ARG2 (c / cell-line :name (n5 / name :op1 "Caski") :ARG3-of (e3 / express-03 :ARG2 (a4 / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op2 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :mod (i2 / intermediate)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) :ARG0-of (h / have-03 :ARG1 (d2 / decrease-01 :ARG1 (a5 / and :op1 (s / survive-01 :ARG1 (c2 / cell) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and :op1 (f2 / figure :mod "4A") :op2 (f3 / figure :mod "4B")))) :op2 (i3 / inhibit-01 :ARG1 (p3 / pathway :ARG0-of (s2 / signal-07 :location (d4 / downstream)) :ARG1-of (m / mean-01 :ARG2 (a7 / and :op1 (p2 / pathway :name (n3 / name :op1 "MAPK")) :op2 (p4 / pathway :name (n6 / name :op1 "AKT"))))) :ARG1-of (d5 / describe-01 :ARG0 (f4 / figure :mod "4C")))) :ARG2 (p / percentage-entity :value "60" :mod (a8 / almost))))) :mod (a3 / also) :mod (i / indeed)) # ::id pmid_1965_4571.128 # ::date 2015-08-04T14:02:11 # ::file pmid_1965_4571_128.txt # ::snt There were no changes in total AKT and MAPK proteins in Caski and C33A cell lines on treatments (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / change-01 :polarity "-" :ARG1 (a / and :op1 (p2 / protein-family :name (n2 / name :op1 "AKT") :mod (t / total)) :op2 (p / protein-family :name (n / name :op1 "MAPK"))) :location (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "Caski")) :op2 (c3 / cell-line :name (n4 / name :op1 "C33A")) :ARG1-of (t2 / treat-04)) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s / show-01 :polarity "-")))) # ::id pmid_1965_4571.129 # ::date 2015-08-04T14:07:16 # ::file pmid_1965_4571_129.txt # ::snt The combination of cetuximab with a TKI inhibits cell proliferation and MAPK phosphorylation in Caski but not in C33A cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (c2 / combine-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "TKI") :xref (x1 / xref :value "PUBCHEM:9886808" :prob "11.258356"))) :ARG1 (a / and :op1 (p3 / proliferate-01 :ARG0 (c3 / cell)) :op2 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :location (c4 / cell-line :name (n4 / name :op1 "Caski"))) :ARG2 (i2 / inhibit-01 :polarity "-" :ARG0 c2 :ARG1 a :location (c5 / cell-line :name (n5 / name :op1 "C33A")))) # ::id pmid_1965_4571.130 # ::date 2015-08-04T14:12:43 # ::file pmid_1965_4571_130.txt # ::snt Based on the idea of an EGFR/HER2 heterodimer signalling dependency of C33A cells, we investigated whether further EGFR inhibition with another targeted drug, such as TKIs, affected more Caski than C33A cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :mode "interrogative" :ARG0 (i2 / inhibit-01 :ARG0 (d / drug :mod (a2 / another) :ARG1-of (t / target-01) :example (s / small-molecule :wiki "Tyrosine-kinase_inhibitor" :name (n2 / name :op1 "TKI") :xref (x2 / xref :value "PUBCHEM:9886808" :prob "11.258356"))) :ARG1 (e / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :degree (f / further)) :ARG1 (c / cell-line :wiki "-" :name (n3 / name :op1 "Caski")) :degree (m2 / more) :compared-to (c2 / cell-line :wiki "-" :name (n4 / name :op1 "C33A"))) :ARG1-of (b / base-02 :ARG0 (i3 / idea :topic (d2 / depend-01 :ARG0 c2 :ARG1 (s2 / signal-07 :ARG1 (h / heterodimer :part e :part (e2 / enzyme :wiki "HER2/neu" :name (n6 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")))))))) # ::id pmid_1965_4571.131 # ::date 2015-08-04T14:20:43 # ::file pmid_1965_4571_131.txt # ::snt Therefore, we tested the combination of cetuximab with a specific EGFR TKI (PD153035). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (c / cause-01 :ARG1 (t / test-01 :ARG0 (w / we) :ARG1 (c2 / combine-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "TKI") :mod (s3 / specific) :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1-of (m / mean-01 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "PD153035") :xref (x3 / xref :value "PUBCHEM:4705" :prob "15.816147"))) :xref (x1 / xref :value "PUBCHEM:9886808" :prob "11.258356"))))) # ::id pmid_1965_4571.132 # ::date 2015-08-05T09:07:28 # ::file pmid_1965_4571_132.txt # ::snt As expected, combined treatments reduced Caski cell survival leading to an additive interaction (R=0.94) when compared to treatments alone (Figure 4E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (r / reduce-01 :ARG0 (t / treat-04 :ARG1-of (c / combine-01)) :ARG1 (s / survive-01 :ARG1 (c2 / cell-line :name (n / name :op1 "Caski"))) :ARG0-of (l / lead-03 :ARG2 (i / interact-01 :ARG1-of (a / add-02) :ARG1-of (m / mean-01 :ARG2 (s2 / string-entity :value "R" :ARG1-of (e2 / equal-01 :ARG2 "0.94")))) :condition (c3 / compare-01 :ARG1 t :ARG2 (t2 / treat-04 :mod (a2 / alone)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4E")) :ARG1-of (e / expect-01)) # ::id pmid_1965_4571.133 # ::date 2015-08-05T09:20:24 # ::file pmid_1965_4571_133.txt # ::snt Additionally, the double treatment in Caski cells was accompanied by a greater reduction of EGFR, HER2, AKT and MAPK phosphorylation (Figure 4G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (a2 / accompany-01 :ARG0 (r / reduce-01 :ARG1 (a3 / and :op1 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op2 (p3 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :op3 (p4 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "AKT") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op4 (p5 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :mod (g / great :degree (m / more))) :ARG1 (t / treat-04 :ARG1 (c / cell-line :name (n4 / name :op1 "Caski")) :mod (d / double))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4G"))) # ::id pmid_1965_4571.134 # ::date 2015-08-05T09:29:36 # ::file pmid_1965_4571_134.txt # ::snt Isolated cetuximab or PD153035 treatments reduced the survival of C33A cells in CA by the same proportion, reaching a more modest inhibition of HER2, AKT and MAPK phosphorylation than in Caski cells (Figures 4E and G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reduce-01 :ARG0 (o / or :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "cetuximab") :ARG1-of (i / isolate-01) :xref (x4 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :op2 (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "PD153035") :xref (x3 / xref :value "PUBCHEM:4705" :prob "15.816147")))) :ARG1 (s4 / survive-01 :ARG1 (c / cell-line :name (n6 / name :op1 "C33A"))) :ARG2 (p3 / proportion-01 :ARG1-of (s5 / same-01)) :ARG0-of (c2 / cause-01 :ARG1 (r2 / reach-01 :ARG1 (i2 / inhibit-01 :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HER2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :op2 (p4 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n8 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op3 (p5 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :mod (m / modest :degree (m2 / more)) :compared-to (c3 / cell-line :name (n9 / name :op1 "Caski"))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "4E") :op2 (f2 / figure :mod "4G"))) :time (a3 / assay-01 :mod (c4 / clonogenic))) # ::id pmid_1965_4571.135 # ::date 2015-08-05T09:46:52 # ::file pmid_1965_4571_135.txt # ::snt In contrast, the combined treatment proved to be antagonistic (R=1.28), with no decrease in phosphorylated proteins when compared to either drug alone (Figures 4E and G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / contrast-01 :ARG2 (a2 / and :op1 (p / prove-01 :ARG1 (a / antagonize-01 :ARG0 (t / treat-04 :ARG1-of (c2 / combine-01)) :ARG1-of (m / mean-01 :ARG2 (s / string-entity :value "R" :ARG1-of (e2 / equal-01 :ARG2 "1.28"))))) :op2 (d / decrease-01 :polarity "-" :ARG1 (p2 / protein :ARG3-of (p3 / phosphorylate-01)) :time (c3 / compare-01 :ARG1 t :ARG2 (d2 / drug :mod (e / either) :mod (a3 / alone))))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "4E") :op2 (f2 / figure :mod "4G")))) # ::id pmid_1965_4571.136 # ::date 2015-08-05T09:57:43 # ::file pmid_1965_4571_136.txt # ::snt Altogether, these data corroborate with our hypothesis that C33A cells are not so dependent on EGFR signalling for proliferation, as double EGFR inhibition with different drugs did not enhance the toxicity achieved by either agent alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (c / corroborate-01 :ARG0 (a / and :op1 (d / data :mod (t2 / this)) :op2 (t / thing :ARG1-of (h / hypothesize-01 :ARG0 (w / we)))) :ARG1 (d2 / depend-01 :polarity "-" :ARG0 (c2 / cell-line :name (n2 / name :op1 "C33A")) :ARG1 (s / signal-07 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :purpose (p / proliferate-01) :ARG1-of (c3 / cause-01 :ARG0 (e2 / enhance-01 :polarity "-" :ARG0 (i / inhibit-01 :ARG0 (d3 / drug :ARG1-of (d4 / differ-02)) :ARG1 e :mod (d5 / double)) :ARG1 (t3 / toxicity :ARG1-of (a2 / achieve-01 :ARG0 (a3 / agent :mod (e3 / either) :mod (a4 / alone)))))) :mod (s2 / so)) :mod (a5 / altogether)) # ::id pmid_1965_4571.137 # ::date 2015-08-05T10:07:59 # ::file pmid_1965_4571_137.txt # ::snt Additionally, the targeting of EGFR and HER2 with two different MAbs showed synergistic inhibitory effects (Figures 4A and B) demonstrating that heterodimer signalling is necessary for C33A cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / and :op2 (s / show-01 :ARG0 (t / target-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n2 / name :op1 "HER2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003"))) :ARG2 (a5 / antibody :ARG1-of (d / differ-02))) :ARG1 (a3 / affect-01 :ARG2 (s2 / synergize-01) :ARG0-of (i / inhibit-01)) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B"))) :ARG0-of (d3 / demonstrate-01 :ARG1 (n3 / need-01 :ARG1 (s4 / signal-07 :ARG1 (h / heterodimer)) :purpose (p / proliferate-01 :ARG0 (c / cell-line :name (n6 / name :op1 "C33A"))))))) # ::id pmid_1965_4571.138 # ::date 2015-08-05T10:15:32 # ::file pmid_1965_4571_138.txt # ::snt Furthermore, these data indicate that the successful inhibition of the MAPK and/or AKT pathways is a determinant factor for cetuximab efficacy in all CC cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (a / and :op2 (i / indicate-01 :ARG0 (d / data :mod (t / this)) :ARG1 (f / factor :domain (i2 / inhibit-01 :ARG1 (a3 / and-or :op1 (p / pathway :name (n / name :op1 "MAPK")) :op2 (p2 / pathway :name (n2 / name :op1 "AKT"))) :ARG0-of (s / succeed-01)) :ARG1-of (d2 / determine-01 :ARG3 (e / efficient-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")) :location (c / cell-line :mod (d3 / disease :name (n4 / name :op1 "CC")) :mod (a2 / all))))))) # ::id pmid_1965_4571.139 # ::date 2015-08-05T10:23:05 # ::file pmid_1965_4571_139.txt # ::snt Cetuximab combined with PD98059 synergistically reduces cell proliferation and MAPK pathway activation in CC cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (r / reduce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "cetuximab") :ARG1-of (c / combine-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD98059") :xref (x / xref :value "PUBCHEM:4713" :prob "18.349844"))) :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (a / and :op1 (p2 / proliferate-01 :ARG0 (c2 / cell)) :op2 (a2 / activate-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")))) :manner (s3 / synergize-01) :location (c3 / cell-line :mod (d / disease :name (n4 / name :op1 "CC")))) # ::id pmid_1965_4571.140 # ::date 2015-08-05T10:29:40 # ::file pmid_1965_4571_140.txt # ::snt To confirm that the MAPK pathway is relevant for cetuximab response, drug combination experiments with PD98059 (MEK1/2 inhibitor) were performed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (p2 / perform-01 :ARG1 (e / experiment-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "PD98059") :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK1/2"))) :xref (x1 / xref :value "PUBCHEM:4713" :prob "18.349844")) :ARG2 (c / combine-01 :ARG1 (d / drug))) :purpose (c2 / confirm-01 :ARG1 (r / relevant-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :ARG2 (r2 / respond-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")))))) # ::id pmid_1965_4571.141 # ::date 2015-08-05T11:05:10 # ::file pmid_1965_4571_141.txt # ::snt Both treatments inhibited Caski and C33A cell proliferation by the same magnitude, with a reduction of 50% and an additive effect for the combination over single-drug treatment in both cell lines (R=0.88 and R=0.92, respectively; Figure 4F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (i / inhibit-01 :ARG0 (t / treat-04 :mod (b / both)) :ARG1 (a / and :op1 (p2 / proliferate-01 :ARG0 (c / cell-line :name (n / name :op1 "Caski"))) :op2 (p3 / proliferate-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "C33A")))) :manner (m / magnitude :ARG1-of (s / same-01)) :ARG0-of (c3 / cause-01 :ARG1 (a2 / and :op1 (r / reduce-01 :ARG2 (p / percentage-entity :value "50") :ARG1-of (m2 / mean-01 :ARG2 (s3 / string-entity :value "R" :ARG1-of (e / equal-01 :ARG2 "0.88")))) :op2 (a3 / affect-01 :ARG1 (c4 / combine-01 :compared-to (t2 / treat-01 :ARG1 (c5 / cell-line) :ARG2 (d / drug :ARG1-of (s2 / single-02)))) :ARG1-of (a4 / add-02) :ARG1-of (m3 / mean-01 :ARG2 (s4 / string-entity :value "R" :ARG1-of (e2 / equal-01 :ARG2 "0.92")))) :mod (r2 / respective))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4F"))) # ::id pmid_1965_4571.142 # ::date 2015-08-05T11:14:16 # ::file pmid_1965_4571_142.txt # ::snt As expected, Figure 4H shows that a strong inhibition of MAPK phosphorylation was seen in both cell lines on treatment with PD98059 alone or in combination with cetuximab. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (f / figure :mod "4H") :ARG1 (s2 / see-01 :ARG1 (i / inhibit-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG1-of (s3 / strong-02)) :location (c / cell-line :mod (b / both) :ARG1-of (t / treat-04 :ARG2 (o / or :op1 (s4 / small-molecule :name (n2 / name :op1 "PD98059") :mod (a / alone) :xref (x3 / xref :value "PUBCHEM:4713" :prob "18.349844")) :op2 (c2 / combine-01 :ARG1 (s5 / small-molecule :name (n3 / name :op1 "PD98059") :xref (x2 / xref :value "PUBCHEM:4713" :prob "18.349844")) :ARG2 (s6 / small-molecule :name (n4 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761"))))))) :ARG1-of (e / expect-01)) # ::id pmid_1965_4571.143 # ::date 2015-08-05T11:26:24 # ::file pmid_1965_4571_143.txt # ::snt As the combination of both treatments led to a near complete MAPK cascade blockage, accompanied by a significant reduction of CC cell proliferation, we confirmed that the inhibition of this pathway plays an important role in cetuximab's efficacy. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (c / confirm-01 :ARG0 (w / we) :ARG1 (p2 / play-02 :ARG0 (i / inhibit-01 :ARG1 "p") :ARG1 (r / role :topic (e / efficient-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :mod (i2 / important))) :ARG1-of (c2 / cause-01 :ARG0 (l / lead-03 :ARG0 (c3 / combine-01 :ARG1 (t / treat-04 :mod (b / both))) :ARG2 (b2 / block-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :ARG1-of (c5 / complete-01 :degree (n3 / near)) :ARG1-of (a / accompany-01 :ARG0 (r2 / reduce-01 :ARG1 (p3 / proliferate-01 :ARG0 (c6 / cell-line :mod (d / disease :wiki "Cervical_cancer" :name (n4 / name :op1 "cervical" :op2 "cancer")))) :ARG1-of (s2 / significant-02))))))) # ::id pmid_1965_4571.144 # ::date 2015-08-05T11:34:29 # ::file pmid_1965_4571_144.txt # ::snt Cetuximab induces ADCC in A431 and Caski, but not in C33A cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (c3 / contrast-01 :ARG1 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (c5 / cytotoxicity :mod (c6 / cellular) :ARG0-of (d / depend-01 :ARG1 (a2 / antibody))) :location (a / and :op1 (c / cell-line :name (n3 / name :op1 "A431")) :op2 (c2 / cell-line :name (n4 / name :op1 "Caski")))) :ARG2 (i2 / induce-01 :polarity "-" :ARG0 s :ARG2 (t / thing) :location (c4 / cell-line :name (n5 / name :op1 "C33A")))) # ::id pmid_1965_4571.145 # ::date 2015-08-05T11:44:06 # ::file pmid_1965_4571_145.txt # ::snt Antibody-dependent cellular cytotoxicity response is dependent on the number of EGFR molecules per cell and on how efficiently cetuximab recognises its target (Vincenzi et al, 2008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (d2 / depend-01 :ARG0 (r / respond-01 :ARG2 (c / cytotoxicity :mod (c2 / cell) :ARG0-of (d3 / depend-01 :ARG1 (a / antibody)))) :ARG1 (a2 / and :op1 (r2 / rate-entity-91 :ARG1 (n2 / number :quant-of (m / molecule :mod (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG2 (c3 / cell)) :op2 (r3 / recognize-02 :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (t2 / thing :ARG1-of (t / target-01 :ARG0 s)) :ARG1-of (e2 / efficient-01))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n4 / name :op1 "Vincenzi")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2008")))) # ::id pmid_1965_4571.146 # ::date 2015-08-05T12:02:50 # ::file pmid_1965_4571_146.txt # ::snt FACS analysis showed that cetuximab detected even more cell surface receptors in A431 and Caski cells (P<0.05), when compared to a commercially available murine anti-EGFR MAb, although the same was not observed for C33A cells (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (s / show-01 :ARG0 (a / analyze-01 :mod (t / thing :name (n / name :op1 "FACS"))) :ARG1 (d / detect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (r / receptor :mod (s3 / surface :mod (c / cell)) :degree (m2 / more :mod (e3 / even))) :location (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "A431")) :op2 (c3 / cell-line :name (n4 / name :op1 "Caski"))) :time (c4 / compare-01 :ARG1 s2 :ARG2 (a4 / antibody :ARG0-of (c5 / counter-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG2-of (a3 / available-02 :manner (c6 / commerce)) :mod (o2 / organism :name (n8 / name :op1 "Muridae")) :mod (m / monoclone))) :concession (o / observe-01 :polarity "-" :ARG1 (s5 / same-01) :location (c7 / cell-line :name (n7 / name :op1 "C33A"))) :ARG1-of (s6 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id pmid_1965_4571.147 # ::date 2015-08-05T12:30:23 # ::file pmid_1965_4571_147.txt # ::snt Accordingly, at E/T ratios of 20 : 1, cetuximab mediated ADCC in 26.4 and 15.1% of A431 and Caski cells, respectively, but not in C33A cells (1.75%; Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (c3 / contrast-01 :ARG1 (m / mediate-01 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (c5 / cytotoxicity :mod (c6 / cellular) :ARG0-of (d2 / depend-01 :ARG1 (a3 / antibody))) :location (a / and :op1 (c / cell-line :name (n3 / name :op1 "A431") :quant (p3 / percentage-entity :value "26.4")) :op2 (c2 / cell-line :name (n4 / name :op1 "Caski") :quant (p / percentage-entity :value "15.1")) :mod (r / respective)) :manner (a2 / accordingly)) :ARG2 (m2 / mediate-01 :polarity "-" :ARG0 s :ARG1 (t / thing) :location (c4 / cell-line :name (n5 / name :op1 "C33A") :quant (p2 / percentage-entity :value "1.75"))) :condition (e / equal-01 :ARG1 (r3 / ratio-of :op1 (e2 / effector) :op2 (t2 / target-01)) :ARG2 (r4 / ratio-of :op1 "20" :op2 "1")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id pmid_1965_4571.148 # ::date 2015-08-05T12:47:00 # ::file pmid_1965_4571_148.txt # ::snt Cetuximab and RxT cooperate in an additive manner to inhibit VEGF secretion # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 12, 2015 (c / cooperate-01 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (r / radiotherapy) :ARG2 (i / inhibit-01 :ARG0 (a2 / and :op1 s :op2 r) :ARG1 (s3 / secrete-01 :ARG1 (p / protein :name (n3 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")))) :manner (a / additive)) # ::id pmid_1965_4571.149 # ::date 2015-08-05T12:52:37 # ::file pmid_1965_4571_149.txt # ::snt Anti-EGFR MAbs show suppressive effects on VEGF expression in vitro and in vivo (Vincenzi et al, 2008; Meira et al, 2009). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (s / show-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "MAbs") :ARG0-of (c / counter-01 :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :ARG1 (a / affect-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n3 / name :op1 "VEGF") :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :manner (a2 / and :op1 (i / in-vitro) :op2 (i2 / in-vivo))) :ARG0-of (s3 / suppress-01)) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (p2 / publication-91 :ARG0 (a4 / and :op1 (p3 / person :name (n4 / name :op1 "Vincenzi")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2008")) :op2 (p5 / publication-91 :ARG0 (a5 / and :op1 (p6 / person :name (n5 / name :op1 "Meira")) :op2 p4) :time (d2 / date-entity :year "2009"))))) # ::id pmid_1965_4571.150 # ::date 2015-08-05T13:41:18 # ::file pmid_1965_4571_150.txt # ::snt To examine whether cetuximab (100 μg ml−1) had this effect in CC cells, we tested it alone or combined with RxT (5 Gy) and VEGF expression was analysed by ELISA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (t / test-01 :ARG0 (w / we) :ARG1 (o / or :op1 "s4" :op2 (c / combine-01 :ARG1 "s4" :ARG2 (r2 / radiotherapy :quant (r / radiation-quantity :quant "5" :unit (g / gray)))))) :op2 (a3 / analyze-01 :ARG0 (t2 / thing :name (n5 / name :op1 "ELISA")) :ARG1 (e / express-03 :ARG2 (p / protein :name (n4 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")))) :purpose (e2 / examine-01 :ARG0 w :ARG1 (h / have-03 :mode "interrogative" :ARG0 (s4 / small-molecule :name (n7 / name :op1 "cetuximab") :quant (v / volume-quantity :quant "100" :unit (m / microgram-per-milliliter)) :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG1 (a4 / affect-01 :location (c2 / cell-line :mod (d / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical" :op2 "cancer"))))))) # ::id pmid_1965_4571.151 # ::date 2015-08-05T13:55:48 # ::file pmid_1965_4571_151.txt # ::snt Cetuximab or RxT treatments decreased VEGF secretion in all cell lines (Figures 5D–F; P<0.05). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / decrease-01 :ARG0 (o / or :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :op2 (t2 / treat-04 :ARG2 (r / radiotherapy))) :ARG1 (s3 / secrete-01 :ARG1 (p / protein :name (n3 / name :op1 "VEGF") :xref (x / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003"))) :location (c / cell-line :mod (a / all)) :ARG1-of (d2 / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "5D") :op2 (f2 / figure :mod "5F"))) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) # ::id pmid_1965_4571.152 # ::date 2015-08-05T13:59:31 # ::file pmid_1965_4571_152.txt # ::snt The combination of cetuximab with RxT for 24 h had an additive effect and, after 48 h of treatment, a further reduction was observed (Figures 5D–F), suggesting that these treatments have the potential of interfering with angiogenesis even in cells that do not express high EGFR levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (h / have-03 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG2 (r2 / radiotherapy) :duration (t / temporal-quantity :quant "24" :unit (h2 / hour))) :ARG1 (a2 / affect-01 :ARG1-of (a3 / add-02))) :op2 (o / observe-01 :ARG1 (r / reduce-01 :degree (f / further) :ARG0-of (s3 / suggest-01 :ARG1 (c2 / capable-01 :ARG1 (t2 / treat-04 :mod (t3 / this)) :ARG2 (i / interfere-01 :ARG0 t2 :ARG1 (a4 / angiogenesis) :location (c3 / cell-line :mod (e2 / even) :ARG3-of (e3 / express-03 :polarity "-" :ARG2 (l / level :quant-of (e4 / enzyme :name (n4 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (h3 / high-02)))))))) :ARG1-of (d / describe-01 :ARG0 (a6 / and :op1 (f2 / figure :mod "5D") :op2 (f3 / figure :mod "5E") :op3 (f4 / figure :mod "5F"))) :time (a5 / after :op1 (t4 / treat-04) :quant (t5 / temporal-quantity :quant "48" :unit (h4 / hour))))) # ::id pmid_2023_3444.1 # ::date 2015-08-03T12:21:47 # ::file pmid_2023_3444_1.txt # ::snt A rapid, sensitive, reproducible and cost-effective method for mutation profiling of colon cancer and metastatic lymph nodes (PMID:20233444) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p3 / publication-91 :ARG8 "PMID20233444" :ARG1 (m / method :ARG1-of (d / describe-01) :mod (r / rapid) :ARG0-of (s / sensitive-03) :ARG1-of (r2 / reproduce-01 :ARG1-of (p2 / possible-01)) :ARG0-of (a2 / affect-01 :ARG1 (c / cost)) :purpose (p / profile-01 :ARG0 (m2 / mutate-01 :ARG1 (a3 / and :op1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon" :op2 "cancer")) :op2 (n / node :mod (l / lymph) :ARG1-of (m3 / metastasize-101))))))) # ::id pmid_2023_3444.7 # ::date 2015-08-03T12:28:45 # ::file pmid_2023_3444_7.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 3, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2023_3444.8 # ::date 2015-08-03T12:33:34 # ::file pmid_2023_3444_8.txt # ::snt Among the 238 common hot-spot cancer mutations in 19 genes interrogated by the OncoCarta panel, mutations were detected in 7 different genes at 26 different nucleotide positions in our colon cancer samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (d / detect-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :quant "7" :ARG1-of (d2 / differ-02) :part (p / position :quant "26" :mod (n / nucleotide) :ARG1-of d2 :location (d3 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer") :ARG1-of (s / sample-01 :ARG0 (w / we))))) :ARG1-of (i2 / include-91 :ARG2 (m2 / mutate-01 :quant "238" :ARG1 (g2 / gene :quant "19" :ARG1-of (i / interrogate-01 :ARG0 (p2 / panel :name (n2 / name :op1 "OncoCarta")))) :ARG1-of (s2 / share-01 :degree (m3 / most)) :mod (h / hotspot))))) # ::id pmid_2023_3444.9 # ::date 2015-08-05T00:19:23 # ::file pmid_2023_3444_9.txt # ::snt Twenty-four assays that detected mutations in more than 1% of the samples were reconfigured into a new multiplexed panel, termed here as ColoCarta. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / configure-01 :ARG1 (a / assay-01 :quant "24" :ARG0-of (d / detect-01 :ARG1 (m / mutate-01) :location (t2 / thing :quant (m2 / more-than :op1 (p / percentage-entity :value "1")) :ARG1-of (s / sample-01)))) :ARG4 (p2 / panel :ARG1-of (n / new-01) :mod (m3 / multiplex) :ARG1-of (t / term-01 :ARG3 (p3 / panel :name (n2 / name :op1 "ColoCarta")) :location (h / here))) :mod (a2 / again)) # ::id pmid_2023_3444.10 # ::date 2015-08-05T00:24:22 # ::file pmid_2023_3444_10.txt # ::snt Mutation profiling was repeated on 32 mutant samples using ColoCarta and the results were identical to results with OncoCarta, demonstrating that this methodology was reproducible. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (r4 / repeat-01 :ARG1 (p2 / profile-01 :ARG1 (m2 / mutate-01)) :ARG3 (m4 / mutate-01 :quant "32" :ARG1-of (s / sample-01)) :manner (u / use-01 :ARG1 (p3 / panel :name (n2 / name :op1 "ColoCarta")))) :op2 (i / identical-01 :ARG1 (t / thing :ARG2-of (r / result-01)) :ARG2 (t2 / thing :ARG2-of (r2 / result-01) :instrument (p / product :name (n / name :op1 "OncoCarta"))) :ARG0-of (d / demonstrate-01 :ARG1 (p4 / possible-01 :ARG1 (r3 / reproduce-01 :ARG0 (m / methodology :mod (t3 / this))))))) # ::id pmid_2023_3444.11 # ::date 2015-08-05T00:28:25 # ::file pmid_2023_3444_11.txt # ::snt Further evidence demonstrating the validity of the data was the fact that the mutation frequencies of the most common colon cancer mutations were similar to the COSMIC (Catalog of Somatic Mutations in Cancer) database. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / evidence-01 :ARG0 (r / resemble-01 :ARG1 (h / have-frequency-91 :ARG1 (m2 / mutate-01 :ARG1 (d4 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon" :op2 "cancer")) :ARG1-of (s / share-01 :degree (m3 / most))) :mod (m / mutate-01)) :ARG2 (m4 / mutate-01 :source (d / database :name (n / name :op1 "COSMIC")))) :degree (f / further) :ARG0-of (d2 / demonstrate-01 :ARG1 (v / valid-02 :ARG1 (d3 / data)))) # ::id pmid_2023_3444.12 # ::date 2015-08-04T03:35:45 # ::file pmid_2023_3444_12.txt # ::snt The frequencies were 43.5% for KRAS, 20.1% for PIK3CA, and 12.1% for BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (a2 / and :op1 (h / have-frequency-91 :ARG1 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG2 (p / percentage-entity :value "43.5")) :op2 (h2 / have-frequency-91 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG2 (p2 / percentage-entity :value "20.1")) :op3 (h3 / have-frequency-91 :ARG1 (g3 / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG2 (p3 / percentage-entity :value "12.1"))) # ::id pmid_2023_3444.13 # ::date 2015-08-03T12:22:30 # ::file pmid_2023_3444_13.txt # ::snt In addition, infrequent mutations in NRAS, AKT1, ABL1, and MET were detected. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (a / and :op2 (d / detect-01 :ARG1 (m / mutate-01 :ARG1 (a2 / and :op1 (g4 / gene :name (n / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op2 (g / gene :name (n2 / name :op1 "AKT1") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.004")) :op3 (g2 / gene :name (n3 / name :op1 "ABL1") :xref (x3 / xref :value "UNIPROT:ABL1_HUMAN" :prob "1.004")) :op4 (g3 / gene :name (n4 / name :op1 "MET") :xref (x1 / xref :value "UNIPROT:MET_HUMAN" :prob "1.004"))) :ARG1-of (f / frequent-02 :polarity "-")))) # ::id pmid_2023_3444.14 # ::date 2015-08-03T12:26:40 # ::file pmid_2023_3444_14.txt # ::snt Mutation profiling of metastatic lymph nodes and their corresponding primary tumors showed that they were 89.7% concordant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (s / show-01 :ARG0 (a / and :op1 (p2 / profile-01 :ARG1 (m / mutate-01 :ARG1 (n / node :mod (l / lymph :mod (m2 / metastasis))))) :op2 (t / tumor :mod (p3 / primary) :ARG1-of (c / correspond-02 :ARG2 n))) :ARG1 (c2 / concordant :domain a :mod (p / percentage-entity :value "89.7"))) # ::id pmid_2023_3444.15 # ::date 2015-08-04T08:48:38 # ::file pmid_2023_3444_15.txt # ::snt All mutations found in the lymph nodes were also found in the corresponding primary tumors, but in 4 cases a mutation was present in the primary tumor only. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (f2 / find-01 :ARG1 (m / mutate-01 :ARG1-of (f / find-01 :location (n / node :mod (l / lymph))) :mod (a / all)) :location (t / tumor :mod (p / primary) :ARG1-of (c2 / correspond-02)) :mod (a2 / also)) :ARG2 (m2 / mutate-01 :quant "1" :mod (c3 / case-04 :quant "4") :location (t2 / tumor :mod p :mod (o / only)))) # ::id pmid_2023_3444.91 # ::date 2015-08-03T12:39:57 # ::file pmid_2023_3444_91.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2023_3444.92 # ::date 2015-08-03T13:08:48 # ::file pmid_2023_3444_92.txt # ::snt Mutations were detected in control DNAs from intact and FFPETsamples # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (d / detect-01 :ARG1 (m / mutate-01) :location (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA") :ARG0-of (c / control-01) :source (a / and :op1 (t2 / thing :mod (i / intact) :ARG1-of (s / sample-01)) :op2 (t3 / thing :name (n / name :op1 "FFPET") :ARG1-of s)))) # ::id pmid_2023_3444.93 # ::date 2015-08-03T14:15:02 # ::file pmid_2023_3444_93.txt # ::snt Previously described mutations in control cell lines were detected. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 3, 2015 (d / detect-01 :ARG1 (m / mutate-01 :ARG1-of (d2 / describe-01 :time (p / previous)) :location (c / cell-line :ARG0-of (c2 / control-01)))) # ::id pmid_2023_3444.94 # ::date 2015-08-03T14:26:58 # ::file pmid_2023_3444_94.txt # ::snt BRAF_V600E, HRAS_G12D, NRAS_Q61L, PIK3CA_E545K, KRAS_G13D, NRAS_Q61K, EGFR1_S125L, and PIK3CA_H1047R were detected in the appropriate cell lines (A2058, HS578T, HL60, MCF7, MDAMB231, NCI-H1299, NCI-H1395, and UACC-893, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (d / detect-01 :ARG1 (a3 / and :op1 (g2 / gene :wiki "BRAF_(gene)" :name (n3 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01 :value "V600E") :xref (x5 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g3 / gene :wiki "-" :name (n4 / name :op1 "HRAS") :ARG1-of (m3 / mutate-01 :value "G12D") :xref (x4 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :op3 (g4 / gene :wiki "-" :name (n5 / name :op1 "NRAS") :ARG1-of (m4 / mutate-01 :value "Q61L") :xref (x3 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op4 (g5 / gene :wiki "-" :name (n6 / name :op1 "PIK3CA") :ARG1-of (m5 / mutate-01 :value "E545K") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op5 (g6 / gene :wiki "-" :name (n7 / name :op1 "KRAS") :ARG1-of (m6 / mutate-01 :value "G13D") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op6 (g7 / gene :wiki "-" :name (n8 / name :op1 "NRAS") :ARG1-of (m7 / mutate-01 :value "Q61K") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op7 (g / gene :wiki "-" :name (n2 / name :op1 "EGFR") :ARG1-of (m9 / mutate-01 :value "S125L") :xref (x7 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op8 (g8 / gene :wiki "-" :name (n / name :op1 "PIK3CA") :ARG1-of (m8 / mutate-01 :value "H1047R") :xref (x6 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :location (c / cell-line :ARG1-of (a / appropriate-02) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (c2 / cell-line :wiki "-" :name (n9 / name :op1 "A2058")) :op2 (c3 / cell-line :wiki "-" :name (n16 / name :op1 "HS578T")) :op3 (c4 / cell-line :wiki "HL60" :name (n12 / name :op1 "HL60")) :op4 (c5 / cell-line :wiki "MCF-7" :name (n15 / name :op1 "MCF7")) :op5 (c6 / cell-line :wiki "-" :name (n13 / name :op1 "MDAMB231")) :op6 (c7 / cell-line :wiki "-" :name (n11 / name :op1 "NCI-H1299")) :op7 (c8 / cell-line :wiki "-" :name (n14 / name :op1 "NCI-H1395")) :op8 (c9 / cell-line :wiki "-" :name (n10 / name :op1 "UACC-893")))))) # ::id pmid_2023_3444.95 # ::date 2015-08-04T07:04:52 # ::file pmid_2023_3444_95.txt # ::snt The appropriate mutation was found in MCF-7 (PIK3CA_E545K) from both intact DNA and DNA isolated from FFPET. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (f / find-01 :ARG1 (m / mutate-01 :ARG1-of (a / appropriate-02)) :location (c / cell-line :name (n / name :op1 "MCF-7") :ARG1-of (m2 / mean-01 :ARG2 (g / gene :name (n2 / name :op1 "PIK3CA") :ARG1-of (m3 / mutate-01 :value "E545K") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :location (a3 / and :op1 (n3 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA") :mod (i / intact)) :op2 (n6 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA") :ARG1-of (i2 / isolate-01 :ARG2 (t / thing :name (n4 / name :op1 "FFPET"))))))) # ::id pmid_2023_3444.96 # ::date 2015-08-04T07:33:58 # ::file pmid_2023_3444_96.txt # ::snt DNAs from clinical samples, control cell lines, and cell lines formalin-fixed, paraffin-embedded cell lines showed the same rates of primer extension and performance on mass spectrometer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (s / show-01 :ARG0 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA") :source (a2 / and :op1 (t / thing :mod (c / clinic) :ARG1-of (s4 / sample-01)) :op2 (c2 / cell-line :ARG1-of (c3 / control-01)) :op3 (c4 / cell-line :ARG0-of (f / fix-01 :ARG1 (f2 / formalin))) :op4 (c5 / cell-line :ARG1-of (e2 / embed-01 :ARG2 (p3 / paraffin))))) :ARG1 (r / rate-entity-91 :ARG1 (a / and :op1 (e / extend-01 :instrument (s3 / spectometer :mod (m / mass)) :mod (p / primer)) :op2 (p2 / perform-01 :instrument s3)) :ARG1-of (s2 / same-01))) # ::id pmid_2023_3444.97 # ::date 2015-08-05T00:02:09 # ::file pmid_2023_3444_97.txt # ::snt The proportion of the mutated alleles in each cell line, as observed from the area under the mutant peak on the spectra, ranged from 0.4-0.6, as expected for a pure clonal population with a heterozygote mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (r / range-01 :ARG1 (p2 / proportion-01 :ARG1 (a / allele :ARG1-of (m2 / mutate-01) :location (c2 / cell-line :mod (e2 / each))) :ARG1-of (o / observe-01 :location (a2 / area :location (u / under :op1 (p3 / peak :ARG0-of (m3 / mutate-01) :location (s / spectrum)))))) :ARG3 "0.4" :ARG4 "0.6" :ARG1-of (e / expect-01 :prep-for (p / population :mod (c / clone) :ARG1-of (m / mutate-01 :ARG3 (h / heterozygote)) :mod (p4 / pure)))) # ::id pmid_2023_3444.98 # ::date 2015-08-04T08:49:31 # ::file pmid_2023_3444_98.txt # ::snt Spectra for cell line UACC-893 had equal fractions of mutant and wt alleles (Fig. 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (h / have-03 :ARG0 (s / spectrum :mod (c / cell-line :name (n / name :op1 "UACC-893"))) :ARG1 (e / equal-01 :ARG1 (f / fraction-01 :ARG1 (a / allele :ARG1-of (m / mutate-01))) :ARG2 (f2 / fraction-01 :ARG1 (a2 / allele :mod (w / wild-type)))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "2A"))) # ::id pmid_2023_3444.99 # ::date 2015-08-04T09:15:40 # ::file pmid_2023_3444_99.txt # ::snt One exception to this distribution among cell lines was seen in A2058, which showed spectra consistent with 2 copies of the WT allele and one mutant BRAF mutant allele (Fig. 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (s / see-01 :ARG1 (t / thing :ARG1-of (e / except-01 :ARG2 (d2 / distribute-01 :ARG1 (c2 / cell-line) :mod (t2 / this)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B")) :location (c / cell-line :name (n / name :op1 "A2058") :ARG0-of (s2 / show-01 :ARG1 (s3 / spectra :ARG1-of (c3 / consistent-01 :ARG2 (a / and :op1 (c4 / copy-01 :quant "2" :ARG1 (a2 / allele :mod (w / wild-type))) :op2 (c5 / copy-01 :ARG1 (a3 / allele :ARG3-of (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))))))))) # ::id pmid_2023_3444.100 # ::date 2015-08-04T09:55:13 # ::file pmid_2023_3444_100.txt # ::snt The 3 alleles of BRAF in A2058 are consistent with the observation that there are 3 copies of chromosome 7 in this cell line (COSMIC in the SNP Array Based LOH and Copy Number Analysis data base) [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (c / consistent-01 :ARG1 (a / allele :quant "3" :mod (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location (c2 / cell-line :name (n2 / name :op1 "A2058"))) :ARG2 (o / observe-01 :ARG1 (b / be-located-at-91 :ARG1 (c3 / copy-01 :quant "3" :ARG1 (c4 / chromosome :mod "7" :xref (x1 / xref :value "GO:0005694" :prob "0.8"))) :ARG2 (c5 / cell-line :mod (t / this)))) :ARG1-of (d / describe-01 :ARG0 (d2 / database :name (n3 / name :op1 "COSMIC") :location (a3 / and :op1 (d5 / database :name (n6 / name :op1 "SNP" :op2 "Array" :op3 "Based" :op4 "LOH")) :op2 (d3 / database :name (n5 / name :op1 "Copy" :op2 "Number" :op3 "Analysis"))))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG0-of (c6 / cite-01 :ARG1 "21")))) # ::id pmid_2023_3444.101 # ::date 2015-08-04T03:40:50 # ::file pmid_2023_3444_101.txt # ::snt The Sequenom platform was sensitive and quantitative # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (a / and :op1 (s / sensitive-03 :ARG0 (p / platform :name (n / name :op1 "Sequenom"))) :op2 (q / quantitative :domain p)) # ::id pmid_2023_3444.102 # ::date 2015-08-04T03:44:51 # ::file pmid_2023_3444_102.txt # ::snt Pilot studies demonstrated that the assays worked with as little as 1 ng of DNA (Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (d / demonstrate-01 :ARG0 (s / study-01 :mod (p / pilot)) :ARG1 (w / work-09 :ARG1 (a / assay-01 :mod (c / concentration-quantity :quant "1" :unit (n / nanogram) :mod (l / little :compared-to (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3"))) # ::id pmid_2023_3444.103 # ::date 2015-08-04T03:51:34 # ::file pmid_2023_3444_103.txt # ::snt The fraction of unextended primer was .09 even when the input DNA was between 1-3 ng, When concentrations of the amount of DNA was between 3-14 ng, the fraction of unextended primer was similar, .07. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (m / multi-sentence :snt1 (f4 / fraction :quant "0.09" :part-of (p / primer :ARG1-of (e / extend-01 :polarity "-")) :condition (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA") :mod (i / input) :quant (b / between :op1 (c / concentration-quantity :quant "1" :unit (n / nanogram)) :op2 (c2 / concentration-quantity :quant "3" :unit n)))) :snt2 (f5 / fraction :part-of (p2 / primer :quant "0.07" :ARG1-of (e2 / extend-01 :polarity "-")) :condition (c3 / concentrate-02 :ARG1 (a / amount-01 :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")) :ARG2 (b2 / between :op1 (c4 / concentration-quantity :quant "3" :unit "n2") :op2 (c5 / concentration-quantity :quant "14" :unit (n2 / nanogram))))) :ARG1-of (r / resemble-01))) # ::id pmid_2023_3444.104 # ::date 2015-08-04T03:28:08 # ::file pmid_2023_3444_104.txt # ::snt Thus, the assays worked well even when only 1 ng of DNA was used. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (c3 / cause-01 :ARG1 (w / work-09 :ARG1 (a / assay-01) :manner (w2 / well) :concession (e / even-when :op1 (u / use-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA") :quant (c2 / concentration-quantity :quant "1" :unit (n / nanogram) :mod (o / only)))))) :ARG2-of (c / contrast-01)) # ::id pmid_2023_3444.105 # ::date 2015-08-04T03:32:50 # ::file pmid_2023_3444_105.txt # ::snt In clinical samples with some assays it was possible to detect mutations that only represented 5% of the total 2 peak areas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (p2 / possible-01 :ARG1 (d / detect-01 :ARG1 (m / mutate-01 :ARG0-of (r / represent-01 :ARG1 (p / percentage-entity :value "5" :ARG3-of (i / include-91 :ARG1 (a2 / area :quant "2" :mod (t / total) :mod (p3 / peak)))) :mod (o / only))) :location (t2 / thing :ARG1-of (s / sample-01 :manner (a / assay-01 :quant (s2 / some)) :mod (c / clinic))))) # ::id pmid_2023_3444.106 # ::date 2015-08-04T05:32:58 # ::file pmid_2023_3444_106.txt # ::snt The spectra in Fig. 4 show a small but clear peak at the expected size for a PIK3CA 1047R mutation in a lymph node. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 17, 2015 (s / show-01 :ARG0 (s2 / spectra :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4"))) :ARG1 (p / peak :mod (s3 / small :ARG1-of (c / contrast-01 :ARG2 (p2 / peak :mod (c2 / clear) :ARG0-of (h / have-03 :ARG1 (s4 / size-01 :ARG1 (m / mutate-01 :value "1047R" :ARG2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :location (n4 / node :mod (l / lymph))) :ARG1-of (e / expect-01)))))))) # ::id pmid_2023_3444.107 # ::date 2015-08-04T03:54:22 # ::file pmid_2023_3444_107.txt # ::snt We also were able to demonstrate the sensitivity of the platform by performing a cell mixing experiment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (p2 / possible-01 :ARG1 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (s / sensitive-03 :ARG0 (p3 / platform)) :mod (a / also) :manner (p / perform-02 :ARG0 w :ARG1 (e / experiment-01 :ARG1 (m / mix-01 :ARG1 (c / cell)))))) # ::id pmid_2023_3444.108 # ::date 2015-08-04T04:11:01 # ::file pmid_2023_3444_108.txt # ::snt Mutation analysis was done using MCF-7 cell line DNA alone or mixed with SKBR3 at various percentages. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (a / analyze-01 :ARG1 (m / mutate-01) :manner (o / or :op1 (u / use-01 :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA") :mod (c / cell-line :name (n / name :op1 "MCF-7")) :mod (a2 / alone))) :op2 (u2 / use-01 :ARG1 (m2 / mix-01 :ARG1 n3 :ARG2 (c2 / cell-line :name (n2 / name :op1 "SKBR3"))) :degree (p / percentage :ARG1-of (v / vary-01))))) # ::id pmid_2023_3444.109 # ::date 2015-08-04T04:19:25 # ::file pmid_2023_3444_109.txt # ::snt MCF-7 cells contain a PIK3CA mutation, and SKBR3 cells do not. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (c / contain-01 :ARG0 (c3 / cell-line :name (n2 / name :op1 "MCF-7")) :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :op2 (c2 / contain-01 :polarity "-" :ARG0 (c4 / cell-line :name (n3 / name :op1 "SKBR3")) :ARG1 g)) # ::id pmid_2023_3444.110 # ::date 2015-08-04T04:23:12 # ::file pmid_2023_3444_110.txt # ::snt Fig. 5 demonstrates that the mutation was detectable even when the MCF-7 cells represented only 5 to 10% of the total DNA and only 5 to 2.5% of the alleles. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / demonstrate-01 :ARG0 (f / figure :mod "5") :ARG1 (h / have-concession-91 :ARG1 (p3 / possible-01 :ARG1 (d2 / detect-01)) :ARG2 (r / represent-01 :ARG0 (c / cell-line :name (n / name :op1 "MCF-7")) :ARG1 (a / and :op1 (b / between :op1 (p4 / percentage-entity :value "5") :op2 (p / percentage-entity :value "10") :ARG3-of (i / include-91 :ARG2 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA") :mod (t / total)))) :op2 (b2 / between :op1 (p6 / percentage-entity :value "5") :op2 (p5 / percentage-entity :value "2.5") :mod (o / only) :ARG3-of (i2 / include-91 :ARG2 (a2 / allele))))))) # ::id pmid_2023_3444.111 # ::date 2015-08-04T04:47:39 # ::file pmid_2023_3444_111.txt # ::snt This sensitivity is important for mutation detection in clinical cancer samples, which usually contain some amount of normal tissue, which dilutes the number of tumor cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / important :domain (s / sensitive-03 :mod (t3 / this)) :purpose (d / detect-01 :ARG1 (m / mutate-01) :location (s2 / sample-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")) :ARG0-of (c / contain-01 :ARG1 (a2 / amount :mod (s3 / some) :quant-of (t / tissue) :ARG1-of (n2 / normal-02) :ARG0-of (d3 / dilute-01 :ARG1 (n / number :quant-of (c2 / cell :mod (t2 / tumor))))) :manner (u / usual)) :mod (c4 / clinic)))) # ::id pmid_2023_3444.112 # ::date 2015-08-04T04:25:20 # ::file pmid_2023_3444_112.txt # ::snt This is of particular concern when profiling lymph nodes, which may contain a minority of tumor cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (c / concern-01 :ARG0 (t2 / this) :time (p / profile-01 :ARG1 (n / node :mod (l / lymph) :ARG0-of (c2 / contain-01 :ARG1 (c3 / cell :mod (t / tumor) :quant (m / minority)) :ARG1-of (p2 / possible-01)))) :mod (p3 / particular)) # ::id pmid_2023_3444.113 # ::date 2015-08-04T04:46:17 # ::file pmid_2023_3444_113.txt # ::snt Frequencies of C-07 mutations in KRAS, NRAS, PIK3CA, and BRAF detected with OncoCarta and the Sequenom platform were similar to previous reports # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (r2 / resemble-01 :ARG1 (h / have-frequency-91 :ARG1 (m / mutate-01 :ARG0 (c / cell-line :name (n8 / name :op1 "C-07")) :ARG1 (a2 / and :op1 (g2 / gene :name (n4 / name :op1 "KRAS") :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n5 / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op3 (g4 / gene :name (n6 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op4 (g5 / gene :name (n7 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1-of (d / detect-01 :ARG2 (a / and :op1 (p2 / platform :name (n / name :op1 "OncoCarta")) :op2 (p3 / platform :name (n3 / name :op1 "Sequenom"))))) :ARG2 (t / thing :ARG1-of (r3 / report-01 :time (p / previous)))) # ::id pmid_2023_3444.114 # ::date 2015-08-04T07:04:07 # ::file pmid_2023_3444_114.txt # ::snt In this preliminary assessment of the feasibility of using the Sequenom platform to do large-scale mutation profiling of colon cancer samples isolated from FFPET, it was essential to determine if our data yielded frequencies typical of what has been seen previously. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / essential :domain (d3 / determine-01 :ARG1 (y / yield-01 :mode "interrogative" :ARG0 (d2 / data :poss (w / we)) :ARG1 (f / frequency :ARG0-of (t / typify-01 :ARG1 (t2 / thing :ARG1-of (s / see-01 :time (p / previous)))))) :time (a / assess-01 :ARG1 (f2 / feasible :mod (u / use-01 :ARG1 (p3 / platform :name (n / name :op1 "Sequenom")) :ARG2 (p4 / profile-01 :ARG0 (m / mutate-01 :mod (l / large-scale)) :ARG1 (s2 / sample-01 :ARG1 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer")) :ARG1-of (i / isolate-01 :ARG2 (t3 / thing :name (n2 / name :op1 "FFPET"))))))) :mod (p2 / preliminary) :mod (t4 / this)))) # ::id pmid_2023_3444.115 # ::date 2015-08-04T07:35:03 # ::file pmid_2023_3444_115.txt # ::snt Table 2 shows the mutation frequencies obtained here and from the COSMIC (Catalog of Somatic Mutations in Cancer) database [21]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (s / show-01 :ARG0 (t / table :mod "2") :ARG1 (h2 / have-frequency-91 :ARG1 (m / mutate-01) :ARG1-of (o / obtain-01 :location (h / here) :source (d2 / database :name (n / name :op1 "COSMIC") :ARG1-of (m2 / mean-01 :ARG2 (t2 / thing :ARG2-of (c2 / catalogue-01 :ARG1 (m3 / mutate-01 :mod (s2 / somatic) :location (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG0-of (c / cite-01 :ARG1 "21")))) # ::id pmid_2023_3444.116 # ::date 2015-08-03T12:36:26 # ::file pmid_2023_3444_116.txt # ::snt The COSMIC frequencies seen in Table 2 are based only on those mutations that are detectable with OncoCarta. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (b / base-02 :ARG1 (h / have-frequency-91 :ARG1-of (s / see-01 :location (t / table :mod "2")) :mod (t4 / thing :name (n / name :op1 "COSMIC"))) :ARG2 (m / mutate-01 :mod (t2 / this) :ARG1-of (d / detect-01 :ARG1-of (p / possible-01) :instrument (p2 / product :name (n2 / name :op1 "OncoCarta")))) :mod (o / only)) # ::id pmid_2023_3444.117 # ::date 2015-08-03T12:36:37 # ::file pmid_2023_3444_117.txt # ::snt OncoCarta assays interrogate 99%, 98%, and 78% of the known colon cancer mutations in BRAF, KRAS, and PIK3CA, respectively, based on a large number of colon cancer samples that have been sequenced in BRAF (n = 4628), KRAS (n = 858) and PIK3CA (n = 247). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (i / interrogate-01 :ARG0 (a / assay-01 :instrument (p4 / product :name (n / name :op1 "OncoCarta"))) :ARG1 (m / mutate-01 :ARG1 (a2 / and :op1 (g / gene :name (n2 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n3 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op3 (g3 / gene :name (n4 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :manner (r / respective) :ARG1-of (k / know-02) :ARG2-of (i2 / include-91 :ARG1 (m2 / mutate-01 :ARG1 a2 :ARG1-of k :mod "d") :ARG3 (a4 / and :op1 (p / percentage-entity :value "99") :op2 (p2 / percentage-entity :value "98") :op3 (p3 / percentage-entity :value "78"))) :mod (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colon" :op2 "cancer"))) :ARG1-of (b / base-02 :ARG2 (n8 / number :mod (l / large) :quant-of (a3 / and :op1 (t / thing :quant "4628" :ARG1-of (s / sample-01 :ARG2 d) :ARG1-of (s2 / sequence-01 :location g)) :op2 (t2 / thing :quant "858" :ARG1-of (s3 / sample-01 :ARG2 d) :ARG1-of (s4 / sequence-01 :location g2)) :op3 (t3 / thing :quant "247" :ARG1-of (s5 / sample-01 :ARG2 d) :ARG1-of (s6 / sequence-01 :location g3)))))) # ::id pmid_2023_3444.118 # ::date 2015-08-03T13:22:27 # ::file pmid_2023_3444_118.txt # ::snt The OncoCarta panel found that the most frequent mutations in C-07 were KRAS (43.5%), PIK3CA (20.1%), and BRAF (12.1%), which are similar to what is seen in COSMIC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (p / panel :name (n / name :op1 "OncoCarta")) :ARG1 (f2 / frequent-02 :ARG1 (a3 / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "KRAS") :frequency (p2 / percentage-entity :value "43.5") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m3 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "PIK3CA") :frequency (p3 / percentage-entity :value "20.1") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :op3 (m4 / mutate-01 :ARG1 (g3 / gene :name (n4 / name :op1 "BRAF") :frequency (p4 / percentage-entity :value "12.1") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG1-of (r / resemble-01 :ARG2 (t3 / thing :ARG1-of (s / see-01 :location (t2 / thing :name (n6 / name :op1 "COSMIC"))))) :location (c / cell-line :name (n5 / name :op1 "C-07"))) :degree (m2 / most))) # ::id pmid_2023_3444.119 # ::date 2015-08-03T13:37:40 # ::file pmid_2023_3444_119.txt # ::snt NRAS mutations, while infrequent, were detected in codons 12, 13 and 61 and represent a sizable minority of the C0-7 samples (3.8%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (a / and :op1 (d / detect-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :wiki "-" :name (n / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :concession (f / frequent-02 :polarity "-" :ARG1 m)) :location (a2 / and :op1 (c / codon :mod "12") :op2 (c2 / codon :mod "13") :op3 (c3 / codon :mod "61"))) :op2 (r / represent-01 :ARG0 m :ARG1 (m2 / minority :mod (s / sizable) :poss (t2 / thing :ARG1-of (s2 / sample-01) :ARG1-of (l / label-01 :ARG2 (s3 / string-entity :value "C0-7"))) :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value "3.8"))))) # ::id pmid_2023_3444.120 # ::date 2015-08-03T13:49:28 # ::file pmid_2023_3444_120.txt # ::snt These data suggest that FFPET samples can be interrogated with the technology described here and yield accurate data. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (a / and :op1 (p / possible-01 :ARG1 (i / interrogate-01 :ARG2 (t3 / thing :name (n / name :op1 "FFPET") :ARG1-of (s2 / sample-01)) :instrument (t2 / technology :ARG1-of (d3 / describe-01 :location (h / here))))) :op2 (y / yield-01 :ARG0 t3 :ARG1 (d2 / data :mod (a2 / accurate))))) # ::id pmid_2023_3444.121 # ::date 2015-08-03T13:54:49 # ::file pmid_2023_3444_121.txt # ::snt While most of the specific amino acid mutations mirror what is seen on the COSMIC database, some unique colon cancer gene mutations were found, which include ABL1-F359V, AKT1-E17K, MET-R970C, and MET-T992I. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-concession-91 :ARG1 (f / find-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :mod (d2 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colon" :op2 "cancer"))) :mod (u / unique) :ARG2-of (i / include-01 :ARG1 (a / and :op1 (g2 / gene :name (n2 / name :op1 "ABL1") :ARG2-of (m7 / mutate-01 :value "F359V") :xref (x3 / xref :value "UNIPROT:ABL1_HUMAN" :prob "1.004")) :op2 (g3 / gene :name (n3 / name :op1 "AKT1") :ARG2-of (m2 / mutate-01 :value "E17K") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.004")) :op3 (g4 / gene :name (n4 / name :op1 "MET") :ARG2-of (m3 / mutate-01 :value "R970C") :xref (x1 / xref :value "UNIPROT:MET_HUMAN" :prob "1.004")) :op3 (g5 / gene :name (n5 / name :op1 "MET") :ARG2-of (m8 / mutate-01 :value "T992I") :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "1.004")))) :mod (s3 / some))) :ARG2 (m4 / mirror-01 :ARG1 (t / thing :ARG1-of (s2 / see-01 :location (d / database :name (n / name :op1 "COSMIC")))) :ARG2 (m5 / mutate-01 :ARG1 (a4 / amino-acid) :ARG1-of (s / specific-02) :ARG1-of (i2 / include-91 :ARG2 (m9 / mutate-01 :ARG1 (a2 / amino-acid) :ARG1-of s) :ARG3 (m6 / most))))) # ::id pmid_2023_3444.122 # ::date 2015-08-03T14:09:31 # ::file pmid_2023_3444_122.txt # ::snt Other amino acid changes that were not in the COSMIC database were amino acid changes R88Q, H701P, and C420R in PIK3CA, BRAF-594V/G, and KRAS-Q61R, and several in NRAS, including G12C, G12D, G13R, G13V, Q61H and Q61K (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (c / change-01 :ARG1 (a / amino-acid) :mod (o / other) :ARG1-of (b / be-located-at-91 :polarity "-" :ARG2 (d / database :name (n16 / name :op1 "COSMIC"))) :ARG1-of (d2 / describe-01 :ARG0 (t / table :mod "2")) :domain (a6 / and :op1 (c3 / change-01 :ARG1 (a7 / amino-acid :part-of (g / gene :name (n4 / name :op1 "PIK3CA") :ARG2-of (m / mutate-01 :value "R88Q") :xref (x5 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :op2 (c4 / change-01 :ARG1 (a8 / amino-acid :part-of (g5 / gene :name (n / name :op1 "PIK3CA") :ARG2-of (m2 / mutate-01 :value "H701P") :xref (x3 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :op3 (c5 / change-01 :ARG1 (a9 / amino-acid :part-of (g6 / gene :name (n2 / name :op1 "PIK3CA") :ARG2-of (m3 / mutate-01 :value "C420R") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :op4 (c6 / change-01 :ARG1 (a10 / amino-acid :part-of (g2 / gene :name (n6 / name :op1 "BRAF") :ARG2-of (m4 / mutate-01 :value "594V/G") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op5 (c7 / change-01 :ARG1 (a11 / amino-acid :part-of (g3 / gene :name (n8 / name :op1 "KRAS") :ARG2-of (m5 / mutate-01 :value "Q61R") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :op6 (c8 / change-01 :ARG1 (a12 / amino-acid :part-of (g4 / gene :name (n9 / name :op1 "NRAS") :ARG2-of (m6 / mutate-01 :ARG2-of (i / include-01 :ARG1 (a4 / and :op1 (m7 / mutate-01 :value "G12C") :op2 (m8 / mutate-01 :value "G12D") :op3 (m9 / mutate-01 :value "G13R") :op4 (m10 / mutate-01 :value "G13V") :op5 (m11 / mutate-01 :value "Q61H") :op6 (m12 / mutate-01 :value "Q61K")))) :xref (x4 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :quant (s / several)))) # ::id pmid_2023_3444.123 # ::date 2015-08-03T14:25:04 # ::file pmid_2023_3444_123.txt # ::snt MET mutations were found in C0-7 and amplified in sometumors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (f / find-01 :ARG1 (m / mutate-01 :ARG1 (p / protein :name (n / name :op1 "MET") :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "1.004"))) :location (t / thing :name (n2 / name :op1 "C0-7"))) :op2 (a2 / amplify-01 :ARG1 m :location (t2 / tumor :quant (s / some)))) # ::id pmid_2023_3444.124 # ::date 2015-08-03T14:28:26 # ::file pmid_2023_3444_124.txt # ::snt MET mutations were found in 3.3% of C-07 samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "MET") :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "1.004"))) :location (t2 / thing :ARG1-of (i / include-91 :ARG2 (t3 / thing :source "c" :ARG1-of (s2 / sample-01 :source (c / cell-line :name (n2 / name :op1 "C-07")))) :ARG3 (p / percentage-entity :value "3.3")) :ARG1-of (s / sample-01))) # ::id pmid_2023_3444.125 # ::date 2015-08-03T14:32:27 # ::file pmid_2023_3444_125.txt # ::snt Interestingly, these mutations were not only unexpected in their appearance within the colon cancer population but also the frequency within the samples was unexpected. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a2 / and :op1 (e / expect-01 :polarity "-" :ARG1 (a / appear-01 :ARG1 (m / mutate-01 :mod (t / this)) :location (p / population :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colon" :op2 "cancer"))))) :op2 (e2 / expect-01 :polarity "-" :ARG1 (f / frequent-02 :ARG1 (t2 / thing :ARG1-of (s / sample-01))) :mod (a3 / also)) :ARG2-of (i / interest-01)) # ::id pmid_2023_3444.126 # ::date 2015-08-03T14:44:03 # ::file pmid_2023_3444_126.txt # ::snt In four of the eight samples with MET mutations, the mutant alleles were present at 58-70%, suggesting an amplification of the mutant allele or a loss of the wt gene (Fig. 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (b / be-located-at-91 :ARG1 (a / allele :ARG2-of (m / mutate-01) :quant (v / value-interval :op1 (p / percentage-entity :value "58") :op2 (p2 / percentage-entity :value "70"))) :ARG2 (s / sample-01 :quant "4" :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "MET") :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "1.004"))) :ARG1-of (i / include-91 :ARG2 (s2 / sample-01 :quant "8" :ARG1 m2))) :ARG0-of (s3 / suggest-01 :ARG1 (o / or :op1 (a2 / amplify-01 :ARG1 (a3 / allele :ARG2-of m)) :op2 (l / lose-02 :ARG1 (g2 / gene :mod (w / wild-type))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6"))) # ::id pmid_2023_3444.127 # ::date 2015-08-03T14:52:59 # ::file pmid_2023_3444_127.txt # ::snt Amplification may represent the best explanation, in that amplification of the MET genomic region, 7q31, has been observed in the Progenetix CGH Database in 23% of colorectal cancers [22] # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (p / possible-01 :ARG1 (r / represent-01 :ARG0 (a2 / amplify-01) :ARG1 (e / explain-01 :ARG2-of (g / good-03 :degree (m / most)))) :ARG0-of (c / cause-01 :ARG1 (o / observe-01 :ARG1 (a / amplify-01 :ARG1 (d5 / dna-sequence :name (n5 / name :op1 "7q31" :op2 "region") :mod (g2 / genome) :mod (g3 / gene :name (n / name :op1 "MET") :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "1.004")))) :location (d / database :name (n2 / name :op1 "Progenetix" :op2 "CGH")) :location (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :ARG1-of (i / include-91 :ARG2 (d3 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal" :op2 "cancer")) :ARG3 (p2 / percentage-entity :value "23"))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "22")))) # ::id pmid_2023_3444.128 # ::date 2015-08-03T15:13:41 # ::file pmid_2023_3444_128.txt # ::snt Sequenom data was reproducible # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (p / possible-01 :ARG1 (r / reproduce-01 :ARG1 (d / data :source (c / company :name (n / name :op1 "Sequenom"))))) # ::id pmid_2023_3444.129 # ::date 2015-08-03T15:15:07 # ::file pmid_2023_3444_129.txt # ::snt Most of the assays in the OncoCarta panel did not detect mutations or the frequency of mutations was very low (below 1%) in our colon cancer samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (o / or :op1 (d / detect-01 :polarity "-" :ARG0 (a / assay-01 :quant (m / most) :ARG1-of (i / include-91 :ARG2 (a2 / assay-01 :location (p / panel :name (n / name :op1 "OncoCarta"))))) :ARG1 (m2 / mutate-01)) :op2 (l / low-04 :ARG1 (f / frequent-02 :ARG1 (m3 / mutate-01 :location (s / sample-01 :ARG0 (w / we) :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon" :op2 "cancer"))))) :ARG3 (b / below :op1 (p2 / percentage-entity :value "1")) :degree (v / very))) # ::id pmid_2023_3444.130 # ::date 2015-08-04T12:18:44 # ::file pmid_2023_3444_130.txt # ::snt OncoCarta assays interrogate mutations in these 19 genes listed in Table 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / interrogate-01 :ARG0 (a / assay-01 :instrument (p / product :name (n / name :op1 "OncoCarta"))) :ARG1 (m / mutate-01) :location (g / gene :quant "19" :mod (t / this) :ARG1-of (l / list-01 :ARG2 (t2 / table :mod "1")))) # ::id pmid_2023_3444.131 # ::date 2015-08-04T12:23:05 # ::file pmid_2023_3444_131.txt # ::snt To reduce the cost, time and the amount of DNA required for profiling, only 24 assays, which detected mutations at a frequency of 1% or greater in C-07, were selected, resorted in 6 pools and included in a new panel, termed ColoCarta (Table 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / and :op1 (s / select-01 :ARG1 (a2 / assay-01 :quant "24" :mod (o / only) :ARG0-of (d / detect-01 :ARG1 (m / mutate-01 :ARG1-of (h / have-frequency-91 :ARG2 (o2 / or :op1 (p / percentage-entity :value "1") :op2 (m2 / more-than :op1 p)) :location (c / cell-line :name (n / name :op1 "C-07"))))))) :op2 (r / resort-00 :ARG1 a2 :location (p2 / pool :quant "6")) :op3 (i / include-01 :ARG1 a2 :ARG2 (p3 / panel :ARG1-of (n2 / new-01) :ARG1-of (t2 / term-01 :ARG3 (t5 / thing :name (n3 / name :op1 "ColoCarta"))))) :purpose (r2 / reduce-01 :ARG1 (a3 / and :op1 (c2 / cost) :op2 (t3 / time) :op3 (a4 / amount :quant-of (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))) :ARG1-of (r3 / require-01 :ARG0 (p4 / profile-01)))) :ARG1-of (d3 / describe-01 :ARG0 (t4 / table :mod "3"))) # ::id pmid_2023_3444.132 # ::date 2015-08-04T12:47:08 # ::file pmid_2023_3444_132.txt # ::snt Mutation profiles of 32 mutant samples with 41 mutations were repeated with the ColoCarta. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (r / repeat-01 :ARG1 (p / profile-01 :ARG1 (t2 / thing :quant "32" :ARG2-of (m / mutate-01) :ARG0-of (h / have-03 :ARG1 (m2 / mutate-01 :quant "41")) :ARG1-of (s / sample-01)) :mod m) :instrument (t / thing :name (n / name :op1 "ColoCarta"))) # ::id pmid_2023_3444.133 # ::date 2015-08-04T12:48:19 # ::file pmid_2023_3444_133.txt # ::snt The mutations detected by the 2 panels (OncoCarta and ColoCarta) were identical, demonstrating the reproducibility of the methodology. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / identical-01 :ARG1 (m / mutate-01 :ARG1-of (d / detect-01 :ARG0 (p / panel :quant "2" :ARG1-of (m3 / mean-01 :ARG2 (a / and :op1 (p3 / panel :name (n / name :op1 "OncoCarta")) :op2 (p4 / panel :name (n2 / name :op1 "ColoCarta"))))))) :ARG0-of (d2 / demonstrate-01 :ARG1 (p2 / possible-01 :ARG1 (r / reproduce-01 :ARG1 (m2 / methodology))))) # ::id pmid_2023_3444.134 # ::date 2015-08-04T13:17:41 # ::file pmid_2023_3444_134.txt # ::snt Multiple mutation frequencies suggest an order to the acquisition of different mutations # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (s / suggest-01 :ARG0 (h / have-frequency-91 :ARG1 (m / mutate-01) :mod (m2 / multiple)) :ARG1 (o / order-03 :ARG1 (a / acquire-01 :ARG1 (m3 / mutate-01 :ARG1-of (d / differ-02))))) # ::id pmid_2023_3444.135 # ::date 2015-08-04T13:22:12 # ::file pmid_2023_3444_135.txt # ::snt A majority of the tumors (64%) contained at least one or more mutations in the following genes: BRAF, KRAS, NRAS, MET, or PIK3CA, and 18% had 2 or more mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (a / and :op1 (c / contain-01 :ARG0 (t / tumor :quant (m / majority :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value "64")))) :ARG1 (m3 / mutate-01 :quant (a2 / at-least :op1 (o / or :op1 "1" :op2 (m4 / more-than :op1 "1")))) :location (g / gene :ARG1-of (f / follow-04) :ARG1-of (m7 / mean-01 :ARG2 (o2 / or :op1 (g2 / gene :name (n / name :op1 "BRAF") :xref (x4 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g3 / gene :name (n2 / name :op1 "KRAS") :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op3 (g4 / gene :name (n3 / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op4 (g5 / gene :name (n4 / name :op1 "MET") :xref (x1 / xref :value "UNIPROT:MET_HUMAN" :prob "1.004")) :op5 (g6 / gene :name (n5 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))))) :op2 (h / have-03 :ARG0 (t2 / tumor :ARG1-of (i / include-91 :ARG2 t :ARG3 (p2 / percentage-entity :value "18"))) :ARG1 (m5 / mutate-01 :quant (o3 / or :op1 "2" :op2 (m6 / more-than :op1 "2"))))) # ::id pmid_2023_3444.136 # ::date 2015-08-04T13:34:35 # ::file pmid_2023_3444_136.txt # ::snt The most common double mutation was in KRAS and PIK3CA, followed by PIK3CA and BRAF (Table 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (m / mutate-01 :ARG1-of (d / double-01) :mod (c / common :degree (m2 / most)) :location (a / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG2-of (f / follow-01 :ARG1 (a2 / and :op1 g2 :op2 (g3 / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG1-of (d2 / describe-01 :ARG0 (t / table :mod "4"))) # ::id pmid_2023_3444.137 # ::date 2015-08-04T13:39:53 # ::file pmid_2023_3444_137.txt # ::snt Most samples with PIK3CA mutations (80%) also had mutations in other genes, the most frequent of which was KRAS; other mutated genes were BRAF, MET, NRAS, and a second PIK3CA mutation (Table 2, last column). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (m / multi-sentence :snt1 (h / have-03 :ARG0 (t2 / thing :ARG1-of (i / include-91 :ARG2 (t3 / thing :ARG1-of (s2 / sample-01) :ARG0-of (h2 / have-03 :ARG1 (m3 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x3 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))) :ARG3 (m4 / most :ARG1-of (m5 / mean-01 :ARG2 (p / percentage-entity :value "80")))) :ARG1-of (s / sample-01)) :ARG1 (m6 / mutate-01 :location (g3 / gene :mod (o / other) :ARG2-of (i2 / include-91 :ARG1 (g4 / gene :name (n3 / name :op1 "KRAS") :ARG1-of (f / frequent-02) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))) :mod (a / also)) :snt2 (g5 / gene :ARG2-of (m7 / mutate-01) :ARG1-of (i3 / include-91 :ARG2 (a2 / and :op1 (g6 / gene :name (n4 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g7 / gene :name (n5 / name :op1 "MET") :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "1.004")) :op3 (g8 / gene :name (n6 / name :op1 "NRAS") :xref (x5 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op4 (g9 / gene :name (n7 / name :op1 "PIK3CA") :ARG1-of (m8 / mutate-01 :ord (o2 / ordinal-entity :value "2")) :xref (x4 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :mod (o3 / other)) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "2" :part (c / column :mod (l / last))))) # ::id pmid_2023_3444.138 # ::date 2015-08-04T14:17:59 # ::file pmid_2023_3444_138.txt # ::snt Tumors with MET and NRAS mutations also have an unexpectedly high frequency of co-occurring mutations, which suggests that they occur as a second mutation and perhaps later in the etiology of the tumor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / have-frequency-91 :ARG1 (m / mutate-01 :location (t / tumor :ARG0-of (h3 / have-03 :ARG1 (m2 / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "MET") :xref (x1 / xref :value "UNIPROT:MET_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))))) :ARG1-of (c / cooccur-00)) :ARG2 (h2 / high :ARG1-of (e / expect-01 :polarity "-")) :mod (a2 / also) :ARG0-of (s / suggest-01 :ARG1 (m3 / mutate-01 :ord (o / ordinal-entity :value "2") :domain t :ARG1-of (b / be-temporally-at-91 :ARG2 (l / late :op1 (e2 / etiology :poss (t3 / tumor)) :degree (m4 / more)) :ARG1-of (p / possible-01))))) # ::id pmid_2023_3444.139 # ::date 2015-08-04T14:53:18 # ::file pmid_2023_3444_139.txt # ::snt Many tumors contain only a KRAS or BRAF mutation, which is consistent with previous reports finding these mutations in earlier stages of colon cancer [23,24]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contain-01 :ARG0 (t / tumor :quant (m / many)) :ARG1 (m2 / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :mod (o / only)) :ARG1-of (c2 / consistent-01 :ARG2 (r / report :time (p / previous) :ARG0-of (f / find-01 :ARG2 m2 :time (e / early :op1 (s / stage :subevent-of (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer"))) :degree (m4 / more))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 (a2 / and :op1 "23" :op2 "24"))))) # ::id pmid_2023_3444.140 # ::date 2015-08-04T15:01:42 # ::file pmid_2023_3444_140.txt # ::snt The multiple mutation frequencies for tumors with KRAS and PIK3CA or with PIK3CA and BRAF were slightly higher and lower, respectively, than expected based on their individual frequencies (Table 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (a / and :op1 (h / high-02 :ARG1 (h3 / have-frequency-91 :ARG1 (m / mutate-01 :mod (m2 / multiple)) :location (t / tumor :ARG0-of (h2 / have-03 :ARG1 (a4 / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))) :ARG1-of (b / base-02 :ARG2 (f2 / frequent-02 :ARG1 t :mod (i / individual)))) :compared-to (e / expect-01)) :op2 (l / low-04 :ARG1 (h4 / have-frequency-91 :ARG1 (m3 / mutate-01) :location (t3 / tumor :ARG0-of (h5 / have-03 :ARG1 (a3 / and :op1 g2 :op2 (g3 / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG1-of b) :compared-to e) :mod (r / respective) :manner (s / slight) :ARG1-of (d / describe-01 :ARG0 (t2 / table :mod "4"))) # ::id pmid_2023_3444.141 # ::date 2015-08-04T15:15:53 # ::file pmid_2023_3444_141.txt # ::snt Conversely, the expected double mutation frequency of BRAF and KRAS would be 5.1%, based on our data, but this combination was not found, also in agreement with previous reports [24] (Table 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (h / have-frequency-91 :ARG1 (m / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1-of (d / double-01) :ARG1-of (e / expect-01)) :ARG2 (p / percentage-entity :value "5.1") :ARG1-of (b / base-02 :ARG2 (d2 / data :poss (w / we))) :concession (f / find-01 :polarity "-" :ARG1 (c / combine-01 :mod (t / this)) :ARG0-of (a2 / agree-01 :ARG2 (r / report :time (p2 / previous)) :mod (a3 / also))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "24"))) :ARG1-of (d4 / describe-01 :ARG0 (t2 / table :mod "4")) :manner (c3 / converse)) # ::id pmid_2023_3444.142 # ::date 2015-08-04T15:29:47 # ::file pmid_2023_3444_142.txt # ::snt Primary tumors with KRAS and PIK3CA mutations vary with respect to the frequency of these mutant alleles # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (v / vary-01 :ARG0 (h2 / have-frequency-91 :ARG1 (a2 / allele :mod (t2 / this) :ARG2-of (m2 / mutate-01))) :ARG1 (t / tumor :mod (p / primary) :ARG0-of (h / have-03 :ARG1 (m / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))))) # ::id pmid_2023_3444.143 # ::date 2015-08-04T15:34:34 # ::file pmid_2023_3444_143.txt # ::snt In the samples with co-occurring mutations, the ratios of KRAS mutation ratio (KRAS mutation peak area/total peak area) to the PIK3CA mutation ratio (PIK3CA mutation peak area/total peak area) was determined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / determine-01 :ARG1 (r / ratio-of :op1 (r2 / ratio-of :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1-of (m2 / mean-01 :ARG2 (r4 / ratio-of :op1 (a / area :ARG1-of (p / peak-01) :mod m) :op2 (a2 / area :ARG1-of (p2 / peak-01) :mod (t / total))))) :op2 (r3 / ratio-of :op1 (m3 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :ARG1-of (m4 / mean-01 :ARG2 (r5 / ratio-of :op1 (a3 / area :ARG1-of (p3 / peak-01) :mod m3) :op2 a2)))) :location (s / sample-01 :ARG1 (m5 / mutate-01 :ARG1-of (c / cooccur-00)))) # ::id pmid_2023_3444.144 # ::date 2015-08-04T15:48:15 # ::file pmid_2023_3444_144.txt # ::snt Twenty-two out of 31 samples (71%) had KRAS/PIK3CA ratios above 1.25 (Table 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (h / have-03 :ARG0 (t3 / thing :quant "22" :ARG1-of (i / include-91 :ARG2 (t2 / thing :quant "31" :ARG1-of (s2 / sample-01)) :ARG3 (p / percentage-entity :value "71")) :ARG1-of (s / sample-01)) :ARG1 (r / ratio-of :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG1-of (e / equal-01 :ARG3 (a / above :op1 "1.25"))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "5"))) # ::id pmid_2023_3444.145 # ::date 2015-08-04T16:03:36 # ::file pmid_2023_3444_145.txt # ::snt PIK3CA mutations were more prevalent in only 2 out of 31 samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (p / prevail-02 :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :degree (m / more) :location (t2 / thing :quant "2" :ARG1-of (i / include-91 :ARG2 (t / thing :quant "31" :ARG1-of (s2 / sample-01))) :mod (o / only) :ARG1-of (s / sample-01))) # ::id pmid_2023_3444.146 # ::date 2015-08-04T16:07:45 # ::file pmid_2023_3444_146.txt # ::snt These differences demonstrate that in a majority of primary tumors with double mutations in KRAS and PIK3CA, the KRAS mutations are more prevalent than the PIK3CA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (d / demonstrate-01 :ARG0 (d2 / differ-02 :mod (t / this)) :ARG1 (p / prevail-02 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :mod (m2 / more) :location (t2 / tumor :quant (m3 / majority) :mod (p2 / primary) :ARG0-of (h / have-03 :ARG1 (m4 / mutate-01 :ARG1 (a / and :op1 g :op2 "g2") :ARG1-of (d3 / double-01)))) :compared-to (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) # ::id pmid_2023_3444.147 # ::date 2015-08-03T05:28:53 # ::file pmid_2023_3444_147.txt # ::snt This unequal distribution of mutant alleles within a tumor may be due to the fact that a majority of the tumor cells have only the KRAS mutation, and cells with a PIK3CA mutation are in the minority, or it could be due to copy number variations in the KRAS and PIK3CA loci. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (p / possible-01 :ARG1 (d / distribute-01 :ARG1 (a / allele :ARG2-of (m / mutate-01)) :mod (e / equal :polarity "-") :mod (t / this) :location (t2 / tumor)) :ARG1-of (c / cause-01 :ARG0 (o / or :op1 (a2 / and :op1 (h / have-03 :ARG0 (c2 / cell :mod (t3 / tumor) :ARG1-of (i / include-91 :ARG2 (c3 / cell) :ARG3 (m2 / majority))) :ARG1 (m3 / mutate-01 :ARG1 (g2 / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :mod (o2 / only)) :op2 (c4 / cell :location-of (m4 / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :quant (m5 / minority))) :op2 (v / vary-01 :ARG1 (n3 / number :quant-of (d2 / dna-sequence :ARG2-of (c7 / copy-01))) :location (a3 / and :op1 (l / locus :ARG0-of (c5 / contain-01 :ARG1 g2)) :op2 (l2 / locus :ARG0-of (c6 / contain-01 :ARG1 g))))))) # ::id pmid_2023_3444.148 # ::date 2015-08-03T12:55:36 # ::file pmid_2023_3444_148.txt # ::snt BRAF mutations were correlated with poorly differentiated tumors and with mucinous tumors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / correlate-01 :ARG1 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (a / and :op1 (t / tumor :ARG1-of (d / differentiate-101 :manner (p / poor))) :op2 (t2 / tumor :mod (p2 / protein :name (n2 / name :op1 "mucin") :xref (x / xref :value "UNIPROT:Q99322_HUMAN" :prob "1.001"))))) # ::id pmid_2023_3444.149 # ::date 2015-08-03T14:28:24 # ::file pmid_2023_3444_149.txt # ::snt The frequency of mutations for KRAS, PIK3CA, and BRAF were tested for correlation to the degree of differentiation and to the prevalence of mucin in the tumor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (t / test-01 :ARG1 (a / and :op1 (h / have-frequency-91 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :op2 (h2 / have-frequency-91 :ARG1 (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :op3 (h3 / have-frequency-91 :ARG1 (m3 / mutate-01 :ARG1 (g3 / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG2 (c / correlate-01 :ARG1 a :ARG2 (a2 / and :op1 (d / degree :degree-of (d2 / differentiate-101)) :op2 (p / prevail-01 :ARG1 (p2 / protein :name (n4 / name :op1 "mucin") :xref (x / xref :value "UNIPROT:Q99322_HUMAN" :prob "1.001")) :location (t2 / tumor))))) # ::id pmid_2023_3444.150 # ::date 2015-08-03T21:23:35 # ::file pmid_2023_3444_150.txt # ::snt BRAF mutations were found in 26.2% of the poorly differentiated tumors and in 8.2% of the moderate and well differentiated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (f / find-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :location (a / and :op1 (t2 / tumor :ARG1-of (i / include-91 :ARG2 (t / tumor :ARG1-of (d / differentiate-01 :manner (p / poor))) :ARG3 (p2 / percentage-entity :value "26.2"))) :op2 (t3 / tumor :ARG1-of (i2 / include-91 :ARG2 (a2 / and :op1 (t4 / tumor :ARG1-of (d2 / differentiate-01 :manner (m2 / moderate))) :op2 (t5 / tumor :ARG1-of (d3 / differentiate-01 :ARG1-of (w / well-09)))) :ARG3 (p3 / percentage-entity :value "8.2"))))) # ::id pmid_2023_3444.151 # ::date 2015-08-03T21:46:11 # ::file pmid_2023_3444_151.txt # ::snt These frequencies were significantly different by Chi square test (p value = 0.001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (d / differ-02 :ARG1 (h / have-frequency-91 :mod (t / this)) :ARG1-of (s / significant-02) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.001" :ARG4 (t3 / thing :wiki "Chi-squared_test" :name (n / name :op1 "Chi" :op2 "square" :op3 "test")))) # ::id pmid_2023_3444.152 # ::date 2015-08-03T22:00:50 # ::file pmid_2023_3444_152.txt # ::snt BRAF mutations were also associated with mucinous tumors: BRAF mutations occurred in 28% of grade 3 mucinous tumors (>50% mucinous tumor cells) but in only 9.4% of the non-mucinous tumors (grade 1 and 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 17, 2015 (a / associate-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (t / tumor :mod (p4 / protein :name (n3 / name :op1 "mucin") :xref (x / xref :value "UNIPROT:Q99322_HUMAN" :prob "1.001"))) :mod (a2 / also) :ARG1-of (m3 / mean-01 :ARG2 (b3 / be-located-at-91 :ARG1 (m4 / mutate-01 :ARG1 g) :ARG2 (a3 / and :op1 (t2 / tumor :ARG1-of (i / include-91 :ARG2 (t3 / tumor :mod (g3 / grade :mod "3") :mod p4) :ARG3 (p2 / percentage-entity :value "28" :ARG1-of (m6 / mean-01 :ARG2 (m2 / more-than :op1 (p / percentage-entity :value "50") :quant-of (c / cell :mod t)))))) :op2 (t5 / tumor :ARG1-of (i2 / include-91 :ARG2 (t6 / tumor :ARG1-of (m9 / mean-01 :ARG2 (a4 / and :op1 (g5 / grade :mod "1") :op2 (g6 / grade :mod "2"))) :ARG1-of (h / have-mod-91 :polarity "-" :ARG2 (p5 / protein :name (n4 / name :op1 "mucin") :xref (x2 / xref :value "UNIPROT:Q99322_HUMAN" :prob "1.001")))) :ARG3 (p3 / percentage-entity :value "9.4")) :mod (o / only)))))) # ::id pmid_2023_3444.153 # ::date 2015-08-03T22:40:48 # ::file pmid_2023_3444_153.txt # ::snt This was significant by the Chi square test at p value = 0.006. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (s / significant-02 :ARG1 (t / this) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.006" :ARG4 (t2 / thing :wiki "Chi-squared_test" :name (n / name :op1 "Chi" :op2 "square" :op3 "test")))) # ::id pmid_2023_3444.154 # ::date 2015-08-03T22:46:52 # ::file pmid_2023_3444_154.txt # ::snt Similar data have been reported previously [25,26]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 3, 2015 (r / report-01 :ARG1 (d / data :ARG1-of (r2 / resemble-01)) :time (p / previous) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 "25" :op2 "26"))))) # ::id pmid_2023_3444.155 # ::date 2015-08-03T23:02:51 # ::file pmid_2023_3444_155.txt # ::snt KRAS and PIK3CA mutations did not correlate with either the degree of differentiation or with prevalence of mucinous cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (c / correlate-01 :polarity "-" :ARG1 (m / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :ARG2 (o / or :op1 (d / degree :degree-of (d2 / differentiate-01)) :op2 (p / prevail-01 :ARG0 (c2 / cell :mod (p2 / protein :name (n3 / name :op1 "mucin") :xref (x / xref :value "UNIPROT:Q99322_HUMAN" :prob "1.001")))))) # ::id pmid_2023_3444.156 # ::date 2015-08-04T08:02:18 # ::file pmid_2023_3444_156.txt # ::snt Mutation profiling demonstrated a majority of primary and lymph node samples were concordant but differences were detected # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (d / demonstrate-01 :ARG0 (p / profile-01 :ARG1 (m / mutate-01)) :ARG1 (c / concordant :domain (a / and :op1 (s / sample-01 :ARG1 (n / node :mod (p2 / primary)) :quant (m2 / majority)) :op2 (s2 / sample-01 :ARG1 (n2 / node :mod (l / lymph)) :quant (m3 / majority)))) :ARG1-of (c2 / contrast-01 :ARG2 (d2 / detect-01 :ARG1 (d3 / differ-02)))) # ::id pmid_2023_3444.157 # ::date 2015-08-04T08:18:41 # ::file pmid_2023_3444_157.txt # ::snt Lymph node metastases were not routinely collected in C-07 but as a pilot study to determine the feasibility of using lymph nodes for mutation profiling was conducted. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / contrast-01 :ARG1 (c / collect-01 :polarity "-" :ARG1 (m / metastasize-101 :ARG2 (n / node :mod (l / lymph))) :manner (r / routine) :location (c4 / cell-line :name (n3 / name :op1 "C-07"))) :ARG2 (c3 / conduct-01 :ARG1 (s / study-01 :ARG1-of (p / pilot-01)) :purpose (d / determine-01 :ARG1 (f / feasibility :poss (u / use-01 :ARG1 (n2 / node :mod (l2 / lymph)) :ARG2 (p2 / profile-01 :ARG1 (m2 / mutate-01))))))) # ::id pmid_2023_3444.158 # ::date 2015-08-04T10:38:36 # ::file pmid_2023_3444_158.txt # ::snt We isolated DNA from 39 lymph nodes containing tumor cells and their corresponding primary tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (i / isolate-01 :ARG0 (w / we) :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")) :ARG2 (a / and :op1 (n / node :quant "39" :mod (l / lymph) :ARG0-of (c / contain-01 :ARG1 (c2 / cell :mod (t / tumor)))) :op2 (t2 / tumor :mod (p / primary) :ARG2-of (c3 / correspond-02 :ARG1 n)))) # ::id pmid_2023_3444.159 # ::date 2015-08-04T10:56:22 # ::file pmid_2023_3444_159.txt # ::snt These primary and lymph nodes samples were profiled with the entire OncoCarta panel. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 17, 2015 (p / profile-01 :ARG1 (a / and :op1 (s / sample-01 :ARG1 (n / node :mod (l / lymph)) :mod (t / this)) :op2 (s2 / sample-01 :ARG1 (n2 / node :mod (p2 / primary)) :mod t)) :instrument (p3 / panel :name (n3 / name :op1 "OncoCarta"))) # ::id pmid_2023_3444.160 # ::date 2015-08-04T11:08:38 # ::file pmid_2023_3444_160.txt # ::snt The majority of lymph nodes and their corresponding primary tumors (89.7%) were concordant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (c2 / concordant :domain (a / and :op1 (n2 / node :ARG1-of (i / include-91 :ARG2 (n / node :mod (l / lymph)) :ARG3 (m / majority))) :op2 (t / tumor :mod (p / primary) :ARG2-of (c / correspond-02 :ARG1 n) :quant (p2 / percentage-entity :value "89.7")))) # ::id pmid_2023_3444.161 # ::date 2015-08-04T11:27:56 # ::file pmid_2023_3444_161.txt # ::snt A total of 26 mutations were detected in lymph nodes, including KRAS, BRAF, PIK3CA, and NRAS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (d / detect-01 :ARG1 (m / mutate-01 :ARG1-of (t / total-01 :ARG2 "26") :ARG2-of (i / include-91 :ARG1 (a / and :op1 (g / gene :name (n2 / name :op1 "KRAS") :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n3 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op3 (g3 / gene :name (n4 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op4 (g4 / gene :name (n5 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))))) :location (n / node :mod (l / lymph))) # ::id pmid_2023_3444.162 # ::date 2015-08-04T11:34:54 # ::file pmid_2023_3444_162.txt # ::snt Thirty-five out of 39 lymph nodes had identical mutation profiles, but in 4 cases mutations in the primary tumors were not found in the corresponding lymph nodes (BRAF [2], PIK3CA [1] and KRAS [1]). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (h / have-03 :ARG0 (n / node :quant "35" :mod (l / lymph) :ARG1-of (i / include-91 :ARG2 (n2 / node :quant "39" :mod l))) :ARG1 (p / profile-01 :ARG1 (m / mutate-01) :ARG1-of (i2 / identical-01))) :ARG2 (f / find-01 :polarity "-" :ARG1 (m2 / mutate-01 :location (t / tumor :mod (p2 / primary))) :mod (c2 / case-04 :quant "4") :location (n3 / node :ARG1-of (m3 / mean-01 :ARG2 (a / and :op1 (g / gene :name (n4 / name :op1 "BRAF") :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "2"))) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n5 / name :op1 "PIK3CA") :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "1"))) :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op3 (g3 / gene :name (n6 / name :op1 "KRAS") :ARG1-of d2 :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG2-of (c6 / correspond-02 :ARG1 t) :mod l))) # ::id pmid_2023_3444.163 # ::date 2015-08-04T12:01:34 # ::file pmid_2023_3444_163.txt # ::snt Mutation profiles demonstrate that tumor cell populations may be different in lymph nodes and in the primary tumors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (d / demonstrate-01 :ARG0 (p / profile-01 :ARG1 (m / mutate-01)) :ARG1 (d2 / differ-02 :ARG1 (p3 / population :mod (c / cell :mod (t / tumor))) :ARG1-of (p2 / possible-01) :location (a / and :op1 (n / node :mod (l / lymph)) :op2 (t2 / tumor :mod (p4 / primary))))) # ::id pmid_2023_3444.164 # ::date 2015-08-04T12:12:36 # ::file pmid_2023_3444_164.txt # ::snt Peak area evaluation of tumors that had 2 mutations and for which a metastatic lymph node was available demonstrated differences between the primary and lymph node samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (d / demonstrate-01 :ARG0 (e / evaluate-01 :ARG1 (t / tumor :ARG0-of (h / have-03 :ARG1 (m / mutate-01 :quant "2")) :ARG1-of (a2 / available-02 :ARG2 (n / node :mod (l / lymph) :ARG1-of (m2 / metastasize-101)))) :location (a / area :mod (p / peak))) :ARG1 (d2 / differ-02 :ARG1 (s / sample-01 :ARG1 (n2 / node :mod (p2 / primary))) :ARG2 (s2 / sample-01 :ARG1 (n3 / node :mod (l2 / lymph))))) # ::id pmid_2023_3444.165 # ::date 2015-08-04T12:37:37 # ::file pmid_2023_3444_165.txt # ::snt Table 6 details the frequency of mutant and wt alleles based on the peak areas for 5 such samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (d / detail-01 :ARG0 (t / table :mod "6") :ARG1 (h / have-frequency-91 :ARG1 (a / and :op1 (a2 / allele :ARG2-of (m / mutate-01)) :op2 (a3 / allele :mod (w / wild-type)))) :ARG1-of (b / base-02 :ARG2 (a4 / area :mod (p / peak))) :beneficiary (s / sample :quant "5" :mod (s2 / such))) # ::id pmid_2023_3444.166 # ::date 2015-08-04T12:49:03 # ::file pmid_2023_3444_166.txt # ::snt KRAS to PIK3CA ratios demonstrated that there were more KRAS mutations than PIK3CA mutations in 4 of 4 primary samples, and in 3 of the 4 lymph node samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (d / demonstrate-01 :ARG0 (r / ratio-of :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :ARG1 (m / mutate-01 :ARG1 g :quant (m2 / more-than :op1 (m3 / mutate-01 :ARG1 g2)) :location (a / and :op1 (s / sample-01 :quant "4" :ARG1-of (i / include-91 :ARG2 (s2 / sample-01 :quant "4" :mod (p2 / primary)))) :op2 (s3 / sample-01 :quant "3" :ARG1 (n5 / node :mod (l2 / lymph)) :ARG1-of (i2 / include-91 :ARG2 (s4 / sample-01 :quant "4" :ARG1 n5)))))) # ::id pmid_2023_3444.167 # ::date 2015-08-04T13:12:10 # ::file pmid_2023_3444_167.txt # ::snt However, it is also notable that the ratio of KRAS/PIK3A was lower in the lymph node compared to their primary tumor in 3 out of 4 samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (c / contrast-01 :ARG2 (n / notable-04 :ARG1 (r / ratio-of :op1 (g / gene :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n3 / name :op1 "PIK3A") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "0.333"))) :ARG2 (l / low-04 :ARG1 r :location (n4 / node :mod (l2 / lymph)) :compared-to (t / tumor :mod (p / primary) :poss n4)) :location (s / sample :quant "3" :ARG1-of (i / include-91 :ARG2 (s2 / sample :quant "4"))) :mod (a / also))) # ::id pmid_2023_3444.168 # ::date 2015-08-04T13:45:09 # ::file pmid_2023_3444_168.txt # ::snt In sample 0940, the KRAS/PIK3CA mutation decreased by almost 1/2 in the lymph node tumor compared to the primary. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (d / decrease-01 :ARG1 (m / mutate-01 :ARG1 (s / slash :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :ARG2 (a / almost :op1 (p2 / product-of :op1 "1/2")) :location (t / tumor :mod (n4 / node :mod (l / lymph)) :compared-to (t2 / tumor :mod (p / primary))) :location (s2 / sample :mod "0940")) # ::id pmid_2023_3444.169 # ::date 2015-08-04T14:14:56 # ::file pmid_2023_3444_169.txt # ::snt Thus, in these samples there is either a loss of KRAS mutations or an accumulation of PIK3CA mutations, suggesting that PIK3CA mutations may impart a selective advantage in the lymph node. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (i / infer-01 :ARG1 (o / or :op1 (l / lose-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :location (s / sample :mod (t / this))) :op2 (a / accumulate-01 :ARG1 (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :location s)) :ARG0-of (s2 / suggest-01 :ARG1 (i2 / impart-01 :ARG0 m2 :ARG1 (a2 / advantage :mod (s3 / selective)) :ARG2 (n4 / node :mod (l2 / lymph)) :ARG1-of (p / possible-01)))) # ::id pmid_2023_3444.170 # ::date 2015-08-04T14:36:55 # ::file pmid_2023_3444_170.txt # ::snt In contrast, two other samples have a less frequent occurrence of their PIK3CA mutation in the lymph node than in the primary tumor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 17, 2015 (c / contrast-01 :ARG2 (h / have-frequency-91 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :location (s / sample :quant "2" :mod (o / other))) :ARG2 (l / less) :location (n2 / node :mod (l2 / lymph) :compared-to (t / tumor :mod (p / primary))))) # ::id pmid_2023_3444.171 # ::date 2015-08-04T14:52:29 # ::file pmid_2023_3444_171.txt # ::snt In sample 2244, the PIK3CA mutation was undetectable in the lymph node (Table 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (d / detect-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :location (n2 / node :mod (l / lymph)) :location (s / sample :mod "2244") :ARG1-of (d2 / describe-01 :ARG0 (t / table :mod "6")) :ARG1-of (p / possible-01 :polarity "-")) # ::id pmid_2023_3444.172 # ::date 2015-08-04T14:57:25 # ::file pmid_2023_3444_172.txt # ::snt In fact, if there was a selection for both mutations in the lymph node, then the PIK3CA mutation frequency would have been the same as that of the KRAS mutation (0.15). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (h / have-condition-91 :ARG1 (s2 / same-01 :ARG1 (h2 / have-frequency-91 :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :ARG2 "f3") :ARG2 (h3 / have-frequency-91 :ARG1 (m3 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG2 (f3 / frequency-quantity :value "0.15"))) :ARG2 (s / select-01 :ARG1 (m / mutate-01 :mod (b / both)) :location (n / node :mod (l / lymph))) :mod (i / in-fact)) # ::id pmid_2023_3444.173 # ::date 2015-08-04T15:16:02 # ::file pmid_2023_3444_173.txt # ::snt On the other hand, if the PIK3CA/KRAS ratio were the same in the primary and lymph node tumor, then the PIK3CA mutation frequency would have been .08, which is still detectable with this technology (Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (c / contrast-01 :ARG2 (h / have-condition-91 :ARG1 (h2 / have-frequency-91 :ARG1 (m / mutate-01 :ARG1 "g") :ARG2 (f2 / frequency-quantity :value "0.08") :ARG1-of (d / detect-01 :ARG2 (t3 / technology :mod (t4 / this)) :mod (s2 / still) :ARG1-of (p2 / possible-01))) :ARG2 (s / same-01 :ARG1 (r / ratio-of :op1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :location (t / tumor :mod (n3 / node :mod (p / primary)))) :ARG2 (r2 / ratio-of :op1 g :op2 g2 :location (t2 / tumor :mod (n4 / node :mod (l / lymph)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3"))) # ::id pmid_2023_3444.174 # ::date 2015-08-04T15:39:34 # ::file pmid_2023_3444_174.txt # ::snt Thus, in sample 2244 there were fewer PIK3CA mutant alleles in the lymph node than in the primary tumor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (i / infer-01 :ARG1 (f / few :quant-of (a / allele :ARG2-of (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :location (n2 / node :mod (l / lymph)) :compared-to (t / tumor :mod (p / primary)) :location (s / sample :mod "2244"))) # ::id pmid_2023_3444.175 # ::date 2015-08-04T15:57:18 # ::file pmid_2023_3444_175.txt # ::snt In sample 1837, mutations in both BRAF and PIK3CA were detected and the BRAF/PIK3CA ratio was 1.67, but increased to 4.4 in the metastatic lymph node. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (c / contrast-01 :ARG1 (a / and :op1 (d / detect-01 :ARG1 (m / mutate-01 :ARG1 (a2 / and :op1 (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))) :op2 (e / equal-01 :ARG1 (r / ratio-of :op1 g :op2 g2) :ARG2 "1.67")) :ARG2 (i / increase-01 :ARG1 r :ARG4 "4.4" :location (n5 / node :mod (l / lymph) :ARG2-of (m2 / metastasize-101))) :location (s / sample :mod "1837")) # ::id pmid_2112_2157.1 # ::date 2015-07-18T17:20:13 # ::file pmid_2112_2157_1.txt # ::snt Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells (PMID:21122157) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (u / upregulate-01 :ARG1 (p / produce-01 :ARG1 (p2 / protein :name (n / name :op1 "interleukin-6") :mod (a / autocrine) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703"))) :ARG2 (a2 / activate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription-3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.693"))) :ARG1-of (m / mean-01 :ARG2 (s / study-01 :ARG1 (a3 / and :op1 (c / cell-line :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")) :ARG1-of (e / establish-01)) :op2 (c2 / cell :mod d :mod (h / human) :ARG1-of (i / isolate-01 :manner (c3 / clinic)))) :mod (b / biochemistry) :mod (g / genetics))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG8 "PMID21122157"))) # ::id pmid_2112_2157.9 # ::date 2015-07-18T17:58:16 # ::file pmid_2112_2157_9.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2112_2157.10 # ::date 2015-07-18T17:59:40 # ::file pmid_2112_2157_10.txt # ::snt Inhibitors of Jak2/Stat3, MEK/Erk and PI3-K/Akt pathways down-regulated IL-6 secretion in the lung adenocarcinoma PC14PE6/AS2 (AS2) cells, which spontaneously secreted IL-6 and possessed constitutively activated Stat3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / downregulate-01 :ARG1 (s / secrete-01 :ARG1 (p / protein :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (a / and :op1 (p2 / pathway :name (n2 / name :op1 "Jak2/Stat3")) :op2 (p3 / pathway :name (n3 / name :op1 "MEK/Erk")) :op3 (p4 / pathway :name (n4 / name :op1 "PI3-K/Akt"))))) :location (c / cell :name (n5 / name :op1 "PC14PE6/AS2") :part-of (l / lung) :ARG0-of (s2 / secrete-01 :ARG1 p :manner (s3 / spontaneous)) :ARG0-of (p5 / possess-01 :ARG1 (p6 / protein :name (n6 / name :op1 "Stat3") :ARG1-of (a3 / activate-01 :manner (c2 / constitutive)) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :mod (m2 / medical-condition :name (n7 / name :op1 "adenocarcinoma")))) # ::id pmid_2112_2157.11 # ::date 2015-07-18T18:20:06 # ::file pmid_2112_2157_11.txt # ::snt Transfection with dominant-negative Stat3, Stat3 siRNA, or Stat3 shRNA decreased IL-6 expression in AS2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (d / decrease-01 :ARG0 (t / transfect-01 :ARG2 (o / or :op1 (p / protein :name (n / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :op2 (n6 / nucleic-acid :name (n2 / name :op1 "siRNA") :mod p) :op3 (n7 / nucleic-acid :name (n3 / name :op1 "shRNA") :mod p) :ARG0-of (d2 / dominate-01) :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :location (c / cell-line :name (n5 / name :op1 "AS2"))) # ::id pmid_2112_2157.12 # ::date 2015-07-18T18:31:11 # ::file pmid_2112_2157_12.txt # ::snt Conversely, transfection with constitutively-activated Stat3 increased the production of IL-6. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 18, 2015 (c / contrast-01 :ARG2 (i / increase-01 :ARG0 (t / transfect-01 :ARG2 (p / protein :name (n / name :op1 "Stat3") :ARG1-of (a / activate-01 :manner (c2 / constitutive)) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :ARG1 (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) # ::id pmid_2112_2157.13 # ::date 2015-07-18T18:36:31 # ::file pmid_2112_2157_13.txt # ::snt In AS2 derived cells, resistance to paclitaxel was positively correlated with Stat3 activation status and the expression of IL-6, which is commonly secreted in drug resistant cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (c / correlate-01 :ARG1 (r / resist-01 :ARG1 (s / small-molecule :name (n / name :op1 "paclitaxel") :xref (x2 / xref :value "PUBCHEM:4666" :prob "15.068933"))) :ARG2 (a / and :op1 (s2 / status :mod (a2 / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :op2 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6") :ARG1-of (s3 / secrete-01 :manner (c2 / common) :location (c3 / cell :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")) :ARG0-of (r2 / resist-01 :ARG1 (d2 / drug-01)))) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :manner (p3 / positive) :location (c4 / cell :ARG1-of (d3 / derive-01 :ARG2 (c5 / cell-line :name (n5 / name :op1 "AS2"))))) # ::id pmid_2112_2157.14 # ::date 2015-07-18T18:53:49 # ::file pmid_2112_2157_14.txt # ::snt The pharmacological inhibition of NF-?B, PI3-K/Akt and MEK/Erk and the pharmacological inhibition and genetic inhibition (Stat3 siRNA) of Jak2/Stat3 pathway decreased IL-6 autocrine production in various drug resistant cancer cell lines and similarly decreased IL-6 autocrine production in clinically isolated lung cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (d / decrease-01 :ARG0 (a2 / and :op1 (i / inhibit-01 :ARG1 (a3 / and :op1 (p / pathway :name (n / name :op1 "NF-κB")) :op2 (p2 / pathway :name (n2 / name :op1 "PI3-K/Akt")) :op3 (p3 / pathway :name (n3 / name :op1 "MEK/Erk"))) :mod (p4 / pharmacology)) :op2 (a4 / and :op1 (i2 / inhibit-01 :ARG1 (p5 / pathway :name (n4 / name :op1 "Jak2/Stat3")) :mod p4) :op2 (i3 / inhibit-01 :ARG0 (n9 / nucleic-acid :name (n5 / name :op1 "siRNA") :mod (p6 / protein :name (n6 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :ARG1 p5 :mod (g / genetics)))) :ARG1 (p7 / produce-01 :ARG1 (p8 / protein :name (n7 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (a5 / autocrine)) :location (c / cell-line :mod (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")) :ARG0-of (r2 / resist-01 :ARG1 (d3 / drug)) :quant (v / various))) :op2 (d4 / decrease-01 :ARG0 a2 :ARG1 p7 :location (c2 / cell :mod d2 :part-of (l / lung) :ARG1-of (i4 / isolate-01 :manner (c3 / clinic))) :ARG1-of (r3 / resemble-01))) # ::id pmid_2112_2157.108 # ::date 2015-07-19T00:46:12 # ::file pmid_2112_2157_108.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2112_2157.109 # ::date 2015-07-19T00:47:17 # ::file pmid_2112_2157_109.txt # ::snt Autocrine IL-6 induced Stat3 activation and paclitaxel resistance in AS2 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (a / and :op1 (a2 / activate-01 :ARG1 (p / protein :name (n / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG2-of (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "IL-6") :mod (a3 / autocrine) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :op2 (r / resist-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "paclitaxel") :xref (x2 / xref :value "PUBCHEM:4666" :prob "15.068933"))) :location (c / cell-line :name (n3 / name :op1 "AS2"))) # ::id pmid_2112_2157.110 # ::date 2015-07-19T00:55:40 # ::file pmid_2112_2157_110.txt # ::snt We previously demonstrated that AS2 cells produced autocrine IL-6 and the secreted IL-6 induced Stat3 activation and subsequently promoted tumor progression [2]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p / produce-01 :ARG0 (c / cell-line :name (n / name :op1 "AS2")) :ARG1 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "IL-6") :mod (a3 / autocrine) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (i / induce-01 :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6") :ARG1-of (s / secrete-01) :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (a4 / activate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))))) :op2 (p5 / promote-01 :ARG0 c :ARG1 (p6 / progress-01 :ARG1 (t / tumor)) :time (s2 / subsequent))) :time (p7 / previous) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 "2")))) # ::id pmid_2112_2157.111 # ::date 2015-07-19T01:06:51 # ::file pmid_2112_2157_111.txt # ::snt We used ELISA and Western blot analysis to measure IL-6 secretion and Stat3 activation (phosphorylation) after medium replacement to remove the existing IL-6 in the old medium and make it possible to measure the amount of newly secreted IL-6 time-dependently in AS2 cells, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (a / and :op1 (a2 / analyze-01 :instrument (t2 / thing :name (n / name :op1 "ELISA"))) :op2 (a3 / analyze-01 :manner (i / immunoblot-01 :ARG0 w))) :ARG2 (m / measure-01 :ARG0 w :ARG1 (a4 / and :op1 (s / secrete-01 :ARG1 (p / protein :name (n3 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op2 (a5 / activate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1-of (m2 / mean-01 :ARG2 (p3 / phosphorylate-01 :ARG1 p2))))) :time (a6 / after :op1 (r / replace-01 :ARG1 (m3 / medium))) :purpose (a7 / and :op1 (r2 / remove-01 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-6") :ARG1-of (e / exist-01) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (m4 / medium :mod (o / old))) :op2 (m5 / make-02 :ARG0 w :ARG1 (p5 / possible-01 :ARG1 (m6 / measure-01 :ARG1 (a8 / amount-01 :ARG1 (p6 / protein :name (n6 / name :op1 "IL-6") :ARG1-of (s2 / secrete-01 :ARG1-of (n7 / new-01)) :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG0-of (d / depend-01 :ARG1 (t / time)) :location (c / cell-line :name (n8 / name :op1 "AS2"))))) :mod (r3 / respective))) # ::id pmid_2112_2157.112 # ::date 2015-07-19T01:42:34 # ::file pmid_2112_2157_112.txt # ::snt We found the constitutive secretion of IL-6 at hours 1 to 24 and the activation of Stat3 peaked at hours 3 and 8, confirming the autocrine production of IL-6 and the subsequent activation of Stat3 in AS2 cells (Figure 1A and 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (a / and :op1 (s / secrete-01 :ARG1 (p / protein :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (c / constitutive) :time (a2 / after :op1 (t / temporal-quantity :quant (v / value-interval :op1 "1" :op2 "24") :unit (h / hour)))) :op2 (p2 / peak-01 :ARG1 (a3 / activate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :time (a4 / after :op1 (a5 / and :op1 (t2 / temporal-quantity :quant "3" :unit h) :op2 (t3 / temporal-quantity :quant "8" :unit h)))) :ARG0-of (c2 / confirm-01 :ARG1 (a6 / and :op1 (p4 / produce-01 :ARG1 p :mod (a7 / autocrine)) :op2 (a8 / activate-01 :ARG1 p3 :time (s2 / subsequent)) :location (c3 / cell-line :name (n3 / name :op1 "AS2"))))) :ARG1-of (d / describe-01 :ARG0 (a9 / and :op1 (f2 / figure :mod "1A") :op2 (f3 / figure :mod "1B")))) # ::id pmid_2112_2157.113 # ::date 2015-07-19T01:59:33 # ::file pmid_2112_2157_113.txt # ::snt It has been shown that cancer cells resistant to chemotherapeutic agents express elevated levels of IL-6, and the IL-6 contributes to the drug resistance of cancer cells [30,39]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (s / show-01 :ARG1 (a / and :op1 (e / express-03 :ARG2 (l / level :quant-of (p / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (e2 / elevate-01)) :ARG3 (c / cell :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")) :ARG0-of (r / resist-01 :ARG1 (a2 / agent :mod (c2 / chemotherapy))))) :op2 (c3 / contribute-01 :ARG0 p :ARG2 (r2 / resist-01 :ARG0 (c4 / cell :mod d) :ARG1 (d2 / drug)))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 (a3 / and :op1 "30" :op2 "39"))))) # ::id pmid_2112_2157.114 # ::date 2015-07-19T02:16:09 # ::file pmid_2112_2157_114.txt # ::snt In our MTT assay of the effect of IL-6 on paclitaxel sensitivity in AS2 cells, we found a significant increase (about 15%) in cell viability in cells pre-treated with exogenous IL-6 and a significant decrease (about 15%) in cell viability in cells treated with anti-IL-6R, compared to the un-pretreated cells (both p < 0.001), indicating that autocrine IL-6 contributed to the paclitaxel resistance in AS2 cells (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (a / and :op1 (i / increase-01 :ARG1 (v / viability :mod (c / cell)) :ARG2 (s / significant-02 :ARG1-of (m / mean-01 :ARG2 (a2 / about :op1 (p / percentage-entity :value "15")))) :location (c2 / cell :ARG1-of (p2 / pretreat-01 :ARG3 (p3 / protein :name (n / name :op1 "IL-6") :mod (e / exogenous) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :op2 (d / decrease-01 :ARG1 v :ARG1-of s :location (c3 / cell :ARG1-of (t / treat-04 :ARG2 (m2 / molecular-physical-entity :ARG0-of (c8 / counter-01 :ARG1 p3))))) :compared-to (a3 / and :op1 (c4 / cell :ARG1-of (p4 / pretreat-01 :polarity "-" :ARG3 p3)) :op2 (c5 / cell :ARG1-of (t2 / treat-04 :polarity "-" :ARG2 m2))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :ARG0-of (i2 / indicate-01 :ARG1 (c7 / contribute-01 :ARG0 (p6 / protein :name (n6 / name :op1 "IL-6") :mod (a6 / autocrine) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (r / resist-01 :ARG1 "s3") :location "c6")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1C")) :time (a4 / assay-01 :ARG0 w :ARG1 (a5 / affect-01 :ARG0 p3 :ARG1 (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "paclitaxel") :xref (x2 / xref :value "PUBCHEM:4666" :prob "15.068933"))) :location (c6 / cell-line :name (n5 / name :op1 "AS2"))) :instrument (s5 / small-molecule :name (n2 / name :op1 "MTT") :xref (x3 / xref :value "PUBCHEM:64965" :prob "17.320225")))) # ::id pmid_2112_2157.115 # ::date 2015-07-19T15:25:41 # ::file pmid_2112_2157_115.txt # ::snt Jak2/Stat3 pathway positively regulated IL-6 autocrine production in AS2 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (r / regulate-01 :ARG0 (p / pathway :name (n / name :op1 "Jak2/Stat3")) :ARG1 (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (a / autocrine)) :location (c / cell-line :name (n3 / name :op1 "AS2")) :manner (p4 / positive)) # ::id pmid_2112_2157.116 # ::date 2015-07-19T15:32:43 # ::file pmid_2112_2157_116.txt # ::snt To investigate whether Jak2/Stat3 as well as the other three IL-6 downstream pathways (PI3-K/Akt, MEK/Erk, and NF-?B) known to be involved in IL-6 expression in various cells would act as an upstream regulator of IL-6 autocrine production in AS2 cells, we used ELISA to measure IL-6 secretion in one control AS2 group and in four different AS2 treatment groups each with one pathway (Jak2/Stat3, PI3-K/Akt, MEK/Erk, or NF-?B) pharmacologically inhibited by the inhibitors AG490, LY294002, U0126, or BAY11-7082, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (t / thing :name (n / name :op1 "ELISA")) :ARG2 (m / measure-01 :ARG0 w :ARG1 (s / secrete-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :location (a / and :op1 (g / group-01 :quant "1" :ARG2 (c / cell-line :name (n3 / name :op1 "AS2")) :ARG2-of (c2 / control-01)) :op2 (g2 / group-01 :quant "4" :mod (t2 / treat-04 :ARG1 c) :ARG1-of (d / differ-02) :mod (p2 / pathway :quant "1" :ARG1-of (m2 / mean-01 :ARG2 (o / or :op1 (p3 / pathway :name (n4 / name :op1 "Jak2/Stat3") :ARG1-of (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "AG490") :xref (x2 / xref :value "PUBCHEM:5328779" :prob "18.349844")) :manner (p4 / pharmacology))) :op2 (p5 / pathway :name (n6 / name :op1 "PI3-K/Akt") :ARG1-of (i2 / inhibit-01 :ARG0 (s3 / small-molecule :name (n7 / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")) :manner p4)) :op3 (p6 / pathway :name (n8 / name :op1 "MEK/Erk") :ARG1-of (i3 / inhibit-01 :ARG0 (s4 / small-molecule :name (n9 / name :op1 "U0126") :xref (x4 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :manner p4)) :op4 (p7 / pathway :name (n10 / name :op1 "NF-κB") :ARG1-of (i4 / inhibit-01 :ARG0 (s5 / small-molecule :name (n11 / name :op1 "BAY11-7082") :xref (x3 / xref :value "PUBCHEM:2301" :prob "21.916582")) :manner p4))))) :mod (e / each))) :purpose (i5 / investigate-01 :ARG0 w :ARG1 (a2 / act-01 :mode "interrogative" :ARG0 (a3 / and :op1 p3 :op2 (p8 / pathway :quant "3" :mod (o2 / other) :direction (d2 / downstream :mod p) :ARG1-of (m3 / mean-01 :ARG2 (a4 / and :op1 p5 :op2 p6 :op3 p7))) :ARG1-of (i6 / involve-01 :ARG2 (e2 / express-03 :ARG2 p :ARG3 (c3 / cell :mod (v / various))) :ARG1-of (k / know-01))) :ARG1 (r / regulate-01 :ARG0 a3 :ARG1 (p9 / produce-01 :ARG1 p :mod (a5 / autocrine)) :direction (u2 / upstream)) :location c))) # ::id pmid_2112_2157.117 # ::date 2015-07-19T16:31:32 # ::file pmid_2112_2157_117.txt # ::snt We found that, compared to the controls, MEK/Erk inhibitor and PI3-K/Akt inhibitor reduced IL-6 secretion in AS2 cells by about 80% and 90% (both p < 0.01), but NF-?B inhibitor decreased it by only 20% (p < 0.05) (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (a / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "MEK/Erk")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3-K/Akt"))))) :ARG1 (s / secrete-01 :ARG1 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (a2 / about :op1 (a3 / and :op1 (p4 / percentage-entity :value "80") :op2 (p5 / percentage-entity :value "90"))) :location (c2 / cell-line :name (n4 / name :op1 "AS2")) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.01"))) :ARG2 (d / decrease-01 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p7 / pathway :name (n5 / name :op1 "NF-κB")))) :ARG1 s :ARG2 (p8 / percentage-entity :value "20") :mod (o / only) :ARG1-of (s3 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.05"))) :ARG1-of (c3 / compare-01 :ARG2 (m4 / molecular-physical-entity :ARG2-of (c4 / control-01)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2A"))) # ::id pmid_2112_2157.118 # ::date 2015-07-19T16:59:11 # ::file pmid_2112_2157_118.txt # ::snt Importantly, Jak2/Stat3 inhibitor also reduced IL-6 secretion by more than 60% (p < 0.01). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (r / reduce-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "Jak2/Stat3")))) :ARG1 (s / secrete-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (m2 / more-than :op1 (p3 / percentage-entity :value "60")) :mod (a / also) :mod (i2 / important) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.01"))) # ::id pmid_2112_2157.119 # ::date 2015-07-19T17:11:30 # ::file pmid_2112_2157_119.txt # ::snt Though Jak2/Stat3 inhibitor was not the most efficient, Jak2/Stat3 pathway clearly participates in the regulation of IL-6 and should be significant an upstream regulator of IL-6 secretion in AS2 cells (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (p / participate-01 :ARG0 (p2 / pathway :name (n / name :op1 "Jak2/Stat3")) :ARG1 (r / regulate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (c / clear-06)) :op2 (r2 / recommend-01 :ARG1 (s / significant-02 :ARG1 p2 :ARG1-of (c3 / cause-01 :ARG0 (r3 / regulate-01 :ARG0 p2 :ARG1 (s2 / secrete-01 :ARG1 p3) :location (u / upstream)))) :location (c2 / cell-line :name (n4 / name :op1 "AS2"))) :concession (e / efficient-01 :polarity "-" :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 p2)) :degree (m2 / most)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2112_2157.120 # ::date 2015-07-19T17:34:19 # ::file pmid_2112_2157_120.txt # ::snt To exclude the possibility that the reduction of IL-6 secretion was mainly caused by the reduction of cell survival, cell viability was measured by MTT assay after being treated with each one of four inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (m / measure-01 :ARG1 (v / viability :mod (c / cell)) :manner (a / assay-01 :instrument (s3 / small-molecule :name (n / name :op1 "MTT") :xref (x1 / xref :value "PUBCHEM:64965" :prob "17.320225"))) :time (a2 / after :op1 (t / treat-04 :ARG1 c :ARG2 (m2 / molecular-physical-entity :quant "4" :ARG0-of (i / inhibit-01) :mod (e / each)))) :purpose (e2 / exclude-01 :ARG1 (p / possible-01 :ARG1 (c2 / cause-01 :ARG0 (r / reduce-01 :ARG1 (s / survive-01 :ARG0 (c3 / cell))) :ARG1 (r2 / reduce-01 :ARG1 (s2 / secrete-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :mod (m3 / main))))) # ::id pmid_2112_2157.121 # ::date 2015-07-19T17:47:34 # ::file pmid_2112_2157_121.txt # ::snt None of these inhibitors compromised the viability of AS2 cells during the treatment period at the indicated doses (Additional file 1, Figure S1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 27, 2015 (c / compromise-02 :polarity "-" :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (t / this) :ARG1-of (d / dose-01 :ARG1-of (i2 / indicate-01))) :ARG1 (v / viability :poss (c2 / cell-line :name (n / name :op1 "AS2"))) :time (p / period :mod (t2 / treat-04)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (a2 / add-02 :ARG1 (f / file)) :op2 (f2 / figure :mod "S1A")))) # ::id pmid_2112_2157.122 # ::date 2015-07-19T17:57:50 # ::file pmid_2112_2157_122.txt # ::snt To confirm our findings, we performed inhibition experiments on AS2 cells using increasing doses of Jak2/Stat3 inhibitor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / perform-01 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG0 w :ARG1 (c / cell-line :name (n / name :op1 "AS2")) :ARG2 (i / inhibit-01)) :ARG2 (d / dose-01 :ARG1 c :ARG2 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "Jak2/Stat3")))) :ARG1-of (i3 / increase-01)) :purpose (c2 / confirm-01 :ARG0 w :ARG1 (t / thing :ARG1-of (f / find-01 :ARG0 w)))) # ::id pmid_2112_2157.123 # ::date 2015-07-19T18:07:59 # ::file pmid_2112_2157_123.txt # ::snt Decrease in Stat3 phosphorylation was confirmed by Western blot analysis, and IL-6 secretion was measured by ELISA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (c / confirm-01 :ARG0 (a2 / analyze-01 :manner (i / immunoblot-01)) :ARG1 (d / decrease-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))))) :op2 (m / measure-01 :ARG1 (s / secrete-01 :ARG1 (p3 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :manner (t / thing :name (n4 / name :op1 "ELISA")))) # ::id pmid_2112_2157.124 # ::date 2015-07-19T18:14:21 # ::file pmid_2112_2157_124.txt # ::snt We found the Jak2/Stat3 inhibitor dose-dependently decreased Stat3 phosphorylation (Figure 2B) and IL-6 secretion (p < 0.05 at doses higher than 20 �M) (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (d / decrease-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "Jak2/Stat3")))) :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2B"))) :op2 (s / secrete-01 :ARG1 (p4 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG1-of (d3 / dose-01 :quant (m3 / more-than :op1 (c / concentration-quantity :quant "20" :unit (m2 / micromolar)))) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "2C")))) :ARG0-of (d5 / depend-01 :ARG1 d3) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05")))) # ::id pmid_2112_2157.125 # ::date 2015-07-19T18:32:17 # ::file pmid_2112_2157_125.txt # ::snt We also used MTT assay to analyze the effect of the increasing doses of AG490 on cell viability and showed that only a minor reduction in cell survival (about 15%) was found when cells exposed to 80 �M AG490 (Additional file 1, Figure S1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (u / use-01 :ARG0 (w / we) :ARG1 (a2 / assay-01 :instrument (s5 / small-molecule :name (n / name :op1 "MTT") :xref (x1 / xref :value "PUBCHEM:64965" :prob "17.320225"))) :ARG2 (a3 / analyze-01 :ARG0 w :ARG1 (a4 / affect-01 :ARG0 (d / dose-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "AG490") :xref (x / xref :value "PUBCHEM:5328779" :prob "18.349844")) :ARG1-of (i / increase-01)) :ARG1 (v / viability :mod (c / cell)))) :mod (a5 / also)) :op2 (s / show-01 :ARG0 w :ARG1 (f / find-01 :ARG0 w :ARG1 (r / reduce-01 :ARG1 (s2 / survive-01 :ARG0 (c2 / cell)) :ARG1-of (m / minor-01 :ARG1-of (m3 / mean-01 :ARG2 (a6 / about :op1 (p / percentage-entity :value "15")))) :mod (o / only)) :time (e / expose-01 :ARG0 w :ARG1 (c3 / cell) :ARG2 (s4 / small-molecule :name (n3 / name :op1 "AG490") :quant (c4 / concentration-quantity :quant "80" :unit (m5 / micromolar)) :xref (x2 / xref :value "PUBCHEM:5328779" :prob "18.349844"))))) :ARG1-of (d2 / describe-01 :ARG0 (a7 / and :op1 (a8 / add-02 :ARG1 (f2 / file :mod "1")) :op2 (f3 / figure :mod "S1B")))) # ::id pmid_2112_2157.126 # ::date 2015-07-19T22:40:30 # ::file pmid_2112_2157_126.txt # ::snt In addition, we showed that treatment with AG490 (40 �M) significantly decreased IL-6 promoter activity (Figure 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (a / and :op1 (s / show-01 :ARG0 (w / we) :ARG1 (d / decrease-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "AG490") :quant (c / concentration-quantity :quant "40" :unit (m / micromolar)) :xref (x1 / xref :value "PUBCHEM:5328779" :prob "18.349844"))) :ARG1 (a2 / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :ARG2 (s3 / significant-02))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2D"))) # ::id pmid_2112_2157.127 # ::date 2015-07-19T22:48:40 # ::file pmid_2112_2157_127.txt # ::snt Our results suggest that Jak2/Stat3 pathway may regulate the autocrine production of IL-6 in AS2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (p / possible-01 :ARG1 (r2 / regulate-01 :ARG0 (p2 / pathway :name (n / name :op1 "Jak2/Stat3")) :ARG1 (p3 / produce-01 :ARG1 (p4 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (a / autocrine) :location (c / cell-line :name (n3 / name :op1 "AS2")))))) # ::id pmid_2112_2157.128 # ::date 2015-07-19T22:54:13 # ::file pmid_2112_2157_128.txt # ::snt Stat3 activation status was positively correlated with IL-6 expression and paclitaxel resistance in AS2-derived cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / correlate-01 :ARG1 (s / status :mod (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :ARG2 (a2 / and :op1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :op2 (r / resist-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "paclitaxel") :xref (x2 / xref :value "PUBCHEM:4666" :prob "15.068933")))) :location (c2 / cell :ARG1-of (d / derive-01 :ARG2 (c3 / cell-line :name (n3 / name :op1 "AS2")))) :manner (p3 / positive)) # ::id pmid_2112_2157.129 # ::date 2015-07-15T23:57:49 # ::file pmid_2112_2157_129.txt # ::snt To clarify the role of Stat3 on IL-6 autocrine production proposed by the biochemical studies, we performed genetic studies to investigate the effect of varying degrees of Stat3 activation and inactivation on the mRNA expression and the secretion of IL-6 using parental AS2 cells and various previously established AS2-derived cell lines with different Stat3 activation status: vector control cells, two AS2/S3C cells, two AS2/S3D cells, and two AS2/S3F cells [2,10]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (h / have-purpose-91 :ARG1 (p4 / perform-01 :ARG0 (w / we) :ARG1 (s2 / study-01 :mod (g / genetic)) :purpose (i / investigate-01 :ARG0 w :ARG1 (a2 / affect-01 :ARG0 (a3 / and :op1 (a4 / activate-01 :ARG1 "p") :op2 (a5 / activate-01 :polarity "-" :ARG1 "p") :degree (d / degree :ARG1-of (v / vary-01))) :ARG1 (a6 / and :op1 (e2 / express-03 :ARG2 (n / nucleic-acid :name (n3 / name :op1 "mRNA"))) :op2 (s3 / secrete-01 :ARG1 (p10 / protein :name (n4 / name :op1 "IL-6") :xref (x2 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG2 (a7 / and :op1 (c2 / cell-line :name (n5 / name :op1 "AS2") :mod (p5 / parent)) :op2 (e4 / establish-01 :ARG1 (c3 / cell-line :ARG1-of (d2 / derive-01 :ARG2 c2) :ARG1-of (v2 / vary-01) :ARG0-of (h3 / have-03 :ARG1 (s4 / status :mod (a8 / activate-01 :ARG1 (p7 / protein :name (n6 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :ARG1-of (d3 / differ-02))) :ARG1-of (m / mean-01 :ARG2 (a9 / and :op1 (c4 / cell :ARG1-of (c5 / control-01 :ARG0 (v3 / vector))) :op2 (c6 / cell-line :quant "2" :name (n7 / name :op1 "AS2/S3C")) :op3 (c7 / cell-line :quant "2" :name (n8 / name :op1 "AS2/S3D")) :op4 (c8 / cell-line :quant "2" :name (n9 / name :op1 "AS2/S3F"))))) :time (p6 / previous)))))) :ARG2 (c / clarify-10 :ARG1 (r / role :poss (p / protein :name n6 :ARG0-of (p2 / produce-01 :ARG1 (p9 / protein :name n4 :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (a / autocrine)) :ARG1-of (p3 / propose-01 :ARG0 (s / study-01 :mod (b / biochimic))) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :ARG1-of (d4 / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c9 / cite-01 :ARG2 (a10 / and :op1 "2" :op2 "10"))))) # ::id pmid_2112_2157.130 # ::date 2015-07-16T01:10:14 # ::file pmid_2112_2157_130.txt # ::snt In this current study, we used S3C as active form Stat3, and S3D and S3F as inactivated forms of Stat3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 8, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "S3C") :mod (c / consider-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Stat3") :ARG0-of (a5 / activity-06) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :op2 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "S3D")) :op2 (p4 / protein :name (n4 / name :op1 "S3F")) :mod (c2 / consider-01 :ARG1 (p5 / protein :name (n5 / name :op1 "Stat3") :ARG0-of (a2 / activity-06 :polarity "-") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))))) :medium (s / study-01 :mod (c3 / current) :mod (t / this))) # ::id pmid_2112_2157.131 # ::date 2015-07-16T01:25:16 # ::file pmid_2112_2157_131.txt # ::snt Western blot analysis showed increased expression of Stat3 protein in all mutant cells, in the AS2/S3C cells (AS2/S3C-A and AS2/S3C-C), in the AS2/S3D cells (AS2/S3D-8 and AS2/S3D-9) and in the AS2/S3F cells (AS2/S3F-3 and AS2/S3F-7), compared to the parental cells (AS2) and vector control cells (AS2/Vec-11) (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (s / show-01 :ARG0 (a / analyze-01 :manner (i2 / immunoblot-01)) :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG3 (c14 / cell :ARG2-of (m4 / mutate-01) :mod (a7 / all) :ARG1-of (m5 / mean-01 :ARG2 (a3 / and :op1 (c5 / cell-line :name (n3 / name :op1 "AS2/S3C") :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (c6 / cell-line :name (n4 / name :op1 "AS2/S3C-A")) :op2 (c7 / cell-line :name (n5 / name :op1 "AS2/S3C-C"))))) :op2 (c8 / cell-line :name (n6 / name :op1 "AS2/S3D") :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (c9 / cell-line :name (n7 / name :op1 "AS2/S3D-8")) :op2 (c10 / cell-line :name (n8 / name :op1 "AS2/S3D-9"))))) :op3 (c11 / cell-line :name (n9 / name :op1 "AS2/S3F") :ARG1-of (m3 / mean-01 :ARG2 (a6 / and :op1 (c12 / cell-line :name (n10 / name :op1 "AS2/S3F-3")) :op2 (c13 / cell-line :name (n11 / name :op1 "AS2/S3F-7")))))))) :ARG1-of (i / increase-01 :ARG1-of (c / compare-01 :ARG2 (a2 / and :op1 (c2 / cell-line :name (n12 / name :op1 "AS2") :mod (p2 / parent)) :op2 (c3 / cell-line :name (n13 / name :op1 "AS2/Vec-11") :mod (c4 / control-01 :ARG0 (v / vector))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2112_2157.132 # ::date 2015-07-16T01:38:44 # ::file pmid_2112_2157_132.txt # ::snt However, only AS2/S3F cells but not AS2/S3C or AS2/S3D cells were found to have decreases in Stat3 phosphorylation (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c5 / contrast-01 :ARG2 (f2 / find-01 :ARG1 (h / have-03 :ARG0 (c2 / cell-line :name (n / name :op1 "AS2/S3F") :mod (o2 / only)) :ARG1 (d2 / decrease-01 :ARG1 (p / protein :name (n2 / name :op1 "Stat3") :ARG1-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :ARG1-of (c3 / contrast-01 :ARG2 (o / or :op1 (c4 / cell-line :name (n3 / name :op1 "AS2/S3C")) :op2 (c / cell-line :name (n4 / name :op1 "AS2/S3D")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A")))) # ::id pmid_2112_2157.133 # ::date 2015-07-16T01:45:37 # ::file pmid_2112_2157_133.txt # ::snt RT-PCR showed that the AS2/S3C cells expressed 3 to 4 times more IL-6 mRNA than the parental and vector control cells and that AS2/S3D and AS2/S3F cells expressed 30 to 70 percent less IL-6 mRNA (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG0 (r / react-01 :ARG0 (p5 / polymerase) :mod (c7 / chain) :subevent (t / transcribe-01 :ARG1-of (r2 / reverse-01))) :ARG1 (a / and :op1 (e / express-03 :ARG2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p4 / protein :name (n4 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG3 (c / cell-line :name (n2 / name :op1 "AS2/S3C")) :quant (p / product-of :op1 (v2 / value-interval :op1 "3" :op2 "4")) :degree (m / more) :compared-to (a2 / and :op1 (c2 / cell :mod (p2 / parent)) :op2 (c3 / cell :mod (c4 / control-01 :ARG0 (v / vector))))) :op2 (e3 / express-03 :ARG2 n7 :ARG3 (a3 / and :op1 (c5 / cell-line :name (n5 / name :op1 "AS2/S3D")) :op2 (c6 / cell-line :name (n6 / name :op1 "AS2/S3F"))) :quant (p3 / percentage-entity :op1 (v3 / value-interval :op1 "30" :op2 "70") :mod (l / less)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2112_2157.134 # ::date 2015-07-16T02:07:56 # ::file pmid_2112_2157_134.txt # ::snt Similarly, transient transfection with S3C plasmid increased IL-6 promoter luciferase activity by more than 70% and transient transfection with S3F plasmid decreased IL-6 promoter luciferase activity by more than 40% compared with the mock and vector control groups (both p < 0.001) (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / compare-01 :ARG1 (a / and :op1 (t / transfect-01 :ARG2 (p9 / plasmid :mod (p / protein :name (n2 / name :op1 "S3C"))) :ARG1-of (t2 / transient-02) :ARG0-of (i / increase-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (p10 / promote-01 :ARG1 (p7 / protein :name (n3 / name :op1 "IL-6") :ARG0-of (a2 / activity-06 :ARG1 (l / luciferase)) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG2 (m4 / more-than :op1 (p3 / percentage-entity :value "70")))) :op2 (t3 / transfect-01 :ARG2 (p8 / plasmid :mod (p4 / protein :name (n5 / name :op1 "S3F"))) :ARG0-of (d / decrease-01 :ARG1 p7 :ARG2 (m / more-than :op1 (p5 / percentage-entity :value "40"))) :ARG1-of t2) :ARG1-of (s / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.001"))) :ARG2 (a3 / and :op1 (g / group :mod (m3 / mock)) :op2 (g2 / group :mod (c2 / control-01 :ARG0 (v / vector)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3C")) :ARG1-of (r / resemble-01)) # ::id pmid_2112_2157.135 # ::date 2015-07-16T02:48:05 # ::file pmid_2112_2157_135.txt # ::snt ELISA showed that AS2/S3C cells secreted 5 to 10 times more IL-6 than the parental and vector control cells (both p < 0.001) (Figure 3D) and AS2/S3D and AS2/S3F cells secreted 40 to 80 percent less IL-6 (both p < 0.01 in AS2/S3D cells and both p < 0.001 in S3F cells) (Figure 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (t / thing :name (n / name :op1 "ELISA")) :ARG1 (a / and :op1 (s2 / secrete-01 :ARG0 (c / cell-line :name (n2 / name :op1 "AS2/S3C")) :ARG1 (p / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :quant (p2 / product-of :op1 (v3 / value-interval :op1 "5" :op2 "10")) :degree (m / more) :compared-to (a2 / and :op1 (c2 / cell :mod (p3 / parent)) :op2 (c3 / cell :mod (c4 / control-01 :ARG0 (v / vector)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3D")) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :op2 (s3 / secrete-01 :ARG0 (a3 / and :op1 (c5 / cell-line :name (n4 / name :op1 "AS2/S3D")) :op2 (c6 / cell-line :name (n5 / name :op1 "AS2/S3F"))) :ARG1 p :quant (p5 / percentage-entity :op1 (v2 / value-interval :op1 "40" :op2 "80") :mod (l2 / less)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3E")) :ARG1-of (s5 / statistical-test-91 :ARG2 (a4 / and :op1 (l3 / less-than :op1 "0.01" :location c5) :op2 (l4 / less-than :op1 "0.001" :location c6)))))) # ::id pmid_2112_2157.136 # ::date 2015-07-16T03:28:23 # ::file pmid_2112_2157_136.txt # ::snt These results show that Stat3 may positively regulate the expression of IL-6 mRNA expression and the secretion of IL-6 in AS2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (t2 / thing :ARG2-of (r / result-01) :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (r2 / regulate-01 :ARG0 (p3 / protein :name (n / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1 (a / and :op1 (e / express-03 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "mRNA") :mod (p4 / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG3 (c / cell-line :name (n4 / name :op1 "AS2"))) :op2 (s2 / secrete-01 :ARG0 c :ARG1 p4)) :mod (p2 / positive)))) # ::id pmid_2112_2157.137 # ::date 2015-07-16T03:41:56 # ::file pmid_2112_2157_137.txt # ::snt To evaluate drug resistance, we treated the parental AS2 cells, vector control cells (AS2/Vec-11), the AS2/S3C cells (AS2/S3C-C), the AS2/S3D cells (AS2/S3D-9), and the AS2/S3F cells (AS2/S3F-3) with paclitaxel for 72 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 8, 2015 (h / have-purpose-91 :ARG1 (t / treat-04 :ARG0 (w / we) :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "AS2") :mod (p2 / parent)) :op2 (c2 / cell-line :name (n2 / name :op1 "AS2/Vec-11") :mod (c3 / control-01 :ARG0 (v / vector))) :op3 (c4 / cell-line :name (n3 / name :op1 "AS2/S3C") :ARG1-of (m / mean-01 :ARG2 (c5 / cell-line :name (n4 / name :op1 "AS2/S3C-C")))) :op4 (c6 / cell-line :name (n5 / name :op1 "AS2/S3D") :ARG1-of (m2 / mean-01 :ARG2 (c8 / cell-line :name (n7 / name :op1 "AS2/S3D-9")))) :op5 (c7 / cell-line :name (n6 / name :op1 "AS2/S3F") :ARG1-of (m3 / mean-01 :ARG2 (c9 / cell-line :name (n8 / name :op1 "AS2/S3F-3"))))) :ARG2 (s / small-molecule :name (n9 / name :op1 "paclitaxel") :xref (x / xref :value "PUBCHEM:4666" :prob "15.068933")) :duration (t2 / temporal-quantity :quant "72" :unit (h2 / hour))) :ARG2 (e / evaluate-01 :ARG0 w :ARG1 (r / resist-01 :ARG1 (d / drug)))) # ::id pmid_2112_2157.138 # ::date 2015-07-16T03:53:44 # ::file pmid_2112_2157_138.txt # ::snt Using MTT assay to access cell viability, we found AS2 cells with increased Stat3 activity (AS2/S3C-C) to be more resistant to paclitaxel than AS2 and AS2/Vec-11 cells (p < 0.05), and AS2 cells with decreased Stat3 activity (AS2/S3D-9 and AS2/S3F-3) to be less resistant to paclitaxel (p < 0.05) (Figure 3F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (a3 / and :op1 (r / resist-01 :ARG0 (c2 / cell-line :name (n / name :op1 "AS2") :ARG0-of (h / have-03 :ARG1 (i / increase-01 :ARG1 (a4 / activity-06 :ARG0 (p / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))))) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :name (n3 / name :op1 "AS2/S2C-C")))) :ARG1 (s / small-molecule :name (n4 / name :op1 "paclitaxel") :xref (x2 / xref :value "PUBCHEM:4666" :prob "15.068933")) :degree (m2 / more) :compared-to (a5 / and :op1 (c4 / cell :name n) :op2 (c5 / cell-line :name (n5 / name :op1 "AS2/Vec-11"))) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) :op2 (r2 / resist-01 :ARG0 (c6 / cell :name n :ARG0-of (h2 / have-03 :ARG1 (d / decrease-01 :ARG1 a4)) :ARG1-of (m3 / mean-01 :ARG2 (a6 / and :op1 (c7 / cell-line :name (n7 / name :op1 "AS2/S3D-9")) :op2 (c8 / cell-line :name (n8 / name :op1 "AS2/S3F-3"))))) :ARG1 s :degree (l2 / less) :ARG1-of (s3 / statistical-test-91 :ARG2 l))) :manner (u / use-01 :ARG0 w :ARG1 (a7 / assay-01 :instrument (s4 / small-molecule :name (n6 / name :op1 "MTT") :xref (x1 / xref :value "PUBCHEM:64965" :prob "17.320225"))) :ARG2 (a2 / access-01 :ARG0 w :ARG1 (v / viability :mod (c / cell)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3F"))) # ::id pmid_2112_2157.139 # ::date 2015-07-16T04:12:04 # ::file pmid_2112_2157_139.txt # ::snt Together, these findings suggest that the activation of Stat3 may contribute to the regulation of IL-6 autocrine production and resistance to paclitaxel in AS2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t3 / thing :ARG1-of (f / find-01) :mod (t / this) :mod (t2 / together)) :ARG1 (p / possible-01 :ARG1 (c / contribute-01 :ARG0 (a / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :ARG2 (a2 / and :op1 (r / regulate-01 :ARG1 (p3 / produce-01 :ARG1 (p5 / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (a3 / autocrine))) :op2 (r2 / resist-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "paclitaxel") :xref (x2 / xref :value "PUBCHEM:4666" :prob "15.068933"))) :location (c2 / cell-line :name (n3 / name :op1 "AS2")))))) # ::id pmid_2112_2157.140 # ::date 2015-07-16T05:32:55 # ::file pmid_2112_2157_140.txt # ::snt Knocking-down Stat3 by transient transfection with synthetic siRNA decreased IL-6 expression in AS2 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (d / decrease-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG5 (t / transfect-01 :ARG1 (c / cell-line :name (n4 / name :op1 "AS2")) :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA") :mod (s / synthetic)) :ARG1-of (t2 / transient-02))) :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG3 c)) # ::id pmid_2112_2157.141 # ::date 2015-07-16T05:39:42 # ::file pmid_2112_2157_141.txt # ::snt To confirm that Stat3 regulated IL-6 expression in cancer cells, we transiently transfected AS2 cells with Stat3 siRNA to knock-down the expression of Stat3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (h / have-purpose-91 :ARG1 (t / transfect-01 :ARG0 (w / we) :ARG1 (c / cell-line :name (n / name :op1 "AS2")) :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :ARG1-of (t2 / transient-02) :purpose (k / knock-down-02 :ARG1 (e / express-03 :ARG2 p))) :ARG2 (c2 / confirm-01 :ARG0 w :ARG1 (r2 / regulate-01 :ARG0 p :ARG1 (p2 / protein :name (n4 / name :op1 "IL-6") :ARG2-of (e3 / express-03 :ARG3 (c3 / cell :mod (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) # ::id pmid_2112_2157.142 # ::date 2015-07-16T05:58:33 # ::file pmid_2112_2157_142.txt # ::snt Western blot analysis showed transfection with Stat3 siRNA (Stat3#1) dose-dependently decreased the total amount of Stat3 protein and phosphorylated Stat3 (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (s / show-01 :ARG0 (a / analyze-01 :manner (i / immunoblot-01)) :ARG1 (t / transfect-01 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA") :mod (p / protein :name (n3 / name :op1 "Stat3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1-of (l / label-01 :ARG2 (n7 / name :op1 "Stat3#1"))) :ARG0-of (d3 / decrease-01 :ARG1 (a2 / amount-01 :ARG1 (a3 / and :op1 (p2 / protein :name n3 :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :op2 (p3 / protein :name n3 :ARG3-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :ARG2 (t2 / total)) :ARG0-of (d2 / depend-01 :ARG1 (d / dose-01 :ARG1 n5)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id pmid_2112_2157.143 # ::date 2015-07-16T06:15:56 # ::file pmid_2112_2157_143.txt # ::snt RT-PCR and ELISA showed transfection with Stat3#1 reduced the expression of IL-6 mRNA (Figure 4B) and the secretion of IL-6 at 3, 8, and 24 hours after medium replacement (p < 0.01 in the lower dose and p < 0.001 in the higher doses) (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (s / show-01 :ARG0 (a / and :op1 (r3 / react-01 :ARG0 (p3 / polymerase) :mod (c / chain) :subevent (t / transcribe-01) :ARG1-of (r / reverse-01)) :op2 (a9 / assay-01 :instrument (i / immunosorbent) :ARG1-of (l4 / link-01 :ARG2 (e2 / enzyme)))) :ARG1 (t3 / transfect-01 :ARG2 (p / protein :name (n3 / name :op1 "Stat3#1") :xref (x1 / xref :value "UNIPROT:EF1A2_HUMAN" :prob "0.262")) :ARG0-of (r2 / reduce-01 :ARG1 (a2 / and :op1 (e / express-03 :ARG2 (n6 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B"))) :op2 (s2 / secrete-01 :ARG1 p2 :time (a4 / and :op1 (a5 / after :op1 (r4 / replace-01 :ARG1 (m / medium)) :quant (t4 / temporal-quantity :quant "3" :unit (h / hour))) :op2 (a6 / after :op1 r4 :quant (t5 / temporal-quantity :quant "8" :unit h)) :op3 (a7 / after :op1 r4 :quant (t6 / temporal-quantity :quant "24" :unit h))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "4C")) :ARG1-of (s3 / statistical-test-91 :ARG2 (a8 / and :op1 (l / less-than :op1 "0.01" :condition (d2 / dose-01 :ARG1-of (l2 / low-04 :degree (m2 / more)))) :op2 (l3 / less-than :op1 "0.001" :condition (d3 / dose-01 :ARG1-of (h2 / high-02 :degree (m3 / more))))))))))) # ::id pmid_2112_2157.144 # ::date 2015-07-16T06:35:09 # ::file pmid_2112_2157_144.txt # ::snt To make sure our results were not confounded by differences in cell viability, we performed MTT assay of the transfected and untransfected cells, and found that these siRNAs did not affect the viability of AS2 cells (Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (p / perform-01 :ARG0 (w / we) :ARG1 (a5 / assay-01 :ARG1 (a3 / and :op1 (c5 / cell :ARG1-of (t4 / transfect-01)) :op2 (c6 / cell :ARG1-of (t5 / transfect-01 :polarity "-"))) :instrument (s / small-molecule :name (n3 / name :op1 "MTT") :xref (x / xref :value "PUBCHEM:64965" :prob "17.320225"))) :purpose (e / ensure-01 :ARG0 w :ARG1 (c2 / confound-01 :ARG0 (d / differ-02 :ARG3 (v / viability :mod (c3 / cell))) :ARG1 (t / thing :ARG2-of (r3 / result-01) :poss w)))) :op2 (f / find-01 :ARG0 w :ARG1 (a4 / affect-01 :polarity "-" :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA") :mod (t3 / this)) :ARG1 (c / cell-line :name (n2 / name :op1 "AS2") :mod (v2 / viability)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4D"))) # ::id pmid_2112_2157.145 # ::date 2015-07-16T07:27:19 # ::file pmid_2112_2157_145.txt # ::snt The findings suggested that the suppression of IL-6 production by knocking-down Stat3 was not likely a result of a decrease in cell number. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t / thing :ARG1-of (f / find-01)) :ARG1 (l / likely-01 :polarity "-" :ARG1 (r / result-01 :ARG1 (d / decrease-01 :ARG1 (n / number-01 :ARG1 (c / cell))) :ARG2 (s2 / suppress-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :ARG1-of (p / produce-01) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :manner (k / knock-down-02 :ARG1 (p2 / protein :name (n3 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))))))) # ::id pmid_2112_2157.146 # ::date 2015-07-16T07:39:36 # ::file pmid_2112_2157_146.txt # ::snt As can be seen in Figures S2A and S2B in Additional file 2, the other Stat3 siRNA (Stat3#2) with a different targeting sequence also knocked-down Stat3 expression and reduced IL-6 secretion but did not compromise cell proliferation (Additional file 3, Figure S3A), a further confirmation of our findings. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (c / contrast-01 :ARG1 (a3 / and :op1 (k / knock-down-02 :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA") :mod (p / protein :name (n2 / name :op1 "Stat3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1-of (m / mean-01 :ARG2 (n6 / nucleic-acid :name (n3 / name :op1 "Stat3#2"))) :mod (o / other) :ARG0-of (h / have-03 :ARG1 (s / sequence :ARG0-of (t / target-01 :ARG1-of (d2 / differ-02))))) :ARG1 (p2 / protein :name n2 :ARG2-of (e / express-03) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :op2 (r4 / reduce-01 :ARG0 n4 :ARG1 (p5 / protein :name (n5 / name :op1 "IL-6") :ARG1-of (s2 / secrete-01) :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :mod (a / also)) :ARG2 (c2 / compromise-02 :polarity "-" :ARG0 n4 :ARG1 (c3 / cell :ARG0-of (p3 / proliferate-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S3A" :part-of (f2 / file :mod "3" :mod (a2 / additional))))) :ARG0-of (c4 / confirm-01 :ARG1 (t2 / thing :ARG1-of (f3 / find-01 :ARG0 (w / we))) :ARG1-of (f4 / further-01)) :ARG1-of (s3 / see-01 :ARG1-of (p4 / possible-01) :location (a5 / and :op1 (f7 / figure :mod "S2A") :op2 (f8 / figure :mod "S2B") :part-of (f6 / file :mod "2" :mod (a4 / additional))))) # ::id pmid_2112_2157.147 # ::date 2015-07-16T07:57:23 # ::file pmid_2112_2157_147.txt # ::snt Knocking-down Stat3 by stable transfection with shRNA decreased the expression of IL-6 in AS2 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / decrease-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :manner (t / transfect-01 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "shRNA")) :ARG1-of (s / stable-03))) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG3 (c / cell-line :name (n4 / name :op1 "AS2")))) # ::id pmid_2112_2157.148 # ::date 2015-07-16T08:01:23 # ::file pmid_2112_2157_148.txt # ::snt To further investigate the possible role of Stat3 in the regulation of IL-6, we stably transfected AS2 cells with the control vector from which we selected one cell line (AS2/shVec) and the vector expressing Stat3 shRNA from which we selected two cell lines (AS2/shStat3-1 and AS2/shStat3-2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (h / have-purpose-91 :ARG1 (t / transfect-01 :ARG1 (c / cell-line :name (n / name :op1 "AS2")) :ARG2 (a / and :op1 (c2 / control-01 :ARG0 (v / vector) :ARG2-of (s / select-01 :ARG0 (w / we) :ARG1 (c3 / cell-line :quant "1" :name (n2 / name :op1 "AS2/shVec")))) :op2 (v2 / vector :ARG1-of (e / express-03 :ARG2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n4 / name :op1 "Stat3") :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))))) :ARG2-of (s2 / select-01 :ARG0 w :ARG1 (a2 / and :quant "2" :op1 (c6 / cell-line :name (n5 / name :op1 "AS2/shStat3-1")) :op2 (c7 / cell-line :name (n7 / name :op1 "AS2/shStat3-2"))))))) :ARG2 (i / investigate-01 :ARG0 w :ARG1 (r2 / role :ARG1-of (p3 / possible-01) :topic (r3 / regulate-01 :ARG1 (p4 / protein :name (n6 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :poss (p2 / protein :name n4 :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :ARG1-of (f / further-01))) # ::id pmid_2112_2157.149 # ::date 2015-07-20T13:30:44 # ::file pmid_2112_2157_149.txt # ::snt Western blot analysis showed a lower expression of Stat3 protein and a lower level of Stat3 phosphorylation in both cell lines expressing Stat3 shRNA than in either the parental cells or the vector control cells (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (s / show-01 :ARG0 (a / analyze-01 :manner (i / immunoblot-01)) :ARG1 (a2 / and :op1 (l / low-04 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :degree (m / more)) :op2 (l3 / low-04 :ARG1 (l2 / level :quant-of (p2 / phosphorylate-01 :ARG3 p)) :degree m)) :location (c / cell-line :mod (b / both) :ARG3-of (e2 / express-03 :ARG2 (n4 / nucleic-acid :name (n3 / name :op1 "shRNA") :mod p)) :compared-to (o / or :op1 (c2 / cell :mod (p3 / parent) :mod (e3 / either)) :op2 (c3 / cell :mod (v / vector) :mod (c4 / control)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id pmid_2112_2157.150 # ::date 2015-07-20T13:31:00 # ::file pmid_2112_2157_150.txt # ::snt RT-PCR showed a continuing decrease in the expression of IL-6 mRNA in both cell lines expressing Stat3 shRNA (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG0 (r3 / react-01 :ARG0 (p3 / polymerase) :mod (c3 / chain) :subevent (t / transcribe-01 :ARG1-of (r / reverse-01))) :ARG1 (d / decrease-01 :ARG1 (e / express-03 :ARG2 (n / nucleic-acid :name (n2 / name :op1 "mRNA") :mod (p / protein :name (n3 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG1-of (c / continue-01) :location (c2 / cell-line :ARG3-of (e2 / express-03 :ARG2 (n6 / nucleic-acid :name (n4 / name :op1 "shRNA") :mod (p2 / protein :name (n5 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :mod (b / both))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id pmid_2112_2157.151 # ::date 2015-07-20T14:09:37 # ::file pmid_2112_2157_151.txt # ::snt ELISA also showed a continuing decrease IL-6 secretion in both cell lines expressing Stat3 shRNA compared to the parental AS2 (90% in AS2/shStat3-1 and 95% AS2/shStat3-2 at 24 hours) (p < 0.001) (Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG0 (t / thing :name (n / name :op1 "ELISA") :mod (i / immunosorbent) :ARG1-of (l2 / link-01 :ARG2 (e2 / enzyme))) :ARG1 (d / decrease-01 :ARG1 (s2 / secrete-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :location (c / cell-line :mod (b / both) :ARG3-of (e / express-03 :ARG2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA") :mod (p8 / protein :name (n7 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) :compared-to (c2 / cell-line :name (n4 / name :op1 "AS2") :mod (p2 / parent))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n5 / name :op1 "AS2/shStat3-1") :quant (p4 / percentage-entity :value "90")) :op2 (c4 / cell-line :name (n6 / name :op1 "AS2/shStat3-2") :quant (p6 / percentage-entity :value "95")) :time (a3 / after :op1 (t2 / temporal-quantity :quant "24" :unit (h / hour))))) :ARG1-of (c5 / continue-01) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5C")) :mod (a2 / also)) # ::id pmid_2112_2157.152 # ::date 2015-07-20T14:22:09 # ::file pmid_2112_2157_152.txt # ::snt We also analyzed the drug resistance of these cells to paclitaxel by MTT assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (r / resist-01 :ARG0 (c / cell :mod (t / this)) :ARG1 (s / small-molecule :name (n / name :op1 "paclitaxel") :xref (x1 / xref :value "PUBCHEM:4666" :prob "15.068933")) :mod (d / drug)) :mod (a2 / also) :manner (a3 / assay-01 :instrument (s2 / small-molecule :name (n2 / name :op1 "MTT") :xref (x / xref :value "PUBCHEM:64965" :prob "17.320225")))) # ::id pmid_2112_2157.153 # ::date 2015-07-20T14:25:48 # ::file pmid_2112_2157_153.txt # ::snt MTT assay showed that the permanent knock-down of Stat3 in AS2/shStat3-1 and AS2/shStat3-2 cells significantly reduced their resistance to paclitaxel (p < 0.001) (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / show-01 :ARG0 (a / assay-01 :instrument (s5 / small-molecule :name (n / name :op1 "MTT") :xref (x2 / xref :value "PUBCHEM:64965" :prob "17.320225"))) :ARG1 (r / reduce-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :location (a2 / and :op1 (c / cell-line :name (n3 / name :op1 "AS2/shStat3-1")) :op2 (c2 / cell-line :name (n4 / name :op1 "AS2/shStat3-2"))) :mod (p3 / permanent)) :ARG1 (r2 / resist-01 :ARG0 a2 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "paclitaxel") :xref (x1 / xref :value "PUBCHEM:4666" :prob "15.068933"))) :ARG2 (s2 / significant-02) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id pmid_2112_2157.154 # ::date 2015-07-20T14:40:15 # ::file pmid_2112_2157_154.txt # ::snt Pretreatment with exogenous IL-6 modestly restored the resistance (p < 0.01) (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (r / restore-01 :ARG0 (p / pretreat-01 :ARG3 (p2 / protein :name (n / name :op1 "IL-6") :mod (e / exogenous) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1 (r2 / resist-01) :degree (m / modest) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5D")) :ARG1-of (s / statistical-test-91 :ARG2 (l / less-than :op1 "0.01"))) # ::id pmid_2112_2157.155 # ::date 2015-07-20T14:44:19 # ::file pmid_2112_2157_155.txt # ::snt These data suggest that the IL-6-induced paclitaxel resistance is mediated by both Stat3-dependent and Stat3-independent pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (m / mediate-01 :ARG0 (a / and :op1 (p2 / pathway :ARG0-of (d2 / depend-01 :ARG1 "p5")) :op2 (p4 / pathway :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 (p5 / protein :name (n4 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))))) :ARG1 (r / resist-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "paclitaxel") :xref (x2 / xref :value "PUBCHEM:4666" :prob "15.068933")) :ARG2-of (i / induce-01 :ARG0 (p / protein :name (n2 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))))) # ::id pmid_2112_2157.156 # ::date 2015-07-20T15:05:24 # ::file pmid_2112_2157_156.txt # ::snt Stat3 contributed to the elevation of IL-6 in drug resistant cancer cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contribute-01 :ARG0 (p / protein :name (n / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1 (e / elevate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (c2 / cell :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ARG0-of (r / resist-01 :ARG1 (d / drug))))) # ::id pmid_2112_2157.157 # ::date 2015-07-20T22:05:22 # ::file pmid_2112_2157_157.txt # ::snt It has been shown that cancer cells resistant to chemotherapeutic agents express elevated levels of IL-6 [30,39]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / show-01 :ARG1 (e / express-03 :ARG2 (l / level :ARG1-of (e2 / elevate-01) :quant-of (p / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG3 (c / cell :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :ARG0-of (r / resist-01 :ARG1 (a / agent :mod (c3 / chemotherapy)))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 (a2 / and :op1 "30" :op2 "39"))))) # ::id pmid_2112_2157.158 # ::date 2015-07-20T22:11:03 # ::file pmid_2112_2157_158.txt # ::snt Thus, drug resistant cancer cells are ideal models for studying IL-6 autocrine production. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / infer-01 :ARG1 (m / model :mod (i2 / ideal) :domain (c / cell :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :ARG0-of (r / resist-01 :ARG1 (d / drug)))) :purpose (s / study-01 :ARG1 (p / produce-01 :ARG1 (p2 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (a / autocrine))))) # ::id pmid_2112_2157.159 # ::date 2015-07-20T22:21:32 # ::file pmid_2112_2157_159.txt # ::snt To find out whether IL-6 would be regulated by Stat3 in cancer cell lines other than AS2, we performed genetic siRNA experiments on two drug resistant cancer cell lines (KB-CPT100 and MCF-7/ADR). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG0 w :ARG1 (c / cell-line :quant "2" :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "KB-CPT100")) :op2 (c4 / cell-line :name (n3 / name :op1 "MCF-7/ADR")))) :mod (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer") :ARG0-of (r / resist-01 :ARG1 (d / drug)))) :mod (g / genetic) :mod (n7 / nucleic-acid :name (n / name :op1 "siRNA"))) :purpose (f / find-out-03 :ARG0 w :ARG1 (r3 / regulate-01 :mode "interrogative" :ARG0 (p2 / protein :name (n4 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (c5 / cell-line :ARG2-of (e2 / except-01 :ARG1 (c7 / cell-line :name (n6 / name :op1 "AS2"))) :mod (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer")))))) # ::id pmid_2112_2157.160 # ::date 2015-07-20T22:30:54 # ::file pmid_2112_2157_160.txt # ::snt MTT assay revealed that KB-CPT100 cells were more resistant to the chemotherapeutic agent camptothecin than the parental KB cells (Figure 6A) and MCF-7/ADR cells were much more resistant to the chemotherapeutic agent epirubicin than the parental MCF-7 cells (p < 0.001) (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (r / reveal-01 :ARG0 (a / assay-01 :instrument (s4 / small-molecule :name (n / name :op1 "MTT") :xref (x1 / xref :value "PUBCHEM:64965" :prob "17.320225"))) :ARG1 (a2 / and :op1 (r2 / resist-01 :ARG0 (c / cell-line :name (n2 / name :op1 "KB-CPT100") :compared-to (c3 / cell-line :name (n4 / name :op1 "KB") :mod (p / parent))) :ARG1 (s / small-molecule :name (n3 / name :op1 "camptothecin") :ARG1-of (m / mean-01 :ARG2 (a3 / agent :mod (c2 / chemotherapy))) :xref (x2 / xref :value "PUBCHEM:2538" :prob "14.853336")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A")) :degree (m2 / more)) :op2 (r3 / resist-01 :ARG0 (c4 / cell-line :name (n5 / name :op1 "MCF-7/ADR") :compared-to (c6 / cell-line :name (n7 / name :op1 "MCF-7") :mod p)) :ARG1 (s2 / small-molecule :name (n6 / name :op1 "epirubicin") :ARG1-of (m5 / mean-01 :ARG2 a3) :xref (x / xref :value "PUBCHEM:41867" :prob "17.186693")) :degree (m3 / more :mod (m4 / much)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6B")) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))))) # ::id pmid_2112_2157.161 # ::date 2015-07-20T22:45:06 # ::file pmid_2112_2157_161.txt # ::snt The two drug resistant cell lines were found by ELISA to secrete more IL-6 than their parental cells (Figures 6C and 6D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (f / find-01 :ARG0 (t / thing :name (n / name :op1 "ELISA")) :ARG1 (s / secrete-01 :ARG0 (c / cell-line :quant "2" :ARG0-of (r / resist-01 :ARG1 (d / drug))) :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :quant (m / more) :compared-to (c2 / cell :mod (p2 / parent) :poss c) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "6C") :op2 (f3 / figure :mod "6D")))) # ::id pmid_2112_2157.162 # ::date 2015-07-20T22:49:59 # ::file pmid_2112_2157_162.txt # ::snt We transiently transfected the two drug resistant cells with Stat3#1 to knock-down Stat3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (t / transfect-01 :ARG0 (w / we) :ARG1 (c / cell :quant "2" :ARG0-of (r / resist-01 :ARG1 (d / drug))) :ARG2 (p / protein :name (n / name :op1 "Stat3#1") :xref (x1 / xref :value "UNIPROT:EF1A2_HUMAN" :prob "0.262")) :ARG1-of (t2 / transient-02) :purpose (k / knock-down-02 :ARG1 (p2 / protein :name (n2 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")))) # ::id pmid_2112_2157.163 # ::date 2015-07-20T22:54:51 # ::file pmid_2112_2157_163.txt # ::snt Western blot analysis confirmed that the total amount of Stat3 protein and phosphorylated Stat3 had been knocked-down in both resistant cells (Figures 6E and 6F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (c / confirm-01 :ARG0 (a / analyze-01 :manner (i / immunoblot-01)) :ARG1 (k / knock-down-02 :ARG1 (a2 / amount :quant-of (a3 / and :op1 (p / protein :wiki "STAT3" :name (n2 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :op2 (p2 / protein :wiki "STAT3" :name (n3 / name :op1 "Stat3") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :mod (t / total)) :location (c2 / cell :mod (b / both) :ARG0-of (r / resist-01))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "6E") :op2 (f2 / figure :mod "6F")))) # ::id pmid_2112_2157.164 # ::date 2015-07-21T10:15:41 # ::file pmid_2112_2157_164.txt # ::snt MTT assay found no change in cell viability (Additional file 3, Figure S3B and S3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (f / find-01 :ARG0 (a / assay-01 :instrument (s / small-molecule :name (n / name :op1 "MTT") :xref (x / xref :value "PUBCHEM:64965" :prob "17.320225"))) :ARG1 (c / change-01 :polarity "-" :ARG1 (v / viability :mod (c2 / cell))) :ARG1-of (d / describe-01 :ARG0 (f2 / file :mod "3" :ARG1-of (a3 / add-02) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (f3 / figure :mod "S3B") :op2 (f4 / figure :mod "S3C")))))) # ::id pmid_2112_2157.165 # ::date 2015-07-21T10:36:30 # ::file pmid_2112_2157_165.txt # ::snt ELISA revealed that knocking-down Stat3 decreased the secretion of IL-6 in KB-CPT100 cells by one-third (p < 0.001) (Figure 6G) and by one-half in MCF-7/ADR cells (p < 0.001) (Figure 6H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (r / reveal-01 :ARG0 (t / thing :name (n / name :op1 "ELISA")) :ARG1 (a / and :op1 (d / decrease-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n2 / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604"))) :ARG1 (s / secrete-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (p5 / product-of :op1 "1/3") :location (c / cell-line :name (n4 / name :op1 "KB-CPT100")) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "6G")) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :op2 (d2 / decrease-01 :ARG0 k :ARG1 s :ARG2 (p6 / product-of :op1 "1/2") :location (c2 / cell-line :name (n5 / name :op1 "MCF-7/ADR")) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "6H")) :ARG1-of (s3 / statistical-test-91 :ARG2 l)))) # ::id pmid_2112_2157.166 # ::date 2015-07-21T11:10:29 # ::file pmid_2112_2157_166.txt # ::snt These results suggest that the Stat3 also contributes to the elevation of IL-6 in drug resistant cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (c / contribute-01 :ARG0 (p / protein :name (n / name :op1 "Stat3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1 (e / elevate-01 :ARG0 p :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (c2 / cell :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ARG0-of (r2 / resist-01 :ARG1 (d / drug)))) :mod (a / also))) # ::id pmid_2112_2157.167 # ::date 2015-07-21T11:14:31 # ::file pmid_2112_2157_167.txt # ::snt Jak2/Stat3 pathway regulated the expression of IL-6 in cooperation with other IL-6 downstream pathways # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 21, 2015 (r / regulate-01 :ARG0 (p / pathway :name (n / name :op1 "Jak2/Stat3") :ARG0-of (c / cooperate-01 :ARG1 (p3 / pathway :mod (o / other) :mod (d / downstream) :mod "p2"))) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) # ::id pmid_2112_2157.168 # ::date 2015-07-21T11:18:37 # ::file pmid_2112_2157_168.txt # ::snt To find out whether IL-6 could be regulated by different combinations of its downstream pathways including Jak2/Stat3 in various cancer cells, we pharmacologically inhibited the four IL-6 downstream pathways in six drug resistant cancer cell lines derived from cervical cancer, breast cancer, and lung cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / inhibit-01 :ARG0 (w / we) :ARG1 (p2 / pathway :quant "4" :name (n / name :op1 "IL-6") :mod (d4 / downstream) :mod "p4") :manner (p / pharmacological) :location (c / cell-line :quant "6" :ARG0-of (r / resist-01 :ARG1 (d / drug)) :ARG1-of (d2 / derive-01 :ARG2 (a / and :op1 (c10 / cell :mod (d5 / disease :wiki "Cervical_cancer" :name (n4 / name :op1 "cervical" :op2 "cancer"))) :op2 (c11 / cell :mod (d6 / disease :wiki "Breast_cancer" :name (n5 / name :op1 "breast" :op2 "cancer"))) :op3 (c5 / cell :mod (d7 / disease :wiki "Lung_cancer" :name (n6 / name :op1 "lung" :op2 "cancer")))))) :purpose (f / find-out-03 :ARG0 w :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (r2 / regulate-01 :ARG0 (c7 / combine-01 :ARG1 (p5 / pathway :ARG2-of (i2 / include-01 :ARG1 (p6 / pathway :name (n3 / name :op1 "Jak2/Stat3")) :location (c8 / cell :mod (v / various) :mod (d8 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")))) :mod d4) :ARG1-of (d3 / differ-02)) :ARG1 (p4 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))))) # ::id pmid_2112_2157.169 # ::date 2015-07-21T11:52:51 # ::file pmid_2112_2157_169.txt # ::snt ELISA revealed that all drug resistant cells secreted more IL-6 than their parental cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 12, 2015 (r / reveal-01 :ARG0 (t / thing :name (n / name :op1 "ELISA")) :ARG1 (s / secrete-01 :ARG0 (c / cell :ARG0-of (r2 / resist-01 :ARG1 (d / drug)) :mod (a / all)) :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :quant (m / more) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :compared-to (c2 / cell :mod (p2 / parent) :poss c))) # ::id pmid_2112_2157.170 # ::date 2015-07-21T11:56:15 # ::file pmid_2112_2157_170.txt # ::snt Different cells used different combinations of signaling pathways, including Jak2/Stat3, to regulate secretion of IL-6 (Figures 7A to 7F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 21, 2015 (u / use-01 :ARG0 (c / cell :ARG1-of (d / differ-02)) :ARG1 (c2 / combine-01 :ARG1 (p / pathway :ARG0-of (s / signal-07) :ARG2-of (i / include-01 :ARG1 (p2 / pathway :name (n / name :op1 "Jak2/Stat3"))))) :ARG2 (r / regulate-01 :ARG0 c :ARG1 (s2 / secrete-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7F")))) # ::id pmid_2112_2157.171 # ::date 2015-07-21T12:03:36 # ::file pmid_2112_2157_171.txt # ::snt To exclude the possibility that the reduction of IL-6 secretion was caused by the reduction of cell survival, we used MTT assay to analyze the effect of these inhibitors on cell viability (Additional file 1, Figure S1C to S1H). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (a / assay-01 :instrument (s3 / small-molecule :name (n / name :op1 "MTT") :xref (x1 / xref :value "PUBCHEM:64965" :prob "17.320225"))) :ARG2 (a2 / analyze-01 :ARG0 w :ARG1 (a3 / affect-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (t / this)) :ARG1 (v / viability :mod (c / cell)))) :purpose (e / exclude-01 :ARG0 w :ARG1 (p / possible-01 :ARG1 (c2 / cause-01 :ARG0 (r / reduce-01 :ARG1 (s / survive-01 :ARG0 (c3 / cell))) :ARG1 (r2 / reduce-01 :ARG1 (s2 / secrete-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "1" :ARG1-of (a5 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (v2 / value-interval :op1 (f2 / figure :mod "S1C") :op2 (f3 / figure :mod "S1H")))))) # ::id pmid_2112_2157.172 # ::date 2015-07-21T12:40:35 # ::file pmid_2112_2157_172.txt # ::snt We showed that the majority of inhibitors had only limited suppressive effect on cell viability (below 25%) (Additional file 1, Figure S1C-S1H) except that the PI3-K/Akt pathway inhibitor LY294002 had more suppressive activity on the cellular viability by 30 to 50% (Additional file 1, Figure S1C-S1F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (s / show-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :ARG0-of (i / inhibit-01) :quant (m / majority)) :ARG1 (v / viability :mod (c / cell) :quant (b / below :op1 (p / percentage-entity :value "25"))) :ARG2 (s3 / suppress-01) :ARG1-of (l / limit-01 :mod (o / only)) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "1" :ARG1-of (a2 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (v2 / value-interval :op1 (f2 / figure :mod "S1C") :op2 (f3 / figure :mod "S1F"))))) :ARG2-of (e / except-01 :ARG1 (a3 / activity-06 :ARG0 (s4 / small-molecule :name (n / name :op1 "LY294002") :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3-K/Akt"))) :xref (x / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (s5 / suppress-01 :ARG1 (v3 / viability :mod c :quant (v4 / value-interval :op1 (p3 / percentage-entity :value "30") :op2 (p4 / percentage-entity :value "50"))) :degree (m3 / more))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / file :mod "1" :ARG1-of (m4 / mean-01 :ARG2 (v5 / value-interval :op1 f2 :op2 (f5 / figure :mod "S1F"))) :ARG1-of a2))))) # ::id pmid_2112_2157.173 # ::date 2015-07-21T13:15:32 # ::file pmid_2112_2157_173.txt # ::snt However, LY294002 induced much greater (75 to 90%) decrease of IL-6 in these cells (Figure 7A to 7D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 3, 2015 (c2 / contrast-01 :ARG2 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG2 (d / decrease-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG2 (v / value-interval :op1 (p2 / percentage-entity :value "75") :op2 (p3 / percentage-entity :value "90")) :location (c / cell :mod (t / this)) :mod (g / great :degree (m / more :mod (m2 / much))))) :ARG1-of (d2 / describe-01 :ARG0 (v2 / value-interval :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7D")))) # ::id pmid_2112_2157.174 # ::date 2015-07-21T13:44:28 # ::file pmid_2112_2157_174.txt # ::snt There is only one exception that the AG490-induced reductions of cell survival and IL-6 secretion were both about 30% in KB-7D cells (Additional file 1, Figure S1F and Figure 7D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 21, 2015 (a / and :op1 (r / reduce-01 :ARG1 (s / survive-01 :ARG0 (c / cell)) :ARG2-of (i / induce-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "AG490") :xref (x1 / xref :value "PUBCHEM:5328779" :prob "18.349844")))) :op2 (s3 / secrete-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :quant (a2 / about :op1 (p2 / percentage-entity :value "30")) :location (c2 / cell-line :name (n3 / name :op1 "KB-7D")) :ARG1-of (e / except-01 :mod "1" :mod (o / only)) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "1" :ARG1-of (a3 / add-02) :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (f2 / figure :mod "S1F") :op2 (f3 / figure :mod "7D")))))) # ::id pmid_2112_2157.175 # ::date 2015-07-21T13:58:05 # ::file pmid_2112_2157_175.txt # ::snt Jak2/Stat3 pathway contributed to IL-6 autocrine production in clinically isolated lung cancer cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contribute-01 :ARG0 (p / pathway :name (n / name :op1 "Jak2/Stat3")) :ARG1 (p2 / produce-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (a / autocrine)) :ARG2 (c2 / cell :ARG1-of (i / isolate-01 :manner (c4 / clinical)) :mod (d / disease :wiki "Lung_cancer" :name (n3 / name :op1 "lung" :op2 "cancer")))) # ::id pmid_2112_2157.176 # ::date 2015-07-21T14:07:47 # ::file pmid_2112_2157_176.txt # ::snt Because previous studies suggesting Stat3 on IL-6 were all in vitro cell line studies, not clinical studies, we also wanted to find out whether IL-6 could be regulated by different combinations of pathways including Jak2/Stat3 in not just cell lines but also in the human body. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 3, 2015 (w / want-01 :ARG0 (w2 / we) :ARG1 (f / find-out-03 :ARG0 w2 :ARG1 (p4 / possible-01 :mode "interrogative" :ARG1 (r / regulate-01 :ARG0 (c / combine-01 :ARG1 (p2 / pathway :ARG2-of (i / include-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "Jak2/Stat3")))) :ARG1-of (d / differ-02)) :ARG1 (p / protein :name (n / name :op1 "IL-6") :xref (x1 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :location (a / and :op1 (c2 / cell-line :mod (j / just :polarity "-")) :op2 (b / body :mod (h / human) :mod (a2 / also)))))) :ARG1-of (c3 / cause-01 :ARG0 (s / study-01 :ARG1 (c5 / cell-line) :mod (i2 / in-vitro :ARG1-of (c6 / contrast-01 :ARG2 (s4 / study-01 :mod (c4 / clinical)))) :domain (s2 / study-01 :ARG0-of (s3 / suggest-01 :ARG1 (r2 / regulate-01 :ARG0 (p5 / protein :name (n3 / name :op1 "Stat3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "0.604")) :ARG1 p)) :time (p6 / previous) :mod (a3 / all)))) :mod a2) # ::id pmid_2112_2157.177 # ::date 2015-07-21T14:33:06 # ::file pmid_2112_2157_177.txt # ::snt We had previously found IL-6 levels to be increased in MPE of patients with lung cancer [2]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :location (m2 / medical-condition :wiki "Malignant_pleural_effusion" :name (n3 / name :op1 "malignant" :op2 "pleural" :op3 "effusion") :poss (p2 / patient :mod (d / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung" :op2 "cancer"))))) :time (p3 / previous)) # ::id pmid_2112_2157.178 # ::date 2015-07-21T14:39:50 # ::file pmid_2112_2157_178.txt # ::snt To do this, we pharmacologically inhibited the four IL-6 downstream pathways in 20 clinical samples of human lung cancer obtained from MPE. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 29, 2015 (i / inhibit-01 :ARG0 (w / we) :ARG1 (p2 / pathway :mod "4" :name (n / name :op1 "IL-6") :mod (d / downstream)) :manner (p / pharmacological) :location (s / sample-01 :quant "20" :ARG1 (d3 / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung" :op2 "cancer") :mod (h / human)) :mod (c / clinical) :ARG1-of (o / obtain-01 :ARG2 (m / medical-condition :wiki "Malignant_pleural_effusion" :name (n3 / name :op1 "malignant" :op2 "pleural" :op3 "effusion")))) :purpose (d2 / do-02 :ARG0 w :ARG1 (t / this))) # ::id pmid_2112_2157.179 # ::date 2015-07-21T14:48:15 # ::file pmid_2112_2157_179.txt # ::snt ELISA revealed that IL-6 was expressed in the conditioned medium of all samples, ranging from 16.58 ± 0.21 to 1016.47 ± 12.45 pg/ml (Figure 8A), with a mean of 393.14 pg/ml. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / reveal-01 :ARG0 (t / thing :name (n / name :op1 "ELISA")) :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "IL-6") :ARG1-of (r2 / range-01 :ARG3 (c2 / concentration-quantity :quant (v / value-interval :op1 (a2 / add-02 :ARG1 "16.58" :ARG2 "0.21") :op2 (s2 / subtract-01 :ARG1 "0.21" :ARG2 "16.58")) :unit (p3 / picogram-per-milliliter)) :ARG4 (c3 / concentration-quantity :quant (v2 / value-interval :op1 (a3 / add-02 :ARG1 "1016.47" :ARG2 "12.45") :op2 (s3 / subtract-01 :ARG1 "12.45" :ARG2 "1016.47")) :unit p3)) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :ARG3 (m / medium :ARG1-of (c / condition-01) :poss (t2 / thing :mod (a / all) :mod (c4 / concentration-quantity :quant "393.14" :unit p3 :mod (m2 / mean)) :ARG1-of (s / sample-01)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8A"))) # ::id pmid_2112_2157.180 # ::date 2015-07-21T15:25:46 # ::file pmid_2112_2157_180.txt # ::snt The four aforementioned inhibitors significantly decreased IL-6 secretion in the clinically isolated cancer cells differently (U0126, p < 0.01; AG490, LY294002 and BAY11-7082, all p < 0.001) (Figure 8A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / decrease-01 :ARG0 (s / small-molecule :quant "4" :ARG1-of (i / inhibit-01) :ARG1-of (m / mention-01 :time (b / before))) :ARG1 (s3 / secrete-01 :ARG1 (p / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))) :ARG2 (s2 / significant-02) :location (c / cell :manner (c3 / clinical) :mod (d4 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :ARG1-of (i2 / isolate-01))) :ARG1-of (d2 / differ-02) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (d5 / decrease-01 :ARG0 (s7 / small-molecule :name (n2 / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1 s3 :location c :ARG1-of (s8 / statistical-test-91 :ARG2 (l / less-than :op1 "0.01")) :location c) :op2 (d6 / decrease-01 :ARG0 (a2 / and :op1 (s4 / small-molecule :name (n3 / name :op1 "AG490") :xref (x4 / xref :value "PUBCHEM:5328779" :prob "18.349844")) :op2 (s5 / small-molecule :name (n4 / name :op1 "LY294002") :xref (x3 / xref :value "PUBCHEM:3973" :prob "18.86067")) :op2 (s6 / small-molecule :name (n5 / name :op1 "BAY11-7082") :xref (x2 / xref :value "PUBCHEM:2301" :prob "21.916582")) :mod (a3 / all)) :ARG1 s3 :ARG1-of (s9 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.001"))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "8A"))) # ::id pmid_2112_2157.181 # ::date 2015-07-21T15:38:17 # ::file pmid_2112_2157_181.txt # ::snt We further analyzed the percent of inhibition by each inhibitor on IL-6 secretion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 21, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (p / percent :quant-of (i / inhibit-01 :ARG0 (s / small-molecule :ARG1-of i :mod (e / each)) :ARG1 (s2 / secrete-01 :ARG1 (p2 / protein :name (n / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))) :time (f / further)) # ::id pmid_2112_2157.182 # ::date 2015-07-21T15:41:32 # ::file pmid_2112_2157_182.txt # ::snt BAY11-7082 had the greatest inhibitory activity on the autocrine production of IL-6 in the clinical samples (BAY11-7082 > LY294002 > AG490 > U0126) (Figure 8B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / have-03 :ARG0 (s / small-molecule :name (n / name :op1 "BAY11-7082") :xref (x5 / xref :value "PUBCHEM:2301" :prob "21.916582")) :ARG1 (a / activity-06 :ARG1 (i / inhibit-01 :ARG1 (p / produce-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6") :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :mod (a2 / autocrine))) :mod (g / great :degree (m / most))) :location (t / thing :mod (c / clinical) :ARG1-of (s2 / sample-01)) :ARG1-of (m2 / mean-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "BAY11-7082") :quant (m3 / more-than :op1 (s4 / small-molecule :name (n4 / name :op1 "LY294002") :quant (m4 / more-than :op1 (s5 / small-molecule :name (n5 / name :op1 "AG490") :quant (m5 / more-than :op1 (s6 / small-molecule :name (n6 / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :xref (x3 / xref :value "PUBCHEM:5328779" :prob "18.349844"))) :xref (x4 / xref :value "PUBCHEM:3973" :prob "18.86067"))) :xref (x1 / xref :value "PUBCHEM:2301" :prob "21.916582"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8B"))) # ::id pmid_2155_9022.1 # ::date 2015-08-06T01:55:21 # ::file pmid_2155_9022_1.txt # ::snt Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer (PMID:21559022) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / associate-01 :ARG1 (u / upregulate-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK"))) :ARG2 (s / survive-01 :ARG1 (d2 / disease :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate" :op2 "cancer") :ARG0-of (r / resist-01 :ARG1 (c2 / castrate-01)))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID21559022"))) # ::id pmid_2155_9022.9 # ::date 2015-08-06T02:35:09 # ::file pmid_2155_9022_9.txt # ::snt Results: # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2155_9022.10 # ::date 2015-08-08T07:15:41 # ::file pmid_2155_9022_10.txt # ::snt Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 vs 3.00 years, P=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 vs 2.62 years, P=0.0005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (n / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (r / rise-01 :time (d / develop-01 :ARG2 (d4 / disease :name (n3 / name :op1 "CRPC"))))) :ARG1-of (c / compare-01 :ARG2 (p3 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 (p4 / patient)) :poss (o2 / or :op1 (e4 / express-03 :ARG1-of (f2 / fall-01)) :op2 (e5 / express-03 :ARG1-of (c3 / change-01 :polarity "-")) :ARG1-of (m5 / mean-01 :ARG2 (t2 / temporal-quantity :quant "1.16" :compared-to (t3 / temporal-quantity :quant "2.62" :unit "y3") :unit (y3 / year))) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.005"))))) :ARG1 (a / and :op1 (t / time :mod (m / median) :ARG1-of (s / short-07 :degree (m2 / more) :ARG1-of (s2 / significant-02) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.0255")) :mod (d2 / die-01 :ARG1-of (f / follow-01 :ARG2 (r2 / relapse-01 :mod (b / biochemistry)))) :ARG1-of (m3 / mean-01 :ARG2 (t4 / temporal-quantity :quant "1.40" :compared-to (t5 / temporal-quantity :quant "3.00" :unit y3) :unit y3))) :op2 (s3 / survive-01 :ARG1-of (r3 / reduce-01) :ARG1-of (s4 / specific-02 :ARG2 (d3 / disease))))) # ::id pmid_2155_9022.11 # ::date 2015-08-12T01:08:14 # ::file pmid_2155_9022_11.txt # ::snt Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (o / observe-01 :ARG1 (c / correlate-01 :ARG1 (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Raf-1") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :location (t3 / tumor :mod (d / disease :name (n7 / name :op1 "CRPC")))) :ARG2 (a2 / and :op1 (e4 / enzyme :name (n5 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :mod (t / type :mod "1") :xref (x1 / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392")) :op2 (e5 / enzyme :name (n3 / name :op1 "Her2") :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603")) :op3 (e6 / enzyme :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.703")) :op4 (p / protein :name (n6 / name :op1 "AP-1") :ARG0-of (t2 / transcribe-01) :mod (f / factor) :xref (x5 / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))) :ARG1-of (s / significant-02))) # ::id pmid_2155_9022.73 # ::date 2015-08-06T02:36:59 # ::file pmid_2155_9022_73.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2155_9022.74 # ::date 2015-08-06T02:38:01 # ::file pmid_2155_9022_74.txt # ::snt Patient cohort characteristics # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / characteristic-02 :ARG1 (c2 / cohort :ARG2-of (i / include-91 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)))))) # ::id pmid_2155_9022.75 # ::date 2015-08-14T11:12:36 # ::file pmid_2155_9022_75.txt # ::snt The clinical data collected and recorded for each patient included age (median: 70 years; inter-quartile range: 66–74 years), PSA level at diagnosis (median: 31 ng ml−1; inter-quartile range: 7.8–109 ng ml−1), PSA level at relapse (median: 10 ng ml−1; inter-quartile range: 4–11 ng ml−1) and Gleason grade at diagnosis (median: 8, inter-quartile range: 7–9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / include-91 :ARG1 (a2 / and :op1 (a / age :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (t / time :mod (m2 / median) :ARG1-of (m3 / mean-01 :ARG2 (t2 / temporal-quantity :quant "70" :unit (y / year)))) :op2 (r3 / range-01 :ARG3 (t3 / temporal-quantity :quant "66" :unit y) :ARG4 (t4 / temporal-quantity :quant "74" :unit y) :mod (i2 / inter-quartile))))) :op2 (l / level :degree-of (e2 / enzyme :name (n / name :op1 "PSA") :xref (x / xref :value "UNIPROT:PSA_HUMAN" :prob "1.003")) :time (d2 / diagnose-01) :ARG1-of (m5 / mean-01 :ARG2 (a4 / and :op1 (c3 / concentration-quantity :quant "31" :mod m2 :unit (n2 / nanogram-per-milliliter)) :op2 (r4 / range-01 :ARG3 (c4 / concentration-quantity :quant "7.8" :unit n2) :ARG4 (c5 / concentration-quantity :quant "109" :unit n2) :mod (i3 / inter-quartile))))) :op3 (l2 / level :degree-of e2 :time (r2 / relapse-01) :ARG1-of (m6 / mean-01 :ARG2 (a5 / and :op1 (c6 / concentration-quantity :quant "10" :mod m2 :unit n2) :op2 (r5 / range-01 :ARG3 (c8 / concentration-quantity :quant "4" :unit n2) :ARG4 (c9 / concentration-quantity :quant "11" :unit n2) :mod (i4 / inter-quartile))))) :op4 (g / grade :time d2 :ARG1-of (m7 / mean-01 :ARG2 (a6 / and :op1 (c7 / concentration-quantity :quant "8" :unit n2) :op2 (r6 / range-01 :ARG3 (c10 / concentration-quantity :quant "7" :unit n2) :ARG4 (c11 / concentration-quantity :quant "9" :unit n2) :mod (i5 / inter-quartile)))) :mod (p3 / person :name (n3 / name :op1 "Gleason")))) :ARG2 (d / data :mod (c / clinic) :ARG1-of (c2 / collect-01 :topic (p / person :mod (e / each) :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)))) :ARG1-of (r / record-01 :topic p))) # ::id pmid_2155_9022.76 # ::date 2015-08-08T08:43:06 # ::file pmid_2155_9022_76.txt # ::snt All patients underwent biochemical relapse (median time to relapse: 2.54 years; inter-quartile range: 1.51–4.62 years). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (u / undergo-28 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :mod (a / all)) :ARG2 (r / relapse-01 :ARG1 p :mod (b / biochemistry) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (t / time :mod (m2 / median) :mod (r3 / relapse-01) :ARG1-of (m3 / mean-01 :ARG2 (t2 / temporal-quantity :quant "2.54" :unit (y / year)))) :op2 (r2 / range-01 :ARG3 (t3 / temporal-quantity :quant "1.51" :unit y) :ARG4 (t4 / temporal-quantity :quant "4.62" :unit y) :mod (i / inter-quartile)))))) # ::id pmid_2155_9022.77 # ::date 2015-08-12T02:30:59 # ::file pmid_2155_9022_77.txt # ::snt All patients included in this study were deceased (median time to death after relapse: 1.37 years; inter-quartile range: 0.82–2.69). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / decease-01 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :mod (a / all) :ARG1-of (i / include-01 :ARG2 (s / study :mod (t / this)))) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (t2 / time :mod (m2 / median) :mod (d2 / die-01) :time (a3 / after :op1 (r / relapse-01)) :ARG1-of (m3 / mean-01 :ARG2 (t3 / temporal-quantity :quant "1.37" :unit (y / year)))) :op2 (r2 / range-01 :ARG3 (t4 / temporal-quantity :quant "0.82" :unit y) :ARG4 (t5 / temporal-quantity :quant "2.69" :unit y) :mod (i2 / inter-quartile))))) # ::id pmid_2155_9022.78 # ::date 2015-08-12T02:56:01 # ::file pmid_2155_9022_78.txt # ::snt This resulted in an overall median survival time of 4.5 years (inter-quartile range: 3.00–7.01). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (r / result-01 :ARG1 (t / this) :ARG2 (t2 / time :mod (s / survive-01) :mod (o / overall) :mod (m / median) :duration (t3 / temporal-quantity :quant "4.5" :unit (y / year))) :ARG1-of (m2 / mean-01 :ARG2 (r2 / range-01 :ARG3 (t4 / temporal-quantity :quant "3.00" :unit (y2 / year)) :ARG4 (t5 / temporal-quantity :quant "7.01" :unit y) :mod (i / inter-quartile)))) # ::id pmid_2155_9022.79 # ::date 2015-08-12T22:50:42 # ::file pmid_2155_9022_79.txt # ::snt Patients were diagnosed with locally advanced (46 patients) or metastatic (19 patients) prostate cancer, and at the time of relapse the number of patients presenting with metastatic disease had risen (40 patients). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 30, 2015 (a / and :op1 (d / diagnose-01 :ARG1 "p4" :ARG2 (o / or :op1 (d3 / disease :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate" :op2 "cancer") :ARG1-of (a2 / advanced-02 :ARG1-of (l / local-02) :ARG1-of (m2 / mean-01 :ARG2 (p2 / person :quant "46" :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)))))) :op2 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ARG1-of (m / metastasize-101 :ARG1-of (m3 / mean-01 :ARG2 (p7 / person :quant "19" :ARG0-of h)))))) :op2 (r / rise-01 :ARG1 (n / number :quant-of (p4 / person :ARG0-of (p / present-102 :ARG1 (d2 / disease :ARG1-of m)) :ARG0-of h)) :time (r2 / relapse-01) :ARG1-of (m4 / mean-01 :ARG2 (p9 / person :quant "40" :ARG0-of h)))) # ::id pmid_2155_9022.80 # ::date 2015-08-12T23:59:28 # ::file pmid_2155_9022_80.txt # ::snt At diagnosis, patients either underwent surgery (27 orchidectomy) or androgen deprivation therapy (59 GnRH analogue and/or anti-androgen deprivation therapy). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (u / undergo-28 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient))) :ARG2 (o / or :op1 (s / surgery-01 :ARG1 p :ARG1-of (m / mean-01 :ARG2 (o2 / orchidectomy :mod "27"))) :op2 (t / therapy :ARG0-of (d2 / deprive-01 :ARG1 (a / androgen)) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and-or :op1 (e / enzyme :mod "59" :name (n / name :op1 "GnRH") :mod (a3 / analogue) :xref (x / xref :value "UNIPROT:GON1_HUMAN" :prob "0.652")) :op2 (t2 / therapy :ARG1-of (d3 / deprive-01) :ARG0-of (o3 / oppose-01 :ARG1 (a4 / androgen))))))) :time (d / diagnose-01)) # ::id pmid_2155_9022.81 # ::date 2015-08-09T02:28:32 # ::file pmid_2155_9022_81.txt # ::snt Most patients were deceased during the course of follow-up (46 patients), although some survived beyond follow-up (19 patients). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / decease-01 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :mod (m / most :ARG1-of (m2 / mean-01 :ARG2 (p3 / person :quant "46" :ARG0-of h)))) :time (f / follow-up-03) :concession (s / survive-01 :ARG1 (s2 / some :ARG1-of (m3 / mean-01 :ARG2 (p5 / person :quant "19" :ARG0-of h))) :mod (b / beyond :op1 f))) # ::id pmid_2155_9022.82 # ::date 2015-08-06T03:38:45 # ::file pmid_2155_9022_82.txt # ::snt The presence of metastatic disease at diagnosis was associated with reduced time to biochemical relapse (P=0.037) and a trend in overall patient survival (P=0.06). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / associate-01 :ARG1 (p / present-02 :ARG1 (d / disease :ARG1-of (m / metastasize-101)) :ARG2 (d2 / diagnose-01)) :ARG2 (a2 / and :op1 (t / time :ARG1-of (r / reduce-01) :mod (r2 / relapse-01 :mod (b / biochemistry) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.037"))) :op2 (t2 / trend-01 :ARG1 (s / survive-01 :ARG0 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient))) :mod (o / overall)) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.06")))) # ::id pmid_2155_9022.83 # ::date 2015-08-13T00:37:57 # ::file pmid_2155_9022_83.txt # ::snt High Gleason scores were associated with more rapid biochemical relapse (P=0.002), time to death after biochemical relapse (P=0.02) and disease-specific survival (P=0.001), confirming the association of these clinical parameters with the progression of prostate cancer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / associate-01 :ARG1 (s / score :ARG1-of (h / high-02) :mod (p6 / person :name (n / name :op1 "Gleason")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.002")) :ARG2 (a2 / and :op1 (r / relapse-01 :mod (r2 / rapid :degree (m / more)) :mod (b / biochemistry)) :op2 (t / time :mod (d / die-01) :time (a3 / after :op1 r) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.02")) :op3 (s2 / survive-01 :ARG1-of (s3 / specific-02 :ARG2 (d2 / disease)) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.001"))) :ARG0-of (c / confirm-01 :ARG1 (a4 / associate-01 :ARG1 a2 :ARG2 (p / progress-01 :ARG1 (d3 / disease :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate" :op2 "cancer")))))) # ::id pmid_2155_9022.84 # ::date 2015-08-07T04:02:06 # ::file pmid_2155_9022_84.txt # ::snt Expression and localisation of Raf-1 and MAPK # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (e / express-03 :ARG2 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :op2 (l / localize-01 :ARG1 a2)) # ::id pmid_2155_9022.85 # ::date 2015-08-14T02:21:34 # ::file pmid_2155_9022_85.txt # ::snt Raf-1 was observed in the cytoplasm and peri-membrane areas (Figure 1A), and the inactive form of Raf-1 was found only in the peri-membrane region (Figure 1B); however, the activated form of Raf-1 was observed in the cytoplasm, nucleus and the cell membrane (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (a / and :op1 (a2 / and :op1 (o / observe-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG0-of (d / describe-01 :ARG1 (f4 / figure :mod "1A")) :location (a8 / and :op1 (a4 / area :part-of (c / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8"))) :op2 (a9 / area :part-of (p / peri-membrane)))) :op2 (f / find-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf-1") :mod (f2 / form :ARG0-of (a3 / activity-06 :polarity "-")) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :location (r / region :mod (o3 / only) :part-of p) :ARG0-of (d2 / describe-01 :ARG1 (f5 / figure :mod "1B")))) :op2 (h / have-concession-91 :ARG1 (o2 / observe-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Raf-1") :mod (f3 / form :ARG0-of (a5 / activate-01)) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :location (a7 / and :op1 c :op2 (n4 / nucleus :xref (x5 / xref :value "GO:0005634" :prob "0.8")) :op3 (m / membrane :part-of (c3 / cell) :xref (x4 / xref :value "GO:0016020" :prob "0.8"))) :ARG0-of (d3 / describe-01 :ARG1 (f6 / figure :mod "1C")))) # ::id pmid_2155_9022.86 # ::date 2015-08-07T03:06:44 # ::file pmid_2155_9022_86.txt # ::snt Mitogen-activated protein kinase and phosphorylated MAPK (pMAPK) (Thr202/204) were observed in the nucleus and cytoplasm (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / observe-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase") :xref (x1 / xref :value "UNIPROT:A0A024QZ12_HUMAN" :prob "0.701")) :op2 (a2 / amino-acid :name (n2 / name :op1 "threonine") :part-of (e / enzyme :name (n3 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG3-of (p / phosphorylate-01) :mod (s / slash :op1 "202" :op2 "204") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252"))) :location (a3 / and :op1 (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :op2 (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8"))) :ARG0-of (d / describe-01 :ARG1 (f / figure :mod "1D"))) # ::id pmid_2155_9022.87 # ::date 2015-08-11T23:11:35 # ::file pmid_2155_9022_87.txt # ::snt Overall, comparison of HNPC tumours and CRPC tumours revealed no differences in total or average expression levels of either Raf-1 (and all phosphorylated forms) (Table 1) or MAPK (activated or inactivate, nuclear or cytoplasmic) (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reveal-01 :ARG0 (c / compare-01 :ARG1 (t / tumor :mod (d4 / disease :name (n / name :op1 "HNPC"))) :ARG2 (t2 / tumor :mod (d5 / disease :name (n2 / name :op1 "CRPC")))) :ARG1 (d / differ-02 :polarity "-" :ARG1 (l / level :degree-of (e / express-03 :ARG2 (o3 / or :op1 (a2 / and :op1 (e2 / enzyme :name (n3 / name :op1 "Raf-1") :xref (x5 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "Raf-1") :ARG3-of (p / phosphorylate-01) :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1-of (d2 / describe-01 :ARG0 (t4 / table :mod "1"))) :op2 (o7 / or :op1 (o8 / or :op1 (e7 / enzyme :name (n5 / name :op1 "MAPK") :ARG1-of (d3 / describe-01 :ARG0 (t5 / table :mod "2")) :ARG0-of (a3 / activate-01) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op2 (e4 / enzyme :name (n7 / name :op1 "MAPK") :ARG0-of (a4 / activate-01 :polarity "-") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :op2 (o9 / or :op1 (e6 / enzyme :name (n8 / name :op1 "MAPK") :location (n9 / nucleus :xref (x6 / xref :value "GO:0005634" :prob "0.8")) :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op2 (e5 / enzyme :name (n10 / name :op1 "MAPK") :location (c3 / cytoplasm :xref (x7 / xref :value "GO:0005737" :prob "0.8")) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))))) :ARG1-of (t3 / total-01) :ARG1-of (a / average-01))) :mod (o / overall)) # ::id pmid_2155_9022.88 # ::date 2015-08-10T11:28:33 # ::file pmid_2155_9022_88.txt # ::snt However, analysis of matched pairs revealed a subgroup that showed significant increases in Raf-1 and MAPK levels in CRPC tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (p / pair :ARG1-of (m / match-01))) :ARG1 (s / subgroup :ARG0-of (s2 / show-01 :ARG1 (i / increase-01 :ARG1 (a3 / and :op1 (l / level :quant-of (e3 / enzyme :name (n3 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :op2 (l2 / level :quant-of (e / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :ARG1-of (s3 / significant-02)) :location (t / tumor :mod (d / disease :name (n / name :op1 "CRPC"))))))) # ::id pmid_2155_9022.89 # ::date 2015-08-13T02:18:07 # ::file pmid_2155_9022_89.txt # ::snt We have previously reported that patients whose Raf-1 expression rose in this cohort with the development of CRPC had a significantly shorter time to relapse than those patients who had a fall or no change (P=0.0005) (Mukherjee et al, 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (r / report-01 :ARG0 (w / we) :ARG1 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :poss (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1-of (r2 / rise-01 :location (c / cohort :mod (t3 / this)) :time (d / develop-01 :ARG2 (d4 / disease :name (n2 / name :op1 "CRPC"))))) :ARG1-of (c3 / compare-01 :ARG2 (p3 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 (p4 / patient)) :mod (t2 / that) :ARG0-of (h4 / have-06 :ARG1 (o / or :op1 (f / fall-01) :op2 (c4 / change-01 :polarity "-")))))) :ARG1 (t / time :ARG1-of (s / short-07 :degree (m / more)) :ARG1-of (s2 / significant-02) :mod (r3 / relapse-01)) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0005")) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a / and :op1 (p7 / person :name (n3 / name :op1 "Mukherjee")) :op2 (p8 / person :mod (o2 / other))) :time (d3 / date-entity :year "2005"))) :time (p9 / previous)) # ::id pmid_2155_9022.90 # ::date 2015-08-14T00:30:22 # ::file pmid_2155_9022_90.txt # ::snt Consistent with this observation, patients with rising levels of nuclear pRaf (Ser338, activated Raf-1) had a significantly shorter time to biochemical relapse (2.2 years; range: 1.84–2.56 years) by 2.4 years when compared with patients who showed a fall in levels (4.6 years; range: 3.4–5.8 years) (P=0.01) (Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h4 / have-03 :ARG1 (l / level :quant-of (a / amino-acid :mod "338" :name (n / name :op1 "serine") :part-of (e / enzyme :name (n2 / name :op1 "Raf") :ARG3-of (p3 / phosphorylate-01) :mod (n3 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (m2 / mean-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Raf-1") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (r2 / rise-01)))) :ARG1 (t5 / time :ARG1-of (s / short-07 :degree (m / more) :ARG1-of (s2 / significant-02) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.01")) :mod (r / relapse-01 :mod (b / biochemistry) :duration (t7 / temporal-quantity :quant "2.4" :unit (y5 / year))) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and :op1 (t / temporal-quantity :quant "2.2" :unit y5) :op2 (r3 / range-01 :ARG3 (t2 / temporal-quantity :quant "1.84" :unit y5) :ARG4 (t3 / temporal-quantity :quant "2.56" :unit y5))))) :ARG1-of (c / consistent-01 :ARG2 (o / observe-01 :mod (t6 / this))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2")) :condition (c2 / compare-01 :ARG1 p :ARG2 (p4 / person :ARG0-of (s3 / show-01 :ARG1 (f / fall-01 :ARG1 (l2 / level :ARG1-of (m5 / mean-01 :ARG2 (a4 / and :op1 (t4 / temporal-quantity :quant "4.6" :unit y5) :op2 (r4 / range-01 :ARG3 (t8 / temporal-quantity :quant "3.4" :unit y5) :ARG4 (t9 / temporal-quantity :quant "5.8" :unit y5))))))) :ARG0-of h2))) # ::id pmid_2155_9022.91 # ::date 2015-08-14T08:54:56 # ::file pmid_2155_9022_91.txt # ::snt Patients whose nuclear MAPK expression rose with the development of CRPC had a significantly shorter time to death from relapse (1.40 (1.20–1.61) years) compared with samples that showed a fall or no change in expression (3.00 (1.43–4.57) years), P=0.0255 (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :poss (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (n2 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (r / rise-01 :time (d / develop-01 :ARG2 (d4 / disease :name (n3 / name :op1 "CRPC"))))) :ARG1-of (c2 / compare-01 :ARG2 (t8 / thing :ARG1-of (s3 / sample-01 :ARG0-of (s4 / show-01 :ARG1 (o / or :op1 (f / fall-01 :ARG1 "e3") :op2 (c3 / change-01 :polarity "-" :ARG1 (e3 / express-03)))) :ARG1-of (m4 / mean-01 :ARG2 (t5 / temporal-quantity :quant "3.00" :unit "y" :ARG1-of (m5 / mean-01 :ARG2 (v2 / value-interval :op1 (t6 / temporal-quantity :quant "1.43" :unit "y") :op2 (t7 / temporal-quantity :quant "4.57" :unit "y"))))))))) :ARG1 (t / time :ARG1-of (s / short-07 :degree (m / more) :ARG1-of (s2 / significant-02) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.0255")) :mod (d2 / die-01 :time (a / after :op1 (r2 / relapse-01))) :ARG1-of (m2 / mean-01 :ARG2 (t2 / temporal-quantity :quant "1.40" :unit (y / year) :ARG1-of (m3 / mean-01 :ARG2 (v / value-interval :op1 (t3 / temporal-quantity :quant "1.20" :unit y) :op2 (t4 / temporal-quantity :quant "1.61" :unit y)))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "3A"))) # ::id pmid_2155_9022.92 # ::date 2015-08-10T10:06:30 # ::file pmid_2155_9022_92.txt # ::snt This translated into a shorter disease-specific survival of 3.37 (1.58–5.16 ) years compared with 6.89 (5.70–8.08) years, P=0.0068 (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (t / translate-01 :ARG1 (t2 / this) :ARG2 (s / survive-01 :ARG1-of (s2 / short-07 :degree (m / more)) :ARG1-of (s3 / specific-02 :ARG2 (d / disease)) :duration (t3 / temporal-quantity :quant "3.37" :unit (y / year) :compared-to (t4 / temporal-quantity :quant "6.89" :unit y :ARG1-of (m3 / mean-01 :ARG2 (v2 / value-interval :op1 (t5 / temporal-quantity :quant "5.70" :unit y) :op2 (t6 / temporal-quantity :quant "8.08" :unit y)))) :ARG1-of (m2 / mean-01 :ARG2 (v / value-interval :op1 (t7 / temporal-quantity :quant "1.58" :unit y) :op2 (t8 / temporal-quantity :quant "5.16" :unit y))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3B")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0068")) # ::id pmid_2155_9022.93 # ::date 2015-08-07T04:21:13 # ::file pmid_2155_9022_93.txt # ::snt Interestingly, there was also an association seen between rising cytoplasmic pMAPK (Thr202/204) expression and reduced time to biochemical relapse (P=0.06). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :ARG1 (a / associate-01 :ARG1 (e / express-03 :ARG2 (a2 / amino-acid :name (n / name :op1 "threonine") :mod (s2 / slash :op1 "202" :op2 "204") :part-of (e2 / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG3-of (p / phosphorylate-01) :mod (c / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1-of (r / rise-01)) :ARG2 (t / time :ARG1-of (r2 / reduce-01) :mod (r3 / relapse-01 :mod (b / biochemistry))) :mod (a3 / also) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.06")) :ARG2-of (i / interest-01)) # ::id pmid_2155_9022.94 # ::date 2015-08-08T23:30:26 # ::file pmid_2155_9022_94.txt # ::snt Relative protein expression levels in hormone-naïve prostate cancer # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (l / level :ARG1-of (r / relative-05) :degree-of (e / express-03 :ARG2 (p / protein)) :location (d / disease :name (n / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer"))) # ::id pmid_2155_9022.95 # ::date 2015-08-08T09:16:33 # ::file pmid_2155_9022_95.txt # ::snt In HNPC tumours, Raf-1 correlated with the inactive form, pRaf (Ser259), before relapse (P=0.0041, r2=0.1201). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / correlate-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG2 (a / amino-acid :mod "259" :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG3-of (p / phosphorylate-01) :mod (f / form :ARG1-of (a2 / activity-06 :polarity "-")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :time (b / before :op1 (r / relapse-01)) :location (t / tumor :mod (d / disease :name (n4 / name :op1 "HNPC"))) :ARG1-of (s / statistical-test-91 :ARG2 "0.0041" :ARG3 "0.1201")) # ::id pmid_2155_9022.96 # ::date 2015-08-08T10:18:21 # ::file pmid_2155_9022_96.txt # ::snt Nuclear pRaf (Ser338) and cytoplasmic pRaf (Ser338) strongly correlated with each other (P=0.0035, r2=0.1381). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / correlate-01 :ARG1 (a2 / amino-acid :mod "338" :name (n / name :op1 "serine") :part-of (e / enzyme :name (n2 / name :op1 "Raf") :mod (n3 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG3-of (p / phosphorylate-01) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (a / amino-acid :mod "338" :name (n4 / name :op1 "serine") :part-of (e2 / enzyme :name (n5 / name :op1 "Raf") :mod (c2 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :ARG3-of p :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (s / strong-02) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0035" :ARG3 "0.1381")) # ::id pmid_2155_9022.97 # ::date 2015-08-08T10:55:26 # ::file pmid_2155_9022_97.txt # ::snt No correlations between total Raf-1 and cytoplasmic pRaf (Ser338) or nuclear pRaf (Ser338) expression were evident. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 19, 2015 (e / evidence-01 :polarity "-" :ARG1 (c / correlate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Raf-1") :mod (t / total) :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG2 (o / or :op1 (e3 / express-03 :ARG2 (a / amino-acid :mod "338" :name (n2 / name :op1 "serine") :part-of (e4 / enzyme :name (n3 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG3-of (p / phosphorylate-01) :mod (c2 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :op2 (e5 / express-03 :ARG2 (a3 / amino-acid :mod "338" :name (n4 / name :op1 "serine") :part-of (e6 / enzyme :name (n6 / name :op1 "Raf") :ARG3-of p :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :mod (n5 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8")))))) # ::id pmid_2155_9022.98 # ::date 2015-08-08T10:40:02 # ::file pmid_2155_9022_98.txt # ::snt In addition no correlations were observed between the inactive form of pRaf (Ser259) and nuclear pRaf (Ser338) or cytoplasmic pRaf (Ser338). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (a / and :op2 (o / observe-01 :polarity "-" :ARG1 (c / correlate-01 :ARG1 (a4 / amino-acid :mod "259" :name (n / name :op1 "serine") :part-of (e / enzyme :name (n4 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG3-of (p / phosphorylate-01) :mod (f / form :ARG0-of (a2 / activity-06 :polarity "-")) :xref (x7 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (o3 / or :op1 (a5 / amino-acid :mod "338" :name (n3 / name :op1 "serine") :part-of (e2 / enzyme :name (n5 / name :op1 "Raf") :ARG3-of p :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :mod (n2 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8")) :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :mod "338" :name (n6 / name :op1 "serine") :part-of (e3 / enzyme :name (n7 / name :op1 "Raf") :ARG3-of p :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :mod (c2 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")))))) # ::id pmid_2155_9022.99 # ::date 2015-08-11T23:40:09 # ::file pmid_2155_9022_99.txt # ::snt Total cytoplasmic expression of MAPK correlated with total nuclear expression of MAPK (P=0.0126, r2=0.1009), activated MAPK (Thr202/204) (P=0.0152, r2=0.1044) and the cytoplasmic expression of MAPK (Thr202/204) (P<0.0001, r2=0.3391). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (c / correlate-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (c2 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8"))) :ARG2 (e3 / express-03 :ARG2 (e5 / enzyme :name (n2 / name :op1 "MAPK") :mod (n3 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8")) :mod (t / total) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0126" :ARG3 "0.1009")) :op2 (c3 / correlate-01 :ARG1 e :ARG2 (a3 / amino-acid :name (n5 / name :op1 "threonine") :part-of (e4 / enzyme :name (n4 / name :op1 "MAPK") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (s / slash :op1 "202" :op2 "204") :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0152" :ARG3 "0.1044")) :op3 (c4 / correlate-01 :ARG1 e :ARG2 (e6 / express-03 :ARG2 (a4 / amino-acid :name (n6 / name :op1 "threonine") :mod s :part-of e2 :xref (x6 / xref :value "PUBCHEM:205" :prob "11.848252")) :mod c2) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001") :ARG3 "0.3391"))) # ::id pmid_2155_9022.100 # ::date 2015-08-11T00:30:06 # ::file pmid_2155_9022_100.txt # ::snt Total nuclear MAPK expression correlated very strongly with the activated form of MAPK (Thr202/204) in the nucleus (P<0.0001, r2=0.3447) and pMAPK (Thr202/204) in the cytoplasm (P=0.0075, r2=0.1250). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a5 / and :op1 (c / correlate-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK") :mod (t / total) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (n2 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8"))) :ARG2 (a / amino-acid :name (n3 / name :op1 "threonine") :mod (s2 / slash :op1 "202" :op2 "204") :part-of (e3 / enzyme :name (n4 / name :op1 "MAPK") :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :xref (x7 / xref :value "PUBCHEM:205" :prob "11.848252")) :location (n5 / nucleus :xref (x5 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0001" :ARG3 "0.3447")) :op2 (c3 / correlate-01 :ARG1 e :ARG2 (a4 / amino-acid :name (n6 / name :op1 "threonine") :part-of (e4 / enzyme :name (n7 / name :op1 "MAPK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod s2 :xref (x6 / xref :value "PUBCHEM:205" :prob "11.848252")) :location (c2 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0075" :ARG3 "0.1250")) :ARG1-of (s / strong-02 :degree (v / very))) # ::id pmid_2155_9022.101 # ::date 2015-08-08T09:38:01 # ::file pmid_2155_9022_101.txt # ::snt Activated cytoplasmic MAPK (Thr202/204) also very strongly associated with its activated expression (MAPK pThr202) in the nucleus (P<0.0001, r2=0.5210). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / associate-01 :ARG1 (a3 / amino-acid :name (n / name :op1 "threonine") :part-of (e2 / enzyme :name (n2 / name :op1 "MAPK") :mod (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (a4 / activate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (s2 / slash :op1 "202" :op2 "204") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 (a5 / amino-acid :mod "202" :name (n3 / name :op1 "threonine") :ARG3-of (p / phosphorylate-01) :part-of (e / enzyme :name (n4 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2-of (e3 / express-03 :ARG3 (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (a6 / activate-01)) :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1-of (s / strong-02 :degree (v / very)) :mod (a2 / also) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001") :ARG3 "0.5210")) # ::id pmid_2155_9022.102 # ::date 2015-08-08T23:42:55 # ::file pmid_2155_9022_102.txt # ::snt In addition, Raf-1 and pRaf (Ser259) both correlated with the cytoplasmic expression of MAPK (P<0.0001, r2=0.2979 and P=0.0005, r2=0.1879, respectively) and activated cytoplasmic MAPK (Thr202/204) (P=0.0007, r2=0.1826 and P=0.0069, r2=0.1214, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (a4 / and :op1 (a7 / and :op1 (c / correlate-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG2 (e14 / express-03 :ARG2 (e4 / enzyme :name (n4 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG3 (c2 / cytoplasm :xref (x4 / xref :value "GO:0005737" :prob "0.8"))) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001") :ARG3 "0.2979")) :op2 (c3 / correlate-01 :ARG1 (a5 / amino-acid :mod "259" :name (n2 / name :op1 "serine") :part-of (e3 / enzyme :name (n3 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG3-of (p / phosphorylate-01) :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 e14 :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0005" :ARG3 "0.1879"))) :op2 (a8 / and :op1 (c4 / correlate-01 :ARG1 e :ARG2 (a2 / amino-acid :name (n5 / name :op1 "threonine") :mod (s / slash :op1 "202" :op2 "204") :part-of (e2 / enzyme :name (n6 / name :op1 "MAPK") :mod c2 :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1-of (a3 / activate-01) :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0007" :ARG3 "0.1826")) :op2 (c5 / correlate-01 :ARG1 a5 :ARG2 a2 :ARG1-of (s5 / statistical-test-91 :ARG2 "0.0069" :ARG3 "0.1214"))))) # ::id pmid_2155_9022.103 # ::date 2015-08-06T02:45:32 # ::file pmid_2155_9022_103.txt # ::snt Raf-1 also correlated with nuclear activated MAPK (Thr202/204) (P=0.0022, r2=0.1525). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / correlate-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "MAPK") :ARG1-of (a / activate-01) :mod (n3 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :part (a2 / amino-acid :name (n4 / name :op1 "threonine") :mod (s / slash :op1 "202" :op2 "204") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (a4 / also) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0022" :ARG3 "0.1525")) # ::id pmid_2155_9022.104 # ::date 2015-08-07T01:06:12 # ::file pmid_2155_9022_104.txt # ::snt There were no correlations seen between pRaf (Ser338) and MAPK or pMAPK (Thr202/204). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :polarity "-" :ARG1 (c / correlate-01 :ARG1 (a / amino-acid :mod "338" :name (n / name :op1 "serine") :part-of (e2 / enzyme :name (n2 / name :op1 "Raf") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (o / or :op1 (e3 / enzyme :name (n3 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op2 (a2 / amino-acid :name (n4 / name :op1 "threonine") :mod (s2 / slash :op1 "202" :op2 "204") :part-of (e / enzyme :name (n5 / name :op1 "MAPK") :ARG3-of p :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252"))))) # ::id pmid_2155_9022.105 # ::date 2015-07-23T06:03:41 # ::file pmid_2155_9022_105.txt # ::snt Relative protein expression levels in CRPC # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (l / level :quant-of (p / protein :ARG2-of (e / express-03 :ARG3 (d2 / disease :name (n2 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")))) :ARG2-of (r / relative-05)) # ::id pmid_2155_9022.106 # ::date 2015-07-23T10:46:51 # ::file pmid_2155_9022_106.txt # ::snt In CRPC tumours, Raf-1 correlated with pRaf (Ser259) strongly (P=0.0003, r2=0.1778). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / correlate-01 :ARG1 (e / enzyme :wiki "C-Raf" :name (n / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG2 (a2 / amino-acid :mod "259" :wiki "Serine" :name (n4 / name :op1 "serine") :part-of (e2 / enzyme :wiki "RAF_kinase" :name (n2 / name :op1 "Raf") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :manner (s / strong-02) :location (t / tumor :mod (d3 / disease :wiki "-" :name (n5 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0003" :ARG3 "0.1778")) # ::id pmid_2155_9022.107 # ::date 2015-07-23T12:54:26 # ::file pmid_2155_9022_107.txt # ::snt The nuclear and cytoplasmic forms of pRaf (Ser338) also strongly correlated with each other (P<0.0001, r2=0.6009). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / correlate-01 :ARG1 (a3 / amino-acid :mod "338" :name (n5 / name :op1 "serine") :mod (n2 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :part-of (e / enzyme :name (n / name :op1 "Raf") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (a / amino-acid :mod "338" :name (n3 / name :op1 "serine") :mod (c2 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :part-of e :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :manner (s / strong-02) :mod (a2 / also) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001") :ARG3 "0.6009")) # ::id pmid_2155_9022.108 # ::date 2015-07-23T13:40:30 # ::file pmid_2155_9022_108.txt # ::snt Similarly to HNPC, protein expression of the inactive form of pRaf (Ser259) and the active forms of pRaf (Ser338) did not correlate in the cell cytoplasm or nucleus. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (c / correlate-01 :polarity "-" :ARG1 (e / express-03 :ARG2 (a2 / amino-acid :mod "259" :wiki "Serine" :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :wiki "RAF_kinase" :name (n / name :op1 "Raf") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG0-of (a / activity-06 :polarity "-") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG2 (e3 / express-03 :ARG2 (a4 / amino-acid :mod "338" :wiki "Serine" :name (n4 / name :op1 "serine") :ARG0-of (a3 / activity-06) :part-of e2 :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :location (o / or :op1 (c2 / cytoplasm :part-of (c3 / cell) :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :op2 (n5 / nucleus :part-of c3 :xref (x2 / xref :value "GO:0005634" :prob "0.8"))) :ARG1-of (r / resemble-01 :ARG2 (d / disease :wiki "-" :name (n3 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer")))) # ::id pmid_2155_9022.109 # ::date 2015-07-23T14:38:53 # ::file pmid_2155_9022_109.txt # ::snt After the development of CRPC, cytoplasmic expression of total MAPK became strongly associated with the expression of total MAPK in the nucleus (P=<0.0001, r2=0.2564) and more weakly with its activated form, pMAPK (Thr202/204), in the nucleus (P=0.0194, r2=0.0864). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (a / associate-01 :ARG1 (e / express-03 :ARG2 (e5 / enzyme :name (n / name :op1 "MAPK") :ARG1-of (t / total-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG3 (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8"))) :ARG2 (e2 / express-03 :ARG2 e5 :ARG3 (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8"))) :manner (s / strong-02) :ARG1-of (s3 / statistical-test-91 :ARG2 (o / or :op1 "0.0001" :op2 (l / less-than :op1 "0.0001")) :ARG3 "0.2564")) :op2 (a3 / associate-01 :ARG1 e :ARG2 (e3 / express-03 :ARG2 (a5 / amino-acid :name (n4 / name :op1 "threonine") :part-of (e4 / enzyme :name (n3 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1-of (a4 / activate-01) :mod (s2 / slash :op1 "202" :op2 "204") :ARG3-of (p / phosphorylate-01) :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG3 n5) :manner (w / weak-02) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0194" :ARG3 "0.0864")) :time (a6 / after :op1 (d / develop-02 :ARG1 (d4 / disease :name (n2 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))))) # ::id pmid_2155_9022.110 # ::date 2015-07-24T03:56:45 # ::file pmid_2155_9022_110.txt # ::snt Cytoplasmic expression of total MAPK continued to show a correlation with its activated form in the cytoplasm (MAPK pThr202/204) (P=0.0004, r2=0.1861). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / continue-01 :ARG0 (e / express-03 :ARG2 (e3 / enzyme :name (n / name :op1 "MAPK") :mod (t / total) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG3 (c2 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8"))) :ARG1 (s / show-01 :ARG0 e :ARG1 (c3 / correlate-01 :ARG1 e :ARG2 (e2 / express-03 :ARG2 (a2 / amino-acid :name (n3 / name :op1 "threonine") :part-of (e4 / enzyme :name (n2 / name :op1 "MAPK") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (s2 / slash :op1 "202" :op2 "204") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG3 (c4 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8"))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0004" :ARG3 "0.1861")))) # ::id pmid_2155_9022.111 # ::date 2015-07-24T08:58:03 # ::file pmid_2155_9022_111.txt # ::snt Activated cytoplasmic MAPK (Thr202/204) remained strongly associated with activated nuclear MAPK (Thr202/204) (P<0.0001, r2=0.5350). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / remain-01 :ARG1 (a / amino-acid :name (n / name :op1 "threonine") :part-of (e / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (c / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (a2 / activate-01) :mod (s2 / slash :op1 "202" :op2 "204") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 (a3 / associate-01 :ARG1 a :ARG2 (a4 / amino-acid :name (n3 / name :op1 "threonine") :part-of e :mod (n4 / nucleus :xref (x2 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of a2 :mod (s3 / slash :op1 "202" :op2 "204") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1-of (s / strong-02) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001") :ARG3 "0.5350"))) # ::id pmid_2155_9022.112 # ::date 2015-07-24T09:15:01 # ::file pmid_2155_9022_112.txt # ::snt Raf-1 showed similar associations with cytoplasmic and nuclear MAPK expression (P<0.0001, r2=0.2141 and P=0.0016, r2=0.1426, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (e / enzyme :name (n / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1 (a5 / and :op1 (a / associate-01 :ARG1 e :ARG2 (e2 / express-03 :ARG2 (e4 / enzyme :name (n2 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG3 (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8"))) :ARG1-of (r / resemble-01) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001") :ARG3 "0.2141")) :op2 (a6 / associate-01 :ARG1 e :ARG2 (e3 / express-03 :ARG2 e4 :ARG3 (n3 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8"))) :ARG1-of r :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0016" :ARG3 "0.1426")))) # ::id pmid_2155_9022.113 # ::date 2015-07-24T09:32:24 # ::file pmid_2155_9022_113.txt # ::snt Cytoplasmic MAPK also correlated with pRaf (Ser259) (P=0.0026, r2=0.1329). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / correlate-01 :ARG1 (e / enzyme :name (n / name :op1 "MAPK") :mod (c2 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2 (a2 / amino-acid :mod "259" :name (n2 / name :op1 "serine") :part-of (p3 / protein-family :name (n3 / name :op1 "Raf") :ARG3-of (p2 / phosphorylate-01)) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :mod (a / also) :ARG1-of (s / statistical-test-91 :ARG2 "0.0026" :ARG3 "0.1329")) # ::id pmid_2155_9022.114 # ::date 2015-07-24T09:40:32 # ::file pmid_2155_9022_114.txt # ::snt Similarly to HNPC tumours, no correlations were noted between pRaf (Ser338) and MAPK in any location or form. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (n / note-01 :polarity "-" :ARG1 (c / correlate-01 :ARG1 (a / amino-acid :mod "338" :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e / enzyme :name (n4 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :location (l / location :mod (a2 / any)) :manner (f / form :mod (a3 / any))) :ARG1-of (r / resemble-01 :ARG2 (t / tumor :mod (d / disease :name (n5 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer"))))) # ::id pmid_2155_9022.115 # ::date 2015-07-24T09:54:43 # ::file pmid_2155_9022_115.txt # ::snt Relative expression levels of Raf-1 and MAPK compared with upstream and downstream targets in hormone-naïve prostate cancer # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c / compare-01 :ARG1 (l / level :degree-of (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG2-of (r / relative-05))) :ARG2 (a3 / and :op1 (t / target-01 :location (u / upstream)) :op2 (t2 / target-01 :location (d / downstream))) :location (d2 / disease :name (n3 / name :op1 "hormone-naïve" :op2 "prostate" :op3 "cancer"))) # ::id pmid_2155_9022.116 # ::date 2015-07-24T10:15:56 # ::file pmid_2155_9022_116.txt # ::snt Analysis of the upstream activators EGFR and Her2, as well as the downstream targets AR and AP-1, has previously been carried out on the same cohort of patients (Edwards et al, 2003a, 2004; Bartlett et al, 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / carry-out-03 :ARG1 (a / analyze-01 :ARG1 (a4 / and :op1 (a2 / activate-01 :ARG0 (a3 / and :op1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n4 / name :op1 "Her2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603"))) :mod (u / upstream)) :op2 (t / target-01 :ARG1 (a5 / and :op1 (e3 / enzyme :name (n2 / name :op1 "AR") :xref (x1 / xref :value "UNIPROT:ANDR_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n3 / name :op1 "AP-1") :xref (x / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))) :mod (d / downstream)))) :time (p3 / previous) :instrument (c2 / cohort :consist-of (p4 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient))) :ARG1-of (s / same-01)) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (p6 / publication-91 :ARG0 (a7 / and :op1 (p7 / person :name (n5 / name :op1 "Edwards")) :op2 (p8 / person :mod (o / other))) :time (a8 / and :op1 (d4 / date-entity :year "2003") :op2 (d5 / date-entity :year "2004"))) :op2 (p9 / publication-91 :ARG0 (a9 / and :op1 (p10 / person :name (n9 / name :op1 "Bartlett")) :op2 p8) :time (d3 / date-entity :year "2005"))))) # ::id pmid_2155_9022.117 # ::date 2015-07-24T10:34:51 # ::file pmid_2155_9022_117.txt # ::snt We therefore correlated Raf-1 and MAPK expression with these previous results, to determine the differences in the entire pathway in the transition from HNPC to CRPC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / cause-01 :ARG1 (c2 / correlate-01 :ARG0 (w / we) :ARG1 (a / and :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :op2 (e3 / express-03 :ARG2 (e5 / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :ARG2 (t3 / thing :time (p2 / previous) :mod (t / this) :ARG2-of (r / result-01)) :purpose (d / determine-01 :ARG0 w :ARG1 (d2 / differ-02 :ARG3 (p3 / pathway :mod (e4 / entire)) :time (t2 / transition-01 :ARG2 (d4 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")) :ARG3 (d3 / disease :name (n4 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer"))))))) # ::id pmid_2155_9022.118 # ::date 2015-07-25T08:53:26 # ::file pmid_2155_9022_118.txt # ::snt In hormone-naïve tumours, expression of the putative growth factor receptor Her2 correlated with Raf-1 expression (P=0.0099, r2=0.1333) and the nuclear and cytoplasmic expression of pMAPK (Thr202/204) (P=0.0150, r2=0.1300 and P=0.0017, r2=0.2074, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / correlate-01 :ARG1 (e / express-03 :ARG2 (e10 / enzyme :name (n7 / name :op1 "growth" :op2 "factor" :op3 "receptor" :op4 "Her2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.323"))) :ARG2 (a / and :op1 (e3 / express-03 :ARG2 (e4 / enzyme :name (n3 / name :op1 "Raf-1") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0099" :ARG3 "0.1333")) :op2 (a2 / and :op1 (e5 / express-03 :ARG2 (a3 / amino-acid :name (n5 / name :op1 "threonine") :part-of (e2 / enzyme :name (n6 / name :op1 "MAPK") :ARG3-of (p3 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (s / slash :op1 "202" :op2 "204") :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG3 (n4 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0150" :ARG3 "0.0150")) :op2 (e6 / express-03 :ARG2 a3 :ARG3 (c2 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0017" :ARG3 "0.2074")))) :location (t / tumor :mod (h / hormone-naive))) # ::id pmid_2155_9022.119 # ::date 2015-07-25T09:31:20 # ::file pmid_2155_9022_119.txt # ::snt Once activated, the phosphorylated form of Her2 (pHer2) showed moderate correlations with Raf-1 (P=0.0056, r2=0.1435), pRaf (Ser259) (P=0.0052, r2=0.1459) and cytoplasmic MAPK expression (P=0.0123, r2=0.1211) (Figure 4), but not the activated forms of Raf or MAPK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (s / show-01 :ARG0 (e / enzyme :name (n / name :op1 "Her2") :ARG3-of (p / phosphorylate-01) :xref (x5 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603")) :ARG1 (a6 / and :op1 (c / correlate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf-1") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1-of (m / moderate-03) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0056" :ARG3 "0.1435")) :op2 (c6 / correlate-01 :ARG1 e :ARG2 (a3 / amino-acid :mod "259" :name (n4 / name :op1 "serine") :part-of (e3 / enzyme :name (n3 / name :op1 "Raf") :ARG3-of p :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x7 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0052" :ARG3 "0.1459")) :op3 (c7 / correlate-01 :ARG1 e :ARG2 (e4 / express-03 :ARG2 (e7 / enzyme :name (n5 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG3 (c2 / cytoplasm :xref (x6 / xref :value "GO:0005737" :prob "0.8"))) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.0123" :ARG3 "0.1211"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4")) :time (a / activate-01 :ARG1 e)) :ARG2 (s2 / show-01 :polarity "-" :ARG0 e :ARG1 (c4 / correlate-01 :ARG1 e :ARG2 (a4 / and :op1 (e5 / enzyme :name (n6 / name :op1 "Raf") :ARG1-of (a5 / activate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op2 (e6 / enzyme :name (n7 / name :op1 "MAPK") :ARG1-of a5 :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))))) # ::id pmid_2155_9022.120 # ::date 2015-07-25T10:05:40 # ::file pmid_2155_9022_120.txt # ::snt No correlations were seen with EGFR in HNPC tumours, except weak correlations with Raf-1 (P=0.0439, r2=0.06008) and pMAPK (Thr202/204) (nuclear) (P=0.0243, r2=0.0844). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :ARG1 (c / correlate-01 :polarity "-" :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG2-of (e2 / except-01 :ARG1 (a3 / and :op1 (c2 / correlate-01 :ARG1 e :ARG2 (e3 / enzyme :name (n2 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0439" :ARG3 "0.06008")) :op2 (c4 / correlate-01 :ARG1 e :ARG2 (a2 / amino-acid :name (n3 / name :op1 "threonine") :part-of (e4 / enzyme :name (n4 / name :op1 "MAPK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (n5 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :mod (s2 / slash :op1 "202" :op2 "204") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0243" :ARG3 "0.0844")) :ARG1-of (w / weak-02)))) :location (t / tumor :mod (d / disease :name (n6 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer")))) # ::id pmid_2155_9022.121 # ::date 2015-07-25T10:30:45 # ::file pmid_2155_9022_121.txt # ::snt However, the mutant variant, EGFR vIII, did correlate strongly with cytoplasmic expression of MAPK (P<0.0001, r2=0.2617) and to a weaker extent with Raf-1 (P=0.025, r2=0.07965) and pRaf (Ser259) (P=0.0323, r2=0.07295). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c4 / contrast-01 :ARG2 (a / and :op1 (c / correlate-01 :ARG1 (v / variant :ARG2-of (m / mutate-01) :ARG1-of (d / describe-01 :ARG2 (e / enzyme :name (n / name :op1 "EGFR" :op2 "vIII") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.243")))) :ARG2 (e2 / express-03 :ARG2 (e6 / enzyme :name (n2 / name :op1 "MAPK") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG3 (c2 / cytoplasm :xref (x4 / xref :value "GO:0005737" :prob "0.8"))) :manner (s / strong-02) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.0001") :ARG3 "0.2617")) :op2 (c3 / correlate-01 :ARG1 v :ARG2 (a2 / and :op1 (e4 / enzyme :name (n3 / name :op1 "Raf-1") :ARG1-of (s3 / statistical-test-91 :ARG2 "0.025" :ARG3 "0.07965") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (a3 / amino-acid :mod "259" :name (n4 / name :op1 "serine") :part-of (e5 / enzyme :name (n5 / name :op1 "Raf") :ARG3-of (p4 / phosphorylate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0323" :ARG3 "0.07295") :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :degree (e3 / extent :ARG1-of (w / weak-02))))) # ::id pmid_2155_9022.122 # ::date 2015-07-26T03:19:12 # ::file pmid_2155_9022_122.txt # ::snt Further downstream, activated pRaf (Ser338) in the cytoplasm strongly correlated with phosphorylated c-jun (P=0.0009, r2=0.2673) and total MAPK (cytoplasmic) correlated weakly with c-Fos (P=0.0453, r2=0.09418) (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a3 / and :op1 (c / correlate-01 :ARG1 (a / amino-acid :mod "338" :name (n2 / name :op1 "serine") :part-of (e / enzyme :name (n / name :op1 "Raf") :ARG3-of (p / phosphorylate-01) :ARG1-of (a2 / activate-01 :location (c2 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8"))) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (p2 / protein :name (n3 / name :op1 "c-jun") :ARG3-of p) :manner (s / strong-02) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0009" :ARG3 "0.2673")) :op2 (c3 / correlate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "MAPK") :mod (c4 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :mod (t / total) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2 (p5 / protein :name (n5 / name :op1 "c-Fos")) :ARG1-of (w / weak-02) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0453" :ARG3 "0.09418")) :location (d / downstream :degree (f / further)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5"))) # ::id pmid_2155_9022.123 # ::date 2015-07-26T03:44:50 # ::file pmid_2155_9022_123.txt # ::snt There were no correlations seen between MAPK and its activated form with c-jun, phospho c-Jun or c-Fos. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :ARG1 (c / correlate-01 :polarity "-" :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op2 (e2 / enzyme :name (n2 / name :op1 "MAPK") :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :ARG2 (o / or :op1 (p3 / protein :name (n3 / name :op1 "c-jun")) :op2 (p4 / protein :name (n4 / name :op1 "c-Jun") :ARG3-of (p5 / phosphorylate-01)) :op3 (p6 / protein :name (n5 / name :op1 "c-Fos"))))) # ::id pmid_2155_9022.124 # ::date 2015-07-26T03:52:13 # ::file pmid_2155_9022_124.txt # ::snt In addition, PSA showed weak correlations with Raf-1 (P=0.0142, r2=0.09604), pRaf (Ser259) (P=0.043, r2=0.06547), and showed links to overall MAPK levels, MAPK (nuclear) (P=0.0029, r2=0.1502) and MAPK (cytoplasmic) (P<0.0001, r2=0.2467), with strong ties to the activated forms, pMAPK (Thr202/204) (cytoplasmic) (P<0.0001, r2=0.2891) and pMAPK (Thr202/204) (nuclear) (P=0.0001, r2=0.2233) (Figure 6), whereas AR showed no correlations with Raf, MAPK or any of their forms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (c4 / contrast-01 :ARG1 (s / show-01 :ARG0 (e4 / enzyme :name (n14 / name :op1 "PSA") :xref (x3 / xref :value "UNIPROT:PSA_HUMAN" :prob "1.003")) :ARG1 (a3 / and :op1 (c / correlate-01 :ARG1 e4 :ARG2 (a5 / and :op1 (e / enzyme :name (n / name :op1 "Raf-1") :ARG1-of (s5 / statistical-test-91 :ARG2 "0.0142" :ARG3 "0.09604") :xref (x8 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (a6 / amino-acid :mod "259" :name (n2 / name :op1 "serine") :part-of (e6 / enzyme :name (n3 / name :op1 "Raf") :ARG3-of (p2 / phosphorylate-01) :xref (x5 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.043" :ARG3 "0.06547") :xref (x15 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1-of (w / weak-02)) :op2 (l / link-01 :ARG1 e4 :ARG2 (a13 / and :op1 (l2 / level :quant-of (e2 / enzyme :name (n4 / name :op1 "MAPK") :xref (x7 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (o / overall)) :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK") :mod (n6 / nucleus :xref (x13 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (s7 / statistical-test-91 :ARG2 "0.0029" :ARG3 "0.1502") :xref (x6 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op3 (e10 / enzyme :name (n7 / name :op1 "MAPK") :mod (c2 / cytoplasm :xref (x12 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (s8 / statistical-test-91 :ARG2 (l3 / less-than :op1 "0.0001") :ARG3 "0.2467") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :op3 (t / tie-01 :ARG1 e4 :ARG2 (a8 / and :op1 (a9 / amino-acid :name (n8 / name :op1 "threonine") :part-of (e9 / enzyme :quant "0.0001" :name (n9 / name :op1 "MAPK") :ARG3-of (p11 / phosphorylate-01) :xref (x9 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (c3 / cytoplasm :xref (x11 / xref :value "GO:0005737" :prob "0.8")) :mod (s4 / slash :op1 "202" :op2 "204") :ARG1-of (s9 / statistical-test-91 :ARG2 (l4 / less-than :op1 "0.0001") :ARG3 "0.2891") :xref (x16 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a10 / amino-acid :name (n10 / name :op1 "threonine") :part-of e9 :mod (n11 / nucleus :xref (x10 / xref :value "GO:0005634" :prob "0.8")) :mod s4 :ARG1-of (s10 / statistical-test-91 :ARG2 "0.0001" :ARG3 "0.2233") :xref (x14 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1-of (a7 / activate-01)) :ARG1-of (s2 / strong-02))) :ARG1-of (d3 / describe-01 :ARG2 (f2 / figure :mod "6"))) :ARG2 (s3 / show-01 :ARG0 (e5 / enzyme :name (n15 / name :op1 "AR") :xref (x / xref :value "UNIPROT:ANDR_HUMAN" :prob "1.003")) :ARG2 (c5 / correlate-01 :polarity "-" :ARG1 e5 :ARG2 (o2 / or :op1 (e8 / enzyme :name (n12 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op2 (e7 / enzyme :name (n13 / name :op1 "MAPK") :xref (x4 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :op3 (f3 / form :mod (a11 / any) :poss (a12 / and :op1 e8 :op2 e7))))))) # ::id pmid_2155_9022.125 # ::date 2015-07-26T05:33:16 # ::file pmid_2155_9022_125.txt # ::snt Relative expression levels of Raf-1 and MAPK compared with upstream and downstream targets in CRPC # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c / compare-01 :ARG1 (l / level :ARG2-of (r / relative-05) :degree-of (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))))) :ARG2 (a2 / and :op1 (t / target-01 :mod (u / upstream)) :op2 (t2 / target-01 :mod (d / downstream))) :location (d2 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))) # ::id pmid_2155_9022.126 # ::date 2015-07-26T05:44:01 # ::file pmid_2155_9022_126.txt # ::snt After the development of CRPC, Her2 no longer showed a correlation with Raf-1 nor a negative association became evident between pRaf (Ser338) both in the cytoplasm (P=0.0035, r2=0.1854) and nucleus (P=0.0068, r2=0.1581) with Her2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / and :op1 (s / show-01 :ARG0 (e / enzyme :name (n / name :op1 "Her2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603")) :ARG1 (c / correlate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n3 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :time (n2 / no-longer)) :op2 (e3 / evident :polarity "-" :domain (a2 / associate-01 :ARG1 (a3 / amino-acid :mod "338" :name (n5 / name :op1 "serine") :part-of (e4 / enzyme :name (n6 / name :op1 "Raf") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :location (a4 / and :op1 (c2 / cytoplasm :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0035" :ARG3 "0.1854") :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :op2 (n7 / nucleus :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0068" :ARG3 "0.1581") :xref (x4 / xref :value "GO:0005634" :prob "0.8"))) :xref (x5 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 e :ARG2-of (n4 / negative-01))) :time (a5 / after :op1 (d / develop-01 :ARG2 (d2 / disease :name (n9 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))))) # ::id pmid_2155_9022.127 # ::date 2015-07-26T07:15:42 # ::file pmid_2155_9022_127.txt # ::snt In addition, the activated form (pHer2) correlated with pRaf (Ser259) (P=0.0008, r2=0.2011). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / and :op2 (c / correlate-01 :ARG1 (f / form :ARG1-of (a2 / activate-01) :ARG1-of (d / describe-01 :ARG2 (e / enzyme :name (n / name :op1 "Her2") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603")))) :ARG2 (a3 / amino-acid :mod "259" :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf") :ARG3-of p :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (s / statistical-test-91 :ARG2 "0.0008" :ARG3 "0.02011"))) # ::id pmid_2155_9022.128 # ::date 2015-07-26T07:24:29 # ::file pmid_2155_9022_128.txt # ::snt Interestingly, the activated cytoplasmic form of Raf showed a positive weak correlation with the pHer2 (P=0.0363, r2=0.09376) (Figure 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (e / enzyme :name (n / name :op1 "Raf") :mod (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1 (c2 / correlate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "Her2") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603")) :mod (p / positive) :ARG1-of (w / weak-02) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0363" :ARG3 "0.09376")) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "7")) :ARG0-of (i / interest-01)) # ::id pmid_2155_9022.129 # ::date 2015-07-26T07:35:47 # ::file pmid_2155_9022_129.txt # ::snt Furthermore, no correlations were evident between Her2 or pHer2 with MAPK in any form. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a3 / and :op2 (e / evident :domain (c / correlate-01 :polarity "-" :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Her2") :xref (x2 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :name (n2 / name :op1 "Her2") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "0.603"))) :ARG2 (f / form :mod (a2 / any) :mod (e4 / enzyme :name (n3 / name :op1 "MAPK") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))))) # ::id pmid_2155_9022.130 # ::date 2015-07-26T07:47:00 # ::file pmid_2155_9022_130.txt # ::snt All associations between EGFR and EGFR vIII disappeared after progression to CRPC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (d / disappear-01 :ARG1 (a / associate-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "EGFR" :op2 "vIII") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.243")) :mod (a2 / all)) :time (a3 / after :op1 (p / progress-01 :ARG4 (d2 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))))) # ::id pmid_2155_9022.131 # ::date 2015-07-26T08:00:19 # ::file pmid_2155_9022_131.txt # ::snt A moderate positive correlation was seen between pRaf (Ser259) and AR (P=0.0035, r2=0.1154), whereas a negative correlation is evident between nuclear MAPK and AR (P=0.0429, r2=0.06066). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / contrast-01 :ARG1 (s / see-01 :ARG1 (c2 / correlate-01 :ARG1 (a / amino-acid :mod "259" :name (n2 / name :op1 "serine") :part-of (e4 / enzyme :name (n / name :op1 "Raf") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG2 (e3 / enzyme :name (n3 / name :op1 "AR") :xref (x2 / xref :value "UNIPROT:ANDR_HUMAN" :prob "1.003")) :ARG1-of (m / moderate-03) :mod (p / positive) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0035" :ARG3 "0.1154"))) :ARG2 (e2 / evidence-01 :ARG1 (c3 / correlate-01 :ARG1 (e / enzyme :name (n5 / name :op1 "MAPK") :mod (n6 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2 e3 :ARG2-of (n4 / negative-01) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0429" :ARG3 "0.06066")))) # ::id pmid_2155_9022.132 # ::date 2015-07-26T12:55:49 # ::file pmid_2155_9022_132.txt # ::snt There was no correlation (positive or negative) shown between total Raf-1 expression and AR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / show-01 :ARG1 (c / correlate-01 :polarity "-" :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf-1") :mod (t / total) :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :ARG2 (e3 / enzyme :name (n3 / name :op1 "AR") :xref (x / xref :value "UNIPROT:ANDR_HUMAN" :prob "1.003")) :mod (o / or :op1 (p / positive) :op2 (n / negative-01)))) # ::id pmid_2155_9022.133 # ::date 2015-07-26T13:03:58 # ::file pmid_2155_9022_133.txt # ::snt In addition, there were no correlations noted between either Raf-1 (any form) or MAPK (any form) and PSA level. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (n / note-01 :ARG1 (c / correlate-01 :polarity "-" :ARG1 (o / or :op1 (f / form :mod (a2 / any) :mod (e / enzyme :name (n2 / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :op2 (f2 / form :mod (a3 / any) :mod (e3 / enzyme :name (n3 / name :op1 "MAPK") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")))) :ARG2 (l / level :quant-of (e2 / enzyme :name (n4 / name :op1 "PSA") :xref (x / xref :value "UNIPROT:PSA_HUMAN" :prob "1.003")))))) # ::id pmid_2155_9022.134 # ::date 2015-07-26T13:18:55 # ::file pmid_2155_9022_134.txt # ::snt More correlations were noted with components of the downstream transcription factor AP-1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (n / note-01 :ARG1 (c / correlate-01 :ARG2 (c2 / component :part-of (p / protein :name (n2 / name :op1 "AP-1") :location (d / downstream) :mod (f / factor) :ARG1-of (t / transcribe-01) :xref (x / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))) :quant (m / more))) # ::id pmid_2155_9022.135 # ::date 2015-07-26T13:30:24 # ::file pmid_2155_9022_135.txt # ::snt Correlations were evident between phosphorylated c-jun and cytoplasmic pRaf (Ser338) (P=0.0026, r2=0.2192) and pRaf (Ser259) (P=0.0278, r2=0.1077). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (e / evidence-01 :ARG1 (a4 / and :op1 (c / correlate-01 :ARG1 (p / protein :name (n / name :op1 "c-jun") :ARG3-of (p2 / phosphorylate-01)) :ARG2 (a2 / amino-acid :mod "338" :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :mod (c2 / cytoplasm :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (s / statistical-test-91 :ARG2 "0.0026" :ARG3 "0.2192")) :op2 (c4 / correlate-01 :ARG1 p :ARG2 (a3 / amino-acid :mod "259" :name (n4 / name :op1 "serine") :part-of e2 :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0278" :ARG3 "0.1077")))) # ::id pmid_2155_9022.136 # ::date 2015-07-26T13:43:33 # ::file pmid_2155_9022_136.txt # ::snt There was also a correlation seen between Raf-1 and c-Fos (P=0.0131, r2=0.1512), and between the nuclear and cytoplasmic expression of pMAPK (Thr202/204) and c-jun (P=0.0146, r2=0.1368 and P=0.0178, r2=0.1295, respectively) (Figure 8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :ARG1 (a / and :op1 (c / correlate-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :ARG2 (p / protein :name (n2 / name :op1 "c-Fos")) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0131" :ARG3 "0.1512")) :op2 (c3 / correlate-01 :ARG1 (a2 / and :op1 (e2 / express-03 :ARG2 (a3 / amino-acid :name (n3 / name :op1 "threonine") :part-of (e4 / enzyme :name (n5 / name :op1 "MAPK") :ARG3-of (p4 / phosphorylate-01) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :mod (s2 / slash :op1 "202" :op2 "204") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG3 (n4 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0146" :ARG3 "0.1368")) :op2 (e3 / express-03 :ARG2 a3 :ARG3 (c2 / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.0178" :ARG3 "0.1295"))) :ARG2 (p5 / protein :name (n6 / name :op1 "c-jun"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "8"))) :mod (a6 / also)) # ::id pmid_2246_3874.1 # ::date 2015-08-05T10:41:21 # ::file pmid_2246_3874_1.txt # ::snt Prognostic value of RKIP and p-ERK in gastric cancer (PMID:22463874) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (v / value-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")) :op2 (e / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :mod (p / prognostic) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG8 "PMID22463874")) :location (d2 / disease :wiki "Stomach_cancer" :name (n3 / name :op1 "stomach" :op2 "cancer"))) # ::id pmid_2246_3874.8 # ::date 2015-08-08T09:55:30 # ::file pmid_2246_3874_8.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 8, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2246_3874.9 # ::date 2015-08-08T10:30:48 # ::file pmid_2246_3874_9.txt # ::snt Expression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (a2 / and :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "RKIP") :xref (x2 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")) :ARG3 (t / tumor :quant "69" :ARG1-of (i / include-91 :ARG2 (t2 / tumor :mod (a / all)) :ARG3 (p2 / percentage-entity :value "66")))) :op2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG3 (t3 / tumor :quant "54" :ARG1-of (i2 / include-91 :ARG2 t2 :ARG3 (p4 / percentage-entity :value "51")))) :op3 (e4 / express-03 :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK") :ARG3-of p3 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG3 (t4 / tumor :quant "64" :ARG1-of (i3 / include-91 :ARG2 t2 :ARG3 (p6 / percentage-entity :value "61")))))) # ::id pmid_2246_3874.10 # ::date 2015-08-08T10:37:52 # ::file pmid_2246_3874_10.txt # ::snt RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and Union for International Cancer Control (UICC) stage (p = 0.007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a2 / and :op1 (c / correlate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002"))) :ARG2 (d / depth :mod (i / invade-01)) :ARG2-of (n / negative-01) :ARG1-of (s / statistical-test-91 :ARG2 (l / less-than :value "0.001"))) :op2 (c2 / correlate-01 :ARG1 e :ARG2 (i2 / involve-01 :ARG1 (n3 / node :mod (l2 / lymph))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.028")) :op3 (c3 / correlate-01 :ARG1 e :ARG2 (s2 / stage :mod (o / organization :name (n5 / name :op1 "UICC"))) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.007"))) # ::id pmid_2246_3874.11 # ::date 2015-08-08T10:58:20 # ::file pmid_2246_3874_11.txt # ::snt RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / contrast-01 :ARG1 (a / associate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002"))) :ARG2 (s / survive-01 :ARG1-of (f / free-04 :ARG2 (r / relapse-01)) :ARG1-of (l / long-03 :degree (m / more) :ARG1-of (s2 / significant-02))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0033")) :ARG2 (a2 / associate-01 :polarity "-" :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG2 s :ARG1-of (s4 / statistical-test-91 :ARG2 "0.79"))) # ::id pmid_2246_3874.12 # ::date 2015-08-08T11:18:24 # ::file pmid_2246_3874_12.txt # ::snt Patients with p-ERK expression had slightly, but not significantly shorter RFS than those without such expression (p = 0.054). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (s / survive-01 :ARG1-of (f / free-04 :ARG2 (r / relapse-01)) :ARG1-of (s2 / short-07 :degree (s5 / slight :ARG1-of (c / contrast-01 :ARG2 (s4 / significant-02 :polarity "-"))) :degree (m / more)) :compared-to (p4 / person :ARG0-of h2 :ARG3-of (e3 / express-03 :polarity "-" :ARG2 e2)) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.054"))) # ::id pmid_2246_3874.13 # ::date 2015-08-08T11:32:19 # ::file pmid_2246_3874_13.txt # ::snt Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :compared-to (p6 / person :mod (o / other) :ARG0-of h2) :ARG3-of (e2 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :mod (p4 / positive)) :ARG3-of (e3 / express-03 :ARG2 (p5 / protein :name (n2 / name :op1 "RKIP") :ARG2-of (m / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")))) :ARG1 (s / survive-01 :ARG1-of (f / free-04 :ARG2 (r / relapse-01)) :ARG1-of (s2 / short-07 :ARG1-of (s3 / significant-02) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :value "0.001"))))) # ::id pmid_2246_3874.14 # ::date 2015-08-08T11:41:45 # ::file pmid_2246_3874_14.txt # ::snt The combination of RKIP and p-ERK expression was an independent prognostic factor (hazard ratio, 2.4; 95% confidence interval, 1.3 - 4.6; p = 0.008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / factor :domain (c / combine-01 :ARG3 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :mod (p3 / prognostic) :ARG0-of (d / depend-01 :polarity "-") :mod (r / ratio :quant "2.4" :mod (h / hazard)) :mod (i / interval :mod (c2 / confidence) :value (v / value-interval :op1 "1.3" :op2 "4.6") :mod (p4 / percentage-entity :value "95")) :ARG1-of (s / statistical-test-91 :ARG2 "0.008")) # ::id pmid_2246_3874.78 # ::date 2015-08-08T11:47:37 # ::file pmid_2246_3874_78.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 8, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2246_3874.79 # ::date 2015-08-08T11:48:03 # ::file pmid_2246_3874_79.txt # ::snt RKIP, p-MEK, and p-ERK were respectively expressed by 69 (66%), 54 (51%), and 64 (61%) of all tumours (Figure 1a-c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "RKIP") :xref (x2 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")) :ARG3 (t / tumor :quant "69" :ARG1-of (i / include-91 :ARG2 (t4 / tumor :mod (a2 / all)) :ARG3 (p4 / percentage-entity :value "66")))) :op2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG3 (t2 / tumor :quant "54" :ARG1-of (i2 / include-91 :ARG2 t4 :ARG3 (p5 / percentage-entity :value "51")))) :op3 (e4 / express-03 :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK") :ARG3-of p2 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG3 (t3 / tumor :quant "64" :ARG1-of (i3 / include-91 :ARG2 t4 :ARG3 (p6 / percentage-entity :value "61")))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1a") :op2 (f2 / figure :mod "1b") :op3 (f3 / figure :mod "1c")))) # ::id pmid_2246_3874.80 # ::date 2015-08-08T11:55:57 # ::file pmid_2246_3874_80.txt # ::snt RKIP expression was mainly observed in the cytoplasm of tumour or non-tumour cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (o / observe-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002"))) :location (c / cytoplasm :part-of (o2 / or :op1 (c2 / cell :mod (t / tumor)) :op2 (c3 / cell :mod (t2 / tumor :polarity "-"))) :xref (x1 / xref :value "GO:0005737" :prob "0.8")) :manner (m / main)) # ::id pmid_2246_3874.81 # ::date 2015-08-08T11:58:30 # ::file pmid_2246_3874_81.txt # ::snt Expressions of p-MEK and p-ERK were found in both the cytoplasm and nucleus. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e3 / enzyme :name (n2 / name :op1 "ERK") :ARG3-of p :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :location (a2 / and :op1 (c / cytoplasm :xref (x2 / xref :value "GO:0005737" :prob "0.8")) :op2 (n3 / nucleus :xref (x3 / xref :value "GO:0005634" :prob "0.8")) :mod (b / both))) # ::id pmid_2246_3874.82 # ::date 2015-08-08T12:02:03 # ::file pmid_2246_3874_82.txt # ::snt Expressions of RKIP, p-MEK, and p-ERK were respectively detected in 5 (19%), 9 (35%), and 21 (81%) of 26 metastatic lymph nodes obtained from patients with recurrent disease (Figure 1d-f). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / detect-01 :ARG1 (a / and :op1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "RKIP") :xref (x2 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")) :ARG3 (n2 / node :quant "5" :ARG1-of (i / include-91 :ARG2 (n7 / node :quant "26" :mod (l / lymph) :mod (m / metastasis) :ARG1-of (o / obtain-01 :ARG2 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :mod (d2 / disease :ARG1-of (r / reoccur-01))))) :ARG3 (p5 / percentage-entity :value "19")))) :op2 (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "MEK") :ARG3-of (p4 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG3 (n4 / node :quant "9" :ARG1-of (i2 / include-91 :ARG2 n7 :ARG3 (p6 / percentage-entity :value "35")))) :op3 (e5 / express-03 :ARG2 (e4 / enzyme :name (n5 / name :op1 "ERK") :ARG3-of p4 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG3 (n6 / node :quant "21" :ARG1-of (i3 / include-91 :ARG2 n7 :ARG3 (p7 / percentage-entity :value "81"))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1d") :op2 (f2 / figure :mod "1e") :op3 (f3 / figure :mod "1f")))) # ::id pmid_2246_3874.83 # ::date 2015-08-08T12:14:06 # ::file pmid_2246_3874_83.txt # ::snt Expression of p-ERK was found mainly in the nuclei of metastatic tumour cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :manner (m / main) :location (n2 / nucleus :part-of (c / cell :mod (t / tumor :ARG1-of (m2 / metastasize-101))) :xref (x1 / xref :value "GO:0005634" :prob "0.8"))) # ::id pmid_2246_3874.84 # ::date 2015-08-08T13:29:32 # ::file pmid_2246_3874_84.txt # ::snt These proteins were also detected in tumour cells associated with venous invasion (Figure 1g-i). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / detect-01 :ARG1 (p / protein :mod (t / this)) :mod (a / also) :location (c / cell :mod (t2 / tumor) :ARG1-of (a2 / associate-01 :ARG2 (i / invade-01 :ARG1 (v / vein)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1g") :op2 (f2 / figure :mod "1h") :op3 (f3 / figure :mod "1i")))) # ::id pmid_2246_3874.85 # ::date 2015-08-08T13:32:16 # ::file pmid_2246_3874_85.txt # ::snt No p-ERK or p-MEK staining was detected in normal gastric mucosa. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / detect-01 :ARG1 (s / stain-01 :polarity "-" :ARG2 (o / or :op1 (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of p :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :location (m / mucosa :mod (s2 / stomach) :ARG1-of (n3 / normal-02))) # ::id pmid_2246_3874.86 # ::date 2015-08-08T14:34:35 # ::file pmid_2246_3874_86.txt # ::snt The expression of p-MEK positively correlated with the expressions of RKIP (p = 0.042) and p-ERK (p = 0.007), whereas there was no relation between RKIP and p-ERK expressions (p = 0.98) (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (a2 / and :op1 (c2 / correlate-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2 (e3 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "RKIP") :xref (x2 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002"))) :manner (p6 / positive) :ARG1-of (s / statistical-test-91 :ARG2 "0.042")) :op2 (c3 / correlate-01 :ARG1 e :ARG2 (e4 / enzyme :name (n3 / name :op1 "ERK") :ARG3-of p :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.007"))) :ARG2 (r / relate-01 :polarity "-" :ARG1 (e5 / express-03 :ARG2 p2) :ARG2 (e6 / express-03 :ARG2 e4) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.098")) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "1"))) # ::id pmid_2246_3874.87 # ::date 2015-08-08T14:42:43 # ::file pmid_2246_3874_87.txt # ::snt RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and UICC stage (p = 0.007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a2 / and :op1 (c / correlate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002"))) :ARG2 (d / depth :mod (i / invade-01)) :ARG2-of (n3 / negative-01) :ARG1-of (s / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.001"))) :op2 (c2 / correlate-01 :ARG1 e :ARG2 (i2 / involve-01 :ARG1 (n2 / node :mod (l / lymph))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.028")) :op3 (c3 / correlate-01 :ARG1 e :ARG2 (s2 / stage :mod (o / organization :name (n5 / name :op1 "UICC"))) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.007"))) # ::id pmid_2246_3874.88 # ::date 2015-08-08T14:50:15 # ::file pmid_2246_3874_88.txt # ::snt RKIP was more commonly found in differentiated type than in undifferentiated type tumours (p = 0.042). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (f / find-01 :ARG1 (p / protein :name (n / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")) :location (t / tumor :mod (t2 / type :ARG1-of (d / differentiate-01)) :compared-to (t3 / tumor :mod (t4 / type :ARG1-of (d2 / differentiate-01 :polarity "-")))) :manner (c / common :degree (m / more)) :ARG1-of (s / statistical-test-91 :ARG2 "0.042")) # ::id pmid_2246_3874.89 # ::date 2015-08-08T15:04:42 # ::file pmid_2246_3874_89.txt # ::snt The expressions of p-ERK and p-MEK significantly correlated with gender (p = 0.027, p = 0.036, respectively), but were not related to any other clinicopathological factor (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (a3 / and :op1 (c2 / correlate-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2 (g / gender) :ARG1-of (s / significant-02) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.027")) :op2 (c4 / correlate-01 :ARG1 (e4 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of p :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2 g :ARG1-of (s3 / statistical-test-91 :ARG2 "0.036"))) :ARG2 (r / relate-01 :polarity "-" :ARG1 e :ARG2 (f / factor :mod (c3 / clinicopathology) :mod (o / other :mod (a2 / any)))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "2"))) # ::id pmid_2246_3874.90 # ::date 2015-08-08T15:08:56 # ::file pmid_2246_3874_90.txt # ::snt RKIP expression was associated with significantly longer RFS (p = 0.003), whereas p-MEK was not (p = 0.79). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / contrast-01 :ARG1 (a / associate-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002"))) :ARG2 (s / survive-01 :ARG1-of (l / long-03 :degree (m / more) :ARG1-of (s2 / significant-02)) :ARG1-of (f / free-04 :ARG2 (r / relapse-01))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.003")) :ARG2 (a2 / associate-01 :polarity "-" :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2 s :ARG1-of (s4 / statistical-test-91 :ARG2 "0.79"))) # ::id pmid_2246_3874.91 # ::date 2015-08-09T06:11:55 # ::file pmid_2246_3874_91.txt # ::snt The presence of p-ERK expression was associated with slightly, but not significantly shorter RFS than the absence of such expression (p = 0.054) (Table 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / associate-01 :ARG1 (p / present-02 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :compared-to (a2 / absent-01 :ARG1 e)) :ARG2 (s / survive-01 :ARG1-of (s2 / short-07 :degree (m / more) :degree (s3 / slight :ARG1-of (c / contrast-01 :ARG2 (s4 / significant-02 :polarity "-")))) :ARG1-of (f / free-04 :ARG2 (r / relapse-01))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "3")) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.054")) # ::id pmid_2246_3874.92 # ::date 2015-08-09T06:16:56 # ::file pmid_2246_3874_92.txt # ::snt Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001) (Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :compared-to (p6 / person :mod (o / other) :ARG0-of h2) :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :mod (p4 / positive)) :ARG3-of (e3 / express-03 :ARG2 (p5 / protein :name (n2 / name :op1 "RKIP") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")))) :ARG1 (s / survive-01 :ARG1-of (s2 / short-07 :ARG1-of (s3 / significant-02) :degree (m / more) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :ARG1-of (f / free-04 :ARG2 (r / relapse-01))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2"))) # ::id pmid_2246_3874.93 # ::date 2015-08-09T06:23:40 # ::file pmid_2246_3874_93.txt # ::snt The prognostic relevance of positive p-ERK expression combined with negative RKIP expression was therefore assessed using a multivariate proportional-hazards model adjusted for established clinical prognostic factors (i.e., age, gender, histopathology, depth of invasion, lymph node involvement). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / assess-01 :ARG1 (r / relevant-01 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (c / combine-01 :ARG2 (e3 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "RKIP") :ARG2-of (m3 / mutate-01 :mod "-/-") :xref (x1 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")))) :mod (p3 / positive)) :mod (p4 / prognostic)) :instrument (m / model-01 :ARG1-of (a2 / adjust-01 :ARG2 (f / factor :mod (c2 / clinic) :ARG1-of (e4 / establish-01) :mod p4 :example (a3 / and :op1 (a4 / age) :op2 (g / gender) :op3 (h / histopathology) :op4 (d / depth :mod (i2 / invade-01)) :op5 (i3 / involve-01 :ARG1 (n4 / node :mod (l / lymph)))))) :mod (h2 / hazard :mod (p5 / proportional)) :mod (m2 / multivariate)) :ARG1-of (c3 / cause-01)) # ::id pmid_2246_3874.94 # ::date 2015-08-09T06:33:02 # ::file pmid_2246_3874_94.txt # ::snt The combination of RKIP and p-ERK expression was found to be an independent prognostic factor (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.3 - 4.6; p = 0.008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG1 (f2 / factor :mod (p3 / prognostic) :ARG0-of (d / depend-01 :polarity "-") :domain (c / combine-01 :ARG1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "RKIP") :xref (x / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :ARG1-of (s / statistical-test-91 :ARG2 "0.008")) :mod (r / ratio :value "2.4" :mod (h / hazard)) :mod (i / interval :mod (c2 / confidence) :mod (p4 / percentage-entity :value "95") :value (v / value-interval :op1 "1.3" :op2 "4.6"))) # ::id pmid_2246_3874.95 # ::date 2015-08-09T06:41:27 # ::file pmid_2246_3874_95.txt # ::snt Histopathological type and depth of invasion were also independent prognostic factors (HR, 2.1; 95% CI, 1.0 - 4.2; p = 0.043 and HR, 4.7; 95% CI, 1.0-22; p = 0.048, respectively) (Table 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (f / factor :mod (p / prognostic) :ARG0-of (d / depend-01 :polarity "-") :domain (a / and :op1 (t / type :mod (h / histopathological) :mod (r / ratio :value "2.1" :mod (h2 / hazard)) :mod (i2 / interval :mod (c / confidence) :mod (p2 / percentage-entity :value "95") :value (b / between :op1 "1.0" :op2 "4.2")) :ARG1-of (s / statistical-test-91 :ARG2 "0.043")) :op2 (d2 / depth :mod (i / invade-01) :mod (r2 / ratio :value "4.7" :mod (h3 / hazard)) :mod (i3 / interval :mod (c2 / confidence) :mod (p4 / percentage-entity :value "95") :value (v / value-interval :op1 "1.0" :op2 "22")) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.048"))) :ARG1-of (d3 / describe-01 :ARG0 (t2 / table :mod "3")) :mod (a2 / also)) # ::id pmid_2247_5322.1 # ::date 2015-08-20T00:52:53 # ::file pmid_2247_5322_1.txt # ::snt Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines (PMID:22475322) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (c / compare-01 :ARG1 (u / utilize-01 :ARG1 (p / pathway :mod (g / growth-factor) :ARG0-of (s2 / signal-07)) :location (a / and :op1 (c2 / cell-line :source (m2 / melanocyte) :ARG1-of (n3 / normal-02)) :op2 (c3 / cell-line :source (m / medical-condition :name (n / name :op1 "melanoma"))) :ARG1-of (c4 / culture-01))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID22475322"))) # ::id pmid_2247_5322.7 # ::date 2015-08-20T02:41:30 # ::file pmid_2247_5322_7.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2247_5322.8 # ::date 2015-08-23T09:36:18 # ::file pmid_2247_5322_8.txt # ::snt Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum, but could be distinguished upon serum starvation, where signalling protein phosphorylation was generally abrogated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / contrast-01 :ARG1 (p2 / possible-01 :polarity "-" :ARG1 (d / distinguish-01 :ARG1 (m / melanocyte :ARG1-of (n / normal-02)) :ARG2 (c2 / cell :source (m2 / medical-condition :name (n2 / name :op1 "melanoma"))) :instrument (u / utilize-01 :ARG1 (p / pathway)) :time (g / grow-01 :ARG1 m :manner (p3 / present-02 :ARG1 (s / serum))))) :ARG2 (p4 / possible-01 :ARG1 (d2 / distinguish-01 :ARG1 m :ARG1-of (c3 / cause-01 :ARG0 (s2 / starve-01 :ARG1 m :ARG2 s)) :time (a / abrogate-01 :ARG1 (p5 / phosphorylate-01 :ARG1 (p6 / protein :ARG0-of (s3 / signal-07))) :ARG1-of (g2 / general-02))))) # ::id pmid_2247_5322.9 # ::date 2015-08-20T08:07:35 # ::file pmid_2247_5322_9.txt # ::snt Surprisingly, the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 1, 2016 (a / associate-01 :polarity "-" :ARG1 (u / utilize-01 :ARG1 (p / pathway :mod (i / individual)) :ARG1-of (d / differentiate-01)) :ARG2 (p2 / present-02 :ARG1 (o / or :op1 (m / mutate-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of (s3 / suppress-01 :ARG1 "g")) :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :op2 (m2 / mutate-01 :ARG1 (m4 / molecular-physical-entity :ARG0-of (s2 / suppress-01 :ARG1 (g / gene)) :mod (t / tumor))) :location p)) :ARG1-of (s / surprise-01) :manner (c / consistent-02)) # ::id pmid_2247_5322.68 # ::date 2015-08-20T02:45:56 # ::file pmid_2247_5322_68.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2247_5322.69 # ::date 2015-08-20T02:46:30 # ::file pmid_2247_5322_69.txt # ::snt NZM cell line mutations in the PI3K and MAPK pathways # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 20, 2015 (m / mutate-01 :ARG1 (c / cell-line :name (n4 / name :op1 "NZM")) :location (a / and :op1 (p2 / pathway :name (n2 / name :op1 "PI3K")) :op2 (p3 / pathway :name (n3 / name :op1 "MAPK")))) # ::id pmid_2247_5322.70 # ::date 2015-08-23T09:43:06 # ::file pmid_2247_5322_70.txt # ::snt In order to determine whether the presence of activating mutations in the PI3K and MAPK signalling pathways correlated with increased utilisation of downstream signalling pathways, we first determined the mutational status of PIK3CA, PTEN, NRAS and BRAF genes in the NZM cell line collection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (d / determine-01 :ARG0 (w / we) :ARG1 (a4 / and :op1 (s / status :topic (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "PIK3CA") :xref (x3 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :op2 (s4 / status :topic (m3 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "PTEN") :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")))) :op3 (s5 / status :topic (m4 / mutate-01 :ARG1 (g3 / gene :name (n4 / name :op1 "NRAS") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))) :op4 (s6 / status :topic (m5 / mutate-01 :ARG1 (g4 / gene :name (n5 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :location (c / collect-01 :ARG1 (c2 / cell-line :name (n / name :op1 "NZM")))) :time (f / first) :purpose (d2 / determine-01 :ARG0 w :ARG1 (c3 / correlate-01 :mode "interrogative" :ARG1 (p / present-02 :ARG1 (m2 / mutate-01 :ARG0-of (a2 / activate-01)) :ARG2 (a3 / and :op1 (p2 / pathway :name (n6 / name :op1 "PI3K")) :op2 (p3 / pathway :name (n7 / name :op1 "MAPK")) :ARG0-of (s2 / signal-07))) :ARG2 (u / utilize-01 :ARG1 (p4 / pathway :ARG0-of (s3 / signal-07 :direction (d3 / downstream))) :ARG1-of (i / increase-01))))) # ::id pmid_2247_5322.71 # ::date 2015-08-20T12:03:19 # ::file pmid_2247_5322_71.txt # ::snt Representative DNA sequences for PTEN, PIK3CA, BRAF and NRAS are provided in Figure 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (p2 / provide-01 :ARG0 (f / figure :mod "1") :ARG1 (d2 / dna-sequence :ARG0-of (r / represent-01 :ARG1 (a / and :op1 (g4 / gene :name (n / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :op2 (g / gene :name (n2 / name :op1 "PIK3CA") :xref (x3 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op3 (g2 / gene :name (n3 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op4 (g3 / gene :name (n4 / name :op1 "NRAS") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))))) # ::id pmid_2247_5322.72 # ::date 2015-08-20T06:23:41 # ::file pmid_2247_5322_72.txt # ::snt As shown in Table 1, we selected cell lines that were characterised by a number of genetic mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / select-01 :ARG0 (w / we) :ARG1 (c / cell-line :ARG1-of (c2 / characterize-01 :ARG2 (m / mutate-01 :ARG1 (g / gene) :quant (n / number)))) :ARG1-of (s2 / show-01 :ARG0 (t / table :mod "1"))) # ::id pmid_2247_5322.73 # ::date 2015-08-20T06:27:04 # ::file pmid_2247_5322_73.txt # ::snt All of the selected cell lines harboured either oncogenic V600E or V600K BRAF or Q61H NRAS mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / harbor-01 :ARG0 (c / cell-line :mod (a / all) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :ARG1-of (s / select-01)))) :ARG1 (o / or :op1 (g2 / gene :name (n2 / name :op1 "BRAF") :ARG1-of (m / mutate-01 :value "V600E") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g / gene :name (n / name :op1 "BRAF") :ARG1-of (m3 / mutate-01 :value "V600K") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op3 (g3 / gene :name (n3 / name :op1 "NRAS") :ARG1-of (m2 / mutate-01 :value "Q61H") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))) # ::id pmid_2247_5322.74 # ::date 2015-08-23T08:49:31 # ::file pmid_2247_5322_74.txt # ::snt Since the tumour suppressor gene PTEN can be functionally lost during melanoma development through both mutation and epigenetic mechanisms [32], we measured PTEN protein expression in the NZM cell lines (Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / cause-01 :ARG0 (p2 / possible-01 :ARG1 (l / lose-02 :ARG1 (g / gene :name (n3 / name :op1 "PTEN") :ARG0-of (s / suppress-01 :ARG1 (t / tumor)) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG1-of (f2 / function-01) :time (d2 / develop-01 :ARG2 (m2 / medical-condition :name (n4 / name :op1 "melanoma")) :manner (a / and :op1 (m3 / mutate-01) :op2 (m4 / mechanism :mod (e2 / epigenetic))))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG0-of (c3 / cite-01 :ARG1 "32")))) :ARG1 (m / measure-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG1 (p / protein :name (n / name :op1 "PTEN") :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG3 (c2 / cell-line :name (n2 / name :op1 "NZM")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2"))) # ::id pmid_2247_5322.75 # ::date 2015-08-23T03:50:48 # ::file pmid_2247_5322_75.txt # ::snt Mutation of the PTEN gene led to loss of functional PTEN protein expression, as seen in Figure 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (l / lead-03 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :ARG2 (l2 / lose-02 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "PTEN") :ARG0-of (f / function-01) :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")))) :ARG1-of (s / see-01 :location (f2 / figure :mod "2"))) # ::id pmid_2247_5322.76 # ::date 2015-08-23T03:55:24 # ::file pmid_2247_5322_76.txt # ::snt The cell lines NZM40, NZM46 and NZM52, which all harbour the oncogenic H1047R PIK3CA mutation, had concurrent BRAF or NRAS mutations (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-03 :ARG0 (a / and :op1 (c / cell-line :name (n2 / name :op1 "NZM40")) :op2 (c2 / cell-line :name (n3 / name :op1 "NZM46")) :op3 (c3 / cell-line :name (n4 / name :op1 "NZM52")) :ARG0-of (h2 / harbor-01 :ARG1 (m / mutate-01 :value "H1047R" :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG0-of (c5 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")))))) :ARG1 (o / or :op1 (m2 / mutate-01 :ARG1 (g2 / gene :name (n6 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (m3 / mutate-01 :ARG1 (g3 / gene :name (n5 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :ARG1-of (c4 / concurrent-02)) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "1"))) # ::id pmid_2247_5322.77 # ::date 2015-08-23T04:01:13 # ::file pmid_2247_5322_77.txt # ::snt Of particular interest was the high degree of expression of PTEN protein in the NZM46 cell line, compared to other cell lines harbouring the PIK3CA oncogenic mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / interest-01 :ARG2 (d / degree :degree-of (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG3 (c / cell-line :name (n3 / name :op1 "NZM46"))) :ARG1-of (h / high-02) :compared-to (c2 / cell-line :ARG0-of (h2 / harbor-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG0-of (c3 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))) :mod (o2 / other))) :mod (p / particular)) # ::id pmid_2247_5322.78 # ::date 2015-08-23T04:06:06 # ::file pmid_2247_5322_78.txt # ::snt Since the presence of an oncogenic mutation or a loss of tumour suppressor function does not dictate whether the cell uses all of the downstream signalling molecules for pathway activation [33,34], we determined the phosphorylation status of the immediate downstream substrates of the PI3K, mTOR and MAPK pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / cause-01 :ARG0 (d3 / dictate-01 :polarity "-" :ARG0 (o2 / or :op1 (p5 / present-02 :ARG1 (m / mutate-01 :ARG0-of (c4 / cause-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))) :op1 (l / lose-02 :ARG1 (f / function-01 :ARG1 (s3 / suppress-01 :ARG1 (t / tumor))))) :ARG1 (u / use-01 :ARG0 (c2 / cell) :ARG1 (m2 / molecule :ARG0-of (s4 / signal-07 :mod "d2")) :ARG2 (a2 / activate-01 :ARG0 c2 :ARG1 (p6 / pathway))) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG0-of (c3 / cite-01 :ARG1 (a3 / and :op1 "33" :op2 "34"))))) :ARG1 (d / determine-01 :ARG0 (w / we) :ARG1 (s / status :topic (p / phosphorylate-01) :poss (s2 / substrate :direction (d2 / downstream :mod (i / immediate)) :poss (a / and :op1 (p2 / pathway :name (n / name :op1 "PI3K")) :op2 (p3 / pathway :name (n2 / name :op1 "mTOR")) :op3 (p4 / pathway :name (n3 / name :op1 "MAPK"))))))) # ::id pmid_2247_5322.79 # ::date 2015-08-20T13:26:35 # ::file pmid_2247_5322_79.txt # ::snt Western blots for phosphorylated molecules were used as surrogate markers for pathway activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (u / use-01 :ARG1 (i / immunoblot-01 :ARG1 (m / molecule :ARG1-of (p2 / phosphorylate-01))) :ARG2 (a / activate-01 :ARG1 (p / pathway)) :manner (t / thing :ARG1-of (m2 / mark-02) :mod (s / surrogate))) # ::id pmid_2247_5322.80 # ::date 2015-08-20T05:56:46 # ::file pmid_2247_5322_80.txt # ::snt Phosphorylation of PKB in melanoma and melanocytes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "PKB") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003")) :location (a / and :op1 (m / medical-condition :name (n2 / name :op1 "melanoma")) :op2 (m2 / melanocyte))) # ::id pmid_2247_5322.81 # ::date 2015-08-23T08:19:19 # ::file pmid_2247_5322_81.txt # ::snt In order to establish whether PIK3CA, PTEN, NRAS and BRAF mutations resulted in constitutive activation of the downstream signalling pathways, we measured PKB activation by western blotting for phosphorylation at two sites, Ser473 and Thr308. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (m / measure-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "PKB") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003"))) :ARG2 (b / blot :purpose (p / phosphorylate-01 :ARG1 (s / site :quant "2" :ARG1-of (m6 / mean-01 :ARG2 (a3 / and :op1 (a4 / amino-acid :mod "473" :name (n3 / name :op1 "serine") :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a5 / amino-acid :mod "308" :name (n4 / name :op1 "threonine") :xref (x5 / xref :value "PUBCHEM:205" :prob "11.848252")))))) :mod (w2 / western)) :purpose (e / establish-01 :ARG0 w :ARG1 (r / result-01 :mode "interrogative" :ARG1 (a6 / and :op1 (m2 / mutate-01 :ARG1 (g / gene :name (n5 / name :op1 "PIK3CA") :xref (x4 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :op2 (m3 / mutate-01 :ARG1 (g4 / gene :name (n6 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :op3 (m4 / mutate-01 :ARG1 (g2 / gene :name (n7 / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :op4 (m5 / mutate-01 :ARG1 (g3 / gene :name (n8 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (a7 / activate-01 :ARG1 (p2 / pathway :ARG0-of (s2 / signal-07 :direction (d / downstream))) :manner (c / constitutive))))) # ::id pmid_2247_5322.82 # ::date 2015-08-23T04:27:40 # ::file pmid_2247_5322_82.txt # ::snt Equal amounts of protein from NZM cell lines were loaded onto the same gel, but for clarity, western blots were segmented to show results for individual NZM cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (c / contrast-01 :ARG1 (l / load-01 :ARG1 (g / gel :ARG1-of (s3 / same-01)) :ARG2 (a / amount-01 :ARG1 (p / protein :source "c3") :ARG1-of (e / equal-01))) :ARG2 (s / segment-01 :ARG1 (i2 / immunoblot-01) :purpose (c2 / clear-06) :purpose (s2 / show-01 :ARG0 i2 :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (c3 / cell-line :name (n2 / name :op1 "NZM") :mod (i / individual))))))) # ::id pmid_2247_5322.83 # ::date 2015-08-23T04:36:09 # ::file pmid_2247_5322_83.txt # ::snt In melanocytes, phosphorylation of PKB on both Ser473 and Thr308 was strongly serum dependent while most of the NZM cell lines in this study showed serum independent phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (h / have-concession-91 :ARG1 (d2 / depend-01 :ARG0 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod "473" :name (n3 / name :op1 "serine") :part-of (e / enzyme :name (n2 / name :op1 "PKB") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :mod "308" :name (n4 / name :op1 "threonine") :part-of e :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :location (m2 / melanocyte))) :ARG1 "s2" :manner "s3") :ARG2 (s / show-01 :ARG0 (c / cell-line :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :name (n / name :op1 "NZM") :ARG1-of (s4 / study-01 :mod (t / this)))) :quant (m / most)) :ARG1 (p2 / phosphorylate-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (s2 / serum) :ARG1-of (s3 / strong-02))))) # ::id pmid_2247_5322.84 # ::date 2015-08-23T08:18:30 # ::file pmid_2247_5322_84.txt # ::snt PKB was phosphorylated independently of serum at the mTORC2 dependent Ser473 site in most of the cell lines, although NZM46 and NZM3 surprisingly had very low levels of phosphorylation even in the presence of serum (Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (h / have-concession-91 :ARG1 (p / phosphorylate-01 :ARG1 (s3 / site :mod (a2 / amino-acid :mod "473" :name (n4 / name :op1 "serine") :part-of (e / enzyme :name (n3 / name :op1 "PKB") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003")) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :ARG0-of (d3 / depend-01 :ARG1 (m / macro-molecular-complex :name (n5 / name :op1 "mTORC2")))) :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 "s") :location (c3 / cell-line :quant (m2 / most) :ARG1-of (i / include-91 :ARG2 (c4 / cell-line)))) :ARG2 (h2 / have-03 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "NZM46")) :op2 (c2 / cell-line :name (n2 / name :op1 "NZM3"))) :ARG1 (l / level :ARG1-of (l2 / low-04 :degree (v / very)) :degree-of (p2 / phosphorylate-01)) :concession (p3 / present-02 :ARG1 (s / serum)) :ARG0-of (s2 / surprise-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3"))) # ::id pmid_2247_5322.85 # ::date 2015-08-23T09:19:10 # ::file pmid_2247_5322_85.txt # ::snt In contrast, phosphorylation at the PIP3-PDK1 dependent Thr308 site tended to be low in the serum starved state in most cell lines and increased with serum (Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (c / contrast-01 :ARG2 (a / and :op1 (t / tend-02 :ARG1 (p2 / phosphorylate-01 :ARG1 (s / site :mod (a2 / amino-acid :mod "308" :name (n / name :op1 "threonine") :xref (x / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG0-of (d / depend-01 :ARG1 (m / macro-molecular-complex :name (n2 / name :op1 "PIP3-PDK1"))))) :ARG2 (l / low-04 :ARG1 p2 :location (s2 / state :topic (s3 / starve-01 :ARG1 (c2 / cell-line :quant (m2 / most)) :ARG2 (s4 / serum))))) :op2 (i / increase-01 :ARG1 p2 :ARG1-of (c3 / cause-01 :ARG0 s4))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3"))) # ::id pmid_2247_5322.86 # ::date 2015-08-20T14:39:48 # ::file pmid_2247_5322_86.txt # ::snt The notable exceptions were cell lines NZM12, NZM40 and NZM52 which have comparatively high Thr308 phosphorylation in serum starved cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (e / except-01 :ARG1 (a / and :op1 (c / cell-line :name (n2 / name :op1 "NZM12")) :op2 (c2 / cell-line :name (n3 / name :op1 "NZM40")) :op3 (c3 / cell-line :name (n4 / name :op1 "NZM52")) :ARG0-of (h / have-03 :ARG1 (p3 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "308" :name (n5 / name :op1 "threonine") :ARG1-of (h2 / high-02 :ARG1-of (c4 / comparable-03)) :xref (x / xref :value "PUBCHEM:205" :prob "11.848252")) :location (c5 / cell :ARG1-of (s / starve-01 :ARG2 (s2 / serum)))))) :ARG1-of (n / notable-04 :ARG1-of (p2 / possible-01))) # ::id pmid_2247_5322.87 # ::date 2015-08-23T02:41:47 # ::file pmid_2247_5322_87.txt # ::snt Phosphorylation of Thr308 in the NZM40 and NZM52 cell lines may be explained by the activating PIK3CA mutation in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (p2 / possible-01 :ARG1 (e / explain-01 :ARG0 (a / activate-01 :ARG1 (m / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :location "a3") :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "308" :name (n3 / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :location (a3 / and :op1 (c / cell-line :name (n / name :op1 "NZM40")) :op2 (c2 / cell-line :name (n4 / name :op1 "NZM52")))))) # ::id pmid_2247_5322.88 # ::date 2015-08-21T15:47:48 # ::file pmid_2247_5322_88.txt # ::snt These two cell lines also have a very low level of total PKB suggesting some feedback regulation of PKB gene expression in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (h / have-03 :ARG0 (c / cell-line :quant "2" :mod (t / this)) :ARG1 (l / level :ARG1-of (l2 / low-04 :degree (v / very)) :quant-of (e / enzyme :name (n / name :op1 "PKB") :ARG2-of (t2 / total-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003"))) :mod (a / also) :ARG0-of (s / suggest-01 :ARG1 (r / regulate-01 :ARG0 (f / feedback :quant (s2 / some)) :ARG1 (e2 / express-03 :ARG1 (g / gene :name (n2 / name :op1 "PKB") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003")) :ARG3 c)))) # ::id pmid_2247_5322.89 # ::date 2015-08-21T15:57:32 # ::file pmid_2247_5322_89.txt # ::snt In support of this, NZM46, which also has a PIK3CA mutation (Figure 3), also has very high PTEN levels (Figure 2) which could explain the low Thr308 phosphorylation in these cells and the higher levels of total PKB compared to NZM40 and NZM52, as PIP3 levels would be predicted to be low despite the PIK3CA mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / support-01 :ARG0 (h / have-03 :ARG0 (c5 / cell-line :name (n7 / name :op1 "NZM46") :ARG0-of (h5 / have-03 :ARG1 (m3 / mutate-01 :ARG1 "g" :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3"))) :mod "a4")) :ARG1 (l5 / level :ARG1-of (h4 / high-02 :degree (v / very) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2"))) :quant-of (p5 / protein :name (n8 / name :op1 "PTEN") :xref (x3 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :ARG0-of (e / explain-01 :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "308" :name (n / name :op1 "threonine") :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :location c5) :op2 (l2 / level :ARG1-of (h2 / high-02 :degree (m / more) :compared-to (a3 / and :op1 (c2 / cell-line :name (n3 / name :op1 "NZM40")) :op2 (c3 / cell-line :name (n4 / name :op1 "NZM52")))) :quant-of (e2 / enzyme :name (n2 / name :op1 "PKB") :ARG1-of (t2 / total-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003")))) :ARG1-of (p / possible-01) :ARG1-of (c4 / cause-01 :ARG0 (p3 / predict-01 :ARG1 (l3 / low-04 :ARG1 (l4 / level :quant-of (p4 / protein :name (n5 / name :op1 "PIP3") :xref (x2 / xref :value "UNIPROT:G3V132_HUMAN" :prob "0.291"))) :concession (m2 / mutate-01 :ARG1 (g / gene :name (n6 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))))) :ARG1-of (l / low-04)) :mod (a4 / also)) :ARG1 (t / this)) # ::id pmid_2247_5322.90 # ::date 2015-08-23T08:57:57 # ::file pmid_2247_5322_90.txt # ::snt NZM46 shows suppression of phosphorylation by serum in the Thr308 site (as with the Ser473 site). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (s / show-01 :ARG0 (c / cell-line :name (n2 / name :op1 "NZM46")) :ARG1 (s2 / suppress-01 :ARG1 (p2 / phosphorylate-01 :ARG0 (s3 / serum) :ARG1 (s4 / site :mod (a / amino-acid :mod "308" :name (n / name :op1 "threonine") :xref (x / xref :value "PUBCHEM:205" :prob "11.848252"))))) :ARG1-of (m / mean-01 :ARG2 (s5 / site :mod (a2 / amino-acid :mod "473" :name (n3 / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))))) # ::id pmid_2247_5322.91 # ::date 2015-08-23T03:02:23 # ::file pmid_2247_5322_91.txt # ::snt Phosphorylation of components of the mTOR pathway in melanoma cells and melanocytes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p2 / phosphorylate-01 :ARG1 (c / component :poss (p / pathway :name (n / name :op1 "mTOR"))) :location (a / and :op1 (c2 / cell :source (m2 / medical-condition :name (n2 / name :op1 "melanoma"))) :op1 (m / melanocyte))) # ::id pmid_2247_5322.92 # ::date 2015-08-23T03:08:49 # ::file pmid_2247_5322_92.txt # ::snt Activation of components of the protein translation machinery has been observed in a large percentage of melanomas and is predictive of a poor prognosis [35]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (a2 / and :op1 (o2 / observe-01 :ARG1 (a / activate-01 :ARG1 (c2 / component :poss (m / machinery :ARG0-of (t / translate-02 :ARG2 (p2 / protein))))) :location (p3 / percentage :mod (l / large) :quant-of (m2 / medical-condition :name (n / name :op1 "melanoma")))) :op2 (p4 / predict-01 :ARG0 a :ARG1 (p5 / prognosis :mod (p6 / poor))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG0-of (c / cite-01 :ARG1 "35")))) # ::id pmid_2247_5322.93 # ::date 2015-08-23T03:19:49 # ::file pmid_2247_5322_93.txt # ::snt The PI3K signalling pathway can regulate protein translation machinery through mTORC1 and subsequent activation of p70S6K and phosphorylation of ribosomal protein S6 (rpS6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p2 / possible-01 :ARG1 (r / regulate-01 :ARG0 (p6 / pathway :name (n5 / name :op1 "PI3K") :ARG0-of (s / signal-07)) :ARG1 (m / machinery :ARG0-of (t / translate-02 :ARG2 (p3 / protein))) :instrument (a / and :op1 (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC1")) :op2 (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "p70S6K") :xref (x1 / xref :value "UNIPROT:KS6B1_HUMAN" :prob "0.333")) :time (s2 / subsequent)) :op3 (p / phosphorylate-01 :ARG1 (p5 / protein :name (n4 / name :op1 "ribosomal" :op2 "protein" :op3 "S6") :xref (x / xref :value "UNIPROT:A0A024RCW3_HUMAN" :prob "0.391")))))) # ::id pmid_2247_5322.94 # ::date 2015-08-20T13:05:14 # ::file pmid_2247_5322_94.txt # ::snt Therefore we next determined the phosphorylation status of p70S6K (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (c / cause-01 :ARG1 (d2 / determine-01 :ARG0 (w / we) :ARG1 (s2 / status :mod (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "p70S6K") :xref (x / xref :value "UNIPROT:KS6B1_HUMAN" :prob "0.333")))) :time (n2 / next)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4"))) # ::id pmid_2247_5322.95 # ::date 2015-08-23T09:01:44 # ::file pmid_2247_5322_95.txt # ::snt The p70S6K was strongly expressed in all cell lines as well as in normal melanocytes but the pattern of phosphorylation of p70S6K and p85S6K at Thr389 did not correlate with the phosphorylation status of PKB nor did it correlate with genotypes (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (c / contrast-01 :ARG1 (a / and :op1 (e / express-03 :ARG1 "e3" :ARG3 (c4 / cell-line :mod (a5 / all)) :manner (s / strong-02)) :op2 (e2 / express-03 :ARG3 (m / melanocyte :ARG1-of (n4 / normal-02)))) :ARG2 (a2 / and :op1 (c2 / correlate-01 :polarity "-" :ARG1 (p / pattern-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a3 / and :op1 (a6 / amino-acid :mod "389" :name (n6 / name :op1 "threonine") :part-of (e3 / enzyme :name (n / name :op1 "p70S6K") :xref (x2 / xref :value "UNIPROT:KS6B1_HUMAN" :prob "0.333")) :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")) :op2 (a4 / amino-acid :mod "389" :name (n3 / name :op1 "threonine") :part-of (e4 / enzyme :name (n2 / name :op1 "p85S6K") :xref (x1 / xref :value "UNIPROT:ARHG7_HUMAN" :prob "0.223")) :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252"))))) :ARG2 (p3 / phosphorylate-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "PKB") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "1.003")))) :op2 (c3 / correlate-01 :polarity "-" :ARG1 p :ARG2 (g / genotype))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "f4"))) # ::id pmid_2247_5322.96 # ::date 2015-08-23T08:37:06 # ::file pmid_2247_5322_96.txt # ::snt In melanocytes, the observed phosphorylation of Ser235/236 was serum dependent while Ser240/244 site, which is phosphorylated by p70S6K, was phosphorylated even in the absence of serum. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (c / contrast-01 :ARG1 (d / depend-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (s3 / slash :op1 (a2 / amino-acid :mod "235" :name (n / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :mod "236" :name (n4 / name :op1 "serine") :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG1-of (o / observe-01 :location (m / melanocyte))) :ARG1 (s2 / serum)) :ARG2 (h / have-concession-91 :ARG1 (p / phosphorylate-01 :ARG1 (s / site :ARG1-of (p5 / phosphorylate-01 :ARG2 (e / enzyme :name (n3 / name :op1 "p70S6K") :xref (x / xref :value "UNIPROT:KS6B1_HUMAN" :prob "0.333"))) :mod (s4 / slash :op1 (a4 / amino-acid :mod "240" :name (n2 / name :op1 "serine") :xref (x4 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a5 / amino-acid :mod "244" :name (n5 / name :op1 "serine") :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))))) :ARG2 (a / absent-01 :ARG1 s2))) # ::id pmid_2247_5322.97 # ::date 2015-08-23T07:20:02 # ::file pmid_2247_5322_97.txt # ::snt In most of the cell lines, we observed serum independent phosphorylation of rpS6 while in NZM43 and to some degree, NZM10 and NZM15 showed serum dependent phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (c6 / contrast-01 :ARG1 (o / observe-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "rpS6") :xref (x / xref :value "UNIPROT:RS6_HUMAN" :prob "0.652")) :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 "s2")) :location (c3 / cell-line :ARG1-of (i / include-91 :ARG2 (c4 / cell-line :quant (m / most))))) :ARG2 (s / show-01 :ARG1 (p2 / phosphorylate-01 :ARG0-of (d / depend-01 :ARG1 (s2 / serum))) :location (a2 / and :op1 (c5 / cell-line :name (n4 / name :op1 "NZM43")) :op2 (a3 / and :op1 (c / cell-line :name (n / name :op1 "NZM10")) :op2 (c2 / cell-line :name (n2 / name :op1 "NZM15")) :degree (s3 / some))))) # ::id pmid_2247_5322.98 # ::date 2015-08-23T04:07:01 # ::file pmid_2247_5322_98.txt # ::snt Interestingly, we observed little phosphorylation of rpS6 at both sites in BRAF mutant cell lines, NZM3 and NZM12 (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "rpS6") :xref (x / xref :value "UNIPROT:RS6_HUMAN" :prob "0.652")) :degree (l / little) :location (s / site :location (a / and :op1 (c / cell-line :name (n3 / name :op1 "NZM3")) :op2 (c2 / cell-line :name (n4 / name :op1 "NZM12")) :mod (m / mutate-01 :ARG3 (g / gene :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :mod (b / both))) :ARG2-of (i / interest-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5"))) # ::id pmid_2247_5322.99 # ::date 2015-08-23T03:34:32 # ::file pmid_2247_5322_99.txt # ::snt Thus, phosphorylation of rpS6 is independent of PI3K pathway activation in these melanoma cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c2 / cause-01 :ARG1 (d2 / depend-01 :polarity "-" :ARG0 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "rpS6") :xref (x / xref :value "UNIPROT:RS6_HUMAN" :prob "0.652"))) :ARG1 (a / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3K")) :location (c / cell-line :mod (t / this) :source (m / medical-condition :name (n3 / name :op1 "melanoma")))))) # ::id pmid_2247_5322.100 # ::date 2015-08-22T08:20:42 # ::file pmid_2247_5322_100.txt # ::snt In these cells the phosphorylation of rpS6 is likely due to input from the ERK signalling cascade as can be seen in other cell types [36]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (l / likely-01 :ARG1 (c / cause-01 :ARG0 (i / input :source (p5 / pathway :name (n / name :op1 "ERK") :ARG0-of (s / signal-07))) :ARG1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "rpS6") :xref (x / xref :value "UNIPROT:RS6_HUMAN" :prob "0.652")) :ARG3 (c2 / cell :mod (t / this)))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG0-of (c5 / cite-01 :ARG1 "36"))) :ARG1-of (s3 / see-01 :ARG1-of (p2 / possible-01) :location (t2 / type-03 :ARG2 (c4 / cell) :mod (o / other)))) # ::id pmid_2247_5322.101 # ::date 2015-08-22T01:43:07 # ::file pmid_2247_5322_101.txt # ::snt Phosphorylation of components of the ERK pathway in melanoma cells and melanocytes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p / phosphorylate-01 :ARG1 (c / component :part-of (p2 / pathway :name (n / name :op1 "ERK"))) :location (a / and :op1 (c2 / cell :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma"))) :op2 (m / melanocyte))) # ::id pmid_2247_5322.102 # ::date 2015-08-22T02:35:13 # ::file pmid_2247_5322_102.txt # ::snt We also analysed the activation status of the MAPK pathway in NZM cell lines with NRAS or BRAF mutations and cell lines which additionally harbour PTEN or PIK3CA mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (s / status :mod (a3 / activate-01 :ARG0 (a4 / and :op1 (o / or :op1 (m / mutate-01 :ARG1 (g2 / gene :name (n6 / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :op2 (m2 / mutate-01 :ARG1 (g3 / gene :name (n5 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (c2 / cell-line :ARG0-of (h / harbor-01 :ARG1 (o2 / or :op1 (m4 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PTEN") :xref (x3 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :op2 (m3 / mutate-01 :ARG1 (g4 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :manner (a5 / additional)))) :ARG1 (p2 / pathway :name (n3 / name :op1 "MAPK") :location (c / cell-line :name (n4 / name :op1 "NZM"))))) :mod (a2 / also)) # ::id pmid_2247_5322.103 # ::date 2015-08-22T04:01:56 # ::file pmid_2247_5322_103.txt # ::snt The activation of MEK and then ERK in response to oncogenic NRAS and BRAF mutations is proposed to be the basis of a MAPK pathway addiction by these cells [37]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p4 / propose-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op2 (a3 / activate-01 :time (t / then) :mod (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2-of (r / respond-01 :ARG1 (a4 / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n4 / name :op1 "NRAS") :xref (x3 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG0-of (c3 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))))) :ARG2 (b / base-02 :ARG0 (a5 / addictive-02 :ARG0 (c / cell :mod (t2 / this)) :ARG1 (p3 / pathway :name (n3 / name :op1 "MAPK"))) :ARG1 a2) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG0-of (c2 / cite-01 :ARG1 "37")))) # ::id pmid_2247_5322.104 # ::date 2015-08-20T12:14:42 # ::file pmid_2247_5322_104.txt # ::snt Total MEK protein was abundantly expressed in all NZM cell lines as well as melanocytes (Figure 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK") :mod (t / total) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG3 (a3 / and :op1 (c / cell-line :name (n2 / name :op1 "NZM") :mod (a2 / all)) :op2 (m / melanocyte)) :ARG1-of (a / abound-01) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6"))) # ::id pmid_2247_5322.105 # ::date 2015-08-20T12:25:21 # ::file pmid_2247_5322_105.txt # ::snt However levels of MEK phosphorylation varied considerably and were not directly related to genotype (Figure 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (h / have-concession-91 :ARG1 (a2 / and :op1 (v / vary-01 :ARG1 (l / level :degree-of (p / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG2 (c3 / considerable)) :op2 (r / relate-01 :polarity "-" :ARG1 l :ARG2 (g / genotype) :ARG1-of (d2 / direct-02))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6"))) # ::id pmid_2247_5322.106 # ::date 2015-08-20T12:31:58 # ::file pmid_2247_5322_106.txt # ::snt Furthermore, NRAS-only mutant NZM cell lines, NZM10, NZM15 and NZM42 showed very low levels of MEK phosphorylation (Figure 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (a2 / and :op1 (s2 / show-01 :ARG0 (c / cell-line :name (n / name :op1 "NZM") :mod (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "NRAS") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (c2 / cell-line :name (n3 / name :op1 "NZM10")) :op2 (c3 / cell-line :name (n4 / name :op1 "NZM15")) :op3 (c4 / cell-line :name (n5 / name :op1 "NZM42")))) :mod (o / only)) :ARG1 (l / level :ARG1-of (l2 / low-04 :degree (v / very)) :degree-of (p / phosphorylate-01 :ARG1 (e / enzyme :name (n6 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6"))) # ::id pmid_2247_5322.107 # ::date 2015-08-23T04:13:43 # ::file pmid_2247_5322_107.txt # ::snt ERK was constitutively phosphorylated in almost all cell lines, and unlike melanocytes, NZM cell lines showed serum independent MEK and ERK phosphorylation patterns (Figures 6 and 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (p4 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :manner (c / constitutive) :location (c2 / cell-line :mod (a2 / all :degree (a3 / almost)))) :op2 (s / show-01 :ARG0 (c3 / cell-line :name (n3 / name :op1 "NZM")) :ARG1 (a4 / and :op1 (p5 / pattern-01 :ARG1 (p7 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :op2 (p6 / pattern-01 :ARG1 (p8 / phosphorylate-01 :ARG1 e)) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (s2 / serum))) :ARG1-of (r2 / resemble-01 :polarity "-" :ARG2 (m / melanocyte))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "6") :op2 (f2 / figure :mod "7")))) # ::id pmid_2247_5322.108 # ::date 2015-08-20T05:05:24 # ::file pmid_2247_5322_108.txt # ::snt Furthermore, MEK phosphorylation status did not correlate with ERK phosphorylation patterns. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op2 (c / correlate-01 :polarity "-" :ARG1 (s / status :mod (p4 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG2 (p5 / pattern-01 :ARG1 (p6 / phosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))) # ::id pmid_2282_9094.1 # ::date 2015-07-23T09:21:35 # ::file pmid_2282_9094_1.txt # ::snt The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma (PMID:22829094) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (r / regulate-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :ARG0-of (i2 / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "JAK") :xref (x / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))) :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (a / and :op1 (p / proliferate-01) :op2 (i3 / immunity)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID22829094")) :location (d2 / disease :name (n4 / name :op1 "Hodgkin" :op2 "lymphoma"))) # ::id pmid_2282_9094.72 # ::date 2015-07-23T09:26:53 # ::file pmid_2282_9094_72.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 23, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2282_9094.73 # ::date 2015-07-23T09:28:28 # ::file pmid_2282_9094_73.txt # ::snt Expression of activated JAK2 in cultured HL cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "JAK2") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :ARG3 (c / cell :ARG1-of (c2 / culture-01) :mod (d / disease :name (n2 / name :op1 "HL")))) # ::id pmid_2282_9094.74 # ::date 2015-07-23T10:10:53 # ::file pmid_2282_9094_74.txt # ::snt To explore the potential therapeutic value of the JAK2 inhibitor AZD1480 in HL, we initially examined the expression pattern of its protein target, the active, phosphorylated form of JAK2 Y1007/1008, in cultured HL cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (p / pattern-01 :ARG1 (e2 / express-03 :ARG2 (t2 / target-01 :ARG0 "s" :ARG1 (a / amino-acid :mod "1007/1008" :name (n2 / name :op1 "tyrosine") :part-of (e3 / enzyme :name (n / name :op1 "JAK2") :mod (f / form) :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :ARG3-of (p3 / phosphorylate-01) :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG3 (c / cell :ARG1-of (c2 / culture-01) :mod (d / disease :name (n4 / name :op1 "HL"))))) :time (i2 / initial) :purpose (e4 / explore-01 :ARG0 w :ARG1 c :ARG2 (v / value-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "AZD1480") :ARG0-of (i / inhibit-01 :ARG1 e3) :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :mod (t3 / therapy) :mod (p4 / potential)))) # ::id pmid_2282_9094.75 # ::date 2015-07-23T12:05:11 # ::file pmid_2282_9094_75.txt # ::snt We hypothesized that cells with high levels of p-JAK2 would be more sensitive to the antiproliferative effect of AZD1480 than cells with lower levels of p-JAK2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (s / sensitive-03 :ARG0 (c / cell :ARG0-of (h2 / have-03 :ARG1 (l2 / level :quant-of (e2 / enzyme :name (n / name :op1 "JAK2") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :ARG1-of (h3 / high-02)))) :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG0-of (c2 / counter-01 :ARG1 (p2 / proliferate-01))) :degree (m2 / more) :compared-to (c3 / cell :ARG0-of (h4 / have-03 :ARG1 (l3 / level :quant-of e2 :ARG1-of (l / low-04 :degree (m / more))))))) # ::id pmid_2282_9094.76 # ::date 2015-07-23T12:13:13 # ::file pmid_2282_9094_76.txt # ::snt We found p-JAK2 to be expressed in two of the four HL cell lines (Figure 1a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "JAK2") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :ARG3 (c / cell-line :quant "2" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "4" :mod (d2 / disease :name (n2 / name :op1 "HL")))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1a"))) # ::id pmid_2282_9094.77 # ::date 2015-07-23T12:18:55 # ::file pmid_2282_9094_77.txt # ::snt None of the HL cell lines expressed p-JAK1 Y1022/1023, two cell lines expressed p-TYK2 Y1054/1055, and only one cell line (L-540) expressed p-JAK3 Y980 (Figure 1a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (a / and :op1 (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "JAK1") :ARG3-of (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "1022/1023" :name (n3 / name :op1 "tyrosine") :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :xref (x2 / xref :value "UNIPROT:JAK1_HUMAN" :prob "1.004")) :ARG3 (c / cell-line :quant (n / none) :mod (d2 / disease :name (n9 / name :op1 "HL")))) :op2 (e3 / express-03 :ARG2 (e4 / enzyme :name (n4 / name :op1 "TYK2") :ARG3-of (p2 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "1054/1055" :name (n5 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :xref (x / xref :value "UNIPROT:TYK2_HUMAN" :prob "1.003")) :ARG3 (c2 / cell-line :quant "2")) :op3 (e5 / express-03 :ARG2 (e6 / enzyme :name (n7 / name :op1 "JAK3") :ARG3-of (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod "980" :name (n8 / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :xref (x1 / xref :value "UNIPROT:JAK3_HUMAN" :prob "1.004")) :ARG3 (c3 / cell-line :quant "1" :mod (o / only) :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :name (n6 / name :op1 "L-540"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1a"))) # ::id pmid_2282_9094.78 # ::date 2015-07-23T12:39:42 # ::file pmid_2282_9094_78.txt # ::snt Thus, the activation pattern of the JAK family members is rather heterogeneous in the HL cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (h / heterogeneity :domain (p / pattern-01 :ARG1 (a / activate-01 :ARG1 (m / member :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n / name :op1 "JAK"))))) :location (c2 / cell-line :mod (d / disease :name (n2 / name :op1 "HL")))))) # ::id pmid_2282_9094.79 # ::date 2015-07-23T12:44:38 # ::file pmid_2282_9094_79.txt # ::snt Next, we investigated the expression pattern of the active phosphorylated form of downstream (p-STATs). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (i / investigate-01 :ARG0 (w / we) :ARG1 (p / pattern-01 :ARG1 (e / express-03 :ARG2 (d / downstream :mod (f / form) :ARG3-of (p2 / phosphorylate-01) :ARG1-of (a / activate-01) :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n2 / name :op1 "STAT") :ARG3-of p2 :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")))))) :time (n / next)) # ::id pmid_2282_9094.80 # ::date 2015-07-23T13:05:30 # ::file pmid_2282_9094_80.txt # ::snt We found p-STAT3, p-STAT5 and p-STAT6 to be expressed in the three cell lines that expressed at least one active phosphorylated member of the JAK family: HD-LM2, L-428 and L-540 (Figure 1a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (a3 / and :op1 (p / protein :name (n / name :op1 "STAT3") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n2 / name :op1 "STAT5") :ARG3-of p2 :xref (x / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :op3 (p5 / protein :name (n3 / name :op1 "STAT6") :ARG3-of p2 :xref (x1 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))) :ARG3 (c / cell-line :quant "3" :ARG1-of (e2 / express-03 :ARG2 (m / member :ARG1-of (a4 / activate-01) :quant (a / at-least :op1 "1") :ARG1-of (i / include-91 :ARG2 (p4 / protein-family :name (n4 / name :op1 "JAK"))) :ARG3-of p2)) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (c2 / cell-line :name (n5 / name :op1 "HD-LM2")) :op2 (c3 / cell-line :name (n6 / name :op1 "L-428")) :op3 (c4 / cell-line :name (n7 / name :op1 "L-540")))))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "1a"))) # ::id pmid_2282_9094.81 # ::date 2015-07-23T13:14:15 # ::file pmid_2282_9094_81.txt # ::snt Consistent with a previous report, the KM-H2 cell line did not express p-JAKs or p-STAT3, pSTAT5 or pSTAT6 proteins;19 neither did the three samples of PBMCs isolated from healthy donors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (a / and :op1 (e / express-03 :polarity "-" :ARG2 (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "JAK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")) :op2 (p3 / protein :name (n3 / name :op1 "STAT3") :ARG3-of p2 :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op3 (p5 / protein :name (n4 / name :op1 "STAT5") :ARG3-of p2 :xref (x3 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :op4 (p7 / protein :name (n5 / name :op1 "STAT6") :ARG3-of p2 :xref (x2 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))) :ARG3 (c / cell-line :name (n / name :op1 "KM-H2")) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "19")))) :op2 (e3 / express-03 :polarity "-" :ARG3 (c2 / cell :quant "3" :name (n6 / name :op1 "PBMC") :ARG1-of (s / sample-01) :ARG1-of (i / isolate-01 :ARG2 (p / person :ARG0-of (d / donate-01) :mod (h / healthy))))) :ARG1-of (c3 / consistent-01 :ARG2 (r / report-01 :time (p10 / previous)))) # ::id pmid_2282_9094.82 # ::date 2015-07-23T13:35:48 # ::file pmid_2282_9094_82.txt # ::snt We found p-STAT1 to be expressed in all HL cell lines and in only one PBMC sample from a healthy donor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "STAT1") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004")) :ARG3 (a / and :op1 (c / cell-line :mod (a2 / all) :mod (d2 / disease :name (n3 / name :op1 "Hodgkin's" :op2 "lymphoma"))) :op2 (s / sample-01 :quant "1" :ARG1 (c2 / cell :name (n2 / name :op1 "PBMC")) :ARG2 (p / person :ARG0-of (d / donate-01) :mod (h2 / healthy)) :mod (o / only))))) # ::id pmid_2282_9094.83 # ::date 2015-07-23T13:41:59 # ::file pmid_2282_9094_83.txt # ::snt AZD1480 inhibits STAT3, STAT5 and STAT6 phosphorylation in HL cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x3 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "STAT3") :xref (x1 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :op2 (p4 / phosphorylate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "STAT5") :xref (x2 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003"))) :op3 (p6 / phosphorylate-01 :ARG1 (p7 / protein :name (n4 / name :op1 "STAT6") :xref (x / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")))) :location (c / cell :mod (d / disease :name (n5 / name :op1 "Hodgkin's" :op2 "lymphoma")))) # ::id pmid_2282_9094.84 # ::date 2015-07-23T14:15:16 # ::file pmid_2282_9094_84.txt # ::snt The differential expression of JAK/STAT family members in HL cell lines gave us an opportunity to determine the biological effect of AZD1480 in cells that have thee different patterns of expression: HD-LM2 and L-428 (which expressed p-JAK2 and p-TYK2), L-540 (which expressed p-JAK3), and KM-H2 (which lacked p-JAKs expression). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (g / give-01 :ARG0 (e / express-03 :ARG2 (m / member :ARG1-of (i / include-91 :ARG2 (s / slash :op1 (p4 / protein-family :name (n2 / name :op1 "JAK")) :op2 (p / protein-family :name (n3 / name :op1 "STAT"))))) :ARG3 (c2 / cell-line :mod (d3 / disease :name (n / name :op1 "HL"))) :ARG1-of (d / differ-02)) :ARG1 (o / opportunity :purpose (d2 / determine-01 :ARG0 "w" :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "AZD1480") :xref (x4 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :mod (b / biology) :location (c3 / cell :ARG0-of (h2 / have-03 :ARG1 (p2 / pattern-01 :quant "3" :ARG1 (e3 / express-03) :ARG1-of d)) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (a3 / and :op1 (c4 / cell-line :name (n5 / name :op1 "HD-LM2")) :op2 (c5 / cell-line :name (n6 / name :op1 "L-428")) :ARG3-of (e4 / express-03 :ARG2 (a4 / and :op1 (e5 / enzyme :name (n7 / name :op1 "JAK2") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :op2 (e6 / enzyme :name (n8 / name :op1 "TYK2") :ARG3-of p3 :xref (x2 / xref :value "UNIPROT:TYK2_HUMAN" :prob "1.003"))))) :op2 (c6 / cell-line :name (n9 / name :op1 "L-540") :ARG3-of (e7 / express-03 :ARG2 (e8 / enzyme :name (n10 / name :op1 "JAK3") :ARG3-of p3 :xref (x1 / xref :value "UNIPROT:JAK3_HUMAN" :prob "1.004")))) :op3 (c7 / cell-line :name (n11 / name :op1 "KM-H2") :ARG0-of (l / lack-01 :ARG1 (e9 / express-03 :ARG2 (e10 / enzyme :name (n12 / name :op1 "JAK") :ARG3-of p3 :xref (x3 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))))))))))) :ARG2 (w / we)) # ::id pmid_2282_9094.85 # ::date 2015-07-25T01:42:52 # ::file pmid_2282_9094_85.txt # ::snt Increasing concentrations of AZD1480 (0.1–5 μ) inhibited STAT1, STAT3, STAT5 and STAT6 phosphorylation in all three cell lines that showed evidence of full JAK/STAT activation: HD-LM2, L-428 and L-540 (Figure 1b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / inhibit-01 :ARG0 (c / concentrate-02 :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x6 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (i2 / increase-01 :ARG2 (v / value-interval :op1 (c2 / concentration-quantity :quant "0.1" :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant "5" :unit m)))) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "STAT1") :xref (x1 / xref :value "UNIPROT:STAT1_HUMAN" :prob "1.004"))) :op2 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "STAT3") :xref (x3 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :op3 (p5 / phosphorylate-01 :ARG1 (p6 / protein :name (n4 / name :op1 "STAT5") :xref (x2 / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003"))) :op4 (p7 / phosphorylate-01 :ARG1 (p8 / protein :name (n5 / name :op1 "STAT6") :xref (x4 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004")))) :location (c4 / cell-line :quant "3" :ARG0-of (s2 / show-01 :ARG1 (e / evidence-01 :ARG1 (a2 / activate-01 :ARG1 (a3 / and :op1 (e2 / enzyme :name (n6 / name :op1 "JAK") :xref (x / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")) :op2 (p9 / protein :name (n7 / name :op1 "STAT") :xref (x5 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))) :degree (f2 / full)))) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 (c5 / cell-line :name (n8 / name :op1 "LM2")) :op2 (c6 / cell-line :name (n9 / name :op1 "L-428")) :op3 (c7 / cell-line :name (n10 / name :op1 "L-540")))) :mod (a5 / all)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1b"))) # ::id pmid_2282_9094.86 # ::date 2015-07-25T01:59:02 # ::file pmid_2282_9094_86.txt # ::snt These results suggest that in addition to JAK2, AZD1480 may also inhibit JAK3 activity in HL cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p / possible-01 :ARG1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n2 / name :op1 "JAK3") :ARG1-of (a3 / add-02 :ARG2 (e2 / enzyme :name (n3 / name :op1 "JAK2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004"))) :xref (x / xref :value "UNIPROT:JAK3_HUMAN" :prob "1.004")) :location (c / cell-line :mod (d / disease :name (n4 / name :op1 "HL")))) :mod (a / also)))) # ::id pmid_2282_9094.87 # ::date 2015-07-25T02:17:16 # ::file pmid_2282_9094_87.txt # ::snt Potent inhibition of STAT3 phosphorylation was observed as soon as after 30 min of incubation with AZD1480 and was maintained up to 72 h (Supplementary Figure S1A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (a3 / and :op1 (o / observe-01 :ARG1 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004"))) :mod (p3 / potent)) :time (a / as-soon-as :op1 (a2 / after :op1 (i2 / incubate-01 :ARG1 i :ARG2 (s / small-molecule :name (n2 / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987"))) :quant (t / temporal-quantity :quant "30" :unit (m / minute))))) :op2 (m2 / maintain-01 :ARG1 i :duration (u / up-to :op1 (t2 / temporal-quantity :quant "72" :unit (h / hour)))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "S1A") :op2 (f2 / figure :mod "S1B") :ARG2-of (s2 / supplement-01)))) # ::id pmid_2282_9094.88 # ::date 2015-07-25T02:29:40 # ::file pmid_2282_9094_88.txt # ::snt Antiproliferative effects of AZD1480 in HL cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG2 (c2 / counter-01 :ARG1 (p / proliferate-01)) :location (c / cell-line :mod (d / disease :name (n2 / name :op1 "HL")))) # ::id pmid_2282_9094.89 # ::date 2015-07-25T02:38:42 # ::file pmid_2282_9094_89.txt # ::snt Previous studies have demonstrated that HL cell lines are addicted to the JAK/STAT pathway, and selective inhibition of STAT proteins by RNA interference has been shown to result in antiproliferative effects in HL cell lines.2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (d / demonstrate-01 :ARG0 (t / thing :ARG1-of (s / study-01) :time (p / previous)) :ARG1 (a2 / addict-01 :ARG1 (c / cell-line :mod (d3 / disease :name (n4 / name :op1 "HL"))) :ARG2 (p2 / pathway :name (n / name :op1 "JAK/STAT")))) :op2 (s2 / show-01 :ARG1 (i / inhibit-01 :ARG0 (i3 / interfere-01 :ARG1 (n5 / nucleic-acid :name (n2 / name :op1 "RNA"))) :ARG1 (p3 / protein :name (n3 / name :op1 "STAT") :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")) :manner (s3 / selective) :ARG1-of (r2 / result-01 :ARG2 (a3 / affect-01 :ARG2 (c2 / counter-01 :ARG1 (p4 / proliferate-01)) :location c)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "2")))) # ::id pmid_2282_9094.90 # ::date 2015-07-25T02:49:26 # ::file pmid_2282_9094_90.txt # ::snt Because AZD1480 inhibited p-STAT3, p-STAT5 and p-STAT6, we investigated the antiproliferative effect of AZD1480 in HL cells by using the MTS assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i2 / investigate-01 :ARG0 (w / we) :ARG1 (a2 / affect-01 :ARG0 "s" :ARG2 (c3 / counter-01 :ARG1 (p7 / proliferate-01)) :location (c2 / cell :mod (d / disease :name (n5 / name :op1 "HL")))) :ARG1-of (c / cause-01 :ARG0 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x4 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (a / and :op1 (p / protein :name (n2 / name :op1 "STAT3") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n3 / name :op1 "STAT5") :ARG3-of p2 :xref (x / xref :value "UNIPROT:STA5A_HUMAN" :prob "1.003")) :op3 (p5 / protein :name (n4 / name :op1 "STAT6") :ARG3-of p2 :xref (x1 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))))) :manner (u / use-01 :ARG1 (a3 / assay-01 :instrument (s2 / small-molecule :name (n6 / name :op1 "MTS") :xref (x3 / xref :value "PUBCHEM:65521" :prob "10.885861"))))) # ::id pmid_2282_9094.91 # ::date 2015-07-25T04:11:11 # ::file pmid_2282_9094_91.txt # ::snt AZD1480 induced antiproliferative effects in a time- and dose-dependent manner (Figure 1c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG2 (a / affect-01 :ARG2 (c / counter-01 :ARG1 (p / proliferate-01))) :manner (d / depend-01 :ARG1 (a2 / and :op1 (t / time) :op2 (d2 / dose-01))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1c"))) # ::id pmid_2282_9094.92 # ::date 2015-07-25T04:21:38 # ::file pmid_2282_9094_92.txt # ::snt After 72 h of incubation, the half maximal inhibitory concentration (IC50) values for AZD1480 ranged from 1 to 8 μ; L-540 cells were the most sensitive to AZD1480 (Figure 1c and d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (r / range-01 :ARG1 (c5 / concentration-quantity :ARG4-of (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG2 "50")) :ARG3 (c2 / concentration-quantity :quant "1" :unit (m2 / micromolar)) :ARG4 (c3 / concentration-quantity :quant "8" :unit m2) :time (a2 / after :op1 (i2 / incubate-01) :quant (t / temporal-quantity :quant "72" :unit (h2 / hour)))) :op2 (s / sensitive-03 :ARG0 (c4 / cell-line :name (n2 / name :op1 "L-540")) :ARG1 s2 :degree (m4 / most)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1c") :op2 (f2 / figure :mod "1d")))) # ::id pmid_2282_9094.93 # ::date 2015-07-25T04:41:53 # ::file pmid_2282_9094_93.txt # ::snt Thus, although submicromolar concentrations of AZD1480 inhibited STAT phosphorylation, these low concentrations were not sufficient to induce a significant antiproliferative activity, especially in the HD-LM2 and L-428 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / cause-01 :ARG1 (h / have-concession-91 :ARG1 (s3 / suffice-01 :polarity "-" :ARG0 (c3 / concentrate-02 :ARG1-of (l / low-04) :mod (t / this)) :ARG1 (i2 / induce-01 :ARG0 c3 :ARG2 (a / activity-06 :ARG0-of (c4 / counter-01 :ARG1 (p3 / proliferate-01)) :ARG1-of (s4 / significant-02)) :location (a2 / and :op1 (c5 / cell-line :name (n3 / name :op1 "HD-LM2")) :op2 (c6 / cell-line :name (n4 / name :op1 "L-428")) :mod (e / especially)))) :ARG2 (i / inhibit-01 :ARG0 (c2 / concentrate-01 :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :mod (s2 / submicromolar)) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "STAT") :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")))))) # ::id pmid_2282_9094.94 # ::date 2015-07-25T04:50:30 # ::file pmid_2282_9094_94.txt # ::snt In contrast, at a higher concentration (5 μ), AZD1480 had a stronger effect in all cell lines, including KM-H2, which lacked active JAK/STAT proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (c / contrast-01 :ARG2 (h2 / have-condition-91 :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (s / strong-02 :degree (m2 / more)) :location (c2 / cell-line :ARG2-of (i / include-01 :ARG1 (c3 / cell-line :name (n2 / name :op1 "KM-H2") :ARG0-of (l / lack-01 :ARG1 (s3 / slash :op1 (e / enzyme :name (n3 / name :op1 "JAK") :xref (x / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")) :op2 (p / protein :name (n4 / name :op1 "STAT") :xref (x1 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")) :ARG1-of (a3 / activate-01))))) :mod (a5 / all))) :ARG2 (c4 / concentrate-02 :ARG1-of (h / high-02 :degree (m / more)) :quant (c5 / concentration-quantity :quant "5" :unit (m3 / micromolar))))) # ::id pmid_2282_9094.95 # ::date 2015-07-25T05:04:30 # ::file pmid_2282_9094_95.txt # ::snt These data suggest that at this higher concentration (5 μ), AZD1480 induced antiproliferative effects in HL cell lines in a JAK/STAT-independent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (i / induce-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG2 (a / affect-01 :ARG2 (c / counter-01 :ARG1 (p / proliferate-01)) :location (c2 / cell-line :mod (d3 / disease :name (n4 / name :op1 "HL")))) :manner (d2 / depend-01 :polarity "-" :ARG1 (s3 / slash :op1 (e / enzyme :name (n2 / name :op1 "JAK") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")) :op2 (p2 / protein :name (n3 / name :op1 "STAT") :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")))) :condition (c3 / concentrate-02 :ARG1 s2 :ARG1-of (h / high-02 :degree (m / more)) :quant (c4 / concentration-quantity :quant "5" :unit (m2 / micromolar))))) # ::id pmid_2282_9094.96 # ::date 2015-07-25T05:09:06 # ::file pmid_2282_9094_96.txt # ::snt To further investigate the mechanisms of the antiproliferative activity of AZD1480, we determined the inhibitor's effect on apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (d / determine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01)) :ARG1 (a2 / apoptosis)) :purpose (i2 / investigate-01 :ARG0 w :ARG1 (m2 / mechanism :poss (a3 / activity-06 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG0-of (c / counter-01 :ARG1 (p / proliferate-01)))) :degree (f / further))) # ::id pmid_2282_9094.97 # ::date 2015-07-25T05:14:50 # ::file pmid_2282_9094_97.txt # ::snt Consistent with the MTS data in Figure 1c, we found that AZD1480 induced apoptotic cell death in a dose-dependent manner (Figure 2a and b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG2 (d / die-01 :ARG1 (c / cell :mod (a / apoptotic))) :manner (d2 / depend-01 :ARG1 (d3 / dose-01))) :ARG1-of (c2 / consistent-01 :ARG2 (d4 / data :location (f2 / figure :mod "1c") :source (a3 / assay-01 :instrument (s2 / small-molecule :name (n2 / name :op1 "MTS") :xref (x / xref :value "PUBCHEM:65521" :prob "10.885861"))))) :ARG1-of (d5 / describe-01 :ARG0 (a2 / and :op1 (f3 / figure :mod "2a") :op2 (f4 / figure :mod "2b")))) # ::id pmid_2282_9094.98 # ::date 2015-07-25T05:18:52 # ::file pmid_2282_9094_98.txt # ::snt At the lower concentration of AZD1480 (1 μ), L-540 cells were the most sensitive (43.3% cell death after 72 h of incubation) and L-428 cells were modestly sensitive (27.6% cell death). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (h / have-condition-91 :ARG1 (a / and :op1 (s / sensitive-03 :ARG0 (c / cell-line :name (n / name :op1 "L-540")) :degree (m2 / most) :ARG1-of (m3 / mean-01 :ARG2 (d / die-01 :ARG1 (c2 / cell :quant (p / percentage-entity :value "43.3")) :time (a2 / after :op1 (i / incubate-01) :quant (t / temporal-quantity :quant "72" :unit (h2 / hour)))))) :op2 (s2 / sensitive-03 :ARG0 (c3 / cell-line :name (n2 / name :op1 "L-428")) :ARG1-of (m4 / mean-01 :ARG2 (d2 / die-01 :ARG1 (c4 / cell :quant (p2 / percentage-entity :value "27.6")))) :degree (m6 / modest))) :ARG2 (c5 / concentrate-02 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (l / low-04 :degree (m / more)) :quant (c6 / concentration-quantity :quant "1" :unit (m5 / micromolar)))) # ::id pmid_2282_9094.99 # ::date 2015-07-25T05:29:00 # ::file pmid_2282_9094_99.txt # ::snt At the higher concentration (5 μ), AZD1480 induced apoptosis in all four cell lines, but L-540 cells remained the most sensitive. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (c / contrast-01 :ARG1 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG2 (a / apoptosis) :location (c2 / cell-line :quant "4" :mod (a2 / all))) :ARG2 (r / remain-01 :ARG1 (c3 / cell-line :name (n2 / name :op1 "L-540")) :ARG3 (s2 / sensitive-03 :degree (m2 / most))) :condition (c4 / concentrate-02 :quant (c5 / concentration-quantity :quant "5" :unit (m3 / micromolar)) :ARG1-of (h / high-02 :degree (m / more)))) # ::id pmid_2282_9094.100 # ::date 2015-07-25T05:36:45 # ::file pmid_2282_9094_100.txt # ::snt Consistent with induction of apoptosis, AZD1480 activated caspases 9 and 3, and induced poly (adenosine diphosphate ribose) polymerase cleavage. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (a2 / activate-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x3 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (a3 / and :op1 (p2 / protein :name (n3 / name :op1 "caspase" :op2 "9") :xref (x / xref :value "UNIPROT:CASP9_HUMAN" :prob "0.662")) :op2 (p3 / protein :name (n4 / name :op1 "caspase" :op2 "3") :xref (x1 / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.662")))) :op2 (i / induce-01 :ARG0 s :ARG2 (c3 / cleave-01 :ARG1 (p / protein :name (n2 / name :op1 "poly" :op2 "adenosine" :op3 "diphosphate" :op4 "ribose" :op5 "polymerase") :xref (x2 / xref :value "UNIPROT:PARP1_HUMAN" :prob "0.212")))) :ARG1-of (c4 / consistent-01 :ARG2 (i2 / induce-01 :ARG2 (a4 / apoptosis)))) # ::id pmid_2282_9094.101 # ::date 2015-07-25T05:41:44 # ::file pmid_2282_9094_101.txt # ::snt (Figure 2c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (f / figure :mod "2c") # ::id pmid_2282_9094.102 # ::date 2015-07-26T11:19:42 # ::file pmid_2282_9094_102.txt # ::snt This was observed as soon as after 24 h of incubation with AZD1480 in all cell lines, when high doses (5 μ) were used (Supplementary Figure S1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (o / observe-01 :ARG1 (t / this) :time (a / as-soon-as :op1 (a2 / after :op1 (i / incubate-01 :ARG2 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :location (c / cell-line :mod (a3 / all))) :quant (t2 / temporal-quantity :quant "24" :unit (h / hour)))) :time (u / use-01 :ARG1 (d / dose-01 :quant (c2 / concentration-quantity :quant "5" :unit (m / micromolar)) :ARG1-of (h2 / high-02))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "S1C" :ARG2-of (s2 / supplement-01)))) # ::id pmid_2282_9094.103 # ::date 2015-07-26T11:39:41 # ::file pmid_2282_9094_103.txt # ::snt AZD1480 induces paradoxical hyperphosphorylation of JAK2 and TYK2 at the activation loop in HL cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG2 (h / hyperphosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "JAK2") :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n3 / name :op1 "TYK2") :xref (x1 / xref :value "UNIPROT:TYK2_HUMAN" :prob "1.003"))) :manner (p / paradox)) :location (l / loop :ARG0-of (a2 / activate-01) :location (c / cell :mod (d / disease :name (n4 / name :op1 "HL"))))) # ::id pmid_2282_9094.104 # ::date 2015-07-26T11:44:30 # ::file pmid_2282_9094_104.txt # ::snt Although AZD1480 inhibited phosphorylation of STATs, its effect on the phosphorylation of the JAK family members in HL cells is unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (k / know-01 :polarity "-" :ARG1 (a / affect-01 :ARG0 "s" :ARG1 (p3 / phosphorylate-01 :ARG1 (m / member :ARG1-of (i2 / include-91 :ARG2 (p4 / protein-family :name (n3 / name :op1 "JAK"))))) :location (c / cell :mod (d / disease :name (n4 / name :op1 "HL"))))) :ARG2 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "STAT") :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))))) # ::id pmid_2282_9094.105 # ::date 2015-07-26T11:50:15 # ::file pmid_2282_9094_105.txt # ::snt Only the Tyr-phosphorylated forms of JAKs are known to exhibit kinase activity, and phosphorylation at two tandem Tyr residues in the activation loop appears to be required for enzymatic activity.20 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (a / and :op1 (k / know-01 :ARG1 (e / enzyme :name (n / name :op1 "JAK") :ARG3-of (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :mod (f2 / form) :mod (o / only) :ARG0-of (e2 / exhibit-01 :ARG1 (a3 / activity-06 :ARG0 (k2 / kinase))) :xref (x / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))) :op2 (a4 / appear-01 :ARG1 (r2 / require-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (r / residue :mod (a5 / amino-acid :name (n3 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :mod (t / tandem :quant "2")) :location (l / loop :ARG0-of (a6 / activate-01))) :purpose (a7 / activity-06 :ARG0 (e3 / enzyme)))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "20")))) # ::id pmid_2282_9094.106 # ::date 2015-07-26T11:58:38 # ::file pmid_2282_9094_106.txt # ::snt As levels of baseline p-JAK2 expression and p-STATs inhibition did not predict sensitivity to AZD1480 in HD-LM2 and L-428 cells, we investigated the effect of AZD1480 on the phosphorylation status of the JAK family members at the activation loop. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (s2 / status :poss (m / member :ARG1-of (i3 / include-91 :ARG2 (p5 / protein-family :name (n2 / name :op1 "JAK")))) :mod (p / phosphorylate-01)) :location (l / loop :ARG0-of (a2 / activate-01))) :ARG1-of (c3 / cause-01 :ARG0 (p2 / predict-01 :polarity "-" :ARG0 (a3 / and :op1 (l2 / level :degree-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "JAK2") :ARG3-of (p3 / phosphorylate-01) :mod (b / baseline) :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")))) :op2 (l3 / level :degree-of (i2 / inhibit-01 :ARG1 (p4 / protein :name (n4 / name :op1 "STAT") :ARG3-of p3 :xref (x1 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))))) :ARG1 (s3 / sensitive-03 :ARG1 s :location (a4 / and :op1 (c / cell-line :name (n6 / name :op1 "HD-LM2")) :op2 (c2 / cell-line :name (n7 / name :op1 "L-428"))))))) # ::id pmid_2282_9094.107 # ::date 2015-07-26T12:23:18 # ::file pmid_2282_9094_107.txt # ::snt To determine the effect of AZD1480 on p-JAKs, we focused our experiments on the three cell lines that expressed active JAK/STAT proteins: HD-LM2, L-428 and L-540 (Figure 3a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (f / focus-01 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG0 w :ARG1 (c / cell-line :quant "3" :ARG3-of (e2 / express-03 :ARG2 (s / slash :op1 (e3 / enzyme :name (n / name :op1 "JAK") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")) :op2 (p / protein :name (n2 / name :op1 "STAT") :xref (x2 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")) :ARG1-of (a / activate-01))) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (c2 / cell-line :name (n3 / name :op1 "HD-LM2")) :op2 (c3 / cell-line :name (n4 / name :op1 "L-428")) :op3 (c4 / cell-line :name (n5 / name :op1 "L-540")))))) :purpose (d / determine-01 :ARG0 w :ARG1 (a4 / affect-01 :ARG0 (s2 / small-molecule :name (n6 / name :op1 "AZD1480") :xref (x3 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (e4 / enzyme :name (n7 / name :op1 "JAK") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263")))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3a"))) # ::id pmid_2282_9094.108 # ::date 2015-07-26T12:30:48 # ::file pmid_2282_9094_108.txt # ::snt In L-540, which was the most sensitive cell line and which expressed only p-JAK3, increasing concentrations of AZD1480 (0.1–5 μ) completely inhibited JAK3 Y980 phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / inhibit-01 :ARG0 (c / concentrate-02 :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x3 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (i2 / increase-01 :ARG2 (v / value-interval :op1 (c2 / concentration-quantity :quant "0.1" :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant "5" :unit m)))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod "980" :name (n2 / name :op1 "tyrosine") :part-of (e / enzyme :name (n3 / name :op1 "JAK3") :xref (x1 / xref :value "UNIPROT:JAK3_HUMAN" :prob "1.004")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :manner (c4 / complete) :location (c5 / cell-line :name (n4 / name :op1 "L-540") :ARG0-of (s2 / sensitive-03 :degree (m3 / most)) :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n5 / name :op1 "JAK3") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:JAK3_HUMAN" :prob "1.004")) :mod (o / only)))) # ::id pmid_2282_9094.109 # ::date 2015-07-26T12:39:58 # ::file pmid_2282_9094_109.txt # ::snt In contrast, when HD-LM2 and L-428 cells were incubated with AZD1480, a paradoxical increase in JAK2 Y1007/1008 and TYK2 Y1054/1055 phosphorylation was observed after 72 h of incubation (Figure 3a). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (a / and :op1 (i / increase-01 :ARG1 (a2 / amino-acid :mod "1007/1008" :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "JAK2") :xref (x1 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :manner (p2 / paradox)) :op2 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "1054/1055" :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n4 / name :op1 "TYK2") :xref (x / xref :value "UNIPROT:TYK2_HUMAN" :prob "1.003")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :time (a4 / after :op1 "i3" :quant (t / temporal-quantity :quant "72" :unit (h / hour))) :condition (i3 / incubate-01 :ARG1 (a5 / and :op1 (c2 / cell-line :name (n5 / name :op1 "HD-LM2")) :op2 (c3 / cell-line :name (n6 / name :op1 "L-428"))) :ARG2 (s / small-molecule :name (n7 / name :op1 "AZD1480") :xref (x4 / xref :value "PUBCHEM:16659841" :prob "18.572987")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3a"))) # ::id pmid_2282_9094.110 # ::date 2015-07-26T12:47:45 # ::file pmid_2282_9094_110.txt # ::snt The hyperphosphorylation of JAK2 at the activation loop was confirmed using two antibodies obtained from different clones. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (c / confirm-01 :ARG1 (h / hyperphosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "JAK2") :xref (x / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :location (l / loop :ARG0-of (a / activate-01))) :manner (u / use-01 :ARG1 (a2 / antibody :quant "2" :ARG1-of (o / obtain-01 :ARG2 (c2 / clone-01 :ARG1-of (d / differ-02)))))) # ::id pmid_2282_9094.111 # ::date 2015-07-26T12:54:04 # ::file pmid_2282_9094_111.txt # ::snt The phosphorylation of the immediate downstream target STAT3 was abrogated at the same time point in all the three cell lines (Figure 1b), suggesting that the function of the JAKs was effectively inhibited by AZD1480. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / abrogate-01 :ARG1 (p / phosphorylate-01 :ARG1 (t2 / target-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :mod (d / downstream) :mod (i / immediacy))) :time (p3 / point :ARG1-of (s / same-01) :mod (t3 / time)) :location (c / cell-line :quant "3" :mod (a2 / all)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1b")) :ARG0-of (s3 / suggest-01 :ARG1 (i2 / inhibit-01 :ARG0 (s4 / small-molecule :name (n3 / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (f2 / function-01 :ARG0 (e / enzyme :name (n2 / name :op1 "JAK") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))) :ARG1-of (e2 / effective-04)))) # ::id pmid_2282_9094.112 # ::date 2015-07-26T13:13:04 # ::file pmid_2282_9094_112.txt # ::snt When JAKs phosphorylation was analyzed over a shorter time period, a strong increase in JAK2 Y1007/1008 phosphorylation was observed in HD-LM2 and L-428 cells after 30 min of incubation with 1 μ AZD1480 (Supplementary Figure S1A), whereas JAK3 Y980 phosphorylation was abrogated in L-540 cells (Supplementary Figure S1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (c / contrast-01 :ARG1 (o / observe-01 :ARG1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "1007/1008" :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "JAK2") :xref (x2 / xref :value "UNIPROT:JAK2_HUMAN" :prob "1.004")) :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :ARG1-of (s / strong-02)) :location (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "HD-LM2")) :op2 (c3 / cell-line :name (n4 / name :op1 "L-428"))) :time (a3 / after :op1 (i2 / incubate-01 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "AZD1480") :quant (c4 / concentration-quantity :quant "1" :unit (m2 / micromolar)) :xref (x3 / xref :value "PUBCHEM:16659841" :prob "18.572987"))) :quant (t / temporal-quantity :quant "30" :unit (m / minute))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S1A" :ARG2-of (s3 / supplement-01)))) :ARG2 (a4 / abrogate-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a5 / amino-acid :mod "980" :name (n6 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n7 / name :op1 "JAK3") :xref (x1 / xref :value "UNIPROT:JAK3_HUMAN" :prob "1.004")) :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :location (c5 / cell-line :name (n8 / name :op1 "L-540")) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "S1A" :ARG2-of (s4 / supplement-01)))) :time (a6 / analyze-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n9 / name :op1 "JAK") :xref (x / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))) :duration (s5 / short-07 :degree (m3 / more)))) # ::id pmid_2282_9094.113 # ::date 2015-07-26T13:27:46 # ::file pmid_2282_9094_113.txt # ::snt The phosphorylation of the immediate downstream target STAT3 was abrogated at the same time point (30 min) in all the three cell lines, suggesting that the function of the JAKs was effectively inhibited after 30 min of incubation with AZD1480 (Supplementary Figure S1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / abrogate-01 :ARG1 (p / phosphorylate-01 :ARG1 (t2 / target-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :mod (d / downstream) :mod (i / immediacy))) :time (p3 / point :mod (t3 / time) :ARG1-of (s2 / same-01) :ARG1-of (m3 / mean-01 :ARG2 (t4 / temporal-quantity :quant "30" :unit (m / minute)))) :location (c / cell-line :quant "3" :mod (a2 / all)) :ARG0-of (s3 / suggest-01 :ARG1 (i2 / inhibit-01 :ARG1 (f / function-01 :ARG0 (e / enzyme :name (n2 / name :op1 "JAK") :xref (x1 / xref :value "UNIPROT:JAK1_HUMAN" :prob "0.263"))) :ARG1-of (e2 / effective-04) :time (a3 / after :op1 (i3 / incubate-01 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987"))) :quant t4))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "S1A" :ARG2-of (s5 / supplement-01)))) # ::id pmid_2282_9094.114 # ::date 2015-07-26T13:38:16 # ::file pmid_2282_9094_114.txt # ::snt AZD1480 induces a negative-feedback loop involving phosphorylation ERK1/2 and p38 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG2 (l / loop :mod (f / feedback :ARG0-of (n2 / negative-03)) :ARG2-of (i2 / involve-01 :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2"))) :op2 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))))))) # ::id pmid_2282_9094.115 # ::date 2015-07-26T13:44:05 # ::file pmid_2282_9094_115.txt # ::snt As AZD1480 inhibition of STATs activity did not translate into antiproliferative activity in two cell lines, we hypothesized that these cells may depend on other signaling pathways to promote their survival. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (d2 / depend-01 :ARG0 (c / cell :mod (t / this)) :ARG1 (p2 / pathway :ARG0-of (s / signal-07) :mod (o / other)) :purpose (p3 / promote-01 :ARG0 p2 :ARG1 (s2 / survive-01 :ARG1 c)))) :ARG1-of (c4 / cause-01 :ARG0 (t2 / translate-01 :polarity "-" :ARG1 (i / inhibit-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (a / activity-06 :ARG0 (p4 / protein :name (n2 / name :op1 "STAT") :xref (x / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003")))) :ARG2 (a2 / activity-06 :ARG0-of (c2 / counter-01 :ARG1 (p5 / proliferate-01))) :location (c3 / cell-line :quant "2")))) # ::id pmid_2282_9094.116 # ::date 2015-07-26T13:54:57 # ::file pmid_2282_9094_116.txt # ::snt To test this hypothesis, we examined the effect of AZD1480 on ERK, p38 and phosphatidylinositol-3 kinase/AKT signaling pathways, which are known to promote HL survival. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 2, 2015 (e2 / examine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (a2 / and :op1 (p / pathway :name (n3 / name :op1 "ERK") :ARG0-of (s2 / signal-07)) :op2 (p2 / pathway :name (n4 / name :op1 "p38") :ARG0-of s2) :op3 (p3 / pathway :name (n5 / name :op1 "phosphatidylinositol-3" :op2 "kinase/AKT") :ARG0-of s2) :ARG0-of (p4 / promote-01 :ARG1 (s5 / survive-01 :ARG1 (d / disease :name (n / name :op1 "HL"))) :ARG1-of (k / know-01)))) :purpose (t2 / test-01 :ARG0 w :ARG1 (t / thing :ARG1-of (h / hypothesize-01) :mod (t3 / this)))) # ::id pmid_2282_9094.117 # ::date 2015-07-26T14:02:45 # ::file pmid_2282_9094_117.txt # ::snt We found that AZD1480 had no effect on phosphatidylinositol-3 kinase/AKT signaling in any of these cell lines (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (a / affect-01 :polarity "-" :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (s2 / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "phosphatidylinositol-3" :op2 "kinase/AKT"))) :location (c / cell-line :mod (a2 / any) :mod (t / this))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s3 / show-01 :polarity "-")))) # ::id pmid_2282_9094.118 # ::date 2015-07-26T14:11:49 # ::file pmid_2282_9094_118.txt # ::snt In contrast, AZD1480 increased the levels of ERK and p38 phosphorylation in the resistant HD-LM2 and L-428 cells, whereas it inhibited ERK and p38 phosphorylation in the sensitive L-540 cells (Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG2 (c2 / contrast-01 :ARG1 (i / increase-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (a / and :op1 (l / level :degree-of (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :op2 (l2 / level :degree-of (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))))) :location (a2 / and :op1 (c3 / cell-line :name (n4 / name :op1 "HD-LM2")) :op2 (c4 / cell-line :name (n5 / name :op1 "L-428")) :ARG0-of (r / resist-01))) :ARG2 (i2 / inhibit-01 :ARG0 s :ARG1 a :location (c5 / cell-line :name (n6 / name :op1 "L-540") :ARG0-of (s2 / sensitive-03)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id pmid_2282_9094.119 # ::date 2015-07-26T14:24:54 # ::file pmid_2282_9094_119.txt # ::snt To define the mechanism of ERK and p38 activation in the two resistant cell lines, we first assessed the expression and activation levels of the Src homology 2 domain-containing protein phosphatase 2 (SHP-2) and SOCS-3 (a STAT3 target gene21), two known regulators of JAK/STAT and mitogen-activated protein kinase (MAPK) signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / assess-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (l / level :degree-of (e / express-03 :ARG2 (a8 / and :op1 (e5 / enzyme :name (n4 / name :op1 "protein" :op2 "phosphatase" :op3 "2") :xref (x2 / xref :value "UNIPROT:PPM1A_HUMAN" :prob "0.392")) :op2 (p4 / protein :name (n5 / name :op1 "SOCS-3") :ARG0-of (t / target-01 :ARG1 (p5 / protein :name (n6 / name :op1 "STAT3") :xref (x4 / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :mod "21"))) :xref (x3 / xref :value "UNIPROT:SOCS3_HUMAN" :prob "1.003")) :ARG0-of (c / contain-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "Src" :op2 "homology" :op3 "2" :op4 "domain"))) :ARG0-of (r2 / regulate-01 :ARG1 (a5 / and :op1 (s / signal-07 :ARG0 (p7 / pathway :name (n7 / name :op1 "JAK-STAT"))) :op2 (s2 / signal-07 :ARG0 (p / pathway :name (n8 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase")))) :ARG1-of (k / know-01))))) :op2 (l2 / level :ARG1-of (a4 / activate-01) :quant-of p2)) :time (f / first) :purpose (d2 / define-01 :ARG0 w :ARG1 (m / mechanism :poss (a6 / activate-01 :ARG1 (a7 / and :op1 (e2 / enzyme :name (n9 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n10 / name :op1 "p38") :xref (x1 / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003"))) :location (c2 / cell-line :quant "2" :ARG0-of (r3 / resist-01)))))) # ::id pmid_2282_9094.120 # ::date 2015-07-23T07:45:53 # ::file pmid_2282_9094_120.txt # ::snt In fact, SHP-2 has been reported to be a negative regulator of the JAK/STAT activation, whereas having a positive effect on ERK activation.22, 23, 24, 25 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / report-01 :ARG1 (d / downregulate-01 :ARG1 (a / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "JAK/STAT"))) :ARG2 (p / protein :name (n / name :op1 "SHP-2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003"))) :manner (i / in-fact) :ARG1-of (c / contrast-01 :ARG2 (a2 / affect-01 :ARG0 p :ARG1 (a3 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :mod (p3 / positive))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG0 (a4 / and :op1 "22" :op2 "23" :op3 "24" :op4 "25"))))) # ::id pmid_2282_9094.121 # ::date 2015-07-24T04:03:11 # ::file pmid_2282_9094_121.txt # ::snt Furthermore, numerous studies have described enhanced SHP-2 and ERK activation after SOCS-3 deletion in both in vitro and in vivo models, postulating a negative-feedback loop between SOCS-3 and SHP-2.22, 23, 26 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / and :op2 (d / describe-01 :ARG0 (s / study-01 :mod (n4 / numerous) :ARG0-of (p / postulate-01 :ARG1 (l / loop-01 :ARG2 (b / between :op1 "p4" :op2 (p3 / protein :name (n3 / name :op1 "SHP-2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003"))) :mod (f / feedback :ARG0-of (n / negative-03))))) :ARG1 (a2 / and :op1 (a3 / activate-01 :ARG1 p3) :op2 (a4 / activate-01 :ARG1 (e / enzyme :name (n5 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :time (a5 / after :op1 (d2 / delete-01 :ARG1 (p4 / protein :name (n6 / name :op1 "SOCS-3") :xref (x2 / xref :value "UNIPROT:SOCS3_HUMAN" :prob "1.003")) :ARG2 (a6 / and :op1 (m / model :mod (i / in-vivo)) :op2 (m2 / model :mod (i2 / in-vitro)))))) :ARG1-of (e2 / enhance-01))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG0-of (c / cite-01 :ARG1 (a7 / and :op1 "22" :op2 "23" :op3 "26"))))) # ::id pmid_2282_9094.122 # ::date 2015-07-25T13:33:25 # ::file pmid_2282_9094_122.txt # ::snt Consistent with the described changes in ERK phosphorylation status, after 72 h of incubation with increasing doses of AZD1480 (0.1–5 μ), an increase in SHP-2 phosphorylation on Tyr542 (the major site of SHP-2 activation) coupled with SOCS3 downregulation was observed in the HD-LM2 and L-428 cell lines, but not in the L-540 cells (Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c8 / contrast-01 :ARG1 (o3 / observe-01 :ARG1 (i3 / increase-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "Tyr542") :ARG1-of (m3 / mean-01 :ARG2 (s2 / site-01 :ARG1 (a3 / activate-01 :ARG1 "p3") :ARG1-of (m4 / major-02)))) :ARG2 (p3 / protein :name (n3 / name :op1 "SHP-2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")) :ARG1-of (c5 / couple-01 :ARG2 (d4 / downregulate-01 :ARG1 (p4 / protein :name (n5 / name :op1 "SOCS3") :xref (x2 / xref :value "UNIPROT:SOCS3_HUMAN" :prob "1.004")))))) :ARG1-of (c / consistent-01 :ARG2 (c2 / change-01 :ARG1 (s / status :topic (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01))) :time (a / after :op1 (i / incubate-01 :ARG2 (d2 / dose-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "AZD1480") :xref (x3 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (i2 / increase-01) :quant (b / between :op1 (c3 / concentration-quantity :quant "0.1" :unit (m / micromolar)) :op2 (c4 / concentration-quantity :quant "5" :unit m)))) :quant (t / temporal-quantity :quant "72" :unit (h / hour))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3b")) :location (a4 / and :op1 (c6 / cell-line :name (n6 / name :op1 "HD-LM2")) :op2 (c7 / cell-line :name (n7 / name :op1 "L-428")))) :ARG2 (o2 / observe-01 :polarity "-" :ARG1 i3 :location (c9 / cell-line :name (n8 / name :op1 "L-540")))) # ::id pmid_2282_9094.123 # ::date 2015-07-25T05:57:53 # ::file pmid_2282_9094_123.txt # ::snt On the other hand, in the L-540 cells, SOCS3 downregulation was not coupled with SHP-2 hyperphosphorylation, and ERK phosphorylation was in fact inhibited after treatment with AZD1480, suggesting a different model of MAPK activation in this cell line. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (a / and :op1 (c2 / couple-01 :polarity "-" :ARG1 (d2 / downregulate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "SOCS3") :xref (x / xref :value "UNIPROT:SOCS3_HUMAN" :prob "1.004")) :location (c3 / cell-line :name (n6 / name :op1 "L-540"))) :ARG2 (h / hyperphosphorylate-01 :ARG1 (p4 / protein :name (n5 / name :op1 "SHP-2") :xref (x2 / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003")))) :op2 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :time (a2 / after :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "AZD1480") :xref (x3 / xref :value "PUBCHEM:16659841" :prob "18.572987")))) :mod (i2 / in-fact)) :ARG0-of (s / suggest-01 :ARG1 (m / model :ARG1-of (d / differ-02) :mod (a3 / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK")) :location c3))))) # ::id pmid_2282_9094.124 # ::date 2015-07-25T06:29:12 # ::file pmid_2282_9094_124.txt # ::snt The activation of p38 signaling observed in the HD-LM2 and L-428 cell lines after incubation with AZD1480 was probably related to the activity of autocrine and paracrine chemokine and cytokine loops, triggered by SHP-2/ERK activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (r / relate-01 :ARG1 (a5 / activate-01 :ARG1 (s / signal-07 :ARG0 (e / enzyme :name (n2 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")) :ARG1-of (o / observe-01 :location (a6 / and :op1 (c3 / cell-line :name (n3 / name :op1 "HD-LM2")) :op2 (c4 / cell-line :name (n4 / name :op1 "L-428"))) :time (a7 / after :op1 (i / incubate-01 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987"))))))) :ARG2 (a / activity-06 :ARG0 (a2 / and :op1 (l3 / loop :mod (c / chemokine :mod (a3 / autocrine))) :op2 (l / loop :mod (c5 / chemokine :mod "p2")) :op3 (l2 / loop :mod (c6 / cytokine :mod a3)) :op4 (l4 / loop :mod (c2 / cytokine :mod (p2 / paracrine))) :ARG1-of (t / trigger-01 :ARG2 (a4 / activate-01 :ARG1 (p3 / pathway :name (n / name :op1 "SHP-2/ERK")))))) :mod (p / probable)) # ::id pmid_2282_9094.125 # ::date 2015-07-26T03:40:24 # ::file pmid_2282_9094_125.txt # ::snt Over a shorter time period, we observed a strong correlation between SOCS-3 downregulation and SHP-2/ERK activation in the HD-LM2 cell line after 6 h of incubation with AZD1480, whereas in the L-540 cell line, ERK phosphorylation was inhibited without an increase in SHP-2 phosphorylation or a decrease in SOCS-3 levels (Supplementary Figure S1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG1 (o / observe-01 :ARG0 (w / we) :ARG1 (c2 / correlate-01 :ARG1 (d / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "SOCS-3") :xref (x1 / xref :value "UNIPROT:SOCS3_HUMAN" :prob "1.003"))) :ARG2 (a / activate-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "SHP-2/ERK"))) :ARG1-of (s2 / strong-02)) :time (o2 / over :op1 (p2 / period :ARG1-of (s / short-07 :degree (m / more)))) :location (c3 / cell-line :name (n3 / name :op1 "HD-LM2")) :time (a2 / after :op1 (i / incubate-01 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :duration (t2 / temporal-quantity :quant "6" :unit (h / hour))))) :ARG2 (i2 / inhibit-01 :polarity "-" :ARG1 (p4 / phosphorylate-01 :ARG1 (p7 / protein-family :name (n5 / name :op1 "ERK"))) :ARG0-of (i3 / increase-01 :polarity "-" :ARG1 (o3 / or :op1 (p5 / phosphorylate-01 :ARG1 (p6 / protein :name (n6 / name :op1 "SHP-2") :xref (x / xref :value "UNIPROT:PTN11_HUMAN" :prob "1.003"))))) :location (c4 / cell-line :name (n8 / name :op1 "L-540")) :ARG0-of (d2 / decrease-01 :polarity "-" :ARG1 (l / level :quant-of p))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "S1D" :ARG2-of (s3 / supplement-01)))) # ::id pmid_2282_9094.126 # ::date 2015-07-24T14:27:39 # ::file pmid_2282_9094_126.txt # ::snt AZD1480 determines increased production of the chemokines IP-10, IL-8 and RANTES in HL cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d2 / determine-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (p / produce-01 :ARG1 (a / and :op1 (c / chemokine :name (n3 / name :op1 "IP-10")) :op2 (c2 / chemokine :name (n4 / name :op1 "IL-8")) :op3 (c3 / chemokine :name (n5 / name :op1 "RANTES")) :location (c4 / cell-line :mod (d / disease :name (n2 / name :op1 "HL")))) :ARG1-of (i / increase-01))) # ::id pmid_2282_9094.127 # ::date 2015-07-24T14:34:32 # ::file pmid_2282_9094_127.txt # ::snt The interaction between HRS cells and the surrounding reactive infiltrate provides an environment that supports the growth and survival of HRS cells through a complex network of autocrine and paracrine loops involving a variety of cytokines and chemokines.1, 27 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 1, 2015 (p / provide-01 :ARG0 (i / interact-01 :ARG0 (c / cell-line :name (n / name :op1 "HRS")) :ARG1 (i2 / infiltrate :ARG0-of (r / react-01) :ARG1-of (s / surround-01))) :ARG1 (e / environment :ARG0-of (s2 / support-01 :ARG1 (a / and :op1 (g / grow-01 :ARG1 c) :op2 (s3 / survive-01 :ARG0 c)) :manner (n2 / network-01 :ARG1 (l / loop-01 :ARG1 (a2 / autocrine)) :ARG2 (l2 / loop-01 :ARG1 (p2 / paracrine)) :ARG2-of (i3 / involve-01 :ARG1 (a3 / and :op1 (v / vary-01 :ARG1 (c2 / cytokine)) :op2 (v2 / vary-01 :ARG1 (c3 / chemokine)))) :mod (c4 / complex)))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG0-of (c5 / cite-01 :ARG1 (a4 / and :op1 "1" :op2 "27"))))) # ::id pmid_2282_9094.128 # ::date 2015-07-25T12:30:33 # ::file pmid_2282_9094_128.txt # ::snt The chemokines IP-10, RANTES and IL-8 are known to be upregulated by MAPK (ERK and p38) activation and have previously been reported to have a role in tumorigenesis and Hodgkin lymphomagenesis by promoting cell proliferation and survival.1, 27, 28, 29, 30, 31 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (k / know-01 :ARG1 (u / upregulate-01 :ARG1 (a3 / and :op1 (c2 / chemokine :name (n3 / name :op1 "IP-10")) :op2 (c3 / chemokine :name (n4 / name :op1 "RANTES")) :op3 (c4 / chemokine :name (n5 / name :op1 "IL-8"))) :ARG2 (a5 / activate-01 :ARG1 (p3 / pathway :name (n6 / name :op1 "MAPK") :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")))))))) :op2 (r / report-01 :ARG1 (h / have-03 :ARG0 a3 :ARG1 (r2 / role :prep-in (c6 / create-01 :ARG1 (a8 / and :op1 (t2 / tumor) :op2 (d2 / disease :name (n8 / name :op1 "Hodgkin" :op2 "lymphoma"))))) :manner (p4 / promote-01 :ARG0 a3 :ARG1 (a7 / and :op1 (p5 / proliferate-01 :ARG0 (c5 / cell)) :op2 (s / survive-01 :ARG0 c5)))) :time (p / previous)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG0-of (c / cite-01 :ARG1 (a2 / and :op1 "1" :op2 "27" :op3 "28" :op4 "29" :op5 "30" :op6 "31"))))) # ::id pmid_2282_9094.129 # ::date 2015-07-25T05:10:48 # ::file pmid_2282_9094_129.txt # ::snt Consistent with the observed changes in SHP2, ERK and p38 phosphorylation, AZD1480 increased the production of IP-10, RANTES and IL-8 in the supernatants of the resistant HD-LM2 and L-428, and not the sensitive L-540 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / increase-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD1480") :xref (x6 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (p / produce-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n5 / name :op1 "IP-10") :xref (x2 / xref :value "UNIPROT:CXL10_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n6 / name :op1 "RANTES") :xref (x3 / xref :value "UNIPROT:CCR1_HUMAN" :prob "0.352")) :op3 (p4 / protein :name (n7 / name :op1 "IL-8") :xref (x5 / xref :value "UNIPROT:IL8_HUMAN" :prob "1.003"))) :location (s / supernatant :poss (a3 / and :op1 (c3 / cell-line :name (n9 / name :op1 "HD-LM2")) :op2 (c4 / cell-line :name (n10 / name :op1 "L-428")) :ARG0-of (r / resist-01)) :ARG1-of (c5 / contrast-01 :ARG2 (c6 / cell-line :name (n8 / name :op1 "L-540") :ARG0-of (s2 / sensitive-03))))) :ARG1-of (c / consistent-01 :ARG2 (c2 / change-01 :ARG1 (p5 / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "SHP2") :xref (x1 / xref :value "UNIPROT:PTN11_HUMAN" :prob "0.673")) :op2 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x4 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op3 (e4 / enzyme :name (n4 / name :op1 "p38") :xref (x / xref :value "UNIPROT:CRK_HUMAN" :prob "1.003")))) :ARG1-of (o / observe-01)))) # ::id pmid_2282_9094.130 # ::date 2015-07-25T05:22:20 # ::file pmid_2282_9094_130.txt # ::snt (Figure 3c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (f / figure :mod "3c") # ::id pmid_2282_9094.131 # ::date 2015-07-25T03:53:53 # ::file pmid_2282_9094_131.txt # ::snt This data suggest that the efficacy of AZD1480 may have been attenuated in the HD-LM2 and L-428 cells by an autocrine negative-feedback loop involving cytokines that activate ERK/p38 survival signaling pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (a / attenuate-01 :ARG0 (l2 / loop-01 :mod (f / feedback :mod (a3 / autocrine) :ARG0-of (n3 / negative-03) :ARG2-of (i / involve-01 :ARG1 (c3 / cytokine :ARG0-of (a4 / activate-01 :ARG1 (p2 / pathway :name (n4 / name :op1 "ERK/p38") :ARG0-of (s2 / signal-07 :ARG1 (s3 / survive-01)))))))) :ARG1 (e / efficacy :poss (s4 / small-molecule :name (n5 / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987"))) :location (a2 / and :op1 (c / cell-line :name (n / name :op1 "HD-LM2")) :op2 (c2 / cell-line :name (n2 / name :op1 "L-428")))))) # ::id pmid_2282_9094.132 # ::date 2015-07-24T14:36:28 # ::file pmid_2282_9094_132.txt # ::snt MEK inhibitors enhance the efficacy of AZD1480 in the HD-LM2 and L-428 cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e2 / enhance-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK")))) :ARG1 (e / efficacy :poss (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987"))) :location (a / and :op1 (c / cell-line :name (n3 / name :op1 "HD-LM2")) :op2 (c2 / cell-line :name (n4 / name :op1 "L-428")))) # ::id pmid_2282_9094.133 # ::date 2015-07-24T14:42:28 # ::file pmid_2282_9094_133.txt # ::snt To assess whether the observed activation of the SHP-2/ERK pathway is involved in the resistance to JAK/STAT inhibition, HL cells were treated with 1 μ AZD1480 in combination with two commercially available MEK inhibitors (UO126 and PD98059). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t2 / treat-04 :ARG1 (c2 / cell-line :mod (d / disease :name (n / name :op1 "HL"))) :ARG2 (s / small-molecule :name (n4 / name :op1 "AZD1480") :quant (c / concentration-quantity :quant "1" :unit (m / micromolar)) :ARG1-of (c3 / combine-01 :ARG2 (m2 / molecular-physical-entity :quant "2" :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n5 / name :op1 "MEK"))) :ARG2-of (a3 / available-02 :manner (c4 / commercial)) :ARG1-of (m3 / mean-01 :ARG2 (a4 / and :op1 (s2 / small-molecule :name (n6 / name :op1 "UO126")) :op2 (s3 / small-molecule :name (n7 / name :op1 "PD98059") :xref (x / xref :value "PUBCHEM:4713" :prob "18.349844")))))) :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :purpose (a / assess-01 :ARG1 (i2 / involve-01 :mode "interrogative" :ARG1 (a2 / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "SHP-2/ERK")) :ARG1-of (o / observe-01)) :ARG2 (r / resist-01 :ARG1 (i3 / inhibit-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "JAK/STAT"))))))) # ::id pmid_2282_9094.134 # ::date 2015-07-25T10:41:30 # ::file pmid_2282_9094_134.txt # ::snt Cells were incubated with increasing concentrations of UO126 or PD98059 (10–100 μ), with or without 1 μ AZD1480 for 24, 48 and 72 h, and cell viability was assessed using the MTS assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (i / incubate-01 :ARG1 (c2 / cell) :ARG2 (c3 / concentrate-01 :ARG1 (o / or :op1 (s2 / small-molecule :name (n2 / name :op1 "UO126")) :op2 (s3 / small-molecule :name (n3 / name :op1 "PD98059") :xref (x / xref :value "PUBCHEM:4713" :prob "18.349844")) :quant (b / between :op1 (c4 / concentration-quantity :quant "10" :unit (m2 / micromolar)) :op2 (c5 / concentration-quantity :quant "100" :unit m2))) :ARG1-of (i2 / increase-01)) :manner (o2 / or :op1 (s / small-molecule :name (n4 / name :op1 "AZD1480") :quant (c6 / concentration-quantity :quant "1" :unit m2) :xref (x3 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :op2 (s4 / small-molecule :polarity "-" :name (n5 / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987"))) :duration (a4 / and :op1 (t2 / temporal-quantity :quant "24" :unit (h / hour)) :op2 (t3 / temporal-quantity :quant "48" :unit (h2 / hour)) :op3 (t4 / temporal-quantity :quant "72" :unit (h3 / hour)))) :op2 (a2 / assess-01 :ARG1 (v2 / viability :poss (c / cell)) :ARG2-of (u / use-01 :ARG1 (a3 / assay-01 :instrument (s5 / small-molecule :name (n / name :op1 "MTS") :xref (x1 / xref :value "PUBCHEM:65521" :prob "10.885861")))))) # ::id pmid_2282_9094.135 # ::date 2015-07-25T04:06:42 # ::file pmid_2282_9094_135.txt # ::snt Both UO126 and PD98059 enhanced the effect of AZD1480 in the HD-LM2 and L-428 cells at 72 h (Figure 3d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 1, 2015 (e / enhance-01 :ARG0 (a / and :op1 (s / small-molecule :name (n2 / name :op1 "UO126")) :op2 (s2 / small-molecule :name (n / name :op1 "PD98059") :xref (x1 / xref :value "PUBCHEM:4713" :prob "18.349844"))) :ARG1 (a2 / affect-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987"))) :location (a3 / and :op1 (c / cell-line :name (n4 / name :op1 "HD-LM2")) :op2 (c2 / cell-line :name (n5 / name :op1 "L-428")) :time (a4 / after :op1 (t / temporal-quantity :quant "72" :unit (h / hour)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3d"))) # ::id pmid_2282_9094.136 # ::date 2015-07-25T04:18:22 # ::file pmid_2282_9094_136.txt # ::snt This effect was associated with inhibition of AZD1480-induced ERK phosphorylation (Figure 3e). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / associate-01 :ARG1 (a2 / affect-01 :mod (t / this)) :ARG2 (i / inhibit-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2-of (i2 / induce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3e"))) # ::id pmid_2282_9094.137 # ::date 2015-07-24T14:43:54 # ::file pmid_2282_9094_137.txt # ::snt Immunoregulatory effects of AZD1480 in HL cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (c / cell-line :mod (d / disease :name (n / name :op1 "HL"))) :ARG2 (i / immunoregulate-00)) # ::id pmid_2282_9094.138 # ::date 2015-07-24T14:49:55 # ::file pmid_2282_9094_138.txt # ::snt PD-L1 and PD-L2 are members of the B7 family, which inhibit T-cell function by interacting with the programmed cell death 1 receptor expressed on T cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (m / member :ARG1-of (i3 / include-91 :ARG2 (f / family :mod (p4 / protein :name (n5 / name :op1 "B7") :xref (x1 / xref :value "UNIPROT:CD80_HUMAN" :prob "1.002")))) :domain (a / and :op1 (p2 / protein :name (n / name :op1 "PD-L1") :xref (x / xref :value "UNIPROT:PD1L1_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n2 / name :op1 "PD-L2") :xref (x2 / xref :value "UNIPROT:PD1L2_HUMAN" :prob "1.002"))) :ARG0-of (i / inhibit-01 :ARG1 (f2 / function-01 :ARG0 (c3 / cell :name (n3 / name :op1 "T"))) :manner (i2 / interact-01 :ARG0 a :ARG1 (p / protein :name (n4 / name :op1 "programmed" :op2 "cell" :op3 "death" :op4 "1" :op5 "receptor") :ARG2-of (e / express-03 :ARG3 c3) :xref (x3 / xref :value "UNIPROT:PD1L1_HUMAN" :prob "0.332"))))) # ::id pmid_2282_9094.139 # ::date 2015-07-24T23:32:16 # ::file pmid_2282_9094_139.txt # ::snt PD-L1 and PD-L2 have been reported to be regulated by the JAK/STAT pathway or the MAPK pathway, depending on the cellular context.9, 11, 13 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (r / report-01 :ARG1 (r2 / regulate-01 :ARG0 (o / or :op1 (p4 / pathway :name (n4 / name :op1 "JAK/STAT")) :op2 (p5 / pathway :name (n5 / name :op1 "MAPK"))) :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "PD-L1") :xref (x / xref :value "UNIPROT:PD1L1_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n3 / name :op1 "PD-L2") :xref (x1 / xref :value "UNIPROT:PD1L2_HUMAN" :prob "1.002"))) :ARG0-of (d / depend-01 :ARG1 (c / context :mod (c2 / cell)))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG0 (a2 / and :op1 "9" :op2 "11" :op3 "13"))))) # ::id pmid_2282_9094.140 # ::date 2015-07-24T23:39:14 # ::file pmid_2282_9094_140.txt # ::snt Therefore, we assessed the effect of AZD1480 on PD-L1 and PD-L2 expression in HL cells by flow cytometry. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (a / assess-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (a3 / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (e2 / express-03 :ARG1 (p / protein :name (n2 / name :op1 "PD-L1") :xref (x1 / xref :value "UNIPROT:PD1L1_HUMAN" :prob "1.002")))) :op2 (a4 / affect-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "PD-L2") :xref (x / xref :value "UNIPROT:PD1L2_HUMAN" :prob "1.002")) :ARG3 (c2 / cell-line :mod (d / disease :name (n4 / name :op1 "HL")))))) :instrument (c3 / cytometry :mod (f / flow)))) # ::id pmid_2282_9094.141 # ::date 2015-07-24T23:57:12 # ::file pmid_2282_9094_141.txt # ::snt After incubation with AZD1480 1 μ for 72 h, we observed a significant downregulation of PD-L1 and PD-L2 in the PD-L1/PD-L2-positive HL cell lines HD-LM2 and L-540 (Figure 4a and b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (d2 / downregulate-01 :ARG1 (a3 / and :op1 (p / protein :name (n4 / name :op1 "PD-L1") :xref (x1 / xref :value "UNIPROT:PD1L1_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n5 / name :op1 "PD-L2") :xref (x / xref :value "UNIPROT:PD1L2_HUMAN" :prob "1.002"))) :ARG1-of (s / significant-02) :location (c4 / cell-line :ARG1-of (m2 / mean-01 :ARG0 (a4 / and :op1 (c2 / cell-line :name (n2 / name :op1 "HD-LM2")) :op2 (c3 / cell-line :name (n3 / name :op1 "L-540")))) :mod (p4 / positive :topic p2) :mod (d3 / disease :name (n6 / name :op1 "HL")))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "4a") :op2 (f2 / figure :mod "4b"))) :time (a2 / after :op1 (i / incubate-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "AZD1480") :quant (c / concentration-quantity :quant "1" :unit (m / micromolar)) :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :duration (t / temporal-quantity :quant "72" :unit (h / hour))))) # ::id pmid_2282_9094.142 # ::date 2015-07-25T02:45:28 # ::file pmid_2282_9094_142.txt # ::snt No significant dowregulation was detected following incubation with MEK inhibitors (UO126 and PD98059 25 μ for 72 h) in the L-540 cell line (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / detect-01 :polarity "-" :ARG1 (d2 / downregulate-01 :ARG1-of (s / significant-02)) :ARG1-of (f / follow-01 :ARG2 (i2 / incubate-01 :ARG2 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :location (c / cell-line :name (n2 / name :op1 "L-540")) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (s3 / small-molecule :name (n3 / name :op1 "UO126")) :op2 (s4 / small-molecule :name (n4 / name :op1 "PD98059") :xref (x / xref :value "PUBCHEM:4713" :prob "18.349844")) :quant (c2 / concentration-quantity :quant "25" :unit (m2 / micromolar))))) :duration (t2 / temporal-quantity :quant "72" :unit (h / hour)))) :ARG1-of (d3 / describe-01 :ARG0 (d4 / data :ARG1-of (s2 / show-01 :polarity "-")))) # ::id pmid_2282_9094.143 # ::date 2015-07-25T03:52:34 # ::file pmid_2282_9094_143.txt # ::snt On the other hand, in the HD-LM2 cell line, an increase in the activation of ERK was observed after incubation with AZD1480, ruling out a role of this pathway in the regulation of PD ligands expression in this cell line (Figure 3b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (c2 / contrast-01 :ARG2 (o / observe-01 :ARG1 (i / increase-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :location (c / cell-line :wiki "-" :name (n3 / name :op1 "HD-LM2"))) :time (a2 / after :op1 (i2 / incubate-01 :ARG2 (s / small-molecule :wiki "-" :name (n / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")))) :ARG0-of (r / rule-out-02 :ARG1 (r2 / role :poss e) :ARG2 (r3 / regulate-01 :ARG0 e :ARG1 (e2 / express-03 :ARG2 (p / protein :wiki "PD-L1" :name (n4 / name :op1 "PD-ligand")) :ARG3 c)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3b"))) # ::id pmid_2282_9094.144 # ::date 2015-07-25T11:29:38 # ::file pmid_2282_9094_144.txt # ::snt Given the potent inhibition of STAT proteins phosphorylation observed with low doses AZD1480 (0.1–1 μ), we also assessed the effect of AZD1480 on the expression of STAT-regulated cytokines and chemokines involved in HL cell survival (IL-6) and immune escape (IL-13, TARC), focusing on the three cell lines with baseline JAK/STAT activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / assess-01 :ARG0 (w / we) :ARG1 (a4 / and :op1 (a5 / affect-01 :ARG0 "s2" :ARG1 (e3 / express-03 :ARG2 (a7 / and :op1 (c4 / cytokine) :op2 (c6 / chemokine) :ARG1-of (r / regulate-01 :ARG0 (p4 / protein :name (n3 / name :op1 "STAT") :xref (x2 / xref :value "UNIPROT:STAT_HUMAN" :prob "1.003"))) :ARG1-of (m3 / mean-01 :ARG2 (a9 / and :op1 (p6 / protein :name (n6 / name :op1 "IL-13") :xref (x / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :op2 (p7 / protein :name (n7 / name :op1 "TARC") :xref (x1 / xref :value "UNIPROT:CCL17_HUMAN" :prob "1.002")) :ARG1-of (i4 / involve-01 :ARG2 (e2 / escape-01 :ARG1 (i3 / immune-02))))) :ARG1-of (m2 / mean-01 :ARG2 (p8 / protein :name (n8 / name :op1 "IL-6") :ARG1-of (i2 / involve-01 :ARG2 (s / survive-01 :ARG0 (c5 / cell-line :mod (d2 / disease :name (n / name :op1 "HL"))))) :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003"))))))) :ARG1-of (c / cause-01 :ARG0 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD1480") :ARG2-of (d / dose-01 :ARG1-of (l / low-04) :quant (a2 / and :op1 (c2 / concentration-quantity :quant "0.1" :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant "1" :unit m))) :xref (x4 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (p / phosphorylate-01 :ARG1 p4) :ARG1-of (o / observe-01) :mod (p3 / potent))) :mod (a3 / also) :ARG1-of (f / focus-01 :ARG2 (c7 / cell-line :quant "3" :mod (a8 / activate-01 :ARG1 (p5 / pathway :name (n5 / name :op1 "JAK/STAT")) :mod (b / baseline))))) # ::id pmid_2282_9094.145 # ::date 2015-07-25T12:31:06 # ::file pmid_2282_9094_145.txt # ::snt Following incubation with AZD1480 1 μ for 72 h, cell culture supernatants were analyzed by enzyme-linked immunosorbent assay; consistent with the inhibition of STAT3 and STAT6 phosphorylation, decreased levels of IL-6, IL-13 and TARC were observed in HD-LM2, L-428 and L-540 (Figure 4b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (a / analyze-01 :ARG0 (a6 / assay-01 :instrument (i / immunosorbent) :ARG1-of (l / link-01 :ARG2 (e / enzyme))) :ARG1 (s / supernatant :ARG0-of (c / culture-01) :mod (c8 / cell)) :ARG1-of (f / follow-01 :ARG2 (i2 / incubate-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "AZD1480") :quant (c3 / concentration-quantity :quant "1" :unit (m2 / micromolar)) :xref (x5 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :duration (t / temporal-quantity :quant "72" :unit (h / hour))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4b")) :snt2 (c4 / consistent-01 :ARG1 (o / observe-01 :ARG1 (l2 / level :quant-of (a4 / and :op1 (p4 / protein :name (n4 / name :op1 "IL-6") :xref (x3 / xref :value "UNIPROT:IL6_HUMAN" :prob "1.003")) :op2 (p5 / protein :name (n5 / name :op1 "IL-13") :xref (x4 / xref :value "UNIPROT:IL13_HUMAN" :prob "1.003")) :op3 (p6 / protein :name (n6 / name :op1 "TARC") :xref (x1 / xref :value "UNIPROT:CCL17_HUMAN" :prob "1.002"))) :ARG1-of (d2 / decrease-01)) :location (a5 / and :op1 (c5 / cell-line :name (n7 / name :op1 "HD-LM2")) :op2 (c6 / cell-line :name (n8 / name :op1 "L-428")) :op3 (c7 / cell-line :name (n9 / name :op1 "L-540")))) :ARG2 (i3 / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :op2 (p3 / protein :name (n3 / name :op1 "STAT6") :xref (x2 / xref :value "UNIPROT:STAT6_HUMAN" :prob "1.004"))))))) # ::id pmid_2282_9094.146 # ::date 2015-07-24T14:07:19 # ::file pmid_2282_9094_146.txt # ::snt High concentrations of AZD1480 promote early G2/M arrest and cell death in HL cells by inhibiting Aurora kinases # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / promote-01 :ARG0 (c / concentrate-02 :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (h / high-02)) :ARG1 (a2 / and :op1 (a / arrest-02 :time (e / event :name (n4 / name :op1 "G2/M"))) :op2 (d / die-01 :ARG1 (c2 / cell)) :location (c3 / cell-line :mod (d2 / disease :name (n2 / name :op1 "HL")))) :manner (i / inhibit-01 :ARG0 c :ARG1 (k / kinase :name (n3 / name :op1 "Aurora") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.352")))) # ::id pmid_2282_9094.147 # ::date 2015-07-24T14:27:09 # ::file pmid_2282_9094_147.txt # ::snt Higher concentrations (5 μ) of AZD1480 promoted a marked increase in the G2/M fraction in all four cell lines after 24 h of incubation, especially pronounced in HD-LM2 and L-428 cells (Figure 5a and b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p / promote-01 :ARG0 (c / concentrate-02 :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (h / high-02 :degree (m / more)) :ARG1-of (m2 / mean-01 :ARG2 (c2 / concentration-quantity :quant "5" :unit (m3 / micromolar)))) :ARG1 (i / increase-01 :ARG1 (f3 / fraction-01 :time (e2 / event :name (n2 / name :op1 "G2/M"))) :location (c3 / cell-line :quant "4") :ARG1-of (p3 / pronounced-02 :mod (e / especially) :location (a3 / and :op1 (c4 / cell-line :name (n3 / name :op1 "HD-LM2")) :op2 (c5 / cell-line :name (n4 / name :op1 "L-428")))) :ARG1-of (m4 / mark-01) :time (a2 / after :op1 (i2 / incubate-01 :duration (t / temporal-quantity :quant "72" :unit (h2 / hour))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "5a") :op2 (f2 / figure :mod "5b")))) # ::id pmid_2282_9094.148 # ::date 2015-07-25T05:23:36 # ::file pmid_2282_9094_148.txt # ::snt In contrast, treatment with a lower AZD1480 concentration (1 μ) for 24 h did not significantly affect the cell cycle fractions (Figure 5a and b). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (a / affect-01 :polarity "-" :ARG0 (t / treat-04 :ARG2 (c4 / concentrate-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (l / low-04 :degree (m2 / more)) :quant (c5 / concentration-quantity :quant "1" :unit (m / micromolar))) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour))) :ARG1 (f / fraction-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell))) :ARG1-of (s / significant-02)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "5a") :op2 (f3 / figure :mod "5b")))) # ::id pmid_2282_9094.149 # ::date 2015-07-25T05:51:04 # ::file pmid_2282_9094_149.txt # ::snt As AZD1480 was reported to inhibit Aurora A kinase in enzymatic assays,14 we assessed whether the significant increase in the G2/M fraction observed in HL cell lines after incubation with 5 μ AZD1480 was related to the inhibition of Aurora A. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / assess-01 :ARG0 (w / we) :ARG1 (r / relate-01 :mode "interrogative" :ARG1 (i / increase-01 :ARG1 (f / fraction-01 :time (e / event :name (n / name :op1 "G2/M"))) :ARG2 (s / significant-02) :ARG1-of (o / observe-01 :location (c / cell-line :mod (d / disease :name (n2 / name :op1 "HL"))) :time (a2 / after :op1 (i2 / incubate-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "AZD1480") :quant (c2 / concentration-quantity :quant "5" :unit (m / micromolar)) :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")))))) :ARG2 (i3 / inhibit-01 :ARG1 "k")) :ARG0-of (c3 / cause-01 :ARG1 (r2 / report-01 :ARG1 (i4 / inhibit-01 :ARG0 s2 :ARG1 (k / kinase :name (n5 / name :op1 "Aurora" :op2 "A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342")) :time (a3 / assay-01 :ARG1 (e2 / enzyme)))))) # ::id pmid_2282_9094.150 # ::date 2015-07-25T00:30:18 # ::file pmid_2282_9094_150.txt # ::snt First, we analyzed the baseline expression of Aurora A and B kinases in exponentially growing HL cells by western blotting. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (a2 / and :op1 (k / kinase :name (n3 / name :op1 "Aurora" :op2 "A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342")) :op2 (k2 / kinase :name (n4 / name :op1 "Aurora" :op2 "B") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342"))) :ARG3 (c / cell-line :ARG1-of (g / grow-01 :manner (e2 / exponential)) :mod (d / disease :name (n / name :op1 "HL"))) :manner (i / immunoblot-01) :mod (b / baseline)) :ord (o / ordinal-entity :value "1")) # ::id pmid_2282_9094.151 # ::date 2015-07-25T00:03:02 # ::file pmid_2282_9094_151.txt # ::snt All four cell lines showed overexpression of Aurora A and B, and histone H3, compared with PBMCs from healthy donors (Figure 5c). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (c2 / cell-line :quant "4" :mod (a / all)) :ARG1 (o / overexpress-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "Aurora" :op2 "A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342")) :op2 (e2 / enzyme :name (n2 / name :op1 "Aurora" :op2 "B") :xref (x2 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342")) :op3 (p3 / protein :name (n3 / name :op1 "histone" :op2 "H3") :xref (x / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "0.701")))) :ARG1-of (c / compare-01 :ARG2 (c3 / cell :name (n4 / name :op1 "PBMC") :source (p / person :mod (h / healthy) :ARG0-of (d / donate-01)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5c"))) # ::id pmid_2282_9094.152 # ::date 2015-07-24T14:50:35 # ::file pmid_2282_9094_152.txt # ::snt Aurora A kinase activity depends on autophosphorylation at Thr288 in the activation loop. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (d / depend-01 :ARG0 (a / activity-06 :ARG0 (k / kinase :name (n / name :op1 "Aurora") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.352"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod "288" :name (n2 / name :op1 "threonine") :part-of k :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 k :location (l / loop-01 :ARG0-of (a4 / activate-01 :ARG1 k)))) # ::id pmid_2282_9094.153 # ::date 2015-07-24T14:54:27 # ::file pmid_2282_9094_153.txt # ::snt Thus, to determine the effect of AZD1480 on Aurora A kinase, we evaluated the levels of autophosphorylation at Thr288 by western blotting. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / cause-01 :ARG1 (e2 / evaluate-01 :ARG0 (w / we) :ARG2 (l / level :degree-of (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "288" :name (n / name :op1 "threonine") :part-of "k" :xref (x2 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 "k")) :manner (i / immunoblot-01)) :purpose (d / determine-01 :ARG0 w :ARG1 (a3 / affect-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "AZD1480") :xref (x1 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1 (k / kinase :name (n4 / name :op1 "Aurora" :op2 "A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342"))))) # ::id pmid_2282_9094.154 # ::date 2015-07-24T23:31:16 # ::file pmid_2282_9094_154.txt # ::snt Cells were pretreated with nocodazole (400 ng/ml) for 18 h, to achieve a mitotic block, and then exposed to AZD1480 (1 or 5 μ) with or without the proteasome inhibitor MG132 (20 μ; to prevent a potential override of the nocodazole-induced mitotic block by proteasome-dependent mechanisms) for 3 h (Figure 5d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / and :op1 (p / pretreat-01 :ARG1 (c / cell) :ARG3 (s2 / small-molecule :name (n / name :op1 "nocodazole") :quant (c2 / concentration-quantity :quant "400" :unit (n2 / nanogram-per-milliliter)) :xref (x2 / xref :value "PUBCHEM:4122" :prob "18.349844")) :duration (t / temporal-quantity :quant "18" :unit (h / hour)) :purpose (a2 / achieve-01 :ARG0 c :ARG1 (b / block :mod (m / mitosis)))) :op2 (e / expose-01 :ARG1 c :ARG2 (s / small-molecule :name (n3 / name :op1 "AZD1480") :quant (o / or :op1 (c3 / concentration-quantity :quant "1" :unit (m2 / micromolar)) :op2 (c4 / concentration-quantity :quant "5" :unit m2)) :accompanier (o2 / or :op1 (s3 / small-molecule :name (n4 / name :op1 "MG132") :mod (c5 / concentration-quantity :quant "20" :unit m2) :ARG0-of (i / inhibit-01 :ARG1 (p2 / proteasome :xref (x / xref :value "GO:0000502" :prob "0.8"))) :purpose (p3 / prevent-01 :ARG1 (o3 / override-01 :ARG0 (m7 / mechanism :ARG0-of (d2 / depend-01 :ARG1 (m3 / macro-molecular-complex :name (n6 / name :op1 "proteasome")))) :ARG1 (b2 / block :mod (m8 / mitosis) :ARG2-of (i2 / induce-01 :ARG0 s2)) :mod (p5 / potential))) :xref (x1 / xref :value "PUBCHEM:462382" :prob "18.349844")) :op2 (s4 / small-molecule :polarity "-" :name (n5 / name :op1 "MG132") :xref (x3 / xref :value "PUBCHEM:462382" :prob "18.349844"))) :xref (x4 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :time (t2 / then) :duration (t3 / temporal-quantity :quant "3" :unit (h2 / hour))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5d"))) # ::id pmid_2282_9094.155 # ::date 2015-07-25T01:10:07 # ::file pmid_2282_9094_155.txt # ::snt Dose-dependent inhibition of Aurora A was detected after 3 h of incubation in all the four cell lines, and Thr288 autophosphorylation was abrogated when a higher dose of AZD1480 (5 μ) was used (Figure 5d). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (d2 / detect-01 :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Aurora" :op2 "A") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342")) :ARG0-of (d4 / depend-01 :ARG1 (d5 / dose-01))) :time (a3 / after :op1 (i2 / incubate-01 :location (c2 / cell-line :quant "4" :mod (a4 / all))) :quant (t / temporal-quantity :quant "3" :unit (h2 / hour)))) :op2 (a2 / abrogate-01 :ARG1 (p / phosphorylate-01 :ARG1 (a6 / amino-acid :mod "288" :name (n3 / name :op1 "Threonine") :part-of e :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 e) :time (u / use-01 :ARG1 (d3 / dose-01 :ARG2 (s / small-molecule :name (n / name :op1 "AZD1480") :xref (x2 / xref :value "PUBCHEM:16659841" :prob "18.572987")) :ARG1-of (h / high-02 :degree (m / more)) :quant (c / concentration-quantity :quant "5" :unit (m2 / micromolar))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5d"))) # ::id pmid_2282_9094.156 # ::date 2015-07-25T00:41:13 # ::file pmid_2282_9094_156.txt # ::snt These findings are consistent with the analysis of the cell cycle fractions, showing major dose-dependent changes in the cell cycle after incubation with AZD1480. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / consistent-01 :ARG1 (t / thing :ARG1-of (f / find-01) :mod (t2 / this) :ARG0-of (s / show-01 :ARG1 (c4 / change-01 :ARG1 (c5 / cycle-02 :ARG1 (c6 / cell)) :ARG0-of (d / depend-01 :ARG1 (d2 / dose)) :ARG1-of (m / major-02) :time (a2 / after :op1 (i / incubate-01 :ARG1 c6 :ARG2 (s2 / small-molecule :name (n / name :op1 "AZD1480") :xref (x / xref :value "PUBCHEM:16659841" :prob "18.572987"))))))) :ARG2 (a / analyze-01 :ARG1 (f2 / fraction :mod c5))) # ::id pmid_2282_9094.157 # ::date 2015-07-25T00:56:01 # ::file pmid_2282_9094_157.txt # ::snt In L-428 and L-540 cells, a dose-dependent inhibition of the phosphorylation of histone H3 at Ser10 was observed, suggesting a dual inhibition of Aurora A and B in these cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (o / observe-01 :ARG1 (i2 / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "10" :name (n4 / name :op1 "Serine") :part-of (p4 / protein :name (n3 / name :op1 "histone" :op2 "H3") :xref (x2 / xref :value "UNIPROT:A8K4Y7_HUMAN" :prob "0.701")) :xref (x3 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :ARG0-of (d2 / depend-01 :ARG1 (d3 / dose))) :ARG0-of (s / suggest-01 :ARG1 (i / inhibit-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Aurora" :op2 "A") :xref (x1 / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342")) :op2 (e2 / enzyme :name (n2 / name :op1 "Aurora" :op2 "B") :xref (x / xref :value "UNIPROT:AURKB_HUMAN" :prob "0.342"))) :location "a3" :mod (d / dual))) :location (a3 / and :op1 (c / cell-line :name (n5 / name :op1 "L-428")) :op2 (c2 / cell-line :name (n6 / name :op1 "L-540")))) # ::id pmid_2290_9976.1 # ::date 2015-08-24T01:18:14 # ::file pmid_2290_9976_1.txt # ::snt K-Ras gene mutation status as a prognostic and predictive factor in patients with colorectal cancer undergoing irinotecan- or oxaliplatin-based chemotherapy (PMID:22909976) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / status :mod (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :condition (f / factor :mod (p / prognostic) :ARG0-of (p2 / predict-01) :location (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (u / undergo-28 :ARG2 (c3 / chemotherapy :ARG1-of (b / base-02 :ARG2 (o / or :op1 (s2 / small-molecule :name (n3 / name :op1 "irinotecan") :xref (x2 / xref :value "PUBCHEM:60838" :prob "16.047258")) :op2 (s3 / small-molecule :name (n4 / name :op1 "oxaliplatin") :xref (x1 / xref :value "PUBCHEM:5310940" :prob "10.634277")))))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication-91 :ARG8 "PMID2909976"))) # ::id pmid_2290_9976.28 # ::date 2015-08-24T02:14:26 # ::file pmid_2290_9976_28.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2290_9976.29 # ::date 2015-08-24T02:14:55 # ::file pmid_2290_9976_29.txt # ::snt Patient characteristics # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (t / thing :ARG2-of (c / characteristic-02 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient))))) # ::id pmid_2290_9976.30 # ::date 2015-08-24T02:16:46 # ::file pmid_2290_9976_30.txt # ::snt Patient characteristics are summarized in Table 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / summarize-01 :ARG1 (t / thing :ARG2-of (c / characteristic-02 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient))))) :ARG2 (t2 / table :mod "1")) # ::id pmid_2290_9976.31 # ::date 2015-08-24T02:19:16 # ::file pmid_2290_9976_31.txt # ::snt The median age of the patients included in this study was 65 y (181 women, 92 men). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / age-01 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (i / include-01 :ARG2 (s / study-01 :mod (t2 / this))) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (w / woman :quant "181") :op2 (m3 / man :quant "92")))) :ARG2 (t / temporal-quantity :quant "65" :unit (y / year)) :mod (m / median)) # ::id pmid_2290_9976.32 # ::date 2015-08-24T02:23:03 # ::file pmid_2290_9976_32.txt # ::snt Most underwent primary tumor resection (260/273 patients, 95.2%), while secondary metastatic disease was diagnosed in 194 patients (71.1%), of whom 70 (36.1%) underwent resection and 22 (11.3%) underwent thermoablation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG1 (u / undergo-28 :ARG1 (p5 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient)) :quant (m / most) :ARG1-of (m2 / mean-01 :ARG2 (i / include-91 :ARG1 (p8 / person :quant "260" :ARG0-of h) :ARG2 (p9 / person :quant "273" :ARG0-of h) :ARG3 (p / percentage-entity :value "95.2")))) :ARG2 (r / resection :mod (t / tumor :mod (p7 / primary)))) :ARG2 (d / diagnose-01 :ARG1 (p10 / person :quant "194" :ARG0-of h :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value "71.1")) :ARG2-of (i2 / include-91 :ARG1 (a / and :op1 (p11 / person :quant "70" :ARG0-of h :ARG1-of (m5 / mean-01 :ARG2 (p3 / percentage-entity :value "36.1")) :ARG1-of (u2 / undergo-28 :ARG2 (r2 / resection))) :op2 (p12 / person :quant "22" :ARG0-of h :ARG1-of (u3 / undergo-28 :ARG2 (t2 / thermoablation)) :ARG1-of (m6 / mean-01 :ARG2 (p4 / percentage-entity :value "11.3")))))) :ARG2 (d2 / disease :mod (s / secondary) :ARG1-of (m3 / metastasize-101)))) # ::id pmid_2290_9976.33 # ::date 2015-08-24T02:30:42 # ::file pmid_2290_9976_33.txt # ::snt The primary tumor was located in the colon in 112 patients (41.1%), sigmoid colon in 100 patients (36.6%) and rectum in 61 patients (22.3%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (b / be-located-at-91 :ARG1 (t / tumor :mod (p4 / primary)) :ARG2 (c / colon) :location (p5 / person :quant "112" :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient)) :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value "41.1")))) :op2 (b2 / be-located-at-91 :ARG1 t :ARG2 (c2 / colon :mod (s / sigmoid)) :location (p7 / person :quant "100" :ARG0-of h :ARG1-of (m2 / mean-01 :ARG2 (p2 / percentage-entity :value "36.6")))) :op3 (b3 / be-located-at-91 :ARG1 t :ARG2 (r / rectum) :location (p8 / person :quant "61" :ARG0-of h :ARG1-of (m3 / mean-01 :ARG2 (p3 / percentage-entity :value "22.3"))))) # ::id pmid_2290_9976.34 # ::date 2015-08-24T02:36:18 # ::file pmid_2290_9976_34.txt # ::snt The metastases were located in the liver in 129 (66.5% of patients with metastases), in the lungs in 39 (20.1%), and in other organs in 126 patients (64.9%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (b / be-located-at-91 :ARG1 (m / metastasize-101) :ARG2 (l2 / liver) :location (p4 / person :quant "129" :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient)) :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value "66.5" :ARG3-of (i / include-91 :ARG2 (p6 / person :ARG0-of h :ARG0-of (h2 / have-03 :ARG1 m))))))) :op2 (b2 / be-located-at-91 :ARG1 m :ARG2 (l4 / lung) :location (p7 / person :quant "39" :ARG0-of h :ARG1-of (m5 / mean-01 :ARG2 (p2 / percentage-entity :value "20.1")))) :op3 (b3 / be-located-at-91 :ARG1 m :ARG2 (o / organ :mod (o2 / other)) :location (p8 / person :quant "126" :ARG0-of h :ARG1-of (m7 / mean-01 :ARG2 (p3 / percentage-entity :value "64.9"))))) # ::id pmid_2290_9976.35 # ::date 2015-08-24T02:41:35 # ::file pmid_2290_9976_35.txt # ::snt Pretreatment carcinoembryonic antigen (CEA) levels were elevated above the normal range in 89 patients (32.6%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / elevate-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "carcinoembryonic" :op2 "antigen") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "0.702")) :time (b / before :op1 (t / treat-04))) :ARG2 (a / above :op1 (r / range :ARG1-of (n2 / normal-02))) :location (p3 / person :quant "89" :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value "32.6")))) # ::id pmid_2290_9976.36 # ::date 2015-08-24T02:45:20 # ::file pmid_2290_9976_36.txt # ::snt Table 1. Patient and tumor characteristics # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / describe-01 :ARG0 (t / table :mod "1") :ARG1 (a / and :op1 (c / characteristic-02 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)))) :op2 (c2 / characteristic-02 :ARG1 (t2 / tumor)))) # ::id pmid_2290_9976.37 # ::date 2015-08-24T02:49:12 # ::file pmid_2290_9976_37.txt # ::snt K-Ras and B-Raf gene mutation status # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (a / and :op1 (s / status :mod (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :op2 (s2 / status :mod (m2 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) # ::id pmid_2290_9976.38 # ::date 2015-08-24T02:50:26 # ::file pmid_2290_9976_38.txt # ::snt K-Ras gene mutations were present in 89 patients (32.6%), of whom 76 (85.4%) had mutations in codon 12 and 10 (11.2%) had mutations in codon 13. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p4 / present-102 :ARG0 (p5 / person :quant "89" :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient)) :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value "32.6")) :ARG2-of (i / include-91 :ARG1 (a / and :op1 (p7 / person :quant "76" :ARG0-of h :ARG1-of (m3 / mean-01 :ARG2 (p2 / percentage-entity :value "85.4")) :ARG0-of (h2 / have-03 :ARG1 (m4 / mutate-01 :ARG1 (c / codon :mod "12")))) :op2 (p8 / person :quant "10" :ARG0-of h :ARG1-of (m5 / mean-01 :ARG2 (p3 / percentage-entity :value "11.2")) :ARG0-of (h3 / have-03 :ARG1 (m6 / mutate-01 :ARG1 (c2 / codon :mod "13"))))))) :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) # ::id pmid_2290_9976.39 # ::date 2015-08-24T02:57:07 # ::file pmid_2290_9976_39.txt # ::snt Women showed a higher incidence of K-Ras gene mutations relative to men (p = 0.0290). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (w / woman) :ARG1 (i / incidence :ARG1-of (h / high-02 :degree (m / more) :compared-to (m3 / man) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0290")) :frequency-of (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) # ::id pmid_2290_9976.40 # ::date 2015-08-24T04:25:35 # ::file pmid_2290_9976_40.txt # ::snt No significant differences were observed with respect to tumor size, lymph node involvement grade, histological grade, histopathological type, primary tumor localization, performance status, age, or pretreatment CEA level. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (o / observe-01 :ARG1 (d / differ-02 :polarity "-" :ARG3 (o2 / or :op1 (s2 / size :poss (t / tumor)) :op2 (g / grade :extent-of (i / involve-01 :ARG1 (n / node :mod (l / lymph)))) :op3 (g2 / grade :mod (h / histology)) :op4 (t2 / type :mod (h2 / histopathology)) :op5 (b2 / be-located-at-91 :ARG1 (t3 / tumor :mod (p / primary))) :op6 (s3 / status :mod (p2 / perform-02)) :op7 (a / age-01) :op8 (l3 / level :quant-of (p3 / protein :name (n2 / name :op1 "CEA") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "1.002")) :time (b / before :op1 (t4 / treat-03)))) :ARG1-of (s / significant-02))) # ::id pmid_2290_9976.41 # ::date 2015-08-24T04:32:41 # ::file pmid_2290_9976_41.txt # ::snt B-Raf gene mutations were present in 17 patients (6.9%), of whom 6 (35.3%) had mutations in exon 15. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p3 / present-102 :ARG0 (p4 / person :quant "17" :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient)) :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value "6.9")) :ARG2-of (i / include-91 :ARG1 (p6 / person :quant "6" :ARG0-of h :ARG0-of (h2 / have-03 :ARG1 (m4 / mutate-01 :ARG1 (e / exon :mod "15")))) :ARG3 (p2 / percentage-entity :value "35.3"))) :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) # ::id pmid_2290_9976.42 # ::date 2015-08-24T04:35:32 # ::file pmid_2290_9976_42.txt # ::snt One patient had a mutation in exon 11, while mutation status was not determined in 10 patients (58.8%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (h / have-03 :ARG0 (p2 / person :quant "1" :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient))) :ARG1 (m / mutate-01 :ARG1 (e / exon :mod "11"))) :ARG2 (d2 / determine-01 :polarity "-" :ARG1 (s / status :mod (m2 / mutate-01)) :location (p4 / person :quant "10" :ARG0-of h2 :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value "58.8"))))) # ::id pmid_2290_9976.43 # ::date 2015-08-24T04:37:58 # ::file pmid_2290_9976_43.txt # ::snt A higher incidence of B-Raf gene mutations was detected in patients with low-grade neoplasm (p < 0.0001), primary tumor localization outside the sigmoid colon (p = 0.0467) and with non-tubular neoplasms (p = 0.0468). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / detect-01 :ARG1 (i / incidence :ARG1-of (h / high-02 :degree (m / more)) :frequency-of (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :location (a / and :op1 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h3 / have-03 :ARG1 (n2 / neoplasm :mod (g2 / grade :ARG1-of (l / low-04)) :ARG1-of (s2 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.0001"))))) :op2 (p4 / person :ARG0-of h2 :ARG0-of (h4 / have-03 :ARG1 (b / be-located-at-91 :ARG1 (t / tumor :mod (p5 / primary) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0467")) :ARG2 (o / outside :op1 (c / colon :mod (s / sigmoid)))))) :op3 (p7 / person :ARG0-of h2 :ARG0-of (h5 / have-03 :ARG1 (n3 / neoplasm :mod (t2 / tubular :polarity "-") :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0468")))))) # ::id pmid_2290_9976.44 # ::date 2015-08-24T04:46:49 # ::file pmid_2290_9976_44.txt # ::snt Other parameters assessed were not statistically different. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (d / differ-02 :polarity "-" :ARG1 (p / parameter :mod (o / other) :ARG1-of (a / assess-01)) :manner (s / statistic)) # ::id pmid_2290_9976.45 # ::date 2015-08-24T04:48:31 # ::file pmid_2290_9976_45.txt # ::snt Prognostic significance of K-Ras and B-Raf gene mutation status # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (s / signify-01 :ARG0 (a / and :op1 (s2 / status :mod (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :op2 (s3 / status :mod (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :mod (p / prognostic)) # ::id pmid_2290_9976.46 # ::date 2015-08-24T04:51:02 # ::file pmid_2290_9976_46.txt # ::snt There were no significant differences in OS rates between patients with K-Ras mutations and wild-type K-Ras genes (p = 0.6869; Fig. 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / differ-02 :polarity "-" :ARG1 (r / rate :mod (s2 / survive-01 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h2 / have-03 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) :mod (o2 / overall))) :ARG2 (r2 / rate :mod (s3 / survive-01 :ARG1 (p3 / person :ARG0-of h :ARG0-of (h3 / have-03 :ARG1 (g2 / gene :name (n2 / name :op1 "K-Ras") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :mod o2)) :ARG1-of (s / significant-02) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.6869")) # ::id pmid_2290_9976.47 # ::date 2015-08-24T04:55:59 # ::file pmid_2290_9976_47.txt # ::snt A perceptible trend to prolongation of OS was apparent when K-Ras mutations were present in codon 13 relative to codon 12 (p = 0.0830; Fig. 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (a / appear-02 :ARG1 (t / trend-01 :ARG1 (p / prolong-01 :ARG1 (s / survive-01 :mod (o2 / overall))) :ARG1-of (p2 / perceptive-02 :ARG1-of (p5 / possible-01))) :time (p3 / present-102 :ARG1 (m / mutate-01 :ARG1 (c / codon :mod "13" :part-of (g / gene :name (n3 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :ARG1-of (r / relative-05 :ARG3 (p4 / present-102 :ARG1 (m2 / mutate-01 :ARG1 (c2 / codon :mod "12" :part-of g))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2")) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0830")) # ::id pmid_2290_9976.48 # ::date 2015-08-24T05:02:20 # ::file pmid_2290_9976_48.txt # ::snt Similarly, mutations in the B-Raf gene showed no prognostic significance (Fig. 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / show-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG1 (s2 / significant-02 :polarity "-" :ARG1 m :mod (p / prognostic)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3")) :ARG1-of (r / resemble-01)) # ::id pmid_2290_9976.49 # ::date 2015-08-24T05:04:05 # ::file pmid_2290_9976_49.txt # ::snt Patients with disseminated CRC (M+) and B-Raf gene mutations tended toward shorter OS relative to those with wild-type B-Raf genes (p = 0.06723). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (t / tend-02 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h2 / have-03 :ARG1 (a / and :op1 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal" :op2 "cancer") :ARG1-of (d2 / disseminate-01) :ARG1-of (l / label-01 :ARG2 (s4 / string-entity :value "M+"))) :op2 (m2 / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))))) :ARG2 (s / short-07 :ARG1 (s2 / survive-01 :ARG0 p :mod (o2 / overall)) :degree (m3 / more) :ARG1-of (r / relative-05 :ARG3 (p3 / person :ARG0-of h :ARG0-of (h4 / have-03 :ARG1 (g2 / gene :name (n / name :op1 "B-Raf") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.06723")) # ::id pmid_2290_9976.50 # ::date 2015-08-24T05:10:17 # ::file pmid_2290_9976_50.txt # ::snt Clinical and pathological variables identified by univariate analysis as potential prognostic factors for OS rate # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (a / and :op1 (v / variable :mod (c / clinic)) :op2 (v2 / variable :mod (p / pathology)) :ARG1-of (i / identify-01 :ARG0 (a2 / analyze-01 :mod (u / univariate)) :ARG2 (f / factor :mod (p2 / prognostic) :mod (p3 / potential) :topic (r / rate :mod (s / survive-01 :mod (o2 / overall)))))) # ::id pmid_2290_9976.51 # ::date 2015-08-24T05:16:05 # ::file pmid_2290_9976_51.txt # ::snt These results are summarized in Table 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (s / summarize-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (t3 / table :mod "2")) # ::id pmid_2290_9976.52 # ::date 2015-08-26T01:05:51 # ::file pmid_2290_9976_52.txt # ::snt Univariate analysis identified the following prognostic factors as influencing OS rate in this patient cohort: Age, patients 75 y and older lived for 36.7 mo relative to those younger than 75 (58.9 mo) (p = 0.0472); Gender, female patients lived for 62.7 mo relative to 42.6 mo for male patients (p = 0.0328); Primary tumor localization, patients with primary tumors in the sigmoid colon lived for 68.0 mo compared with 43.5 mo in patients with primary tumors located in the colon or rectum (p = 0.0039); Performance status, patients with a good performance score e.g., WHO 0–1 (58.4 mo) and Karnofsky status 81–100% (58.1 mo) lived longer relative to those with poor performance status (19.0 and 19.4 mo for patients with WHO 2–3 and Karnofsky status ≤ 80%, respectively) (p = 0.0027 and p = 0.0036, respectively); Lymph node involvement grade, survival in patients without lymph node metastases was 65.3 mo relative to 46.3 mo in patients presenting with metastases (p = 0.0031); Pretreatment CEA level, median time to progression in patients with normal pretreatment CEA level ≤ 5 ng/ml was 76.3 mo relative to 25.6 mo in patients with increased pretreatment CEA level (p < 0.0001; Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / identify-01 :ARG0 (a / analyze-01 :mod (u / univariate)) :ARG1 (f / factor :ARG1-of (f2 / follow-04) :mod (p / prognostic) :ARG0-of (i2 / influence-01 :ARG1 (r / rate :mod (s11 / survive-01 :mod (o6 / overall))) :location (c / cohort :mod (t / this) :consist-of (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient))))) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (a3 / age-01 :ARG1-of (m2 / mean-01 :ARG2 (l / live-01 :ARG0 (p4 / person :ARG0-of h :age (a5 / and :op1 (t2 / temporal-quantity :quant "75" :unit (y / year)) :op2 (m3 / more-than :op1 t2))) :duration (t3 / temporal-quantity :quant "36.7" :unit (m4 / month) :ARG1-of (r2 / relative-05 :ARG3 (p5 / person :ARG0-of h :age (l2 / less-than :op1 t2) :ARG0-of (l3 / live-01 :duration (t4 / temporal-quantity :quant "58.9" :unit m4))))))) :ARG1-of (s12 / statistical-test-91 :ARG2 "0.0472")) :op2 (g / gender :ARG1-of (m5 / mean-01 :ARG2 (l4 / live-01 :ARG0 (p7 / person :mod (f3 / female) :ARG0-of h) :duration (t5 / temporal-quantity :quant "62.7" :unit m4 :ARG1-of (r3 / relative-05 :ARG3 (t6 / temporal-quantity :quant "42.6" :unit m4 :duration-of (l5 / live-01 :ARG0 (p8 / person :mod (m6 / male) :ARG0-of h))))))) :ARG1-of (s13 / statistical-test-91 :ARG2 "0.0328")) :op3 (b6 / be-located-at-91 :ARG1 (t7 / tumor :mod (p10 / primary)) :ARG1-of (m7 / mean-01 :ARG2 (l7 / live-01 :ARG0 (p11 / person :ARG0-of h :ARG0-of (h2 / have-03 :ARG1 t7 :location (c2 / colon :mod (s / sigmoid)))) :duration (t8 / temporal-quantity :quant "68.0" :unit m4 :compared-to (t9 / temporal-quantity :quant "43.5" :unit m4 :duration-of (l8 / live-01 :ARG0 (p12 / person :ARG0-of h :ARG0-of (h3 / have-03 :ARG1 t7 :location (o2 / or :op1 (c3 / colon) :op2 (r4 / rectum))))))))) :ARG1-of (s14 / statistical-test-91 :ARG2 "0.0039")) :op4 (s2 / status :mod (p14 / perform-01) :ARG1-of (m8 / mean-01 :ARG2 (l9 / live-01 :ARG0 (p15 / person :ARG0-of h :ARG1-of (s3 / score-01 :ARG2 (a7 / and :op1 (s4 / status :value (b / between :op1 "0" :op2 "1") :mod (o / organization :wiki "World_Health_Organization" :name (n6 / name :op1 "World" :op2 "Health" :op3 "Organization"))) :op2 (s5 / status :value (b2 / between :op1 (p16 / percentage-entity :value "81") :op2 (p17 / percentage-entity :value "100")) :mod (p34 / person :name (n / name :op1 "Karnofsky")))) :ARG3 p14 :ARG1-of (g2 / good-02))) :ARG1-of (l10 / long-03 :ARG2 (m9 / more) :ARG1-of (r5 / relative-05 :ARG3 (p18 / person :ARG0-of h :ARG0-of (h4 / have-03 :ARG1 (s6 / status :mod p14 :mod (p19 / poor))) :ARG1-of (m10 / mean-01 :ARG2 (a8 / and :op1 (t12 / temporal-quantity :quant "19.0" :unit m4 :duration-of (l11 / live-01 :ARG0 (p20 / person :ARG0-of h :ARG0-of (h5 / have-03 :ARG1 (s7 / status :value (b3 / between :op1 "2" :op2 "3") :mod o)))) :ARG1-of (s15 / statistical-test-91 :ARG2 "0.0027")) :op2 (t13 / temporal-quantity :quant "19.4" :unit m4 :duration-of (l12 / live-01 :ARG0 (p21 / person :ARG0-of h :ARG0-of (h6 / have-03 :ARG1 (s8 / status :value (o4 / or :op1 (l13 / less-than :op1 (p22 / percentage-entity :value "80")) :op2 p22) :mod p34)))) :ARG1-of (s16 / statistical-test-91 :ARG2 "0.0036")))))) :ARG1-of (m15 / mean-01 :ARG2 (a9 / and :op1 (t10 / temporal-quantity :quant "58.4" :unit m4 :condition s4) :op2 (t11 / temporal-quantity :quant "58.1" :unit m4 :condition s5))))))) :op5 (g3 / grade :degree-of (i3 / involve-01 :ARG1 (n2 / node :mod (l14 / lymph))) :ARG1-of (m11 / mean-01 :ARG2 (s9 / survive-01 :ARG0 (p25 / person :ARG0-of h :ARG0-of (h7 / have-03 :polarity "-" :ARG1 (m12 / metastasize-101 :ARG2 n2))) :duration (t14 / temporal-quantity :quant "65.3" :unit m4 :ARG1-of (r6 / relative-05 :ARG3 (t15 / temporal-quantity :quant "46.3" :unit m4 :duration-of (s10 / survive-01 :ARG0 (p26 / person :ARG0-of h :ARG0-of (p27 / present-102 :ARG1 m12)))))))) :ARG1-of (s17 / statistical-test-91 :ARG2 "0.0031")) :op6 (l15 / level :time (b4 / before :op1 (t16 / treat-03)) :quant-of (p29 / protein :name (n3 / name :op1 "CEA") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "1.002")) :ARG1-of (m13 / mean-01 :ARG2 (t17 / time :time (b5 / before :op1 (p30 / progress-01)) :mod (m14 / median) :location (p31 / person :ARG0-of h :ARG0-of (h8 / have-03 :ARG1 (l16 / level :ARG1-of (n4 / normal-02) :time b4 :quant (o5 / or :op1 (c4 / concentration-quantity :quant "5" :unit (n5 / nanogram-per-milliliter)) :op2 (l17 / less-than :op1 c4)) :quant-of p29))) :duration (t18 / temporal-quantity :quant "76.3" :unit m4 :ARG1-of (r7 / relative-05 :ARG3 (t19 / temporal-quantity :quant "25.6" :unit m4 :duration-of (t20 / time :location (p32 / person :ARG0-of h :ARG0-of (h9 / have-03 :ARG1 (l18 / level :ARG1-of (i4 / increase-01) :quant-of p29 :time b4))) :mod m14 :time b5)))))) :ARG1-of (d / describe-01 :ARG0 (t21 / table :mod "2")) :ARG1-of (s18 / statistical-test-91 :ARG2 "0.0001")))))) # ::id pmid_2290_9976.53 # ::date 2015-08-24T05:18:34 # ::file pmid_2290_9976_53.txt # ::snt Table 2. Univariate and multivariate analysis of OS rate (log-rank test) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (d / describe-01 :ARG0 (t / table :mod "2") :ARG1 (a / and :op1 (a2 / analyze-01 :ARG1 (r / rate :mod (s / survive-01 :mod (o2 / overall))) :mod (u / univariate)) :op2 (a3 / analyze-01 :ARG1 r :mod (m / multivariate)) :ARG1-of (m2 / mean-01 :ARG2 (t2 / test-01 :mod (l / log-rank))))) # ::id pmid_2290_9976.54 # ::date 2015-08-24T05:20:26 # ::file pmid_2290_9976_54.txt # ::snt Other clinical parameters such as histological differentiation grade and primary tumor size showed no significant differences between groups. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / show-01 :ARG0 (p / parameter :mod (o / other) :mod (c / clinic) :example (a / and :op1 (g / grade :degree-of (d / differentiate-01 :mod (h / histology))) :op2 (s2 / size :poss (t / tumor :mod (p2 / primary))))) :ARG1 (d2 / differ-02 :polarity "-" :ARG1 (g2 / group) :ARG3 p :ARG1-of (s3 / significant-02))) # ::id pmid_2290_9976.55 # ::date 2015-08-24T05:24:10 # ::file pmid_2290_9976_55.txt # ::snt Clinical and pathological variables identified by multivariate analysis as potential prognostic factors for OS rate # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (a / and :op1 (v / variable :mod (c / clinic)) :op2 (v2 / variable :mod (p / pathology)) :ARG1-of (i / identify-01 :ARG0 (a2 / analyze-01 :mod (m / multivariate)) :ARG2 (f / factor :mod (p2 / potential) :mod (p3 / prognostic) :topic (r / rate :mod (s / survive-01 :mod (o2 / overall)))))) # ::id pmid_2290_9976.56 # ::date 2015-08-24T05:26:02 # ::file pmid_2290_9976_56.txt # ::snt These results are summarized in Table 2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (s / summarize-01 :ARG1 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG2 (t3 / table :mod "2")) # ::id pmid_2290_9976.57 # ::date 2015-08-26T00:29:29 # ::file pmid_2290_9976_57.txt # ::snt Multivariate analysis identified the following independent prognostic factors affecting OS rates: Primary tumor localization (HR 0.53; p = 0.0032); Pretreatment CEA level (HR 2.68; p < 0.0001); WHO performance status (HR 0.34; p = 0.0008); Lymph node involvement grade (HR 1.94; p = 0.0107). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (i / identify-01 :ARG0 (a / analyze-01 :mod (m / multivariate)) :ARG1 (f / factor :ARG1-of (f2 / follow-04) :ARG0-of (d / depend-01 :polarity "-") :mod (p / prognostic) :ARG0-of (a2 / affect-01 :ARG1 (r / rate :mod (s2 / survive-01 :mod (o3 / overall)))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (b2 / be-located-at-91 :ARG1 (t / tumor :mod (p2 / primary)) :ARG1-of (m3 / mean-01 :ARG2 (r2 / ratio-of :quant "0.53" :op1 (h / hazard))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0032")) :op2 (l2 / level :quant-of (p4 / protein :name (n / name :op1 "CEA") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "1.002")) :time (b / before :op1 (t2 / treat-03)) :ARG1-of (m4 / mean-01 :ARG2 (r3 / ratio-of :quant "2.68" :op1 h)) :ARG1-of (s4 / statistical-test-91 :ARG2 (l3 / less-than :op1 "0.0001"))) :op3 (s / status :mod (p6 / perform-02 :ARG2 (o2 / organization :wiki "World_Health_Organization" :name (n2 / name :op1 "World" :op2 "Health" :op3 "Organization"))) :ARG1-of (m5 / mean-01 :ARG2 (r4 / ratio-of :quant "0.34" :op1 h)) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.0008")) :op4 (g / grade :degree-of (i2 / involve-01 :ARG1 (n3 / node :mod (l4 / lymph))) :ARG1-of (m6 / mean-01 :ARG2 (r5 / ratio-of :quant "1.94" :op1 h)) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.01077")))))) # ::id pmid_2290_9976.58 # ::date 2015-08-24T05:27:22 # ::file pmid_2290_9976_58.txt # ::snt Other clinical parameters such as age, gender, and Karnofsky performance status showed no significant differences in this analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 14, 2015 (s / show-01 :ARG0 (p / parameter :mod (o / other) :mod (c / clinic) :example (a / and :op1 (a2 / age-01) :op2 (g / gender) :op3 (s2 / status :mod (p2 / perform-02) :mod (p3 / person :name (n / name :op1 "Karnofsky"))))) :ARG1 (d / differ-02 :polarity "-" :ARG1 p :time (a3 / analyze-01 :mod (t / this)) :ARG1-of (s3 / significant-02))) # ::id pmid_2290_9976.59 # ::date 2015-08-25T07:37:22 # ::file pmid_2290_9976_59.txt # ::snt Predictive roles of K-Ras and B-Raf mutations on time to progression in CRC patients treated with irinotecan-based first-line palliative chemotherapy on the basis of univariate analysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p / play-02 :ARG0 (a / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :ARG1 (p2 / predict-01 :ARG0 a :ARG1 (t2 / time :time (b2 / before :op1 (p6 / progress-01 :ARG1 (d / disease))))) :location (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG1-of (t / treat-03 :ARG2 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer")) :ARG3 (c / chemotherapy :mod (p5 / palliative) :ARG1-of (b / base-02 :ARG2 (s / small-molecule :name (n4 / name :op1 "irinotecan") :xref (x2 / xref :value "PUBCHEM:60838" :prob "16.047258"))) :mod (l / line :ord (o / ordinal-entity :value "1"))))) :ARG1-of (b3 / base-02 :ARG2 (a2 / analyze-01 :mod (u / univariate)))) # ::id pmid_2290_9976.60 # ::date 2015-08-25T07:51:16 # ::file pmid_2290_9976_60.txt # ::snt These results are summarized in Table 3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (s / summarize-01 :ARG1 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG2 (t3 / table :mod "3")) # ::id pmid_2290_9976.61 # ::date 2015-08-25T07:54:08 # ::file pmid_2290_9976_61.txt # ::snt Patients with higher pretreatment levels of CEA (> 5 ng/ml) showed a median time to progression of 9.0 mo relative to 13.0 mo in patients with normal levels (≤ 5 ng/ml, p = 0.0085). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h2 / have-03 :ARG1 (l / level :ARG1-of (h3 / high-02 :degree (m / more)) :quant-of (p3 / protein :name (n / name :op1 "CEA") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "1.002")) :ARG1-of (m2 / mean-01 :ARG2 (m3 / more-than :op1 (c / concentration-quantity :quant "5" :unit (n2 / nanogram-per-milliliter)))) :time (b / before :op1 (t / treat-03))))) :ARG1 (t2 / time :time (b2 / before :op1 (p4 / progress-01)) :mod (m4 / median) :ARG1-of (r / relative-05 :ARG3 (t4 / time :ARG1-of (s2 / show-01 :ARG0 (p5 / person :ARG0-of h :ARG0-of (h4 / have-03 :ARG1 (l2 / level :ARG1-of (n3 / normal-02) :ARG1-of (m6 / mean-01 :ARG2 (o / or :op1 (l3 / less-than :op1 c) :op2 c)) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0085"))))) :duration (t5 / temporal-quantity :quant "13" :unit "m5") :time b2)) :duration (t3 / temporal-quantity :quant "9" :unit (m5 / month)))) # ::id pmid_2290_9976.62 # ::date 2015-08-25T08:11:40 # ::file pmid_2290_9976_62.txt # ::snt Patients without resection of metastases showed a median time to progression of 9.0 mo relative to 14.0 mo in patients who underwent resection (p = 0.0131). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (u / undergo-28 :polarity "-" :ARG2 (r / resection :mod (m / metastasize-101)))) :ARG1 (t / time :mod (m2 / median) :time (b / before :op1 (p3 / progress-01)) :ARG1-of (r2 / relative-05 :ARG3 (t3 / time :ARG1-of (s2 / show-01 :ARG0 (p4 / person :ARG0-of h :ARG1-of (u2 / undergo-28 :ARG2 r))) :duration (t4 / temporal-quantity :quant "14" :unit "m3") :time b)) :duration (t2 / temporal-quantity :quant "9" :unit (m3 / month))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0131")) # ::id pmid_2290_9976.63 # ::date 2015-08-25T08:19:47 # ::file pmid_2290_9976_63.txt # ::snt Patients with K-Ras gene mutations showed a median time to progression of 9.0 mo relative to 11.0 mo in those with the wild-type K-Ras gene (p = 0.05883). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h2 / have-03 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) :ARG1 (t / time :mod (m2 / median) :time (b / before :op1 (p3 / progress-01)) :ARG1-of (r / relative-05 :ARG3 (t3 / time :ARG1-of (s2 / show-01 :ARG0 (p4 / person :ARG0-of h :ARG0-of (h3 / have-03 :ARG1 (g2 / gene :name (n2 / name :op1 "K-Ras") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) :duration (t4 / temporal-quantity :quant "11" :unit "m3") :time b)) :duration (t2 / temporal-quantity :quant "9" :unit (m3 / month))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.05883")) # ::id pmid_2290_9976.64 # ::date 2015-08-25T08:24:18 # ::file pmid_2290_9976_64.txt # ::snt Other clinical parameters including histological differentiation grade, primary tumor location and size, lymph node involvement grade, and B-Raf gene mutation status showed no predictive significance in this analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (s / show-01 :ARG0 (p / parameter :mod (o / other) :mod (c / clinic) :ARG2-of (i / include-91 :ARG1 (a / and :op1 (g / grade :degree-of (d / differentiate-01 :mod (h / histology))) :op2 (b / be-located-at-91 :ARG1 (t / tumor :mod (p2 / primary))) :op3 (s2 / size :poss t) :op4 (g2 / grade :degree-of (i2 / involve-01 :ARG1 (n3 / node :mod (l2 / lymph)))) :op5 (s3 / status :mod (m / mutate-01 :ARG1 (g3 / gene :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))))) :ARG1 (s4 / significant-02 :polarity "-" :ARG1 p :ARG0-of (p3 / predict-01)) :time (a2 / analyze-01 :mod (t2 / this))) # ::id pmid_2290_9976.65 # ::date 2015-08-25T08:34:33 # ::file pmid_2290_9976_65.txt # ::snt Table 3. Univariate and multivariate analysis of time to progression (log-rank test) for irinotecan-based chemotherapy # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (d / describe-01 :ARG0 (t / table :mod "3") :ARG1 (a / and :op1 (a2 / analyze-01 :ARG1 (t2 / time :time (b / before :op1 (p / progress-01))) :mod (u / univariate)) :op2 (a3 / analyze-01 :ARG1 t2 :mod (m / multivariate)) :ARG1-of (m2 / mean-01 :ARG2 (t3 / test-01 :mod (l / log-rank))) :condition (c / chemotherapy :ARG1-of (b2 / base-02 :ARG2 (s / small-molecule :name (n / name :op1 "irinotecan") :xref (x / xref :value "PUBCHEM:60838" :prob "16.047258")))))) # ::id pmid_2290_9976.66 # ::date 2015-08-25T08:38:35 # ::file pmid_2290_9976_66.txt # ::snt Predictive roles of K-Ras and B-Raf mutations on time to progression in CRC patients treated with irinotecan-based first-line palliative chemotherapy on the basis of multivariate analysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p / play-02 :ARG0 (a / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :ARG1 (p2 / predict-01 :ARG0 a :ARG1 (t / time :time (b / before :op1 (p3 / progress-01 :ARG1 (d / disease))))) :location (p4 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (t2 / treat-03 :ARG2 (c / chemotherapy :ARG1-of (b2 / base-02 :ARG2 (s / small-molecule :name (n4 / name :op1 "irinotecan") :xref (x2 / xref :value "PUBCHEM:60838" :prob "16.047258"))) :mod (p6 / palliative) :mod (l / line :ord (o / ordinal-entity :value "1"))))) :ARG1-of (b3 / base-02 :ARG2 (a2 / analyze-01 :mod (m3 / multivariate)))) # ::id pmid_2290_9976.67 # ::date 2015-08-25T08:52:20 # ::file pmid_2290_9976_67.txt # ::snt These results are summarized in Table 3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (s / summarize-01 :ARG1 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG2 (t3 / table :mod "3")) # ::id pmid_2290_9976.68 # ::date 2015-08-25T08:57:13 # ::file pmid_2290_9976_68.txt # ::snt Multivariate analysis identified the following independent favorable predictive factors in patients with disseminated CRC treated with irinotecan-based first-line palliative chemotherapy: Wild-type K-Ras gene (HR 0.59; p = 0.0459) and normal pretreatment CEA levels (HR 0.52; p = 0.0065). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (i / identify-01 :ARG0 (a / analyze-01 :mod (m / multivariate)) :ARG1 (f / factor :ARG1-of (f2 / follow-04) :ARG0-of (d / depend-01 :polarity "-") :ARG0-of (p / predict-01) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (g / gene :name (n3 / name :op1 "K-Ras") :mod (w / wild-type) :ARG1-of (m3 / mean-01 :ARG2 (r / ratio-of :quant "0.59" :op1 (h3 / hazard))) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0459") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (l2 / level :ARG1-of (n4 / normal-02) :time (b2 / before :op1 (t2 / treat-03)) :quant-of (p6 / protein :name (n5 / name :op1 "CEA") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "1.002")) :ARG1-of (m4 / mean-01 :ARG2 (r2 / ratio-of :quant "0.52" :op1 h3)) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.065")))) :mod (f3 / favorable)) :location (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer") :ARG1-of (d3 / disseminate-01))) :ARG1-of (t / treat-03 :ARG2 (c / chemotherapy :ARG1-of (b / base-02 :ARG2 (s / small-molecule :name (n2 / name :op1 "irinotecan") :xref (x2 / xref :value "PUBCHEM:60838" :prob "16.047258"))) :mod (l / line :ord (o / ordinal-entity :value "1")) :mod (p4 / palliative))))) # ::id pmid_2290_9976.69 # ::date 2015-08-25T08:57:38 # ::file pmid_2290_9976_69.txt # ::snt However, this analysis did not reveal any significant differences between patients with and without resection of metastases, with different histological types of neoplasms and B-Raf gene mutation status. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG2 (r / reveal-01 :polarity "-" :ARG0 (a / analyze-01 :mod (t2 / this)) :ARG1 (d / differ-02 :ARG1 (a2 / and :op1 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h3 / have-03 :ARG1 (r2 / resection :mod (m / metastasize-101)))) :op2 (p3 / person :ARG0-of h2 :ARG0-of (h4 / have-03 :polarity "-" :ARG1 r2))) :ARG2 (a3 / and :op1 (p4 / person :ARG0-of h2 :ARG0-of (h5 / have-03 :ARG1 (t / type :mod (n3 / neoplasm) :mod (h6 / histology) :ARG1-of (d2 / differ-02)))) :op2 (p5 / person :ARG0-of h2 :ARG0-of (h7 / have-03 :ARG1 (s2 / status :ARG1-of d2 :mod (m2 / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))))) :ARG1-of (s / significant-02)))) # ::id pmid_2290_9976.70 # ::date 2015-08-25T09:08:09 # ::file pmid_2290_9976_70.txt # ::snt Predictive roles of K-Ras and B-Raf mutations on time to progression in CRC patients treated with oxaliplatin-based first-line palliative chemotherapy on the basis of univariate analysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p / play-02 :ARG0 (a / and :op1 (m / mutate-01 :ARG1 (g / gene :wiki "-" :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m2 / mutate-01 :ARG2 (g2 / gene :wiki "BRAF_(gene)" :name (n3 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :ARG1 (p2 / predict-01 :ARG0 a :ARG1 (t / time :time (b / before :op1 (p3 / progress-01 :ARG1 (d / disease))))) :location (p4 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (t2 / treat-03 :ARG2 (c / chemotherapy :mod (p6 / palliative) :ARG1-of (b2 / base-02 :ARG2 (s / small-molecule :wiki "Oxaliplatin" :name (n4 / name :op1 "oxaliplatin") :xref (x2 / xref :value "PUBCHEM:5310940" :prob "10.634277"))) :mod (l / line :ord (o / ordinal-entity :value "1"))))) :ARG1-of (b3 / base-02 :ARG2 (a2 / analyze-01 :mod (u / univariate)))) # ::id pmid_2290_9976.71 # ::date 2015-08-25T09:11:40 # ::file pmid_2290_9976_71.txt # ::snt These results are summarized in Table 4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (s / summarize-01 :ARG1 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG2 (t3 / table :mod "4")) # ::id pmid_2290_9976.72 # ::date 2015-08-25T09:12:43 # ::file pmid_2290_9976_72.txt # ::snt Univariate analysis of time to progression in patients treated with oxaliplatin-based first-line chemotherapy regimens reveals that increased CEA levels and resection of metastases exerted significant influences on median time to progression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (t / time :time (b / before :op1 (p / progress-01))) :mod (u / univariate)) :ARG1 (e / exert-01 :ARG0 (a2 / and :op1 (l2 / level :quant-of (p4 / protein :name (n2 / name :op1 "CEA") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "1.002")) :ARG1-of (i / increase-01)) :op2 (r3 / resection :mod (m / metastasize-101))) :ARG1 (i2 / influence-01 :ARG1-of (s2 / significant-02)) :ARG2 (t3 / time :time b :mod (m2 / median))) :location (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :ARG1-of (t2 / treat-03 :ARG2 (r2 / regimen :mod (c / chemotherapy :ARG1-of (b2 / base-02 :ARG2 (s / small-molecule :name (n / name :op1 "oxaliplatin") :xref (x1 / xref :value "PUBCHEM:5310940" :prob "10.634277"))) :mod (l / line :ord (o / ordinal-entity :value "1"))))))) # ::id pmid_2290_9976.73 # ::date 2015-08-25T09:17:59 # ::file pmid_2290_9976_73.txt # ::snt Patients with increased pretreatment CEA levels had a time to progression of 8.0 mo compared with 13.0 mo in patients with normal CEA levels (p = 0.0084). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h3 / have-03 :ARG1 (l / level :quant-of (p3 / protein :name (n / name :op1 "CEA") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "1.002")) :ARG1-of (i / increase-01) :time (b / before :op1 (t / treat-03))))) :ARG1 (t2 / time :time (b2 / before :op1 (p4 / progress-01)) :duration (t3 / temporal-quantity :quant "8" :unit (m / month)) :compared-to (t4 / time :time b2 :duration (t5 / temporal-quantity :quant "13" :unit m) :ARG1-of (h4 / have-03 :ARG0 (p5 / person :ARG0-of h2 :ARG0-of (h5 / have-03 :ARG1 (l2 / level :ARG1-of (n2 / normal-02) :quant-of p3)))))) :ARG1-of (s / statistical-test-91 :ARG2 "0.0084")) # ::id pmid_2290_9976.74 # ::date 2015-08-25T09:27:02 # ::file pmid_2290_9976_74.txt # ::snt Patients without resection of metastases had a time to progression of 9.0 mo relative to 16.0 mo in patients who underwent resection (p = 0.0226). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (u / undergo-28 :polarity "-" :ARG2 (r / resection :mod (m / metastasize-101)))) :ARG1 (t / time :time (b / before :op1 (p3 / progress-01)) :duration (t2 / temporal-quantity :quant "9" :unit (m2 / month)) :ARG1-of (r2 / relative-05 :ARG3 (t3 / time :time b :duration (t4 / temporal-quantity :quant "16" :unit m2) :ARG1-of (h3 / have-03 :ARG0 (p4 / person :ARG0-of h2 :ARG1-of (u2 / undergo-28 :ARG2 r)))))) :ARG1-of (s / statistical-test-91 :ARG2 "0.0226")) # ::id pmid_2290_9976.75 # ::date 2015-08-25T09:37:34 # ::file pmid_2290_9976_75.txt # ::snt Patients with tubular tumors showed a time to progression of 9.0 mo compared with 13.0 mo in those with other histological types (p = 0.0462). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h2 / have-03 :ARG1 (t / tumor :mod (t2 / tubular)))) :ARG1 (t3 / time :time (b / before :op1 (p3 / progress-01)) :duration (t4 / temporal-quantity :quant "9" :unit (m / month)) :compared-to (t5 / time :time b :duration (t6 / temporal-quantity :quant "13" :unit m) :ARG1-of (s2 / show-01 :ARG0 (p4 / person :ARG0-of h :mod (t7 / type :mod (h3 / histology) :mod (o / other)))))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0462")) # ::id pmid_2290_9976.76 # ::date 2015-08-25T09:41:49 # ::file pmid_2290_9976_76.txt # ::snt Patients with K-Ras gene mutations did not show a significant difference in time to progression when treated with oxaliplatin chemotherapy, when compared with those with the wild-type K-Ras gene (Fig. 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / show-01 :polarity "-" :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h2 / have-03 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) :ARG1 (d / differ-02 :ARG1 (t / time :time (b / before :op1 (p3 / progress-01))) :ARG1-of (s2 / significant-02)) :time (t2 / treat-03 :ARG1 p :ARG2 (c / chemotherapy :mod (s3 / small-molecule :name (n2 / name :op1 "oxaliplatin") :xref (x2 / xref :value "PUBCHEM:5310940" :prob "10.634277")))) :compared-to (p4 / person :ARG0-of h :mod (g2 / gene :name (n3 / name :op1 "K-Ras") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4"))) # ::id pmid_2290_9976.77 # ::date 2015-08-25T09:46:40 # ::file pmid_2290_9976_77.txt # ::snt The significance of B-Raf gene status, WHO performance status, and Karnofsky performance status could not be assessed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (p2 / possible-01 :polarity "-" :ARG1 (a / assess-01 :ARG1 (s / signify-01 :ARG0 (a2 / and :op1 (s2 / status :mod (g / gene :name (n / name :op1 "B-RAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "0.673"))) :op2 (s3 / status :mod (p3 / perform-02) :mod (o / organization :wiki "World_Health_Organization" :name (n2 / name :op1 "World" :op2 "Health" :op3 "Organization"))) :op3 (s4 / status :mod (p4 / perform-02) :mod (p / person :name (n3 / name :op1 "Karnofsky"))))))) # ::id pmid_2290_9976.78 # ::date 2015-08-25T09:49:45 # ::file pmid_2290_9976_78.txt # ::snt Table 4. Univariate and multivariate analysis of time to progression (log-rank test) for oxaliplatin-based chemotherapy # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (d / describe-01 :ARG0 (t / table :mod "4") :ARG1 (a / and :op1 (a2 / analyze-01 :ARG1 (t2 / time :time (b / before :op1 (p / progress-01))) :mod (u / univariate)) :op2 (a3 / analyze-01 :ARG1 t2 :mod (m / multivariate)) :ARG1-of (m2 / mean-01 :ARG2 (t3 / test-01 :mod (l / log-rank))) :condition (c / chemotherapy :ARG1-of (b2 / base-02 :ARG2 (s / small-molecule :name (n / name :op1 "oxaliplatin") :xref (x / xref :value "PUBCHEM:5310940" :prob "10.634277")))))) # ::id pmid_2290_9976.79 # ::date 2015-08-25T09:52:58 # ::file pmid_2290_9976_79.txt # ::snt Predictive roles of K-Ras and B-Raf mutations on time to progression in CRC patients treated with oxaliplatin-based first-line palliative chemotherapy on the basis of multivariate analysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p / play-02 :ARG0 (a / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :ARG1 (p2 / predict-01 :ARG0 a :ARG1 (t / time :time (b / before :op1 (p3 / progress-01 :ARG1 (d / disease))))) :location (p4 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (t2 / treat-03 :ARG2 (c / chemotherapy :mod (p6 / palliative) :ARG1-of (b2 / base-02 :ARG2 (s / small-molecule :name (n4 / name :op1 "oxaliplatin") :xref (x2 / xref :value "PUBCHEM:5310940" :prob "10.634277"))) :mod (l / line :ord (o / ordinal-entity :value "1"))))) :ARG1-of (b3 / base-02 :ARG2 (a2 / analyze-01 :mod (m3 / multivariate)))) # ::id pmid_2290_9976.80 # ::date 2015-08-25T10:00:53 # ::file pmid_2290_9976_80.txt # ::snt These results are summarized in Table 4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (s / summarize-01 :ARG1 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG2 (t3 / table :mod "4")) # ::id pmid_2290_9976.81 # ::date 2015-08-25T10:01:37 # ::file pmid_2290_9976_81.txt # ::snt Multivariate analysis identified resection of metastases (HR 0.43; p = 0.0249) and wild-type K-Ras gene (HR 0.49; p = 0.0451) as independent favorable predictive factors in patients with disseminated CRC who were treated with oxaliplatin-based first-line palliative chemotherapy regimens. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (i / identify-01 :ARG0 (a / analyze-01 :mod (m / multivariate)) :ARG1 (a2 / and :op1 (r / resection :mod (m2 / metastasize-101) :ARG1-of (m3 / mean-01 :ARG2 (r2 / ratio-of :quant "0.43" :op1 (h / hazard))) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0249")) :op2 (g / gene :name (n / name :op1 "K-Ras") :mod (w / wild-type) :ARG1-of (m4 / mean-01 :ARG2 (r3 / ratio-of :quant "0.49" :op1 h)) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0451") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG2 (f / factor :ARG0-of (d / depend-01 :polarity "-") :ARG0-of (p3 / predict-01) :mod (f3 / favorable)) :location (p4 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p5 / patient)) :ARG0-of (h3 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer") :ARG1-of (d3 / disseminate-01))) :ARG1-of (t / treat-03 :ARG2 (r4 / regimen :mod (c / chemotherapy :ARG1-of (b / base-02 :ARG2 (s / small-molecule :name (n3 / name :op1 "oxaliplatin") :xref (x1 / xref :value "PUBCHEM:5310940" :prob "10.634277"))) :mod (l / line :ord (o / ordinal-entity :value "1")) :mod (p6 / palliative)))))) # ::id pmid_2290_9976.82 # ::date 2015-08-25T10:01:56 # ::file pmid_2290_9976_82.txt # ::snt However, no statistically significant effects of CEA levels and types of neoplasm could be seen. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (h / have-concession-91 :ARG1 (p / possible-01 :ARG1 (s / see-01 :ARG1 (a / affect-01 :polarity "-" :ARG0 (a2 / and :op1 (l / level :quant-of (p2 / protein :name (n / name :op1 "CEA") :xref (x / xref :value "UNIPROT:CEAM5_HUMAN" :prob "1.002"))) :op2 (t / type :mod (n2 / neoplasm))) :ARG1-of (s2 / significant-02 :manner (s3 / statistic)))))) # ::id pmid_2290_9976.83 # ::date 2015-08-25T10:04:26 # ::file pmid_2290_9976_83.txt # ::snt The significance of B-Raf gene status, WHO performance status, and Karnofsky performance status could not be assessed due to the small number of patients. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p2 / possible-01 :polarity "-" :ARG1 (a / assess-01 :ARG1 (s2 / signify-01 :ARG0 (a2 / and :op1 (s / status :mod (g / gene :name (n2 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :op2 (s3 / status :mod (p3 / perform-02) :mod (o / organization :wiki "World_Health_Organization" :name (n3 / name :op1 "World" :op2 "Health" :op3 "Organization"))) :op3 (s4 / status :mod (p4 / perform-02) :mod (p / person :name (n4 / name :op1 "Karnofsky")))))) :ARG1-of (c / cause-01 :ARG0 (n / number :mod (s5 / small) :quant-of (p5 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient)))))) # ::id pmid_2303_9341.1 # ::date 2015-06-23T00:51:05 # ::file pmid_2303_9341_1.txt # ::snt Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status (PMID:23039341) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / associate-01 :ARG1 (s / sensitive-03 :ARG0 (c / cell :mod (m2 / medical-condition :wiki "Melanoma" :name (n3 / name :op1 "melanoma"))) :ARG1 (s4 / small-molecule :wiki "-" :name (n / name :op1 "E6201") :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :wiki "Mitogen-activated_protein_kinase_kinase" :name (n2 / name :op1 "MEK"))) :xref (x2 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG2 (a2 / and :op1 (s2 / status :mod (g / gene :wiki "BRAF_(gene)" :name (n4 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (s3 / status :mod (g2 / gene :wiki "PTEN_(gene)" :name (n5 / name :op1 "PTEN") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID23039341"))) # ::id pmid_2303_9341.8 # ::date 2015-06-23T01:05:59 # ::file pmid_2303_9341_8.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 23, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2303_9341.9 # ::date 2015-06-23T01:06:58 # ::file pmid_2303_9341_9.txt # ::snt The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (o / or :op1 (s / sensitive-03 :ARG0 (c / cell-line :quant "24" :quant (m / majority) :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "31" :mod (m2 / medical-condition :name (n / name :op1 "melanoma")))) :ARG0-of (h2 / have-03 :ARG1 (c6 / concentrate-02 :mod (i3 / inhibit-01 :degree (p / percentage-entity :degree "50")) :quant (l3 / less-than :op1 (c2 / concentration-quantity :quant "500" :unit (n3 / nanomolar)))))) :ARG1 (s3 / small-molecule :name (n2 / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :op2 (s2 / sensitive-03 :ARG0 (c4 / cell-line :quant "18" :ARG1-of (i2 / include-91 :ARG2 c3) :ARG0-of (h3 / have-03 :ARG1 (c7 / concentrate-02 :mod i3 :quant (l / less-than :op1 (c5 / concentration-quantity :quant "100" :unit n3)))) :quant (m3 / majority) :mod m2) :ARG1 s3 :degree (h / hyper))) # ::id pmid_2303_9341.10 # ::date 2015-06-23T01:34:19 # ::file pmid_2303_9341_10.txt # ::snt This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (c2 / correlate-01 :ARG1 (s / sensitive-03 :mod (t / this)) :ARG2 (a / and :op1 (s2 / status :mod (g / gene :name (n2 / name :op1 "PTEN") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :op2 (s3 / status :mod (g2 / gene :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG2 (a2 / associate-01 :ARG1 (a6 / and :op1 (g3 / gene :name (n3 / name :op1 "RAS") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op2 (p / pathway :name (n4 / name :op1 "PI3K") :ARG1-of (a7 / activate-01))) :ARG2 (r / resist-01))) # ::id pmid_2303_9341.11 # ::date 2015-06-23T01:42:45 # ::file pmid_2303_9341_11.txt # ::snt Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e2 / elicit-01 :ARG0 (s4 / small-molecule :name (n2 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1 (a / affect-01 :ARG0 s4 :ARG1 (l / line :ARG0-of (s / sensitive-03) :quant (m / most) :ARG1-of (i2 / include-91 :ARG2 (l2 / line :ARG0-of (s2 / sensitive-03) :ARG1-of (s3 / study-01)))) :ARG2 (c / cytocide :mod (p / potent))) :concession (e3 / exert-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p5 / protein-family :name (n3 / name :op1 "MEK")))) :ARG2 (a2 / affect-01 :ARG0 m2 :ARG2 (c2 / cytostatic) :ARG1-of (p4 / predominate-01))) :ARG1-of (e5 / evidence-01 :ARG0 (a3 / and :op1 (p2 / positive :domain (p3 / protein :name (n4 / name :op1 "Annexin") :xref (x / xref :value "UNIPROT:A0A024R5Z7_HUMAN" :prob "1.001"))) :op2 (c3 / cell :ARG1-of (d / die-01))) :instrument (t / thing :name (n / name :op1 "ELISA")))) # ::id pmid_2303_9341.12 # ::date 2015-06-23T02:02:29 # ::file pmid_2303_9341_12.txt # ::snt Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c3 / contrast-01 :ARG2 (i / induce-01 :polarity "-" :ARG0 (s / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1 (c / cell-line :quant "2" :mod (m / medical-condition :name (n2 / name :op1 "melanoma")) :ARG0-of (r / resist-01) :ARG1-of (t2 / test-01)) :ARG2 (d2 / die-01 :ARG1 (c2 / cell)))) # ::id pmid_2303_9341.13 # ::date 2015-06-23T04:24:49 # ::file pmid_2303_9341_13.txt # ::snt E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1 (g / grow-01 :ARG1 (t2 / tumor :mod (x / xenograft))) :location (c2 / cell-line :quant "4" :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma")) :mod (a / all) :ARG1-of (s / study-01)) :degree (d3 / degree :ARG1-of (v / vary-01))) :ARG2 (o / observe-01 :ARG1 (a2 / affect-01 :ARG1 (c3 / cell-line :ARG0-of (d2 / demonstrate-01 :ARG1 (r / respond-01 :ARG0 c3 :ARG2 (c4 / cytocide)) :manner (i2 / in-vitro) :time (p2 / previous))) :ARG2 (c5 / counter-01 :ARG1 (t3 / tumor)) :ARG1-of (p / pronounce-01 :degree (m / more))))) # ::id pmid_2303_9341.14 # ::date 2015-06-23T04:50:20 # ::file pmid_2303_9341_14.txt # ::snt In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / show-01 :ARG0 (c / combine-01 :ARG1 (a2 / and :op1 (s4 / study-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :op2 (s5 / study-01 :ARG1 (s6 / small-molecule :name (n2 / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")))) :manner (i3 / in-vitro) :ARG1-of (d2 / define-01 :ARG0 (i / index :mod (c3 / combine-01 :mod (m / mean)) :value (l / less-than :op1 "1")))) :ARG1 (s3 / synergism) :location (c2 / cell-line :quant "6" :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma")) :ARG1-of (t3 / test-01) :mod (a / all))) # ::id pmid_2303_9341.44 # ::date 2015-06-23T05:14:58 # ::file pmid_2303_9341_44.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 23, 2015 (t / thing :ARG1-of (r / result-01)) # ::id pmid_2303_9341.45 # ::date 2015-06-23T05:15:43 # ::file pmid_2303_9341_45.txt # ::snt Sensitivity to E6201 in a melanoma cell line panel # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / sensitive-03 :ARG0 (p / panel :consist-of (c / cell-line :mod (m / medical-condition :name (n2 / name :op1 "melanoma")))) :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134"))) # ::id pmid_2303_9341.46 # ::date 2015-06-23T05:17:12 # ::file pmid_2303_9341_46.txt # ::snt Sensitivity to E6201 was assessed in a panel of 31 cell lines for which the mutation status of common melanoma genes was known (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / assess-01 :ARG1 (s / sensitive-03 :ARG1 (s3 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :location (p / panel :consist-of (c / cell-line :quant "31" :mod (k / know-01 :ARG1 (s2 / status :mod (m / mutate-01 :ARG1 (g / gene :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma")) :mod (c2 / common))))))) :ARG1-of (d2 / describe-01 :ARG0 (t2 / table :mod "1"))) # ::id pmid_2303_9341.47 # ::date 2015-06-23T05:31:03 # ::file pmid_2303_9341_47.txt # ::snt These lines were chosen to represent different mutational profiles from a larger panel of more than one hundred melanoma cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / choose-01 :ARG1 (l / line :mod (t / this)) :ARG2 (p2 / panel :mod (l2 / large :degree (m3 / more)) :consist-of (c2 / cell-line :mod (m2 / medical-condition :name (n / name :op1 "melanoma")) :quant (m4 / more-than :op1 "100"))) :ARG4 (r / represent-01 :ARG0 l :ARG1 (p / profile :mod (m / mutate-01) :ARG1-of (d / differ-02)))) # ::id pmid_2303_9341.48 # ::date 2015-06-23T05:41:06 # ::file pmid_2303_9341_48.txt # ::snt Western blots in Additional file 1: Figure S1 confirm that E6201 efficiently inhibits MEK1/2 activity by virtue of its ability to abrogate phosphorylation of ERK1/2 in our entire panel of melanoma cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / confirm-01 :ARG0 (i2 / immunoblot-01 :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S1" :location (f2 / file :mod "1" :mod (a / additional))))) :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEK1/2"))) :ARG2-of (e / efficient-01 :ARG1 s) :ARG1-of (c4 / cause-01 :ARG0 (c3 / capable-01 :ARG1 s :ARG2 (a4 / abrogate-01 :ARG0 s :ARG1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "ERK1/2"))) :location (p3 / panel :consist-of (c2 / cell-line :mod (m / medical-condition :name (n6 / name :op1 "melanoma"))) :mod (e4 / entire) :poss (w2 / we))))))) # ::id pmid_2303_9341.49 # ::date 2015-06-23T05:53:27 # ::file pmid_2303_9341_49.txt # ::snt The majority (24/31) of the melanoma cell lines were sensitive to E6201 (IC50 <500 nM) (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / sensitive-03 :ARG0 (c / cell-line :quant "24" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "31" :mod (m2 / medical-condition :name (n / name :op1 "melanoma"))) :ARG3 (m / majority)) :mod (c4 / concentrate-02 :mod (i2 / inhibit-01 :degree (p / percentage-entity :value "50")) :quant (l2 / less-than :op1 (c3 / concentration-quantity :quant "500" :unit (n3 / nanomolar))))) :ARG1 (s2 / small-molecule :name (n2 / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1"))) # ::id pmid_2303_9341.50 # ::date 2015-06-23T05:58:14 # ::file pmid_2303_9341_50.txt # ::snt MAPK activation due to mutations in BRAF and NRAS was not significantly associated with increased sensitivity to E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / associate-01 :ARG1 (a2 / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK")) :ARG1-of (c / cause-01 :ARG0 (m / mutate-01 :ARG1 (a3 / and :op1 (g / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n4 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))))) :ARG2 (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "E6201") :xref (x2 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1-of (i / increase-01)) :ARG1-of (s / significant-02 :polarity "-")) # ::id pmid_2303_9341.51 # ::date 2015-06-23T06:07:34 # ::file pmid_2303_9341_51.txt # ::snt In the 26 cell lines carrying mutations in BRAF, NRAS, or HRAS, sensitivity to E6201 was statistically associated with wildtype PTEN status (p = 0.02). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / associate-01 :ARG1 (s / sensitive-03 :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201") :xref (x4 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG2 (s3 / status :mod (g / gene :name (n2 / name :op1 "PTEN") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :mod (s2 / statistic) :location (c / cell-line :quant "26" :ARG0-of (c2 / carry-01 :ARG1 (m / mutate-01 :ARG1 (o / or :op1 (g2 / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g3 / gene :name (n4 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op3 (g4 / gene :name (n5 / name :op1 "HRAS") :xref (x3 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))))) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.02")) # ::id pmid_2303_9341.52 # ::date 2015-06-23T06:14:43 # ::file pmid_2303_9341_52.txt # ::snt Specifically, of the 18 cell lines with wildtype PTEN, 17 were sensitive whereas in the 8 cell lines with mutant PTEN, only 4 were sensitive. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (s / sensitive-03 :ARG0 (c2 / cell-line :quant "17" :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "18" :ARG0-of (h / have-03 :ARG1 (g / gene :name (n / name :op1 "PTEN") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))))) :ARG2 (s2 / sensitive-03 :ARG0 (c4 / cell-line :quant "4" :ARG1-of (i2 / include-91 :ARG2 (c5 / cell-line :quant "8" :ARG0-of (h2 / have-03 :ARG1 (g2 / gene :name (n2 / name :op1 "PTEN") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))) :mod (o / only))) :ARG1-of (s3 / specific-02)) # ::id pmid_2303_9341.53 # ::date 2015-06-23T06:28:29 # ::file pmid_2303_9341_53.txt # ::snt Moreover, even if PTEN status alone is examined, E6201 sensitivity is associated, albeit non-significantly, with wildtype PTEN status; 23/31 cell lines are wildtype for PTEN and of these 20 are sensitive (whereas only 4/8 cell lines with mutant PTEN are sensitive) (p = 0.053). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (m / multi-sentence :snt1 (a / and :op2 (a2 / associate-01 :ARG1 (s / sensitive-03 :ARG1 (s7 / small-molecule :name (n / name :op1 "E6201") :xref (x4 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG2 (s2 / status :mod (g4 / gene :name (n2 / name :op1 "PTEN") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :ARG1-of (s3 / significant-02 :polarity "-" :concession-of a2) :concession (e2 / even-if :op1 (e3 / examine-01 :ARG1 (s4 / status :mod (g3 / gene :name (n3 / name :op1 "PTEN") :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :mod (a3 / alone)))))) :snt2 (c / contrast-01 :ARG1 (a4 / and :op1 (c2 / cell-line :quant "23" :mod (g2 / gene :name (n4 / name :op1 "PTEN") :mod (w2 / wild-type) :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "31"))) :op2 (s5 / sensitive-03 :ARG0 (c4 / cell-line :quant "20" :ARG1-of (i2 / include-91 :ARG2 c2)))) :ARG2 (s6 / sensitive-03 :ARG0 (c5 / cell-line :quant "4" :ARG1-of (i3 / include-91 :ARG2 (c6 / cell-line :quant "8" :ARG0-of (h2 / have-03 :ARG1 (m2 / mutate-01 :ARG2 (g / gene :name (n5 / name :op1 "PTEN") :xref (x3 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")))))) :mod (o / only))) :ARG1-of (s8 / statistical-test-91 :ARG2 "0.053"))) # ::id pmid_2303_9341.54 # ::date 2015-06-23T06:53:58 # ::file pmid_2303_9341_54.txt # ::snt Interestingly, 18 of the 24 sensitive cell lines also demonstrated hypersensitivity to E6201, with an IC50 < 100 nM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (d / demonstrate-01 :ARG0 (c / cell-line :quant "18" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "24" :ARG0-of (s2 / sensitive-03))) :ARG0-of (h2 / have-03 :ARG1 (c4 / concentrate-02 :mod (i3 / inhibit-01 :degree (p / percentage-entity :value "50")) :mod (l2 / less-than :op1 (c3 / concentration-quantity :quant "100" :unit (n2 / nanomolar)))))) :ARG1 (s3 / sensitive-03 :ARG0 c :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :degree (h / hyper)) :mod (a / also) :ARG0-of (i2 / interest-01)) # ::id pmid_2303_9341.55 # ::date 2015-06-23T06:59:57 # ::file pmid_2303_9341_55.txt # ::snt Using this criterion, BRAF mutation status correlated with E6201 hypersensitivity (p < 0.03), with 15 out of the 18 hypersensitive cell lines possessing a BRAF mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / correlate-01 :ARG1 (s / status :mod (g / gene :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (s2 / sensitive-03 :ARG1 (s5 / small-molecule :name (n2 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :degree (h / hyper)) :condition (u / use-01 :ARG1 (c2 / criterion :mod (t2 / this))) :prep-with (c3 / cell-line :quant "15" :ARG0-of (p2 / possess-01 :ARG1 g) :ARG1-of (i / include-91 :ARG2 (c4 / cell-line :quant "18" :ARG0-of (s4 / sensitive-03 :degree (h3 / hyper))))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.03"))) # ::id pmid_2303_9341.56 # ::date 2015-06-23T07:30:16 # ::file pmid_2303_9341_56.txt # ::snt In contrast, of the 11 cell lines with wildtype BRAF, only 3 were hypersensitive. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (c / contrast-01 :ARG2 (c2 / cell-line :quant "3" :ARG0-of (s / sensitive-03 :degree (h / hyper)) :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "11" :ARG0-of (h2 / have-03 :ARG1 (g / gene :name (n / name :op1 "BRAF") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :mod (o / only))) # ::id pmid_2303_9341.57 # ::date 2015-06-23T07:34:35 # ::file pmid_2303_9341_57.txt # ::snt In those cell lines carrying mutations in BRAF (21 cell lines), sensitivity to E6201 was not statistically associated with wildtype PTEN status. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / associate-01 :polarity "-" :ARG1 (s / sensitive-03 :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201") :xref (x2 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG2 (s2 / status :mod (g2 / gene :name (n2 / name :op1 "PTEN") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :mod (s3 / statistic) :location (c / cell-line :quant "21" :ARG0-of (c2 / carry-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :mod (t / that))) # ::id pmid_2303_9341.58 # ::date 2015-06-23T07:42:00 # ::file pmid_2303_9341_58.txt # ::snt NRAS/HRAS mutation status correlated with E6201 resistance, where none of the 5 NRAS/HRAS mutant cell lines were hypersensitive to E6201 and 18 of the 26 NRAS/HRAS wildtype cell lines were hypersensitive (p < 0.01). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / correlate-01 :ARG1 (s / status :mod (m / mutate-01 :ARG1 (s2 / slash :op1 (g5 / gene :name (n2 / name :op1 "NRAS") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op2 (g6 / gene :name (n3 / name :op1 "HRAS") :xref (x / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003"))))) :ARG2 (r / resist-01 :ARG1 (s8 / small-molecule :name (n / name :op1 "E6201") :xref (x2 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :example (a / and :op1 (c2 / cell-line :quant "0" :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "5" :mod (m2 / mutate-01 :ARG2 (s3 / slash :op1 g5 :op2 g6)))) :ARG0-of (s4 / sensitive-03 :ARG1 s8 :degree (h / hyper))) :op2 (c4 / cell-line :quant "18" :ARG1-of (i2 / include-91 :ARG2 (c5 / cell-line :quant "26" :mod (s5 / slash :op1 g5 :op2 g6 :mod (w / wild-type)))) :ARG0-of s4)) :ARG1-of (s6 / statistical-test-91 :ARG2 (l / less-than :op1 "0.01"))) # ::id pmid_2303_9341.59 # ::date 2015-06-23T08:00:55 # ::file pmid_2303_9341_59.txt # ::snt Neither CDKN2A, CDK4 or TP53 mutational status in our panel of melanoma cell lines, irrespective of their BRAF and RAS mutational status, was associated with E6201 sensitivity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (a / associate-01 :ARG1 (s / status :mod (m / mutate-01 :ARG1 (o / or :op1 (g / gene :name (n3 / name :op1 "CDKN2A") :xref (x4 / xref :value "UNIPROT:CD2A1_HUMAN" :prob "1.002")) :op2 (g2 / gene :name (n4 / name :op1 "CDK4") :xref (x3 / xref :value "UNIPROT:CDK4_HUMAN" :prob "1.003")) :op3 (g3 / gene :name (n5 / name :op1 "TP53") :xref (x2 / xref :value "UNIPROT:P53_HUMAN" :prob "1.003")))) :mod (n6 / neither) :location (p / panel :poss (w / we) :consist-of (c / cell-line :mod (m3 / medical-condition :name (n7 / name :op1 "melanoma"))))) :ARG2 (s2 / sensitive-03 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "E6201") :xref (x5 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG1-of (r / regardless-91 :ARG2 (s3 / status :mod (m2 / mutate-01 :ARG1 (a2 / and :op1 (g4 / gene :name (n8 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g5 / gene :name (n9 / name :op1 "RAS") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")))) :poss c))) # ::id pmid_2303_9341.60 # ::date 2015-06-23T08:15:10 # ::file pmid_2303_9341_60.txt # ::snt E6201 sensitivity and downstream pathway activation # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jun 24, 2015 (a / and :op1 (s2 / small-molecule :name (n / name :op1 "E6201") :ARG1-of (s / sensitive-03) :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :op2 (a2 / activate-01 :ARG1 (p / pathway :mod (d / downstream)))) # ::id pmid_2303_9341.61 # ::date 2015-06-23T08:16:54 # ::file pmid_2303_9341_61.txt # ::snt To determine whether E6201 responsiveness correlated with direct Akt or ERK1/2 activation, the phosphorylation status of Akt and ERK1/2 proteins was evaluated following serum starvation (Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / evaluate-01 :ARG1 (a / and :op1 (s / status :mod (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :op2 (s2 / status :mod (p3 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))))) :ARG1-of (f / follow-01 :ARG2 (s3 / starve-01 :ARG2 (s4 / serum))) :purpose (d / determine-01 :ARG1 (c / correlate-01 :mode "interrogative" :ARG1 (r / respond-01 :ARG1 (s5 / small-molecule :name (n3 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG2 (a2 / activate-01 :ARG1 (a3 / and :op1 e3 :op2 e2) :ARG1-of (d2 / direct-02)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "2"))) # ::id pmid_2303_9341.62 # ::date 2015-06-23T08:33:20 # ::file pmid_2303_9341_62.txt # ::snt Phosphorylated (p) Akt (Ser473) was detectable in 7/7 cell lines with mutant PTEN. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / detect-01 :ARG1 (a / amino-acid :mod "473" :name (n2 / name :op1 "serine") :part-of (e / enzyme :name (n4 / name :op1 "Akt") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :location (c / cell-line :quant "7" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "7" :ARG0-of (h / have-03 :ARG1 (m2 / mutate-01 :ARG2 (p3 / protein :name (n3 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))))) :ARG1-of (p2 / possible-01)) # ::id pmid_2303_9341.63 # ::date 2015-06-23T08:39:33 # ::file pmid_2303_9341_63.txt # ::snt In addition, pAkt was present in 5/23 cell lines with wildtype PTEN although the mechanism responsible for phosphorylation of Akt in these cell lines is unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op2 (h2 / have-concession-91 :ARG1 (p / present-02 :ARG1 (e / enzyme :name (n / name :op1 "Akt") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG2 (c2 / cell-line :quant "5" :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "23" :ARG0-of (h / have-03 :ARG1 (g / gene :name (n2 / name :op1 "PTEN") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))))) :ARG2 (k / know-01 :polarity "-" :ARG1 (m / mechanism :ARG0-of (r / responsible-01 :ARG1 (p5 / phosphorylate-01 :ARG1 (p4 / protein) :location c3)))))) # ::id pmid_2303_9341.64 # ::date 2015-06-23T08:50:06 # ::file pmid_2303_9341_64.txt # ::snt Phosphorylated (p) ERK1/2 was detected in all cell lines with mutant BRAF (20/20). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (d / detect-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :location (c / cell-line :quant "20" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "20" :ARG0-of (h / have-03 :ARG1 (m / mutate-01 :ARG2 (g / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) :mod (a / all))) # ::id pmid_2303_9341.65 # ::date 2015-06-23T08:56:33 # ::file pmid_2303_9341_65.txt # ::snt Consistent with previous reports [13,26], elevated pERK1/2 was detected in 3/5 cell lines with mutant NRAS or HRAS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 15, 2015 (d / detect-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01) :ARG1-of (e2 / elevate-01)) :location (c / cell-line :quant "3" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "5" :ARG0-of (h / have-03 :ARG1 (m / mutate-01 :ARG2 (o / or :op1 (g2 / gene :name (n2 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op2 (g / gene :name (n3 / name :op1 "HRAS") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))))))) :ARG1-of (c3 / consistent-01 :ARG2 (r / report-01 :time (p2 / previous)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 (a / and :op1 "13" :op2 "26")))))) # ::id pmid_2303_9341.66 # ::date 2015-06-23T09:09:28 # ::file pmid_2303_9341_66.txt # ::snt All five cell lines with wildtype BRAF and NRAS also had elevated ERK1/2 phosphorylation, as reported previously [26,27], although the mechanism responsible for ERK1/2 activation in these cell lines is unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (h3 / have-concession-91 :ARG1 (c2 / cell-line :quant "5" :ARG0-of (h / have-03 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n2 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :mod (w / wild-type)) :mod (a3 / also)) :ARG0-of (h2 / have-03 :ARG1 (p3 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2")) :ARG1-of (e4 / elevate-01))) :mod (a2 / all) :ARG1-of (r / report-01 :time (p2 / previous) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 "26" :op2 "27")))))) :ARG2 (k / know-01 :polarity "-" :ARG1 (m / mechanism :ARG0-of (r2 / responsible-01 :ARG1 (a5 / activate-01 :ARG1 e3)) :location (c4 / cell-line :mod (t / this))))) # ::id pmid_2303_9341.67 # ::date 2015-06-23T09:20:39 # ::file pmid_2303_9341_67.txt # ::snt When the cell lines were classified based on phospho-ERK levels rather than BRAF mutation status, there was no correlation with the degree of cell growth inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / correlate-01 :polarity "-" :ARG2 (d / degree :degree-of (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (c2 / cell)))) :condition (c3 / classify-01 :ARG1 (c4 / cell-line) :ARG1-of (b / base-02 :ARG2 (l / level :quant-of (p / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (i2 / instead-of-91 :ARG2 (s / status :mod (g2 / gene :name (n2 / name :op1 "BRAF") :ARG1-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))))) # ::id pmid_2303_9341.68 # ::date 2015-06-23T09:32:31 # ::file pmid_2303_9341_68.txt # ::snt In contrast, high levels of pAkt (3+) in BRAF/RAS mutant cell lines were strongly suggestive of insensitivity to E6201 (p = 0.057). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (s / suggest-01 :ARG0 (l / level :ARG1-of (h / high-02) :quant-of (p / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :location (c2 / cell-line :mod (m / mutate-01 :ARG2 (a / and :op1 (g / gene :name (n2 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n3 / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263"))))) :value (m2 / more-than :op1 "3")) :ARG1 (s4 / sensitive-03 :polarity "-" :ARG1 (s3 / small-molecule :name (n4 / name :op1 "E6201") :xref (x3 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG1-of (s2 / strong-02) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.057"))) # ::id pmid_2303_9341.69 # ::date 2015-06-24T00:19:27 # ::file pmid_2303_9341_69.txt # ::snt Furthermore, high levels of pAkt (3+) significantly correlated with E6201 insensitivity independent of BRAF or PTEN status (p < 0.02). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op2 (c / correlate-01 :ARG1 (l / level :quant-of (p / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG1-of (h / high-02) :value (m / more-than :op1 "3")) :ARG2 (s5 / sensitive-03 :polarity "-" :ARG1 (s4 / small-molecule :name (n2 / name :op1 "E6201") :xref (x3 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a2 / and :op1 (s2 / status :mod (g / gene :name (n3 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (s3 / status :mod (g2 / gene :name (n4 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))) :ARG1-of (s / significant-02) :ARG1-of (s6 / statistical-test-91 :ARG2 (l2 / less-than :op1 "0.02")))) # ::id pmid_2303_9341.70 # ::date 2015-06-24T00:34:02 # ::file pmid_2303_9341_70.txt # ::snt PTEN protein was present in 20 of the melanoma cell lines tested with a lack of the tumour suppressor being suggestive of resistance to E6201 in not only BRAF/RAS mutant lines (p = 0.12) but also if all lines are considered (p = 0.14). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a3 / and :op1 (p4 / present-02 :ARG1 (p2 / protein :name (n / name :op1 "PTEN") :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG2 (c / cell-line :quant "20" :mod (m3 / medical-condition :name (n2 / name :op1 "melanoma")) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :ARG1-of (t / test-01))))) :op2 (s / suggest-01 :ARG0 (l / lack-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (s5 / suppress-01 :ARG1 (t3 / tumor)))) :ARG1 (r / resist-01 :ARG0 (a4 / and :op1 (l2 / line :mod (m / mutate-01 :ARG2 (s3 / slash :op1 (g / gene :name (n4 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n5 / name :op1 "RAS") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")))) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.12")) :op2 (l3 / line :ARG1-of (c3 / consider-01) :mod (a5 / all) :mod (a / also) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.14"))) :ARG1 (s4 / small-molecule :name (n3 / name :op1 "E3201"))))) # ::id pmid_2303_9341.71 # ::date 2015-06-25T13:29:16 # ::file pmid_2303_9341_71.txt # ::snt Characterization of E6201 response in vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (c / characterize-01 :ARG1 (r / respond-01 :ARG1 (s / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :manner (i / in-vitro))) # ::id pmid_2303_9341.72 # ::date 2015-06-25T14:15:20 # ::file pmid_2303_9341_72.txt # ::snt MEK inhibitors have been previously shown to have a predominantly cytostatic effect on melanoma cells, although some clinically relevant inhibitors, such as CI-1040, PD0325901 and AZD6244, have been shown to induce cell death [10,12,13]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (s5 / show-01 :ARG1 (a3 / affect-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p4 / protein-family :name (n4 / name :op1 "MEK")))) :ARG1 (c5 / cell :source (m / medical-condition :name (n5 / name :op1 "melanoma"))) :ARG2 (c6 / cytostasis) :ARG1-of (p2 / predominate-01)) :time (p3 / previous)) :ARG2 (s / show-01 :ARG1 (i / induce-01 :ARG0 (m3 / molecular-physical-entity :ARG1-of (r / relevant-01 :manner (c4 / clinical)) :mod (s6 / some) :ARG0-of i3 :example (a2 / and :op1 (s2 / small-molecule :name (n / name :op1 "CI-1040") :xref (x1 / xref :value "PUBCHEM:6918454" :prob "17.207357")) :op2 (s3 / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :op3 (s4 / small-molecule :name (n3 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")))) :ARG2 (d2 / die-01 :ARG1 (c3 / cell)))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "10" :op2 "12" :op3 "13"))))) # ::id pmid_2303_9341.73 # ::date 2015-06-25T16:05:00 # ::file pmid_2303_9341_73.txt # ::snt We sought to further evaluate the mechanism of sensitivity to E6201, as an equivocal cytocidal response in vitro may equate to the poor clinical response observed with current MEK inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / cause-01 :ARG0 (p / possible-01 :ARG1 (e3 / equate-01 :ARG1 (t2 / thing :ARG2-of (r / respond-01 :manner (i2 / in-vitro)) :mod (c2 / cytocidal)) :ARG2 (t3 / thing :ARG2-of (r2 / respond-01 :ARG1-of (o / observe-01 :prep-with (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"))) :time (c4 / current)))) :mod (p2 / poor) :mod (c3 / clinic) :mod (e4 / equivocal)))) :ARG1 (s / seek-01 :ARG0 (w / we) :ARG1 (e2 / evaluate-01 :ARG0 w :ARG1 (m / mechanism :ARG0-of (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")))) :degree (f / further)))) # ::id pmid_2303_9341.74 # ::date 2015-06-25T14:16:10 # ::file pmid_2303_9341_74.txt # ::snt Fifteen melanoma cell lines were selected such that 13 cell lines demonstrated sensitivity to E6201 and 2 cell lines were insensitive to E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (s / select-01 :ARG1 (c / cell-line :quant "15" :source (m / medical-condition :name (n2 / name :op1 "melanoma"))) :purpose (a / and :op1 (d / demonstrate-01 :ARG0 (c2 / cell-line :quant "13") :ARG1 (s3 / sensitive-03 :ARG0 c2 :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")))) :op2 (s2 / sensitive-03 :polarity "-" :ARG0 (c3 / cell-line :quant "2") :ARG1 s4))) # ::id pmid_2303_9341.75 # ::date 2015-06-25T14:26:51 # ::file pmid_2303_9341_75.txt # ::snt Of these cell lines, seven were mutant for BRAF but wildtype for PTEN, five were mutant for both BRAF/NRAS and PTEN, and three were wildtype for both BRAF and PTEN. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (c / cell-line :quant "7" :mod (g4 / gene :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :ARG1-of (c5 / contrast-01 :ARG2 (g5 / gene :name (n2 / name :op1 "PTEN") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (c2 / cell-line :quant "5" :mod (s / slash :op1 (g / gene :name (n4 / name :op1 "BRAF") :xref (x5 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n3 / name :op1 "NRAS") :xref (x3 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op3 (g3 / gene :name (n5 / name :op1 "PTEN") :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :ARG2-of (m / mutate-01))) :op3 (c3 / cell-line :quant "3" :mod (e3 / enzyme :name (n6 / name :op1 "BRAF") :mod (w2 / wild-type) :xref (x4 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod g5) :ARG1-of (i / include-91 :ARG2 (c4 / cell-line :mod (t / this)))) # ::id pmid_2303_9341.76 # ::date 2015-06-25T15:29:41 # ::file pmid_2303_9341_76.txt # ::snt E6201 treatment induced G1 arrest in all of the sensitive cell lines and had little to no effect on cell cycle progression in the two insensitive cell lines (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (i / induce-01 :ARG0 (t / treat-04 :ARG2 (s3 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG2 (a2 / arrest-02 :time (e / event :name (n2 / name :op1 "G1"))) :location (c / cell-line :mod (a3 / all) :ARG0-of (s / sensitive-03))) :op2 (o2 / or :op1 (a4 / affect-01 :ARG0 t :ARG1 (p3 / progress-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell)) :location (c4 / cell-line :quant "2" :ARG0-of (s2 / sensitive-03 :polarity "-"))) :degree (l / little)) :op2 (a5 / affect-01 :polarity "-" :ARG0 t :ARG1 p3)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2303_9341.77 # ::date 2015-06-25T14:56:45 # ::file pmid_2303_9341_77.txt # ::snt E6201 treatment resulted in a greater than 2-fold increase in Annexin-positive staining in eleven out of fifteen cell lines, including eleven out of thirteen sensitive cell lines (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG2 (s3 / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG2 (i2 / increase-01 :ARG1 (s / stain-01 :ARG2 (p / protein :name (n2 / name :op1 "Annexin") :xref (x / xref :value "UNIPROT:A0A024R5Z7_HUMAN" :prob "1.001")) :mod (p2 / positive)) :ARG2 (m / more-than :op1 (p3 / product-of :op1 "2")) :location (c / cell-line :quant "11" :ARG1-of (i3 / include-91 :ARG2 (c2 / cell-line :quant "15") :ARG2-of (i4 / include-91 :ARG1 (c3 / cell-line :quant "11" :ARG1-of (i5 / include-91 :ARG2 (c4 / cell-line :quant "13" :ARG0-of (s2 / sensitive-03)))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2303_9341.78 # ::date 2015-06-25T15:03:23 # ::file pmid_2303_9341_78.txt # ::snt Two sensitive cell lines, SKMEL13 and BL, did not demonstrate E6201-induced Annexin staining although both of these cell lines underwent cell cycle arrest with E6201 treatment and were hypersensitive to E6201 (IC50 < 100 nM). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h2 / have-concession-91 :ARG1 (d / demonstrate-01 :polarity "-" :ARG0 (c2 / cell-line :quant "2" :ARG0-of (s2 / sensitive-03) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (c3 / cell-line :name (n2 / name :op1 "SKMEL13")) :op2 (c4 / cell-line :name (n3 / name :op1 "BL"))))) :ARG1 (s3 / stain-01 :ARG2 (p / protein :name (n4 / name :op1 "Annexin") :xref (x / xref :value "UNIPROT:A0A024R5Z7_HUMAN" :prob "1.001")) :ARG2-of (i / induce-01 :ARG0 "s4"))) :ARG2 (a / and :op1 (u / undergo-28 :ARG1 a2 :ARG2 (a3 / arrest-02 :ARG0 (t / treat-04 :ARG2 "s4") :ARG1 (c5 / cycle-02 :ARG1 (c6 / cell)))) :op2 (s / sensitive-03 :ARG0 a2 :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :degree (h / hyper) :mod (c7 / concentrate-02 :quant (l / less-than :op1 (c / concentration-quantity :quant "100" :unit (n5 / nanomolar))) :mod (i2 / inhibit-01 :degree (p2 / percentage-entity :value "50")))))) # ::id pmid_2303_9341.79 # ::date 2015-06-25T14:27:32 # ::file pmid_2303_9341_79.txt # ::snt These experiments were repeated in duplicate to confirm this finding. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (r / repeat-01 :ARG1 (e / experiment-01 :mod (t / this)) :ARG3 (d / duplicate-01 :ARG1 e) :purpose (c / confirm-01 :ARG0 "r" :ARG1 (t2 / thing :ARG1-of (f / find-01)))) # ::id pmid_2303_9341.80 # ::date 2015-06-25T14:35:57 # ::file pmid_2303_9341_80.txt # ::snt E6201 induced a less than two-fold increase in Annexin staining in the E6201-insensitive cell lines (IC50 > 500 nM) (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (i / induce-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG2 (i2 / increase-01 :ARG1 (s / stain-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Annexin") :xref (x / xref :value "UNIPROT:A0A024R5Z7_HUMAN" :prob "1.001"))) :ARG2 (l / less-than :op1 (p / product-of :op1 "2")) :location (c / cell-line :ARG0-of (s2 / sensitive-03 :polarity "-" :ARG1 s3) :ARG1-of (m2 / mean-01 :ARG2 (c3 / concentrate-02 :quant (m / more-than :op1 (c2 / concentration-quantity :quant "500" :unit (n3 / nanomolar))) :mod (i3 / inhibit-01 :degree (p3 / percentage-entity :value "50")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2303_9341.81 # ::date 2015-06-25T14:36:59 # ::file pmid_2303_9341_81.txt # ::snt Three of the five PTEN-mutant cell lines exhibited a cytocidal response to E6201, demonstrating that PTEN mutation does not preclude a cytocidal response to E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG0 (e / exhibit-01 :ARG0 (c2 / cell-line :quant "3" :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "5" :mod (g / gene :name (n / name :op1 "PTEN") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))) :ARG1 (t / thing :mod (c4 / cytocidal) :ARG2-of (r / respond-01 :ARG0 c2 :ARG1 (s / small-molecule :name (n2 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134"))))) :ARG1 (d / demonstrate-01 :ARG0 c2 :ARG1 (p2 / preclude-01 :polarity "-" :ARG0 g :ARG1 t))) # ::id pmid_2303_9341.82 # ::date 2015-06-25T14:45:07 # ::file pmid_2303_9341_82.txt # ::snt E6201 also induced cell cycle arrest and cell death in cell lines with constitutively active Akt, suggesting that although high pAkt correlates with E6201 insensitivity, cell lines with high pAkt can still undergo a cytocidal response to E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / induce-01 :ARG0 (s4 / small-molecule :name (n / name :op1 "E6201") :xref (x2 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG2 (a2 / and :op1 (a3 / arrest-02 :ARG1 (c / cycle-02 :ARG1 (c2 / cell))) :op2 (d / die-01 :ARG1 c) :location (c3 / cell-line :mod (e / enzyme :name (n2 / name :op1 "Akt") :ARG0-of (a4 / activity-06 :manner (c4 / constitutive)) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :ARG0-of (s / suggest-01 :ARG1 (h2 / have-concession-91 :ARG1 (p / possible-01 :ARG1 (u / undergo-28 :ARG1 (c7 / cell-line :mod "e2") :ARG2 (t / thing :ARG2-of (r / respond-01 :ARG0 c7 :ARG1 s4 :mod (c5 / cytocidal))) :mod (s3 / still))) :ARG2 (c6 / correlate-01 :ARG1 (e2 / enzyme :name n2 :ARG3-of (p2 / phosphorylate-01) :ARG1-of (h / high-02) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG2 (s2 / sensitive-03 :polarity "-" :ARG1 s4)))) :mod (a / also)) # ::id pmid_2303_9341.83 # ::date 2015-06-26T01:13:24 # ::file pmid_2303_9341_83.txt # ::snt To confirm our Annexin V results we also performed an enzyme-linked immunosorbent assay (ELISA) to determine the degree of DNA fragmentation as an indicator of cell death with E6201 treatment (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p / perform-01 :ARG0 (w / we) :ARG1 (a2 / assay-01 :purpose (d / determine-01 :ARG0 w :ARG1 (d2 / degree :degree-of (f / fragment-01 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))) :ARG0-of (i / indicate-01 :ARG1 (d4 / die-01 :ARG1 (c2 / cell) :ARG0-of (c3 / cause-01 :ARG1 (t3 / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")))))))) :instrument (i2 / immunosorbent :ARG1-of (l / link-01 :ARG2 (e / enzyme))) :ARG1-of (d3 / describe-01 :ARG2 (t / thing :name (n2 / name :op1 "ELISA")))) :purpose (c / confirm-01 :ARG0 w :ARG1 (t2 / thing :ARG2-of (r / result-01 :ARG1 (p2 / protein :name (n / name :op1 "Annexin" :op2 "V") :xref (x / xref :value "UNIPROT:ANXA5_HUMAN" :prob "1.002"))))) :mod (a / also) :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure :mod "3C"))) # ::id pmid_2303_9341.84 # ::date 2015-06-26T01:37:39 # ::file pmid_2303_9341_84.txt # ::snt The results from the cell death ELISA were very similar to that obtained from the Annexin studies with 10 out of 13 sensitive melanoma lines demonstrating a greater than two-fold increase in DNA fragmentation with E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (r2 / resemble-01 :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (d / die-01 :ARG1 (c / cell) :mod (a / assay-01 :mod (t2 / thing :name (n / name :op1 "ELISA")))))) :ARG2 (t3 / thing :ARG2-of (r3 / result-01 :ARG1-of (o / obtain-01 :ARG2 (s / study-01 :ARG1 (p / protein :name (n2 / name :op1 "Annexin") :prep-with (c2 / cell-line :quant "10" :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "13" :ARG0-of (s2 / sensitive-03) :source (m / medical-condition :name (n6 / name :op1 "melanoma"))))) :xref (x / xref :value "UNIPROT:A0A024R5Z7_HUMAN" :prob "1.001")))))) :degree (v / very) :ARG0-of (d2 / demonstrate-01 :ARG1 (i2 / increase-01 :ARG1 (f / fragment-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))) :ARG2 (m2 / more-than :op1 (p2 / product-of :op1 "2"))))) # ::id pmid_2303_9341.85 # ::date 2015-06-26T01:46:00 # ::file pmid_2303_9341_85.txt # ::snt Of the three sensitive lines that did not exhibit a cytocidal response by ELISA, SKMEL13 and BL also demonstrated no induction of cell death with E6201 by Annexin positivity, as stated previously. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (d3 / demonstrate-01 :ARG0 (a4 / and :op1 (c2 / cell-line :name (n2 / name :op1 "SKMEL13")) :op2 (c3 / cell-line :name (n3 / name :op1 "BL")) :ARG1-of (i / include-91 :ARG2 (c4 / cell-line :quant "3" :ARG0-of (s2 / sensitive-03) :ARG0-of (e / exhibit-01 :polarity "-" :ARG1 (r / respond-01 :ARG0 c4 :mod (c5 / cytocidal)) :manner (a / assay-01 :mod (t / thing :name (n / name :op1 "ELISA"))))))) :ARG1 (i2 / induce-01 :polarity "-" :ARG0 (s3 / small-molecule :name (n4 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG2 (d2 / die-01 :ARG1 (c6 / cell))) :manner (p2 / positive :domain (p3 / protein :name (n5 / name :op1 "Annexin") :xref (x / xref :value "UNIPROT:A0A024R5Z7_HUMAN" :prob "1.001"))) :ARG1-of (s / state-01 :time (p / previous)) :mod (a3 / also)) # ::id pmid_2303_9341.86 # ::date 2015-06-25T14:45:42 # ::file pmid_2303_9341_86.txt # ::snt There was no significant induction of DNA fragmentation in any of the E6201-resistant melanoma cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / induce-01 :ARG2 (f / fragment-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"))) :location (c / cell-line :mod (a / any) :ARG0-of (r / resist-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :source (m / medical-condition :name (n4 / name :op1 "melanoma"))) :ARG1-of (s / significant-02 :polarity "-")) # ::id pmid_2303_9341.87 # ::date 2015-06-25T14:52:44 # ::file pmid_2303_9341_87.txt # ::snt Characterization of E6201 response in vivo in melanoma xenografts # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / characterize-01 :ARG1 (r / respond-01 :ARG1 (s / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :location (x / xenograft :source (m / medical-condition :name (n2 / name :op1 "melanoma"))) :manner (i / in-vivo))) # ::id pmid_2303_9341.88 # ::date 2015-06-25T14:55:55 # ::file pmid_2303_9341_88.txt # ::snt We evaluated the in vivo activity of E6201 in two melanoma cell lines that exhibited a cytocidal response (MM540, MM604) and two melanoma cell lines that exhibited a cytostatic response (SKMEL13, BL) to E6201 in vitro (Figure 4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (e / evaluate-01 :ARG0 (w / we) :ARG1 (a2 / activity-06 :ARG0 (s / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :manner (i / in-vivo) :location (a5 / and :op1 (c / cell-line :quant "2" :ARG0-of (e2 / exhibit-01 :ARG1 (t / thing :ARG2-of (r / respond-01 :ARG1 s :mod (c2 / cytocidal)))) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and :op1 (c3 / cell-line :name (n2 / name :op1 "MM540")) :op2 (c4 / cell-line :name (n3 / name :op1 "MM604")))) :source (m / medical-condition :name (n6 / name :op1 "melanoma"))) :op2 (c5 / cell-line :quant "2" :source (m2 / melanoma) :ARG0-of (e3 / exhibit-01 :ARG1 (r2 / respond-01 :ARG1 s :ARG2 (c6 / cytostasis) :manner (i2 / in-vitro))) :ARG1-of (m4 / mean-01 :ARG2 (a4 / and :op1 (c7 / cell-line :name (n4 / name :op1 "SKMEL13")) :op2 (c8 / cell-line :name (n5 / name :op1 "BL"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4"))) # ::id pmid_2303_9341.89 # ::date 2015-06-26T02:17:34 # ::file pmid_2303_9341_89.txt # ::snt Given that the majority of sensitive melanoma cell lines in our cell line panel exhibited a cytocidal response to E6201 in vitro, we hypothesized that E6201 would induce tumour regression in a xenograft model of these cell lines as well, and to a greater extent in those cell lines that demonstrated a cytocidal response to E6201 in vitro compared to those with a cytostatic response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (h / hypothesize-01 :ARG0 "w" :ARG1 (a / and :op1 (i2 / induce-01 :ARG0 "s2" :ARG2 (r2 / regress-01 :ARG1 (t2 / tumor)) :manner (a2 / as-well) :location (m4 / model :mod (x / xenograft) :source "c2")) :op2 (i3 / induce-01 :ARG0 "s2" :degree (e2 / extent :mod (g / great :degree (m5 / more))) :location (c3 / cell-line :mod (t3 / that) :ARG0-of (d / demonstrate-01 :ARG1 (r3 / respond-01 :ARG0 "c2" :ARG1 "s2" :mod (c4 / cytocidal) :manner "i")) :compared-to (c5 / cell-line :ARG0-of (r4 / respond-01 :ARG2 (c6 / cytostasis)))))) :ARG1-of (c / cause-01 :ARG0 (e / exhibit-01 :ARG0 (c2 / cell-line :ARG1-of (i4 / include-91 :ARG2 (c7 / cell-line :location (p / panel :mod c2 :poss (w / we)) :ARG0-of (s / sensitive-03) :source (m / medical-condition :name (n2 / name :op1 "melanoma"))) :ARG3 (m2 / majority))) :ARG1 (t / thing :ARG2-of (r / respond-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :manner (i / in-vitro)) :mod c4)))) # ::id pmid_2303_9341.90 # ::date 2015-06-26T02:55:10 # ::file pmid_2303_9341_90.txt # ::snt Administration of E6201 at all doses (10, 20 and 40 mg/kg) to MM540 tumour-bearing mice completely abrogated tumour growth and caused transient, partial tumour regression for the two weeks of drug treatment, although tumour growth recommenced following drug withdrawal, indicating not all cells were killed in this two week period (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (a2 / abrogate-01 :ARG0 (a4 / administer-01 :ARG1 (s / small-molecule :name (n / name :op1 "E6201") :ARG2-of (d3 / dose-01 :mod (a5 / all)) :quant (c6 / concentration-quantity :quant (a6 / and :op1 "10" :op2 "20" :op3 "40") :unit (m / milligram-per-kilogram)) :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG2 (m2 / mouse :ARG0-of (b / bear-01 :ARG1 (t4 / tumor :mod (c5 / cell-line :name (n2 / name :op1 "MM540")))))) :ARG1 "g" :degree (c4 / complete)) :op2 (c2 / cause-01 :ARG0 a4 :ARG1 (r2 / regress-01 :ARG1 "t" :ARG1-of (t2 / transient-02) :degree (p / part) :duration (t3 / temporal-quantity :quant "2" :unit (w2 / week) :time-of (t5 / treat-04 :ARG2 "d2"))) :concession (r / recommence-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :ARG0-of (i / indicate-01 :ARG1 (k / kill-01 :ARG1 (c3 / cell :mod (a3 / all :polarity "-")))) :ARG1-of (f2 / follow-01 :ARG2 (w / withdraw-01 :ARG1 (d2 / drug))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id pmid_2303_9341.91 # ::date 2015-06-26T04:10:38 # ::file pmid_2303_9341_91.txt # ::snt E6201 at 40 mg/kg in MM604 and SKMEL13 xenografts prevented tumour progression for the two weeks of drug treatment, with tumour growth recommencing following drug removal, while lower doses of drug (10 and 20 mg/kg) only attenuated, rather than prevented, tumour growth in vivo (Figure 4B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG1 (a4 / and :op1 (p / prevent-01 :ARG0 (s / small-molecule :name (n / name :op1 "E6201") :quant (c2 / concentration-quantity :quant "40" :unit (m2 / milligram-per-kilogram)) :location (a / and :op1 (x / xenograft :mod (c3 / cell-line :name (n2 / name :op1 "MM604"))) :op2 (x2 / xenograft :mod (c4 / cell-line :name (n3 / name :op1 "SKMEL13")))) :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1 (p2 / progress-01 :ARG1 "t3") :time (t2 / treat-04 :ARG2 (d / drug) :duration (t / temporal-quantity :quant "2" :unit (w / week)))) :op2 (r / recommence-01 :ARG1 (g / grow-01 :ARG1 (t3 / tumor)) :ARG1-of (f / follow-01 :ARG2 (r2 / remove-01 :ARG1 d)))) :ARG2 (i2 / instead-of-91 :ARG1 (a2 / attenuate-01 :ARG0 (d2 / dose-01 :ARG2 d :ARG1-of (l / low-04 :degree (m / more)) :quant (a5 / and :op1 (c5 / concentration-quantity :quant "10" :unit (m3 / milligram-per-kilogram)) :op2 (c6 / concentration-quantity :quant "20" :unit (m4 / milligram-per-kilogram)))) :mod (o / only)) :ARG2 (p3 / prevent-01 :ARG0 d2 :ARG1 (g2 / grow-01 :ARG1 t3 :manner (i / in-vivo)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "4B") :op2 (f3 / figure :mod "4C")))) # ::id pmid_2303_9341.92 # ::date 2015-06-26T04:32:02 # ::file pmid_2303_9341_92.txt # ::snt Only the highest dose of E6201 (40 mg/kg) had any significant inhibitory effect on tumour growth in BL tumour-bearing mice, while lower drug doses had little or no effect on tumour progression (Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / contrast-01 :ARG1 (a / affect-01 :ARG0 (d4 / dose-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "E6201") :quant (c3 / concentration-quantity :quant "40" :unit (m3 / milligram-per-kilogram)) :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1-of (h / high-02 :degree (m2 / most)) :mod (o2 / only)) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 "t" :location (m4 / mouse :ARG0-of (b / bear-01 :ARG1 (t2 / tumor :mod (c2 / cell-line :name (n2 / name :op1 "BL"))))))) :ARG1-of (s2 / significant-02) :mod (a4 / any)) :ARG2 (o / or :op1 (a2 / affect-01 :ARG0 (d2 / dose-01 :ARG1 (d3 / drug) :ARG1-of (l2 / low-04 :degree (m / more))) :ARG1 (p / progress-01 :ARG1 (t / tumor)) :mod (l / little)) :op2 (a3 / affect-01 :polarity "-" :ARG0 d2 :ARG1 p)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4D"))) # ::id pmid_2303_9341.93 # ::date 2015-06-26T04:44:08 # ::file pmid_2303_9341_93.txt # ::snt As such our hypothesis was confirmed, with E6201 inhibiting xenograft tumour growth in all four melanoma cell lines studied, and enhanced in vivo activity observed for those cell lines that demonstrated a cytocidal response in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / confirm-01 :ARG0 (a2 / and :op1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1 (g / grow-01 :ARG1 (t2 / tumor :mod (x / xenograft))) :location (c2 / cell-line :quant "4" :mod (a3 / all) :ARG1-of (s / study-01) :mod (t4 / that) :source (m / medical-condition :name (n2 / name :op1 "melanoma")))) :op2 (e / enhance-01 :ARG1 (a4 / activity-06 :manner (i2 / in-vivo) :ARG1-of (o / observe-01 :location (c3 / cell-line :ARG0-of (d / demonstrate-01 :ARG1 (t3 / thing :ARG2-of (r / respond-01 :mod (c4 / cytocidal) :manner (i3 / in-vitro)))) :mod (t5 / that)))))) :ARG1 (t / thing :ARG1-of (h / hypothesize-01 :ARG0 (w / we))) :mod (a / as-such)) # ::id pmid_2303_9341.94 # ::date 2015-06-24T05:45:08 # ::file pmid_2303_9341_94.txt # ::snt E6201 and LY294002 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 2, 2015 (a / and :op1 (s / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :op2 (s2 / small-molecule :name (n2 / name :op1 "LY294002") :xref (x / xref :value "PUBCHEM:3973" :prob "18.86067"))) # ::id pmid_2303_9341.95 # ::date 2015-06-24T06:29:32 # ::file pmid_2303_9341_95.txt # ::snt Given our previous data suggesting that E6201 resistance is associated with mutation of PTEN and high levels of pAkt, we hypothesized that combining E6201 with an inhibitor of the PI3K pathway in these cell lines might result in either an additive or synergistic effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (h3 / hypothesize-01 :ARG0 (w2 / we) :ARG1 (r2 / result-01 :ARG1 (c / combine-01 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "E6201") :xref (x2 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG2 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p4 / pathway :name (n5 / name :op1 "PI3K")))) :location (c2 / cell-line :mod (t / this))) :ARG2 (a3 / affect-01 :ARG2 (o / or :op1 (a4 / add-02) :op2 (s2 / synergize-01))) :ARG1-of (p5 / possible-01)) :ARG1-of (i / infer-01 :ARG2 (d / data :poss (w / we) :time (p / previous) :ARG0-of (s / suggest-01 :ARG1 (r / resist-01 :ARG0 s3 :ARG1-of (a / associate-01 :ARG2 (a2 / and :op1 (m2 / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :op2 (l / level :ARG1-of (h / high-02) :quant-of (e / enzyme :name (n3 / name :op1 "Akt") :ARG3-of (p6 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))))))))) # ::id pmid_2303_9341.96 # ::date 2015-06-24T06:32:09 # ::file pmid_2303_9341_96.txt # ::snt Additional file 2: Figure S2 demonstrates that LY294002 effectively inhibits PI3K by evidence of reduced phosphorylated AKT protein levels in the four PTEN-mutant melanoma cell lines that normally express high levels of pAKT (UACC647, UACC558, UACC903 and MM622). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / demonstrate-01 :ARG0 (a2 / and :op1 (f / file :mod "2" :mod (a3 / additional)) :op2 (f2 / figure :mod "2")) :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "LY294002") :xref (x3 / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (e6 / enzyme :name (n2 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :ARG1-of (e / effective-04)) :ARG1-of (e2 / evidence-01 :ARG0 (l / level :mod (e7 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (r / reduce-01)) :location (c / cell-line :quant "4" :ARG3-of (e3 / express-03 :ARG2 (l2 / level :ARG1-of (h / high-02) :quant-of e7) :ARG1-of (n5 / normal-02)) :example (a / and :op1 (c2 / cell-line :name (n7 / name :op1 "UACC647")) :op2 (c3 / cell-line :name (n8 / name :op1 "UACC558")) :op3 (c4 / cell-line :name (n9 / name :op1 "UACC903")) :op4 (c5 / cell-line :name (n10 / name :op1 "MM622"))) :source (m / medical-condition :name (n6 / name :op1 "melanoma") :mod (g / gene :name (n4 / name :op1 "PTEN") :ARG2-of (m4 / mutate-01) :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")))))) # ::id pmid_2303_9341.97 # ::date 2015-06-24T06:32:41 # ::file pmid_2303_9341_97.txt # ::snt In addition, Additional file 3: Figures S3 and Additional file 4: Figure S4 show the concentration-effect curves for single-agent LY294002 and E6201 respectively, where both drugs were added 24 hours following plating. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op2 (s / show-01 :ARG0 (a2 / and :op1 (f / figure :mod "S3" :location (f3 / file :mod "3" :mod (a7 / additional))) :op2 (f2 / figure :mod "S4" :location (f4 / file :mod "4" :mod a7))) :ARG1 (a8 / and :op1 (c / curve :beneficiary (a4 / agent :ARG1-of (s2 / single-02) :mod (s3 / small-molecule :name (n / name :op1 "LY294002") :xref (x / xref :value "PUBCHEM:3973" :prob "18.86067"))) :topic (a3 / affect-01 :ARG0 (c2 / concentrate-02))) :op2 (c3 / curve :beneficiary (a5 / agent :mod (s5 / small-molecule :name (n2 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :topic a3) :location-of (a6 / add-on-05 :ARG1 (a10 / and :op1 s3 :op2 s5) :ARG1-of (f5 / follow-01 :ARG2 (p / plate-00) :quant (t / temporal-quantity :quant "24" :unit (h / hour))))))) # ::id pmid_2303_9341.98 # ::date 2015-06-24T06:33:01 # ::file pmid_2303_9341_98.txt # ::snt The six melanoma cell lines tested displayed similar trends in E6201 sensitivity compared to our previous experiments, with MM622, MM540, UACC903, and WM35 being the most sensitive (IC50 = 40-61 nM) and UACC558 and UACC647 being less sensitive (302 and 2310 nM, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / display-01 :ARG0 (c / cell-line :quant "6" :ARG1-of (t / test-01) :mod (m / medical-condition :name (n12 / name :op1 "melanoma"))) :ARG1 (t2 / trend-01 :ARG2 (s / sensitive-03 :ARG0 (a / and :op1 (c4 / cell-line :name (n2 / name :op1 "MM622")) :op2 (c5 / cell-line :name (n3 / name :op1 "MM540")) :op3 (c6 / cell-line :name (n4 / name :op1 "UACC903")) :op4 (c9 / cell-line :name (n5 / name :op1 "WM35")) :ARG1-of (c3 / contrast-01 :ARG2 (a2 / and :op1 (c8 / cell-line :name (n6 / name :op1 "UACC558")) :op1 (c7 / cell-line :name (n7 / name :op1 "UACC647")) :ARG1-of (s2 / sensitive-03 :degree (l / less)) :mod (c12 / concentrate-02 :ARG1-of (e3 / equal-01 :ARG2 (c11 / concentration-quantity :unit (n9 / nanomolar) :quant (a3 / and :op1 "302" :op2 "2310"))) :mod (i / inhibit-01 :degree (p2 / percentage-entity :value "50"))))) :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c10 / concentration-quantity :quant (v / value-interval :op1 "40" :op2 "61") :unit (n8 / nanomolar)))) :ARG1 (s3 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG1-of (r / resemble-01) :ARG1-of (c2 / compare-01 :ARG2 (e / experiment-01 :ARG0 (w / we) :time (p / previous)))) :degree (m2 / most)) # ::id pmid_2303_9341.99 # ::date 2015-06-24T22:33:34 # ::file pmid_2303_9341_99.txt # ::snt Surprisingly, all cell lines showed similar sensitivity to LY294002, with IC50 ranging from 11 μM to 17 μM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / show-01 :ARG0 (c / cell-line :mod (a / all) :ARG0-of (h / have-03 :ARG1 (c4 / concentrate-02 :ARG1-of (r2 / range-01 :ARG3 (c2 / concentration-quantity :quant "11" :unit (m / micromolar)) :ARG4 (c3 / concentration-quantity :quant "17" :unit m)) :mod (i / inhibit-01 :degree (p / percentage-entity :value "50"))))) :ARG1 (s2 / sensitive-03 :ARG0 c :ARG1 (s4 / small-molecule :name (n / name :op1 "LY294002") :xref (x / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1-of (r / resemble-01)) :ARG0-of (s3 / surprise-01)) # ::id pmid_2303_9341.100 # ::date 2015-06-24T22:52:13 # ::file pmid_2303_9341_100.txt # ::snt This was unexpected, as one would predict MM540 and WM35 cells to be relatively resistant to PI3K inhibition given the lack of detectable levels of pAkt indicating no constitutive PI3K activation in these cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (e / expect-01 :polarity "-" :ARG1 (t / this) :ARG0-of (c / cause-01 :ARG1 (p / predict-01 :ARG0 (p2 / person) :ARG1 (r / resist-01 :ARG0 (a / and :op1 (c2 / cell-line :name (n / name :op1 "MM540")) :op2 (c3 / cell-line :name (n2 / name :op1 "WM35"))) :ARG1 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG2-of (r2 / relative-05) :ARG1-of (c4 / cause-01 :ARG0 (l / lack-01 :ARG1 (l2 / level :ARG1-of (d / detect-01 :ARG1-of (p4 / possible-01)) :quant-of (e3 / enzyme :name (n4 / name :op1 "Akt") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG0-of (i2 / indicate-01 :ARG1 (a2 / activate-01 :polarity "-" :ARG1 e2 :manner (c5 / constitutive) :location a)))))))) # ::id pmid_2303_9341.101 # ::date 2015-06-25T07:34:37 # ::file pmid_2303_9341_101.txt # ::snt A previous study by Smalley and others [26], however, reported a similar sensitivity of WM35 cells to LY294002. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 14, 2015 (r / report-01 :ARG0 (s / study-01 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Smalley")) :op2 (p4 / person :mod (o / other))) :time (p / previous) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0-of (c / cite-01 :ARG2 "26")))) :ARG1 (s2 / sensitive-03 :ARG0 (c2 / cell-line :name (n2 / name :op1 "WM35")) :ARG1 (s3 / small-molecule :name (n3 / name :op1 "LY294002") :xref (x / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1-of (r2 / resemble-01)) :ARG2-of (c3 / contrast-01)) # ::id pmid_2303_9341.102 # ::date 2015-06-25T10:02:39 # ::file pmid_2303_9341_102.txt # ::snt The concentration response curves for E6201 and LY294002 combinations, normalized to a dimethyl sulfoxide (DMSO) control are given in Additional file 4: Figure S4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (g / give-01 :ARG1 (c / curve :mod (r / respond-01 :ARG1 (c2 / concentrate-02 :ARG1 (c3 / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "E6201") :xref (x2 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067"))))) :ARG1-of (n3 / normalize-01 :topic (c4 / control-01 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "DMSO") :xref (x / xref :value "PUBCHEM:679" :prob "16.740406"))))) :location (f / figure :mod "S4" :location (f2 / file :mod "4" :mod (a / additional)))) # ::id pmid_2303_9341.103 # ::date 2015-06-25T11:35:00 # ::file pmid_2303_9341_103.txt # ::snt As differences in synergy may exist at different drug effect levels, we graphed individual combination index values for LY294002 with increasing concentrations of E6201 for each cell line (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / cause-01 :ARG0 (p / possible-01 :ARG1 (e / exist-01 :ARG1 (d / differ-02 :ARG2 (s / synergize-01)) :location (l / level :ARG1-of (d2 / differ-02) :degree-of (a / affect-01 :ARG0 (d3 / drug))))) :ARG1 (g / graph-00 :ARG0 (w / we) :ARG1 (v / value :mod (i / individual) :mod (c2 / combine-01) :mod (i2 / index)) :value-of (s2 / small-molecule :name (n / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")) :accompanier (c3 / concentrate-02 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1-of (i3 / increase-01)) :location (c4 / cell-line :mod (e2 / each)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "5A")))) # ::id pmid_2303_9341.104 # ::date 2015-06-25T12:30:04 # ::file pmid_2303_9341_104.txt # ::snt As shown in Figure 5A, evaluating the individual combination index for all combinations tested revealed that E6201 and LY294002 exhibit synergistic activity in all six melanoma cell lines, irrespective of E6201 sensitivity or PTEN or pAkt status. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (r / reveal-01 :ARG0 (e / evaluate-01 :ARG1 (i / index :mod (c / combine-01 :manner (i2 / individual)) :beneficiary (c2 / combine-01 :mod (a / all) :ARG1-of (t / test-01)))) :ARG1 (e2 / exhibit-01 :ARG0 (a2 / and :op1 (s5 / small-molecule :name (n / name :op1 "E6201") :xref (x3 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :op2 (s6 / small-molecule :name (n2 / name :op1 "LY294002") :xref (x2 / xref :value "PUBCHEM:3973" :prob "18.86067"))) :ARG1 (a3 / activity-06 :ARG1 (s / synergize-01) :location (c3 / cell-line :quant "6" :mod (m / medical-condition :name (n3 / name :op1 "melanoma")) :mod (a4 / all)) :ARG1-of (r2 / regardless-91 :ARG2 (o / or :op1 (s2 / sensitive-03 :ARG1 s5) :op2 (s3 / status :poss (a5 / and :op1 (p / protein :name (n5 / name :op1 "PTEN") :xref (x1 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n6 / name :op1 "Akt") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))))))) :ARG1-of (s4 / show-01 :ARG0 (f / figure :mod "5A"))) # ::id pmid_2303_9341.105 # ::date 2015-06-25T13:16:21 # ::file pmid_2303_9341_105.txt # ::snt Interestingly, different patterns of synergy were observed among the groups of cell lines tested. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (o / observe-01 :ARG1 (p / pattern-01 :ARG1 (s / synergize-01) :ARG1-of (d / differ-02) :ARG1-of (i / include-91 :ARG2 (g / group :consist-of (c / cell-line :ARG1-of (t / test-01))))) :ARG2-of (i2 / interest-01)) # ::id pmid_2303_9341.106 # ::date 2015-06-25T13:27:52 # ::file pmid_2303_9341_106.txt # ::snt While most (4/6) of the cell lines showed an increasing combination index (and thus decreasing synergy) at higher concentrations of E6201, UACC647 and UACC558 cells showed a decreasing combination index or enhanced synergy with increasing concentrations of E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (c2 / cell-line :quant "4" :ARG1-of (i5 / include-91 :ARG2 (c8 / cell-line :quant "6") :ARG3 (m / most))) :ARG1 (i / index :mod (c3 / combine-01 :ARG1-of (i2 / increase-01))) :ARG0-of (c4 / cause-01 :ARG1 (d2 / decrease-01 :ARG1 (s2 / synergize-01))) :condition (c5 / concentrate-02 :ARG1 (s5 / small-molecule :name (n / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG1-of (h / high-02))) :ARG2 (s3 / show-01 :ARG0 (a / and :op1 (c9 / cell-line :name (n2 / name :op1 "UACC647")) :op2 (c10 / cell-line :name (n3 / name :op1 "UACC558"))) :ARG1 (o / or :op1 (i3 / index :mod (c6 / combine-01 :ARG1-of (d / decrease-01))) :op2 (s4 / synergize-01 :ARG1-of (e / enhance-01) :condition (c7 / concentrate-02 :ARG1 s5 :ARG1-of (i4 / increase-01)))))) # ::id pmid_2303_9341.107 # ::date 2015-06-25T21:58:06 # ::file pmid_2303_9341_107.txt # ::snt Notably, this pattern observed for UACC647 and UACC558 cells occurs within the context of high pAkt and relative resistance to E6201, supporting the hypothesis that administration of a PI3K inhibitor can sensitize E6201-resistant cells with high pAkt levels to E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p3 / pattern :ARG1-of (n6 / notable-04) :mod (t / this) :ARG1-of (o2 / observe-01) :topic (a / and :op1 (c3 / cell-line :name (n / name :op1 "UACC647")) :op2 (c4 / cell-line :name (n2 / name :op1 "UACC558"))) :time (c / context :poss (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "Akt") :ARG3-of (p6 / phosphorylate-01) :ARG1-of (h2 / high-02) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op2 (r / resist-01 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG2-of (r2 / relative-05)))) :ARG0-of (s / support-01 :ARG1 (h / hypothesize-01 :ARG1 (s2 / sensitize-01 :ARG0 (a3 / administer-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K"))))) :ARG1 (c2 / cell :ARG0-of (r3 / resist-01 :ARG1 s3) :mod (l / level :quant-of e :degree h2)) :ARG2 s3 :ARG1-of (p4 / possible-01))))) # ::id pmid_2303_9341.108 # ::date 2015-06-25T23:17:47 # ::file pmid_2303_9341_108.txt # ::snt In summary, the combination of E6201 and LY294002 resulted in synergistic activity in all six melanoma cell lines tested, as defined by a combination index < 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (r / result-01 :ARG1 (c / combine-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201") :xref (x1 / xref :value "PUBCHEM:10172827" :prob "19.266134")) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "LY294002") :xref (x / xref :value "PUBCHEM:3973" :prob "18.86067"))) :ARG2 (a / activity-06 :ARG1 (s / synergize-01)) :location (c2 / cell-line :quant "6" :mod (a2 / all) :ARG1-of (t / test-01) :mod (m / medical-condition :name (n3 / name :op1 "melanoma"))) :ARG1-of (d / define-01 :ARG0 (i / index :mod (c3 / combine-01) :value (l / less-than :op1 "1"))) :ARG2-of (s4 / summarize-01)) # ::id pmid_2303_9341.109 # ::date 2015-06-28T11:07:11 # ::file pmid_2303_9341_109.txt # ::snt Interestingly, enhanced synergy of E6201 with LY294002 treatment in the E6201-resistant cell lines UACC647 and UACC558 was observed at high concentrations of E6201. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (o / observe-01 :ARG1 (s / synergize-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067"))) :ARG1 (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "E6201") :xref (x / xref :value "PUBCHEM:10172827" :prob "19.266134"))) :ARG1-of (e / enhance-01) :location (c / cell-line :ARG0-of (r / resist-01) :ARG2-of (i / include-91 :ARG1 (a / and :op1 (c3 / cell-line :name (n4 / name :op1 "UACC647")) :op2 (c4 / cell-line :name (n5 / name :op1 "UACC558")))))) :condition (c2 / concentrate-02 :ARG1 s3 :ARG1-of (h / high-02)) :ARG2-of (i2 / interest-01)) # ::id pmid_2325_9591.1 # ::date 2015-08-22T01:09:11 # ::file pmid_2325_9591_1.txt # ::snt Alternative dosing of dual PI3K and MEK inhibition in cancer therapy (PMID:23259591) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d2 / dose-01 :ARG1 (i / inhibit-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (d3 / dual)) :mod (a / alternative) :location (t / therapy :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID23259591"))) # ::id pmid_2325_9591.10 # ::date 2015-08-22T01:15:00 # ::file pmid_2325_9591_10.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2325_9591.11 # ::date 2015-08-22T01:15:38 # ::file pmid_2325_9591_11.txt # ::snt Two of the 12 NSCLC cell lines tested, H3122 (ALK translocated) and H1437 (triple-negative), showed increased cytotoxicity upon dual MEK and PI3K inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / show-01 :ARG0 (c / cell-line :quant "2" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "12" :ARG1-of (t / test-01) :mod (d2 / disease :name (n2 / name :op1 "NSCLC")))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n4 / name :op1 "H3122") :ARG2-of (t2 / translocate-01 :ARG1 (e / enzyme :name (n5 / name :op1 "ALK") :xref (x2 / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003")))) :op2 (c4 / cell-line :name (n6 / name :op1 "H1437") :ARG1-of (n3 / negative-01 :ARG1-of (t3 / triple-01)))))) :ARG1 (c5 / cytotoxicity :ARG1-of (i2 / increase-01 :time (a2 / after :op1 (i3 / inhibit-01 :ARG1 (a3 / and :op1 (e2 / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e3 / enzyme :name (n8 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :mod (d / dual)))))) # ::id pmid_2325_9591.12 # ::date 2015-08-22T01:08:49 # ::file pmid_2325_9591_12.txt # ::snt Furthermore, MDA-MB231 (breast) and HCT116 (colon), showed increased cytotoxicity upon dual inhibition, as in previous studies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (a / and :op2 (s / show-01 :ARG0 (a2 / and :op1 (c / cell-line :name (n / name :op1 "MDA-MB231") :mod (b / breast)) :op2 (c2 / cell-line :name (n2 / name :op1 "HCT116") :mod (c3 / colon))) :ARG1 (c4 / cytotoxicity :ARG1-of (i / increase-01 :ARG1-of (r / resemble-01 :ARG2 (s2 / study-01 :time (p / previous))) :time (a3 / after :op1 (i2 / inhibit-01 :mod (d / dual))))))) # ::id pmid_2325_9591.13 # ::date 2015-08-22T02:25:46 # ::file pmid_2325_9591_13.txt # ::snt Activation of parallel pathways in the dual inhibition-sensitive lines was also noted in response to single inhibitor treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (n / note-01 :ARG1 (a2 / activate-01 :ARG1 (p / pathway :ARG1-of (p2 / parallel-01)) :location (c / cell-line :ARG0-of (s / sensitive-03 :ARG1 (i2 / inhibit-01 :mod (d / dual))))) :mod (a / also) :ARG2-of (r / respond-01 :ARG1 (t2 / treat-04 :ARG2 (s2 / small-molecule :ARG0-of (i / inhibit-01) :ARG1-of (s3 / single-02))))) # ::id pmid_2325_9591.14 # ::date 2015-08-22T02:30:54 # ::file pmid_2325_9591_14.txt # ::snt Otherwise, no significant differences in downstream intracellular pathway activity (S6 and 4E-BPI) were noted between PI3K alone and dual inhibition other than the increased cytotoxicity of the latter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (h2 / have-condition-91 :ARG1 (n / note-01 :ARG1 (d / differ-02 :polarity "-" :ARG1 (p4 / protein-family :name (n4 / name :op1 "PI3K") :mod (a3 / alone)) :ARG2 (i2 / inhibit-01 :mod (d3 / dual)) :ARG3 (a / activity-06 :ARG0 (p / pathway :mod (i / intracellular) :location (d2 / downstream) :ARG1-of (m / mean-01 :ARG2 (a4 / activity-06 :ARG0 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "S6")) :op2 (p3 / protein :name (n3 / name :op1 "4E-BPI") :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "0.292"))))))) :ARG1-of (s / significant-02) :ARG2-of (e2 / except-01 :ARG1 (c / cytotoxicity :ARG1-of (i3 / increase-01) :topic i2))))) # ::id pmid_2325_9591.15 # ::date 2015-08-22T02:48:35 # ::file pmid_2325_9591_15.txt # ::snt In the alternative dosing schedules two out of the four dual inhibition-sensitive cell lines showed similar cytotoxicity to continuous PI3K and short (15min) MEK inhibition treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (s / show-01 :ARG0 (c / cell-line :quant "2" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "4" :ARG0-of (s2 / sensitive-03 :ARG1 (i2 / inhibit-01 :mod (d / dual)))))) :ARG1 (c3 / cytotoxicity :ARG1-of (r2 / resemble-01)) :ARG2 (t / treat-04 :ARG2 (a2 / and :op1 (s4 / small-molecule :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K")) :mod (c4 / continuity))) :op2 (s6 / small-molecule :ARG0-of (i4 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK")) :ARG1-of (s5 / short-07 :duration (t2 / temporal-quantity :quant "15" :unit (m / minute))))))) :location (s3 / schedule-01 :ARG1 (d2 / dose-01 :mod (a / alternative)))) # ::id pmid_2325_9591.79 # ::date 2015-08-22T03:49:06 # ::file pmid_2325_9591_79.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2325_9591.80 # ::date 2015-08-22T03:50:45 # ::file pmid_2325_9591_80.txt # ::snt Dual inhibition of PI3K and MEK in cancer cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / inhibit-01 :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (d2 / dual) :location (c / cell-line :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) # ::id pmid_2325_9591.81 # ::date 2015-08-22T03:52:47 # ::file pmid_2325_9591_81.txt # ::snt The inhibitors used were ZSTK474 (PI3K inhibitor) and PI-103 (PI3K and mTOR inhibitor) and CI-1040 (MEK inhibitor). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 22, 2015 (u / use-01 :ARG1 (s / small-molecule :ARG0-of (i2 / inhibit-01) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "ZSTK474") :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n3 / name :op1 "PI3K"))) :xref (x2 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :op2 (s3 / small-molecule :name (n4 / name :op1 "PI-103") :ARG0-of (i4 / inhibit-01 :ARG1 (a2 / and :op1 p2 :op2 (p3 / protein :name (n5 / name :op1 "mTOR") :xref (x / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")))) :xref (x1 / xref :value "PUBCHEM:9884685" :prob "14.194942")) :op3 (s4 / small-molecule :name (n6 / name :op1 "CI-1040") :ARG0-of (i5 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :xref (x3 / xref :value "PUBCHEM:6918454" :prob "17.207357")))))) # ::id pmid_2325_9591.82 # ::date 2015-08-22T04:02:16 # ::file pmid_2325_9591_82.txt # ::snt We first addressed the effects of these inhibitors alone in the NSCLC lines A549 (K-Ras mutant), HCC827 (EGFR mutant) and H3122 (EML4-ALK translocated), representing the three most frequent oncogenic genotypes of the disease, to establish concentration frames for the target inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / address-02 :ARG0 (w / we) :ARG1 (a2 / affect-01 :ARG0 (s / small-molecule :mod (t2 / this) :mod (a3 / alone) :ARG0-of (i2 / inhibit-01)) :location (c / cell-line :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (c3 / cell-line :name (n5 / name :op1 "A549") :mod (g / gene :name (n4 / name :op1 "K-Ras") :ARG2-of (m2 / mutate-01) :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (c2 / cell-line :name (n6 / name :op1 "HCC827") :mod (g2 / gene :name (n7 / name :op1 "EGFR") :ARG2-of (m3 / mutate-01) :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :op3 (c4 / cell-line :name (n8 / name :op1 "H3122") :ARG2-of (t3 / translocate-01 :ARG1 (e2 / enzyme :name (n9 / name :op1 "EML4-ALK") :xref (x / xref :value "UNIPROT:J7MA22_HUMAN" :prob "1.001")))) :ARG1-of (r / represent-01 :ARG2 (g3 / genotype :quant "3" :ARG1-of (i3 / include-91 :ARG2 (g4 / genotype :ARG1-of (f2 / frequent-02 :degree (m4 / most)) :poss (d / disease) :ARG0-of (c6 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))))))) :mod (d2 / disease :name (n / name :op1 "NSCLC")))) :time (f / first) :purpose (e3 / establish-01 :ARG0 w :ARG1 (f3 / frame :mod (c5 / concentrate-02)) :ARG3 (i4 / inhibit-01 :ARG1-of (t4 / target-01)))) # ::id pmid_2325_9591.83 # ::date 2015-08-22T04:21:32 # ::file pmid_2325_9591_83.txt # ::snt In the Western blots ZSTK474 at a 3.3μM concentration induced complete downregulation of pAKT, an immediate downstream target of PI3K, while PI-103 induced a similar inhibition at concentrations of 1 to 3.3 μM (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (c / contrast-01 :ARG1 (i / induce-01 :ARG0 (c3 / concentrate-02 :ARG1 (s / small-molecule :name (n / name :op1 "ZSTK474") :xref (x2 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :quant (c2 / concentration-quantity :quant "3.3" :unit (m / micromolar))) :ARG2 (d / downregulate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (c4 / complete-02) :ARG1-of (t2 / target-01 :ARG0 (p2 / protein-family :name (n4 / name :op1 "PI3K")) :location (d2 / downstream) :time (i2 / immediate))) :location (i5 / immunoblot-01)) :ARG2 (i3 / induce-01 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PI-103") :xref (x1 / xref :value "PUBCHEM:9884685" :prob "14.194942")) :ARG2 (i4 / inhibit-01 :ARG1-of (r / resemble-01)) :condition (c5 / concentrate-02 :ARG1 s2 :quant (v / value-interval :op1 (c6 / concentration-quantity :quant "1" :unit m) :op2 c2))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_2325_9591.84 # ::date 2015-08-22T04:38:54 # ::file pmid_2325_9591_84.txt # ::snt pS6 downregulation correlated highly with pAKT downregulation (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / correlate-01 :ARG1 (d / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "S6") :ARG3-of (p2 / phosphorylate-01))) :ARG2 (d2 / downregulate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT") :ARG3-of p2 :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG1-of (h / high-02) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_2325_9591.85 # ::date 2015-08-22T04:56:44 # ::file pmid_2325_9591_85.txt # ::snt The MTS cytotoxicity assay showed a major reduction in the number of viable cells in all the cell lines with similar concentrations of both inhibitors, which were closely correlated with the concentrations inducing complete inhibition of pAKT in Western blot analysis (Figure 1A,C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / show-01 :ARG0 (a / assay-01 :ARG1 (c / cytotoxicity) :mod (s3 / small-molecule :name (n2 / name :op1 "MTS") :xref (x1 / xref :value "PUBCHEM:65521" :prob "10.885861"))) :ARG1 (r2 / reduce-01 :ARG1 (n / number :quant-of (c2 / cell :mod (v / viable))) :ARG1-of (m / major-02) :location (c3 / cell-line :ARG0-of (h / have-03 :ARG1 (c4 / concentrate-02 :ARG1 (s2 / small-molecule :ARG0-of (i2 / inhibit-01) :mod (b / both)) :ARG1-of (r3 / resemble-01) :ARG1-of (c5 / correlate-01 :ARG2 (c6 / concentrate-02 :ARG0-of (i3 / induce-01 :ARG2 (i4 / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (c7 / complete-02)) :time (a2 / analyze-01 :manner (i / immunoblot-01)))) :ARG1-of (c8 / close-10)))) :mod (a4 / all))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1A") :op2 (f2 / figure :mod "1C")))) # ::id pmid_2325_9591.86 # ::date 2015-08-22T05:24:22 # ::file pmid_2325_9591_86.txt # ::snt CI-1040 induced complete inhibition of ERK1/2, an immediate downstream target of MEK, at a 1 μM concentration (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / induce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "CI-1040") :ARG1-of (c2 / concentrate-02 :quant (c3 / concentration-quantity :quant "1" :unit (m / micromolar))) :xref (x1 / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG2 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2") :ARG1-of (t / target-01 :ARG0 (e2 / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :location (d / downstream) :time (i3 / immediate))) :ARG1-of (c / complete-02)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id pmid_2325_9591.87 # ::date 2015-08-22T05:37:16 # ::file pmid_2325_9591_87.txt # ::snt Only the H3122 line showed any marked reduction in cell viability in the MTS assays in response to increasing concentrations of the inhibitor, correlating with maximal target inhibition, while the other lines displayed minor changes in viability, except for the 10 μM treatment in HCC827, despite the achieving of complete inhibition of pERK1/2 in all the lines tested at 1 μM (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c13 / contrast-01 :ARG1 (s / show-01 :ARG0 (c / cell-line :name (n / name :op1 "H3122") :mod (o / only)) :ARG1 (r / reduce-01 :ARG1 (v / viable :mod (c2 / cell) :location (a / assay-01 :mod (s4 / small-molecule :name (n2 / name :op1 "MTS") :xref (x / xref :value "PUBCHEM:65521" :prob "10.885861")))) :manner (m / marked) :mod (a2 / any) :ARG2-of (r2 / respond-01 :ARG1 (c3 / concentrate-02 :ARG1 (s2 / small-molecule :ARG0-of (i3 / inhibit-01)) :ARG1-of (i2 / increase-01) :ARG1-of (c4 / correlate-01 :ARG2 (i4 / inhibit-01 :ARG1-of (t3 / target-01) :degree (m2 / maximum))))))) :ARG2 (d / display-01 :ARG0 (c6 / cell-line :mod (o2 / other) :ARG2-of (e / except-01 :ARG1 (t4 / treat-04 :ARG1 (c8 / cell-line :name (n3 / name :op1 "HCC827")) :ARG2 (s3 / small-molecule :quant (c9 / concentration-quantity :quant "10" :unit (m4 / micromolar)))))) :ARG1 (c7 / change-01 :ARG1 (v2 / viability) :ARG1-of (m3 / minor-01)) :concession (a3 / achieve-01 :ARG1 (i5 / inhibit-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (c10 / complete-02) :location (c11 / cell-line :mod (a4 / all) :ARG1-of (t5 / test-01 :manner (c12 / concentration-quantity :quant "1" :unit (m5 / micromolar))))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id pmid_2325_9591.88 # ::date 2015-08-22T06:16:49 # ::file pmid_2325_9591_88.txt # ::snt Dual inhibition of PI3K and MEK was tested in a panel of NSCLC lines (n=12) with the K-Ras (n=3), EGFR (n=3), ALK (n=3), or triple-negative (n=3) oncogenic genotypes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (t / test-01 :ARG1 (i / inhibit-01 :ARG1 (a / and :op1 (e / enzyme :name (n4 / name :op1 "PI3K") :xref (x4 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (d / dual)) :location (p4 / panel :consist-of (c / cell-line :ARG0-of (h / have-03 :ARG1 (o / or :op1 (g4 / genotype :mod (g / gene :name (n6 / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1-of (n3 / number-01 :ARG2 "3")) :op2 (g5 / genotype :mod (g2 / gene :name (n7 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :ARG1-of (n10 / number-01 :ARG2 "3")) :op3 (g6 / genotype :mod (g3 / gene :name (n8 / name :op1 "ALK") :xref (x / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003")) :ARG1-of (n11 / number-01 :ARG2 "3")) :op4 (g7 / genotype :ARG1-of (n9 / negative-01 :ARG1-of (t2 / triple-01)) :ARG1-of (n12 / number-01 :ARG2 "3")) :ARG0-of (c2 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))) :ARG1-of (n2 / number-01 :ARG2 "12") :mod (d2 / disease :name (n13 / name :op1 "NSCLC"))))) # ::id pmid_2325_9591.89 # ::date 2015-08-22T06:38:01 # ::file pmid_2325_9591_89.txt # ::snt Analogously to the cell lines in the preliminary experiments, all the cell lines tested here showed a major reduction in cell growth in response to the PI3K inhibitors alone, with no significant differences between ZSTK474 or PI-103 (Figure 2A, eight of the twelve lines presented graphically). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / show-01 :ARG0 (c / cell-line :mod (a / all) :ARG1-of (t2 / test-01 :location (h / here)) :ARG1-of (r3 / resemble-01 :ARG2 (c3 / cell-line :location (e / experiment-01 :mod (p2 / preliminary))))) :ARG1 (a3 / and :op1 (r / reduce-01 :ARG1 (g / grow-01 :ARG1 (c2 / cell)) :ARG1-of (m / major-02) :ARG2-of (r2 / respond-01 :ARG1 (s2 / small-molecule :mod (a2 / alone) :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "PI3K")))))) :op2 (d / differ-02 :polarity "-" :ARG1 (s4 / small-molecule :name (n2 / name :op1 "ZSTK474") :xref (x1 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :ARG2 (s5 / small-molecule :name (n3 / name :op1 "PI-103") :xref (x / xref :value "PUBCHEM:9884685" :prob "14.194942")) :ARG1-of (s3 / significant-02))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2A") :op2 (c4 / cell-line :quant "8" :ARG1-of (i3 / include-01 :ARG2 (c5 / cell-line :quant "12" :ARG1-of (p3 / present-02 :manner (g2 / graphic)))))))) # ::id pmid_2325_9591.90 # ::date 2015-08-22T08:27:49 # ::file pmid_2325_9591_90.txt # ::snt The MEK inhibitor CI-1040 elicited variable responses with the majority of cell lines, showing only minor inhibition of growth or none at all. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (e / elicit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "CI-1040") :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG1 (r / respond-01 :ARG1 (c / cell-line :ARG1-of (i3 / include-91 :ARG2 (c2 / cell-line)) :quant (m / majority)) :ARG1-of (v2 / vary-01)) :ARG0-of (s2 / show-01 :ARG1 (o / or :op1 (i4 / inhibit-01 :ARG1-of (m2 / minor-01) :mod (o2 / only)) :op2 (i5 / inhibit-01 :polarity "-" :mod (a / at-all))))) # ::id pmid_2325_9591.91 # ::date 2015-08-22T10:06:00 # ::file pmid_2325_9591_91.txt # ::snt When the cell lines were exposed to dual, concurrent inhibition of PI3K and MEK, two out of 12 tested cell lines, H3122 and H1437, showed marked additional cytotoxicity compared with treatment with a single agent (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / show-01 :ARG0 (c / cell-line :quant "2" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "12" :ARG1-of (t / test-01))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n2 / name :op1 "H3122")) :op2 (c4 / cell-line :name (n3 / name :op1 "H1437"))))) :ARG1 (c5 / cytotoxicity :ARG1-of (a2 / add-02) :mod (m2 / marked) :compared-to (t2 / treat-04 :ARG2 (a3 / agent :ARG1-of (s2 / single-02)))) :time (e / expose-01 :ARG1 c2 :ARG2 (i2 / inhibit-01 :ARG1 (a4 / and :op1 (e2 / enzyme :name (n4 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e3 / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1-of (c6 / concurrent-02) :mod (d / dual))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2325_9591.92 # ::date 2015-08-22T10:18:55 # ::file pmid_2325_9591_92.txt # ::snt The results were submitted to combination index (CI) analysis and average CI values were calculated based on combinations of ZSTK474 and PI-103. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (a / and :op1 (s / submit-01 :ARG1 (t / thing :ARG2-of (r / result-01)) :ARG2 (a2 / analyze-01 :ARG1 (i / index-01 :mod (c / combine-01)))) :op2 (c2 / calculate-01 :ARG1 (a3 / average-01 :ARG1 (v / value-01 :ARG1 i)) :ARG1-of (b / base-02 :ARG2 (c3 / combine-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474") :xref (x / xref :value "PUBCHEM:11647372" :prob "18.167522")) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "PI-103") :xref (x1 / xref :value "PUBCHEM:9884685" :prob "14.194942")))))) # ::id pmid_2325_9591.93 # ::date 2015-08-22T10:26:43 # ::file pmid_2325_9591_93.txt # ::snt This analysis grouped the cell lines into three categories: antagonism (n=5, CI 1.10-3.3), nearly additive or slight synergy (n=5, CI 0.7-1.10), and synergy or strong synergy (n=2, CI <0.7) (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (g / group-01 :ARG0 (a / analyze-01 :mod (t / this)) :ARG1 (c / cell-line) :ARG2 (c2 / category :quant "3" :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (a3 / antagonize-01 :ARG1-of (n / number-01 :ARG2 "5") :ARG1-of (i / index-01 :ARG2 (b / between :op1 "1.10" :op2 "3.3") :mod (c3 / combine-01))) :op2 (o / or :op1 (a4 / additive :mod (n2 / near)) :op2 (s / synergize-01 :mod (s2 / slight)) :ARG1-of (n3 / number-01 :ARG2 "5") :ARG1-of (i2 / index-01 :ARG2 (b2 / between :op1 "0.7" :op2 "1.10"))) :op2 (o2 / or :op1 (s3 / synergize-01) :op2 (s4 / synergize-01 :ARG1-of (s5 / strong-02)) :ARG1-of (n4 / number-01 :ARG2 "2") :ARG1-of (i3 / index-01 :ARG2 (l / less-than :op1 "0.7")))))) :ARG1-of (d / describe-01 :ARG0 (t2 / table :mod "1"))) # ::id pmid_2325_9591.94 # ::date 2015-08-22T10:51:19 # ::file pmid_2325_9591_94.txt # ::snt Visual assessment of the dual inhibition in MTS curves did not suggest any major antagonism of treatment in any of the lines tested, however, since the combination treatment curves in the cell lines with antagonistic CI values closely followed the single PI3K inhibitor treatment curves (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (h / have-concession-91 :ARG1 (s / suggest-01 :polarity "-" :ARG0 (a / assess-01 :ARG1 (i2 / inhibit-01 :mod (d / dual) :location (c / curve-01 :mod (t2 / thing :name (n / name :op1 "MTS")))) :mod (v / visual)) :ARG1 (a2 / antagonize-01 :ARG1 (t3 / treat-04) :location (c2 / cell-line :mod (a3 / any) :ARG1-of (t4 / test-01)) :ARG1-of (m / major-02))) :ARG2 (f / follow-01 :ARG1 (c4 / curve-01 :location (c5 / cell-line) :ARG0-of (h2 / have-03 :ARG1 (v2 / value-01 :mod (i3 / index-01 :mod (c6 / combine-01) :ARG0-of (a4 / antagonize-01)))) :ARG1-of (t5 / treat-04 :mod (c3 / combine-01))) :ARG2 (c7 / curve-01 :ARG1-of (t6 / treat-04 :ARG2 (s2 / small-molecule :ARG0-of (i4 / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "PI3K"))) :ARG1-of (s3 / single-02)))) :ARG1-of (c8 / close-10)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2A"))) # ::id pmid_2325_9591.95 # ::date 2015-08-22T11:30:04 # ::file pmid_2325_9591_95.txt # ::snt There was no correlation between the cancer genotypes in responsiveness to the dual inhibition, since an ALK translocated line (H3122) and a triple-negative negative line (H1437) showed synergistic responses to dual inhibition (Figure 2A, Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / correlate-01 :polarity "-" :ARG1 (g / genotype :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :ARG2-of (r / respond-01 :ARG1 (i / inhibit-01 :mod (d2 / dual))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2A") :op2 (t4 / table :mod "1"))) :ARG1-of (c7 / cause-01 :ARG0 (s / show-01 :ARG0 (a / and :op1 (c3 / cell-line :ARG2-of (t / translocate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "ALK") :xref (x / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003"))) :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :name (n3 / name :op1 "H3122")))) :op2 (c5 / cell-line :ARG1-of (n4 / negative-01 :ARG1-of (t2 / triple-01)) :ARG1-of (m2 / mean-01 :ARG2 (c6 / cell-line :name (n5 / name :op1 "H1437"))))) :ARG1 (t3 / thing :ARG2-of (r2 / respond-01 :ARG1 i) :ARG0-of (s2 / synergize-01))))) # ::id pmid_2325_9591.96 # ::date 2015-08-22T23:02:38 # ::file pmid_2325_9591_96.txt # ::snt The NSCLC lines showing synergistic responses to dual inhibition seemed to be more responsive to low concentrations (<1 μM) of the MEK inhibitor alone (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (s / seem-01 :ARG1 (r2 / responsive-02 :ARG0 (c / cell-line :ARG0-of (s2 / show-01 :ARG1 (t2 / thing :ARG2-of (r / respond-01 :ARG1 (i2 / inhibit-01 :mod (d / dual))) :ARG0-of (s3 / synergize-01))) :mod (d3 / disease :name (n3 / name :op1 "NSCLC"))) :ARG1 (c2 / concentrate-02 :ARG1 (s4 / small-molecule :ARG0-of (i3 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :mod (a / alone)) :ARG1-of (l / low-04) :quant (l2 / less-than :op1 (c3 / concentration-quantity :quant "1" :unit (m / micromolar))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2325_9591.97 # ::date 2015-08-23T03:48:22 # ::file pmid_2325_9591_97.txt # ::snt Analogously to the single inhibitor results, the lines sensitive to dual inhibition showed only a minor difference between the activities of the different PI3K inhibitors in combination with the MEK inhibitor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (s / show-01 :ARG0 (c / cell-line :ARG0-of (s2 / sensitive-03 :ARG1 (i2 / inhibit-01 :mod (d / dual)))) :ARG1 (d2 / differ-02 :ARG1 (a / activity-06 :ARG0 (s3 / small-molecule :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"))) :ARG1-of (d3 / differ-02) :ARG1-of (c2 / combine-01 :ARG2 (s4 / small-molecule :ARG0-of (i4 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))))) :ARG1-of (m / minor-01)) :ARG1-of (r / resemble-01 :ARG2 (t / thing :ARG2-of (r2 / result-01 :ARG1 (s5 / small-molecule :ARG0-of (i / inhibit-01) :ARG1-of (s6 / single-02)))))) # ::id pmid_2325_9591.98 # ::date 2015-08-23T03:55:07 # ::file pmid_2325_9591_98.txt # ::snt Based on a literature search [4,7], additional cell lines known to be responsive to dual PI3K and MEK inhibition were studied. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / study-01 :ARG1 (c / cell-line :ARG1-of (a / add-02) :ARG0-of (r / responsive-02 :ARG1 (i / inhibit-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (d / dual)) :ARG1-of (k / know-01))) :ARG1-of (b / base-02 :ARG2 (s2 / search-01 :ARG1 (l / literature) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 "4" :op2 "7"))))))) # ::id pmid_2325_9591.99 # ::date 2015-08-23T04:00:16 # ::file pmid_2325_9591_99.txt # ::snt MDA-MB231, a basal-like breast cancer line, and HCT116, a KRas mutant colorectal line, were exposed to single inhibitors or dual inhibition and analyzed with the MTS assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a2 / and :op1 (e / expose-01 :ARG1 (a / and :op1 (c / cell-line :name (n3 / name :op1 "MDA-MB231") :ARG1-of (r / resemble-01 :ARG2 (c3 / cell-line :mod (b2 / basal) :mod (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer"))))) :op2 (c4 / cell-line :name (n4 / name :op1 "HCT116") :ARG1-of (m / mean-01 :ARG2 (c5 / cell-line :mod (c6 / colon) :mod (g / gene :name (n5 / name :op1 "KRas") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.631")))))) :ARG2 (o / or :op1 (s / small-molecule :ARG1-of (s2 / single-02) :ARG0-of (i2 / inhibit-01)) :op2 (i3 / inhibit-01 :mod (d2 / dual)))) :op2 (a3 / analyze-01 :ARG1 a :instrument (a4 / assay-01 :mod (s3 / small-molecule :name (n / name :op1 "MTS") :xref (x1 / xref :value "PUBCHEM:65521" :prob "10.885861"))))) # ::id pmid_2325_9591.100 # ::date 2015-08-23T04:19:32 # ::file pmid_2325_9591_100.txt # ::snt As in the previous work, both the cell lines showed synergistic responses to dual inhibition (Figure 2B, Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / show-01 :ARG0 (c / cell-line :mod (b / both)) :ARG1 (t / thing :ARG2-of (r / respond-01 :ARG1 (i / inhibit-01 :mod (d / dual))) :ARG0-of (s2 / synergize-01)) :ARG1-of (r2 / resemble-01 :ARG2 (w / work-01 :time (p / previous))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2B") :op2 (t2 / table :mod "1")))) # ::id pmid_2325_9591.101 # ::date 2015-08-23T04:28:30 # ::file pmid_2325_9591_101.txt # ::snt PI-103 was markedly less effective than ZSTK474 in the HCT116 cell line, while, like all the NSCLC cell lines, MDA-MB231 responded similarly to both PI3K inhibitors (Figure 2B, Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (c / contrast-01 :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "PI-103") :xref (x1 / xref :value "PUBCHEM:9884685" :prob "14.194942")) :degree (l / less) :manner (m / marked) :compared-to (s2 / small-molecule :name (n2 / name :op1 "ZSTK474") :xref (x / xref :value "PUBCHEM:11647372" :prob "18.167522")) :location (c2 / cell-line :name (n3 / name :op1 "HCT116"))) :ARG2 (r / respond-01 :ARG1 (c3 / cell-line :name (n4 / name :op1 "MDA-MB231") :ARG1-of (r2 / resemble-01 :ARG2 (c4 / cell-line :mod (a2 / all) :mod (d2 / disease :name (n7 / name :op1 "NSCLC"))))) :ARG2 (s3 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n6 / name :op1 "PI3K"))) :mod (b / both)) :ARG1-of (r3 / resemble-01)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "2B") :op2 (t2 / table :mod "1")))) # ::id pmid_2325_9591.102 # ::date 2015-08-23T04:42:59 # ::file pmid_2325_9591_102.txt # ::snt Interestingly, we did not see any differences in target inhibition between ZSTK474 and PI-103 in the HCT116 line (Figure 3A), so that the mechanism of differential efficiency remains unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / see-01 :polarity "-" :ARG0 (w / we) :ARG1 (d / differ-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474") :xref (x1 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "PI-103") :xref (x / xref :value "PUBCHEM:9884685" :prob "14.194942")) :ARG3 (i / inhibit-01 :ARG1-of (t / target-01)) :mod (a / any) :location (c / cell-line :name (n3 / name :op1 "HCT116"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A")) :ARG2-of (i3 / interest-01) :ARG0-of (c2 / cause-01 :ARG1 (r / remain-01 :ARG1 (m / mechanism :ARG1-of (e / efficient-01 :mod (d3 / differential))) :ARG3 (k / know-01 :polarity "-" :ARG1 m)))) # ::id pmid_2325_9591.103 # ::date 2015-08-23T05:02:06 # ::file pmid_2325_9591_103.txt # ::snt The lines H3122, H1437, MDA-MB231, and HCT116, which were sensitive to dual inhibition, were further analyzed with Western blot analysis for cleaved PARP, a well-characterized marker of apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / analyze-01 :ARG1 (a2 / and :op1 (c / cell-line :name (n2 / name :op1 "H3122")) :op2 (c2 / cell-line :name (n3 / name :op1 "H1437")) :op3 (c3 / cell-line :name (n4 / name :op1 "MDA-MB231")) :op4 (c4 / cell-line :name (n5 / name :op1 "HCT116")) :ARG0-of (s / sensitive-03 :ARG1 (i / inhibit-01 :mod (d / dual)))) :degree (f / further) :manner (i2 / immunoblot-01 :ARG1 (p / protein :name (n7 / name :op1 "PARP") :ARG1-of (c5 / cleave-01) :ARG0-of (m / mark-02 :ARG1 (a4 / apoptosis) :ARG1-of (c6 / characterize-01) :ARG1-of (w / well-09)) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :ARG2 a2)) # ::id pmid_2325_9591.104 # ::date 2015-08-23T05:45:54 # ::file pmid_2325_9591_104.txt # ::snt No cleaved PARP was detected in any of the cell lines following the single agent treatments (Figure 4A), but when dual inhibition with either ZSTK474 or PI-103 was administered, marked PARP cleavage was seen in the H3122 line but not in the other lines tested (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (d / detect-01 :polarity "-" :ARG1 (p / protein :name (n / name :op1 "PARP") :ARG1-of (c2 / cleave-01) :xref (x1 / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :location (c3 / cell-line :mod (a / any)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4A")) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG2 (a2 / agent :ARG1-of (s / single-02))))) :ARG2 (s2 / see-01 :ARG1 (p2 / protein :name (n2 / name :op1 "PARP") :ARG1-of (c4 / cleave-01 :ARG1-of (m / mark-01)) :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :location (c5 / cell-line :name (n3 / name :op1 "H3122")) :ARG1-of (c6 / contrast-01 :ARG2 (s3 / see-01 :polarity "-" :ARG1 p2 :location (c7 / cell-line :mod (o / other) :ARG1-of (t2 / test-01)))) :time (a3 / administer-01 :ARG1 (i / inhibit-01 :ARG0 (o2 / or :op1 (s4 / small-molecule :name (n4 / name :op1 "ZSTK474") :xref (x3 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :op2 (s5 / small-molecule :name (n5 / name :op1 "PI-103") :xref (x2 / xref :value "PUBCHEM:9884685" :prob "14.194942"))) :mod (d3 / dual))) :ARG1-of d2)) # ::id pmid_2325_9591.105 # ::date 2015-08-23T06:54:57 # ::file pmid_2325_9591_105.txt # ::snt Effect of dual inhibition on cell signaling # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (a / affect-01 :ARG0 (i / inhibit-01 :mod (d / dual)) :ARG1 (s / signal-07 :ARG1 (c / cell))) # ::id pmid_2325_9591.106 # ::date 2015-08-23T06:58:06 # ::file pmid_2325_9591_106.txt # ::snt The NSCLC (H3122 and H1437), breast cancer (MDA-MB231) and colon cancer (HCT116) lines, which showing major synergy upon dual inhibition, were further studied for cell signaling in response to the inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / study-01 :ARG1 (a / and :op1 (c / cell-line :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "H3122")) :op2 (c3 / cell-line :name (n4 / name :op1 "H1437")))) :mod (d / disease :name (n / name :op1 "NSCLC"))) :op2 (c4 / cell-line :ARG1-of (m2 / mean-01 :ARG2 (c6 / cell-line :name (n5 / name :op1 "MDA-MB231"))) :mod (d3 / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer"))) :op3 (c7 / cell-line :ARG1-of (m3 / mean-01 :ARG2 (c10 / cell-line :name (n6 / name :op1 "HCT116"))) :mod (d4 / disease :wiki "Colorectal_cancer" :name (n7 / name :op1 "colon" :op2 "cancer"))) :ARG0-of (s2 / show-01 :ARG1 (s3 / synergize-01 :ARG1-of (m4 / major-02)) :time (a3 / after :op1 (i2 / inhibit-01 :mod (d2 / dual))))) :degree (f / further) :purpose (s4 / signal-07 :ARG1 (c11 / cell) :ARG2-of (r / respond-01 :ARG1 (s5 / small-molecule :ARG0-of (i3 / inhibit-01))))) # ::id pmid_2325_9591.107 # ::date 2015-08-23T07:03:47 # ::file pmid_2325_9591_107.txt # ::snt All the cell lines downregulated pAKT and its downstream target pS6 completely in response to 6h of treatment with the PI3K inhibitor ZSTK474 or PI-103 (3.3 μM) (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / downregulate-01 :ARG0 (c / cell-line :mod (a / all)) :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op2 (p3 / protein :name (n2 / name :op1 "S6") :ARG3-of p :ARG1-of (t2 / target-01 :ARG0 e :location (d2 / downstream)))) :ARG2-of (r / respond-01 :ARG1 (t3 / treat-04 :ARG2 (o / or :op1 (s / small-molecule :name (n3 / name :op1 "ZSTK474") :quant (c3 / concentration-quantity :quant "3.3" :unit (m / micromolar)) :xref (x2 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :op2 (s2 / small-molecule :name (n4 / name :op1 "PI-103") :quant c3 :xref (x1 / xref :value "PUBCHEM:9884685" :prob "14.194942")) :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K")))) :duration (t4 / temporal-quantity :quant "6" :unit (h / hour))) :ARG1-of (c2 / complete-02)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2325_9591.108 # ::date 2015-08-23T07:38:50 # ::file pmid_2325_9591_108.txt # ::snt Downregulation of p4E-BP1 was also noted with all the cell lines tested, but it was complete only in the H3122 cell line (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (c2 / contrast-01 :ARG1 (n / note-01 :ARG1 (d / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "4E-BP1") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002")) :location (c / cell-line :ARG1-of (t / test-01)))) :ARG2 (c3 / complete-02 :ARG1 d :location (c4 / cell-line :name (n3 / name :op1 "H3122") :mod (o / only))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2325_9591.109 # ::date 2015-08-23T07:45:17 # ::file pmid_2325_9591_109.txt # ::snt Furthermore, concurrent activation of pERK1/2 was recognized in the H3122, MDA-MB231 and HCT116 cell lines during PI3K inhibitor treatment (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (a / and :op2 (r / recognize-01 :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (c / concurrent-02)) :location (a3 / and :op1 (c2 / cell-line :name (n2 / name :op1 "H3122")) :op2 (c3 / cell-line :name (n3 / name :op1 "MDA-MB231")) :op3 (c4 / cell-line :name (n4 / name :op1 "HCT116"))) :time (t2 / treat-04 :ARG2 (s / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2325_9591.110 # ::date 2015-08-23T08:05:45 # ::file pmid_2325_9591_110.txt # ::snt When the cell lines were treated with the MEK inhibitor CI-1040 (1 μM, 6 h), complete (H3122, H1437) or marked (MDA-MB231, HCT116) downregulation of pERK1/2 was seen (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / see-01 :ARG1 (o / or :op1 (d / downregulate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)) :ARG1-of (c3 / complete-02) :location (a / and :op1 (c4 / cell-line :name (n4 / name :op1 "H3122")) :op2 (c5 / cell-line :name (n5 / name :op1 "H1437")))) :op2 (d2 / downregulate-01 :ARG1 e :location (a2 / and :op1 (c6 / cell-line :name (n6 / name :op1 "MDA-MB231")) :op2 (c7 / cell-line :name (n7 / name :op1 "HCT116"))) :degree (m3 / marked))) :time (t2 / treat-04 :ARG1 (c / cell-line) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "CI-1040") :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :quant (c2 / concentration-quantity :quant "1" :unit (m / micromolar)) :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357")) :duration (t3 / temporal-quantity :quant "6" :unit (h / hour))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2325_9591.111 # ::date 2015-08-23T08:15:41 # ::file pmid_2325_9591_111.txt # ::snt This was accompanied by upregulation of pAKT in the H3122 and MDA-MB231 lines, but not by upregulation of pS6 or p4E-BP1 (H3122) (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (a / accompany-01 :ARG0 (u / upregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :location (a2 / and :op1 (c2 / cell-line :name (n2 / name :op1 "H3122")) :op2 (c3 / cell-line :name (n3 / name :op1 "MDA-MB231")))) :ARG1 (t / this)) :ARG2 (a3 / accompany-01 :polarity "-" :ARG0 (u2 / upregulate-01 :ARG1 (o / or :op1 (p3 / protein :name (n4 / name :op1 "S6") :ARG3-of p) :op2 (p2 / protein :name (n5 / name :op1 "4E-BP1") :ARG3-of p :xref (x1 / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002"))) :location c2) :ARG1 t) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2325_9591.112 # ::date 2015-08-23T08:21:01 # ::file pmid_2325_9591_112.txt # ::snt p4E-BP1 was markedly upregulated in the MDA-MB231 line in response to CI-1040 treatment (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (u / upregulate-01 :ARG1 (p / protein :name (n / name :op1 "4E-BP1") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002")) :manner (m / marked) :location (c / cell-line :name (n2 / name :op1 "MDA-MB231")) :ARG2-of (r / respond-01 :ARG1 (t / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "CI-1040") :xref (x1 / xref :value "PUBCHEM:6918454" :prob "17.207357")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2325_9591.113 # ::date 2015-08-23T08:40:22 # ::file pmid_2325_9591_113.txt # ::snt When the PI3K and MEK inhibitors were administered simultaneously the inhibition of the targets was similar to that seen with single inhibitor treatment (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (r2 / resemble-01 :ARG1 (i2 / inhibit-01 :ARG1 (t / thing :ARG1-of (t2 / target-01))) :ARG2 (i3 / inhibit-01 :ARG1-of (s / see-01) :time (t3 / treat-04 :ARG2 (s2 / small-molecule :ARG0-of (i4 / inhibit-01) :ARG1-of (s3 / single-02)))) :time (a / administer-01 :ARG1 (a2 / and :op1 (s5 / small-molecule :ARG0-of (i5 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K")))) :op2 (s6 / small-molecule :ARG0-of (i6 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))) :manner (s4 / simultaneous)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2325_9591.114 # ::date 2015-08-23T08:46:57 # ::file pmid_2325_9591_114.txt # ::snt Dual inhibition was able to overcome the single inhibitor-induced stimulation of parallel pathway activation (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (c / capable-01 :ARG1 (i / inhibit-01 :mod (d / dual)) :ARG2 (o / overcome-01 :ARG0 i :ARG1 (s3 / stimulate-01 :ARG1 (a / activate-01 :ARG1 (p2 / pathway :ARG1-of (p3 / parallel-01))) :ARG2-of (i3 / induce-01 :ARG0 (s / small-molecule :ARG1-of (s2 / single-02) :ARG0-of (i2 / inhibit-01))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2325_9591.115 # ::date 2015-08-23T08:58:04 # ::file pmid_2325_9591_115.txt # ::snt We were not able to detect any significant difference in the activity of either pS6 or p4E-BP1 following dual inhibitor treatment as compared with the single PI3K inhibitor treatments (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / capable-01 :polarity "-" :ARG1 (w / we) :ARG2 (d / detect-01 :ARG0 w :ARG1 (d2 / differ-02 :ARG3 (a2 / activity-06 :ARG0 (o / or :op1 (p / protein :name (n / name :op1 "S6") :ARG3-of (p2 / phosphorylate-01)) :op2 (p3 / protein :name (n2 / name :op1 "4E-BP1") :ARG3-of p2 :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002"))) :ARG1-of (f / follow-01 :ARG2 (t2 / treat-04 :ARG2 (s2 / small-molecule :ARG0-of (i2 / inhibit-01 :mod (d3 / dual))) :compared-to (t3 / treat-04 :ARG2 (s3 / small-molecule :ARG1-of (s4 / single-02) :ARG0-of (i3 / inhibit-01 :ARG1 (p4 / protein-family :name (n3 / name :op1 "PI3K")))))))) :mod (a / any) :ARG1-of (s / significant-02))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "3A"))) # ::id pmid_2325_9591.116 # ::date 2015-08-23T09:05:22 # ::file pmid_2325_9591_116.txt # ::snt Further analysis of the dual inhibition of the central RTKs and signaling nodes was carried out with the PathScan Antibody Array, which investigates the phosphorylation status of 28 RTKs and 11 signaling nodes concurrently. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / carry-out-03 :ARG0 (p3 / product :name (n3 / name :op1 "PathScan" :op2 "Antibody" :op3 "Array") :ARG0-of (i2 / investigate-01 :ARG1 (s2 / status :mod (p4 / phosphorylate-01 :ARG1 (a4 / and :op1 (p5 / protein :quant "28" :ARG1-of (i3 / include-91 :ARG2 (p6 / protein-family :name (n4 / name :op1 "RTK")))) :op2 (n5 / node :quant "11" :ARG0-of (s3 / signal-07))))) :ARG1-of (c3 / concurrent-02))) :ARG1 (a / and :op1 (a2 / analyze-01 :ARG1 (a3 / and :op1 (i / inhibit-01 :ARG1 (p / protein :name (n / name :op1 "RTK") :mod (c2 / central) :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")) :mod (d / dual)) :op2 (n2 / node :ARG0-of s3)) :degree (f / further)))) # ::id pmid_2325_9591.117 # ::date 2015-08-23T09:15:57 # ::file pmid_2325_9591_117.txt # ::snt Attention was focused on the dual inhibition-sensitive H1437 and MDA-MB231 lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 23, 2015 (f / focus-01 :ARG1 (a / attend-02 :ARG1 "a2") :ARG2 (a2 / and :op1 (c / cell-line :name (n / name :op1 "H1437") :ARG0-of (s / sensitive-03 :ARG1 (i / inhibit-01 :mod (d / dual)))) :op2 (c2 / cell-line :name (n2 / name :op1 "MDA-MB231") :ARG0-of s))) # ::id pmid_2325_9591.118 # ::date 2015-08-25T23:59:57 # ::file pmid_2325_9591_118.txt # ::snt A low level of RTK activation was noted in untreated cells of both cell lines, H1437 showing some activity with c-MET (Figure 5), while in the signaling nodes, pAKT, S6 and ERK1/2 showed activity in both cell lines and Src activity was also noted in H1437. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (n / note-02 :ARG1 (l / level :ARG1-of (l2 / low-04) :degree-of (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "RKT") :xref (x4 / xref :value "UNIPROT:PAQR3_HUMAN" :prob "0.262")))) :location (c / cell-line :ARG1-of (t / treat-04 :polarity "-") :mod (b / both) :ARG1-of (m / mean-01 :ARG2 (c2 / cell-line :name (n3 / name :op1 "H1437") :ARG0-of (s / show-01 :ARG1 (a / activity-06 :condition (t2 / treat-04 :ARG1 c2 :ARG2 (p / protein :name (n4 / name :op1 "c-MET"))) :mod (s5 / some)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5"))))))) :ARG2 (a5 / and :op1 (s2 / show-01 :ARG0 (a4 / and :op1 (e2 / enzyme :name (n5 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op2 (p4 / protein :name (n6 / name :op1 "S6")) :op3 (s3 / slash :op1 (e4 / enzyme :name (n7 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e5 / enzyme :name (n8 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :ARG1 (a3 / activity-06 :location c) :location (n9 / node :ARG0-of (s4 / signal-07))) :op2 (n10 / note-02 :ARG1 (a6 / activity-06 :ARG0 (p3 / protein :name (n11 / name :op1 "Src") :xref (x3 / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) :location c2 :mod (a7 / also)))) # ::id pmid_2325_9591.119 # ::date 2015-08-26T00:31:17 # ::file pmid_2325_9591_119.txt # ::snt In the drug-treated cells, ZSTK474 (24 h) was able to inhibit both AKT and S6 phosphorylation, S6 showing a more pronounced effect (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / capable-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474") :xref (x1 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :ARG2 (i / inhibit-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op2 (p / protein :name (n3 / name :op1 "S6") :ARG0-of (s / show-01 :ARG1 (a2 / affect-01 :ARG1-of (p3 / pronounced-02)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5")))))) :time (a3 / after :op1 (t / temporal-quantity :quant "24" :unit (h / hour)))) :location (c2 / cell :ARG1-of (t2 / treat-04 :ARG2 (d / drug)))) # ::id pmid_2325_9591.120 # ::date 2015-08-26T00:46:10 # ::file pmid_2325_9591_120.txt # ::snt Furthermore, ZSTK474 induced a marked broad feedback RTK activation in the H1437 cell line (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (a / and :op2 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "ZSTK474") :xref (x1 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :ARG2 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "RTK") :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")) :mod (f / feedback) :mod (b / broad) :ARG1-of (m / mark-01)) :location (c / cell-line :name (n3 / name :op1 "H1437")) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5")))) # ::id pmid_2325_9591.121 # ::date 2015-08-26T00:49:57 # ::file pmid_2325_9591_121.txt # ::snt CI-1040 (24 h) effects were limited to the inhibition of ERK1/2 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (l / limit-01 :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "CI-1040") :xref (x2 / xref :value "PUBCHEM:6918454" :prob "17.207357")) :time (a3 / after :op1 (t / temporal-quantity :quant "24" :unit (h / hour)))) :ARG2 (i / inhibit-01 :ARG1 (a2 / activity-06 :ARG0 (s / slash :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))))) # ::id pmid_2325_9591.122 # ::date 2015-08-26T00:54:29 # ::file pmid_2325_9591_122.txt # ::snt When dual inhibition with ZSTK474 and CI-1040 was administered, downregulation of both pAKT/S6 and ERK1/2 was noted, but otherwise no marked difference was evident relative to the single agent treatments (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (n / note-02 :ARG1 (d / downregulate-01 :ARG1 (a / and :op1 (s / slash :op1 (e / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op2 (p2 / protein :name (n3 / name :op1 "S6"))) :op2 (s2 / slash :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n5 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))))) :condition (a2 / administer-01 :ARG1 (i / inhibit-01 :ARG0 (a3 / and :op1 (s3 / small-molecule :name (n6 / name :op1 "ZSTK474") :xref (x3 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :op2 (s4 / small-molecule :name (n7 / name :op1 "CI-1040") :xref (x4 / xref :value "PUBCHEM:6918454" :prob "17.207357")))))) :ARG2 (e7 / evidence-01 :polarity "-" :ARG1 (d2 / differ-02 :ARG1-of (m / mark-01)) :ARG1-of (r / relative-05 :ARG3 (t / treat-04 :ARG2 (o / or :op1 s3 :op2 s4)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5"))) # ::id pmid_2325_9591.123 # ::date 2015-08-26T01:02:47 # ::file pmid_2325_9591_123.txt # ::snt The results suggest specificity of the inhibitors for their targets and the existence of broad feedback activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (s2 / suggest-01 :ARG0 (t2 / thing :ARG2-of (r / result-01)) :ARG1 (a / and :op1 (s / specific-02 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01)) :ARG2 (m2 / molecular-physical-entity :ARG1-of (t / target-01 :ARG0 m))) :op2 (a2 / activate-01 :mod (f / feedback) :mod (b / broad)))) # ::id pmid_2325_9591.124 # ::date 2015-08-26T01:07:04 # ::file pmid_2325_9591_124.txt # ::snt Alternative dosing of dual inhibition # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (d / dose-01 :ARG1 (i / inhibit-01 :mod (d2 / dual)) :mod (a / alternative)) # ::id pmid_2325_9591.125 # ::date 2015-08-26T01:08:08 # ::file pmid_2325_9591_125.txt # ::snt Even though dual inhibition of PI3K and MEK was identified as an effective form of cancer therapy based on the in vitro models, administration of both drugs at doses inducing major downregulation of the target for long periods of time may be too toxic in a clinical setting. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (h / have-concession-91 :ARG1 (p2 / possible-01 :ARG1 (t2 / toxic :degree (t3 / too) :domain (a3 / administer-01 :ARG1 (d3 / drug :mod (b2 / both) :ARG1-of (d4 / dose-01 :ARG0-of (i4 / induce-01 :ARG2 (d5 / downregulate-01 :ARG1 (m3 / molecular-physical-entity :ARG1-of (t4 / target-01)) :time (p3 / period :ARG1-of (l / long-03)) :ARG1-of (m2 / major-02)))))) :condition (s / setting :mod (c / clinical)))) :ARG2 (i / identify-01 :ARG1 (i2 / inhibit-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG2 (f / form :topic (t / therapy :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :ARG0-of (e3 / effective-04)) :ARG1-of (b / base-02 :ARG2 (m / model :mod (i3 / in-vitro))))) # ::id pmid_2325_9591.126 # ::date 2015-08-26T01:49:39 # ::file pmid_2325_9591_126.txt # ::snt We therefore set out to investigate concurrent administration of PI3K and MEK inhibitors to cell lines sensitive to dual inhibition with alternative dosing schedules. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / set-out-07 :ARG0 (w / we) :ARG1 (i2 / investigate-01 :ARG0 w :ARG1 (a2 / administer-01 :ARG1 (a3 / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"))))) :ARG2 (c3 / cell-line :ARG0-of (s2 / sensitive-03 :ARG1 (i4 / inhibit-01 :ARG0 (s3 / schedule-01 :ARG1 (d2 / dose-01) :ARG1-of (a4 / alternate-01)) :mod (d / dual)))) :ARG1-of (c2 / concurrent-02))) :ARG1-of (c / cause-01)) # ::id pmid_2325_9591.127 # ::date 2015-08-26T02:00:30 # ::file pmid_2325_9591_127.txt # ::snt The MTS assays showed that for maximal reduction in the number of living cells in all the lines, dual inhibition needed to be administered for longer periods of time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / show-01 :ARG0 (a / assay-01 :instrument (s2 / small-molecule :name (n3 / name :op1 "MTS") :xref (x / xref :value "PUBCHEM:65521" :prob "10.885861"))) :ARG1 (n / need-01 :ARG0 (r / reduce-01 :ARG1 (n2 / number :quant-of (c / cell :ARG0-of (l2 / live-01) :part-of (c2 / cell-line :mod (a3 / all)))) :ARG2 (m3 / maximum)) :ARG1 (a2 / administer-01 :ARG1 (i / inhibit-01 :mod (d / dual)) :duration (p / period :ARG1-of (l / long-03 :degree (m2 / more)))))) # ::id pmid_2325_9591.128 # ::date 2015-08-26T02:06:10 # ::file pmid_2325_9591_128.txt # ::snt The therapy was significantly more effective when it was administered throughout the 72 h experiment as compared with 15 min, 4 h or 24 h periods (Figure 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (e / effective-04 :ARG0 (t / therapy) :ARG1-of (s / significant-02) :condition (a / administer-01 :ARG1 t :time (e2 / experiment-01 :duration (t2 / temporal-quantity :quant "72" :unit (h / hour) :compared-to (o / or :op1 (p / period :consist-of (t3 / temporal-quantity :quant "15" :unit (m2 / minute))) :op2 (p2 / period :consist-of (t4 / temporal-quantity :quant "4" :unit (h2 / hour))) :op3 (p3 / period :consist-of (t5 / temporal-quantity :quant "24" :unit (h3 / hour))))))) :degree (m / more) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6"))) # ::id pmid_2325_9591.129 # ::date 2015-08-26T02:12:31 # ::file pmid_2325_9591_129.txt # ::snt Interestingly, maximal cytotoxicity was seen in the ALK translocated H3122 line even with short courses of ALK inhibition (15 min), while similar cytotoxicity was seen with 72 h inhibition of PI3K and MEK concurrently (Figure 6), even though both approaches induced major inhibition of phosphorylated AKT and ERK in Western blots after 6 h treatments (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h2 / have-concession-91 :ARG1 (c3 / contrast-01 :ARG1 (s / see-01 :ARG1 (c4 / cytotoxic :degree (m / maximal) :condition (c2 / course-01 :ARG1-of (s2 / short-07) :consist-of (i2 / inhibit-01 :ARG1 "e5") :ARG1-of (m2 / mean-01 :ARG2 (t3 / temporal-quantity :quant "15" :unit (m3 / minute))))) :ARG2-of (i / interest-01) :location (c / cell-line :name (n4 / name :op1 "H3122") :ARG1-of (t2 / translocate-01 :ARG0 (e5 / enzyme :name (n5 / name :op1 "ALK") :xref (x3 / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003"))))) :ARG2 (s3 / see-01 :ARG1 (c5 / cytotoxic :ARG1-of (r2 / resemble-01 :ARG2 c4)) :concession (i3 / inhibit-01 :ARG1 (a / and :op1 (e / enzyme :name (n6 / name :op1 "PI3K") :xref (x4 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n7 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (c6 / concurrent-02)) :duration (t / temporal-quantity :quant "72" :unit (h / hour))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6")))) :ARG2 (i4 / induce-01 :ARG0 (a2 / approach-02 :mod (b / both)) :ARG2 (i5 / inhibit-01 :ARG1 (a3 / and :op1 (e3 / enzyme :name (n8 / name :op1 "AKT") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op2 (e4 / enzyme :name (n9 / name :op1 "ERK") :ARG3-of p3 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (m4 / major-02)) :time (a4 / after :op1 (t4 / treat-04 :duration (t5 / temporal-quantity :quant "6" :unit (h3 / hour)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3A")) :location (i6 / immunoblot-01))) # ::id pmid_2325_9591.130 # ::date 2015-08-26T03:28:52 # ::file pmid_2325_9591_130.txt # ::snt Since the results showed that dual inhibition needed to be administered for longer periods of time for maximal cytotoxicity, we turned next to investigating whether both inhibitors are required throughout the period of exposure. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 14, 2015 (c / cause-01 :ARG0 (s / show-01 :ARG0 (t2 / thing :ARG2-of (r / result-01)) :ARG1 (n / need-01 :ARG0 (i / inhibit-01 :mod (d / dual)) :ARG1 (a / administer-01 :ARG1 i :duration (p / period :consist-of (t3 / time) :ARG1-of (l / long-03 :degree (m / more)))) :purpose (c2 / cytotoxic :degree (m2 / maximal)))) :ARG1 (t / turn-02 :ARG1 (w / we) :ARG2 (i2 / investigate-01 :ARG0 w :ARG1 (r2 / require-01 :mode "interrogative" :ARG1 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01) :mod (b / both)) :time (p2 / period :duration-of (e / expose-01)))) :time (n2 / next))) # ::id pmid_2325_9591.131 # ::date 2015-08-26T03:37:33 # ::file pmid_2325_9591_131.txt # ::snt The dual inhibition-sensitive cell lines were exposed to one inhibitor throughout the treatment period (72 h) while the other inhibitor was administered concurrently for 15 min, 4 h or 24 h at the beginning of the drug exposure. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (c2 / contrast-01 :ARG1 (e / expose-01 :ARG1 (c / cell-line :ARG0-of (s / sensitive-03 :ARG1 (i2 / inhibit-01 :mod (d / dual)))) :ARG2 (m / molecular-physical-entity :quant "1" :ARG0-of (i / inhibit-01)) :duration (t2 / treat-04 :ARG1-of (m2 / mean-01 :ARG2 (t3 / temporal-quantity :quant "72" :unit (h / hour))))) :ARG2 (a / administer-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of i) :ARG1-of (c3 / concurrent-02) :duration (o / or :op1 (t4 / temporal-quantity :quant "15" :unit (m4 / minute)) :op2 (t5 / temporal-quantity :quant "4" :unit (h2 / hour)) :op3 (t6 / temporal-quantity :quant "24" :unit (h3 / hour))) :time (b / begin-01 :ARG1 (e2 / expose-01 :ARG2 (d2 / drug))))) # ::id pmid_2325_9591.132 # ::date 2015-08-27T02:55:02 # ::file pmid_2325_9591_132.txt # ::snt The results varied significantly between the cell lines tested. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (v / vary-01 :ARG1 (t / thing :ARG2-of (r / result-01)) :ARG5 (c / cell-line :ARG1-of (t2 / test-01)) :ARG1-of (s / significant-02)) # ::id pmid_2325_9591.133 # ::date 2015-08-27T03:01:13 # ::file pmid_2325_9591_133.txt # ::snt In the H1437 and MDA-MB231 lines concurrent inhibition of PI3K and MEK for 15 min with continued PI3K inhibition for 72 h achieved similar cytotoxicity to concurrent inhibition for 72 h (Figure 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 14, 2015 (a / achieve-01 :ARG0 (a2 / and :op1 (i / inhibit-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1-of (c / concurrent-02) :duration (t / temporal-quantity :quant "15" :unit (m / minute)) :location (a4 / and :op1 (c2 / cell-line :name (n4 / name :op1 "H1437")) :op2 (c3 / cell-line :name (n5 / name :op1 "MDA-MB231")))) :op2 (i2 / inhibit-01 :ARG1 e :duration (t2 / temporal-quantity :quant "72" :unit (h / hour)) :ARG1-of (c4 / continue-01))) :ARG1 (c5 / cytotoxic :ARG1-of (r / resemble-01 :ARG2 (i3 / inhibit-01 :ARG1-of c :duration (t3 / temporal-quantity :quant "72" :unit (h2 / hour))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6"))) # ::id pmid_2325_9591.134 # ::date 2015-08-27T03:13:55 # ::file pmid_2325_9591_134.txt # ::snt Conversely, when these lines were exposed to the MEK inhibitor throughout the treatment period, short concurrent exposures (15 min, 4 h or 24 h) to PI3K inhibitors did not induce any comparable cytotoxicity (Figure 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG2 (i2 / induce-01 :polarity "-" :ARG0 (e / expose-01 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "PI3K")))) :ARG1-of (c2 / concurrent-02) :ARG1-of (s / short-07) :duration (o / or :op1 (t2 / temporal-quantity :quant "15" :unit (m / minute)) :op2 (t3 / temporal-quantity :quant "4" :unit (h / hour)) :op3 (t4 / temporal-quantity :quant "24" :unit h))) :ARG2 (c3 / cytotoxic :ARG1-of (c4 / comparable-03) :mod (a / any))) :time (e3 / expose-01 :ARG1 (c5 / cell-line :mod (t5 / this)) :ARG2 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK")))) :duration (p2 / period :duration-of (t7 / treat-04))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6"))) # ::id pmid_2325_9591.135 # ::date 2015-08-27T03:35:24 # ::file pmid_2325_9591_135.txt # ::snt On the other hand, the effects of dual inhibition with PI-103 occurred faster in the H1437 line than with ZSTK474, since shorter exposures to the drug (24 h) seemed to be sufficient for maximal cytotoxicity as compared with 72h of ZSTK474 (Figure 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (c / contrast-01 :ARG2 (a / affect-01 :ARG0 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "PI-103") :xref (x1 / xref :value "PUBCHEM:9884685" :prob "14.194942")) :mod (d / dual)) :location (c2 / cell-line :name (n2 / name :op1 "H1437")) :ARG1-of (f / fast-02 :degree (m / more) :compared-to (i2 / inhibit-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ZSTK474") :xref (x / xref :value "PUBCHEM:11647372" :prob "18.167522"))))) :ARG1-of (c3 / cause-01 :ARG0 (s5 / seem-01 :ARG1 (s3 / suffice-01 :ARG0 (e / expose-01 :ARG2 s :ARG1-of (s4 / short-07 :degree (m2 / more)) :ARG1-of (m3 / mean-01 :ARG2 (t / temporal-quantity :quant "24" :unit (h / hour))) :compared-to (e2 / expose-01 :ARG2 s2 :duration (t2 / temporal-quantity :quant "72" :unit (h2 / hour)))) :ARG1 (c4 / cytotoxic :mod (m4 / maximal))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "6"))) # ::id pmid_2325_9591.136 # ::date 2015-08-27T03:49:23 # ::file pmid_2325_9591_136.txt # ::snt In the case of the H3122 and HCT116 lines, both the PI3K and MEK inhibitors needed to be administered throughout the treatment period for maximal cytotoxicity (Figure 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (n2 / need-01 :ARG0 (c / cytotoxicity :mod (m3 / maximal)) :ARG1 (a2 / administer-01 :ARG1 (a / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n3 / name :op1 "PI3K")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"))))) :duration (p2 / period :duration-of (t2 / treat-04))) :location (a3 / and :op1 (c2 / cell-line :name (n5 / name :op1 "H3122")) :op2 (c3 / cell-line :name (n6 / name :op1 "HCT116"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6"))) # ::id pmid_2325_9591.137 # ::date 2015-08-27T03:57:54 # ::file pmid_2325_9591_137.txt # ::snt We next investigated alternative dosing of the dual inhibition of cell signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (i / investigate-01 :ARG0 (w / we) :ARG1 (d / dose-01 :ARG1 (i2 / inhibit-01 :ARG1 (s / signal-07 :ARG0 (c / cell)) :mod (d2 / dual)) :ARG1-of (a / alternate-01)) :time (n / next)) # ::id pmid_2325_9591.138 # ::date 2015-08-27T04:02:57 # ::file pmid_2325_9591_138.txt # ::snt The dual inhibition-sensitive lines were exposed to the PI3K inhibitors and MEK inhibitor concurrently for 15 min, after which treatment was continued with a single inhibitor for the remainder of the 6 h period. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c3 / continue-01 :ARG1 (t3 / treat-04 :ARG2 (m4 / molecular-physical-entity :ARG1-of (s2 / single-02) :ARG0-of (i4 / inhibit-01))) :duration (p / period :ARG1-of (r / remain-01) :ARG1-of (m5 / mean-01 :ARG2 (t4 / temporal-quantity :quant "6" :unit (h / hour)))) :time (a2 / after :op1 (e / expose-01 :ARG1 (c / cell-line :ARG0-of (s / sensitive-03 :ARG1 (i2 / inhibit-01 :mod (d / dual)))) :ARG2 (a / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p3 / protein-family :name (n3 / name :op1 "MEK"))))) :ARG1-of (c2 / concurrent-02) :duration (t2 / temporal-quantity :quant "15" :unit (m3 / minute))))) # ::id pmid_2325_9591.139 # ::date 2015-08-27T04:39:59 # ::file pmid_2325_9591_139.txt # ::snt pAKT downregulation was complete or nearly complete when the cells were treated for only 15 min and with PI3K inhibitors for 6 h (Figure 3B), while conversely, pERK1/2 recovered completely in 6 h when the cells were treated with the MEK inhibitor for 15 min (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c4 / contrast-01 :ARG1 (o / or :op1 (c / complete-02 :ARG1 (d / downregulate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :condition (a / and :op1 (t2 / treat-04 :ARG1 (c3 / cell) :duration (t3 / temporal-quantity :quant "15" :unit (m / minute) :mod (o2 / only))) :op2 (t4 / treat-04 :ARG1 c3 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n4 / name :op1 "PI3K")))) :duration (t5 / temporal-quantity :quant "6" :unit (h / hour))))) :op2 (c2 / complete-02 :ARG1 d :ARG1-of (n3 / near-01) :condition a) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3B"))) :ARG2 (r / recover-01 :ARG1 (s / slash :op1 (e3 / enzyme :name (n5 / name :op1 "ERK1") :ARG3-of (p3 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n6 / name :op1 "ERK2") :ARG3-of p3 :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1-of (c5 / complete-02) :time (a2 / after :op1 t5) :condition (t6 / treat-04 :ARG1 (c6 / cell) :ARG2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p4 / protein-family :name (n7 / name :op1 "MEK")))) :duration t3) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "3B")))) # ::id pmid_2325_9591.140 # ::date 2015-08-27T04:52:47 # ::file pmid_2325_9591_140.txt # ::snt Interestingly, we were able to see some recovery in the activity of the downstream targets of AKT when the PI3K inhibitors were administered for 15min despite the remaining pAKT downregulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / capable-01 :ARG1 (w / we) :ARG2 (s / see-01 :ARG0 w :ARG1 (r / recover-02 :ARG1 (a / activity-06 :ARG0 (m3 / molecular-physical-entity :ARG1-of (t2 / target-01 :ARG0 (e / enzyme :name (n / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :mod (d / downstream))) :mod (s2 / some)) :condition (a2 / administer-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "PI3K")))) :duration (t3 / temporal-quantity :quant "15" :unit (m2 / minute)))) :concession (d2 / downregulate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of (r2 / remain-01)) :ARG2-of (i2 / interest-01)) # ::id pmid_2325_9591.141 # ::date 2015-08-27T04:59:57 # ::file pmid_2325_9591_141.txt # ::snt The pS6 signal was able to recovery in the MDA-MB231 (with ZSTK474) and HCT116 (with both PI3K inhibitors) lines after short PI3K administration (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (c / capable-01 :ARG1 (s / signal-07 :ARG0 (p3 / protein :name (n / name :op1 "S6") :ARG3-of (p2 / phosphorylate-01))) :ARG2 (r / recover-01 :ARG1 s :location (c2 / cell-line :name (n2 / name :op1 "MDA-MB231")) :condition (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "ZSTK474") :xref (x / xref :value "PUBCHEM:11647372" :prob "18.167522"))))) :op2 (c3 / capable-01 :ARG1 s :ARG2 (r2 / recover-01 :location (c4 / cell-line :name (n4 / name :op1 "HCT116")) :condition (t3 / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K"))) :mod (b / both))))) :time (a3 / after :op1 (a4 / administer-01 :ARG1 p :ARG1-of (s3 / short-07))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2325_9591.142 # ::date 2015-08-27T05:08:03 # ::file pmid_2325_9591_142.txt # ::snt Furthermore, p4E-BP1 recovery was noted in the H3122 (with ZSTK474), MDA-MB231 (with ZSTK474), and HCT116 (with both PI3K inhibitors) lines (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (n / note-02 :ARG1 (a2 / and :op1 (r / recover-01 :ARG1 (p2 / protein :name (n2 / name :op1 "4E-BP1") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002")) :location (c / cell-line :name (n3 / name :op1 "H3122")) :condition (t2 / treat-04 :ARG2 (s / small-molecule :name (n4 / name :op1 "ZSTK474") :xref (x1 / xref :value "PUBCHEM:11647372" :prob "18.167522")))) :op2 (r2 / recover-01 :ARG1 p2 :location (c2 / cell-line :name (n5 / name :op1 "MDA-MB231")) :condition t2) :op3 (r3 / recover-01 :ARG1 p2 :location (c3 / cell-line :name (n6 / name :op1 "HCT116")) :condition (t3 / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n7 / name :op1 "PI3K"))) :mod (b / both))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B")))) # ::id pmid_2325_9591.143 # ::date 2015-08-27T05:15:29 # ::file pmid_2325_9591_143.txt # ::snt Interestingly, MEK inhibitor treatment induced upregulation of p4E-BP1 in the MDA-MB231 line (Figure 3A), and marked downregulation p4E-BP1 was noted only with PI-103 (PI3K and mTOR inhibitor) in the alternative dosing experiments, but not with ZSTK474 (with a PI3K inhibitor alone) (Figure 5), suggesting mTOR-mediated activation of 4E-BP1 in response to MEK inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i2 / induce-01 :ARG0 (t2 / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :ARG2 (u / upregulate-01 :ARG1 (p4 / protein :name (n3 / name :op1 "4E-BP1") :ARG3-of (p2 / phosphorylate-01) :xref (x3 / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002")) :location (c / cell-line :name (n4 / name :op1 "MDA-MB231"))) :ARG2-of (i3 / interest-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A")) :location (e4 / experiment-01 :ARG2 (d3 / dose-01 :ARG1-of (a3 / alternate-01)))) :op2 (c2 / contrast-01 :ARG1 (n5 / note-02 :ARG1 (d2 / downregulate-01 :ARG1 p4 :ARG1-of (m2 / mark-01)) :condition (t3 / treat-04 :ARG2 (s / small-molecule :name (n6 / name :op1 "PI-103") :ARG0-of (i4 / inhibit-01 :ARG1 (a2 / and :op1 (p5 / protein-family :name (n7 / name :op1 "PI3K")) :op2 (p3 / protein :name (n8 / name :op1 "mTOR") :xref (x1 / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")))) :xref (x5 / xref :value "PUBCHEM:9884685" :prob "14.194942")) :mod (o / only)) :location e4) :ARG2 (n9 / note-02 :polarity "-" :ARG1 d2 :condition (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n10 / name :op1 "ZSTK474") :ARG1-of (m3 / mean-01 :ARG2 (m4 / molecular-physical-entity :ARG0-of (i5 / inhibit-01 :ARG1 p5) :mod (a4 / alone))) :xref (x4 / xref :value "PUBCHEM:11647372" :prob "18.167522")))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "5"))) :ARG0-of (s3 / suggest-01 :ARG1 (a5 / activate-01 :ARG1 (p / protein :name (n11 / name :op1 "4E-BP1") :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002")) :ARG1-of (m5 / mediate-01 :ARG0 p3) :ARG2-of (r / respond-01 :ARG1 i)))) # ::id pmid_2325_9591.144 # ::date 2015-08-27T05:48:36 # ::file pmid_2325_9591_144.txt # ::snt TAE684, an ALK inhibitor, treatment was also included in the experiments conducted with the H3122 line, and this induced comparable pAKT, pERK1/2, and pS6 downregulation to that achieved with dual inhibition, whereas no change in p4E-BPI was noted (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c4 / contrast-01 :ARG1 (a / and :op1 (i2 / include-01 :ARG1 (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "TAE684") :ARG0-of (i / inhibit-01 :ARG1 (e6 / enzyme :name (n2 / name :op1 "ALK") :xref (x2 / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003"))) :xref (x5 / xref :value "PUBCHEM:16038120" :prob "18.013371")) :mod (a4 / also)) :ARG2 (e / experiment-01 :ARG1 (c2 / cell-line :name (n3 / name :op1 "H3122")) :ARG1-of (c / conduct-01))) :op2 (i3 / induce-01 :ARG0 i2 :ARG2 (d / downregulate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n4 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x4 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op2 (s2 / slash :op1 (e3 / enzyme :name (n5 / name :op1 "ERK1") :ARG3-of p :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n6 / name :op1 "ERK2") :ARG3-of p :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :op3 (p3 / protein :name (n7 / name :op1 "S6") :ARG3-of p)) :ARG1-of (c3 / comparable-03 :ARG2 (d2 / downregulate-01 :ARG1 a2 :ARG1-of (a3 / achieve-01 :ARG0 (i4 / inhibit-01 :mod (d3 / dual)))))))) :ARG2 (n8 / note-02 :polarity "-" :ARG1 (c5 / change-01 :ARG1 (p2 / protein :name (n9 / name :op1 "4E-BPI") :ARG3-of p :xref (x1 / xref :value "UNIPROT:4EBP1_HUMAN" :prob "0.292")))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2325_9591.145 # ::date 2015-08-27T09:02:39 # ::file pmid_2325_9591_145.txt # ::snt Some recovery of pAKT and pS6 was seen after a short treatment with TAE684 (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :ARG1 (r / recover-02 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op2 (p2 / protein :name (n2 / name :op1 "S6") :ARG3-of p)) :degree (s4 / some)) :time (a2 / after :op1 (t / treat-04 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "TAE684") :xref (x1 / xref :value "PUBCHEM:16038120" :prob "18.013371")) :ARG1-of (s2 / short-07))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2325_9591.146 # ::date 2015-08-27T09:21:34 # ::file pmid_2325_9591_146.txt # ::snt We went on further to analyze whether the alternative dosing could also result in apoptosis in the H3122 cell line, the only line identified as inducing apoptosis in response to dual inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (g / go-06 :ARG0 (w / we) :ARG1 (a / analyze-01 :ARG0 w :ARG1 (p2 / possible-01 :mode "interrogative" :ARG1 (r / result-01 :ARG1 (d / dose-01 :ARG1-of (a2 / alternate-01)) :ARG2 (a3 / apoptosis) :location (c / cell-line :name (n / name :op1 "H3122") :ARG1-of (i / identify-01 :ARG2 (i2 / induce-01 :ARG0 c :ARG2 a3 :ARG2-of (r2 / respond-01 :ARG1 (i3 / inhibit-01 :mod (d2 / dual))))) :mod (o / only)) :mod (a4 / also)))) :ARG2 (f / further)) # ::id pmid_2325_9591.147 # ::date 2015-08-27T23:28:08 # ::file pmid_2325_9591_147.txt # ::snt When the cells was treated for 15 min with dual inhibition and treatment with either the PI3K inhibitors or the MEK inhibitor was continued for 48 h, marked PARP cleavage was seen in all the treatments (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / see-01 :ARG1 (c / cleave-01 :ARG1 (p2 / protein :name (n2 / name :op1 "PARP") :xref (x / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :ARG1-of (m / mark-01) :location (t3 / treat-04 :mod (a / all))) :condition (a2 / and :op1 (t2 / treat-04 :ARG1 (c2 / cell) :ARG2 (i2 / inhibit-01 :mod (d / dual)) :duration (t4 / temporal-quantity :quant "15" :unit (m2 / minute))) :op2 (c3 / continue-01 :ARG1 (t5 / treat-04 :ARG2 (o / or :op1 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "PI3K")))) :op2 (m4 / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK")))))) :duration (t6 / temporal-quantity :quant "48" :unit (h / hour)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id pmid_2325_9591.148 # ::date 2015-08-27T23:45:35 # ::file pmid_2325_9591_148.txt # ::snt Furthermore, 15 min treatment with an ALK inhibitor resulted in marked PARP cleavage (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 28, 2015 (a / and :op2 (r / result-01 :ARG1 (t2 / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "ALK") :xref (x / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003")))) :duration (t3 / temporal-quantity :quant "15" :unit (m2 / minute))) :ARG2 (c / cleave-01 :ARG1 (p / protein :name (n2 / name :op1 "PARP") :xref (x1 / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :ARG1-of (m3 / mark-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B")))) # ::id pmid_2325_9591.149 # ::date 2015-08-27T23:50:24 # ::file pmid_2325_9591_149.txt # ::snt Cleaved PARP results were further verified with western blot analysis for cleaved caspase-3, another marker for apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (v / verify-01 :ARG1 (r / result-01 :ARG1 (p / protein :name (n2 / name :op1 "PARP") :ARG1-of (c / cleave-01) :xref (x1 / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352"))) :mod (f / further) :purpose (f2 / find-01 :ARG1 (p2 / protein :name (n3 / name :op1 "caspase-3") :ARG1-of (c2 / cleave-01) :ARG1-of (m2 / mean-01 :ARG2 (t / thing :ARG0-of (m / mark-01 :ARG1 (a2 / apoptosis)) :mod (a3 / another))) :xref (x / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.702"))) :instrument (a / analyze-01 :manner (i / immunoblot-01))) # ::id pmid_2325_9591.150 # ::date 2015-08-27T23:56:19 # ::file pmid_2325_9591_150.txt # ::snt Cleaved caspase-3 was detected with concurrent PI3K and MEK, or ALK inhibition while no signal was seen in PI3K or MEK inhibitor treatments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c2 / contrast-01 :ARG1 (d / detect-01 :ARG1 (p2 / protein :name (n2 / name :op1 "caspase-3") :ARG1-of (c / cleave-01) :xref (x1 / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.702")) :condition (t2 / treat-04 :ARG2 (o / or :op1 (a / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n3 / name :op1 "PI3K")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"))))) :op2 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "ALK") :xref (x / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003"))))) :ARG1-of (c3 / concurrent-02))) :ARG2 (s / see-01 :polarity "-" :ARG1 (s2 / signal-07) :condition (t3 / treat-04 :ARG2 (o2 / or :op1 m :op2 m2)))) # ::id pmid_2325_9591.151 # ::date 2015-08-28T00:08:26 # ::file pmid_2325_9591_151.txt # ::snt Conversely to cleaved PARP, the cleaved caspase-3 signal was much lower in alternative dosing schedules compared to continuous, concurrent PI3K and MEK inhibition (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (c / contrast-01 :ARG1 (l2 / low-04 :ARG1 (s / signal-07 :ARG0 (p3 / protein :name (n3 / name :op1 "caspase-3") :ARG1-of (c3 / cleave-01) :xref (x2 / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.702"))) :degree (m2 / more :mod (m3 / much)) :location (s2 / schedule-01 :mod (d / dose-01 :ARG1-of (a / alternate-01))) :compared-to (i / inhibit-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n4 / name :op1 "PI3K") :xref (x3 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (e2 / enzyme :name (n5 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1-of (c4 / continue-01) :ARG1-of (c5 / concurrent-02))) :ARG2 (p2 / protein :name (n2 / name :op1 "PARP") :ARG1-of (c2 / cleave-01) :xref (x1 / xref :value "UNIPROT:PARI_HUMAN" :prob "0.352")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id pmid_2337_4602.1 # ::date 2015-08-04T00:48:12 # ::file pmid_2337_4602_1.txt # ::snt Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes (PMID:23374602) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (b4 / biomarker :ARG0-of (b / benefit-01) :topic (t / therapy :ARG1-of (b3 / base-02 :ARG2 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :ARG1-of (m2 / mean-01 :ARG2 (i / interact-01 :ARG0 (e2 / express-03 :ARG2 (l / ligand :name (n2 / name :op1 "EGFR"))) :ARG1 (a / and :op1 (g2 / genotype :mod (p2 / pathway :name (n4 / name :op1 "RAS/RAF"))) :op2 (g4 / genotype :mod (g / gene :name (n3 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID23374602")) :location (d2 / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal" :op2 "cancer") :ARG1-of (m / metastasize-101))) # ::id pmid_2337_4602.8 # ::date 2015-08-04T01:14:14 # ::file pmid_2337_4602_8.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2337_4602.9 # ::date 2015-08-04T01:15:22 # ::file pmid_2337_4602_9.txt # ::snt Only PIK3CA mutations occasionally coexisted with other gene mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (c / coexist-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :mod (o / only)) :ARG2 (m2 / mutate-01 :ARG2 (g2 / gene :mod (o3 / other))) :frequency (o2 / occasional)) # ::id pmid_2337_4602.10 # ::date 2015-08-04T01:17:18 # ::file pmid_2337_4602_10.txt # ::snt In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / see-01 :ARG1 (s2 / signify-01 :ARG0 (a / and :op1 (m2 / mutate-01 :ARG1 (e5 / enzyme :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and :op1 (r4 / ratio-of :quant "8.1" :op1 (h2 / hazard)) :op2 (i / interval :value (b / between :op1 "3.4" :op2 "19") :quant (p / percentage-entity :value "95") :mod (c2 / confidence))))) :op2 (m3 / mutate-01 :ARG1 (c / codon :mod "12" :mod (o / only) :part-of (e6 / enzyme :name (n3 / name :op1 "KRAS") :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1-of (m6 / mean-01 :ARG2 (a3 / and :op1 (r5 / ratio-of :quant "1.62" :op1 h2) :op2 (i2 / interval :value (b2 / between :op1 "1.1" :op2 "2.4") :quant p :mod c2)))) :op3 (e / express-03 :ARG2 (n10 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p3 / protein :name (n5 / name :op1 "AREG") :xref (x / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")))) :ARG3 (d / disease :name (n6 / name :op1 "CRC") :mod o :mod (e7 / enzyme :name (n7 / name :op1 "KRAS") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1-of (h / high-02) :ARG1-of (m7 / mean-01 :ARG2 (a4 / and :op1 (r6 / ratio-of :quant "0.47" :op1 h2) :op2 (i3 / interval :value (b3 / between :op1 "0.3" :op2 "0.7") :quant p :mod c2)))) :op4 (e3 / express-03 :ARG2 (n11 / nucleic-acid :name (n8 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (p4 / protein :name (n9 / name :op1 "EREG") :xref (x4 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))) :ARG1-of (m8 / mean-01 :ARG2 (a5 / and :op1 (r7 / ratio-of :quant "0.45" :op1 h2) :op2 (i4 / interval :value (b4 / between :op1 "0.28" :op2 "0.7") :quant p :mod c2))) :ARG1-of h :ARG1-of (r / regardless-91 :ARG2 (s4 / status :mod (m4 / mutate-01 :ARG2 e6))))) :ARG1 (s3 / survive-01 :time (a6 / after :op1 (m / metastasize-101)) :time (u2 / until :op1 (d2 / die-01))) :mod (p2 / prognostic)) :time (a7 / analyze-01 :mod (u / univariate))) # ::id pmid_2337_4602.11 # ::date 2015-08-04T01:53:43 # ::file pmid_2337_4602_11.txt # ::snt EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (a / associate-01 :ARG1 (e / express-03 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))) :ARG0-of (c / cause-01 :ARG1 (t / tumor))) :ARG2 (l / likely-01 :ARG1 (t2 / thing :ARG2-of (r2 / respond-01 :ARG1 (t3 / therapy :mod (s / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :mod (o / objective)) :ARG1-of (i / increase-01 :ARG2 (p2 / product-of :op1 "2.26")) :ARG1-of (m / mean-01 :ARG2 (t4 / thing :value "1.1" :name (n4 / name :op1 "RECIST")))) :ARG1-of (s2 / significant-02)) # ::id pmid_2337_4602.12 # ::date 2015-08-04T02:07:44 # ::file pmid_2337_4602_12.txt # ::snt In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (a / and :op1 (n8 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG") :xref (x / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))) :ARG1-of (h / high-02) :location (t / tumor :mod (g / gene :name (n3 / name :op1 "KRAS") :mod (w / wild-type) :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :op2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "EREG") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004"))) :ARG1-of h) :op3 (n10 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (p3 / protein :name (n7 / name :op1 "Ephrin" :op2 "A2" :op3 "receptor") :xref (x2 / xref :value "UNIPROT:EPHA1_HUMAN" :prob "0.313"))) :ARG1-of (l / low-04)) :domain (f / factor :ARG0-of (p4 / predict-01) :ARG0-of (f2 / favor-01)) :time (a2 / analyze-01 :mod (m / multivariate))) # ::id pmid_2337_4602.13 # ::date 2015-08-04T02:21:44 # ::file pmid_2337_4602_13.txt # ::snt Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (f / fare-01 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (t / treat-03 :ARG3 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x3 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :ARG0-of (h2 / have-03 :ARG1 (d / disease :name (n2 / name :op1 "CRC") :mod (g / gene :name (n3 / name :op1 "KRAS") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (l / low-04 :ARG2 (p3 / protein :name (n4 / name :op1 "AREG") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")))))) :manner (p4 / poor :degree (v / very)) :ARG1-of (c / cause-01 :ARG0 (r / resemble-01 :ARG1 (s2 / survive-01 :ARG0 p) :ARG2 (s3 / survive-01 :ARG1 (d2 / disease :name (n5 / name :op1 "CRC") :mod (g2 / gene :name (n6 / name :op1 "KRAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))))) # ::id pmid_2337_4602.14 # ::date 2015-08-04T02:30:20 # ::file pmid_2337_4602_14.txt # ::snt Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15–26). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (h3 / have-03 :ARG0 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :ARG0-of (h2 / have-03 :ARG1 (o / or :op1 (m / mutate-01 :ARG1 (c2 / codon :mod "13" :part-of (g / gene :name (n3 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :op2 (m2 / mutate-01 :ARG1 (c4 / codon :mod "12" :polarity "-" :part-of g) :mod (o2 / other))))) :ARG1 (s / survive-01 :ARG0 p2 :mod (m3 / median) :ARG1-of (r / resemble-01 :ARG2 (s2 / survive-01 :ARG0 (p4 / person :ARG0-of h :ARG0-of (h4 / have-03 :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG1-of (m6 / mean-01 :ARG2 (a2 / and :op1 (s3 / survive-01 :duration (t2 / temporal-quantity :quant "29" :unit "m5") :mod m3) :op2 (i / interval :value (b3 / between :op1 (t6 / temporal-quantity :quant "25" :unit "m5") :op2 "t5") :quant "p" :mod (c3 / confidence))))))) :ARG1-of (m4 / mean-01 :ARG2 (a / and :op1 (t / temporal-quantity :quant "30" :unit (m5 / month)) :op2 (i2 / interval :value (b2 / between :op1 (t4 / temporal-quantity :quant "20" :unit m5) :op2 (t5 / temporal-quantity :quant "35" :unit m5)) :quant (p / percentage-entity :value "95") :mod c3))) :ARG1-of (c / contrast-01 :ARG2 (p5 / person :ARG0-of h :ARG0-of (h5 / have-03 :ARG1 (m8 / mutate-01 :ARG1 (c5 / codon :mod "12" :part-of g))) :ARG0-of (f / fare-01 :ARG1-of (b / bad-07 :degree (m9 / more) :ARG1-of (m10 / mean-01 :ARG2 (a3 / and :op1 (s4 / survive-01 :duration (t3 / temporal-quantity :quant "19" :unit m5) :mod m3) :op2 (i3 / interval :value (b4 / between :op1 (t7 / temporal-quantity :quant "15" :unit m5) :op2 (t8 / temporal-quantity :quant "26" :unit m5)) :quant p :mod c3)))))))) # ::id pmid_2337_4602.81 # ::date 2015-08-04T02:59:40 # ::file pmid_2337_4602_81.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2337_4602.82 # ::date 2015-08-04T04:52:38 # ::file pmid_2337_4602_82.txt # ::snt Patient and tumour demographics # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (d / demographic :mod (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)))) :op2 (d2 / demographic :mod (t / tumor))) # ::id pmid_2337_4602.83 # ::date 2015-08-04T04:53:58 # ::file pmid_2337_4602_83.txt # ::snt A total of 226 patients of a median age of 62.6 years (range 26–85) underwent excisional or incisional biopsy of colorectal adenocarcinoma, of whom 83 (36.8%) were diagnosed with localised (stage I-III) colon cancer and 137 (60.6%) with metastatic disease (Table  1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (u / undergo-28 :ARG1 (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG1-of (t / total-01 :ARG2 "226") :ARG1-of (a / age-01 :ARG2 (t2 / temporal-quantity :quant "62.6" :unit (y / year)) :mod (m / median) :ARG1-of (r / range-01 :ARG3 (t3 / temporal-quantity :quant "26" :unit y) :ARG4 (t4 / temporal-quantity :quant "85" :unit y))) :ARG2-of (i2 / include-91 :ARG1 (a3 / and :op1 (p5 / person :quant "83" :ARG0-of h :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value "36.8")) :ARG1-of (d2 / diagnose-01 :ARG2 (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG1-of (l / local-02 :ARG2 (c3 / colon)) :ARG1-of (r2 / range-01 :ARG3 (s / stage :ord (o / ordinal-entity :value "1")) :ARG4 (s2 / stage :ord (o3 / ordinal-entity :value "3")))))) :op2 (p6 / person :quant "137" :ARG0-of h :ARG1-of (m3 / mean-01 :ARG2 (p2 / percentage-entity :value "60.6")) :ARG1-of (d3 / diagnose-01 :ARG2 (d4 / disease :ARG1-of (m4 / metastasize-101))))))) :ARG2 (o2 / or :op1 (b / biopsy-101 :ARG1 (m5 / medical-condition :name (n2 / name :op1 "adenocarcinoma") :mod (c / colorectal)) :ARG0-of (e / excise-01)) :op2 (b2 / biopsy-101 :ARG1 (a2 / adenocarcinoma) :ARG0-of (i / incise-01))) :ARG1-of (d / describe-01 :ARG0 (t5 / table :mod "1"))) # ::id pmid_2337_4602.84 # ::date 2015-08-04T05:10:55 # ::file pmid_2337_4602_84.txt # ::snt The primary tumour was located in the left colon (distal transverse to rectum) in 165 (73.0%) of cases and in the right colon (caecum to proximal transverse) in 60 (26.6%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (l / locate-02 :ARG1 (t / tumor :mod (p3 / primary)) :location (c / colon :ARG1-of (l2 / left-20) :ARG1-of (m / mean-01 :ARG2 (b / between :op1 (t2 / transverse :mod (d / distal)) :op2 (r / rectum)))) :location (c2 / case-04 :quant "165" :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value "73.0")))) :op2 (l3 / locate-02 :ARG1 t :location (c3 / colon :ARG1-of (m2 / mean-01 :ARG2 (b2 / between :op1 (c4 / caecum) :op2 (t3 / transverse :mod (p4 / proximal)))) :ARG1-of (r2 / right-04)) :location (c5 / case-04 :quant "60" :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value "26.6"))))) # ::id pmid_2337_4602.85 # ::date 2015-08-04T05:20:07 # ::file pmid_2337_4602_85.txt # ::snt Rectal tumours accounted for 71 cases (31%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / account-01 :ARG0 (t / tumor :mod (r / rectum)) :ARG1 (c / case-04 :quant "71" :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value "31")))) # ::id pmid_2337_4602.86 # ::date 2015-08-04T05:22:11 # ::file pmid_2337_4602_86.txt # ::snt From May 2004 until December 2008, cetuximab had been administered as an intravenous infusion according to standard regimens (loading dose 400 mg/m2 followed by weekly 250 mg/m2) as monotherapy (42, 13.4%) or with regimes based on irinotecan (153, 48.7%), oxaliplatin (84, 26.7%) or both agents (29, 9.2%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (o / or :op1 (a / administer-01 :ARG1 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :ARG2 (c3 / case-04 :quant "42" :ARG1-of (m4 / mean-01 :ARG2 (p / percentage-entity :value "13.4"))) :ARG1-of (i / infuse-01 :mod (i2 / intravenous)) :ARG1-of (a2 / accord-02 :ARG2 (r / regimen :ARG1-of (s2 / standard-02) :ARG1-of (m / mean-01 :ARG2 (d3 / dose-01 :ARG2-of (l / load-01) :quant (c / concentration-quantity :quant "400" :unit (m2 / milligram-per-square-meter)) :ARG2-of (f / follow-01 :ARG1 (d4 / dose-01 :frequency (w / week) :quant (c2 / concentration-quantity :quant "250" :unit m2))))))) :manner (m3 / monotherapy)) :op2 (a3 / administer-01 :ARG1 s :ARG2 (c4 / case-04 :quant "153" :ARG1-of (m5 / mean-01 :ARG2 (p2 / percentage-entity :value "48.7"))) :ARG1-of i :prep-with (r2 / regimen :ARG1-of (b / base-02 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "irinotecan") :xref (x / xref :value "PUBCHEM:60838" :prob "16.047258")))) :ARG1-of a2) :op3 (a4 / administer-01 :ARG1 s :ARG2 (c5 / case-04 :quant "84" :ARG1-of (m6 / mean-01 :ARG2 (p3 / percentage-entity :value "26.7"))) :ARG1-of i :prep-with (r3 / regimen :ARG1-of (b2 / base-02 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "oxaliplatin") :xref (x1 / xref :value "PUBCHEM:5310940" :prob "10.634277")))) :ARG1-of a2) :op4 (a5 / administer-01 :ARG1 s :ARG2 (c6 / case-04 :quant "29" :ARG1-of (m7 / mean-01 :ARG2 (p4 / percentage-entity :value "9.2"))) :ARG1-of i :prep-with (r4 / regimen :ARG1-of (b3 / base-02 :ARG2 (a6 / and :op1 s3 :op2 s4))) :ARG1-of a2) :time (d5 / date-interval :op1 (d / date-entity :month "5" :year "2004") :op2 (d2 / date-entity :month "12" :year "2008"))) # ::id pmid_2337_4602.87 # ::date 2015-08-04T05:45:23 # ::file pmid_2337_4602_87.txt # ::snt The lines of therapy during which cetuximab was administered were 1st line in 38 (16.8%), 2nd line in 108 (47.8%), 3rd and beyond in 80 (35.4%) (Table  1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (l2 / line :ord (o / ordinal-entity :value "1") :location (c / case-04 :quant "38" :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value "16.8")))) :op2 (l3 / line :ord (o2 / ordinal-entity :value "2") :location (c2 / case-04 :quant "108" :ARG1-of (m2 / mean-01 :ARG2 (p2 / percentage-entity :value "47.8")))) :op3 (a3 / and :op1 (l4 / line :ord (o3 / ordinal-entity :value "3")) :op2 (l5 / line :mod (b / beyond :op1 l4)) :location (c3 / case-04 :quant "80" :ARG1-of (m3 / mean-01 :ARG2 (p3 / percentage-entity :value "35.4")))) :domain (l / line :mod (t / therapy) :time-of (a2 / administer-01 :ARG1 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :ARG1-of (d / describe-01 :ARG0 (t2 / table :mod "1"))) # ::id pmid_2337_4602.88 # ::date 2015-08-04T05:52:55 # ::file pmid_2337_4602_88.txt # ::snt Of note, as the period of therapy extended from 2004 until December 2008, an unselected patient population received cetuximab-based therapies, irrespective of KRAS mutational status. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (r / receive-01 :ARG0 (p / population :consist-of (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :ARG1-of (s / select-01 :polarity "-"))) :ARG1 (t / therapy :ARG1-of (b / base-02 :ARG2 (s2 / small-molecule :name (n / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :ARG1-of (n3 / note-02) :ARG1-of (c / cause-01 :ARG0 (e2 / extend-01 :ARG1 (p4 / period :duration-of t) :ARG3 (d / date-entity :year "2004") :ARG4 (d2 / date-entity :month "12" :year "2008"))) :ARG1-of (r2 / regardless-91 :ARG2 (s3 / status :mod (m / mutate-01 :ARG2 (g / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))))) # ::id pmid_2337_4602.89 # ::date 2015-08-04T05:59:19 # ::file pmid_2337_4602_89.txt # ::snt mRNA markers and somatic genotypes # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (a / and :op1 (m / marker :mod (n2 / nucleic-acid :name (n / name :op1 "mRNA"))) :op2 (g / genotype :mod (s / somatic))) # ::id pmid_2337_4602.90 # ::date 2015-08-04T06:07:58 # ::file pmid_2337_4602_90.txt # ::snt Out of the 199 samples tested for mRNA expression, three were found not eligible for all targets. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (f / find-02 :ARG1 (t / thing :quant "3" :ARG1-of (s / sample-01) :ARG1-of (q / qualify-02 :polarity "-" :ARG2 (t3 / thing :ARG1-of (t2 / target-01) :mod (a / all))) :ARG1-of (i / include-91 :ARG2 (t4 / thing :quant "199" :ARG1-of s :ARG1-of (t5 / test-01 :ARG2 (e2 / express-03 :ARG2 (n2 / nucleic-acid :name (n / name :op1 "mRNA")))))))) # ::id pmid_2337_4602.91 # ::date 2015-08-04T06:25:07 # ::file pmid_2337_4602_91.txt # ::snt In total, 84.4% of samples were eligible for AREG analysis; 83.9% for EGF; 84.4% for EGFR; 80.4% for EREG; and 81.4% for TGFa. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p7 / possible-01 :ARG1 (a / and :op1 (q / qualify-02 :ARG1 (t / thing :ARG1-of (s / sample-01) :ARG1-of (i / include-91 :ARG2 (t7 / thing :ARG1-of s) :ARG3 (p / percentage-entity :value "84.4"))) :ARG2 (a2 / analyze-01 :ARG1 (p6 / protein :name (n2 / name :op1 "AREG") :xref (x2 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")))) :op2 (q2 / qualify-02 :ARG1 (t2 / thing :ARG1-of s :ARG1-of (i2 / include-91 :ARG2 t7 :ARG3 (p2 / percentage-entity :value "83.9"))) :ARG2 (a3 / analyze-01 :ARG1 (p9 / protein :name (n3 / name :op1 "EGF") :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :op3 (q3 / qualify-02 :ARG1 t :ARG2 (a4 / analyze-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :op4 (q4 / qualify-02 :ARG1 (t4 / thing :ARG1-of s :ARG1-of (i3 / include-91 :ARG2 t7 :ARG3 (p4 / percentage-entity :value "80.4"))) :ARG2 (a5 / analyze-01 :ARG1 (p3 / protein :name (n4 / name :op1 "EREG") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))) :op5 (q5 / qualify-02 :ARG1 (t5 / thing :ARG1-of s :ARG1-of (i4 / include-91 :ARG2 t7 :ARG3 (p5 / percentage-entity :value "81.4"))) :ARG2 (a6 / analyze-01 :ARG1 (p8 / protein :name (n5 / name :op1 "TGFa") :xref (x4 / xref :value "UNIPROT:TGFA_HUMAN" :prob "0.653"))))) :ARG1-of (t6 / total-01)) # ::id pmid_2337_4602.92 # ::date 2015-08-04T06:35:32 # ::file pmid_2337_4602_92.txt # ::snt Out of the 226 DNA samples screened for the presence of mutations, genotyping was successful in 205 samples for KRAS (90.8%), 159 (70.4%) for NRAS, 220 for BRAF and 220 for PIK3CA (97.3% in each case) (Table  2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a2 / and :op1 (s / succeed-01 :ARG0 (g5 / genotyping) :ARG1 (e4 / enzyme :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :location (s7 / sample-01 :quant "205" :ARG2 "n2" :ARG1-of (i / include-91 :ARG2 (s6 / sample-01 :quant "226" :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")) :ARG1-of (s8 / screen-01 :ARG2 (p4 / present-02 :ARG1 (m / mutate-01)))) :ARG3 (p / percentage-entity :value "90.8")))) :op2 (s3 / succeed-01 :ARG0 g5 :ARG1 (e / enzyme :name (n4 / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :location (s9 / sample-01 :quant "159" :ARG2 n2 :ARG1-of (i2 / include-91 :ARG2 s6 :ARG3 (p2 / percentage-entity :value "70.4")))) :op3 (s4 / succeed-01 :ARG0 g5 :ARG1 (e3 / enzyme :name (n5 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location (s10 / sample-01 :quant "220" :ARG2 n2 :ARG1-of (i3 / include-91 :ARG2 s6 :ARG3 (p3 / percentage-entity :value "97.3")))) :op4 (s5 / succeed-01 :ARG0 g5 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x3 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :location (s2 / sample-01 :quant "220" :ARG2 n2 :ARG1-of i3)) :ARG1-of (d / describe-01 :ARG0 (t6 / table :mod "2"))) # ::id pmid_2337_4602.93 # ::date 2015-08-04T06:46:24 # ::file pmid_2337_4602_93.txt # ::snt KRAS mutations were detected in 72 tumours (31.9%), mostly in exon 2, in codon 12 in 45 cases (20.0%) and in codon 13 in 16 cases (7.0%), while BRAF V600E mutations were found in 6 cases (2.6%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (d / detect-01 :ARG1 (m / mutate-01 :ARG2 (e / exon :mod "2" :part-of (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :degree (m2 / most))) :location (t / tumor :quant "72" :ARG1-of (m6 / mean-01 :ARG2 (p / percentage-entity :value "31.9")) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (c2 / case-04 :quant "45" :ARG1-of (m7 / mean-01 :ARG2 (p2 / percentage-entity :value "20.0")) :ARG0-of (h / have-03 :ARG1 (m3 / mutate-01 :ARG2 (c5 / codon :mod "12" :part-of g)))) :op2 (c3 / case-04 :quant "16" :ARG1-of (m8 / mean-01 :ARG2 (p3 / percentage-entity :value "7.0")) :ARG0-of (h2 / have-03 :ARG1 (m4 / mutate-01 :ARG2 (c6 / codon :mod "13")))))))) :ARG2 (f / find-01 :ARG1 (m5 / mutate-01 :value "V600E" :ARG2 (e2 / enzyme :name (n5 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :location (c4 / case-04 :quant "6" :ARG1-of (m9 / mean-01 :ARG2 (p4 / percentage-entity :value "2.6"))))) # ::id pmid_2337_4602.94 # ::date 2015-08-04T06:58:07 # ::file pmid_2337_4602_94.txt # ::snt NRAS mutations were also quite rare, found only in 7 cases (3.1%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (r / rare-02 :ARG1 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :mod (a / also)) :degree (q / quite) :ARG1-of (i / infer-01 :ARG2 (f / find-01 :ARG1 m :mod (o / only) :location (c / case-04 :quant "7" :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value "3.1")))))) # ::id pmid_2337_4602.95 # ::date 2015-08-04T07:01:49 # ::file pmid_2337_4602_95.txt # ::snt PIK3CA mutations were detected in 37 tumours (16.4%), 20 in exon 9 (8.8%) and only five in exon 20 (2.2%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d2 / detect-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :location (t / tumor :quant "37" :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value "16.4")) :ARG2-of (i / include-91 :ARG1 (a / and :op1 (t2 / tumor :quant "20" :ARG0-of (h / have-03 :ARG1 (m3 / mutate-01 :ARG1 (e / exon :mod "9"))) :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value "8.8"))) :op2 (t3 / tumor :quant "5" :mod (o / only) :ARG0-of (h2 / have-03 :ARG1 (m5 / mutate-01 :ARG1 (e2 / exon :mod "20"))) :ARG1-of (m6 / mean-01 :ARG2 (p3 / percentage-entity :value "2.2"))))))) # ::id pmid_2337_4602.96 # ::date 2015-08-04T07:07:42 # ::file pmid_2337_4602_96.txt # ::snt This genotypic analysis was included in a previous publication [8]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (i / include-01 :ARG1 (a / analyze-01 :ARG1 (g / genotype) :mod (t / this)) :ARG2 (t2 / thing :time (p2 / previous) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "8"))) :ARG1-of (p / publish-01))) # ::id pmid_2337_4602.97 # ::date 2015-08-04T07:09:02 # ::file pmid_2337_4602_97.txt # ::snt Correlation analysis revealed that mutations in KRAS, BRAF, NRAS genes were mutually exclusive in all evaluable cases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (c / correlate-01)) :ARG1 (e / exclude-01 :ARG1 (a2 / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op3 (m3 / mutate-01 :ARG1 (g3 / gene :name (n3 / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))) :manner (m4 / mutual) :location (c2 / case-04 :ARG1-of (e2 / evaluate-101 :ARG1-of (p / possible-01)) :mod (a3 / all)))) # ::id pmid_2337_4602.98 # ::date 2015-08-04T07:12:53 # ::file pmid_2337_4602_98.txt # ::snt On the contrary, mutations in the PIK3CA gene co-existed with KRAS mutations in 17 cases and with NRAS mutations in two. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG2 (a / and :op1 (c2 / coexist-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :ARG2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :location (t / thing :ARG1-of (c3 / case-04 :quant "17"))) :op2 (c4 / coexist-01 :ARG1 m :ARG2 (m3 / mutate-01 :ARG1 (g3 / gene :name (n3 / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :location (t2 / thing :ARG1-of (c5 / case-04 :quant "2"))))) # ::id pmid_2337_4602.99 # ::date 2015-08-04T07:16:30 # ::file pmid_2337_4602_99.txt # ::snt Statistically significant associations at the 2-sided p<0.05 level were seen between wild type status of KRAS, BRAF genes and high AREG, EREG, EGFR mRNA levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (s / see-01 :ARG1 (a / associate-01 :ARG1 (a2 / and :op1 (g / gene :name (n2 / name :op1 "KRAS") :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (w / wild-type)) :ARG1-of (s2 / significant-02 :manner (s3 / statistic))) :ARG2 (a4 / and :op1 (l / level :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n7 / name :op1 "AREG") :xref (x4 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))))) :op2 (l4 / level :quant-of (n10 / nucleic-acid :name (n5 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n8 / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004"))))) :op3 (l5 / level :quant-of (n11 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) :ARG1-of (h / high-02)) :condition (s5 / statistical-test-91 :ARG2 (l3 / less-than :op1 "0.05") :mod (s4 / side :quant "2"))) # ::id pmid_2337_4602.100 # ::date 2015-08-04T07:18:16 # ::file pmid_2337_4602_100.txt # ::snt Among KRAS-wild type cases, 81.4% were seen in AREG-high and 57.4% in EREG-high tumours, while of KRAS-mutated cases only 63.9% were observed in AREG-high and only 35.7% in EREG-high tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (a / and :op1 (s / see-01 :ARG1 (c2 / case-04 :ARG1-of (i / include-91 :ARG2 (c4 / case-04 :ARG1 (g / gene :name (n3 / name :op1 "KRAS") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG3 (p / percentage-entity :value "81.4"))) :location (t / tumor :ARG1-of (h / high-02 :ARG2 (p5 / protein :name (n / name :op1 "AREG") :xref (x3 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))))) :op2 (s2 / see-01 :ARG1 (c3 / case-04 :ARG1-of (i3 / include-91 :ARG2 c4 :ARG3 (p2 / percentage-entity :value "57.4"))) :location (t2 / tumor :ARG1-of (h2 / high-02 :ARG2 (p6 / protein :name (n2 / name :op1 "EREG") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))))) :ARG2 (a2 / and :op1 (o / observe-01 :ARG1 (c5 / case-04 :ARG1-of (i2 / include-91 :ARG2 (c6 / case-04 :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG3 (p3 / percentage-entity :value "63.9" :mod (o2 / only)))) :location t) :op2 (o3 / observe-01 :ARG1 (c7 / case-04 :ARG1-of (i4 / include-91 :ARG2 c6 :ARG3 (p4 / percentage-entity :value "35.7" :mod o2))) :location t2))) # ::id pmid_2337_4602.101 # ::date 2015-08-04T07:27:06 # ::file pmid_2337_4602_101.txt # ::snt Similarly, among BRAF-wild type cases, 76.1% were seen in AREG-high and 50.7% in EREG-high tumours, while of BRAF-mutated cases only two out of six (33.3%) were observed in AREG-high and none in EREG-high tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (a / and :op1 (s / see-01 :ARG1 (c2 / case-04 :ARG1-of (i / include-91 :ARG2 (c3 / case-04 :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG3 (p / percentage-entity :value "76.1"))) :location (t / tumor :ARG1-of (h / high-02 :ARG2 (p4 / protein :name (n2 / name :op1 "AREG") :xref (x2 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))))) :op2 (s2 / see-01 :ARG1 (c4 / case-04 :ARG1-of (i3 / include-91 :ARG2 c3 :ARG3 (p2 / percentage-entity :value "50.7"))) :location (t2 / tumor :ARG1-of (h2 / high-02 :ARG2 (p5 / protein :name (n3 / name :op1 "EREG") :xref (x3 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))))) :ARG2 (a2 / and :op1 (o / observe-01 :ARG1 (c5 / case-04 :quant "2" :ARG1-of (i2 / include-91 :ARG2 (c6 / case-04 :quant "6" :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG3 (p3 / percentage-entity :value "33.3")) :mod (o2 / only)) :location t) :op2 (o3 / observe-01 :ARG1 (c7 / case-04 :polarity "-" :ARG1-of i2) :location t2)) :ARG1-of (r / resemble-01)) # ::id pmid_2337_4602.102 # ::date 2015-08-04T07:34:54 # ::file pmid_2337_4602_102.txt # ::snt Regarding the primary location, 64.8% of KRAS mutations (p=0.07) and 58% of PIK3CA mutations (p=0.036) occurred in left-sided colorectal tumours, whereas four (66.7%) of BRAF mutations in right-sided colon carcinomas (p=0.024). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (a2 / and :op1 (m2 / mutate-01 :ARG1-of (i / include-91 :ARG2 (m / mutate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG3 (p / percentage-entity :value "64.8")) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.07")) :op2 (m9 / mutate-01 :ARG1-of (i2 / include-91 :ARG2 (m3 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :ARG3 (p2 / percentage-entity :value "58")) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.036")) :location (t / tumor :mod (c2 / colorectal) :location (s / side :ARG1-of (l / left-20)))) :ARG2 (m7 / mutate-01 :quant "4" :location (c3 / carcinoma :location (s2 / side :poss (c4 / colon) :ARG1-of (r / right-04))) :ARG1-of (i3 / include-91 :ARG2 (m6 / mutate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG3 (p3 / percentage-entity :value "66.7")) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.024")) :topic (l2 / location :mod (p7 / primary))) # ::id pmid_2337_4602.103 # ::date 2015-08-04T07:51:06 # ::file pmid_2337_4602_103.txt # ::snt mRNA RQ values were examined as continuous variables and significant correlations at Spearmann’s R>0.4 were found between AREG and EREG mRNA (R=0.63, 95% CI 0.53-0.72, p=0.0005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / and :op1 (e / examination-02 :ARG1 (v / value :ARG2-of (r / result-01 :ARG1 (q / quantify-01 :ARG1-of (r6 / relative-05))) :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA"))) :manner (v2 / variable :ARG1-of (c / continue-01))) :op2 (f / find-01 :ARG1 (c2 / correlate-01 :ARG1 (n8 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "AREG") :xref (x / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")))) :ARG2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p3 / protein :name (n6 / name :op1 "EREG") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))) :ARG1-of (s / significant-02) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (r5 / rho :value "0.63") :op2 (i / interval :value (b2 / between :op1 "0.53" :op2 "0.72") :quant (p / percentage-entity :value "95") :mod (c3 / confidence))))) :manner (v3 / value :mod (p5 / person :name (n / name :op1 "Spearmann")) :value (m2 / more-than :op1 "0.4") :mod (s3 / string-entity :value "R"))) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0005")) # ::id pmid_2337_4602.104 # ::date 2015-08-04T07:58:14 # ::file pmid_2337_4602_104.txt # ::snt Factors with predictive significance at univariate analysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (f / factor :ARG1-of (s / significant-02 :ARG0-of (p / predict-01) :time (a / analyze-01 :mod (u / univariate)))) # ::id pmid_2337_4602.105 # ::date 2015-08-04T08:02:19 # ::file pmid_2337_4602_105.txt # ::snt At a median follow-up of 73.6 months, 215 patients (95.1%) had experienced disease progression and 163 (93.1%) had died. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (e / experience-01 :ARG0 (p3 / person :quant "215" :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value "95.1"))) :ARG1 (p5 / progress-01 :ARG1 (d / disease))) :op2 (d2 / die-01 :ARG1 (p6 / person :quant "163" :ARG0-of h :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value "93.1")))) :time (f / follow-up-03 :mod (m / median) :time (a2 / after :op1 (t / temporal-quantity :quant "73.6" :unit (m2 / month))))) # ::id pmid_2337_4602.106 # ::date 2015-08-04T08:07:20 # ::file pmid_2337_4602_106.txt # ::snt The median survival was was 27 months (95% CI 25–31). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (t2 / temporal-quantity :quant "27" :unit (m / month) :domain (s / survive-01 :mod (m2 / median)) :condition (i / interval :value (b / between :op1 (t / temporal-quantity :quant "25" :unit m) :op2 (t3 / temporal-quantity :quant "31" :unit m)) :quant (p / percentage-entity :value "95") :mod (c / confidence))) # ::id pmid_2337_4602.107 # ::date 2015-08-04T08:09:31 # ::file pmid_2337_4602_107.txt # ::snt At univariate analysis, in the present cohort of patients treated with cetuximab the presence of BRAF mutations was significantly associated with an 8.1-fold increased risk of death compared to patients harbouring BRAF-wild type tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / associate-01 :ARG1 (p / present-02 :ARG1 (m / mutate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (c / cohort :ARG1-of (p2 / present-02) :consist-of (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG1-of (t / treat-03 :ARG3 (s2 / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")))))) :ARG2 (r / risk-01 :ARG1 (d / die-01) :ARG1-of (i / increase-01 :ARG2 (p5 / product-of :op1 "8.1"))) :ARG1-of (s / significant-02) :compared-to (p6 / person :ARG0-of h :ARG0-of (h2 / harbor-01 :ARG1 (t2 / tumor :mod (e / enzyme :name (n3 / name :op1 "BRAF") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :time (a2 / analyze-01 :mod (u / univariate))) # ::id pmid_2337_4602.108 # ::date 2015-08-05T05:55:36 # ::file pmid_2337_4602_108.txt # ::snt When all types of mutations were pooled for each gene, KRAS (HR 1.28, p=0.14), NRAS (HR 1.43, p=0.36) and PIK3CA (HR 1.27, p=0.25) mutations did not have prognostic/predictive utility. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :polarity "-" :ARG0 (a2 / and :op1 (m / mutate-01 :ARG2 (e2 / enzyme :name (n / name :op1 "KRAS") :mod (r / ratio-of :quant "1.28" :op1 (h2 / hazard)) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (s / statistical-test-91 :ARG2 "0.14")) :op2 (m3 / mutate-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "NRAS") :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :mod (r2 / ratio-of :quant "1.43" :op1 h2) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.36")) :op3 (m4 / mutate-01 :ARG2 (g2 / gene :name (n3 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :mod (r3 / ratio-of :quant "1.27" :op1 h2) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.25"))) :ARG1 (u / utility :mod (p / prognostic) :ARG0-of (p2 / predict-01)) :time (p3 / pool-01 :ARG1 (m2 / mutate-01 :mod (t / type :mod (a / all))) :topic (g / gene :mod (e / each)))) # ::id pmid_2337_4602.109 # ::date 2015-08-05T07:23:09 # ::file pmid_2337_4602_109.txt # ::snt However, when types of mutations were analysed separately for each gene, KRAS codon 12 mutations were predictive for increased risk of death (HR 1.62, p=0.014). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (p / predict-01 :ARG0 (m / mutate-01 :ARG1 (c2 / codon :mod "12" :part-of (e / enzyme :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :mod (r2 / ratio-of :quant "1.62" :op1 (h / hazard))) :ARG1 (r / risk-01 :ARG2 (d / die-01)) :time (a / analyze-01 :ARG1 (m2 / mutate-01 :mod (t / type)) :manner (s / separate-02 :ARG1 (g / gene :mod (e2 / each)))) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.014"))) # ::id pmid_2337_4602.110 # ::date 2015-08-05T07:34:05 # ::file pmid_2337_4602_110.txt # ::snt Among parameters studied for gene expression, only the 25th percentile of AREG mRNA values and the 75th percentile of EREG mRNA values dichotomized cases into groups with different outcome and were selected as optimal cut-offs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (d / dichotomize-00 :ARG0 (a2 / and :op1 (v / value :mod (p / percentile :ARG3-of (i / include-91 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p5 / protein :name (n3 / name :op1 "AREG") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))))) :mod (o2 / only) :ord (o5 / ordinal-entity :value "25"))) :op2 (v2 / value :mod (p2 / percentile :ARG3-of (i2 / include-91 :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p4 / protein :name (n4 / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004"))))) :mod (o3 / only) :ord (o6 / ordinal-entity :value "75"))) :ARG1-of (i3 / include-91 :ARG2 (p3 / parameter :ARG1-of (s2 / study-01 :purpose (e / express-03 :ARG1 (g2 / gene)))))) :ARG1 (c / case-04) :ARG2 (g / group :ARG0-of (h / have-03 :ARG1 (o / outcome :ARG1-of (d2 / differ-02))))) :op2 (s / select-01 :ARG1 a2 :ARG3 (t / thing :mod (o4 / optimal) :ARG3-of (c2 / cut-off-04)))) # ::id pmid_2337_4602.111 # ::date 2015-08-06T03:41:49 # ::file pmid_2337_4602_111.txt # ::snt None of EGF, TGFa, EGFR mRNA levels disclosed cut-off points of prognostic significance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / disclose-01 :ARG0 (a / and :op1 (l / level :quant-of (n / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))))) :op2 (l2 / level :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "TGFa") :xref (x1 / xref :value "UNIPROT:TGFA_HUMAN" :prob "0.653"))))) :op3 (l3 / level :quant-of (n10 / nucleic-acid :name (n6 / name :op1 "mRNA") :ARG0-of (e4 / encode-01 :ARG1 (e / enzyme :name (n7 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))))) :quant (n8 / none)) :ARG1 (p4 / point :mod (c / cut-off-04) :ARG0-of (h / have-03 :ARG1 (t / thing :mod (p5 / prognostic) :ARG1-of (s / significant-02))))) # ::id pmid_2337_4602.112 # ::date 2015-08-06T03:42:10 # ::file pmid_2337_4602_112.txt # ::snt Cetuximab therapy in patients harbouring AREG-high (HR 0.47, p=0.0002) or EREG-high (HR 0.45, p=0.0009) tumours resulted in reduced risk of death. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 5, 2016 (r / result-01 :ARG1 (t / therapy :mod (s / small-molecule :name (n / name :op1 "Cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")) :location (p / person :ARG0-of (h / harbor-01 :ARG1 (o / or :op1 (t2 / tumor :ARG1-of (h2 / high-02 :ARG2 (p2 / protein :name (n2 / name :op1 "AREG") :xref (x / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))) :mod (r4 / ratio-of :quant "0.47" :op1 (h5 / hazard)) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0002")) :op2 (t3 / tumor :ARG1-of (h3 / high-02 :ARG2 (p3 / protein :name (n3 / name :op1 "EREG") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004"))) :mod (r5 / ratio-of :quant "0.45" :op1 (h6 / hazard)) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.0009")))) :ARG0-of (h4 / have-rel-role-91 :ARG2 (p6 / patient)))) :ARG2 (r2 / risk-01 :ARG2 (d / die-01) :ARG1-of (r3 / reduce-01))) # ::id pmid_2337_4602.113 # ::date 2015-08-06T07:19:05 # ::file pmid_2337_4602_113.txt # ::snt EGFR, EGF, TGFa mRNA expression had no significant prognostic/predictive value, either in the entire cohort or in the KRAS-wild type versus KRAS mutant cases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :polarity "-" :ARG0 (e2 / express-03 :ARG1 (n / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "EGFR") :xref (x2 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op2 (p4 / protein :name (n4 / name :op1 "EGF") :xref (x3 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op3 (p5 / protein :name (n5 / name :op1 "TGFa") :xref (x4 / xref :value "UNIPROT:TGFA_HUMAN" :prob "0.653")))))) :ARG1 (v / value :ARG1-of (s / significant-02) :mod (p / prognostic) :ARG0-of (p2 / predict-01)) :location (o2 / or :op1 (c / cohort :mod (e4 / entire)) :op2 (c2 / compare-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "KRAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG2 (e6 / enzyme :name (n7 / name :op1 "KRAS") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))) # ::id pmid_2337_4602.114 # ::date 2015-08-06T07:34:32 # ::file pmid_2337_4602_114.txt # ::snt Regarding objective tumour response to any line of cetuximab-based therapy, tumoural AREG and EREG mRNA expression levels were associated with tumour shrinkage as continuous variables. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 16, 2015 (a / associate-01 :ARG1 (l / level :quant-of (e / express-03 :ARG1 (a2 / and :op1 (n6 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")))) :op2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))))) :location (t / tumor)) :ARG2 (s / shrink-01 :ARG1 t) :purpose (v / variable :ARG1-of (c / continue-01)) :topic (r3 / respond-01 :ARG0 t :ARG1 (l2 / line :mod (a3 / any) :part-of (t2 / therapy :ARG1-of (b / base-02 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761"))))) :mod (o / objective))) # ::id pmid_2337_4602.115 # ::date 2015-08-06T08:22:39 # ::file pmid_2337_4602_115.txt # ::snt AREG was not statistically significant as categorical variable but EREG mRNA at the 75th percentile was associated with a 2.26-fold increased likelihood of tumour response to cetuximab compared to tumours with lower EREG mRNA expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 16, 2015 (c / contrast-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG") :ARG1-of (s / significant-02 :polarity "-" :mod (s2 / statistic) :purpose (v / variable :mod (c2 / categorical))) :xref (x2 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")) :ARG2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004"))) :location (p3 / percentile :ord (o / ordinal-entity :value "75")) :ARG1-of (a / associate-01 :ARG2 (l / likely-01 :ARG1 (r / respond-01 :ARG0 (t / tumor) :ARG1 (s3 / small-molecule :name (n / name :op1 "cetuximab") :xref (x3 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :ARG1-of (i / increase-01 :ARG2 (p4 / product-of :op1 "2.26")) :compared-to (t2 / tumor :ARG3-of (e / express-03 :ARG1 (n8 / nucleic-acid :name (n5 / name :op1 "mRNA")) :ARG2 (p5 / protein :name (n6 / name :op1 "EREG") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")) :ARG2-of (l2 / low-04 :degree (m / more)))))))) # ::id pmid_2337_4602.116 # ::date 2015-08-06T09:13:58 # ::file pmid_2337_4602_116.txt # ::snt AREG failed to predict response in either KRAS wild type or mutated cases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (f / fail-01 :ARG1 (p / protein :name (n / name :op1 "AREG") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")) :ARG2 (p2 / predict-01 :ARG0 p :ARG1 (r / respond-01 :prep-in (o / or :op1 (c / case-04 :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (c2 / case-04 :ARG1 (e2 / enzyme :name (n3 / name :op1 "KRAS") :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))))) # ::id pmid_2337_4602.117 # ::date 2015-08-06T09:20:34 # ::file pmid_2337_4602_117.txt # ::snt The expression levels of EREG in the tumours of responding and non-responding patients by KRAS gene status is depicted in a waterfall plot (Figure  1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / depict-01 :ARG1 (l / level :quant-of (e / express-03 :ARG2 (p / protein :name (n / name :op1 "EREG") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")) :ARG3 (t / tumor :source (a / and :op1 (p2 / person :ARG0-of (r / respond-01) :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient))) :op2 (p3 / person :ARG0-of (r2 / respond-01 :polarity "-") :ARG0-of h) :ARG1-of (s / say-01 :ARG0 (s2 / status :poss (g / gene :name (n2 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))))))) :location (p4 / plot :mod (w / waterfall)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1"))) # ::id pmid_2337_4602.118 # ::date 2015-08-06T10:01:23 # ::file pmid_2337_4602_118.txt # ::snt Of note, in an exploratory analysis, the predictive significance for objective response was maintained only in KRAS mutated CRC, in which EREG had an odds ratio for response of 5.4 (95% CI 1.2-23.8, p=0.024). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (n / note-02 :ARG1 (m / maintain-01 :ARG1 (s / significant-02 :ARG1 (r / respond-01 :mod (o / objective)) :ARG0-of (p2 / predict-01)) :location (d / disease :name (n2 / name :op1 "CRC") :mod (m2 / mutate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :location-of (h / have-03 :ARG0 (p3 / protein :name (n4 / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")) :ARG1 (e3 / equal-01 :ARG1 (r2 / ratio :mod (o2 / odds) :prep-for (r3 / respond-01)) :ARG2 (r4 / ratio-of :op1 "5.4") :mod (i / interval :quant (v / value-interval :op1 "1.2" :op2 "23.8") :mod (p4 / percentage-entity :quant "95") :mod (c / confidence)))) :mod (o3 / only)) :time (a / analyze-01 :quant "1" :ARG0-of (e2 / explore-01)) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.024"))) # ::id pmid_2337_4602.119 # ::date 2015-08-06T10:36:10 # ::file pmid_2337_4602_119.txt # ::snt By contrast, in KRAS-wild type tumours EREG failed to significantly predict for response to therapy (OR 2.2, 95% CI 0.83-5.86, p=0.11). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (f / fail-01 :ARG1 (p2 / protein :name (n / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")) :ARG2 (p3 / predict-01 :ARG0 p2 :ARG1 (r / respond-01 :ARG1 (t / therapy)) :ARG1-of (s / significant-02)) :location (t2 / tumor :mod (e / enzyme :name (n2 / name :op1 "KRAS") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :mod (i / interval :mod (p4 / percentage-entity :quant "95") :quant (v / value-interval :op1 "0.83" :op2 "5.86") :mod (c2 / confidence)) :mod (r2 / ratio :quant "2.2" :mod (o / odds)) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.11"))) # ::id pmid_2337_4602.120 # ::date 2015-08-06T10:51:53 # ::file pmid_2337_4602_120.txt # ::snt EGF, TGFa and EGFR mRNA expression had no predictive utility for response to cetuximab in the whole cohort, neither in KRAS wild-type or KRAS mutated cases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (h / have-03 :polarity "-" :ARG0 (e2 / express-03 :ARG1 (n / nucleic-acid :name (n2 / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (a / and :op1 (p / protein :name (n3 / name :op1 "EGF") :xref (x4 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")) :op2 (p2 / protein :name (n4 / name :op1 "TGFa") :xref (x1 / xref :value "UNIPROT:TGFA_HUMAN" :prob "0.653")) :op2 (e / enzyme :name (n5 / name :op1 "EGFR") :xref (x3 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))))) :ARG1 (u / utility :ARG0-of (p4 / predict-01 :ARG1 (r2 / respond-01 :ARG1 (s / small-molecule :name (n6 / name :op1 "cetuximab") :xref (x5 / xref :value "PUBCHEM:56842117" :prob "9.083761"))))) :location (c2 / cohort :mod (w / whole)) :topic (o / or :op1 (c / case-04 :ARG1 (e4 / enzyme :name (n7 / name :op1 "KRAS") :mod (w2 / wild-type) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (c3 / case-04 :ARG1 (e5 / enzyme :name (n8 / name :op1 "KRAS") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))) # ::id pmid_2337_4602.121 # ::date 2015-08-06T11:27:36 # ::file pmid_2337_4602_121.txt # ::snt All factors with potential predictive utility for cetuximab benefit are summarized in Table  3. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 14, 2015 (s / summarize-01 :ARG1 (f / factor :mod (a / all) :poss (u / utility :ARG0-of (p / predict-01 :ARG1 (b / benefit-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "cetuximab") :xref (x / xref :value "PUBCHEM:56842117" :prob "9.083761")))))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "3"))) # ::id pmid_2337_4602.122 # ::date 2015-08-06T13:00:11 # ::file pmid_2337_4602_122.txt # ::snt Interactions and factors with predictive utility at multivariate analysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 6, 2015 (h / have-03 :ARG0 (a / and :op1 (i / interact-01) :op2 (f / factor)) :ARG1 (u / utility :ARG0-of (p / predict-01)) :location (a2 / analyze-01 :mod (m / multivariate))) # ::id pmid_2337_4602.123 # ::date 2015-08-06T13:07:39 # ::file pmid_2337_4602_123.txt # ::snt Significant interactions (at the 1% significance level) between study variables for prognostic/predictive utility (survival, ORR) were sought. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 18, 2015 (s / seek-01 :ARG1 (i / interact-01 :ARG0 (v / variable :mod (s4 / study-01)) :ARG1-of (s2 / significant-02) :prep-at (l / level :ARG1-of (s3 / significant-02) :mod (p / percentage-entity :value "1")) :purpose (u / utility :ARG0-of (p2 / predict-01) :mod (p3 / prognostic) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (s5 / survive-01) :op2 (r / rate :mod (r2 / respond-01) :mod (o / overall))))))) # ::id pmid_2337_4602.124 # ::date 2015-08-06T13:57:22 # ::file pmid_2337_4602_124.txt # ::snt In terms of impact on survival, significant interactions were found between AREG mRNA levels and mutational status of the KRAS gene (p=0.0033). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (f / find-01 :ARG1 (i / interact-01 :ARG0 (l / level :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))))) :ARG1 (s2 / status :mod (m / mutate-01) :poss (g / gene :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1-of (s / significant-02)) :topic (i2 / impact-01 :ARG1 (s3 / survive-01)) :ARG1-of (s4 / statistical-test-91 :ARG2 "0.0033")) # ::id pmid_2337_4602.125 # ::date 2015-08-06T13:57:35 # ::file pmid_2337_4602_125.txt # ::snt High mRNA levels of AREG predicted for longer survival in patients with KRAS wild-type (median survival 33 vs. 15 months, p=0.0005, Figure  2), but not in KRAS mutant tumours (median survival 22 vs. 17 months, p=0.64). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / contrast-01 :ARG1 (p / predict-01 :ARG0 (l / level :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "AREG") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")))) :ARG1-of (h / high-02)) :ARG1 (s / survive-01 :ARG0 (p3 / person :poss (t / tumor :mod (e / enzyme :name (n3 / name :op1 "KRAS") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p8 / patient))) :ARG1-of (l2 / long-03 :degree (m / more)) :mod (c2 / contrast-01 :ARG1 (s3 / survive-01 :mod (m3 / median) :duration (t3 / temporal-quantity :quant "33" :unit (m5 / month))) :ARG2 (s4 / survive-01 :duration (t4 / temporal-quantity :quant "15" :unit m5) :mod m3) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2"))) :ARG1-of (s7 / statistical-test-91 :ARG2 "0.0005"))) :ARG2 (p4 / predict-01 :polarity "-" :ARG0 l :ARG1 (s2 / survive-01 :ARG0 (p5 / person :poss (t2 / tumor :mod (m2 / mutate-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG0-of h2) :mod (c3 / contrast-01 :ARG1 (s5 / survive-01 :duration (t5 / temporal-quantity :quant "22" :unit m5) :mod m3) :ARG2 (s6 / survive-01 :mod m3 :duration (t6 / temporal-quantity :quant "17" :unit m5))) :ARG1-of (s8 / statistical-test-91 :ARG2 "0.64")))) # ::id pmid_2337_4602.126 # ::date 2015-08-07T04:43:40 # ::file pmid_2337_4602_126.txt # ::snt In contrast, high mRNA levels of EREG were associated with favourable prognosis irrespective of KRAS mutational status. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (c / contrast-01 :ARG2 (a / associate-01 :ARG1 (l / level :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "EREG") :xref (x1 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))) :ARG1-of (h / high-02)) :ARG2 (p2 / prognosis :mod (f / favourable)) :ARG1-of (r / regardless-91 :ARG2 (s / status :mod (m / mutate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))))) # ::id pmid_2337_4602.127 # ::date 2015-08-07T04:44:15 # ::file pmid_2337_4602_127.txt # ::snt In KRAS wild type cases, the median survival was 37 months for EREG-high as compared to 23 months for EREG-low expressing tumours (p=0.01), while in KRAS mutated tumours median survival was 33 versus 19 months (p=0.02) in EREG-high vs. low cases (Figure  3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (c2 / compare-01 :ARG1 (s / survive-01 :condition (t / tumor :ARG3-of (e / express-03 :ARG2 (p / protein :wiki "Epiregulin" :name (n / name :op1 "EREG") :ARG1-of (h / high-02) :xref (x3 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))) :mod (m / median) :duration (t2 / temporal-quantity :quant "37" :unit (m2 / month)) :ARG1-of (s5 / statistical-test-91 :ARG2 "0.01")) :ARG2 (s2 / survive-01 :condition (t3 / tumor :ARG3-of (e2 / express-03 :ARG2 (p2 / protein :wiki "Epiregulin" :name (n2 / name :op1 "EREG") :ARG1-of (l / low-04) :xref (x2 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")))) :mod m :duration (t4 / temporal-quantity :quant "23" :unit m2)) :topic (c3 / case-04 :ARG1 (e3 / enzyme :wiki "KRAS" :name (n3 / name :op1 "KRAS") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG2 (c4 / compare-01 :ARG1 (s3 / survive-01 :mod m :duration (t6 / temporal-quantity :quant "33" :unit m2) :condition (c5 / case-04 :ARG1 p) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.02")) :ARG2 (s4 / survive-01 :mod m :duration (t7 / temporal-quantity :quant "19" :unit m2) :condition (c6 / case-04 :ARG1 p2)) :condition (t5 / tumor :mod (e4 / enzyme :wiki "KRAS" :name (n4 / name :op1 "KRAS") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3"))) # ::id pmid_2337_4602.128 # ::date 2015-08-07T04:46:09 # ::file pmid_2337_4602_128.txt # ::snt Similar findings for EREG high vs. low were seen when we examined complex cancer genotypes: a) KRAS+BRAF, both wild type vs. any mutant, b) KRAS+BRAF+PIK3CA+NRAS, all wild type vs. any mutant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :ARG1 (t / thing :ARG1-of (f / find-01) :topic (c / compare-01 :ARG1 (p / protein :name (n2 / name :op1 "EREG") :ARG1-of (h / high-02) :xref (x5 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004")) :ARG2 (p2 / protein :name (n3 / name :op1 "EREG") :ARG1-of (l / low-04) :xref (x4 / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004"))) :ARG1-of (r / resemble-01)) :time (e / examine-01 :ARG0 (w / we) :ARG1 (g / genotype :mod (c3 / complex) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (c4 / compare-01 :li "a" :ARG1 (a / and :op1 (g5 / gene :name (n4 / name :op1 "KRAS") :mod (w2 / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g4 / gene :name (n5 / name :op1 "BRAF") :mod w2 :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG2 (m2 / molecular-physical-entity :ARG2-of (m3 / mutate-01) :mod (a2 / any))) :op2 (c5 / compare-01 :li "b" :ARG1 (a5 / and :op1 g5 :op2 g4 :op3 (g2 / gene :name (n8 / name :op1 "PIK3CA") :mod w2 :xref (x3 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op4 (g3 / gene :name (n9 / name :op1 "NRAS") :mod w2 :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :ARG2 m2))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))) # ::id pmid_2337_4602.129 # ::date 2015-08-07T04:49:01 # ::file pmid_2337_4602_129.txt # ::snt AREG mRNA had a favourable predictive significance in wild type cases only, whereas EREG mRNA preserved its significance in wild type as well as in mutant cases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))) :ARG1-of (s / significant-02 :mod (f / favourable) :ARG0-of (p2 / predict-01) :topic (c2 / case-04 :mod (w / wild-type) :mod (o / only)))) :ARG2 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA") :ARG0-of (e2 / encode-01 :ARG1 (p3 / protein :name (n4 / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004"))) :ARG0-of (p4 / preserve-01 :ARG1 (s2 / significant-02 :ARG1 n6) :topic (a / and :op1 (c3 / case-04 :mod w) :op2 (c4 / case-04 :ARG2-of (m / mutate-01)))))) # ::id pmid_2337_4602.130 # ::date 2015-08-07T04:50:36 # ::file pmid_2337_4602_130.txt # ::snt A multivariate analysis was performed in the context of a broader mRNA profiling project of several biomarkers (IGFBP2, IGF1R, cMET, EGFR, TGFa, EphA2, HER2, HER3, HER4, Table  4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-02 :ARG1 (a / analyze-01 :mod (m / multivariate)) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "4")) :time (p2 / project :ARG0-of (p3 / profile-01 :ARG1 (b2 / biomarker :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "IGFBP2") :xref (x4 / xref :value "UNIPROT:IBP2_HUMAN" :prob "1.002")) :op2 (p5 / protein :name (n6 / name :op1 "IGF1R") :xref (x5 / xref :value "UNIPROT:IGF1R_HUMAN" :prob "1.004")) :op3 (p6 / protein :name (n7 / name :op1 "cMET")) :op4 (e / enzyme :name (n / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")) :op5 (p8 / protein :name (n9 / name :op1 "TGFa") :xref (x6 / xref :value "UNIPROT:TGFA_HUMAN" :prob "0.653")) :op6 (p9 / protein :name (n10 / name :op1 "EphA2") :xref (x7 / xref :value "UNIPROT:EPHA2_HUMAN" :prob "0.634")) :op7 (e2 / enzyme :name (n11 / name :op1 "HER2") :xref (x3 / xref :value "UNIPROT:ERBB2_HUMAN" :prob "1.003")) :op8 (e3 / enzyme :name (n12 / name :op1 "HER3") :xref (x2 / xref :value "UNIPROT:ERBB3_HUMAN" :prob "1.003")) :op9 (e4 / enzyme :name (n13 / name :op1 "HER4") :xref (x / xref :value "UNIPROT:ERBB4_HUMAN" :prob "1.003")))) :quant (s / several)) :instrument (n2 / nucleic-acid :name (n4 / name :op1 "mRNA"))) :ARG1-of (b / broad-02 :degree (m3 / more)))) # ::id pmid_2337_4602.131 # ::date 2015-08-09T13:32:22 # ::file pmid_2337_4602_131.txt # ::snt In the presence of wild-type KRAS, high AREG mRNA levels were independently associated with 83.0% reduction in the risk of death compared to patients with AREG-low tumours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / associate-01 :ARG1 (l / level :quant-of (n3 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "AREG") :xref (x1 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003")))) :ARG1-of (h / high-02)) :ARG2 (r2 / reduce-01 :ARG1 (r3 / risk-01 :ARG2 (d / die-01)) :ARG2 (p3 / percentage-entity :value "83") :compared-to (p4 / person :poss (t / tumor :ARG1-of (l2 / low-04 :ARG2 p2)) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p / patient)))) :ARG0-of (d2 / depend-01 :polarity "-") :condition (p5 / present-02 :ARG1 (e2 / enzyme :name (n4 / name :op1 "KRAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) # ::id pmid_2337_4602.132 # ::date 2015-08-09T14:32:03 # ::file pmid_2337_4602_132.txt # ::snt High EREG tumoural mRNA was a favourable outcome predictor for cetuximab-treated patients, irrespective of KRAS mutation status. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 7, 2016 (t / thing :ARG0-of (p / predict-01 :ARG1 (o / outcome)) :domain (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "EREG") :xref (x / xref :value "UNIPROT:EREG_HUMAN" :prob "1.004"))) :mod (h / high)) :mod (f / favourable) :topic (p3 / patient :ARG1-of (t2 / treat-03 :ARG3 (s / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761")))) :ARG1-of (r / regardless-91 :ARG2 (s2 / status :mod (m / mutate-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))))) # ::id pmid_2337_4602.133 # ::date 2015-08-09T15:13:08 # ::file pmid_2337_4602_133.txt # ::snt High Ephrin A2 (EphA2) mRNA and advanced age were adverse independent prognosticators. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Oct 14, 2015 (p / prognosticator :domain (a / and :op1 (n3 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Ephrin" :op2 "A2") :ARG1-of (h / high-02) :xref (x / xref :value "UNIPROT:EFNA2_HUMAN" :prob "0.693")))) :op2 (a2 / age :ARG1-of (a3 / advance-01))) :ARG0-of (d / depend-01 :polarity "-") :mod (a4 / adverse)) # ::id pmid_2337_4602.134 # ::date 2015-08-09T15:17:22 # ::file pmid_2337_4602_134.txt # ::snt Finally, among cetuximab-treated patients with AREG-low tumours, those with mutant KRAS fared significantly better than patients harbouring colon cancer with KRAS wild type (81% decreased risk of death). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (f / fare-01 :ARG0 (p6 / person :ARG1-of (i / include-91 :ARG2 (p / person :ARG1-of (t2 / treat-03 :ARG3 (s2 / small-molecule :name (n3 / name :op1 "cetuximab") :xref (x3 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :poss (t / tumor :mod (p5 / protein :name (n4 / name :op1 "AREG") :ARG1-of (l / low-04) :xref (x2 / xref :value "UNIPROT:AREG_HUMAN" :prob "1.003"))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p4 / patient)))) :mod (e2 / enzyme :name (n / name :op1 "KRAS") :ARG2-of (m4 / mutate-01) :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1-of (w2 / well-09 :mod (m2 / more) :ARG1-of (s / significant-02) :ARG1-of (m3 / mean-01 :ARG2 (r / risk-01 :ARG2 (d2 / die-01) :ARG1-of (d3 / decrease-01 :ARG2 (p3 / percentage-entity :value "81")))) :degree (m / more)) :compared-to (p2 / person :ARG0-of (h / harbor-01 :ARG1 (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colon" :op2 "cancer") :mod (e / enzyme :name (n2 / name :op1 "KRAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG0-of h2) :time (f2 / final)) # ::id pmid_2337_4602.135 # ::date 2015-08-09T15:29:57 # ::file pmid_2337_4602_135.txt # ::snt Impact of distinct types of KRAS and PIK3CA mutations on outcome of cetuximab-treated patients # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / impact-01 :ARG0 (t / type :mod (d / distinct) :mod (m / mutate-01 :ARG1 (a / and :op1 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n3 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))) :ARG1 (o / outcome :topic (p / person :ARG1-of (t2 / treat-03 :ARG3 (s / small-molecule :name (n4 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient))))) # ::id pmid_2337_4602.136 # ::date 2015-08-09T23:28:02 # ::file pmid_2337_4602_136.txt # ::snt We examined different types of KRAS and PIK3CA mutations for potentially distinct impact on patient survival. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (t / type :mod (m / mutate-01 :ARG2 (a / and :op1 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n3 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :ARG1-of (d / differ-02)) :ARG2 (i / impact-01 :ARG0 t :ARG1 (s / survive-01 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)))) :mod (d2 / distinct :mod (p2 / potential)))) # ::id pmid_2337_4602.137 # ::date 2015-08-09T23:33:11 # ::file pmid_2337_4602_137.txt # ::snt Regarding KRAS, cetuximab-treated patients with codon 12 mutations had a median survival of 19 months (95% CI 15–26), significantly lower (p=0.033) than the median survival of patients with other KRAS mutations (30 months, 95% CI 20–35) and that of patients with wild-type KRAS (29 months, 95% CI 25–35). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (h / have-03 :ARG0 (p / person :ARG1-of (t / treat-03 :ARG3 (s / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :poss (m2 / mutate-01 :ARG1 (c / codon :mod "12")) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient))) :ARG1 (s2 / survive-01 :mod (m3 / median) :duration (t2 / temporal-quantity :quant "19" :unit (m4 / month)) :ARG1-of (m5 / mean-01 :ARG2 (i / interval :mod (p3 / percentage-entity :value "95") :mod (v / value-interval :op1 "15" :op2 "26") :mod (c2 / confidence))) :ARG1-of (l / low-04 :degree (m6 / more) :ARG1-of (s3 / significant-02) :compared-to (a / and :op1 (s4 / survive-01 :ARG0 (p5 / person :poss (m8 / mutate-01 :ARG1 "g" :mod (o / other)) :ARG0-of h2) :mod m3 :ARG1-of (m9 / mean-01 :ARG2 (i2 / interval :mod (v2 / value-interval :op1 "20" :op2 "35") :mod p3 :mod c2) :duration (t3 / temporal-quantity :quant "30" :unit m4))) :op2 (s5 / survive-01 :ARG0 (p6 / person :poss (g2 / gene :name (n3 / name :op1 "KRAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG0-of h2) :ARG1-of (m10 / mean-01 :ARG2 (i3 / interval :mod (v3 / value-interval :op1 "25" :op2 "35") :mod c2) :duration (t4 / temporal-quantity :quant "29" :unit m4)))) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.033"))) :topic (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) # ::id pmid_2337_4602.138 # ::date 2015-08-10T00:18:36 # ::file pmid_2337_4602_138.txt # ::snt Further subgroup analyses showed that the median survival in patients with codon 12 KRAS mutations was also lower than the median survival of all other patient subgroups (other KRAS mutations or KRAS wild-type). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (s2 / subgroup) :degree (f / further)) :ARG1 (s3 / survive-01 :ARG0 (p / person :poss (m3 / mutate-01 :ARG1 (c / codon :mod "12" :part-of (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient))) :mod (m2 / median) :ARG1-of (l / low-04 :degree (m4 / more) :compared-to (s4 / survive-01 :ARG0 (s5 / subgroup :mod (o / other) :mod (a2 / all) :ARG1-of (m5 / mean-01 :ARG2 (o2 / or :op1 (m6 / mutate-01 :ARG2 g :mod (o3 / other)) :op2 (g2 / gene :name (n2 / name :op1 "KRAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :consist-of (p3 / person :ARG0-of h)) :mod m2) :mod (a3 / also)))) # ::id pmid_2337_4602.139 # ::date 2015-08-10T00:49:50 # ::file pmid_2337_4602_139.txt # ::snt Specifically, patients with codon 13 mutations reached a median survival of 28 months (95% CI 16–39), those with other rarer KRAS mutations a median survival of 33 months (95% CI 16–42) and patients with KRAS wild-type tumours a median survival of 29 months (95% CI 25–35). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (p / person :poss (m / mutate-01 :ARG1 (c / codon :mod "13")) :ARG0-of (r / reach-01 :ARG1 (s2 / survive-01 :mod (m2 / median) :duration (t / temporal-quantity :quant "28" :unit (m3 / month)) :ARG1-of (m4 / mean-01 :ARG2 (i / interval :mod (p3 / percentage-entity :value "95") :mod (v / value-interval :op1 "16" :op2 "39") :mod (c2 / confidence))))) :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient))) :op2 (p2 / person :poss (m5 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :mod (o / other) :ARG1-of (r4 / rare-02 :degree (m8 / more))) :ARG0-of (r2 / reach-01 :ARG1 (s3 / survive-01 :mod m2 :duration (t2 / temporal-quantity :quant "33" :unit m3) :ARG1-of (m6 / mean-01 :ARG2 (i2 / interval :mod (v2 / value-interval :op1 "16" :op2 "42") :mod p3 :mod c2)))) :ARG0-of h) :op3 (p4 / person :poss (t3 / tumor :mod (g2 / gene :name (n2 / name :op1 "KRAS") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG0-of (r3 / reach-01 :ARG1 (s4 / survive-01 :mod m2 :duration (t4 / temporal-quantity :quant "29" :unit m3) :ARG1-of (m7 / mean-01 :ARG2 (i3 / interval :mod (v3 / value-interval :op1 "25" :op2 "35") :mod p3 :mod c2)))) :ARG0-of h) :ARG1-of (s / specific-02)) # ::id pmid_2337_4602.140 # ::date 2015-08-10T01:00:58 # ::file pmid_2337_4602_140.txt # ::snt Despite the rather small size of compared subgroups, a trend for statistical significance was evident (p=0.068, Figure  4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (e / evidence-01 :ARG1 (t / trend-01 :ARG2 (s / signify-01 :mod (s2 / statistic))) :concession (s3 / size-01 :ARG1 (s5 / subgroup :ARG1-of (c / compare-01)) :ARG2 (s4 / small :degree (r / rather))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4")) :ARG1-of (s6 / statistical-test-91 :ARG2 "0.068")) # ::id pmid_2337_4602.141 # ::date 2015-08-10T01:07:42 # ::file pmid_2337_4602_141.txt # ::snt No difference in patient outcomes was found when we compared tumours with PIK3CA exon 9 versus exon 20 mutations versus PIK3CA wild-type status, as survival times clustered from 25 to 29 months (p=0.31). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (f / find-01 :polarity "-" :ARG1 (d / differ-02 :ARG1 (o / outcome :poss-of (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient))))) :time (c / compare-01 :ARG0 (w / we) :ARG1 (t / tumor :poss (a / and :op1 (m / mutate-01 :ARG2 (e / exon :mod "9" :part-of (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :op2 (m2 / mutate-01 :ARG2 (e2 / exon :mod "20" :part-of g2)) :op3 (g3 / gene :name (n3 / name :op1 "PIK3CA") :poss (s / status :mod (w2 / wild-type)) :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))) :ARG1-of (c2 / cause-01 :ARG0 (t2 / time :duration-of (s2 / survive-01) :ARG1-of (c3 / cluster-01 :duration (v / value-interval :op1 (t3 / temporal-quantity :quant "25" :unit (m3 / month)) :op2 (t4 / temporal-quantity :quant "29" :unit m3))))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.31")) # ::id pmid_2337_4602.142 # ::date 2015-08-10T01:33:42 # ::file pmid_2337_4602_142.txt # ::snt The only complex genotype that harboured significance for cetuximab benefit was CG3 (p=0.019): Patients with tumours wild-type for all PIK3CA, KRAS, BRAF reached a median survival of 32 months (95% CI 25–36), those with a PIK3CA mutation along with KRAS or BRAF mutation had a median survival of 26 months (95% CI 16–32) while patients with any single mutation in KRAS, BRAF or PIK3CA genes had a median survival of 22 months (95% CI 19–28). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (h / harbor-01 :ARG0 (g2 / genotype :mod (c / complex) :mod (o / only) :domain (d / dna-sequence :name (n / name :op1 "CG3"))) :ARG1 (s / significant-02 :ARG1 (b / benefit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab") :xref (x3 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :ARG1-of (s7 / statistical-test-91 :ARG2 "0.019"))) :snt2 (a / and :op1 (r / reach-01 :ARG0 (p / person :poss (t / tumor :mod (g / gene :name (n3 / name :op1 "PIK3CA") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :ARG0-of (h4 / have-rel-role-91 :ARG2 (p5 / patient)) :poss (t6 / tumor :mod (e2 / enzyme :name (n4 / name :op1 "KRAS") :mod w :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :poss (t7 / tumor :mod (e3 / enzyme :name (n5 / name :op1 "BRAF") :mod w :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1 (s3 / survive-01 :ARG0 p :mod (m2 / median) :duration (t2 / temporal-quantity :quant "32" :unit (m3 / month)) :ARG1-of (m4 / mean-01 :ARG2 (i / interval :mod (p4 / percentage-entity :value "95") :mod (v / value-interval :op1 "25" :op2 "36") :mod (c2 / confidence))))) :op2 (h2 / have-03 :ARG0 (p7 / person :poss (a4 / and :op1 (m5 / mutate-01 :ARG2 g) :op2 (o2 / or :op1 (m6 / mutate-01 :ARG2 e2) :op2 (m7 / mutate-01 :ARG2 e3))) :ARG0-of h4) :ARG1 (s4 / survive-01 :ARG0 p7 :mod m2 :duration (t3 / temporal-quantity :quant "26" :unit m3) :ARG1-of (m8 / mean-01 :ARG2 (i2 / interval :mod (v2 / value-interval :op1 "16" :op2 "32") :mod p4 :mod c2)))) :op3 (h3 / have-03 :ARG0 (p3 / person :poss (m9 / mutate-01 :ARG2 (o3 / or :op1 g :op2 e2 :op3 e3) :ARG1-of (s5 / single-02)) :ARG0-of h4) :ARG1 (s6 / survive-01 :ARG0 p3 :mod m2 :duration (t5 / temporal-quantity :quant "22" :unit m3) :ARG1-of (m10 / mean-01 :ARG2 (i3 / interval :mod (v3 / value-interval :op1 "19" :op2 "28") :mod p4 :mod c2)))))) # ::id pmid_2337_4602.143 # ::date 2015-08-10T02:09:16 # ::file pmid_2337_4602_143.txt # ::snt Apparently, concurrent mutations in PIK3CA along with KRAS or BRAF mutations carried rather weak additional adverse prediction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / carry-01 :ARG0 (a4 / and :op1 (m / mutate-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "PIK3CA") :xref (x1 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG1-of (c2 / concurrent-02)) :op2 (m2 / mutate-01 :ARG2 (o / or :op1 (e / enzyme :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG1 (p / predict-01 :mod (a2 / adverse) :mod (a3 / additional) :ARG1-of (w / weak-02 :degree (r / rather))) :manner (a / apparent)) # ::id pmid_2352_4590.1 # ::date 2015-07-23T06:02:47 # ::file pmid_2352_4590_1.txt # ::snt MEK inhibitors as a chemotherapeutic intervention in multiple myeloma (PMID:23524590) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / inhibit-01 :ARG0 (m / molecular-physical-entity :prep-as (i2 / intervene-01 :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")) :mod (c / chemotherapy))) :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID23524590"))) # ::id pmid_2352_4590.2 # ::date 2015-07-23T23:15:50 # ::file pmid_2352_4590_2.txt # ::snt The Ras/Raf/MEK/extracellular signal regulated kinase (ERK) (Ras/mitogen-activated protein kinases (MAPK)) signal transduction pathway is a crucial mediator of many fundamental biological processes, including cellular proliferation, survival, angiogenesis and migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / mediate-01 :ARG0 (p3 / pathway :name (n / name :op1 "MAPK") :ARG0-of (t / transduce-01 :ARG1 (s2 / signal-07)) :mod (c2 / crucial)) :ARG1 (p / process-02 :ARG1 (b / biology) :mod (f / fundamental) :mod (m2 / many) :ARG2-of (i / include-91 :ARG1 (a / and :op1 (p2 / proliferate-01 :ARG0 (c / cell)) :op2 (s / survive-01 :ARG0 c) :op3 (a2 / angiogenesis :mod c) :op4 (m3 / migrate-01 :ARG0 c))))) # ::id pmid_2352_4590.3 # ::date 2015-07-23T23:31:20 # ::file pmid_2352_4590_3.txt # ::snt Aberrant signalling through the Ras/MAPK cascade is common in a wide array of malignancies, including multiple myeloma (MM), making it an appealing candidate for the development of novel targeted therapies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / common :domain (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Ras/MAPK")) :mod (a / aberrant)) :location (a2 / array :ARG1-of (w / wide-02) :consist-of (m / malignancy :ARG2-of (i / include-91 :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))))) :ARG0-of (m2 / make-02 :ARG1 (c3 / candidate :ARG0-of (a3 / appeal-03) :purpose (d2 / develop-02 :ARG1 (t / therapy :ARG0-of (t2 / target-01) :mod (n3 / novel))) :domain s))) # ::id pmid_2352_4590.4 # ::date 2015-07-23T23:44:37 # ::file pmid_2352_4590_4.txt # ::snt In this review, we explore our current understanding of the Ras/MAPK pathway and its role in MM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (e / explore-01 :ARG0 (w / we) :ARG1 (u / understand-01 :ARG0 w :ARG1 (a / and :op1 (p / pathway :name (n / name :op1 "Ras/MAPK")) :op2 (r / role :topic (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")) :poss p)) :mod (c / current)) :medium (r2 / review :mod (t / this))) # ::id pmid_2352_4590.5 # ::date 2015-07-23T23:48:15 # ::file pmid_2352_4590_5.txt # ::snt Additionally, we summarise the current status of small molecule inhibitors of MEK under clinical evaluation, and discuss future approaches required to optimise their use. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (s / summarize-01 :ARG0 (w / we) :ARG2 (s2 / status :mod (c / current) :mod (s4 / small-molecule :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :mod (m2 / molecule :mod (s3 / small)) :ARG1-of (e2 / evaluate-01 :mod (c2 / clinic))))) :op2 (d / discuss-01 :ARG0 w :ARG1 (a2 / approach-02 :mod (f / future) :ARG1-of (r / require-01 :ARG0 (o / optimize-01 :ARG1 (u / use-01 :ARG1 s4))))) :manner (a3 / additional)) # ::id pmid_2352_4590.6 # ::date 2015-07-23T23:58:30 # ::file pmid_2352_4590_6.txt # ::snt Introduction # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (i / introduce-01) # ::id pmid_2352_4590.7 # ::date 2015-07-23T23:59:32 # ::file pmid_2352_4590_7.txt # ::snt Mitogen-activated protein kinases (MAPKs) are a family of ubiquitously expressed serine/threonine kinases that transmit diverse cell surface signals throughout the cell. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / protein-family :mod (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "serine" :op2 "kinase") :xref (x2 / xref :value "UNIPROT:SRR_HUMAN" :prob "0.282")) :op2 (e3 / enzyme :name (n3 / name :op1 "threonine" :op2 "kinase") :xref (x1 / xref :value "UNIPROT:TASP1_HUMAN" :prob "0.272")) :ARG2-of (e / express-03 :manner (u / ubiquitous)) :ARG0-of (t2 / transmit-01 :ARG1 (s2 / signal-07 :mod (s3 / surface :mod (c / cell)) :mod (d / diverse)) :ARG2 (t3 / throughout :op1 (c2 / cell)))) :domain (e4 / enzyme :name (n4 / name :op1 "Mitogen-activated" :op2 "protein" :op3 "kinase") :xref (x / xref :value "UNIPROT:A0A024QZ12_HUMAN" :prob "1.001"))) # ::id pmid_2352_4590.8 # ::date 2015-07-24T00:08:59 # ::file pmid_2352_4590_8.txt # ::snt MAPK pathways consist of a three-tiered signalling module activated via a phosphorylation cascade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (c / consist-01 :ARG1 (p / pathway :name (n / name :op1 "MAPK")) :ARG2 (m / module :ARG0-of (s / signal-07) :ARG1-of (a / activate-01 :instrument (c2 / cascade :mod (p2 / phosphorylate-01))) :mod (t / tier :quant "3"))) # ::id pmid_2352_4590.9 # ::date 2015-07-24T00:14:02 # ::file pmid_2352_4590_9.txt # ::snt The most proximal kinase in these pathways, the MAPK kinase kinase (MAPKKK or MAP3k), engaged by extracellular signals, phosphorylates a dual specificity MAPK kinase (MAPKK or MAP2K), which in turn phosphorylates and actives the distil effector MAPK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / phosphorylate-01 :ARG1 (e6 / enzyme :name (n2 / name :op1 "MAPK") :mod (s2 / specificity :mod (d / dual)) :ARG1-of (m2 / mean-01 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MAPK" :op2 "kinase" :op3 "kinase") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG2-of (p8 / phosphorylate-01 :ARG1 (e7 / effector :mod (d2 / distal) :mod (e3 / enzyme :name (n / name :op1 "MAPK") :xref (x3 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))) :mod (i3 / in-turn)) :ARG0-of (a / activate-01 :ARG1 e7 :manner i3) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG2 (e5 / enzyme :name (n4 / name :op1 "MAPK" :op2 "kinase" :op3 "kinase") :ARG1-of (i / include-91 :ARG2 (p3 / pathway :mod (t / this))) :ARG1-of (e / engage-01 :ARG0 (s / signal-07 :mod (e2 / extracellular))) :mod (p4 / proximal :degree (m / most)) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) # ::id pmid_2352_4590.10 # ::date 2015-07-24T00:33:32 # ::file pmid_2352_4590_10.txt # ::snt Mammalian MAPK pathways are represented by the Extracellular Signal Regulated Kinase (ERK), c-Jun N-terminal kinase, p38, ERK 5, ERK 3/4 and ERK 7/8 pathways.1 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (r / represent-01 :ARG0 (a / and :op1 (p2 / pathway :name (n2 / name :op1 "ERK")) :op2 (p3 / pathway :name (n3 / name :op1 "c-Jun" :op2 "N-terminal" :op3 "kinase")) :op3 (p4 / pathway :name (n4 / name :op1 "p38")) :op4 (p5 / pathway :name (n5 / name :op1 "ERK5")) :op5 (p6 / pathway :name (n6 / name :op1 "ERK3/4")) :op6 (p7 / pathway :name (n7 / name :op1 "ERK7/8"))) :ARG1 (p / pathway :name (n / name :op1 "MAPK") :mod (m / mammal)) :ARG1-of (d / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c / cite-01 :ARG2 "1")))) # ::id pmid_2352_4590.11 # ::date 2015-07-23T06:04:41 # ::file pmid_2352_4590_11.txt # ::snt The Ras/MAPK pathway is the best characterised of the mammalian MAPK signal transduction networks, consisting of the Ras proteins, a family of small G-coupled molecules, the Raf kinases (MAP3K), the MAP2K kinases (MEK1 and MEK2) and the pathway distil kinases ERK1 and ERK2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / characterize-01 :ARG1 (p / pathway :name (n / name :op1 "Ras/MAPK") :ARG1-of (i / include-91 :ARG2 (n2 / network :ARG2-of (t / transduce-01 :ARG1 (s / signal-07)) :mod (p2 / pathway :name (n3 / name :op1 "MAPK")) :mod (m2 / mammal) :ARG1-of (c2 / consist-01 :ARG2 (a / and :op1 (p3 / protein-family :name (n4 / name :op1 "Ras")) :op2 (f / family :ARG2-of (i3 / include-91 :ARG1 (m3 / molecule :mod (s2 / small) :ARG1-of (c3 / couple-01 :ARG2 (p4 / protein :name (n5 / name :op1 "G") :xref (x6 / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601")))))) :op3 (p6 / protein-family :name (n6 / name :op1 "Raf") :ARG2-of (i4 / include-91 :ARG1 (k7 / kinase :name (n12 / name :op1 "MAP3K") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.333")))) :op4 (k2 / kinase :name (n7 / name :op1 "MAP2K") :ARG2-of (i2 / include-91 :ARG1 (a2 / and :op1 (k3 / kinase :name (n8 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (k4 / kinase :name (n9 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.333")) :op5 (a3 / and :op1 (k5 / kinase :name (n10 / name :op1 "ERK1") :mod (d / distal) :mod (p5 / pathway) :xref (x5 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (k6 / kinase :name (n11 / name :op1 "ERK2") :mod d :mod p5 :xref (x4 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))))))) :ARG1-of (g / good-02 :degree (m / most))) # ::id pmid_2352_4590.12 # ::date 2015-07-24T00:59:06 # ::file pmid_2352_4590_12.txt # ::snt The Ras/MAPK network is frequently deregulated in malignancy and contributes to many of the hallmarks of oncogenesis, including abnormal cellular proliferation, impaired apoptosis, enhanced angiogenesis, metastasis and the development of drug resistance.2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (d / deregulate-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "Ras/MAPK")) :ARG1-of (f / frequent-02) :location (m / malignancy)) :op2 (c / contribute-01 :ARG0 p3 :ARG2 (h / hallmark :quant (m2 / many) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (p / proliferate-01 :ARG0 (c3 / cell) :mod (a3 / abnormal)) :op2 (a4 / apoptosis :ARG1-of (i2 / impair-01)) :op3 (a5 / angiogenesis :ARG1-of (e / enhance-01)) :op4 (m3 / metastasis) :op5 (d2 / develop-01 :ARG2 (r / resist-01 :ARG1 (d3 / drug))))) :mod (d5 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ARG1-of (o / originate-01)))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "2")))) # ::id pmid_2352_4590.13 # ::date 2015-07-24T01:08:33 # ::file pmid_2352_4590_13.txt # ::snt MEK lies at a critical juncture within the Ras/MAPK pathway, having a limited number of direct upstream MAP3K activators and ERK1/2 as its only known cellular targets, thereby making it an attractive target for cancer therapy. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (l / lie-07 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :ARG0-of (h / have-03 :ARG1 (a2 / and :op1 (n3 / number :ARG1-of (l2 / limit-01) :quant-of (m / molecular-physical-entity :ARG0-of (a / activate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "MAP3K") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.333"))) :ARG1-of (d / direct-02) :mod (u / upstream))) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK1/2")) :ARG1-of (t / target-01 :ARG1-of (k / know-01) :mod (o / only) :mod (c2 / cell)))) :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG2 (j / juncture :ARG1-of (c / critical-02) :location (p / pathway :name (n2 / name :op1 "Ras/MAPK"))) :ARG0-of (m2 / make-02 :ARG1 (t2 / target-01 :ARG0 (t4 / therapy :mod (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :ARG1 e :ARG0-of (a3 / attract-01)))) # ::id pmid_2352_4590.14 # ::date 2015-07-24T01:26:56 # ::file pmid_2352_4590_14.txt # ::snt Several MEK inhibitors have been developed and investigated in preclinical and clinical models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (d / develop-02 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))) :quant (s / several))) :op2 (i2 / investigate-01 :ARG1 m) :location (a2 / and :op1 (m2 / model :mod (p / preclinical)) :op2 (m3 / model :mod (c / clinic)))) # ::id pmid_2352_4590.15 # ::date 2015-07-24T01:30:47 # ::file pmid_2352_4590_15.txt # ::snt Results from these studies have been promising and suggest that MEK inhibitors, whether alone or in combination with other anticancer therapies, may have a significant role to play in the future management of malignancy. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (p / promise-01 :ARG0 (t / thing :ARG2-of (r / result-01 :ARG1 (s / study-01 :mod (t2 / this))))) :op2 (s2 / suggest-01 :ARG0 t :ARG1 (p2 / possible-01 :ARG1 (p3 / play-08 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK")))) :ARG1 (m2 / manage-01 :ARG1 (m3 / malignancy) :mod (f / future)) :ARG1-of (s3 / significant-02) :manner (o / or :op1 (a2 / alone) :op2 (c / combine-01 :ARG1 m :ARG2 (t3 / therapy :ARG0-of (c2 / counter-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :mod (o2 / other)))))))) # ::id pmid_2352_4590.16 # ::date 2015-07-24T01:43:42 # ::file pmid_2352_4590_16.txt # ::snt Current management strategies for multiple myeloma (MM) involve conventional chemotherapeutics and novel anti-MM agents (thalidomide, lenalidomide and bortezomib), with or without subsequent autologous stem cell transplantation.3 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (i / involve-01 :ARG1 (a / and :op1 (t / thing :mod (c2 / chemotherapy) :mod (c3 / conventional)) :op2 (a2 / agent :mod (n2 / novel) :ARG0-of (c4 / counter-01 :ARG1 "d") :ARG2-of (i2 / include-91 :ARG1 (a3 / and :op1 (s4 / small-molecule :name (n3 / name :op1 "thalidomide") :xref (x2 / xref :value "PUBCHEM:5426" :prob "16.152618")) :op2 (s5 / small-molecule :name (n4 / name :op1 "lenalidomide") :xref (x1 / xref :value "PUBCHEM:216326" :prob "17.251232")) :op3 (s6 / small-molecule :name (n5 / name :op1 "bortezomib") :xref (x / xref :value "PUBCHEM:387447" :prob "17.186693")))))) :ARG2 (s / strategy :mod (m / manage-01) :mod (c / current) :prep-for (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG1-of (c6 / cite-01 :ARG2 "3"))) :manner (o / or :op1 (a4 / accompany-01 :ARG0 (t3 / transplant-01 :ARG1 (c5 / cell :mod (s2 / stem)) :mod (a5 / autologous)) :ARG1 a :mod (s3 / subsequent)) :op2 (a6 / accompany-01 :polarity "-" :ARG0 t3 :ARG1 a))) # ::id pmid_2352_4590.17 # ::date 2015-07-24T01:54:22 # ::file pmid_2352_4590_17.txt # ::snt Although these anticancer therapies are typically effective initially, MM remains a fatal and largely incurable disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (h / have-concession-91 :ARG1 (r / remain-01 :ARG1 (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")) :ARG3 (a / and :op1 (d2 / disease :mod (f / fatal)) :op2 (d3 / disease :ARG2-of (c3 / cure-01 :manner (l / large) :ARG1-of (p / possible-01 :polarity "-"))))) :ARG2 (e / effective-04 :ARG0 (t / therapy :ARG0-of (c / counter-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :mod (t2 / this)) :time (i / initial) :ARG1-of (t3 / typical-02))) # ::id pmid_2352_4590.18 # ::date 2015-07-24T02:00:59 # ::file pmid_2352_4590_18.txt # ::snt This is due to the high frequency of relapse and the eventual development of drug resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / cause-01 :ARG0 (a / and :op1 (f / frequent-02 :ARG1 (r / relapse-01) :ARG1-of (h / high-02)) :op2 (d / develop-01 :ARG2 (r2 / resist-01 :ARG1 (d2 / drug)) :mod (e / eventual))) :ARG1 (t / this)) # ::id pmid_2352_4590.19 # ::date 2015-07-24T04:09:09 # ::file pmid_2352_4590_19.txt # ::snt Accumulative genetic changes within malignant plasma cells, together with MM interplay with the bone marrow microenvironment (BMME), potentiate disease progression by promoting the deregulation of multiple signal transduction networks, one of which is the Ras/MAPK pathway.4, 5 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (p / potentiate-01 :ARG1 (p3 / progress-01 :ARG1 (d2 / disease)) :ARG2 (a / and :op1 (c / change-01 :ARG1-of (a2 / accumulate-01) :mod (g / genetics) :location (c2 / cell :mod (p2 / plasma) :ARG1-of (m / malignant-02))) :op2 (i / interplay-00 :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")) :prep-with (m2 / microenvironment :mod (m3 / marrow :mod (b / bone))))) :manner (p4 / promote-01 :ARG0 a :ARG1 (d3 / deregulate-01 :ARG1 (n2 / network :quant (m4 / multiple) :ARG2-of (t / transduce-01 :ARG1 (s / signal-07)) :ARG2-of (i2 / include-91 :ARG1 (p5 / pathway :name (n3 / name :op1 "Ras/MAPK")))))) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 "4" :op2 "5"))))) # ::id pmid_2352_4590.20 # ::date 2015-07-24T04:23:20 # ::file pmid_2352_4590_20.txt # ::snt This suggests that MM patients may benefit from the abrogation of this kinase network through the administration of a MEK inhibitor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (p / possible-01 :ARG1 (b / benefit-01 :ARG0 (a / abrogate-01 :ARG1 (n2 / network :mod (k / kinase) :mod (t / this)) :manner (a2 / administer-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK")))))) :ARG1 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")))) :ARG1-of (s / suggest-01 :ARG0 (t2 / this))) # ::id pmid_2352_4590.21 # ::date 2015-07-24T04:32:59 # ::file pmid_2352_4590_21.txt # ::snt Here, we discuss the Ras/MAPK pathway, its involvement in MM and the role of MEK inhibitors in the future management of the disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (d / discuss-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p / pathway :name (n / name :op1 "Ras/MAPK")) :op2 (i / involve-01 :ARG1 p :ARG2 (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :op3 (r / role :poss (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n3 / name :op1 "MEK")))) :purpose (m2 / manage-01 :ARG1 d2 :mod (f / future)))) :medium (h / here)) # ::id pmid_2352_4590.22 # ::date 2015-07-24T04:39:27 # ::file pmid_2352_4590_22.txt # ::snt Overview of the Ras/Raf/MEK/ERK pathway # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (o / overview :poss (p / pathway :name (n / name :op1 "Ras/Raf/MEK/ERK"))) # ::id pmid_2352_4590.23 # ::date 2015-07-24T04:40:21 # ::file pmid_2352_4590_23.txt # ::snt Members of the Ras protein subfamily (H-, K- and N-Ras) function as molecular switches in cellular signal transduction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (f / function-01 :ARG0 (m / member :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n / name :op1 "Ras"))) :ARG1-of (m3 / mean-01 :ARG2 (a / and :op1 (e / enzyme :name (n2 / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e2 / enzyme :name (n3 / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op3 (e3 / enzyme :name (n4 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))))) :ARG1 (s2 / switch-01 :mod (m2 / molecule)) :time (t / transduce-01 :ARG1 (s3 / signal-07 :location (c / cell)))) # ::id pmid_2352_4590.24 # ::date 2015-07-24T04:54:43 # ::file pmid_2352_4590_24.txt # ::snt Diverse growth factor, mitogen and cytokine engagement of cognate receptors leads to the recruitment of the GDP/GTP exchange factors, growth-factor-receptor bound protein 2 (Grp2) and Sons of Sevenless (SOS) to the plasma membrane where Ras resides. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (l / lead-03 :ARG0 (e / engage-01 :ARG0 (a / and :op1 (g / growth-factor) :op2 (m / mitogen) :op3 (c / cytokine)) :ARG1 (r / receptor :mod (c2 / cognate)) :mod (d / diverse)) :ARG2 (r2 / recruit-01 :ARG1 (a2 / and :op1 (f / factor :ARG0-of (e3 / exchange-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "GDP") :xref (x5 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG3 (s2 / small-molecule :name (n6 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :op2 (p / protein :name (n3 / name :op1 "growth-factor-receptor" :op2 "bound" :op3 "protein2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.693")) :op3 (p3 / protein :name (n4 / name :op1 "Sons" :op2 "of" :op3 "Sevenless") :xref (x1 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.283"))) :ARG2 (m2 / membrane :mod (p2 / plasma) :ARG1-of (r3 / reside-01 :ARG0 (e4 / enzyme :name (n5 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :xref (x3 / xref :value "GO:0016020" :prob "0.8")))) # ::id pmid_2352_4590.25 # ::date 2015-07-24T05:17:19 # ::file pmid_2352_4590_25.txt # ::snt The grp2/SOS complex then promotes inactive Ras to exchange GDP with GTP and enters an activated state.6 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (p / promote-01 :ARG0 (m / macro-molecular-complex :part (p3 / protein :name (n / name :op1 "grp2") :xref (x / xref :value "UNIPROT:GRP2_HUMAN" :prob "0.604")) :part (p4 / protein :name (n5 / name :op1 "SOS") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.263"))) :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (a2 / activate-01 :polarity "-") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (a / and :op1 (e2 / exchange-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "GDP") :xref (x4 / xref :value "PUBCHEM:8977" :prob "14.712257")) :ARG3 (s2 / small-molecule :name (n4 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :op2 (e3 / enter-01 :ARG0 e :ARG1 (s3 / state :ARG1-of (a3 / activate-01)))) :time (t / then) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c / cite-01 :ARG2 "6")))) # ::id pmid_2352_4590.26 # ::date 2015-07-24T05:30:21 # ::file pmid_2352_4590_26.txt # ::snt Activated Ras then recruits Raf to the cell membrane, where it is activated by phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (r / recruit-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG2 (m / membrane :mod (c / cell) :location-of (a2 / activate-01 :ARG1 e2 :manner (p / phosphorylate-01)) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :time (t / then)) # ::id pmid_2352_4590.27 # ::date 2015-07-24T05:35:25 # ::file pmid_2352_4590_27.txt # ::snt This process is antagonised by GTPase-activating proteins, which promote GTP hydrolysis and the formation of inactive Ras-GDP complexes.7 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (a / antagonize-02 :ARG1 (p2 / protein :ARG0-of (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "GTPase") :xref (x1 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312"))) :ARG0-of (p3 / promote-01 :ARG1 (a3 / and :op1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :op2 (f / form-01 :ARG1 (m / macro-molecular-complex :ARG1-of (a4 / activate-01 :polarity "-") :part (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part (s2 / small-molecule :name (n4 / name :op1 "GDP") :xref (x2 / xref :value "PUBCHEM:8977" :prob "14.712257"))))))) :ARG2 (p / process-02 :mod (t / this)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "7")))) # ::id pmid_2352_4590.28 # ::date 2015-07-24T05:41:23 # ::file pmid_2352_4590_28.txt # ::snt Approximately 30% of malignancies contain activating mutations in a Ras proto-oncogene, with pancreatic (90%), colon (50%) and thyroid (50%) carcinomas demonstrating the highest prevalence. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (c / contain-01 :ARG0 (m / malignancy :ARG2-of (i2 / include-91 :ARG1 (a2 / and :op1 (c5 / carcinoma :value (p4 / percentage-entity :value "90") :mod (p3 / pancreas)) :op2 (c4 / carcinoma :value (p5 / percentage-entity :value "50") :mod (c6 / colon)) :op3 (c7 / carcinoma :value (p6 / percentage-entity :value "50") :mod (t2 / thyroid)) :ARG0-of (d / demonstrate-01 :ARG1 (p7 / prevalence :ARG1-of (h / high-02 :degree (m3 / most)))))) :ARG1-of (i3 / include-91 :ARG2 (m4 / malignancy) :ARG3 (a3 / approximately :op1 (p / percentage-entity :value "30")))) :ARG1 (m2 / mutate-01 :ARG1 (p8 / proto-oncogene :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n / name :op1 "Ras")))) :ARG0-of (a / activate-01))) # ::id pmid_2352_4590.29 # ::date 2015-07-24T05:52:02 # ::file pmid_2352_4590_29.txt # ::snt Mutations typically affect K-Ras and N-Ras, but rarely H-Ras, and occur in a mutually exclusive manner.8 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (a2 / affect-01 :ARG0 (m / mutate-01) :ARG1 (a3 / and :op1 (e / enzyme :wiki "KRAS" :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :wiki "Neuroblastoma_RAS_viral_oncogene_homolog" :name (n2 / name :op1 "N-Ras") :xref (x2 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")) :ARG1-of (c / contrast-01 :ARG2 (e3 / enzyme :wiki "HRAS" :name (n3 / name :op1 "H-Ras") :ARG1-of (a4 / affect-01 :ARG0 m :ARG1-of (r / rare-02)) :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))) :ARG1-of (t / typical-02)) :op2 (e4 / exclude-01 :manner (m2 / mutual) :manner-of m) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG1-of (c2 / cite-01 :ARG2 "8")))) # ::id pmid_2352_4590.30 # ::date 2015-07-24T06:03:21 # ::file pmid_2352_4590_30.txt # ::snt The Raf family of serine/threonine kinases (A-, B- and c-Raf (Raf-1)) lie at the apex of the MEK/ERK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (l / lie-07 :ARG1 (p2 / protein-family :name (n / name :op1 "Raf") :ARG2-of (i2 / include-91 :ARG1 (o / or :op1 (e7 / enzyme :name (n2 / name :op1 "serine" :op2 "kinase") :xref (x3 / xref :value "UNIPROT:SRR_HUMAN" :prob "0.282")) :op2 (e2 / enzyme :name (n3 / name :op1 "threonine" :op2 "kinase") :xref (x4 / xref :value "UNIPROT:TASP1_HUMAN" :prob "0.272")) :ARG2-of (i / include-91 :ARG1 (a / and :op1 (e4 / enzyme :name (n4 / name :op1 "A-Raf") :xref (x2 / xref :value "UNIPROT:ARAF_HUMAN" :prob "0.593")) :op2 (e5 / enzyme :name (n5 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op3 (e6 / enzyme :name (n6 / name :op1 "c-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))))))) :ARG2 (a2 / apex :poss (p / pathway :name (n7 / name :op1 "MEK/ERK")))) # ::id pmid_2352_4590.31 # ::date 2015-07-24T06:11:10 # ::file pmid_2352_4590_31.txt # ::snt All three Raf isoforms share similar structural characteristics. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (s / share-01 :ARG0 (i / isoform :quant (t / three) :mod (a / all) :mod (e / enzyme :name (n / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG1 (t2 / thing :ARG2-of (c / characteristic-02 :ARG1 (s2 / structure)) :ARG1-of (r / resemble-01))) # ::id pmid_2352_4590.32 # ::date 2015-07-23T20:40:07 # ::file pmid_2352_4590_32.txt # ::snt However, they differ in their ability to phosphorylate and activate MEK, with B-Raf demonstrating higher basal kinase activity compared with Raf-1 and A-Raf.9, 10 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c3 / contrast-01 :ARG2 (d / differ-02 :ARG1 (t / they) :ARG3 (c / capable-01 :ARG1 t :ARG2 (a / and :op1 (p / phosphorylate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op2 (a2 / activate-01 :ARG1 e4))) :manner (d2 / demonstrate-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (a3 / activity-06 :ARG0 (k / kinase :mod (b / basal)) :ARG1-of (h / high-02 :degree (m / more)) :compared-to (a4 / and :op1 (e2 / enzyme :name (n2 / name :op1 "Raf-1") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "A-Raf") :xref (x1 / xref :value "UNIPROT:ARAF_HUMAN" :prob "0.593")))))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 "9" :op2 "10"))))) # ::id pmid_2352_4590.33 # ::date 2015-07-23T20:57:07 # ::file pmid_2352_4590_33.txt # ::snt Activating B-Raf mutations have been described in 66% of melanomas and to a lesser degree in other solid tumours.11 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (d / describe-01 :ARG1 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG0-of (a / activate-01)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "11"))) :location (a2 / and :op1 (m5 / medical-condition :name (n2 / name :op1 "melanoma") :ARG1-of (i / include-91 :ARG3 (p / percentage-entity :value "66"))) :op2 (t / tumor :mod (o / other) :ARG1-of (s / solid-02) :quant (d2 / degree :mod (l / less :degree (m4 / more)) :compared-to p)))) # ::id pmid_2352_4590.34 # ::date 2015-07-23T21:08:06 # ::file pmid_2352_4590_34.txt # ::snt The clinical relevance of this association is reinforced by the exquisite sensitivity of these B-Raf mutated tumours to MEK inhibition.12 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (r / reinforce-01 :ARG1 (r2 / relevance :mod (c / clinical) :poss (a / associate-01 :mod (t / this))) :ARG2 (s / sensitive-03 :ARG0 (t2 / tumor :ARG2-of (m / mutate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :mod t) :ARG1 (i / inhibit-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :mod (e / exquisite)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "12")))) # ::id pmid_2352_4590.35 # ::date 2015-07-23T21:20:50 # ::file pmid_2352_4590_35.txt # ::snt Despite a high prevalence of activating B-Raf mutations in melanoma and solid tumours, these mutations are infrequent in MM.13 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (h / have-concession-91 :ARG1 (f2 / frequent-02 :polarity "-" :ARG1 "m" :location (d3 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))) :ARG2 (p / prevail-02 :ARG1 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG0-of (a / activate-01) :mod (t2 / this)) :ARG1-of (h2 / high-02) :location (a2 / and :op1 (m2 / medical-condition :name (n2 / name :op1 "melanoma")) :op2 (t / tumor :ARG1-of (s / solid-02)))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "13")))) # ::id pmid_2352_4590.36 # ::date 2015-07-23T21:40:30 # ::file pmid_2352_4590_36.txt # ::snt This suggests that molecules other than B-Raf or alternative kinase pathways may have a crucial role in MM tumourigenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (s / suggest-01 :ARG0 (t / this) :ARG1 (p / possible-01 :ARG1 (h / have-03 :ARG0 (m / molecule :ARG2-of (e2 / except-01 :ARG1 (o / or :op1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (p2 / pathway :mod (k / kinase) :mod (a / alternative))))) :ARG1 (r / role :mod (c / crucial) :topic (t3 / tumourigenesis :mod (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))))))) # ::id pmid_2352_4590.37 # ::date 2015-07-24T10:59:24 # ::file pmid_2352_4590_37.txt # ::snt MEK is a unique dual specificity kinase that phosphorylates both serine/threonine and tyrosine residues.14 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (k / kinase :mod (s / specificity :mod (d / dual) :mod (u / unique)) :domain (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG2-of (p / phosphorylate-01 :ARG1 (a / and :op1 (s2 / slash :op1 (a2 / amino-acid :name (n2 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :op2 (a3 / amino-acid :name (n3 / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252"))) :op2 (r / residue :mod (a4 / amino-acid :name (n4 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :mod (b / both))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "14")))) # ::id pmid_2352_4590.38 # ::date 2015-07-24T11:09:53 # ::file pmid_2352_4590_38.txt # ::snt MEK consists of two isoforms, MEK1 and MEK2, which in turn phosphorylate ERK1 and ERK2.15 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / consist-01 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK")) :ARG2 (i / isoform :quant "2" :mod (i2 / in-turn) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (e3 / enzyme :name (n2 / name :op1 "MEK1") :ARG2-of (p2 / phosphorylate-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))) :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e4 / enzyme :name (n3 / name :op1 "MEK2") :ARG1-of (p3 / phosphorylate-01 :ARG2 (e6 / enzyme :name (n5 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "15")))) # ::id pmid_2352_4590.39 # ::date 2015-07-24T11:24:03 # ::file pmid_2352_4590_39.txt # ::snt Activated ERK1/2 control a diverse range of cellular processes through their many substrates (>160) that are located in cellular membranes, the cytoplasm and nucleus. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / control-01 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1-of (a2 / activate-01)) :ARG1 (r / range-01 :ARG1 (p / process :mod (c2 / cell)) :mod (d / diverse)) :ARG2 (s / substrate :poss a :quant (m2 / many) :ARG1-of (l / locate-01 :location (a4 / and :op1 (m4 / membrane :mod (c3 / cell) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :op2 (c4 / cytoplasm :xref (x3 / xref :value "GO:0005737" :prob "0.8")) :op3 (n4 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8")))) :quant (m3 / more-than :op1 "160"))) # ::id pmid_2352_4590.40 # ::date 2015-07-24T11:44:30 # ::file pmid_2352_4590_40.txt # ::snt Many of these are transcription factors that are important in cellular proliferation, differentiation, survival, angiogenesis and migration.16 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (f / factor :ARG0-of (t / transcribe-01) :mod (i / important :topic (a / and :op1 (p / proliferate-01 :ARG0 (c / cell)) :op2 (d / differentiate-01 :ARG1 c) :op3 (s / survive-01 :ARG0 c) :op4 (a2 / angiogenesis) :op5 (m2 / migrate-01 :ARG0 c))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "16"))) :ARG1-of (i2 / include-91 :ARG2 (t3 / this)) :quant (m / many)) # ::id pmid_2352_4590.41 # ::date 2015-07-24T14:41:56 # ::file pmid_2352_4590_41.txt # ::snt Physiological activation of the Ras/MAPK pathway is also influenced by multiple mechanisms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (i / influence-01 :ARG0 (m / mechanism :quant (m2 / multiple)) :ARG1 (a / activate-01 :ARG1 (p2 / pathway :name (n / name :op1 "Ras/MAPK")) :mod (p / physiology)) :mod (a2 / also)) # ::id pmid_2352_4590.42 # ::date 2015-07-24T14:46:30 # ::file pmid_2352_4590_42.txt # ::snt Inhibitory molecules, such as Sprouty proteins (SPRY) and MAPK phosphatases (MKP or DUSPs), engage the pathway at different points to negatively regulate signalling.17, 18 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (e / engage-01 :ARG0 (m / molecule :ARG0-of (i / inhibit-01) :example (a / and :op1 (p5 / protein :name (n5 / name :op1 "Sprouty")) :op2 (e6 / enzyme :name (n2 / name :op1 "phosphatase") :mod (e4 / enzyme :name (n6 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313")) :ARG1-of (m3 / mean-01 :ARG0 (o / or :op1 (e3 / enzyme :name (n / name :op1 "MKP") :xref (x3 / xref :value "UNIPROT:DUS1_HUMAN" :prob "0.262")) :op2 (e5 / enzyme :name (n7 / name :op1 "DUSP") :xref (x / xref :value "UNIPROT:DUS1_HUMAN" :prob "0.312")))) :xref (x2 / xref :value "UNIPROT:Q59GM9_HUMAN" :prob "0.291")))) :ARG1 (p3 / pathway :location (p4 / point) :ARG1-of (d / differ-02)) :ARG2 (d3 / downregulate-01 :ARG1 (s3 / signal-07) :ARG2 p3) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "17" :op2 "18"))))) # ::id pmid_2352_4590.43 # ::date 2015-07-25T12:54:55 # ::file pmid_2352_4590_43.txt # ::snt Activated ERK induces the expression of these inhibitory factors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (i / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2 (e2 / express-03 :ARG1 (f / factor :ARG1-of (i2 / inhibit-01) :mod (t / this)))) # ::id pmid_2352_4590.44 # ::date 2015-07-25T12:58:39 # ::file pmid_2352_4590_44.txt # ::snt For example, certain DUSPs, induced by ERK-regulated transcription factors, dephosphorylate ERK.19 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (e / exemplify-01 :ARG0 (d / dephosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2 (e3 / enzyme :name (n3 / name :op1 "DUSP") :mod (c / certain) :ARG2-of (i / induce-01 :ARG0 (f / factor :ARG0-of (t / transcribe-01) :ARG1-of (r / regulate-01 :ARG0 e2))) :xref (x / xref :value "UNIPROT:DUS1_HUMAN" :prob "0.312"))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "19")))) # ::id pmid_2352_4590.45 # ::date 2015-07-25T13:10:05 # ::file pmid_2352_4590_45.txt # ::snt Downstream signalling from B-Raf, Raf-1 and MEK1 may also be diminished following ERK-mediated phosphorylation.20, 21 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (p / possible-01 :ARG1 (d / diminish-01 :ARG1 (s / signal-07 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "Raf-1") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n3 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :direction (d2 / downstream))) :mod (a / also) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "20" :op2 "21")))) :ARG1-of (f / follow-01 :ARG2 (p2 / phosphorylate-01 :ARG1-of (m / mediate-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))) # ::id pmid_2352_4590.46 # ::date 2015-07-25T13:54:36 # ::file pmid_2352_4590_46.txt # ::snt These various mechanisms fine tune the activity of the Ras/MAPK cascade through the creation of a negative-feedback loop. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (f / finetune-01 :ARG0 (m / mechanism :mod (v / various) :mod (t / this)) :ARG1 (a / activity-06 :ARG0 (c / cascade-01 :ARG1 (p / pathway :name (n3 / name :op1 "Ras/MAPK"))) :manner (c2 / create-01 :ARG1 (l / loop-01 :mod (f2 / feedback :ARG0-of (n / negative-03)))))) # ::id pmid_2352_4590.47 # ::date 2015-07-25T14:23:55 # ::file pmid_2352_4590_47.txt # ::snt As will be discussed later, this mode of regulation has implications for inhibitors targeting the pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (d / discuss-01 :ARG1 (i / implicate-01 :ARG0 (r / regulate-01 :mod (m2 / mode :mod (t / this))) :ARG1 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01) :ARG0-of (t3 / target-01 :ARG1 (p / pathway)))) :time (l / late :degree (m / more))) # ::id pmid_2352_4590.48 # ::date 2015-07-25T14:33:49 # ::file pmid_2352_4590_48.txt # ::snt The Ras/MAPK pathway and MM # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (a / and :op1 (p / pathway :name (n / name :op1 "Ras/MAPK")) :op2 (d2 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))) # ::id pmid_2352_4590.49 # ::date 2015-07-25T23:20:13 # ::file pmid_2352_4590_49.txt # ::snt The genetic changes associated with MM are complex and heterogeneous. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (a / and :op1 (c / complex) :op2 (h / heterogeneous) :domain (c2 / change-01 :ARG1-of (a2 / associate-01 :ARG2 (d2 / disease :name (n / name :op1 "multiple" :op2 "myeloma"))) :mod (g2 / genetic))) # ::id pmid_2352_4590.50 # ::date 2015-07-25T23:28:40 # ::file pmid_2352_4590_50.txt # ::snt Increasing evidence suggests that the disease evolves through a multistep transformation process, involving the gain or loss of whole chromosomes, nonrandom chromosomal translocations involving the IgH locus and point mutations.4 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / suggest-01 :ARG0 (e / evidence :ARG1-of (i / increase-01)) :ARG1 (e2 / evolve-01 :ARG1 (d / disease) :manner (p / process-01 :ARG1 (t / transform-01 :mod (m / multistep)) :ARG0-of (i2 / involve-01 :ARG1 (a / and :op1 (o / or :op1 (g / gain-02 :ARG1 (c / chromosome :mod (w / whole) :xref (x2 / xref :value "GO:0005694" :prob "0.8"))) :op2 (l / lose-02 :ARG1 c)) :op2 (t2 / translocate-01 :ARG1 (c2 / chromosome :xref (x1 / xref :value "GO:0005694" :prob "0.8")) :mod (r / random :polarity "-") :ARG0-of (i3 / involve-01 :ARG1 (a2 / and :op1 (l3 / locus :location-of (g2 / gene :name (n2 / name :op1 "IgH") :xref (x / xref :value "UNIPROT:Q9UGP3_HUMAN" :prob "1.001"))) :op2 (m2 / mutate-01 :ARG1 (p2 / point))))))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "4")))) # ::id pmid_2352_4590.51 # ::date 2015-07-25T23:51:41 # ::file pmid_2352_4590_51.txt # ::snt These aberrations, which influence the clinical and pathological features of MM are manifest in variable disease progression and therapeutic outcomes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (m / manifest-01 :ARG1 (a / aberration :mod (t / this) :ARG0-of (i / influence-01 :ARG1 (f / feature-01 :ARG1 (d3 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")) :mod (c2 / clinic) :mod (p2 / pathology)))) :ARG3 (a2 / and :op1 (p / progress-01 :ARG1 (d / disease :mod (v / variable))) :op2 (o / outcome :mod (t2 / therapy)))) # ::id pmid_2352_4590.52 # ::date 2015-07-26T00:24:34 # ::file pmid_2352_4590_52.txt # ::snt Several of these molecular alterations lead to deregulated activation of the Ras/MAPK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (l / lead-03 :ARG0 (a / alter-01 :quant (s / several) :ARG1-of (i / include-91 :ARG2 (a3 / alter-01 :ARG1 (m / molecule) :mod (t2 / this)))) :ARG2 (a2 / activate-01 :ARG1 (p / pathway :name (n / name :op1 "Ras/MAPK")) :ARG1-of (d / deregulate-01))) # ::id pmid_2352_4590.53 # ::date 2015-07-26T00:44:29 # ::file pmid_2352_4590_53.txt # ::snt The t(4;14) translocation that juxtaposes the fibroblast growth factor receptor 3 gene and a strong IgH enhancer, resulting in fibroblast growth factor receptor 3 overexpression, stimulates the Ras/MAPK pathway, an outcome typically associated with abnormal cellular proliferation and apoptosis.22 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (s / stimulate-01 :ARG0 (t / translocate-01 :ARG2 "14" :ARG3 "4" :ARG0-of (j / juxtapose-01 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "fibroblast" :op2 "growth" :op3 "factor" :op4 "receptor" :op5 "3") :xref (x1 / xref :value "UNIPROT:FGFR3_HUMAN" :prob "0.703")) :op2 (t3 / thing :ARG0-of (e / enhance-01 :ARG1 (g2 / gene :name (n5 / name :op1 "IgH") :xref (x / xref :value "UNIPROT:Q9UGP3_HUMAN" :prob "1.001")) :ARG1-of (s2 / strong-02)))) :ARG1-of (r / result-01 :ARG2 (o / overexpress-01 :ARG1 g)))) :ARG1 (p / pathway :name (n3 / name :op1 "Ras/MAPK") :ARG1-of (m2 / mean-01 :ARG2 (o2 / outcome :ARG1-of (a2 / associate-01 :ARG2 (a3 / and :op1 (p2 / proliferate-01 :ARG0 (c / cell) :ARG1-of (n4 / normal-02 :polarity "-")) :op2 (a4 / apoptosis)) :ARG1-of (t2 / typical-02))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "22")))) # ::id pmid_2352_4590.54 # ::date 2015-07-26T01:14:13 # ::file pmid_2352_4590_54.txt # ::snt Activating Ras mutations, which have a reported incidence varying between 32–50% in MM, are also thought to deregulate this pathway.23, 24, 25 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (t / think-01 :ARG1 (d3 / deregulate-01 :ARG0 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG0-of (h / have-03 :ARG1 (i / incidence :ARG1-of (r / report-01) :ARG1-of (v / vary-01 :ARG3 (p2 / percentage-entity :value "32") :ARG4 (p3 / percentage-entity :value "50") :location (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))))) :ARG1 (p / pathway :mod (t2 / this))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "23" :op2 "24" :op3 "25"))))) # ::id pmid_2352_4590.55 # ::date 2015-07-26T01:34:15 # ::file pmid_2352_4590_55.txt # ::snt K-Ras and N- Ras are the most frequently mutated, with oncogenic H-Ras being a rare phenomenon.25 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m / mutate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras") :xref (x2 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))) :manner (p / phenomenon :domain (e3 / enzyme :name (n3 / name :op1 "H-Ras") :ARG0-of (c3 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG1-of (r / rare-02)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "25"))) :ARG1-of (f2 / frequent-02 :degree (m2 / most))) # ::id pmid_2352_4590.56 # ::date 2015-07-26T01:50:17 # ::file pmid_2352_4590_56.txt # ::snt While certain genetic lesions common to MM (for example, t(14;16), t(4;14) and hyperdiploidy) are also present in the asymptomatic precursor to MM, monoclonal gammopathy of unknown significance,26 Ras mutations occur almost exclusively in MM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (h / have-concession-91 :ARG1 (m3 / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :location (d / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")) :ARG0-of (e4 / exclusive-02 :mod (a / almost))) :ARG2 (p / present-02 :ARG1 (l / lesion :mod (g / genetics) :mod (c2 / certain) :ARG1-of (s / share-01 :ARG2 d) :example (a3 / and :op1 (t / translocate-01 :ARG2 "16" :ARG3 "14") :op2 (t2 / translocate-01 :ARG2 "14" :ARG3 "4") :op3 (h3 / hyperdiploidy))) :ARG2 (p2 / precursor :mod (s2 / symptom :polarity "-") :location d) :mod (a2 / also) :ARG1-of (m2 / mean-01 :ARG2 (g2 / gammopathy :ARG0-of (s3 / signify-01 :ARG1-of (k / know-01 :polarity "-")) :mod (m4 / monoclone))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 "26"))))) # ::id pmid_2352_4590.57 # ::date 2015-07-26T03:06:23 # ::file pmid_2352_4590_57.txt # ::snt This indicates that Ras mutations are likely to contribute to the transition of the disease from a premalignant state.27 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (i / indicate-01 :ARG0 (t / this) :ARG1 (l / likely-01 :ARG1-of (c / contribute-01 :ARG0 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 (t2 / transition-01 :ARG1 (d / disease) :ARG3 (s / state :mod (p / premalignant))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "27")))) # ::id pmid_2352_4590.58 # ::date 2015-07-26T03:47:40 # ::file pmid_2352_4590_58.txt # ::snt In the case of the t(4:14) lesion that can activate the Ras/MAPK pathway, this raises the interesting possibility that deregulation of the Ras/MAPK pathway in monoclonal gammopathy of unknown significance precedes constitutive MAPK activation associated with Ras mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (r / raise-01 :ARG0 (t2 / this) :ARG1 (p / possible-01 :ARG1 (p4 / precede-01 :ARG1 (d / deregulate-01 :ARG1 "p3" :location (g / gammopathy :mod (m / monoclonal) :ARG0-of (s / signify-01 :ARG1-of (k / know-01 :polarity "-")))) :ARG2 (a2 / activate-01 :ARG1 (p5 / pathway :name (n3 / name :op1 "MAPK")) :ARG1-of (a3 / associate-01 :ARG2 (m2 / mutate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :mod (c2 / constitutive))) :ARG2-of (i / interest-01)) :condition (l / lesion :mod (t / translocate-01 :ARG2 "14" :ARG3 "4") :ARG0-of (a / activate-01 :ARG1 (p3 / pathway :name (n / name :op1 "Ras/MAPK")) :ARG1-of (p2 / possible-01)))) # ::id pmid_2352_4590.59 # ::date 2015-07-26T04:07:18 # ::file pmid_2352_4590_59.txt # ::snt Patients with MM harbouring oncogenic K-Ras often have a worse clinical outcomes compared with those with N-Ras mutations or wild-type Ras 24 This link is exemplified by Ras mutations being associated with the evolution of MM from an intermedullary disease to a more advanced extramedullary phenotype.28 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (m3 / multi-sentence :snt1 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :ARG0-of (h3 / have-03 :ARG1 (d6 / disease :name (n7 / name :op1 "multiple" :op2 "myeloma") :ARG0-of (h5 / harbor-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG0-of (c6 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :xref (x3 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))))) :ARG1 (o / outcome :mod (c2 / clinical) :ARG1-of (b / bad-07 :degree (m / more)) :ARG1-of (c3 / compare-01 :ARG2 (p3 / person :ARG0-of (h6 / have-03 :ARG1 (o3 / or :op1 (m2 / mutate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "N-Ras") :xref (x2 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))) :op2 (e3 / enzyme :name (n4 / name :op1 "Ras") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG0-of (h7 / have-rel-role-91 :ARG2 (p4 / patient))))) :frequency (o2 / often) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 "24")))) :snt2 (e4 / exemplify-01 :ARG0 (m4 / mutate-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (a / associate-01 :ARG2 (e6 / evolve-01 :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")) :ARG2 (p5 / phenotype :mod (e7 / extramedullary) :ARG1-of (a2 / advance-01 :degree (m5 / more))) :ARG3 (d4 / disease :mod (i / intermedullary))))) :ARG1 (l / link-01 :mod (t / this)) :ARG1-of (d5 / describe-01 :ARG0 (p6 / publication :ARG1-of (c5 / cite-01 :ARG2 "28"))))) # ::id pmid_2352_4590.60 # ::date 2015-07-26T04:56:01 # ::file pmid_2352_4590_60.txt # ::snt These observations suggest that aberrant MEK/ERK signalling has an important role in MM disease progression and prognosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (s / suggest-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (h / have-03 :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK") :ARG0-of (s2 / signal-07 :manner (a / aberrant))) :ARG1 (r / role :mod (i / important) :topic (a2 / and :op1 (p2 / progress-01 :ARG1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))) :op2 (p3 / prognosis :mod d2))))) # ::id pmid_2352_4590.61 # ::date 2015-07-26T05:06:28 # ::file pmid_2352_4590_61.txt # ::snt Malignant plasma cell and BMME interactions are thought to contribute to disease progression through the induction of various cytokines and growth factors, a number of which mediate their effects through the Ras/MAPK cascade.5, 29, 30 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (t / think-01 :ARG1 (c / contribute-01 :ARG0 (a / and :op1 (c2 / cell :mod (p / plasma) :ARG1-of (m / malignant-02)) :op2 (i / interact-01 :ARG0 (m2 / microenvironment :mod (m4 / marrow :part-of (b / bone))))) :ARG2 (p2 / progress-01 :ARG1 (d / disease) :manner (i2 / induce-01 :ARG2 (a2 / and :op1 (c3 / cytokine :mod (v / various)) :op2 (f / factor :mod (g / growth)) :quant (n2 / number :ARG0-of (m3 / mediate-01 :ARG1 (a3 / affect-01 :ARG0 a2 :ARG2 (c4 / cascade-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "Ras/MAPK")))))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 (a4 / and :op1 "5" :op2 "29" :op3 "30"))))) # ::id pmid_2352_4590.62 # ::date 2015-07-26T10:27:01 # ::file pmid_2352_4590_62.txt # ::snt In addition to a number of these cytokines being able to activate MEK/ERK via the classical Ras/Raf link, another MAP3K, Tpl2 (Cot, MAP3K8), a known oncogene, has emerged as being important in the cytokine-induced activation of ERK in various cell types, in particular hemopoietic cells.31 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (a / add-02 :ARG1 (g / gene :name (n6 / name :op1 "MAP3K") :mod (a3 / another) :domain (o / oncogene :ARG1-of (k / know-01)) :ARG1-of (m / mean-01 :ARG2 (g2 / gene :name (n8 / name :op1 "Tpl2") :xref (x2 / xref :value "UNIPROT:M3K8_HUMAN" :prob "0.592"))) :ARG0-of (e4 / emerge-02 :ARG1 (i / important :topic (a4 / activate-01 :ARG1 (e5 / enzyme :name (n7 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :location (c4 / cell :ARG1-of (t2 / type-03 :mod (v / various))) :manner (p3 / particular :location (c5 / cell :mod (h / hematopoiesis))) :ARG2-of (i2 / induce-01 :ARG0 (c3 / cytokine))) :domain g)) :xref (x4 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.333")) :ARG2 (n5 / number-01 :ARG1 (c / cytokine :mod (t / this) :ARG0-of (a2 / activate-01 :ARG1 (p2 / pathway :name (n / name :op1 "MEK/ERK")) :manner (l / link-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (e2 / enzyme :name (n4 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :mod (c2 / classical)) :ARG1-of (p / possible-01)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 "31")))) # ::id pmid_2352_4590.63 # ::date 2015-07-28T02:20:52 # ::file pmid_2352_4590_63.txt # ::snt The observation that the tumour necrosis factor receptor superfamily cytokines (tumour necrosis factor-α, BAFF), CD40 and RANK ligands, all of which have been implicate in MM, activate MEK/ERK via Tpl2 raises the likelihood that the MEK/ERK arm of this MAPK pathway can be activated through different MAP3K.32 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (r / raise-01 :ARG0 (o / observe-02 :ARG1 (a3 / activate-01 :ARG0 (a4 / and :op1 (p4 / protein-family :name (n6 / name :op1 "tumour" :op2 "necrosis" :op3 "factor" :op4 "receptor") :ARG2-of (i2 / include-91 :ARG1 (a5 / and :op1 (c4 / cytokine :name (n7 / name :op1 "tumour" :op2 "necrosis" :op3 "factor-α")) :op2 (c5 / cytokine :name (n8 / name :op1 "BAFF"))))) :op2 (l2 / ligand :name (n9 / name :op1 "CD40")) :op3 (l3 / ligand :name (n10 / name :op1 "RANK")) :mod (a6 / all :ARG1-of (i / implicate-01 :ARG2 (d4 / disease :name (n13 / name :op1 "multiple" :op2 "myeloma"))))) :ARG1 (p / pathway :name (n / name :op1 "MEK/ERK")) :instrument (e4 / enzyme :name (n12 / name :op1 "Tpl2") :xref (x2 / xref :value "UNIPROT:M3K8_HUMAN" :prob "0.592")))) :ARG1 (l / likely-01 :ARG1 (p3 / possible-01 :ARG1 (a2 / activate-01 :ARG0 (e3 / enzyme :name (n5 / name :op1 "MAP3K") :ARG1-of (d / differ-02) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.333")) :ARG1 (a / arm :consist-of (s / slash :op1 (e / enzyme :name (n3 / name :op1 "MEK") :xref (x3 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :part-of p)))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "32")))) # ::id pmid_2352_4590.64 # ::date 2015-07-28T02:46:09 # ::file pmid_2352_4590_64.txt # ::snt With aberrant MEK/ERK signalling thought to be important in regulating the growth, survival, migration and drug resistance of MM, it will be interesting to determine if specific MAP3Ks differentially control these particular features of the disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (i / interest-01 :ARG0 (t2 / think-01 :ARG1 (i2 / important :domain (s2 / signal-07 :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK")) :mod (a / aberrant)) :purpose (r / regulate-01 :ARG1 (a2 / and :op1 (g / grow-01 :ARG1 (d3 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :op2 (s3 / survive-01 :ARG0 d3) :op3 (m / migrate-01 :ARG0 d3) :op3 (r2 / resist-01 :ARG0 d3 :ARG1 (d5 / drug)))))) :ARG2 (d / determine-01 :ARG1 (c / control-01 :mode "interrogative" :ARG0 (e / enzyme :name (n2 / name :op1 "MAP3K") :ARG1-of (s / specific-02) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.333")) :ARG1 (f / feature :mod (t / this) :mod (p2 / particular) :poss d3) :manner (d2 / differential)))) # ::id pmid_2352_4590.65 # ::date 2015-07-28T03:05:56 # ::file pmid_2352_4590_65.txt # ::snt Interactions between Bcl-2-like prosurvival and BH3-only pro-apoptotic family members play an integral role in controlling the balance between cell survival and death though the intrinsic apoptosis pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (p / play-08 :ARG0 (i / interact-01 :ARG0 (m / member :ARG0-of (f2 / favor-01 :ARG1 (s / survive-01)) :part-of (f4 / family :ARG1-of (r / resemble-01 :ARG2 (p2 / protein :name (n / name :op1 "Bcl-2") :xref (x / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.701"))))) :ARG1 (m2 / member :part-of (p4 / protein-family :name (n2 / name :op1 "BH3") :mod (o / only)) :ARG0-of (f3 / favor-01 :ARG1 (a2 / apoptosis)))) :ARG1 (c / control-01 :ARG0 i :ARG1 (b2 / balance-01 :ARG1 (s2 / survive-01 :ARG0 (c2 / cell)) :ARG2 (d / die-01 :ARG1 c2)) :ARG2 (p3 / pathway :mod (i3 / intrinsic) :mod a2)) :mod (i2 / integral)) # ::id pmid_2352_4590.66 # ::date 2015-07-28T03:51:41 # ::file pmid_2352_4590_66.txt # ::snt Aberrant expression of these apoptotic regulatory molecules in diverse cancers, including MM, contributes to drug resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contribute-01 :ARG0 (e / express-03 :ARG2 (m / molecule :mod (t / this) :ARG0-of (r / regulate-01 :ARG1 (a2 / apoptosis))) :ARG3 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod (d / diverse) :ARG2-of (i / include-01 :ARG1 (d4 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))) :mod (a / aberrant)) :ARG2 (r2 / resist-01 :ARG1 (d3 / drug))) # ::id pmid_2352_4590.67 # ::date 2015-07-28T03:55:05 # ::file pmid_2352_4590_67.txt # ::snt Importantly, the activity of a number of these proteins is modulated by MEK/ERK signalling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (m / modulate-01 :ARG0 (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK"))) :ARG1 (a / activity-06 :ARG0 (n2 / number :quant-of (p2 / protein :mod (t / this)))) :mod (i / important)) # ::id pmid_2352_4590.68 # ::date 2015-07-28T03:59:46 # ::file pmid_2352_4590_68.txt # ::snt For example, ERK-mediated phosphorylation of the antiapoptotic molecule, Mcl-1, decreases its degradation, thereby promoting cell survival.33 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 29, 2015 (d / decrease-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "Mcl-1") :ARG0-of (c / counter-01 :ARG1 (a / apoptosis)) :xref (x / xref :value "UNIPROT:MCL1_HUMAN" :prob "0.592")) :ARG1-of (m / mediate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1 (d2 / degrade-01 :ARG1 p4) :ARG0-of (c2 / cause-01 :ARG1 (p3 / promote-02 :ARG0 p2 :ARG1 (s / survive-01 :ARG0 (c3 / cell)))) :ARG0-of (e / exemplify-01) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c4 / cite-01 :ARG2 "33")))) # ::id pmid_2352_4590.69 # ::date 2015-07-28T04:08:14 # ::file pmid_2352_4590_69.txt # ::snt With the overexpression of Mcl-1, a common feature of MM associated with greater relapse and shorter survival,34 constitutive MEK/ERK activity almost certainly contributes to elevated Mcl-1 expression in those MM with lesions in the Ras/ERK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contribute-01 :ARG0 (a2 / activity-06 :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK")) :mod (c3 / constitutive)) :ARG1 (o / overexpress-01 :ARG1 "p2" :mod (f / feature :mod (c4 / common) :ARG1-of (a3 / associate-01 :ARG2 (a4 / and :op1 (r / relapse-01 :mod (g2 / great :degree (m2 / more))) :op2 (s / survive-01 :ARG1-of (s2 / short-07 :degree (m3 / more))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "34"))) :poss "d3")) :ARG2 (e / express-03 :ARG1 (p2 / protein :name (n2 / name :op1 "Mcl-1") :xref (x / xref :value "UNIPROT:MCL1_HUMAN" :prob "0.592")) :ARG3 (d3 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma") :mod (t / that) :mod (l / lesion :mod (p3 / pathway :name (n4 / name :op1 "Ras/ERK")))) :ARG1-of (e2 / elevate-01)) :manner (c2 / certain :degree (a / almost))) # ::id pmid_2352_4590.70 # ::date 2015-07-28T04:16:58 # ::file pmid_2352_4590_70.txt # ::snt In contrast, Bim, a proapoptotic Bcl-2 family member that can bind to and neutralize Mcl-1, is targeted by ERK phosphorylation for proteasome-dependent degradation.35 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c / contrast-01 :ARG2 (t / target-01 :ARG0 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1 (p2 / protein :name (n2 / name :op1 "Bim") :ARG0-of (f2 / favor-01 :ARG1 (a / apoptosis)) :ARG1-of (b / bind-01 :ARG2 (p5 / protein :name (n5 / name :op1 "Mcl-1") :xref (x2 / xref :value "UNIPROT:MCL1_HUMAN" :prob "0.592")) :ARG1-of (p6 / possible-01)) :ARG0-of (n6 / neutralize-01 :ARG1 p5 :ARG1-of p6) :ARG1-of (i / include-91 :ARG2 (p4 / protein-family :name (n4 / name :op1 "Bcl-2"))) :xref (x / xref :value "UNIPROT:BIM_HUMAN_PROMOTER_PROBE" :prob "0.671")) :purpose (d / degrade-01 :ARG0-of (d2 / depend-01 :ARG1 (m / macro-molecular-complex :name (n3 / name :op1 "proteasome"))))) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 "35")))) # ::id pmid_2352_4590.71 # ::date 2015-07-28T04:27:07 # ::file pmid_2352_4590_71.txt # ::snt Hence, constitutive ERK signalling is likely to contribute significantly to MM survival by stabilising Mcl-1 and diminishing Bim expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (i / infer-01 :ARG1 (l / likely-01 :ARG1 (c / contribute-01 :ARG0 (s / signal-07 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :mod (c2 / constitutive)) :ARG1 (a / and :op1 (s4 / stabilize-01 :ARG0 s :ARG1 (p / protein :name (n3 / name :op1 "Mcl-1") :xref (x2 / xref :value "UNIPROT:MCL1_HUMAN" :prob "0.592"))) :op2 (d2 / diminish-01 :ARG0 s :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "Bim") :xref (x / xref :value "UNIPROT:BIM_HUMAN_PROMOTER_PROBE" :prob "0.671"))))) :ARG2 (s2 / survive-01 :ARG0 (d3 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma"))) :ARG1-of (s3 / significant-02)))) # ::id pmid_2352_4590.72 # ::date 2015-07-28T04:32:26 # ::file pmid_2352_4590_72.txt # ::snt The activity of other prosurvival (Bcl-2 and Bcl-xL) and proapoptotic (Bad) Bcl-2-like proteins, that are also known to be regulated by ERK signalling, represent additional candidates that may contribute to the enhanced survival of MM cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (r / represent-01 :ARG0 (a / activity-06 :ARG0 (a2 / and :op1 (p / protein :ARG0-of (f / favor-01 :ARG1 (s / survive-01)) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "Bcl-2") :xref (x / xref :value "UNIPROT:A9QXG9_HUMAN" :prob "0.701")) :op2 (p3 / protein :name (n3 / name :op1 "Bcl-xL") :xref (x2 / xref :value "UNIPROT:BCL9_HUMAN" :prob "0.232"))))) :op2 (p4 / protein :ARG0-of (f2 / favor-01 :ARG1 (a4 / apoptosis)) :ARG1-of (m2 / mean-01 :ARG2 (p5 / protein :name (n4 / name :op1 "Bad") :xref (x1 / xref :value "UNIPROT:BAD_HUMAN" :prob "0.604"))) :ARG1-of (r2 / resemble-01 :ARG2 p2)) :mod (o / other) :ARG1-of (r3 / regulate-01 :ARG0 (s2 / signal-07 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (k / know-01 :mod (a5 / also))))) :ARG1 (c / candidate :mod (a6 / additional) :ARG0-of (c2 / contribute-01 :ARG2 (s3 / survive-01 :ARG0 (c3 / cell :mod (d / disease :name (n6 / name :op1 "multiple" :op2 "myeloma"))) :ARG1-of (e2 / enhance-01)) :ARG1-of (p6 / possible-01)))) # ::id pmid_2352_4590.73 # ::date 2015-07-28T04:42:51 # ::file pmid_2352_4590_73.txt # ::snt MEK inhibitors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK")))) # ::id pmid_2352_4590.74 # ::date 2015-07-28T04:44:13 # ::file pmid_2352_4590_74.txt # ::snt MEK1 and MEK2 are homologous dual specificity kinases that share ERK as their only known catalytic substrate,15 making MEK an appealing target for cancer drug development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (k / kinase :mod (h / homologous) :domain (a / and :op1 (k2 / kinase :name (n5 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (k3 / kinase :name (n6 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG0-of (s / share-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :ARG0-of (h2 / have-rel-role-91 :ARG2 (s2 / substrate :ARG0-of (c / catalyze-01) :ARG1-of (k4 / know-01) :mod (o / only) :poss a)) :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "15"))) :ARG0-of (m / make-02 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :ARG1-of (t / target-01 :ARG0-of (a2 / appeal-03 :ARG1 (d4 / develop-02 :ARG1 (d5 / drug :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))))) :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :mod (s3 / specificity :mod (d / dual))) # ::id pmid_2352_4590.75 # ::date 2015-07-28T04:56:03 # ::file pmid_2352_4590_75.txt # ::snt Although many kinase inhibitors target the ATP-binding region of an enzyme, MEK contains a hydrophobic allosteric pocket adjacent to the ATP-binding site that is not shared with other kinases.36 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (h / have-concession-91 :ARG1 (c / contain-01 :ARG0 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1 (p / pocket :mod (a / allosteric) :mod (h2 / hydrophobic) :ARG1-of (s3 / share-01 :polarity "-" :ARG0 e :ARG2 (k2 / kinase :mod (o / other))) :ARG1-of (b2 / border-01 :ARG2 (s2 / site :ARG2-of "b")))) :ARG2 (t2 / target-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (k / kinase)) :quant (m2 / many)) :ARG1 (r / region :ARG2-of (b / bind-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "ATP") :xref (x1 / xref :value "PUBCHEM:5957" :prob "14.368295"))) :part-of (e2 / enzyme))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "36")))) # ::id pmid_2352_4590.76 # ::date 2015-07-28T05:10:34 # ::file pmid_2352_4590_76.txt # ::snt This offers the opportunity to design highly selective inhibitors of MEK that do not simply target the conserved ATP region of the kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (o / offer-01 :ARG0 (t2 / this) :ARG1 (o2 / opportunity :topic (d / design-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :ARG0-of (s / select-01 :ARG1-of (h / high-02)) :ARG0-of (t / target-01 :polarity "-" :ARG1 (r / region :part-of (k / kinase) :mod (s3 / small-molecule :name (n2 / name :op1 "ATP") :xref (x / xref :value "PUBCHEM:5957" :prob "14.368295")) :ARG1-of (c / conserve-01)) :ARG1-of (s2 / simple-02)))))) # ::id pmid_2352_4590.77 # ::date 2015-07-28T05:41:09 # ::file pmid_2352_4590_77.txt # ::snt In the remainder of the review, we describe some of the various MEK inhibitors currently being investigated and their future role in cancer therapy. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d2 / describe-01 :ARG0 (w / we) :ARG1 (a / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))) :ARG1-of (i2 / include-91 :ARG2 (m2 / molecular-physical-entity :ARG0-of i :mod (v / various) :ARG1-of (i3 / investigate-01 :time (c / current))) :ARG3 (s / some))) :op2 (p / play-08 :ARG0 m :ARG1 (t / therapy :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :time (f / future))) :medium (r / remainder :part-of (r2 / review))) # ::id pmid_2352_4590.78 # ::date 2015-07-28T05:48:17 # ::file pmid_2352_4590_78.txt # ::snt Prototypic MEK inhibitors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))) :mod (p / prototype)) # ::id pmid_2352_4590.79 # ::date 2015-07-28T06:14:28 # ::file pmid_2352_4590_79.txt # ::snt Despite demonstrating in vitro activity, major in vivo limitations were identified for the early first generation MEK inhibitors, PD09805937 and U0126.38 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i2 / identify-01 :ARG1 (l / limit-01 :manner (i3 / in-vivo) :ARG1-of (m / major-02)) :location (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"))) :time (e2 / early) :mod (g / generation :ord (o2 / ordinal-entity :value "1")) :ARG1-of (m3 / mean-01 :ARG2 (a / and :op1 (s / small-molecule :name (n2 / name :op1 "PD098059") :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "37")))) :op2 (s2 / small-molecule :name (n3 / name :op1 "U0126") :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "38"))) :xref (x / xref :value "PUBCHEM:3006531" :prob "17.656696"))))) :concession (d3 / demonstrate-01 :ARG0 a :ARG1 (a2 / activity-06 :ARG0 a :manner (i4 / in-vitro)))) # ::id pmid_2352_4590.80 # ::date 2015-07-28T06:20:56 # ::file pmid_2352_4590_80.txt # ::snt Although both compounds were deemed unsuitable for clinical consideration they have proven to be invaluable tools for investigating the Ras/MAPK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (h / have-concession-91 :ARG1 (p / prove-01 :ARG0 "c" :ARG1 (t / tool :domain "c" :ARG1-of (v / value-02 :degree (e / extreme) :purpose (i / investigate-01 :ARG1 (p2 / pathway :name (n / name :op1 "Ras/MAPK")))))) :ARG2 (d / deem-01 :ARG1 (s / suitable-04 :polarity "-" :ARG1 (c / compound :mod (b / both)) :ARG2 (c2 / consider-02 :ARG1 c :manner (c3 / clinic))))) # ::id pmid_2352_4590.81 # ::date 2015-07-28T06:30:07 # ::file pmid_2352_4590_81.txt # ::snt CI-1040 (PD184352) was the first MEK inhibitor to demonstrate tumour inhibitory activity in vivo.39 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))) :ord (o / ordinal-entity :value "1") :domain (s / small-molecule :name (n2 / name :op1 "CI-1040") :ARG1-of (m3 / mean-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD184352") :xref (x / xref :value "PUBCHEM:6918454" :prob "18.013371"))) :xref (x1 / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG0-of (d / demonstrate-01 :ARG1 (a / activity-06 :ARG0 "m" :ARG1 (i2 / inhibit-01 :ARG0 "m" :ARG1 (t / tumor))) :manner (i3 / in-vivo)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "39")))) # ::id pmid_2352_4590.82 # ::date 2015-07-28T06:36:43 # ::file pmid_2352_4590_82.txt # ::snt Encouraging phase I results in advanced cancer patients, where one patient with pancreatic cancer achieved a partial response (PR) lasting 12 months, prompted a phase II study of CI-1040 in patients with advanced solid tumours.40 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (p / prompt-01 :ARG0 (t2 / thing :ARG2-of (r / result-01 :ARG1 (p2 / phase :ord (o / ordinal-entity :value "1"))) :ARG0-of (e / encourage-02) :topic (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG2-of (i / include-91 :ARG1 (p7 / person :ARG0-of h :ARG0-of (a2 / achieve-01 :ARG1 (t4 / thing :ARG2-of (r2 / respond-01 :degree (p9 / part) :duration (t / temporal-quantity :quant "12" :unit (m / month))))) :mod (d3 / disease :wiki "Pancreatic_cancer" :name (n3 / name :op1 "pancreatic" :op2 "cancer")))) :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG1-of (a / advance-01)))) :ARG1 (s / study-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "CI-1040") :xref (x / xref :value "PUBCHEM:6918454" :prob "17.207357")) :mod (p5 / phase :ord (o2 / ordinal-entity :value "2")) :location (p6 / person :ARG0-of h :ARG0-of (h2 / have-03 :ARG1 (t3 / tumor :ARG1-of (s2 / solid-02) :ARG1-of a)))) :ARG1-of (d / describe-01 :ARG0 (p11 / publication :ARG1-of (c3 / cite-01 :ARG2 "40")))) # ::id pmid_2352_4590.83 # ::date 2015-07-28T06:52:25 # ::file pmid_2352_4590_83.txt # ::snt However, in contrast to the phase I trial, no PR was observed.41 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (c3 / contrast-01 :ARG1 (t / trial-06 :mod (p2 / phase :ord (o2 / ordinal-entity :value "1"))) :ARG2 (o / observe-02 :polarity "-" :ARG1 (t2 / thing :ARG2-of (r / respond-01 :degree (p / part))) :ARG1-of (c / contrast-01)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "41")))) # ::id pmid_2352_4590.84 # ::date 2015-07-28T06:58:45 # ::file pmid_2352_4590_84.txt # ::snt As a result of its weak antitumour activity, development of CI-1040 was terminated in favour of the more potent PD0325901. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (t / terminate-01 :ARG1 (d / develop-02 :ARG1 (s / small-molecule :name (n / name :op1 "CI-1040") :xref (x1 / xref :value "PUBCHEM:6918454" :prob "17.207357"))) :purpose (f / favor-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "PD0325901") :mod (p / potent :degree (m3 / more)) :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987"))) :ARG2-of (r / result-01 :ARG1 (a / activity-06 :ARG0 s :ARG1-of (w / weak-02) :ARG0-of (c2 / counter-01 :ARG1 (t2 / tumor))))) # ::id pmid_2352_4590.85 # ::date 2015-07-28T07:05:02 # ::file pmid_2352_4590_85.txt # ::snt Compared with CI-1040, PD0325901 demonstrates significantly improved potency in cell-based assays (100-fold), oral bioavailability and metabolic stability.42 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 29, 2015 (d / demonstrate-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (a / and :op1 (p / potency :ARG1-of (i / improve-02 :ARG2 (p2 / product-of :op1 "100") :ARG1-of (s / significant-02)) :condition (a2 / assay-01 :ARG1-of (b / base-02 :ARG2 (c / cell)))) :op2 (b2 / bioavailability :mod (o / oral)) :op3 (s2 / stability :mod (m2 / metabolize-01))) :compared-to (s4 / small-molecule :name (n2 / name :op1 "CI-1040") :xref (x1 / xref :value "PUBCHEM:6918454" :prob "17.207357")) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "42")))) # ::id pmid_2352_4590.86 # ::date 2015-07-28T07:11:43 # ::file pmid_2352_4590_86.txt # ::snt Phase I investigation of PD0325901 was conducted in 66 advanced cancer patients. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c / conduct-01 :ARG1 (i / investigate-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :mod (p / phase :ord (o / ordinal-entity :value "1"))) :location (p2 / person :quant "66" :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG1-of (a / advance-01)))) # ::id pmid_2352_4590.87 # ::date 2015-07-28T07:15:45 # ::file pmid_2352_4590_87.txt # ::snt Three of 48 evaluable patients with melanoma achieved PR, while 10 had stable disease (s.d.) for ≥4 months. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / contrast-01 :ARG1 (a / achieve-01 :ARG0 (p / person :quant "3" :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (i / include-91 :ARG2 (p3 / person :quant "48" :ARG0-of h :ARG1-of (e / evaluate-01 :ARG1-of (p6 / possible-01)) :mod (m3 / medical-condition :name (n / name :op1 "melanoma"))))) :ARG1 (t2 / thing :ARG2-of (r / respond-01 :degree (p4 / part)))) :ARG2 (h2 / have-03 :ARG0 (p5 / person :quant "10" :ARG0-of h :ARG1-of i) :ARG1 (d2 / disease :ARG1-of (s / stable-03)) :duration (o / or :op1 (t / temporal-quantity :quant "4" :unit (m / month)) :op2 (m2 / more-than :op1 t)))) # ::id pmid_2352_4590.88 # ::date 2015-07-28T07:22:39 # ::file pmid_2352_4590_88.txt # ::snt A subset of these patients developed retinal vein occlusion.43 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (d / develop-01 :ARG1 (s / subset :ARG1-of (i / include-91 :ARG2 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :mod (t / this)))) :ARG2 (o / occlude-01 :ARG1 (v / vein :mod (r / retina))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "43")))) # ::id pmid_2352_4590.89 # ::date 2015-07-28T07:26:30 # ::file pmid_2352_4590_89.txt # ::snt A phase II study of PD0325901 was assessed in 34 advanced non-small cell lung carcinoma patients, but was eventually terminated owing to lack of objective responses and increasing concerns about ocular function and neurotoxicity at therapeutic doses.44 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c / contrast-01 :ARG1 (a / assess-01 :ARG1 (s / study-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :mod (p / phase :ord (o / ordinal-entity :value "2"))) :location (p2 / person :quant "34" :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :mod (c2 / carcinoma :mod (l / lung) :mod (c3 / cell :mod (s2 / small :polarity "-")) :ARG1-of (a2 / advance-01)))) :ARG2 (t / terminate-01 :ARG1 s :time (e / eventual) :ARG1-of (c4 / cause-01 :ARG0 (a3 / and :op1 (l2 / lack-01 :ARG1 (t2 / thing :ARG2-of (r / respond-01) :mod (o2 / objective))) :op2 (c5 / concern-01 :ARG0 (a4 / and :op1 (f / function-01 :ARG0 (e2 / eye)) :op2 (n2 / neurotoxicity)) :ARG1-of (i / increase-01) :condition (d / dose-01 :mod (t3 / therapy)))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 "44")))) # ::id pmid_2352_4590.90 # ::date 2015-07-28T07:38:44 # ::file pmid_2352_4590_90.txt # ::snt Investigation of these treatment-related toxicities was conducted in animal models, where PD0325901 was found to cause retinal vein occlusion in rabbits. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / conduct-01 :ARG1 (i / investigate-01 :ARG1 (t / toxicity :mod (t2 / this) :ARG1-of (r / relate-01 :ARG2 (t3 / treat-04)))) :location (m / model :mod (a / animal) :location-of (f / find-01 :ARG1 (o / occlude-01 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (v / vein :mod (r2 / retina)) :location (r3 / rabbit))))) # ::id pmid_2352_4590.91 # ::date 2015-07-28T07:43:38 # ::file pmid_2352_4590_91.txt # ::snt This adverse effect was attributed to the abrogation of phosphorylated-ERK (p-ERK) within the brain.45 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (a / attribute-01 :ARG1 (a2 / affect-01 :mod (a3 / adverse) :mod (t / this)) :ARG2 (a4 / abrogate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :location (b / brain)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "45")))) # ::id pmid_2352_4590.92 # ::date 2015-07-28T07:46:09 # ::file pmid_2352_4590_92.txt # ::snt In light of these observations, development of PD0325901 has been suspended. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 29, 2015 (s / suspend-01 :ARG1 (d / develop-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987"))) :ARG1-of (c / cause-01 :ARG0 (t / thing :mod (t2 / this) :ARG1-of (o / observe-01)))) # ::id pmid_2352_4590.93 # ::date 2015-07-28T07:47:41 # ::file pmid_2352_4590_93.txt # ::snt MEK inhibitors in development # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / develop-02 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))) # ::id pmid_2352_4590.94 # ::date 2015-07-28T07:48:36 # ::file pmid_2352_4590_94.txt # ::snt AZD6244/ARRY-142886 (selumetinib) is a potent MEK inhibitor that has demonstrated significant tumour suppressive activity in a number of preclinical solid tumour models.46, 47, 48 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p6 / protein-family :name (n / name :op1 "MEK"))) :domain (s5 / small-molecule :name (n2 / name :op1 "AZD6244/ARRY-142886") :ARG1-of (m3 / mean-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.561386")))) :mod (p / potent) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "46")) :op2 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "47")) :op3 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 "48")))) :ARG0-of (d / demonstrate-01 :ARG1 (a / activity-06 :ARG0 "m" :ARG1 (s2 / suppress-01 :ARG0 "m" :ARG1 (t / tumor)) :ARG1-of (s3 / significant-02)) :location (n4 / number :quant-of (m4 / model :mod (t2 / tumor :ARG1-of (s4 / solid-02)) :mod (p2 / preclinical))))) # ::id pmid_2352_4590.95 # ::date 2015-07-28T07:54:32 # ::file pmid_2352_4590_95.txt # ::snt In cell-based enzymatic assays, AZD6244 inhibited purified MEK at an IC50 of 14.1±0.79 nM, with no inhibition observed at 10 μℳ against 40 other kinases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a2 / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244") :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c / concentration-quantity :quant (v / value-interval :op1 (a3 / add-02 :ARG1 "0.79" :ARG2 "14.1") :op2 (s2 / subtract-01 :ARG1 "0.79" :ARG2 "14.1")) :unit (n3 / nanomolar))) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG1 (e / enzyme :name (n2 / name :op1 "MEK") :ARG1-of (p / purify-01) :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :condition (a / assay-01 :ARG1 (e2 / enzyme) :ARG1-of (b / base-02 :ARG2 (c2 / cell)))) :op2 (o / observe-02 :polarity "-" :ARG1 (i3 / inhibit-01) :ARG1-of (c4 / contrast-01 :ARG2 (k / kinase :quant "40" :mod (o3 / other))) :condition (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c3 / concentration-quantity :quant "10" :unit (m / micromolar))))) # ::id pmid_2352_4590.96 # ::date 2015-07-28T08:06:36 # ::file pmid_2352_4590_96.txt # ::snt Cell lines harbouring oncogenic B-Raf and N-Ras mutations displayed enhanced sensitivity to AZD6244, whereas K-Ras mutated tumours showed variable responsiveness.47 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG1 (d / display-01 :ARG0 (c2 / cell-line :ARG0-of (h / harbor-01 :ARG1 (m / mutate-01 :ARG2 (a / and :op1 (e4 / enzyme :name (n5 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op2 (e5 / enzyme :name (n6 / name :op1 "N-Ras") :xref (x / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))) :ARG0-of (c3 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))))) :ARG1 (s2 / sensitive-03 :ARG0 c2 :ARG1 (s / small-molecule :name (n3 / name :op1 "AZD6244") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG1-of (e6 / enhance-01))) :ARG2 (s3 / show-01 :ARG0 (t / tumor :mod (e3 / enzyme :name (n4 / name :op1 "K-Ras") :ARG2-of (m2 / mutate-01) :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG1 (r / responsiveness :ARG1-of (v / vary-01))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 "47")))) # ::id pmid_2352_4590.97 # ::date 2015-07-28T08:13:24 # ::file pmid_2352_4590_97.txt # ::snt In 2004, a total of 57 patients with advanced cancer were treated in a phase I evaluation of AZD6244. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (t / treat-03 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG1-of (t2 / total-01 :ARG2 "57") :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG1-of (a / advance-01)))) :time (d / date-entity :year "2004") :time (e / evaluate-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :mod (p3 / phase :ord (o / ordinal-entity :value "1")))) # ::id pmid_2352_4590.98 # ::date 2015-07-28T08:18:58 # ::file pmid_2352_4590_98.txt # ::snt The best clinical response achieved was s.d. ≥ for 5 months in 9 patients, with 2 patients maintaining s.d. for 19 and 22 months. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (t2 / thing :ARG2-of (r / respond-01) :ARG1-of (g / good-02 :degree (m2 / most)) :mod (c / clinic) :ARG1-of (a / achieve-01) :domain (d / disease :duration (o2 / or :op1 (t3 / temporal-quantity :quant "5" :unit (m3 / month)) :op2 (m5 / more-than :op1 t3)) :location (p / person :quant "9" :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (p3 / person :ARG0-of h :ARG0-of (m6 / maintain-01 :ARG1 "d2") :duration (t4 / temporal-quantity :quant "19" :unit (m4 / month))) :op2 (p4 / person :ARG0-of h :ARG0-of (m7 / maintain-01 :ARG1 (d2 / disease :ARG1-of "s") :duration (t5 / temporal-quantity :quant "22" :unit (m / month))))))) :ARG1-of (s / stable-03))) # ::id pmid_2352_4590.99 # ::date 2015-07-28T08:26:08 # ::file pmid_2352_4590_99.txt # ::snt Similar to PD0325901, blurred vision was reported in 7 patients; however, neurotoxicity was not observed.49 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r2 / report-01 :ARG1 (s2 / see-01 :ARG1-of (b / blur-01)) :location (p / person :quant "7" :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient))) :ARG1-of (r / resemble-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "49"))) :concession-of (o / observe-01 :polarity "-" :ARG1 (n / neurotoxicity))) # ::id pmid_2352_4590.100 # ::date 2015-07-28T08:32:04 # ::file pmid_2352_4590_100.txt # ::snt Several phase II trials have since examined the effectiveness of AZD6244 in a diverse range of solid tumours.50, 51, 52 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / examine-01 :ARG0 (t2 / trial-06 :mod (p / phase :ord (o / ordinal-entity :value "2")) :quant (s3 / several)) :ARG1 (e2 / effective-04 :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG1 (r / range-01 :ARG1 (t / tumor :ARG1-of (s2 / solid-02)) :mod (d / diverse))) :time (s4 / since) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "50")) :op2 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "51")) :op3 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "52"))))) # ::id pmid_2352_4590.101 # ::date 2015-07-28T08:36:40 # ::file pmid_2352_4590_101.txt # ::snt In each of these studies, the efficacy and tolerability of AZD6244 was compared with a conventional chemotherapeutic agent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 4, 2015 (c / compare-01 :ARG1 (a / and :op1 (e / effective-04 :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :op2 (t / tolerate-01 :ARG1 s :ARG1-of (p / possible-01))) :ARG2 (a2 / agent :mod (c2 / conventional) :mod (c3 / chemotherapy)) :manner (s2 / study-01 :mod (e2 / each) :mod (t2 / this))) # ::id pmid_2352_4590.102 # ::date 2015-07-28T05:41:33 # ::file pmid_2352_4590_102.txt # ::snt However, even though some objective responses were observed, AZD6244 failed to demonstrate superior clinical responses over established treatment modalities. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (h / have-concession-91 :ARG2 (f / fail-01 :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG2 (d / demonstrate-01 :ARG0 s :ARG1 (r / respond-01 :ARG1-of (s2 / superior-01 :compared-to (m / modality :mod (t / treat-04) :ARG1-of (e / establish-01))) :mod (c / clinic))) :concession (o / observe-01 :ARG1 (r2 / respond-01 :mod (o2 / objective) :quant (s3 / some))))) # ::id pmid_2352_4590.103 # ::date 2015-07-28T09:33:39 # ::file pmid_2352_4590_103.txt # ::snt As a result of these studies there has not been an advocacy for AZD6244 as a monotherapy. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (a / advocate-01 :polarity "-" :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244") :mod (m / monotherapy) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG2-of (r / result-01 :ARG1 (t / thing :ARG1-of (s2 / study-01) :mod (t2 / this)))) # ::id pmid_2352_4590.104 # ::date 2015-07-28T09:54:00 # ::file pmid_2352_4590_104.txt # ::snt AS703026/MSC1935369 demonstrates IC50 values in the subnanomolar range and potently inhibits tumour growth in vivo.53 Eighty-five advanced cancer patients were recruited for the phase I trial of AS703026. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (m / multi-sentence :snt1 (a / and :op1 (d / demonstrate-01 :ARG0 (s / small-molecule :name (n / name :op1 "AS703026/MSC1935369")) :ARG1 (c / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG1 s) :ARG1-of (r / range-01 :ARG2 (s2 / subnanomolar)))) :op2 (i / inhibit-01 :ARG0 s :ARG1 (g / grow-01 :ARG1 (t2 / tumor)) :manner (p / potent) :manner (i2 / in-vivo)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "53")))) :snt2 (r2 / recruit-01 :ARG1 (p2 / person :quant "85" :ARG0-of (h / have-org-role-91 :ARG2 (p4 / patient)) :mod (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :ARG1-of (a2 / advance-01))) :purpose (t3 / trial-06 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "AS703026") :xref (x / xref :value "PUBCHEM:44187362" :prob "18.349844")) :mod (p3 / phase :ord (o / ordinal-entity :value "1"))))) # ::id pmid_2352_4590.105 # ::date 2015-07-28T10:10:43 # ::file pmid_2352_4590_105.txt # ::snt Visual disturbances were reported in a subset of patients, including some cases of serous macular detachment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (r / report-01 :ARG1 (d / disturb-01 :mod (v / visual) :location (s / subset :ARG2-of (i2 / include-91 :ARG1 (p / person :ARG0-of (h / have-org-role-91 :ARG2 (p2 / patient))))) :ARG2-of (i / include-01 :ARG1 (c / case-04 :ARG1 (d2 / detach-01 :mod (s2 / serum) :mod (m / macular)) :quant (s3 / some))))) # ::id pmid_2352_4590.106 # ::date 2015-07-28T10:16:36 # ::file pmid_2352_4590_106.txt # ::snt Tumour shrinkage was witnessed in four melanoma patients, three of whom (all bearing B-Raf mutations) demonstrated PR.54 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (w / witness-01 :ARG1 (s / shrink-01 :ARG1 (t / tumor)) :location (p / person :quant "4" :ARG2-of (i / include-91 :ARG1 (p2 / person :quant "3" :ARG0-of (d / demonstrate-01 :ARG1 (r / respond-01 :degree (p3 / part))) :ARG0-of (b / bear-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :mod (a / all)) :ARG0-of (h / have-org-role-91 :ARG2 (p5 / patient)))) :mod (m / medical-condition :name (n2 / name :op1 "melanoma"))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "54")))) # ::id pmid_2352_4590.107 # ::date 2015-07-28T10:28:53 # ::file pmid_2352_4590_107.txt # ::snt XL-518/GDC-0973 is a potent, orally bioavailable inhibitor that blocks MEK1 function with an IC50<1 nℳ in enzymatic assays measuring ERK phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01) :domain (s / small-molecule :name (n / name :op1 "XL-518/GDC-0973")) :mod (p / potent) :mod (b / bioavailable :manner (o / oral)) :ARG0-of (b2 / block-01 :ARG1 (f / function-01 :ARG0 (e / enzyme :name (n2 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")))) :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (l / less-than :op1 (c / concentration-quantity :quant "1" :unit (n4 / nanomolar)))) :time (a / assay-01 :ARG1 (e2 / enzyme) :ARG0-of (m2 / measure-01 :manner (p2 / phosphorylate-01 :ARG2 (e3 / enzyme :name (n5 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))) # ::id pmid_2352_4590.108 # ::date 2015-07-28T10:42:50 # ::file pmid_2352_4590_108.txt # ::snt Pharmacodynamic studies have demonstrated that a single dose of GDC-0973 inhibits p-ERK in xenograft tumours for up to 48 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (d / demonstrate-01 :ARG0 (s / study-01 :mod (p / pharmacodynamic)) :ARG1 (i / inhibit-01 :ARG0 (d2 / dose-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "GDC-0973") :xref (x2 / xref :value "PUBCHEM:16222096" :prob "19.10556")) :ARG1-of (s2 / single-02)) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :location (t2 / tumor :mod (x / xenograft)) :duration (u / up-to :op1 (t / temporal-quantity :quant "48" :unit (h / hour))))) # ::id pmid_2352_4590.109 # ::date 2015-07-28T11:13:57 # ::file pmid_2352_4590_109.txt # ::snt In contrast to PD0325901, p-ERK levels in mouse brain tissue were not significantly suppressed following the administration of GDC-0973, suggesting reduced potential for adverse CNS events.55 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (s / suppress-01 :polarity "-" :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :location (t / tissue :mod (b / brain :mod (m / mouse)))) :ARG1-of (s2 / significant-02) :ARG2-of (f / follow-01 :ARG1 (a / administer-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "GDC-0973") :xref (x1 / xref :value "PUBCHEM:16222096" :prob "19.10556")))) :ARG0-of (s4 / suggest-01 :ARG1 (p2 / potential :ARG1-of (r / reduce-01) :beneficiary (e2 / event :mod (s6 / system :mod (n4 / nerve) :mod (c / central)) :mod (a2 / adverse)))) :ARG1-of (c2 / contrast-01 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "PD0325901") :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "55")))) # ::id pmid_2352_4590.110 # ::date 2015-07-28T11:27:35 # ::file pmid_2352_4590_110.txt # ::snt A phase I study of GDC-0972 in patients with solid tumour was initiated in 2007. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / initiate-01 :ARG1 (s / study-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "GDC-0972")) :mod (p / phase :ord (o / ordinal-entity :value "1")) :location (p2 / person :ARG0-of (h / have-03 :ARG1 (t / tumor :ARG1-of (s3 / solid-02))) :ARG0-of (h2 / have-org-role-91 :ARG2 (p3 / patient)))) :time (d / date-entity :year "2007")) # ::id pmid_2352_4590.111 # ::date 2015-07-28T11:37:04 # ::file pmid_2352_4590_111.txt # ::snt Confirmed PR were witnessed in three melanoma patients, two of which harboured B-Raf V600E mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (w / witness-01 :ARG1 (r / respond-01 :ARG1-of (c / confirm-01) :degree (p / part)) :location (p2 / person :quant "3" :ARG2-of (i / include-91 :ARG1 (p3 / patient :quant "2" :ARG0-of (h / harbor-01 :ARG1 (m2 / mutate-01 :value "V600E" :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))))) :ARG0-of (h2 / have-org-role-91 :ARG2 (p4 / patient)) :mod (m / medical-condition :name (n2 / name :op1 "melanoma")))) # ::id pmid_2352_4590.112 # ::date 2015-07-28T11:40:57 # ::file pmid_2352_4590_112.txt # ::snt Six patients with prolonged s.d. (≥5 months) have been observed to date.56 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (o / observe-01 :ARG1 (p / patient :quant "6" :ARG0-of (h / have-03 :ARG1 (d / disease :ARG1-of (s / stable-03) :ARG1-of (p2 / prolong-01 :ARG1-of (m / mean-01 :ARG2 (o2 / or :op1 (e / equal-01 :ARG1 (t2 / temporal-quantity :quant "5" :unit (m2 / month))) :op2 (m3 / more-than :op1 (t3 / temporal-quantity :quant "5" :unit m2)))))))) :time (t / to-date) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "56")))) # ::id pmid_2352_4590.113 # ::date 2015-07-28T11:50:29 # ::file pmid_2352_4590_113.txt # ::snt The MEK inhibitor, BAY869766/RDEA119, specifically inhibits MEK1 (IC50=19 nℳ) and MEK2 (IC50=47 nℳ) when compared with 205 other kinases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a2 / and :op1 (i4 / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "BAY869766/RDEA119") :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"))) :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c2 / concentration-quantity :quant "19" :unit (n5 / nanomolar)))) :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (i / inhibit-01 :ARG0 (s3 / small-molecule :name (n6 / name :op1 "BAY869766/RDEA119") :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (c3 / concentration-quantity :quant "47" :unit (n7 / nanomolar)))) :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))) :ARG1-of (s2 / specific-02) :condition (c / compare-01 :ARG1 s :ARG2 (k / kinase :quant "205" :mod (o / other)))) # ::id pmid_2352_4590.114 # ::date 2015-07-28T12:13:39 # ::file pmid_2352_4590_114.txt # ::snt The antitumour effect of BAY8697655 has been established in mouse xenograft models, with potent growth inhibition observed during drug treatment.57 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (e / establish-01 :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "BAY8697655")) :ARG2 (c2 / counter-01 :ARG1 (t / tumor))) :location (m / model :mod (x / xenograft) :mod (m2 / mouse) :ARG0-of (h / have-03 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01 :mod (p / potent)) :ARG1-of (o2 / observe-01 :time (t2 / treat-03 :ARG3 (d / drug)))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "57")))) # ::id pmid_2352_4590.115 # ::date 2015-07-28T12:32:28 # ::file pmid_2352_4590_115.txt # ::snt Early data from the BAY8679655 phase I trial demonstrates good drug tolerability, with rash being the most prevalent treatment-related adverse effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / demonstrate-01 :ARG0 (d2 / data :time (e / early) :source (t / trial-06 :ARG2 (s / small-molecule :name (n / name :op1 "BAY8679655")) :mod (p / phase :ord (o / ordinal-entity :value "1")))) :ARG1 (a3 / and :op1 (t2 / tolerate-01 :ARG1 (d3 / drug) :ARG1-of (g / good-02) :ARG2-of (e2 / except-01)) :op2 (r / rash :domain (a / affect-01 :mod (a2 / adverse) :ARG1-of (p2 / prevail-02 :degree (m / most)) :ARG1-of (r2 / relate-01 :ARG2 (t3 / treat-03)))))) # ::id pmid_2352_4590.116 # ::date 2015-07-28T12:37:34 # ::file pmid_2352_4590_116.txt # ::snt Among the 69 advanced cancer patients enroled in the trial, 10 achieved s.d. with a mean duration of 10 months. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (a2 / achieve-01 :ARG0 (p2 / person :quant "10" :ARG0-of (h / have-org-role-91 :ARG2 (p3 / patient)) :ARG1-of (i / include-91 :ARG2 (p / person :quant "69" :ARG1-of (e / enroll-01 :ARG2 (t / trial-06)) :ARG0-of h :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG1-of (a / advance-01))))) :ARG1 (d / disease :duration (t2 / temporal-quantity :quant "10" :unit (m / month) :mod (m2 / mean)) :ARG1-of (s / stable-03))) # ::id pmid_2352_4590.117 # ::date 2015-07-28T12:44:24 # ::file pmid_2352_4590_117.txt # ::snt Phase II development of BAY867966 is currently being pursued in light of these findings.58 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (p / pursue-01 :ARG1 (d / develop-01 :ARG2 (s / small-molecule :name (n / name :op1 "BAY867966")) :mod (p2 / phase :ord (o / ordinal-entity :value "2"))) :time (c / current) :ARG1-of (c2 / cause-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "58")))) # ::id pmid_2352_4590.118 # ::date 2015-07-28T12:49:35 # ::file pmid_2352_4590_118.txt # ::snt GSK1120212 is a structurally novel allosteric MEK inhibitor with an in vitro IC50 of 0.4±00.1 nℳ for MEK1 activation by B-Raf and 10±2 nℳ for p-MEK1 activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / small-molecule :name (n / name :op1 "GSK1120212") :mod (a / allosteric) :mod (n3 / novel) :mod (s2 / structural) :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"))) :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG3 (a4 / activate-01 :ARG0 (e3 / enzyme :name (n5 / name :op1 "B-Raf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG1 (e4 / enzyme :name (n6 / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG4 (c / concentration-quantity :quant (v / value-interval :op1 (s3 / subtract-01 :ARG1 "0.001" :ARG2 "0.4") :op2 (a3 / add-02 :ARG1 "0.001" :ARG2 "0.4")) :unit (n9 / nanomolar)) :manner "i2") :ARG1-of (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG3 (a6 / activity-06 :ARG0 (e6 / enzyme :name (n8 / name :op1 "MEK1") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG4 (c2 / concentration-quantity :quant (v2 / value-interval :op1 (s4 / subtract-01 :ARG1 "2" :ARG2 "10") :op2 (a5 / add-02 :ARG1 "2" :ARG2 "10")) :unit (n4 / nanomolar)) :manner (i2 / in-vitro)) :xref (x3 / xref :value "PUBCHEM:11707110" :prob "18.349844")) # ::id pmid_2352_4590.119 # ::date 2015-07-29T12:21:05 # ::file pmid_2352_4590_119.txt # ::snt In cell lines harbouring activating Ras or B-Raf mutations, GSK1120212 inhibited cell proliferation at IC50 values <50 nℳ, but demonstrated decreased activity against those cells with wild-type Ras or wild-type-B-Raf.59 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "GSK1120212") :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (l / less-than :op1 (c2 / concentration-quantity :quant "50" :unit (n3 / nanomolar)))) :xref (x4 / xref :value "PUBCHEM:11707110" :prob "18.349844")) :ARG1 (p / proliferate-01 :ARG0 (c / cell)) :ARG1-of (c6 / contrast-01 :ARG2 (d / demonstrate-01 :ARG0 s :ARG1 (a / activity-06 :ARG0 s :ARG1 (c3 / cell :mod (t2 / that) :ARG0-of (h3 / have-03 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Ras") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n5 / name :op1 "B-Raf") :mod w :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :ARG1-of (d2 / decrease-01)))) :location (c4 / cell-line :ARG0-of (h4 / harbor-01 :ARG1 (o / or :op1 (m / mutate-01 :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG0-of (a3 / activate-01)) :op2 (m2 / mutate-01 :ARG1 (e5 / enzyme :name (n7 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG0-of a3)))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "59")))) # ::id pmid_2352_4590.120 # ::date 2015-07-29T12:47:50 # ::file pmid_2352_4590_120.txt # ::snt These results are consistent with other MEK inhibitors, where cells with constitutively active Ras/MAPK signalling demonstrate a reliance on these oncogenic pathways, thereby making them hypersensitive to MEK inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / consistent-01 :ARG1 (t / thing :ARG2-of (r / result-01)) :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"))) :mod (o / other) :location-of (d / demonstrate-01 :ARG0 (c2 / cell :location-of (s / signal-07 :ARG1 (p2 / pathway :name (n2 / name :op1 "Ras/MAPK")) :ARG0-of (a / activity-06 :manner (c3 / constitutive)))) :ARG1 (r2 / rely-01 :ARG1 (p / pathway :mod (t3 / this) :ARG0-of (c5 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :ARG0-of (c4 / cause-01 :ARG1 (m / make-02 :ARG0 p :ARG1 (s2 / sensitive-03 :ARG0 p :ARG1 (i2 / inhibit-01 :ARG1 p3) :degree (h / hyper)))))))) # ::id pmid_2352_4590.121 # ::date 2015-07-29T13:15:18 # ::file pmid_2352_4590_121.txt # ::snt In melanoma xenografted mouse models, GSK1120212 administered orally once daily demonstrated an effective t1/2 of 36 h with sustained suppression of p-ERK for >24 h.60 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (d / demonstrate-01 :ARG1 (a2 / and :op1 (h3 / have-half-life-01 :ARG1 "s" :ARG2 (t3 / temporal-quantity :quant "36" :unit (h / hour)) :ARG1-of (e / effective-04)) :op2 (s2 / suppress-01 :ARG0 "s" :ARG1 (e3 / enzyme :name (n3 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (s3 / sustain-01) :duration (m / more-than :op1 (t4 / temporal-quantity :quant "24" :unit h)))) :location (m2 / model :mod (m3 / mouse) :ARG1-of (x / xenograft-00) :mod (m4 / medical-condition :name (n2 / name :op1 "melanoma"))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "60"))) :condition (a / administer-01 :ARG1 (s / small-molecule :name (n / name :op1 "GSK1120212") :xref (x2 / xref :value "PUBCHEM:11707110" :prob "18.349844")) :frequency (r / rate-entity-91 :ARG1 "1" :ARG2 (t / temporal-quantity :quant "1" :unit (d2 / day))) :manner (o / oral))) # ::id pmid_2352_4590.122 # ::date 2015-07-29T13:33:33 # ::file pmid_2352_4590_122.txt # ::snt Notably, inhibition of p-ERK was not observed within brain samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (o / observe-01 :polarity "-" :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :location (s / sample-01 :ARG1 (b / brain)) :ARG1-of (n2 / notable-04)) # ::id pmid_2352_4590.123 # ::date 2015-07-29T13:38:49 # ::file pmid_2352_4590_123.txt # ::snt Phase I results of this compound have recently been presented by Gordon et al.61 For 22 patients with B-Raf mutant melanoma, 1 CR and 9 PR were observed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (m / multi-sentence :snt1 (p / present-01 :ARG0 (p3 / publication-91 :ARG0 (a / and :op1 (p4 / person :name (n / name :op1 "Gordon")) :op2 (p5 / person :mod (o / other)))) :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (c / compound-01 :mod (t2 / this))) :mod (p2 / phase :ord (o3 / ordinal-entity :value "1"))) :time (r2 / recent) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 "61")))) :snt2 (o2 / observe-01 :ARG1 (a2 / and :op1 (r3 / respond-01 :quant "1" :ARG1-of (c3 / complete-01)) :op2 (r4 / respond-01 :quant "9" :degree (p9 / part))) :location (p7 / person :quant "22" :ARG0-of (h / have-03 :ARG1 (m4 / medical-condition :name (n3 / name :op1 "melanoma") :mod (e / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))) :ARG0-of (h2 / have-org-role-91 :ARG2 (p8 / patient))))) # ::id pmid_2352_4590.124 # ::date 2015-07-29T13:50:54 # ::file pmid_2352_4590_124.txt # ::snt For 22 patients with pancreatic cancer, 1 PR and 9 s.d. were reported. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / report-01 :ARG1 (a / and :op1 (r2 / respond-01 :quant "1" :degree (p / part)) :op2 (d / disease :quant "9" :ARG1-of (s / stable-03))) :location (p2 / patient :quant "22" :ARG0-of (h / have-03 :ARG1 (d2 / disease :wiki "Pancreatic_cancer" :name (n / name :op1 "pancreatic" :op2 "cancer"))))) # ::id pmid_2352_4590.125 # ::date 2015-07-29T13:55:50 # ::file pmid_2352_4590_125.txt # ::snt Early data from a phase I/II trial examining GSK1120212 in patients with relapsed/refractory myeloid malignancies harbouring Ras mutations has also recently been reported. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / report-01 :ARG1 (d / data :time (e / early) :source (t / trial-06 :mod (s / slash :op1 (p / phase :ord (o / ordinal-entity :value "1")) :op2 (p2 / phase :ord (o2 / ordinal-entity :value "2"))) :ARG0-of (e2 / examine-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "GSK1120212") :xref (x1 / xref :value "PUBCHEM:11707110" :prob "18.349844")) :location (p3 / person :ARG0-of (h / have-03 :ARG1 (s3 / slash :op1 (m / malignancy :mod (m2 / myeloid) :ARG1-of (r2 / relapse-01)) :op2 (m3 / malignancy :mod (r3 / refractory) :mod m2) :ARG0-of (h2 / harbor-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m4 / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG0-of (h3 / have-org-role-91 :ARG2 (p4 / patient)))))) :time (r4 / recent) :mod (a / also)) # ::id pmid_2352_4590.126 # ::date 2015-07-29T14:04:52 # ::file pmid_2352_4590_126.txt # ::snt Patients were prospectively screened for K- and N-Ras mutations before receiving daily treatment with GSK1120212. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / screen-01 :ARG1 (p / person :ARG0-of (h / have-org-role-91 :ARG2 (p3 / patient))) :ARG2 (a / and :op1 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m2 / mutate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")))) :time (b / before :op1 (r / receive-01 :ARG0 p :ARG1 (t / treat-03 :ARG3 (s2 / small-molecule :name (n3 / name :op1 "GSK1120212") :xref (x2 / xref :value "PUBCHEM:11707110" :prob "18.349844"))) :frequency (d / day))) :manner (p2 / prospective)) # ::id pmid_2352_4590.127 # ::date 2015-07-29T14:10:15 # ::file pmid_2352_4590_127.txt # ::snt Encouraging signs of clinical activity with manageable adverse effects have been observed.62 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (o / observe-01 :ARG1 (s / signal-07 :ARG1 (a / activity-06 :mod (c / clinic) :ARG0-of (a2 / affect-01 :mod (a3 / adverse) :ARG1-of (m / manage-01 :ARG1-of (p / possible-01)))) :ARG0-of (e / encourage-01)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "62")))) # ::id pmid_2352_4590.128 # ::date 2015-07-29T14:18:39 # ::file pmid_2352_4590_128.txt # ::snt Enhancing effectiveness with combination therapies # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (e / enhance-01 :ARG1 (e2 / effective-04) :ARG2 (c / combine-01 :ARG1 (t / therapy))) # ::id pmid_2352_4590.129 # ::date 2015-07-29T14:20:20 # ::file pmid_2352_4590_129.txt # ::snt Despite improvements in clinical potency and pharmacokinetics, MEK inhibitors have generally shown limited effectiveness as monotherapeutic agents. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (s / show-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK")))) :ARG1 (e2 / effective-04 :ARG1 (a / agent :mod (m / monotherapeutic)) :ARG1-of (l / limit-01)) :ARG1-of (g / general-02)) :ARG2 (i2 / improve-01 :ARG1 (a2 / and :op2 (p / potency :mod (c / clinic)) :op2 (p2 / pharmacokinetics)))) # ::id pmid_2352_4590.130 # ::date 2015-07-29T14:30:11 # ::file pmid_2352_4590_130.txt # ::snt Several reasons may account for this observation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (p / possible-01 :ARG1 (a / account-01 :ARG0 (r / reason :quant (s / several)) :ARG1 (o / observe-01 :mod (t / this)))) # ::id pmid_2352_4590.131 # ::date 2015-07-29T14:33:39 # ::file pmid_2352_4590_131.txt # ::snt Abrogation of Ras/MAPK signalling appears to be mainly cytostatic, and suggests that an additional therapeutic modality is required to maximise the antitumour effectiveness of MEK inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (a2 / appear-02 :ARG1 (c / cytostatic :mod (m / main) :domain (a3 / abrogate-01 :ARG1 (s2 / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Ras/MAPK")))))) :op2 (s / suggest-01 :ARG0 a3 :ARG1 (r / require-01 :ARG0 (m3 / maximize-01 :ARG1 (e / effective-04 :ARG0 (m4 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK")))) :ARG1 (o / oppose-01 :ARG0 i :ARG1 (t3 / tumor)))) :ARG1 (m2 / modality :mod (t / therapy) :ARG1-of (a4 / add-02))))) # ::id pmid_2352_4590.132 # ::date 2015-07-29T14:46:33 # ::file pmid_2352_4590_132.txt # ::snt In hepatocellular carcinoma xenograft models, AZD6244 in conjunction with doxorubicin demonstrated enhanced growth suppression (76%±7), compared with AZD6244 (52±15%) and doxorubicin (12±9%) alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (d / demonstrate-01 :ARG0 (a / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x4 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "doxorubicin") :xref (x1 / xref :value "PUBCHEM:31703" :prob "15.249751"))) :ARG1 (s3 / suppress-01 :ARG1 (g / grow-01) :ARG1-of (e / enhance-01 :compared-to (a3 / and :op1 (s5 / small-molecule :name (n3 / name :op1 "AZD6244") :quant (p3 / percentage-entity :value "52" :ARG2-of (a4 / add-02 :ARG1 (p4 / percentage-entity :value "15")) :ARG2-of (s7 / subtract-01 :ARG1 p4)) :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s6 / small-molecule :name (n4 / name :op1 "doxorubicin") :quant (p5 / percentage-entity :value "12" :ARG2-of (a5 / add-02 :ARG1 (p6 / percentage-entity :value "9")) :ARG2-of (s8 / subtract-01 :ARG1 p6)) :xref (x2 / xref :value "PUBCHEM:31703" :prob "15.249751")) :mod (a6 / alone))) :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value "76" :ARG2-of (a2 / add-02 :ARG1 (p2 / percentage-entity :value "7")) :ARG2-of (s4 / subtract-01 :ARG1 p2)))) :location (m2 / model :mod (x / xenograft) :mod (h / hepatocellular) :mod (m3 / medical-condition :name (n5 / name :op1 "carcinoma")))) # ::id pmid_2352_4590.133 # ::date 2015-07-29T15:14:31 # ::file pmid_2352_4590_133.txt # ::snt This synergy was associated with increased apoptosis.63 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / associate-01 :ARG1 (s / synergize-01 :mod (t / this)) :ARG2 (a2 / apoptosis :ARG1-of (i / increase-01)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "63")))) # ::id pmid_2352_4590.134 # ::date 2015-07-29T15:17:30 # ::file pmid_2352_4590_134.txt # ::snt Similar effects have been observed with AZD6244 and docetaxel in malignant melanoma,64 and AZD6244 and cytarabine in acute myelogenous leukaemia.65 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (o / observe-01 :ARG1 (a / and :op1 (a2 / affect-01 :ARG0 (a3 / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "docetaxel") :xref (x1 / xref :value "PUBCHEM:148124" :prob "15.881744"))) :ARG1 (m4 / medical-condition :name (n5 / name :op1 "melanoma") :ARG2-of (m2 / malignant-02)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "64"))) :ARG1-of (r / resemble-01)) :op2 (a4 / affect-01 :ARG0 (a5 / and :op1 s :op2 (s3 / small-molecule :name (n3 / name :op1 "cytarabine") :xref (x / xref :value "PUBCHEM:6253" :prob "16.175093"))) :ARG1 (d3 / disease :name (n4 / name :op1 "leukaemia") :mod (m3 / myelogenous) :mod (a6 / acute)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "65"))) :mod r))) # ::id pmid_2352_4590.135 # ::date 2015-07-29T15:28:23 # ::file pmid_2352_4590_135.txt # ::snt The mechanism by which these agents cooperate is not entirely clear, but the available evidence suggests that many of these drugs can activate the Ras/MAPK pathway through diverse processes, thereby increasing the effectiveness of MEK inhibitors.66 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (c / clear-06 :polarity "-" :ARG1 (m / mechanism :instrument-of (c2 / cooperate-01 :ARG0 (a / agent :mod (t / this)))) :mod (e / entire)) :ARG2 (s / suggest-01 :ARG0 (e2 / evidence :ARG2-of (a2 / available-02)) :ARG1 (p / possible-01 :ARG1 (a4 / activate-01 :ARG0 (d / drug :mod t :quant (m2 / many)) :ARG1 (p2 / pathway :name (n / name :op1 "Ras/MAPK")) :instrument (p3 / process-02 :mod (d2 / diverse)) :ARG0-of (c3 / cause-01 :ARG1 (i / increase-01 :ARG1 (e3 / effective-04 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p5 / protein-family :name (n2 / name :op1 "MEK")))))))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "66")))) # ::id pmid_2352_4590.136 # ::date 2015-07-29T15:39:30 # ::file pmid_2352_4590_136.txt # ::snt However, the inhibitory effects of MEK on cell cycle progression may potentially reduce the effectiveness of many standard chemotherapeutic agents in combination therapy, due to the reliance of these agents on killing malignant cells that are rapidly dividing. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (h / have-concession-91 :ARG2 (p / possible-01 :ARG1 (r / reduce-01 :ARG0 (a / affect-01 :ARG0 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1 (p2 / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell))) :ARG2 (i / inhibit-01)) :ARG1 (e2 / effective-04 :ARG0 (a2 / agent :mod (c3 / chemotherapy) :ARG1-of (s / standard-02) :quant (m / many)) :ARG1 (t / therapy :ARG1-of (c4 / combine-01))) :manner (p3 / potential) :ARG1-of (c5 / cause-01 :ARG0 (r2 / rely-01 :ARG0 a2 :ARG1 (k / kill-01 :ARG1 (c6 / cell :ARG1-of (m2 / malignant-02) :ARG1-of (d / divide-02 :manner (r3 / rapid))))))))) # ::id pmid_2352_4590.137 # ::date 2015-07-29T15:48:22 # ::file pmid_2352_4590_137.txt # ::snt Therefore, drug scheduling may have a critical role in the optimal utilisation of MEK inhibitors when combined with traditional chemotherapeutic drugs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / cause-01 :ARG1 (p / possible-01 :ARG1 (h / have-03 :ARG0 (s / schedule-01 :ARG1 (d / drug)) :ARG1 (r / role :ARG1-of (c2 / critical-02 :ARG2 (u / utilize-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))) :mod (o / optimal)) :condition (c3 / combine-01 :ARG1 m :ARG2 (d2 / drug :mod (t2 / traditional) :mod (c4 / chemotherapy)))))))) # ::id pmid_2352_4590.138 # ::date 2015-07-29T15:59:18 # ::file pmid_2352_4590_138.txt # ::snt In this regard, Yu et al.67 have demonstrated that incubating leukaemic cells with paclitaxel before PD98059 exposure significantly increased cell death. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / demonstrate-01 :ARG0 (a / and :op1 (p / person :name (n / name :op1 "Yu")) :op2 (p2 / person :mod (o / other))) :ARG1 (i / increase-01 :ARG0 (i2 / incubate-01 :ARG1 (c2 / cell :mod (l / leukaemic)) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "paclitaxel") :xref (x1 / xref :value "PUBCHEM:4666" :prob "15.068933")) :time (b / before :op1 (e / expose-01 :ARG1 c2 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "PD98059") :xref (x / xref :value "PUBCHEM:4713" :prob "18.349844"))))) :ARG1 (d2 / die-01 :ARG1 (c3 / cell)) :ARG2 (s / significant-02)) :purpose (t / this) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "67")))) # ::id pmid_2352_4590.139 # ::date 2015-07-29T16:09:40 # ::file pmid_2352_4590_139.txt # ::snt In contrast, pretreatment with the MEK inhibitor reduced the susceptibility of cells to paclitaxel-induced apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / contrast-01 :ARG2 (r / reduce-01 :ARG0 (p / pretreat-01 :ARG3 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))))) :ARG1 (s / susceptibility :poss (c2 / cell) :prep-to (a / apoptosis :ARG2-of (i2 / induce-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "paclitaxel") :xref (x / xref :value "PUBCHEM:4666" :prob "15.068933"))))))) # ::id pmid_2352_4590.140 # ::date 2015-07-29T16:17:55 # ::file pmid_2352_4590_140.txt # ::snt Activating mutations within the Ras/MAPK network also contribute to the mechanisms of resistance to MEK inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contribute-01 :ARG0 (m / mutate-01 :ARG0-of (a / activate-01 :location (p / pathway :name (n2 / name :op1 "Ras/MAPK")))) :ARG1 (m2 / mechanism :mod (r / resist-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n3 / name :op1 "MEK")))))) :mod (a2 / also)) # ::id pmid_2352_4590.141 # ::date 2015-07-29T16:22:01 # ::file pmid_2352_4590_141.txt # ::snt A number of studies have demonstrated that oncogenic amplification of K-Ras and B-Raf confers decreased susceptibility to AZD6244.68, 69 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / demonstrate-01 :ARG0 (n / number :quant-of (t / thing :ARG1-of (s / study-01))) :ARG1 (c / confer-01 :ARG0 (a / amplify-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n3 / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG0-of (c3 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG1 (s2 / susceptibility :ARG1-of (d2 / decrease-01) :prep-to (s3 / small-molecule :name (n4 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG0 (a3 / and :op1 "68" :op2 "69"))))) # ::id pmid_2352_4590.142 # ::date 2015-07-29T16:27:35 # ::file pmid_2352_4590_142.txt # ::snt Point mutations within MEK1 may also significantly attenuate the ability of MEK inhibitors to block ERK signalling in B-Raf V600E mutated tumours.70 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p2 / possible-01 :ARG1 (a / attenuate-01 :ARG0 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :mod (p / point)) :ARG1 (c / capable-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK")))) :ARG2 (b / block-01 :ARG0 m3 :ARG1 (s2 / signal-07 :ARG0 (e3 / enzyme :name (n3 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2 (t / tumor :mod (e4 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :ARG1-of (s / significant-02)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 "70"))) :mod (a2 / also)) # ::id pmid_2352_4590.143 # ::date 2015-07-30T08:01:09 # ::file pmid_2352_4590_143.txt # ::snt These oncogenic events result in constitutive ERK pathway activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / result-01 :ARG1 (e / event :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :mod (t / this)) :ARG2 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "ERK")) :mod (c3 / constitutive))) # ::id pmid_2352_4590.144 # ::date 2015-07-30T08:14:05 # ::file pmid_2352_4590_144.txt # ::snt In the absence of oncogenic Ras and Raf mutations, other oncogenic events that engage the Ras/MAPK pathway are also likely to stimulate normal feedback mechanisms that may increase the activity of various intermediaries in the Ras/MAPK signalling module, thereby promoting the ongoing activation of ERK kinase signalling.71 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (l / likely-01 :ARG1 (s / stimulate-01 :ARG0 (e / event :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :mod (o / other) :ARG0-of (e2 / engage-01 :ARG1 (p / pathway :name (n2 / name :op1 "Ras/MAPK")))) :ARG1 (m / mechanism :mod (f / feedback) :ARG1-of (n / normal-02) :ARG0-of (i / increase-01 :ARG1 (a / activity-06 :ARG0 (i2 / intermediary :mod (v / various)) :ARG1 (m2 / module :ARG0-of (s2 / signal-07 :ARG1 p))) :ARG1-of (p2 / possible-01)))) :condition (a2 / absent-01 :ARG1 (a3 / and :op1 (m3 / mutate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (m4 / mutate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG0-of c)) :ARG0-of (p3 / promote-01 :ARG1 (a4 / activate-01 :ARG1 (s3 / signal-07 :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (g / go-on-15))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "71"))) :mod (a5 / also)) # ::id pmid_2352_4590.145 # ::date 2015-07-30T08:16:00 # ::file pmid_2352_4590_145.txt # ::snt For either scenario, the activity of ERK and its target substrates may be maintained at levels that are sufficient to drive key cellular functions even in the presence of a MEK inhibitor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / possible-01 :ARG1 (m / maintain-01 :ARG1 (a / activity-06 :ARG0 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (s / substrate :ARG1-of (t2 / target-01) :poss e3))) :ARG2 (l / level :ARG0-of (s2 / suffice-01 :ARG1 (d2 / drive-02 :ARG0 l :ARG1 (f / function-01 :ARG0 (c / cell) :ARG1-of (k / key-02)) :concession (p2 / present-02 :ARG1 (s4 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK"))))))))) :topic (s3 / scenario :mod (e / either))) # ::id pmid_2352_4590.146 # ::date 2015-07-30T09:37:05 # ::file pmid_2352_4590_146.txt # ::snt These observations suggest that targeting multiple nodes within the Ras/MAPK network may be a more efficacious clinical strategy than single target therapy. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (s / suggest-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (s2 / strategy :mod (c / clinic) :mod (e / efficacious :degree (m2 / more)) :compared-to (t3 / therapy :mod (t4 / target :ARG1-of (s3 / single-02))) :domain (t2 / target-01 :ARG1 (n / node :quant (m / multiple)) :location (p2 / pathway :name (n2 / name :op1 "Ras/MAPK")))))) # ::id pmid_2352_4590.147 # ::date 2015-07-30T11:28:37 # ::file pmid_2352_4590_147.txt # ::snt The contribution of multiple signalling networks to tumorigenesis also accounts for the limited responses seen with MEK inhibitors alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / account-01 :ARG0 (c / contribute-01 :ARG0 (n2 / network :ARG0-of (s / signal-07) :quant (m / multiple)) :ARG2 (c2 / create-01 :ARG1 (t2 / tumor))) :ARG1 (r / respond-01 :ARG1-of (l / limit-01) :ARG1-of (s2 / see-01 :condition (s3 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"))) :mod (a3 / alone)))) :mod (a2 / also)) # ::id pmid_2352_4590.148 # ::date 2015-07-30T12:13:32 # ::file pmid_2352_4590_148.txt # ::snt For example, the phosphatidylinositol 3-kinase (PI3K/Akt/mTOR) and MAPK pathways share Ras as a common upstream effector.72 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (s / share-01 :ARG0 (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "phosphatidylinositol" :op2 "3-kinase") :ARG1-of (m / mean-01 :ARG2 (p2 / pathway :name (n4 / name :op1 "PI3K/Akt/mTOR"))) :xref (x1 / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.701")) :op2 (p3 / pathway :name (n5 / name :op1 "MAPK"))) :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras") :ARG1-of (m2 / mean-01 :ARG2 (e5 / effector :direction (u / upstream))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "72"))) :ARG0-of (e / exemplify-01)) # ::id pmid_2352_4590.149 # ::date 2015-07-30T12:14:07 # ::file pmid_2352_4590_149.txt # ::snt Consequently, activation of Ras, despite the downregulation of ERK activity by MKPs and SPRYs, could lead to compensatory signalling through this parallel network. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 31, 2015 (c2 / cause-01 :ARG1 (p2 / possible-01 :ARG1 (l / lead-03 :ARG0 (a / activate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :concession (d / downregulate-01 :ARG1 (a2 / activity-06 :ARG0 (e4 / enzyme :name (n5 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2 (a3 / and :op1 (e5 / enzyme :name (n6 / name :op1 "MKP") :xref (x1 / xref :value "UNIPROT:DUS1_HUMAN" :prob "0.262")) :op2 (p4 / protein :name (n7 / name :op1 "SPRY") :xref (x / xref :value "UNIPROT:SPY1_HUMAN" :prob "0.312"))))) :ARG2 (s / signal-07 :ARG0-of (c / compensate-01) :instrument (n4 / network :mod (p3 / parallel) :mod (t / this)))))) # ::id pmid_2352_4590.150 # ::date 2015-07-30T12:14:29 # ::file pmid_2352_4590_150.txt # ::snt Alternatively, oncogenic mutations within the PI3K/Akt axis may enhance MEK/ERK signal transduction. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (p2 / possible-01 :ARG1 (e / enhance-01 :ARG0 (m / mutate-01 :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :location (a2 / axis :mod (p / pathway :name (n / name :op1 "PI3K/Akt")))) :ARG1 (t / transduce-01 :ARG1 (s / signal-07 :ARG0 (p3 / pathway :name (n2 / name :op1 "MEK/ERK"))))) :manner (a / alternative)) # ::id pmid_2352_4590.151 # ::date 2015-07-30T12:14:47 # ::file pmid_2352_4590_151.txt # ::snt Indeed, dysregulation of the PI3K/Akt pathway has been shown to correlate with the decreased sensitivity to MEK inhibition.73 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (s / show-01 :ARG1 (c / correlate-01 :ARG1 (d / dysregulate-01 :ARG1 (p2 / pathway :name (n3 / name :op1 "PI3K/Akt"))) :ARG2 (s2 / sensitive-03 :ARG1 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1-of (d2 / decrease-01))) :mod (i2 / indeed) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "73")))) # ::id pmid_2352_4590.152 # ::date 2015-07-30T12:15:06 # ::file pmid_2352_4590_152.txt # ::snt Predictably targeting both pathways simultaneously has proven effective in several studies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 15, 2015 (p / prove-01 :ARG1 (e / effective-04 :ARG0 (t / target-01 :ARG1 (p2 / pathway :mod (b / both)) :manner (s / simultaneous))) :medium (t2 / thing :ARG1-of (s2 / study-01) :quant (s3 / several)) :ARG1-of (p3 / predict-01 :ARG1-of (p4 / possible-01))) # ::id pmid_2352_4590.153 # ::date 2015-07-30T12:15:39 # ::file pmid_2352_4590_153.txt # ::snt In AZD6244-resistant gastric cancer cell lines, activation of Akt through the EGFR/PI3K/Akt pathway was still observed following MEK inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (o / observe-01 :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :instrument (p / pathway :name (n4 / name :op1 "EGFR/PI3K/Akt"))) :mod (s / still) :ARG1-of (f / follow-01 :ARG2 (i / inhibit-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :location (c / cell-line :ARG0-of (r / resist-01 :ARG1 (s3 / small-molecule :name (n6 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :source (d / disease :wiki "Stomach_cancer" :name (n / name :op1 "stomach" :op2 "cancer")))) # ::id pmid_2352_4590.154 # ::date 2015-07-30T12:15:55 # ::file pmid_2352_4590_154.txt # ::snt Blockade of this pathway using the EGFR inhibitor, gefitinib, synergistically enhanced tumour apoptosis in vitro and in vivo.74 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (e2 / enhance-01 :ARG0 (b / blockade-01 :ARG1 (p / pathway :mod (t2 / this)) :ARG2 (s3 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :ARG1-of (m2 / mean-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "gefitinib") :xref (x1 / xref :value "PUBCHEM:123631" :prob "16.963549"))))) :ARG1 (a / apoptosis :poss (t / tumor)) :manner (s2 / synergize-01) :manner (a2 / and :op1 (i3 / in-vitro) :op2 (i4 / in-vivo)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "74")))) # ::id pmid_2352_4590.155 # ::date 2015-07-30T12:16:15 # ::file pmid_2352_4590_155.txt # ::snt Treatment of mutant murine lung cancers with the dual PI3K/mTOR inhibitor, NVP-BEZ235 and AZD6244 produced similar results.75 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (p / produce-01 :ARG0 (t3 / treat-04 :ARG1 (d3 / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer") :mod (o / organism :name (n5 / name :op1 "Muridae")) :ARG2-of (m2 / mutate-01)) :ARG2 (s2 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3K/mTOR"))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (s3 / small-molecule :name (n3 / name :op1 "NVP-BEZ235") :xref (x / xref :value "PUBCHEM:11977753" :prob "20.132469")) :op2 (s4 / small-molecule :name (n4 / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")))) :mod (d2 / dual))) :ARG1 (t2 / thing :ARG2-of (r2 / result-01) :ARG1-of (r3 / resemble-01)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "75")))) # ::id pmid_2352_4590.156 # ::date 2015-07-30T12:16:34 # ::file pmid_2352_4590_156.txt # ::snt Recently, preliminary results from a phase I trial evaluating the combined activity of GDC-0973/XL-518 and the Akt inhibitor, GDC-0941, found that in a cohort of 27 advanced solid tumour patients, three patients achieved prolonged s.d. ≥6 months when treated with both agents.76 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (t3 / thing :ARG2-of (r / result-01 :ARG1 (t4 / trial-06 :mod (p2 / phase :ord (o / ordinal-entity :value "1")) :ARG0-of (e / evaluate-01 :ARG1 (a / activity-06 :ARG0 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "GDC-0973/XL-518")) :op2 (s2 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p6 / protein-family :name (n3 / name :op1 "Akt"))) :ARG1-of (m2 / mean-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "GDC-0941") :xref (x / xref :value "PUBCHEM:17755052" :prob "19.120691"))))) :ARG3-of (c3 / combine-01))))) :mod (p / preliminary)) :ARG1 (a3 / achieve-01 :ARG0 (p3 / person :quant "3" :part-of (c / cohort :consist-of (p7 / person :quant "27" :mod (t / tumor :ARG1-of (s5 / solid-02) :ARG1-of (a5 / advance-01)) :ARG0-of "h")) :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient))) :ARG1 (d2 / disease :ARG1-of (p4 / prolong-01) :ARG1-of (s4 / stable-03) :duration (o2 / or :op1 (t2 / temporal-quantity :quant "6" :unit (m / month)) :op2 (m3 / more-than :op1 t2))) :condition (t6 / treat-03 :ARG1 p3 :ARG3 (a4 / agent :mod (b / both)))) :time (r2 / recent) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 "76")))) # ::id pmid_2352_4590.157 # ::date 2015-07-30T12:16:51 # ::file pmid_2352_4590_157.txt # ::snt Promising clinical activity has also been observed in the phase I trial of GSK1120212 in conjunction with the Akt inhibitor, GSK2141795.77 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o / observe-01 :ARG1 (a / activity-06 :mod (c / clinic) :ARG2-of (p / promise-01)) :location (t / trial-06 :ARG2 (a3 / and :op1 (s / small-molecule :name (n / name :op1 "GSK1120212") :xref (x1 / xref :value "PUBCHEM:11707110" :prob "18.349844")) :op2 (s2 / small-molecule :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "Akt"))) :ARG1-of (m / mean-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "GSK2141795") :xref (x / xref :value "PUBCHEM:51042438" :prob "18.86067"))))) :mod (p2 / phase :ord (o2 / ordinal-entity :value "1")) :manner (c2 / conjunction)) :mod (a2 / also) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "77")))) # ::id pmid_2352_4590.158 # ::date 2015-07-30T12:22:39 # ::file pmid_2352_4590_158.txt # ::snt The number of preclinical and clinical studies investigating dual Ras/MAPK and PI3K/Akt inhibition indicates a growing trend to using these combinations to maximise antitumour response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Oct 15, 2015 (i / indicate-01 :ARG0 (n2 / number :quant-of (a3 / and :op1 (s / study-01 :mod (p2 / preclinical)) :op2 (s2 / study-01 :mod (c / clinical)) :ARG0-of (i2 / investigate-01 :ARG1 (i3 / inhibit-01 :ARG1 (a2 / and :op1 (p3 / pathway :name (n3 / name :op1 "Ras/MAPK")) :op2 (p4 / pathway :name (n4 / name :op1 "PI3K/Akt"))) :mod (d / dual))))) :ARG1 (t2 / trend-01 :ARG2 (u / use-01 :ARG1 (c2 / combine-01 :mod (t3 / this)) :ARG2 (m / maximize-01 :ARG1 (r / respond-01 :ARG2 (c3 / counter-01 :ARG1 (t4 / tumor))))) :ARG1-of (g / grow-01))) # ::id pmid_2352_4590.159 # ::date 2015-07-30T12:22:56 # ::file pmid_2352_4590_159.txt # ::snt Aberrant signalling through additional kinase pathways may also contribute to MEK inhibitor resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / possible-01 :ARG1 (c / contribute-01 :ARG0 (s / signal-07 :manner (p2 / pathway :mod (k / kinase) :mod (a2 / additional)) :manner (a / aberrant)) :ARG2 (r / resist-01 :ARG1 (s2 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"))))) :mod (a3 / also))) # ::id pmid_2352_4590.160 # ::date 2015-07-31T01:39:05 # ::file pmid_2352_4590_160.txt # ::snt For example, although non-small cell lung carcinomas carry both K-Ras and PTEN mutations, resistance of these cell lines to AZD6244 coincides with activation of the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT) following MEK inhibition.78 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (c / coincide-01 :ARG1 (r / resist-01 :ARG0 (c2 / cell-line :mod (t2 / this)) :ARG1 (s2 / small-molecule :name (n4 / name :op1 "AZD6244") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :ARG2 (a2 / activate-01 :ARG1 (p / pathway :name (n5 / name :op1 "Janus" :op2 "kinase/signal" :op3 "transducer" :op4 "and" :op5 "activator" :op6 "of" :op7 "transcription")) :ARG1-of (f / follow-01 :ARG2 (i / inhibit-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :ARG0-of (e4 / exemplify-01) :concession (c3 / carry-01 :ARG0 (c4 / carcinoma :mod (l / lung) :mod (c6 / cell :polarity "-" :mod (s / small))) :ARG1 (a3 / and :op1 (m / mutate-01 :ARG1 (e6 / enzyme :name (n7 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m2 / mutate-01 :ARG1 (p3 / protein :name (n8 / name :op1 "PTEN") :xref (x2 / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "78")))) # ::id pmid_2352_4590.161 # ::date 2015-07-31T02:03:21 # ::file pmid_2352_4590_161.txt # ::snt AZD6244 combined with STAT3 inhibition synergistically induced apoptosis in these cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (i / induce-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD6244") :ARG1-of (c / combine-01 :ARG2 (i2 / inhibit-01 :ARG1 (p / protein :name (n3 / name :op1 "STAT3") :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")))) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG2 (a2 / apoptosis :location (c2 / cell :mod (t / this))) :manner (s / synergize-01)) # ::id pmid_2352_4590.162 # ::date 2015-07-31T02:08:52 # ::file pmid_2352_4590_162.txt # ::snt This effect can be explained by STAT3 suppressing the proapoptotic protein Bim through upregulation of miRNA-17, which antagonises the Bim expression induced by AZD6244.79 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p / possible-01 :ARG1 (e / explain-01 :ARG0 (p2 / protein :wiki "STAT3" :name (n / name :op1 "STAT3") :ARG0-of (s / suppress-01 :ARG1 (p3 / protein :wiki "BCL2L11" :name (n2 / name :op1 "Bim") :ARG0-of (f / favor-01 :ARG1 (a2 / apoptosis)) :xref (x1 / xref :value "UNIPROT:BIM_HUMAN_PROMOTER_PROBE" :prob "0.671")) :instrument (u / upregulate-01 :ARG1 (n5 / nucleic-acid :wiki "Mir-17_microRNA_precursor_family" :name (n3 / name :op1 "miRNA-17")) :ARG1-of (a3 / antagonize-02 :ARG2 (e2 / express-03 :ARG2 p3 :ARG2-of (i / induce-01 :ARG0 (s2 / small-molecule :wiki "Selumetinib" :name (n4 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056"))))))) :xref (x / xref :value "UNIPROT:STAT3_HUMAN" :prob "1.004")) :ARG1 (a / affect-01 :mod (t / this))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 "79")))) # ::id pmid_2352_4590.163 # ::date 2015-07-31T02:27:12 # ::file pmid_2352_4590_163.txt # ::snt Collectively, these results provide a rationale for combining inhibitors of the JAK/STAT pathway and MEK inhibitors to reduce the potential impact of drug resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / provide-01 :ARG0 (t2 / thing :ARG2-of (r / result-01) :mod (t / this)) :ARG1 (r2 / rationale) :ARG2 (c2 / combine-01 :ARG1 (s / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "JAK/STAT")))) :ARG2 (s2 / small-molecule :ARG0-of (i3 / inhibit-01 :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK")))) :purpose (r3 / reduce-01 :ARG1 (i4 / impact-01 :ARG0 (r4 / resist-01 :ARG1 (d / drug)) :mod (p3 / potential)))) :manner (c / collective)) # ::id pmid_2352_4590.164 # ::date 2015-07-31T02:35:14 # ::file pmid_2352_4590_164.txt # ::snt Information about the use of MEK inhibitors and other kinase pathway inhibitors is unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (k / know-01 :polarity "-" :ARG1 (i2 / information :topic (u / use-01 :ARG1 (a / and :op1 (s / small-molecule :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK")))) :op2 (s2 / small-molecule :ARG0-of (i4 / inhibit-01 :ARG1 (p / pathway :mod (k2 / kinase) :mod (o / other)))))))) # ::id pmid_2352_4590.165 # ::date 2015-07-31T02:39:57 # ::file pmid_2352_4590_165.txt # ::snt The role of MEK inhibitors in MM # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / role :poss (s / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK")))) :topic (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))) # ::id pmid_2352_4590.166 # ::date 2015-07-31T02:45:26 # ::file pmid_2352_4590_166.txt # ::snt The advent of novel anti-MM agents has improved the management and prognosis of MM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 16, 2015 (i / improve-01 :ARG0 (a / advent :mod (a2 / agent :ARG0-of (c / counter-01 :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))) :mod (n / novel))) :ARG1 (a3 / and :op1 (m2 / manage-01 :ARG1 d) :op2 (p / prognosis :topic d))) # ::id pmid_2352_4590.167 # ::date 2015-07-31T02:52:04 # ::file pmid_2352_4590_167.txt # ::snt With the immunomodulatory drugs, thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib, able to abrogate the survival advantage created by the BMME, current research has focussed on combining these novel therapies to improve patient outcomes.80 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (f / focus-01 :ARG0 (r / research-01 :mod (c / current)) :ARG2 (c2 / combine-01 :ARG1 (t2 / therapy :mod (n / novel) :mod (t / this))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "80"))) :ARG1-of (c6 / cause-01 :ARG0 (a / and :op1 (d / drug :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (s3 / small-molecule :name (n3 / name :op1 "thalidomide") :xref (x / xref :value "PUBCHEM:5426" :prob "16.152618")) :op2 (s4 / small-molecule :name (n4 / name :op1 "lenalidomide") :xref (x2 / xref :value "PUBCHEM:216326" :prob "17.251232")))) :ARG0-of (i / immunomodulate-00)) :op2 (s / small-molecule :ARG0-of (i4 / inhibit-01 :ARG1 (m3 / macro-molecular-complex :name (n2 / name :op1 "proteasome"))) :ARG1-of (m4 / mean-01 :ARG2 (s5 / small-molecule :name (n5 / name :op1 "bortezomib") :xref (x1 / xref :value "PUBCHEM:387447" :prob "17.186693")))) :ARG1-of (c3 / capable-01 :ARG2 (a3 / abrogate-01 :ARG1 (a4 / advantage :mod (s2 / survive-01) :ARG1-of (c4 / create-01 :ARG0 (m / microenvironment :mod (m5 / marrow :part-of (b / bone))))))))) :purpose (i2 / improve-01 :ARG0 r :ARG1 (o / outcome :poss (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)))))) # ::id pmid_2352_4590.168 # ::date 2015-07-31T03:31:18 # ::file pmid_2352_4590_168.txt # ::snt To date, promising results have been obtained in several clinical trials.81, 82 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (o / obtain-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG2-of (p / promise-01)) :ARG2 (t2 / trial-06 :mod (c / clinic) :quant (s / several)) :time (t3 / to-date) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "81" :op2 "82"))))) # ::id pmid_2352_4590.169 # ::date 2015-07-31T03:35:45 # ::file pmid_2352_4590_169.txt # ::snt However, despite the clinical success of thalidomide, lenalidomide and bortezomib, a subset of patients do not initially respond to or ultimately become refractory to these agents.83 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-concession-91 :ARG1 (o / or :op1 (r / respond-01 :polarity "-" :ARG0 (p / person :ARG1-of (i2 / include-91 :ARG2 (s / subset)) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient))) :ARG1 "a" :time (i / initial)) :op2 (b / become-01 :ARG1 p :ARG2 (r2 / refractory :prep-to (a / agent :mod (t / this) :ARG1-of (m / mean-01 :ARG2 "a2"))) :manner (u / ultimate))) :ARG2 (s2 / succeed-01 :ARG0 (a2 / and :op1 (s3 / small-molecule :name (n / name :op1 "thalidomide") :xref (x / xref :value "PUBCHEM:5426" :prob "16.152618")) :op2 (s4 / small-molecule :name (n2 / name :op1 "lenalidomide") :xref (x2 / xref :value "PUBCHEM:216326" :prob "17.251232")) :op3 (s5 / small-molecule :name (n3 / name :op1 "bortezomib") :xref (x1 / xref :value "PUBCHEM:387447" :prob "17.186693"))) :mod (c / clinic)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "83")))) # ::id pmid_2352_4590.170 # ::date 2015-07-31T04:05:20 # ::file pmid_2352_4590_170.txt # ::snt This emphasises the need for innovative anti-MM therapies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 16, 2015 (e / emphasize-01 :ARG0 (t / this) :ARG1 (n / need-01 :ARG1 (t2 / therapy :ARG1-of (i / innovate-01) :ARG0-of (c / counter-01 :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))))) # ::id pmid_2352_4590.171 # ::date 2015-07-31T04:09:13 # ::file pmid_2352_4590_171.txt # ::snt The impact of AZD6244 has been investigated in MM cells within the BMME.84 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 16, 2015 (i / investigate-01 :ARG1 (i2 / impact-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :location (c / cell :part-of (m / microenvironment :mod (m2 / marrow :part-of (b / bone))) :source (d2 / disease :name (n / name :op1 "multiple" :op2 "myeloma"))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "84")))) # ::id pmid_2352_4590.172 # ::date 2015-07-31T04:12:34 # ::file pmid_2352_4590_172.txt # ::snt This compound specifically abrogated constitutive and cytokine-stimulated ERK phosphorylation and induced cytotoxicity in a panel of human myeloma cell lines (HMCL). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (a2 / abrogate-01 :ARG0 (c3 / compound :mod (t / this)) :ARG1 (a3 / and :op1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :mod (c / constitutive)) :op2 (p3 / phosphorylate-01 :ARG1 e2 :ARG1-of (s / stimulate-01 :ARG0 (c5 / cytokine)))) :ARG1-of (s2 / specific-02)) :op2 (i / induce-01 :ARG0 c3 :ARG2 (c2 / cytotoxicity)) :location (p5 / panel :consist-of (c4 / cell-line :mod (d / disease :name (n / name :op1 "myeloma") :mod (h / human))))) # ::id pmid_2352_4590.173 # ::date 2015-07-31T04:30:45 # ::file pmid_2352_4590_173.txt # ::snt Responses to AZD6244 were also witnessed in tumour cells derived from MM patients with advanced disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (w / witness-01 :ARG1 (t / thing :ARG2-of (r / respond-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")))) :mod (a / also) :location (c / cell :mod (t2 / tumor) :ARG1-of (d / derive-01 :ARG2 (p / patient :mod (d3 / disease :name (n / name :op1 "multiple" :op2 "myeloma") :ARG1-of (a2 / advance-01)))))) # ::id pmid_2352_4590.174 # ::date 2015-07-30T10:46:07 # ::file pmid_2352_4590_174.txt # ::snt These results suggest that AZD6244 is effective at advanced stages of disease, where MM cells are less reliant on the growth factors produced by the BMME. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (e / effective-04 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :time (s3 / stage-02 :ARG1 (d / disease) :ARG1-of (a / advance-01) :time-of (r2 / rely-01 :ARG0 (c / cell :mod (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :ARG2 (g / growth-factor :ARG1-of (p / produce-01 :ARG0 (m / microenvironment :mod (m2 / marrow :mod (b / bone))))) :degree (l / less))))) # ::id pmid_2352_4590.175 # ::date 2015-07-30T11:01:57 # ::file pmid_2352_4590_175.txt # ::snt Furthermore, culturing of HMCL and patient-derived samples in the presence of exogenous interleukin-6 or bone marrow stromal cells did not protect against AZD6244-induced apoptosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (a / and :op2 (p / protect-01 :polarity "-" :ARG0 (c / culture-01 :ARG1 (a2 / and :op1 (c2 / cell-line :mod (d3 / disease :name (n4 / name :op1 "myeloma") :mod (h / human))) :op2 (t / thing :ARG1-of (d2 / derive-01 :ARG2 (p2 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p4 / patient)))) :ARG1-of (s / sample-01))) :condition (p5 / present-02 :ARG1 (o / or :op1 (p6 / protein :name (n / name :op1 "interleukin-6") :mod (e / exogenous) :xref (x / xref :value "UNIPROT:IL6_HUMAN" :prob "0.703")) :op2 (c3 / cell :mod (s2 / stroma :mod (m / marrow :mod (b / bone))))))) :ARG2 (a3 / apoptosis :ARG2-of (i / induce-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")))))) # ::id pmid_2352_4590.176 # ::date 2015-07-30T11:10:54 # ::file pmid_2352_4590_176.txt # ::snt Synergistically enhanced cell death was noted in combinations of AZD6244 with conventional (dexamethasone) and novel (bortezomib, lenalidomide, perifisone) anti-MM agents. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (n / note-01 :ARG1 (d / die-01 :ARG1 (c / cell) :ARG1-of (e / enhance-01 :manner (s / synergize-01))) :location (c2 / combine-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG2 (a / and :op1 (a2 / agent :ARG0-of (c3 / counter-01 :ARG1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))) :mod (c4 / conventional) :ARG2-of (i / include-91 :ARG1 (d3 / dexamethasone))) :op2 (a3 / agent :ARG0-of c3 :mod (n4 / novel) :ARG2-of (i2 / include-91 :ARG1 (a4 / and :op1 (s3 / small-molecule :name (n5 / name :op1 "bortezomib") :xref (x / xref :value "PUBCHEM:387447" :prob "17.186693")) :op2 (s4 / small-molecule :name (n6 / name :op1 "lenalidomide") :xref (x2 / xref :value "PUBCHEM:216326" :prob "17.251232")) :op3 (s5 / small-molecule :name (n7 / name :op1 "perifisone")))))))) # ::id pmid_2352_4590.177 # ::date 2015-07-30T11:22:25 # ::file pmid_2352_4590_177.txt # ::snt AZD6244 as a single agent was also examined in an in vivo human plasmocytoma xenograft model and demonstrated prolonged survival when compared with control animals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (a / and :op1 (e / examine-01 :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :manner (a2 / agent :ARG1-of (s2 / single-02)) :mod (a3 / also) :location (x2 / xenograft :manner (i / in-vivo) :mod (m / model) :mod (p2 / plasmocytoma) :mod (h / human))) :op2 (d / demonstrate-01 :ARG0 s :ARG1 (s3 / survive-01 :ARG1-of (p / prolong-01) :compared-to (a4 / animal :mod (c / control))))) # ::id pmid_2352_4590.178 # ::date 2015-07-30T11:30:32 # ::file pmid_2352_4590_178.txt # ::snt Breitkreutz et al.85 have also investigated the consequences of AZD6244 administration on osteoclast differentiation, function and cytokine secretion in MM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / investigate-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Breitkreutz")) :op2 (p3 / person :mod (o / other))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "85")))) :ARG1 (c2 / consequence :poss (a3 / administer-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :prep-on (a4 / and :op1 (d / differentiate-01 :mod (o2 / osteoclast)) :op2 (f / function-01 :mod o2) :op3 (s2 / secrete-01 :ARG1 (p4 / protein :name (n3 / name :op1 "cytokine") :xref (x / xref :value "UNIPROT:RED_HUMAN" :prob "0.342")) :mod o2)) :location (m / multiple :name (n4 / name :op1 "myeloma"))) :mod (a2 / also)) # ::id pmid_2352_4590.179 # ::date 2015-07-30T11:47:02 # ::file pmid_2352_4590_179.txt # ::snt AZD6244 blocked osteoclast differentiation and bone reabsorption in a dose-dependent manner. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (b / block-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG1 (a / and :op1 (d / differentiate-01 :ARG1 (o / osteoclast)) :op2 (r / reabsorb-00 :ARG1 (b2 / bone))) :manner (d2 / depend-01 :ARG1 (d3 / dose))) # ::id pmid_2352_4590.180 # ::date 2015-07-30T11:52:34 # ::file pmid_2352_4590_180.txt # ::snt Furthermore, critical MM growth factors produced by the BMME, including interleukin-6, BAFF, APRIL and MIP-1α were all significantly reduced following AZD6244 treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (a / and :op2 (r / reduce-01 :ARG1 (g / growth-factor :mod (d / disease :name (n9 / name :op1 "multiple" :op2 "myeloma")) :ARG1-of (c / critical-02) :ARG1-of (p / produce-01 :ARG0 (m / microenvironment :mod (m2 / marrow :mod (b / bone)))) :mod (a3 / all) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (p2 / pritein :name (n / name :op1 "interleukin-6")) :op2 (p3 / protein :name (n4 / name :op1 "BAFF") :xref (x1 / xref :value "UNIPROT:TN13B_HUMAN" :prob "1.002")) :op3 (p4 / protein :name (n5 / name :op1 "APRIL") :xref (x / xref :value "UNIPROT:AN32B_HUMAN" :prob "1.002")) :op4 (p5 / protein :name (n6 / name :op1 "MIP-1α") :xref (x2 / xref :value "UNIPROT:TNPO1_HUMAN" :prob "0.623"))))) :ARG2 (s2 / significant-02) :time (a4 / after :op1 (t / treat-04 :ARG1 g :ARG2 (s3 / small-molecule :name (n7 / name :op1 "AZD6244") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")))))) # ::id pmid_2352_4590.181 # ::date 2015-07-30T12:03:53 # ::file pmid_2352_4590_181.txt # ::snt Taken together, these results indicate that AZD6244 is able to abrogate paracrine signal dependent MM cell survival within the bone marrow niche. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i2 / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this) :ARG1-of (t3 / take-01 :manner (t4 / together))) :ARG1 (p / possible-01 :ARG1 (a / abrogate-01 :ARG1 (s2 / survive-01 :ARG0 (c / cell :mod (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))) :ARG0-of (d2 / depend-01 :ARG1 (s3 / signal-07 :ARG0 (p2 / paracrine)))) :ARG2 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :location (n3 / niche :mod (m / marrow :mod (b / bone)))))) # ::id pmid_2352_4590.182 # ::date 2015-07-30T12:12:55 # ::file pmid_2352_4590_182.txt # ::snt Both these studies provide a preclinical rationale for the further evaluation of AZD6244. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (p / provide-01 :ARG0 (s / study-01 :mod (t / this) :mod (b / both)) :ARG1 (r / rationale :mod (p2 / preclinical) :purpose (e / evaluate-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :degree (f / further)))) # ::id pmid_2352_4590.183 # ::date 2015-07-30T12:16:14 # ::file pmid_2352_4590_183.txt # ::snt A phase II trial examining the compound in MM is presently ongoing. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (g / go-on-15 :ARG1 (t / trial-06 :ARG2 (e / examine-01 :ARG1 (c / compound) :location (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))) :mod (p / phase :ord (o / ordinal-entity :value "2"))) :time (p2 / present)) # ::id pmid_2352_4590.184 # ::date 2015-07-30T12:21:00 # ::file pmid_2352_4590_184.txt # ::snt Treatment with AS703026 has also been explored in MM.86 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (e / explore-01 :ARG1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "AS703026") :xref (x / xref :value "PUBCHEM:44187362" :prob "18.349844"))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 "86"))) :mod (a / also) :location (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))) # ::id pmid_2352_4590.185 # ::date 2015-07-30T12:24:13 # ::file pmid_2352_4590_185.txt # ::snt AS703026 inhibits HMCL and cytokine-induced osteoclast differentiation more potently (9- to 10-fold) than AZD6244, with an IC50 ranging from 0.005–2 μℳ. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "AS703026") :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50" :ARG4 (v / value-interval :op1 (c2 / concentration-quantity :quant "0.005" :unit (n5 / nanomolar)) :op2 (c4 / concentration-quantity :quant "2" :unit (n6 / nanomolar)))) :xref (x1 / xref :value "PUBCHEM:44187362" :prob "18.349844")) :ARG1 (a / and :op1 (c / cell-line :mod (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma") :mod (h / human))) :op2 (d2 / differentiate-01 :ARG1 (o / osteoclast) :ARG2-of (i2 / induce-01 :ARG0 (p / protein :name (n3 / name :op1 "cytokine") :xref (x / xref :value "UNIPROT:RED_HUMAN" :prob "0.342"))))) :manner (p2 / potent :degree (m2 / more)) :quant (b / between :op1 (p3 / product-of :op1 "9") :op2 (p4 / product-of :op1 "10")) :ARG1-of (c3 / compare-01 :ARG2 (s / small-molecule :name (n4 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")))) # ::id pmid_2352_4590.186 # ::date 2015-07-30T12:38:51 # ::file pmid_2352_4590_186.txt # ::snt No discernable relationship between Ras or Raf mutational status and the sensitivity of HMCL to AS703026 was observed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (o / observe-01 :polarity "-" :ARG1 (r / relation-03 :ARG0 (o2 / or :op1 (s / status :mod (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (s2 / status :mod (m2 / mutate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))) :ARG2 (s3 / sensitive-03 :ARG0 (c / cell-line :mod (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma") :mod (h / human))) :ARG1 (s4 / small-molecule :name (n4 / name :op1 "AS703026") :xref (x2 / xref :value "PUBCHEM:44187362" :prob "18.349844"))) :ARG1-of (d / discern-01 :ARG1-of (p2 / possible-01)))) # ::id pmid_2352_4590.187 # ::date 2015-07-30T12:44:45 # ::file pmid_2352_4590_187.txt # ::snt This compound also induced apoptosis in HMCL cultured in the presence of bone marrow stromal cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / induce-01 :ARG0 (c / compound :mod (t / this)) :ARG2 (a / apoptosis) :mod (a2 / also) :condition (p / present-02 :ARG1 (c2 / cell-line :ARG1-of (c4 / culture-01 :condition (c3 / cell :mod (s / stroma :mod (m / marrow :mod (b / bone))))) :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma") :mod (h / human))))) # ::id pmid_2352_4590.188 # ::date 2015-07-30T12:46:51 # ::file pmid_2352_4590_188.txt # ::snt Further evaluation of AS703026 in conjunction with conventional (dexamethasone, melphalan) and novel (lenalidomide, bortezomib, perifisone, rapamycin) anti-MM therapies revealed synergistic cytotoxicity against HMCL and patient samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / reveal-01 :ARG0 (e / evaluate-01 :ARG1 (s9 / small-molecule :name (n / name :op1 "AS703026") :xref (x / xref :value "PUBCHEM:44187362" :prob "18.349844")) :degree (f / further) :ARG1-of (a2 / accompany-01 :ARG0 (a3 / and :op1 (t / therapy :ARG0-of (c3 / counter-01 :ARG1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))) :mod (c4 / conventional) :ARG2-of (i / include-91 :ARG1 (a4 / and :op1 (s3 / small-molecule :name (n5 / name :op1 "dexamethasone") :xref (x2 / xref :value "PUBCHEM:5743" :prob "14.701785")) :op2 (s4 / small-molecule :name (n6 / name :op1 "melphalan") :xref (x5 / xref :value "PUBCHEM:460612" :prob "16.348362"))))) :op2 (t2 / therapy :ARG0-of c3 :mod (n4 / novel) :ARG2-of (i2 / include-91 :ARG1 (a5 / and :op1 (s5 / small-molecule :name (n7 / name :op1 "lenalidomide") :xref (x4 / xref :value "PUBCHEM:216326" :prob "17.251232")) :op2 (s6 / small-molecule :name (n8 / name :op1 "bortezomib") :xref (x3 / xref :value "PUBCHEM:387447" :prob "17.186693")) :op3 (s7 / small-molecule :name (n9 / name :op1 "perifisone")) :op4 (s8 / small-molecule :name (n10 / name :op1 "rapamycin") :xref (x1 / xref :value "PUBCHEM:5040" :prob "15.003454")))))))) :ARG1 (c / cytotoxicity :ARG0-of (s / synergize-01) :prep-against (a / and :op1 (c2 / cell-line :mod (d / disease :name (n2 / name :op1 "myeloma") :mod (h / human))) :op2 (t3 / thing :ARG1-of (s2 / sample-01 :ARG2 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)))))))) # ::id pmid_2352_4590.189 # ::date 2015-07-30T12:56:06 # ::file pmid_2352_4590_189.txt # ::snt Lastly, for tumour cells isolated from patients with relapsed/refractory MM treated with AS703026 at concentrations below 200 nℳ, dose-dependent cytotoxicity was observed for 15 of 18 patient MM samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (o / observe-01 :ARG1 (c / cytotoxicity :ARG0-of (d / depend-01 :ARG1 (d2 / dose))) :condition (c3 / cell :source (p2 / person :ARG1-of (t2 / treat-03 :ARG3 (s2 / small-molecule :name (n2 / name :op1 "AS703026") :quant (b / below :op1 (c2 / concentration-quantity :quant "200" :unit (n3 / nanomolar))) :xref (x / xref :value "PUBCHEM:44187362" :prob "18.349844"))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p4 / patient)) :ARG0-of (h3 / have-03 :ARG1 (o2 / or :op1 (d5 / disease :name (n6 / name :op1 "multiple" :op2 "myeloma") :ARG1-of (r / relapse-01)) :op2 (d4 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma") :mod (r2 / refract))))) :mod (t / tumor) :ARG1-of (i2 / isolate-01)) :time (l / last) :location (d6 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma") :ARG1-of (s3 / sample-01 :quant "15" :ARG2 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient))) :ARG1-of (i / include-91 :ARG2 (t3 / thing :quant "18" :ARG1-of (s / sample-01)))))) # ::id pmid_2352_4590.190 # ::date 2015-07-30T13:10:53 # ::file pmid_2352_4590_190.txt # ::snt In this cohort of MM patient samples, while six and two of the patient samples harboured K-Ras/N-Ras and B-Raf mutations, respectively, the presence or absence of Ras or B-Raf mutations did not correlate with the sensitivity to MEK inhibition by AS703026. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c / contrast-01 :ARG1 (a / and :op1 (h / harbor-01 :ARG0 (t3 / thing :quant "6" :ARG1-of (s / sample-01 :ARG2 "p2")) :ARG1 (o / or :op1 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x4 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m2 / mutate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "N-Ras") :xref (x3 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))))) :op2 (h2 / harbor-01 :ARG0 (t2 / thing :quant "2" :ARG1-of (s2 / sample-01)) :ARG1 (m3 / mutate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :ARG2 (c2 / correlate-01 :polarity "-" :ARG1 (o2 / or :op1 (p / present-02 :ARG1 (o3 / or :op1 (m4 / mutate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 m3)) :op2 (a2 / absent-01 :ARG1 o3)) :ARG2 (s3 / sensitive-03 :ARG1 (i / inhibit-01 :ARG0 (s5 / small-molecule :name (n6 / name :op1 "AS703026") :xref (x5 / xref :value "PUBCHEM:44187362" :prob "18.349844")) :ARG1 (e5 / enzyme :name (n5 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :location (c3 / cohort :mod (t / this) :consist-of (d / disease :name (n8 / name :op1 "multiple" :op2 "myeloma") :ARG1-of (s4 / sample-01 :ARG2 (p2 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 (p3 / patient))))))) # ::id pmid_2352_4590.191 # ::date 2015-07-30T14:28:14 # ::file pmid_2352_4590_191.txt # ::snt Despite these encouraging findings, outcomes from solid tumour models suggest that combination regimes are required to maximise the effectiveness of MEK inhibitors in MM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (h / have-concession-91 :ARG1 (s / suggest-01 :ARG0 (o / outcome :source (t3 / tumor :mod (m / model :ARG1-of (s2 / solid-02)))) :ARG1 (r / require-01 :ARG0 (m2 / maximize-01 :ARG1 (e2 / effective-04 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK")))) :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))) :ARG1 (r2 / regime :ARG3-of (c / combine-01)))) :ARG2 (f / find-01 :ARG0-of (e / encourage-02) :mod (t / this))) # ::id pmid_2352_4590.192 # ::date 2015-07-30T14:36:31 # ::file pmid_2352_4590_192.txt # ::snt AZD6244 and AS703026 have demonstrated improved potency when used in combination with other anti-MM agents.84, 85, 86 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (d / demonstrate-01 :ARG0 (a / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "AS703026") :xref (x / xref :value "PUBCHEM:44187362" :prob "18.349844"))) :ARG1 (p3 / potency :ARG1-of (i / improve-01)) :condition (u / use-01 :ARG0 a :manner (c / combine-01 :ARG1 a :ARG2 (a2 / agent :ARG0-of (c2 / counter-01 :ARG1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))) :mod (o / other)))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 "84" :op2 "85" :op3 "86"))))) # ::id pmid_2352_4590.193 # ::date 2015-07-30T14:40:00 # ::file pmid_2352_4590_193.txt # ::snt The contribution of additional signalling pathways to MM tumorigenesis also offers the opportunity to target MEK in conjunction with the inhibition of these biochemical networks. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (o / offer-01 :ARG0 (c / contribute-01 :ARG0 (p / pathway :ARG0-of (s / signal-07) :mod (a / additional)) :ARG2 (c2 / create-01 :ARG1 (t / tumor :mod (d / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))))) :ARG1 (o2 / opportunity :purpose (t2 / target-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :manner (a2 / accompany-01 :ARG1 (i / inhibit-01 :ARG0 (n2 / network :mod (b / biochemistry) :mod (t3 / this)))))) :mod (a3 / also)) # ::id pmid_2352_4590.194 # ::date 2015-07-30T14:46:09 # ::file pmid_2352_4590_194.txt # ::snt Chatterjee et al.30 have determined that the combined disruption of the Ras/MAPK and JAK/STAT pathway is required to induce MM apoptosis in the presence of bone marrow stromal cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (d / determine-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n4 / name :op1 "Chatterjee")) :op2 (p6 / person :mod (o / other))) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 "30")))) :ARG1 (r / require-01 :ARG0 (i / induce-01 :ARG2 (a2 / apoptosis :mod (d3 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))) :ARG1 (d2 / disrupt-01 :ARG1 (a / and :op1 (p / pathway :name (n / name :op1 "Ras/MAPK")) :op2 (p2 / pathway :name (n2 / name :op1 "JAK/STAT"))) :ARG1-of (c3 / combine-01)) :condition (p3 / present-02 :ARG1 (c / cell :mod (s / stroma :mod (m / marrow :mod (b / bone))))))) # ::id pmid_2352_4590.195 # ::date 2015-07-30T14:53:51 # ::file pmid_2352_4590_195.txt # ::snt Similarly, the contribution PI3K/Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway deregulation exerts on MM and drug resistance also makes these pathways attractive targets for co-inhibition with MEK specific agents.5, 29 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (m / make-02 :ARG0 (e / exert-01 :ARG0 (d / deregulate-01 :ARG1 (a3 / and :op1 (p / pathway :name (n / name :op1 "PI3K/Akt")) :op2 (p2 / pathway :name (n2 / name :op1 "NFκB")))) :ARG1 (c / contribute-01) :ARG2 (a / and :op1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")) :op2 (r / resist-01 :ARG1 (d3 / drug)))) :ARG1 (t / target-01 :ARG0 (c2 / coinhibit-00 :instrument (a5 / agent :ARG1-of (s / specific-02 :ARG2 (p3 / protein-family :name (n4 / name :op1 "MEK"))))) :ARG1 a3 :ARG0-of (a4 / attract-01)) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 "5" :op2 "29")))) :mod (a7 / also) :ARG1-of (r2 / resemble-01)) # ::id pmid_2352_4590.196 # ::date 2015-07-30T15:11:00 # ::file pmid_2352_4590_196.txt # ::snt Several other small molecule inhibitors have also recently emerged as promising therapies in MM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (e / emerge-02 :ARG0 (s3 / small-molecule :ARG0-of (i / inhibit-01) :mod (o / other) :quant (s2 / several)) :ARG1 (t / therapy :ARG0-of (p / promise-01) :location (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))) :mod (a / also) :time (r / recent)) # ::id pmid_2352_4590.197 # ::date 2015-07-30T15:14:53 # ::file pmid_2352_4590_197.txt # ::snt Histone deacetylases (HDAC) represent a family of enzymes that control transcription by modifying histones. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / represent-01 :ARG0 (e2 / enzyme :name (n / name :op1 "histone" :op2 "deacetylase") :xref (x1 / xref :value "UNIPROT:B3KUJ5_HUMAN" :prob "0.701")) :ARG1 (f / family :consist-of (e / enzyme) :ARG0-of (c / control-01 :ARG1 (t / transcribe-01) :ARG2 (m / modify-01 :ARG0 f :ARG1 (p / protein :name (n2 / name :op1 "histone") :xref (x / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332")))))) # ::id pmid_2352_4590.198 # ::date 2015-07-30T15:18:51 # ::file pmid_2352_4590_198.txt # ::snt Overexpression of HDAC in MM prevents the transcription of various tumour-suppressor genes, which in turn enhances cellular proliferation and represses cell death.87 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (p / prevent-01 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "HDAC") :xref (x / xref :value "UNIPROT:HDAC1_HUMAN" :prob "0.312")) :location (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))) :ARG1 (t / transcribe-01 :ARG1 (g / gene :ARG0-of (s / suppress-01 :ARG1 (t2 / tumor)) :mod (v / various))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "87"))) :ARG0-of (e2 / enhance-01 :ARG1 (p2 / proliferate-01 :ARG0 (c / cell))) :ARG0-of (r / repress-01 :ARG1 (d2 / die-01 :ARG1 c)) :manner (i2 / in-turn)) # ::id pmid_2352_4590.199 # ::date 2015-07-30T15:26:17 # ::file pmid_2352_4590_199.txt # ::snt Inhibition of HDAC activity reverses these outcomes, culminating in the accumulation of acetylated histones that promote the apoptosis of malignant cells.88 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / reverse-01 :ARG0 (i / inhibit-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "HDAC") :xref (x1 / xref :value "UNIPROT:HDAC1_HUMAN" :prob "0.312")))) :ARG1 (o / outcome :mod (t / this)) :ARG2 (c / culminate-01 :ARG2 (a2 / accumulate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "histone") :ARG3-of (a3 / acetylate-01) :ARG0-of (p / promote-01 :ARG1 (a4 / apoptosis :poss (c2 / cell :ARG1-of (m / malignant-02)))) :xref (x / xref :value "UNIPROT:H2A1J_HUMAN" :prob "0.332")))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "88")))) # ::id pmid_2352_4590.200 # ::date 2015-07-30T15:35:05 # ::file pmid_2352_4590_200.txt # ::snt Clinical evaluation of the HDAC inhibitors as single agents in relapsed/refractory MM patients has yielded modest response rates.89, 90 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (y / yield-01 :ARG0 (e / evaluate-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "HDAC") :xref (x / xref :value "UNIPROT:HDAC1_HUMAN" :prob "0.312"))) :manner (a / agent :ARG2-of (s / single-02))) :mod (c / clinical) :location (o / or :op1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG0-of (h3 / have-03 :ARG1 (d / disease :name (n4 / name :op1 "multiple" :op2 "myeloma") :ARG1-of (r / relapse-01)))) :op2 (p2 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p5 / patient)) :ARG0-of (h4 / have-03 :ARG1 (d2 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma") :mod (r2 / refract)))))) :ARG1 (r3 / rate :mod (r4 / respond-01) :quant (m2 / modest)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "89" :op2 "90"))))) # ::id pmid_2352_4590.201 # ::date 2015-07-30T22:59:21 # ::file pmid_2352_4590_201.txt # ::snt Nevertheless, several studies have reported a significant increase in the anti-MM effect of these agents, when used in conjunction with conventional anti-MM chemotherapeutics,91 lenalidomide and bortezomib.92 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG1 (r / report-01 :ARG0 (s / study-01 :quant (s2 / several)) :ARG1 (i / increase-01 :ARG1 (a / affect-01 :ARG0 (a2 / agent :mod (t / this)) :ARG2 (c / counter-01 :ARG1 (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")))) :ARG2 (s3 / significant-02) :condition (u / use-01 :ARG1 a2 :manner (a3 / accompany-01 :ARG0 (c2 / chemotherapy :ARG0-of c :mod (c3 / conventional) :ARG2-of (i2 / include-91 :ARG1 (a4 / and :op1 (s4 / small-molecule :name (n2 / name :op1 "lenalidomide") :xref (x1 / xref :value "PUBCHEM:216326" :prob "17.251232")) :op2 (s5 / small-molecule :name (n3 / name :op1 "bortezomib") :xref (x / xref :value "PUBCHEM:387447" :prob "17.186693")) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "92")))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c4 / cite-01 :ARG2 "91")))))))) # ::id pmid_2352_4590.202 # ::date 2015-07-30T23:07:42 # ::file pmid_2352_4590_202.txt # ::snt Combinations of MEK and HDAC inhibitors have been limited to preclinical studies involving chronic myelogenous leukaemia and non-small cell lung carcinoma cell lines, but preliminary results have been promising.93, 94 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (c / contrast-01 :ARG1 (l / limit-01 :ARG1 (c2 / combine-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "HDAC") :xref (x / xref :value "UNIPROT:HDAC1_HUMAN" :prob "0.312"))))) :ARG2 (s / study-01 :mod (p / preclinical) :ARG0-of (i3 / involve-01 :ARG1 (a / and :op1 (d / disease :name (n3 / name :op1 "myelogenous" :op2 "leukaemia") :mod (c3 / chronic)) :op2 (c4 / cell-line :source (c5 / carcinoma :mod (l2 / lung) :mod (c6 / cell :mod (s2 / small :polarity "-")))))))) :ARG2 (p2 / promise-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (p3 / preliminary)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c7 / cite-01 :ARG2 (a2 / and :op1 "93" :op2 "94")))))) # ::id pmid_2352_4590.203 # ::date 2015-07-30T23:18:20 # ::file pmid_2352_4590_203.txt # ::snt Heat shock protein 90 (HSP90) is a molecular chaperone that regulates many of the proteins involved in Ras/MAPK, PI3K/Akt, JAK/STAT and NFκB signalling, as well other biochemical pathways that control apoptosis and cell cycle progression.95 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c6 / chaperone :ARG1-of (d / describe-01 :ARG0 (p10 / publication :ARG1-of (c5 / cite-01 :ARG2 "95"))) :mod (m / molecule) :ARG0-of (r / regulate-01 :ARG1 (p2 / protein :quant (m2 / many) :ARG1-of (i / include-91 :ARG2 (p3 / protein :ARG1-of (i2 / involve-01 :ARG2 (a / and :op1 (a2 / and :op1 (s / signal-07 :ARG0 (p4 / pathway :name (n2 / name :op1 "Ras/MAPK"))) :op2 (s2 / signal-07 :ARG0 (p5 / pathway :name (n3 / name :op1 "PI3K/Akt"))) :op3 (s3 / signal-07 :ARG0 (p6 / pathway :name (n4 / name :op1 "JAK/STAT"))) :op4 (s4 / signal-07 :ARG0 (p7 / pathway :name (n5 / name :op1 "NFκB")))) :op2 (p8 / pathway :ARG0-of (c2 / control-01 :ARG1 (a3 / and :op1 (a4 / apoptosis) :op2 (p9 / progress-01 :ARG1 (c / cycle-02 :ARG1 (c4 / cell))))) :mod (b / biochemistry) :mod (o / other)))))))) :domain (p / protein :mod "90" :name (n / name :op1 "Heat" :op2 "shock" :op3 "protein") :xref (x / xref :value "UNIPROT:DNJB1_HUMAN" :prob "0.392"))) # ::id pmid_2352_4590.204 # ::date 2015-07-30T23:27:56 # ::file pmid_2352_4590_204.txt # ::snt Consistent with these properties, inhibition of HSP90 has been shown to disrupt multiple pathways crucial to MM survival.96, 97 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 10, 2015 (s / show-01 :ARG1 (d4 / disrupt-01 :ARG0 (i / inhibit-01 :ARG1 (p / protein :name (n / name :op1 "HSP90") :xref (x / xref :value "UNIPROT:HS90B_HUMAN" :prob "0.682"))) :ARG1 (p2 / pathway :quant (m / multiple) :mod (c / crucial :purpose (s2 / survive-01 :ARG0 (d2 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))))) :ARG1-of (c2 / consistent-01 :ARG2 (p3 / property :mod (t / this))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a / and :op1 "96" :op2 "97"))))) # ::id pmid_2352_4590.205 # ::date 2015-07-30T23:33:59 # ::file pmid_2352_4590_205.txt # ::snt While co-treatment of MM cells with a MEK and HSP90 inhibitors might serve as a means of attenuating the feedback mechanisms that promote resistance to MEK inhibitors, the clinical efficacy of these approaches is dependent upon how selective and active these combination regimes are in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c5 / contrast-01 :ARG1 (d2 / depend-01 :ARG0 (e2 / efficient-01 :ARG1 (a3 / approach-02 :mod (t / this)) :mod (c4 / clinic)) :ARG1 (a4 / and :op1 (t2 / thing :degree-of (s2 / selective)) :op2 (t3 / thing :degree-of (a5 / activity-06)) :domain (r2 / regime :ARG3-of (c3 / combine-01)) :manner (i3 / in-vivo))) :ARG2 (p / possible-01 :ARG1 (s / serve-01 :ARG0 (t4 / treat-04 :ARG1 (c2 / cell :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))) :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (p2 / protein :name (n3 / name :op1 "HSP90") :xref (x / xref :value "UNIPROT:HS90B_HUMAN" :prob "0.682")))))) :ARG1 (m2 / mean :ARG0-of (a2 / attenuate-01 :ARG1 (m3 / mechanism :mod (f / feedback) :ARG0-of (p3 / promote-01 :ARG1 (r / resist-01 :ARG1 (m4 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 e)))))))))) # ::id pmid_2352_4590.206 # ::date 2015-07-30T02:15:05 # ::file pmid_2352_4590_206.txt # ::snt In particular, the potential interrupting multiple kinase networks has for increasing the likelihood of adverse effects and drug toxicity is likely to be an important factor in determining the optimal use of these agents. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (l / likely-01 :ARG1 (f / factor :domain (i / interrupt-01 :ARG1 (n / network-01 :ARG1 (k / kinase) :quant (m / multiple)) :ARG0-of (h / have-03 :ARG1 (p / potential) :purpose (i2 / increase-01 :ARG1 (l2 / likely-01 :ARG1 (a / and :op1 (a2 / affect-01 :mod (a3 / adverse)) :op2 (t / toxicity :mod (d / drug))))))) :purpose (d2 / determine-01 :ARG1 (u / use-01 :ARG1 (a4 / agent :mod (t2 / this)) :mod (o / optimal))) :mod (i3 / important)) :mod (p2 / particular)) # ::id pmid_2352_4590.207 # ::date 2015-07-30T15:34:46 # ::file pmid_2352_4590_207.txt # ::snt Predicting patient responses to MEK inhibitors: identification of relevant biomarkers # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / predict-01 :ARG1 (t / thing :ARG2-of (r / respond-01 :ARG0 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient))) :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK")))))) :ARG1-of (m2 / mean-01 :ARG2 (i2 / identify-01 :ARG1 (b / biomarker :ARG1-of (r2 / relevant-01))))) # ::id pmid_2352_4590.208 # ::date 2015-07-30T15:43:20 # ::file pmid_2352_4590_208.txt # ::snt As all MEK inhibitors tested to date demonstrate potent and selective activity against MEK1/2, toxicity profiles and drug exposure are likely to be the key criteria that refine these drugs for therapeutic use. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (l / likely-01 :ARG1 (r / refine-01 :ARG0 (a / and :op1 (p / profile-01 :ARG1 (t / toxicity)) :op2 (e / expose-01 :ARG2 (d / drug)) :mod (c / criteria :ARG1-of (k / key-02))) :ARG1 (d2 / drug :mod (t2 / this)) :purpose (u / use-01 :mod (t3 / therapy))) :ARG1-of (c2 / cause-01 :ARG0 (d3 / demonstrate-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"))) :ARG1-of (t4 / test-01 :time (t5 / to-date)) :mod (a2 / all)) :ARG1 (a3 / activity-06 :ARG0 m :ARG0-of (c3 / counter-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "MEK1/2"))) :mod (p2 / potent) :mod (s / selective))))) # ::id pmid_2352_4590.209 # ::date 2015-07-30T16:03:34 # ::file pmid_2352_4590_209.txt # ::snt Furthermore, it has become clear that certain genetic sub-types in solid tumours are associated with increased susceptibility or resistance to MEK inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / and :op2 (b / become-01 :ARG2 (c / clear-06 :ARG1 (a2 / associate-01 :ARG1 (s / subtype :mod (g / genetics) :mod (c2 / certain) :location (t / tumor :ARG1-of (s2 / solid-02))) :ARG2 (o / or :op1 (s3 / susceptible :ARG1-of (i / increase-01) :domain s :topic (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))) :op2 (r / resist-01 :ARG0 s :ARG1 m)))))) # ::id pmid_2352_4590.210 # ::date 2015-07-30T16:26:02 # ::file pmid_2352_4590_210.txt # ::snt This observation highlights the need for a reliable marker of responsiveness to MEK inhibitors, allowing tailoring of individualised therapies and reducing the occurrence of adverse events. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 28, 2016 (h / highlight-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (n / need-01 :ARG1 (m3 / molecular-physical-entity :ARG0-of (m / mark-01 :ARG1 (r / responsive-02 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK")))))) :ARG1-of (r2 / rely-01 :ARG1-of (p / possible-01)))) :ARG0-of (a / allow-01 :ARG1 (a2 / and :op1 (t2 / tailor-01 :ARG1 (t3 / therapy :ARG1-of (i2 / individualize-02))) :op2 (r3 / reduce-01 :ARG1 (e2 / event :mod (a3 / adverse)))))) # ::id pmid_2352_4590.211 # ::date 2015-07-30T16:41:04 # ::file pmid_2352_4590_211.txt # ::snt Currently it remains difficult to determine which patients will benefit most from MEK inhibitor treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / remain-01 :ARG1 (d / difficult :domain (d2 / determine-01 :ARG1 (b / benefit-01 :ARG0 (t / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"))))) :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :mod (a / amr-unknown)) :degree (m2 / most)))) :time (c / current)) # ::id pmid_2352_4590.212 # ::date 2015-07-30T16:53:00 # ::file pmid_2352_4590_212.txt # ::snt Whilst activating B-Raf mutations are associated with exquisite sensitivity against these agents, other biochemical markers demonstrate less predictability. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (c / contrast-01 :ARG1 (a / associate-01 :ARG1 (m / mutate-01 :ARG2 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :ARG0-of (a2 / activate-01)) :ARG2 (s / sensitive-03 :ARG0 m :ARG1 (a3 / agent :mod (t / this)) :degree (e2 / exquisite))) :ARG2 (d / demonstrate-01 :ARG0 (m2 / marker :mod (b / biochemistry) :mod (o / other)) :ARG1 (p / possible-01 :ARG1 (p2 / predict-01) :quant (l / less)))) # ::id pmid_2352_4590.213 # ::date 2015-07-30T17:07:23 # ::file pmid_2352_4590_213.txt # ::snt For example, the poor correlation between MEK inhibitor susceptibility Ras genotypes and p-ERK expression is well documented.12, 41, 46, 47, 48, 60 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (e / exemplify-01 :ARG0 (d / document-01 :ARG1 (c / correlate-01 :ARG1 (s / susceptible :domain (g / genotype :mod (e2 / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :mod (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK"))))) :ARG2 (e4 / express-03 :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :degree (p2 / poor)) :ARG1-of (w / well-09)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 "12" :op2 "41" :op3 "46" :op4 "47" :op5 "48" :op6 "60"))))) # ::id pmid_2352_4590.214 # ::date 2015-07-30T17:23:53 # ::file pmid_2352_4590_214.txt # ::snt In one study, analysis of transcriptional pathway signatures in various solid tumours, identified a panel of 18 genes, the expression of which correlated with responsiveness to AZD6244.98 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (i / identify-01 :ARG0 (a / analyze-01 :ARG1 (s / signature :mod (p / pathway :ARG1-of (t / transcribe-01))) :location (t2 / tumor :ARG1-of (s2 / solid-02) :mod (v / various))) :ARG1 (p2 / panel :consist-of (g / gene :quant "18" :ARG1-of (e / express-03 :ARG1-of (c / correlate-01 :ARG2 (r / responsive-02 :ARG1 (s3 / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056"))))))) :medium (s4 / study :quant "1") :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 "98")))) # ::id pmid_2352_4590.215 # ::date 2015-07-30T17:35:07 # ::file pmid_2352_4590_215.txt # ::snt This signature contained transcriptional targets of ERK involved in negative-feedback regulation (DUSP4/6 and SPRY2), members of the Ets family of transcription factors (ETV4, ETV5 and ELF1) and other genes associated with MAPK signalling, cell cycle progression and tumour prognosis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / contain-01 :ARG0 (s / signature :mod (t / this)) :ARG1 (a / and :op1 (a2 / and :op1 (p8 / protein :name (n / name :op1 "DUSP4/6")) :op2 (p9 / protein :name (n2 / name :op1 "SPRY2") :xref (x4 / xref :value "UNIPROT:SPY2_HUMAN" :prob "1.002")) :ARG1-of (t2 / target-01 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (t3 / transcribe-01) :ARG1-of (i / involve-01 :ARG2 (r / regulate-01 :ARG1 (f / feedback :ARG0-of (n4 / negative-03)))))) :op2 (m / member :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n5 / name :op1 "Ets"))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (p5 / protein :name (n6 / name :op1 "ETV4") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")) :op2 (p6 / protein :name (n7 / name :op1 "ETV5") :xref (x1 / xref :value "UNIPROT:ETV5_HUMAN" :prob "1.003")) :op3 (p7 / protein :name (n8 / name :op1 "ELF1") :xref (x3 / xref :value "UNIPROT:ELF1_HUMAN" :prob "1.003"))))) :op3 (g6 / gene :ARG1-of (a4 / associate-01 :ARG2 (a5 / and :op1 (s2 / signal-07 :ARG0 (p2 / pathway :name (n9 / name :op1 "MAPK"))) :op2 (p3 / progress-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell))) :op3 (p4 / prognosis :mod (t4 / tumor)))) :mod (o / other)))) # ::id pmid_2352_4590.216 # ::date 2015-07-30T17:55:56 # ::file pmid_2352_4590_216.txt # ::snt A 13-gene signature was also identified that was predictive of resistance to AZD6244. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (i / identify-01 :ARG1 (s / signature :mod (g / gene :quant "13")) :mod (a / also) :ARG0-of (p / predict-01 :ARG1 (r / resist-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056"))))) # ::id pmid_2352_4590.217 # ::date 2015-07-30T18:02:47 # ::file pmid_2352_4590_217.txt # ::snt This diverse set of genes shared common links with transforming growth factor-β (TGF-β), tumour necrosis factor-α and NFκB signalling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (s / share-01 :ARG0 (s2 / set :consist-of (g / gene) :mod (d / diverse) :mod (t / this)) :ARG1 (l / link-01 :mod (c / common)) :ARG2 (s3 / signal-07 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "transforming" :op2 "growth" :op3 "factor-β") :xref (x2 / xref :value "UNIPROT:TGFA_HUMAN" :prob "0.392")) :op2 (p2 / protein :name (n2 / name :op1 "tumour" :op2 "necrosis" :op3 "factor-α") :xref (x / xref :value "UNIPROT:TNFA_HUMAN" :prob "0.392")) :op3 (p3 / protein :name (n3 / name :op1 "NFκB") :xref (x1 / xref :value "UNIPROT:RRP5_HUMAN" :prob "0.202"))))) # ::id pmid_2352_4590.218 # ::date 2015-07-30T18:11:08 # ::file pmid_2352_4590_218.txt # ::snt The role of these genes in MM and their potential predictive value for MEK inhibitor responsiveness has not been appraised. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / appraise-02 :polarity "-" :ARG1 (a2 / and :op1 (r / role :poss (g / gene :mod (t / this)) :topic (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))) :op2 (v / value :mod (p / predict-01 :ARG0 g :ARG1 (r2 / responsive-02 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK")))))) :mod (p2 / potential) :poss g))) # ::id pmid_2352_4590.219 # ::date 2015-07-30T18:24:48 # ::file pmid_2352_4590_219.txt # ::snt Recent data published by Annuziata et al.99 has reported the use of the musculoaponeurotic fibrosarcoma (MAF) oncogene as a potential biomarker for MEK inhibitor responses in MM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / report-01 :ARG0 (d / data :time (r2 / recent) :ARG1-of (p / publish-01 :ARG0 (p2 / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n / name :op1 "Annuziata")) :op2 (p4 / person :mod (o / other))) :ARG1-of (c / cite-01 :ARG2 "99")))) :ARG1 (u / use-01 :ARG0 (g / gene :name (n5 / name :op1 "musculoaponeurotic" :op2 "fibrosarcoma") :ARG0-of (c2 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))) :ARG2 (b / biomarker :mod (p5 / potential) :purpose (t / thing :ARG2-of (r3 / respond-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p6 / protein-family :name (n3 / name :op1 "MEK")))) :location (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))))))) # ::id pmid_2352_4590.220 # ::date 2015-07-30T18:36:58 # ::file pmid_2352_4590_220.txt # ::snt In approximately 10% of cases, aberrant MAF expression is due to a (14;16) translocation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / cause-01 :ARG0 (t / translocate-01 :ARG1 (a / and :op1 (c2 / chromosome :mod "14" :xref (x2 / xref :value "GO:0005694" :prob "0.8")) :op2 (c3 / chromosome :mod "16" :xref (x1 / xref :value "GO:0005694" :prob "0.8")))) :ARG1 (e / express-03 :ARG2 (p / protein :name (n3 / name :op1 "MAF") :xref (x / xref :value "UNIPROT:MAF_HUMAN" :prob "1.003")) :mod (a2 / aberrant)) :ARG1-of (i / include-91 :ARG2 (c4 / case-04) :ARG3 (p2 / percentage-entity :value "10" :ARG1-of (a3 / approximate-01)))) # ::id pmid_2352_4590.221 # ::date 2015-07-30T18:52:39 # ::file pmid_2352_4590_221.txt # ::snt High levels of MAF were also observed in patient samples with t(4;14) translocations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (o / observe-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "MAF") :xref (x / xref :value "UNIPROT:MAF_HUMAN" :prob "1.003")) :ARG1-of (h / high-02)) :location (s / sample-01 :ARG2 (p2 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient))) :location-of (t / translocate-01 :ARG1 (a / and :op1 (c / chromosome :mod "4" :xref (x1 / xref :value "GO:0005694" :prob "0.8")) :op2 (c2 / chromosome :mod "14" :xref (x2 / xref :value "GO:0005694" :prob "0.8"))))) :mod (a2 / also)) # ::id pmid_2352_4590.222 # ::date 2015-07-30T18:59:00 # ::file pmid_2352_4590_222.txt # ::snt Both t(4:16) and t(4;14) translocations correlate with disease progression and worse overall survival. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / correlate-01 :ARG1 (a / and :op1 (t / translocate-01 :ARG1 (a2 / and :op1 (c2 / chromosome :mod "4" :xref (x1 / xref :value "GO:0005694" :prob "0.8")) :op2 (c3 / chromosome :mod "16" :xref (x / xref :value "GO:0005694" :prob "0.8")))) :op2 (t2 / translocate-01 :ARG1 (a3 / and :op1 c2 :op2 (c4 / chromosome :mod "14" :xref (x2 / xref :value "GO:0005694" :prob "0.8"))))) :ARG2 (a4 / and :op1 (p / progress-01 :ARG1 (d / disease)) :op2 (s / survive-01 :mod (o / overall) :ARG1-of (b / bad-07 :degree (m / more))))) # ::id pmid_2352_4590.223 # ::date 2015-07-30T19:06:23 # ::file pmid_2352_4590_223.txt # ::snt The MEK/ERK pathway was found to regulate transcription of the MAF proto-oncogene through ERK activation of FOS, a finding consistent with MAF protein and mRNA levels being downregulated following MEK inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG1 (r / regulate-01 :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK")) :ARG1 (t / transcribe-01 :ARG1 (p2 / proto-oncogene :mod "p3")) :manner (a / activate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK") :xref (x3 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1 (e3 / enzyme :name (n4 / name :op1 "FOS") :xref (x / xref :value "UNIPROT:FOS_HUMAN" :prob "1.003")))) :ARG1-of (c / consistent-01 :ARG2 (d / downregulate-01 :ARG1 (a2 / and :op1 (l / level :quant-of (p3 / protein :name (n5 / name :op1 "MAF") :xref (x2 / xref :value "UNIPROT:MAF_HUMAN" :prob "1.003"))) :op2 (l2 / level :quant-of (n8 / nucleic-acid :name (n6 / name :op1 "mRNA")))) :ARG1-of (f2 / follow-01 :ARG2 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))))) # ::id pmid_2352_4590.224 # ::date 2015-07-30T19:18:35 # ::file pmid_2352_4590_224.txt # ::snt To examine the dependence of MM cells on MEK/ERK signalling, U0126 was administered to 16 HMCL that represented the heterogeneous onco-genetics of the disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / administer-01 :ARG1 (s / small-molecule :name (n / name :op1 "U0126") :xref (x / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG2 (c / cell-line :quant "16" :name (n2 / name :op1 "HMCL") :ARG0-of (r / represent-01 :ARG1 (o / oncogenetics :mod (h / heterogeneity) :poss (d / disease)))) :purpose (e / examine-01 :ARG1 (d2 / depend-01 :ARG0 (c2 / cell :mod (d4 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))) :ARG1 (s2 / signal-07 :ARG0 (p / pathway :name (n5 / name :op1 "MEK/ERK")))))) # ::id pmid_2352_4590.225 # ::date 2015-07-30T19:26:45 # ::file pmid_2352_4590_225.txt # ::snt Of the 10 HMCL killed by this MEK inhibitor in a dose-dependent manner, 9 cell lines exhibited a t(4;16) or t(4;14) translocation and over expressed MAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (e / exhibit-01 :ARG0 (c / cell-line :quant "9") :ARG1 (o / or :op1 (t / translocate-01 :value (a2 / and :op1 "4" :op2 "16")) :op2 (t2 / translocate-01 :value (a3 / and :op1 "4" :op2 "14")))) :op2 (o2 / overexpress-01 :ARG1 (p2 / protein :name (n / name :op1 "MAF") :xref (x / xref :value "UNIPROT:MAF_HUMAN" :prob "1.003")) :location c) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "10" :ARG1-of (k / kill-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"))) :mod (t3 / this)) :ARG0-of (d / depend-01 :ARG1 (d2 / dose-01))) :mod (d3 / disease :name (n2 / name :op1 "myeloma") :mod (h / human))))) # ::id pmid_2352_4590.226 # ::date 2015-07-30T19:40:31 # ::file pmid_2352_4590_226.txt # ::snt Moreover, the cytotoxic effect of U0126 was not neutralised by the presence of bone marrow stromal cells and remarkably, the impact of MEK inhibition on MM viability could be rescued by exogenous MAF expression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op2 (a2 / and :op1 (n / neutralize-01 :polarity "-" :ARG0 (p / present-02 :ARG1 (c / cell :mod (s / stromal) :part-of (m / marrow :mod (b / bone)))) :ARG1 (a3 / affect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG2 (c2 / cytotoxicity))) :op2 (p2 / possible-01 :ARG1 (r / rescue-01 :ARG0 (e / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "MAF") :xref (x1 / xref :value "UNIPROT:MAF_HUMAN" :prob "1.003")) :mod (e2 / exogenous)) :ARG1 (i / impact-01 :ARG0 (i2 / inhibit-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1 (v / viability :mod (d2 / disease :name (n6 / name :op1 "multiple" :op2 "myeloma"))))) :ARG1-of (r2 / remarkable-02)))) # ::id pmid_2352_4590.227 # ::date 2015-07-30T19:50:59 # ::file pmid_2352_4590_227.txt # ::snt Importantly, this study provides a mechanistic rationale for using MEK inhibitor therapy in MM patients that overexpress c-MAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / provide-01 :ARG0 (s / study-01 :mod (t / this)) :ARG1 (r / rationale :mod (m / mechanism)) :ARG2 (u / use-01 :ARG1 (t2 / therapy :mod (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p5 / protein-family :name (n / name :op1 "MEK"))))) :location (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :location-of (o / overexpress-01 :ARG1 (p4 / protein :name (n3 / name :op1 "c-MAF"))) :mod (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")))) :mod (i2 / important)) # ::id pmid_2352_4590.228 # ::date 2015-07-30T20:03:04 # ::file pmid_2352_4590_228.txt # ::snt These findings emphasise the potential benefit of genetic profiling to identify patients with MAF-expressing MM who may benefit from this class of agents. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / emphasize-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (b / benefit-01 :ARG0 (p / profile-01 :mod (g / genetics) :ARG0-of (i / identify-01 :ARG1 (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient)) :ARG0-of (h2 / have-03 :ARG1 (c / cell :ARG3-of (e2 / express-03 :ARG2 (p5 / protein :name (n2 / name :op1 "MAF") :xref (x / xref :value "UNIPROT:MAF_HUMAN" :prob "1.003"))) :mod (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))) :ARG1-of (b2 / benefit-01 :ARG0 (c2 / class :mod (a / agent) :mod (t3 / this)) :ARG1-of (p6 / possible-01))))) :mod (p2 / potential))) # ::id pmid_2352_4590.229 # ::date 2015-07-30T20:14:05 # ::file pmid_2352_4590_229.txt # ::snt As part of the phase II trial of AZD6244 in relapsed/refractory MM, extensive molecular profiling of a subset of patients was conducted to correlate the genetic characteristics of MM with clinical outcomes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / conduct-01 :ARG1 (p / profile-01 :ARG1 (s / subset :consist-of (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)))) :mod (m / molecule) :ARG1-of (e / extensive-03)) :purpose (c2 / correlate-01 :ARG1 (c3 / characteristic-02 :ARG1 (d4 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma")) :ARG2 (g / genetics)) :ARG2 (o / outcome :mod (c4 / clinic))) :part-of (t / trial-06 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :mod (p4 / phase :value "2") :condition (s3 / slash :op1 (d / disease :name (n / name :op1 "multiple" :op2 "myeloma") :ARG1-of (r2 / relapse-01)) :op2 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma") :mod (r / refractory))))) # ::id pmid_2352_4590.230 # ::date 2015-07-30T20:26:39 # ::file pmid_2352_4590_230.txt # ::snt To date, detailed clinical data from eight patients has been analysed, four of whom overexpress c-MAF or MAF-B. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / analyze-01 :ARG1 (d / data :mod (c / clinic) :ARG1-of (d2 / detail-01) :source (p / person :quant "8" :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :ARG2-of (i / include-91 :ARG1 (p3 / person :quant "4" :ARG0-of h :location-of (o / overexpress-01 :ARG1 (o2 / or :op1 (p4 / protein :name (n / name :op1 "c-MAF")) :op2 (p5 / protein :name (n2 / name :op1 "MAF-B") :xref (x / xref :value "UNIPROT:MAFB_HUMAN" :prob "0.672")))))))) :time (t / to-date)) # ::id pmid_2352_4590.231 # ::date 2015-07-30T20:33:09 # ::file pmid_2352_4590_231.txt # ::snt One patient (fibroblast growth factor receptor 3) had a very good PR lasting 8 months. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (h / have-03 :ARG0 (p / person :quant "1" :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :mod (p3 / protein :name (n / name :op1 "fibroblast" :op2 "growth" :op3 "factor" :op4 "receptor-3") :xref (x / xref :value "UNIPROT:FGFR3_HUMAN" :prob "0.693"))) :ARG1 (t / thing :ARG2-of (r / respond-01 :degree (p4 / part)) :ARG1-of (g / good-02 :degree (v / very)) :duration (t2 / temporal-quantity :quant "8" :unit (m / month)))) # ::id pmid_2352_4590.232 # ::date 2015-07-30T20:39:59 # ::file pmid_2352_4590_232.txt # ::snt Another patient (MAF-B) had a PR of 6 months. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-03 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient)) :mod (p3 / protein :name (n / name :op1 "MAF-B") :xref (x / xref :value "UNIPROT:MAFB_HUMAN" :prob "0.672")) :mod (a / another)) :ARG1 (t / thing :ARG2-of (r / respond-01 :duration (t2 / temporal-quantity :quant "6" :unit (m / month)) :degree (p4 / part)))) # ::id pmid_2352_4590.233 # ::date 2015-07-30T20:44:09 # ::file pmid_2352_4590_233.txt # ::snt Finally, two patients (one MAF-B, one pending results) demonstrated s.d. of >5 and 13 months, respectively.100 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a3 / and :op1 (d / demonstrate-01 :ARG0 (p / person :quant "1" :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :mod (p4 / protein :name (n / name :op1 "MAF-B") :xref (x / xref :value "UNIPROT:MAFB_HUMAN" :prob "0.672"))) :ARG1 (d4 / disease :duration (m2 / more-than :op1 (t4 / temporal-quantity :quant "5" :unit "m3")) :ARG1-of (s / stable-03))) :op2 (d3 / demonstrate-01 :ARG0 (p5 / person :quant "1" :ARG0-of h :mod (t / thing :ARG2-of (r / result-01) :ARG1-of (p6 / pend-01))) :ARG1 (d5 / disease :duration (t3 / temporal-quantity :quant "13" :unit (m3 / month)) :ARG1-of (s2 / stable-03))) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 "100"))) :mod (f / final)) # ::id pmid_2352_4590.234 # ::date 2015-07-30T20:56:36 # ::file pmid_2352_4590_234.txt # ::snt Additional studies with larger sample sizes are required to support or refute MAF expression as a reliable biomarker for MEK inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / require-01 :ARG0 (o / or :op1 (s / support-01 :ARG0 (s2 / study-01 :ARG1-of (a / add-02) :mod (s3 / size-01 :ARG1 (t / thing :ARG1-of (s4 / sample-01)) :ARG2 (l / large :degree (m / more)))) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "MAF") :xref (x / xref :value "UNIPROT:MAF_HUMAN" :prob "1.003")) :mod (b / biomarker :ARG1-of (r2 / rely-01 :ARG1-of (p2 / possible-01)) :purpose (i / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))))) :op2 (r3 / refute-01 :ARG0 s2 :ARG1 e)) :ARG1 s2) # ::id pmid_2352_4590.235 # ::date 2015-07-30T21:13:04 # ::file pmid_2352_4590_235.txt # ::snt Conclusion # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (t / thing :ARG1-of (c / conclude-01)) # ::id pmid_2352_4590.236 # ::date 2015-07-30T21:15:20 # ::file pmid_2352_4590_236.txt # ::snt The Ras/Raf/MEK/ERK pathway has an established role in the various neoplastic phenotypes observed in many malignancies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 5, 2015 (h / have-03 :ARG0 (p / pathway :name (n / name :op1 "Ras/Raf/MEK/ERK")) :ARG1 (r / role :topic (p2 / phenotype :mod (n2 / neoplasm) :mod (v / various) :ARG1-of (o / observe-01 :location (m / malignancy :quant (m2 / many)))) :ARG1-of (e / establish-01))) # ::id pmid_2352_4590.237 # ::date 2015-07-30T21:20:22 # ::file pmid_2352_4590_237.txt # ::snt Deregulation of this pathway is also a common feature of MM, and contributes to the relapsing and refractory nature of the disease. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 17, 2015 (a / and :op1 (f / feature :domain (d / deregulate-01 :ARG1 (p / pathway :mod (t / this))) :mod (c / common) :mod (a2 / also) :mod (d3 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :op2 (c2 / contribute-01 :ARG0 f :ARG2 (a3 / and :op1 (r / relapse-01 :ARG1 d3) :op2 (r2 / refractory :domain d3)))) # ::id pmid_2352_4590.238 # ::date 2015-07-30T21:31:21 # ::file pmid_2352_4590_238.txt # ::snt These observations make this pathway an attractive target for pharmaceutical investigation, with a number of MEK inhibitors having been developed and evaluated clinically. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / make-02 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (t2 / target-01 :ARG0 (i / investigate-01 :mod (p / pharmaceutical)) :ARG1 (p2 / pathway :mod t) :ARG2-of (a / attract-01)) :accompanier (a2 / and :op1 (d / develop-02 :ARG1 (n / number :quant-of (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK")))))) :op2 (e2 / evaluate-01 :ARG1 n) :manner (c / clinical))) # ::id pmid_2352_4590.239 # ::date 2015-07-30T21:44:35 # ::file pmid_2352_4590_239.txt # ::snt Although preclinical studies of MEK inhibitors in MM have demonstrated a capacity to induce MM apoptosis by overcoming the prosurvival effects of the BMME, solid tumour studies indicate that the therapeutic benefit of MEK inhibitors alone are likely to be of limited benefit. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (i / indicate-01 :ARG0 (s / study-01 :ARG1 (t / tumor :ARG1-of (s2 / solid-02))) :ARG1 (l / likely-01 :ARG1 (b / benefit-01 :ARG0 (b2 / benefit-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))) :mod (t2 / therapy) :mod (a / alone)) :ARG1-of (l2 / limit-01)))) :ARG2 (d / demonstrate-01 :ARG0 (s3 / study-01 :ARG1 m :mod (p / preclinical) :location (d3 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :ARG1 (c / capable-01 :ARG1 m :ARG2 (i3 / induce-01 :ARG0 m :ARG2 (a2 / apoptosis :mod (c2 / cell :mod d3)) :manner (o / overcome-01 :ARG1 (a3 / affect-01 :ARG0 (m2 / microenvironment :mod (m3 / marrow :part-of (b3 / bone))) :ARG2 (f / favor-01 :ARG1 (s4 / survive-01)))))))) # ::id pmid_2352_4590.240 # ::date 2015-07-30T22:05:21 # ::file pmid_2352_4590_240.txt # ::snt Therefore, future clinical approaches require a shift towards using MEK inhibitors in combination with current anti-MM compounds and other novel small molecule inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / cause-01 :ARG1 (r / require-01 :ARG0 (a / approach-01 :mod (c2 / clinic) :time (f / future)) :ARG1 (s / shift-01 :ARG1 a :ARG2 (u / use-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :ARG1-of (c3 / combine-01 :ARG2 (a2 / and :op1 (c4 / compound :ARG0-of (c5 / counter-01 :ARG1 (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :mod (c6 / current)) :op2 (s2 / small-molecule :ARG0-of (i2 / inhibit-01) :mod (n3 / novel) :mod (o / other))))))))) # ::id pmid_2352_4590.241 # ::date 2015-07-30T22:13:11 # ::file pmid_2352_4590_241.txt # ::snt The identification of relevant biomarkers of MEK inhibitor responses remains a high priority that can be used to predict patient sensitivity and to tailor individualised therapies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / remain-01 :ARG1 (i / identify-01 :ARG1 (b / biomarker :ARG1-of (r2 / relevant-01) :mod (t / thing :ARG2-of (r3 / respond-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p6 / protein-family :name (n / name :op1 "MEK")))))))) :ARG3 (p / priority :ARG1-of (h / high-02) :ARG1-of (u / use-01 :ARG2 (a / and :op1 (p2 / predict-01 :ARG1 (s / sensitive-03 :ARG0 (p3 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p4 / patient))))) :op2 (t2 / tailor-01 :ARG1 (t3 / therapy :ARG1-of (i3 / individualize-02)))) :ARG1-of (p5 / possible-01)))) # ::id pmid_2354_8132.1 # ::date 2015-08-25T17:18:50 # ::file pmid_2354_8132_1.txt # ::snt High resolution melting analysis of KRAS, BRAF and PIK3CA in KRAS exon 2 wild-type metastatic colorectal cancer (PMID:23548132) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / analyze-01 :ARG1 (a2 / and :op1 (g / gene :name (n / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op3 (g3 / gene :name (n3 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))) :manner (m2 / melt-01 :mod (r / resolution :ARG1-of (h / high-02))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID23548132")) :location (d4 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colorectal" :op2 "cancer") :ARG1-of (m / metastasize-101) :mod (w / wild-type) :mod (e / exon :mod "2" :part-of g))) # ::id pmid_2354_8132.9 # ::date 2015-08-25T19:01:11 # ::file pmid_2354_8132_9.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2354_8132.10 # ::date 2015-08-25T19:28:11 # ::file pmid_2354_8132_10.txt # ::snt One mutation was present in 23.4% (47/201) of the cases and 3.0% additional cases (6/201) had two concomitant mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (p / present-02 :ARG1 (m / mutate-01 :quant "1") :ARG2 (c / case-04 :quant "47" :ARG1-of (i / include-91 :ARG2 (c2 / case-04 :quant "201") :ARG3 (p2 / percentage-entity :value "23.4")))) :op2 (h / have-03 :ARG0 (c3 / case-04 :quant "6" :ARG1-of (i2 / include-91 :ARG2 c2 :ARG3 (p3 / percentage-entity :value "3.0")) :ARG1-of (a2 / add-02)) :ARG1 (m2 / mutate-01 :quant "2" :mod (c4 / concomitant)))) # ::id pmid_2354_8132.11 # ::date 2015-08-26T02:51:01 # ::file pmid_2354_8132_11.txt # ::snt A total of 53 cases showed 59 mutations, with the following distribution: 44.1% (26/59) in KRAS (13 in exon 3 and 13 in exon 4), 18.6% (11/59) in BRAF (two in exon 11 and nine in exon 15) and 37.3% (22/59) in PIK3CA (16 in exon 9 and six in exon 20). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (s / show-01 :ARG0 (c / case-04 :quant "53" :ARG1-of (t / total-01)) :ARG1 (m / mutate-01 :quant "59" :ARG1-of (d / distribute-01 :ARG2 (a / and :op1 (m2 / mutate-01 :quant "26" :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (i / include-91 :ARG2 m :ARG3 (p / percentage-entity :value "44.1")) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and :op1 (m4 / mutate-01 :quant "13" :location (e6 / exon :mod "3")) :op2 (m5 / mutate-01 :quant "13" :location (e5 / exon :mod "4"))))) :op2 (m6 / mutate-01 :quant "11" :ARG1 (g2 / gene :name (n4 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (i2 / include-91 :ARG2 m :ARG3 (p2 / percentage-entity :value "18.6")) :ARG1-of (m7 / mean-01 :ARG2 (a3 / and :op1 (m8 / mutate-01 :quant "2" :location (e3 / exon :mod "11")) :op2 (m9 / mutate-01 :quant "9" :location (e4 / exon :mod "15"))))) :op3 (m10 / mutate-01 :quant "22" :ARG1 (g3 / gene :name (n7 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG1-of (i3 / include-91 :ARG2 m :ARG3 (p3 / percentage-entity :value "37.3")) :ARG1-of (m11 / mean-01 :ARG2 (a4 / and :op1 (m12 / mutate-01 :quant "16" :location (e / exon :mod "9")) :op2 (m13 / mutate-01 :quant "6" :location (e2 / exon :mod "20")))))) :ARG1-of (f / follow-01)))) # ::id pmid_2354_8132.12 # ::date 2015-08-26T15:50:30 # ::file pmid_2354_8132_12.txt # ::snt In total, 26.4% (53/201) of the cases had at least one mutation and the remaining 73.6% (148/201) were wild-type for all regions studied. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (h / have-03 :ARG0 (c / case-04 :quant "53" :ARG1-of (i / include-91 :ARG2 (c2 / case-04 :quant "201") :ARG3 (p / percentage-entity :value "26.4"))) :ARG1 (m / mutate-01 :quant (a2 / at-least :op1 "1"))) :op2 (w / wild-type :domain (c3 / case-04 :quant "148" :ARG1-of (i2 / include-91 :ARG2 c2 :ARG3 (p2 / percentage-entity :value "73.6")) :ARG1-of (r / remain-01)) :location (r2 / region :mod (a3 / all) :ARG1-of (s / study-01))) :ARG1-of (t / total-01)) # ::id pmid_2354_8132.13 # ::date 2015-08-27T11:54:07 # ::file pmid_2354_8132_13.txt # ::snt Five of the mutations we report, four in KRAS and one in BRAF, have not previously been described in CRC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (d / describe-01 :polarity "-" :ARG1 (m / mutate-01 :quant "5" :ARG1-of (i / include-91 :ARG2 (m2 / mutate-01 :ARG1-of (r / report-01 :ARG0 (w / we)))) :ARG2-of (i2 / include-91 :ARG1 (a / and :op1 (m3 / mutate-01 :quant "4" :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m4 / mutate-01 :quant "1" :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))))) :time (p / previous) :location (d2 / disease :name (n3 / name :op1 "CRC"))) # ::id pmid_2354_8132.14 # ::date 2015-08-27T12:05:21 # ::file pmid_2354_8132_14.txt # ::snt BRAF and PIK3CA mutations were more frequent in the colon than in the sigmoid or rectum: 20.8% vs. 1.6% vs. 0.0% (P=0.000) for BRAF and 23.4% vs. 12.1% vs. 5.4% (P=0.011) for PIK3CA mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (f / frequent-02 :ARG1 (a / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :degree (m3 / more) :location (c / colon) :compared-to (o / or :op1 (s / sigmoid) :op2 (r / rectum)) :ARG1-of (m4 / mean-01 :ARG2 (a2 / and :op1 (m5 / mutate-01 :ARG1 g :quant (p / percentage-entity :value "20.8") :location c :compared-to (m6 / mutate-01 :ARG1 g :quant (p2 / percentage-entity :value "1.6") :location s) :compared-to (m7 / mutate-01 :ARG1 g :quant (p3 / percentage-entity :value "0.0") :location r) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.000")) :op2 (m8 / mutate-01 :ARG1 g2 :quant (p5 / percentage-entity :value "23.4") :location c :compared-to (m9 / mutate-01 :ARG1 g2 :quant (p6 / percentage-entity :value "12.1") :location s) :compared-to (m10 / mutate-01 :ARG1 g2 :quant (p7 / percentage-entity :value "5.4") :location r) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.011"))))) # ::id pmid_2354_8132.74 # ::date 2015-08-27T12:33:07 # ::file pmid_2354_8132_74.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2354_8132.75 # ::date 2015-08-27T12:34:49 # ::file pmid_2354_8132_75.txt # ::snt Mutation frequencies # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (f / frequent-02 :ARG1 (m / mutate-01)) # ::id pmid_2354_8132.76 # ::date 2015-08-27T12:36:42 # ::file pmid_2354_8132_76.txt # ::snt A total of 201 KRAS exon 2 wild-type mCRC samples were screened by HRM for mutations in exons 3 and 4 of KRAS, exons 11 and 15 of BRAF, and exons 9 and 20 of PIK3CA (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / screen-01 :ARG1 (s2 / sample-01 :ARG1 (d / disease :name (n / name :op1 "mCRC") :mod (w / wild-type) :mod (e / exon :mod "2" :part-of (g / gene :name (n3 / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :ARG1-of (t / total-01 :ARG2 "201")) :manner (t2 / thing :name (n4 / name :op1 "HRM")) :purpose (a / and :op1 (m / mutate-01 :location (a2 / and :op1 (e2 / exon :mod "3") :op2 (e3 / exon :mod "4") :part-of g)) :op2 (m2 / mutate-01 :location (a3 / and :op1 (e4 / exon :mod "11") :op2 (e5 / exon :mod "15") :part-of (g2 / gene :name (n9 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op3 (m3 / mutate-01 :location (a4 / and :op1 (e6 / exon :mod "9") :op2 (e7 / exon :mod "20") :part-of (g3 / gene :name (n12 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))) :ARG1-of (d9 / describe-01 :ARG0 (f / figure :mod "1"))) # ::id pmid_2354_8132.77 # ::date 2015-08-27T12:56:55 # ::file pmid_2354_8132_77.txt # ::snt Subsequent automated sequencing of HRM positive cases confirmed the presence of 59 mutations in 53 cases, with the following distribution: 44.1% (26/59) in KRAS (13 in exon 3 and 13 in exon 4), 18.6% (11/59) in BRAF (two in exon 11 and nine in exon 15) and 37.3% (22/59) in PIK3CA (16 in exon 9 and six in exon 20). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / confirm-01 :ARG0 (s / sequence-01 :ARG1 (c2 / case-04 :ARG1 (t / thing :name (n / name :op1 "HRM")) :mod (p / positive)) :ARG1-of (a / automate-01) :time (s2 / subsequent)) :ARG1 (p2 / present-02 :ARG1 (m / mutate-01 :quant "59") :ARG2 (c3 / case-04 :quant "53") :ARG1-of (d / distribute-01 :ARG2 (a2 / and :op1 (m2 / mutate-01 :quant "26" :ARG1 (g / gene :name (n2 / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (i / include-91 :ARG2 m :ARG3 (p3 / percentage-entity :value "44.1")) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and :op1 (m4 / mutate-01 :quant "13" :location (e / exon :mod "3")) :op2 (m5 / mutate-01 :quant "13" :location (e2 / exon :mod "4"))))) :op2 (m6 / mutate-01 :quant "11" :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (i2 / include-91 :ARG2 m :ARG3 (p4 / percentage-entity :value "18.6")) :ARG1-of (m7 / mean-01 :ARG2 (a4 / and :op1 (m8 / mutate-01 :quant "2" :location (e3 / exon :mod "11")) :op2 (m9 / mutate-01 :quant "9" :location (e4 / exon :mod "15"))))) :op3 (m10 / mutate-01 :quant "22" :ARG1 (g3 / gene :name (n8 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG1-of (i3 / include-91 :ARG2 m :ARG3 (p5 / percentage-entity :value "37.3")) :ARG1-of (m11 / mean-01 :ARG2 (a5 / and :op1 (m12 / mutate-01 :quant "16" :location (e5 / exon :mod "9")) :op2 (m13 / mutate-01 :quant "6" :location (e6 / exon :mod "20")))))) :ARG1-of (f / follow-01)))) # ::id pmid_2354_8132.78 # ::date 2015-08-27T13:30:31 # ::file pmid_2354_8132_78.txt # ::snt One mutation was present in 23.4% (47/201) of the cases and 3.0% additional cases (6/201) had two concomitant mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (p / present-02 :ARG1 (m / mutate-01 :quant "1") :ARG2 (c / case-04 :quant "47" :ARG1-of (i / include-91 :ARG2 (c2 / case-04 :quant "201") :ARG3 (p2 / percentage-entity :value "23.4")))) :op2 (h / have-03 :ARG0 (c3 / case-04 :quant "6" :ARG1-of (i2 / include-91 :ARG2 c2 :ARG3 (p3 / percentage-entity :value "3.0")) :ARG1-of (a2 / add-02)) :ARG1 (m2 / mutate-01 :quant "2" :mod (c4 / concomitant)))) # ::id pmid_2354_8132.79 # ::date 2015-08-27T14:55:59 # ::file pmid_2354_8132_79.txt # ::snt In total, 26.4% (53/201) of the cases had at least one mutation and the remaining 73.6% (148/201) were wild-type for all regions studied. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op1 (h / have-03 :ARG0 (c / case-04 :quant "53" :ARG1-of (i / include-91 :ARG2 (c2 / case-04 :quant "201") :ARG3 (p / percentage-entity :value "26.4"))) :ARG1 (m / mutate-01 :quant (a2 / at-least :op1 "1"))) :op2 (w / wild-type :domain (c3 / case-04 :quant "148" :ARG1-of (i2 / include-91 :ARG2 c2 :ARG3 (p2 / percentage-entity :value "73.6")) :ARG1-of (r / remain-01)) :location (r2 / region :mod (a3 / all) :ARG1-of (s / study-01))) :ARG1-of (t / total-01)) # ::id pmid_2354_8132.80 # ::date 2015-08-27T15:05:50 # ::file pmid_2354_8132_80.txt # ::snt All mutations were found in heterozygosity and were confirmed in a second HRM and DNA sequence analysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (a / and :op1 (f / find-01 :ARG1 (m / mutate-01 :mod (a2 / all)) :manner (h / heterozygosity)) :op2 (c / confirm-01 :ARG0 (a3 / and :op1 (a4 / analyze-01 :ARG1 m :manner (m2 / melt-01 :mod (r / resolution :ARG1-of (h2 / high-02)))) :op2 (a5 / analyze-01 :ARG1 m :mod (d / dna-sequence)) :ord (o / ordinal-entity :value "2")) :ARG1 m)) # ::id pmid_2354_8132.81 # ::date 2015-08-30T17:47:13 # ::file pmid_2354_8132_81.txt # ::snt Samples with single mutations were distributed as follows: 10.0% (20/201) were KRAS mutated, 5.0% (10/201) in exon 3 and 5.0% (10/201) in exon 4; 5.0% (10/201) had one BRAF mutation, 0.5% (1/201) in exon 11 and 4.5% (9/201) in exon 15; 8.5% (17/201) were PIK3CA mutated, 7.0% (14/201) in exon 9 and 1.5% (3/201) in exon 20 (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (d / distribute-01 :ARG1 (t / thing :ARG1-of (s / sample-01) :ARG0-of (h / have-03 :ARG1 (m / mutate-01 :ARG1-of (s2 / single-02)))) :ARG2 (a / and :op1 (t3 / thing :quant "20" :ARG1-of (i / include-91 :ARG2 (t4 / thing :quant "201" :ARG1-of (s4 / sample-01)) :ARG3 (p / percentage-entity :value "10.0" :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (t5 / thing :quant "10" :ARG1-of (i2 / include-91 :ARG2 t4 :ARG3 (p2 / percentage-entity :value "5.0")) :ARG2-of (m3 / mutate-01 :location (e / exon :mod "3"))) :op2 (t6 / thing :quant "10" :ARG1-of i2 :ARG2-of (m4 / mutate-01 :location (e2 / exon :mod "4"))))))) :location-of (m5 / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :op2 (t7 / thing :quant "10" :ARG1-of (i3 / include-91 :ARG2 t4 :ARG3 (p3 / percentage-entity :value "5.0" :ARG1-of (m6 / mean-01 :ARG2 (a3 / and :op1 (t8 / thing :quant "1" :ARG1-of (i4 / include-91 :ARG2 t4 :ARG3 (p4 / percentage-entity :value "0.5")) :ARG2-of (m7 / mutate-01 :location (e3 / exon :mod "11"))) :op2 (t9 / thing :quant "9" :ARG1-of (i5 / include-91 :ARG2 t4 :ARG3 (p5 / percentage-entity :value "4.5")) :ARG2-of (m8 / mutate-01 :location (e4 / exon :mod "15"))))))) :ARG0-of (h2 / have-03 :ARG1 (m9 / mutate-01 :quant "1" :ARG1 (g2 / gene :name (n6 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :op3 (t10 / thing :quant "17" :ARG1-of (i6 / include-91 :ARG2 t4 :ARG3 (p6 / percentage-entity :value "8.5" :ARG1-of (m10 / mean-01 :ARG2 (a4 / and :op1 (t11 / thing :quant "14" :ARG1-of (i7 / include-91 :ARG2 t4 :ARG3 (p7 / percentage-entity :value "7.0")) :ARG2-of (m11 / mutate-01 :location (e5 / exon :mod "9"))) :op2 (t12 / thing :quant "3" :ARG1-of (i8 / include-91 :ARG2 t4 :ARG3 (p8 / percentage-entity :value "1.5")) :ARG2-of (m12 / mutate-01 :location (e6 / exon :mod "20"))))))) :location-of (m13 / mutate-01 :ARG1 (g3 / gene :name (n9 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))) :ARG1-of (f / follow-01) :ARG1-of (d8 / describe-01 :ARG0 (t2 / table :mod "1"))) # ::id pmid_2354_8132.82 # ::date 2015-08-27T16:34:18 # ::file pmid_2354_8132_82.txt # ::snt Concomitant mutations were found with the following distribution: 2.0% (4/201) of cases had simultaneous mutations in PIK3CA and KRAS, 0.5% (1/201) in PIK3CA and BRAF, and 0.5% (1/201) two mutations in KRAS (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (f / find-01 :ARG1 (m / mutate-01 :mod (c / concomitant) :ARG1-of (d / distribute-01 :ARG2 (a / and :op1 (h / have-03 :ARG0 (c2 / case-04 :quant "4" :ARG1-of (i / include-91 :ARG2 (c3 / case-04 :quant "201") :ARG3 (p / percentage-entity :value "2.0"))) :ARG1 (m2 / mutate-01 :ARG1 (a2 / and :op1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :mod (s / simultaneous))) :op2 (h2 / have-03 :ARG0 (c4 / case-04 :quant "1" :ARG1-of (i2 / include-91 :ARG2 c3 :ARG3 (p2 / percentage-entity :value "0.5"))) :ARG1 (m3 / mutate-01 :ARG1 (a3 / and :op1 g :op2 (g3 / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :op3 (h3 / have-03 :ARG0 c4 :ARG1 (m4 / mutate-01 :quant "2" :ARG1 g2))) :ARG1-of (f2 / follow-01))) :ARG1-of (d2 / describe-01 :ARG0 (t / table :mod "2"))) # ::id pmid_2354_8132.83 # ::date 2015-08-27T17:12:25 # ::file pmid_2354_8132_83.txt # ::snt Of all mutations here reported, five have not been previously described in colorectal cancer [23-25]: two duplications, one deletion, and one point mutation in KRAS and one point mutation in BRAF (Figure 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (d / describe-01 :polarity "-" :ARG1 (m / mutate-01 :quant "5" :ARG1-of (i / include-91 :ARG2 (m2 / mutate-01 :mod (a / all) :ARG1-of (r / report-01 :location (h / here)))) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and :op1 (d2 / duplicate-01 :quant "2") :op2 (d3 / delete-01 :quant "1") :op3 (a3 / and :op1 (m4 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :degree (p / point :quant "1")) :op2 (m5 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :degree p))))) :time (p2 / previous) :location (d4 / disease :name (n3 / name :op1 "colorectal" :op2 "cancer")) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 "23" :op2 "25")))) :ARG1-of (d6 / describe-01 :ARG0 (f / figure :mod "2"))) # ::id pmid_2354_8132.84 # ::date 2015-08-27T17:25:27 # ::file pmid_2354_8132_84.txt # ::snt KRAS mutations # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) # ::id pmid_2354_8132.85 # ::date 2015-08-27T17:27:13 # ::file pmid_2354_8132_85.txt # ::snt The eight KRAS codon 61 mutations present in our series result in four different amino acid substitutions (p.Gln61His, p.Gln61Lys, p.Gln61Leu, and p.Gln61Arg), with the p.Gln61Leu being the most frequent codon 61 mutation in this series (37.5%; 3/8). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / result-01 :ARG1 (m / mutate-01 :quant "8" :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :location (c / codon :mod "61") :ARG1-of (p / present-02 :ARG2 (s / series :poss (w / we)))) :ARG2 (s2 / substitute-01 :quant "4" :ARG2 (a / amino-acid) :ARG1-of (d2 / differ-02) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (s3 / substitute-01 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "histidine") :xref (x1 / xref :value "PUBCHEM:6274" :prob "11.959939")) :ARG2 (a4 / amino-acid :mod "61" :name (n4 / name :op1 "glutamine") :xref (x3 / xref :value "PUBCHEM:738" :prob "11.972775"))) :op2 (s4 / substitute-01 :ARG1 (a5 / amino-acid :name (n5 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG2 a4) :op3 (s5 / substitute-01 :ARG1 (a6 / amino-acid :name (n6 / name :op1 "leucine") :xref (x5 / xref :value "PUBCHEM:857" :prob "10.872692")) :ARG2 a4 :ARG1-of (f / frequent-02 :degree (m3 / most) :location (s6 / series :mod (t / this)) :ARG1-of (m5 / mean-01 :ARG2 (m6 / mutate-01 :quant "3" :location c :ARG1-of (i / include-91 :ARG2 m :ARG3 (p2 / percentage-entity :value "37.5")))))) :op4 (s7 / substitute-01 :ARG1 (a7 / amino-acid :name (n7 / name :op1 "arginine") :xref (x4 / xref :value "PUBCHEM:232" :prob "11.348415")) :ARG2 a4))))) # ::id pmid_2354_8132.86 # ::date 2015-08-29T04:21:32 # ::file pmid_2354_8132_86.txt # ::snt Mutations found in codon 146 were restricted to the p.Ala146Thr substitution. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / restrict-01 :ARG1 (f / find-01 :ARG1 (m / mutate-01) :location (c / codon :mod "146")) :ARG2 (s / substitute-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "threonine") :xref (x / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG2 (a2 / amino-acid :mod "146" :name (n3 / name :op1 "alanine") :xref (x1 / xref :value "PUBCHEM:602" :prob "10.089661")))) # ::id pmid_2354_8132.87 # ::date 2015-08-29T04:28:03 # ::file pmid_2354_8132_87.txt # ::snt Besides those in codons 61 and 146, other KRAS exon 3 mutations represented 19% (5/26) of all KRAS changes, including one deletion (p.Ala59del), two point mutations (p.Glu49Lys and p.Gly60Val) and two large in frame duplications (p.Cys51_Ser65dup and p.Thr58_Met72dup). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / represent-01 :ARG0 (a / and :op1 (m / mutate-01 :location (a2 / and :op1 (c4 / codon :mod "61") :op2 (c5 / codon :mod "146"))) :op2 (m2 / mutate-01 :ARG1 (g / gene :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :location (e / exon :mod "3") :mod (o / other))) :ARG1 (c / change-01 :quant "5" :ARG1-of (i / include-91 :ARG2 (c2 / change-01 :quant "26") :ARG3 (p / percentage-entity :value "19")) :ARG1-of (i2 / include-91 :ARG2 (c3 / change-01 :ARG1 g :mod (a3 / all))) :ARG2-of (i3 / include-01 :ARG1 (a4 / and :op1 (d4 / delete-01 :quant "1" :ARG1 (a5 / amino-acid :mod "59" :name (n5 / name :op1 "alanine") :xref (x8 / xref :value "PUBCHEM:602" :prob "10.089661"))) :op2 (m3 / mutate-01 :quant "2" :ARG1-of (m4 / mean-01 :ARG2 (a6 / and :op1 (m5 / mutate-01 :ARG2 (a7 / amino-acid :name (n6 / name :op1 "lysine") :xref (x9 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG3 (a8 / amino-acid :mod "49" :name (n7 / name :op1 "glutamic" :op2 "acid") :xref (x3 / xref :value "PUBCHEM:611" :prob "7.558843"))) :op2 (m6 / mutate-01 :ARG2 (a9 / amino-acid :name (n8 / name :op1 "valine") :xref (x2 / xref :value "PUBCHEM:6287" :prob "10.890044")) :ARG3 (a10 / amino-acid :mod "60" :name (n9 / name :op1 "glycine") :xref (x5 / xref :value "PUBCHEM:750" :prob "9.915467"))))) :degree (p2 / point)) :op3 (d5 / duplicate-01 :quant "2" :ARG1-of (m7 / mean-01 :ARG2 (a11 / and :op1 (d6 / duplicate-01 :ARG0 (a12 / amino-acid :mod "51" :name (n10 / name :op1 "cysteine") :xref (x7 / xref :value "PUBCHEM:594" :prob "11.272514")) :ARG1 (a13 / amino-acid :mod "65" :name (n11 / name :op1 "serine") :xref (x6 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :op2 (d7 / duplicate-01 :ARG0 (a14 / amino-acid :mod "58" :name (n12 / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1 (a15 / amino-acid :mod "72" :name (n13 / name :op1 "methionine") :xref (x4 / xref :value "PUBCHEM:876" :prob "11.787682"))))) :mod (l / large) :mod (i4 / in-frame)))))) # ::id pmid_2354_8132.88 # ::date 2015-08-30T04:22:04 # ::file pmid_2354_8132_88.txt # ::snt Of these five mutations, only p.Gly60Val has been recently reported in CRC [26], whereas the other four are novel mutations in CRC [23]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (c / contrast-01 :ARG1 (r / report-01 :ARG1 (m / mutate-01 :ARG2 (a / amino-acid :name (n / name :op1 "valine") :xref (x1 / xref :value "PUBCHEM:6287" :prob "10.890044")) :ARG3 (a2 / amino-acid :mod "60" :name (n2 / name :op1 "glycine") :xref (x / xref :value "PUBCHEM:750" :prob "9.915467")) :mod (o / only) :ARG1-of (i / include-91 :ARG2 (m2 / mutate-01 :quant "5" :mod (t / this)))) :time (r2 / recent) :location (d / disease :name (n3 / name :op1 "CRC")) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "26")))) :ARG2 (m3 / mutate-01 :quant "4" :mod (n4 / novel) :mod (o2 / other) :location d :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "23"))))) # ::id pmid_2354_8132.89 # ::date 2015-08-30T04:29:42 # ::file pmid_2354_8132_89.txt # ::snt One of the cases carrying a KRAS p.Gln61His mutation had a concomitant PIK3CA p.Glu542Lys substitution. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (h / have-03 :ARG0 (c / case-04 :quant "1" :ARG0-of (c2 / carry-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG2 (a / amino-acid :name (n2 / name :op1 "histidine") :xref (x5 / xref :value "PUBCHEM:6274" :prob "11.959939")) :ARG3 (a2 / amino-acid :mod "61" :name (n3 / name :op1 "glutamine") :xref (x3 / xref :value "PUBCHEM:738" :prob "11.972775")))) :ARG1-of (i / include-91 :ARG2 (c3 / case-04 :ARG0-of c2))) :ARG1 (s / substitute-01 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG2 (a4 / amino-acid :mod "542" :name (n5 / name :op1 "glutamic" :op2 "acid") :xref (x4 / xref :value "PUBCHEM:611" :prob "7.558843")) :ARG3 (g2 / gene :name (n6 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :mod (c4 / concomitant))) # ::id pmid_2354_8132.90 # ::date 2015-08-30T04:39:32 # ::file pmid_2354_8132_90.txt # ::snt The p.Thr58_Met72dup duplication occurred in one tumor carrying a PIK3CA p.His1047Tyr substitution. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (d / duplicate-01 :ARG0 (a / amino-acid :mod "58" :name (n / name :op1 "threonine") :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG1 (a2 / amino-acid :mod "72" :name (n2 / name :op1 "methionine") :xref (x3 / xref :value "PUBCHEM:876" :prob "11.787682")) :location (t / tumor :quant "1" :ARG0-of (c / carry-01 :ARG1 (s / substitute-01 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine") :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2 (a4 / amino-acid :mod "1047" :name (n4 / name :op1 "histidine") :xref (x4 / xref :value "PUBCHEM:6274" :prob "11.959939")) :ARG3 (g / gene :name (n5 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))))) # ::id pmid_2354_8132.91 # ::date 2015-08-30T04:56:54 # ::file pmid_2354_8132_91.txt # ::snt Two tumors with KRAS Ala146Thr mutations also had a PIK3CA mutation, either p.Glu545Lys or p.His1046Arg. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 20, 2015 (h / have-03 :ARG0 (t / tumor :quant "2" :poss (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG2 (a / amino-acid :name (n2 / name :op1 "threonine") :xref (x7 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG3 (a2 / amino-acid :mod "146" :name (n3 / name :op1 "alanine") :xref (x3 / xref :value "PUBCHEM:602" :prob "10.089661")))) :ARG1 (o / or :op1 (m2 / mutate-01 :ARG1 (g2 / gene :name (n8 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG2 (a3 / amino-acid :name (n4 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG3 (a4 / amino-acid :mod "545" :name (n5 / name :op1 "glutamic" :op2 "acid") :xref (x5 / xref :value "PUBCHEM:611" :prob "7.558843"))) :op2 (m3 / mutate-01 :ARG1 g2 :ARG2 (a5 / amino-acid :name (n6 / name :op1 "arginine") :xref (x4 / xref :value "PUBCHEM:232" :prob "11.348415")) :ARG3 (a6 / amino-acid :mod "1046" :name (n7 / name :op1 "histidine") :xref (x6 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :mod (e / either)) :mod (a7 / also)) # ::id pmid_2354_8132.92 # ::date 2015-08-30T05:04:01 # ::file pmid_2354_8132_92.txt # ::snt In addition, one case harbored two KRAS mutations, namely p.Glu49Lys and p.Ala146Thr. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op2 (h / harbor-01 :ARG0 (c / case-04 :quant "1") :ARG1 (m / mutate-01 :quant "2" :ARG1 (a2 / and :op1 (m2 / mutate-01 :ARG2 (a3 / amino-acid :name (n2 / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG3 (a4 / amino-acid :mod "49" :name (n3 / name :op1 "glutamic" :op2 "acid") :xref (x4 / xref :value "PUBCHEM:611" :prob "7.558843"))) :op2 (m3 / mutate-01 :ARG2 (a5 / amino-acid :name (n4 / name :op1 "threonine") :xref (x3 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG3 (a6 / amino-acid :mod "146" :name (n5 / name :op1 "alanine") :xref (x1 / xref :value "PUBCHEM:602" :prob "10.089661"))) :mod (n6 / namely)) :ARG2 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))) # ::id pmid_2354_8132.93 # ::date 2015-08-30T05:10:03 # ::file pmid_2354_8132_93.txt # ::snt BRAF mutations # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) # ::id pmid_2354_8132.94 # ::date 2015-08-30T05:13:03 # ::file pmid_2354_8132_94.txt # ::snt The frequency of BRAF p.Val600Glu mutations found in this series was 4.0% (8/201). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (f / frequent-02 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG2 (a / amino-acid :name (n2 / name :op1 "glutamic" :op2 "acid") :xref (x1 / xref :value "PUBCHEM:611" :prob "7.558843")) :ARG3 (a2 / amino-acid :mod "600" :name (n3 / name :op1 "valine") :xref (x2 / xref :value "PUBCHEM:6287" :prob "10.890044")) :ARG1-of (f2 / find-01 :location (s / series :mod (t / this)))) :quant (p / percentage-entity :value "4.0" :ARG1-of (m2 / mean-01 :ARG2 (m3 / mutate-01 :quant "8" :ARG1 g :ARG2 a :ARG3 a2 :ARG1-of (i / include-91 :ARG2 (m4 / mutate-01 :quant "201")))))) # ::id pmid_2354_8132.95 # ::date 2015-08-30T05:23:48 # ::file pmid_2354_8132_95.txt # ::snt This mutation represented 89% (8/9) of exon 15 mutations and 73% (8/11) of all BRAF mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / represent-01 :ARG0 (m / mutate-01 :mod (t / this)) :ARG1 (a / and :op1 (m2 / mutate-01 :quant "8" :mod t :ARG1-of (i / include-91 :ARG2 (m3 / mutate-01 :quant "9") :ARG3 (p / percentage-entity :value "89")) :location (e / exon :mod "15")) :op2 (m4 / mutate-01 :quant "8" :mod t :ARG1-of (i2 / include-91 :ARG2 (m5 / mutate-01 :quant "11" :ARG1 (g / gene :name (n2 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (a2 / all)) :ARG3 (p2 / percentage-entity :value "73"))))) # ::id pmid_2354_8132.96 # ::date 2015-08-30T05:41:42 # ::file pmid_2354_8132_96.txt # ::snt We also found mutations in codons 601 (p.Lys601Glu), 466 (p.Gly466Glu), and 471 (p.Val471Ala) of BRAF, the latter not previously described in mCRC [23]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (a / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG2 (a8 / amino-acid :name (n2 / name :op1 "glutamic" :op2 "acid") :xref (x5 / xref :value "PUBCHEM:611" :prob "7.558843")) :ARG3 (a3 / amino-acid :mod "601" :name (n3 / name :op1 "lysine") :xref (x1 / xref :value "PUBCHEM:866" :prob "11.053295")) :location (c2 / codon :mod "601")) :op2 (m2 / mutate-01 :ARG1 g :ARG2 a8 :ARG3 (a4 / amino-acid :mod "466" :name (n5 / name :op1 "glycine") :xref (x3 / xref :value "PUBCHEM:750" :prob "9.915467")) :location (c3 / codon :mod "466")) :op3 (m3 / mutate-01 :ARG1 g :ARG2 (a5 / amino-acid :name (n6 / name :op1 "alanine") :xref (x2 / xref :value "PUBCHEM:602" :prob "10.089661")) :ARG3 (a6 / amino-acid :mod "471" :name (n7 / name :op1 "valine") :xref (x4 / xref :value "PUBCHEM:6287" :prob "10.890044")) :location (c4 / codon :mod "471") :ARG1-of (d4 / describe-01 :polarity "-" :ARG0 (d5 / disease :name (n10 / name :op1 "mCRC")) :time (p / previous)))) :mod (a7 / also) :ARG1-of (d6 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "23")))) # ::id pmid_2354_8132.97 # ::date 2015-08-30T05:54:05 # ::file pmid_2354_8132_97.txt # ::snt One BRAF mutation, p.Val471Ala, occurred in a tumor also carrying a PIK3CA p.His1047Arg mutation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (m / mutate-01 :quant "1" :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG2 (a / amino-acid :name (n2 / name :op1 "alanine") :xref (x2 / xref :value "PUBCHEM:602" :prob "10.089661")) :ARG3 (a2 / amino-acid :mod "471" :name (n3 / name :op1 "valine") :xref (x4 / xref :value "PUBCHEM:6287" :prob "10.890044")) :location (t / tumor :ARG0-of (c / carry-01 :ARG1 (m2 / mutate-01 :ARG1 (g2 / gene :name (n4 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG2 (a3 / amino-acid :name (n5 / name :op1 "arginine") :xref (x3 / xref :value "PUBCHEM:232" :prob "11.348415")) :ARG3 (a4 / amino-acid :mod "1047" :name (n6 / name :op1 "histidine") :xref (x5 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :mod (a5 / also)))) # ::id pmid_2354_8132.98 # ::date 2015-08-30T05:58:36 # ::file pmid_2354_8132_98.txt # ::snt PIK3CA # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) # ::id pmid_2354_8132.99 # ::date 2015-08-30T06:12:00 # ::file pmid_2354_8132_99.txt # ::snt PIK3CA mutations were present in 10.9% (22/201) of the tumors, unequally distributed between exons 9 and 20: 73% (16/22) were helical domain mutants (p.Glu542Lys, p.Glu545Lys, p.Glu545Asp, and p.Gln546Lys) and 27% (6/22) kinase domain mutants (p.Met1043Ile, p.His1047Arg, p.His1047Leu, and p.His1047Tyr). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (p / present-02 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG1-of (d / distribute-01 :ARG2 (b / between :op1 (e2 / exon :mod "9") :op2 (e3 / exon :mod "20")) :manner (e / equal-01 :polarity "-") :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (m3 / mutate-01 :quant "16" :ARG1 (d4 / domain :mod (h / helical)) :ARG1-of (i / include-91 :ARG2 (m4 / mutate-01 :quant "22") :ARG3 (p2 / percentage-entity :value "73")) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and :op1 (m6 / mutate-01 :ARG2 (a3 / amino-acid :name (n4 / name :op1 "lysine") :xref (x6 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG3 (a4 / amino-acid :mod "542" :name (n5 / name :op1 "glutamic" :op2 "acid") :xref (x8 / xref :value "PUBCHEM:611" :prob "7.558843"))) :op2 (m7 / mutate-01 :ARG2 a3 :ARG3 (a5 / amino-acid :mod "545" :name (n6 / name :op1 "glutamic" :op2 "acid") :xref (x7 / xref :value "PUBCHEM:611" :prob "7.558843"))) :op3 (m8 / mutate-01 :ARG2 (a6 / amino-acid :name (n7 / name :op1 "aspartic" :op2 "acid") :xref (x10 / xref :value "PUBCHEM:424" :prob "7.741247")) :ARG3 a5) :op4 (m9 / mutate-01 :ARG2 a3 :ARG3 (a7 / amino-acid :mod "546" :name (n8 / name :op1 "glutamine") :xref (x9 / xref :value "PUBCHEM:738" :prob "11.972775")))))) :op2 (m10 / mutate-01 :quant "6" :ARG1 (d5 / domain :mod (k / kinase)) :ARG1-of (i2 / include-91 :ARG2 m4 :ARG3 (p3 / percentage-entity :value "27")) :ARG1-of (m11 / mean-01 :ARG2 (a8 / and :op1 (m12 / mutate-01 :ARG2 (a9 / amino-acid :name (n9 / name :op1 "isoleucine") :xref (x11 / xref :value "PUBCHEM:791" :prob "12.011956")) :ARG3 (a10 / amino-acid :mod "1043" :name (n10 / name :op1 "methionine") :xref (x3 / xref :value "PUBCHEM:876" :prob "11.787682"))) :op2 (m13 / mutate-01 :ARG2 (a11 / amino-acid :name (n11 / name :op1 "arginine") :xref (x2 / xref :value "PUBCHEM:232" :prob "11.348415")) :ARG3 (a12 / amino-acid :mod "1047" :name (n12 / name :op1 "histidine") :xref (x5 / xref :value "PUBCHEM:6274" :prob "11.959939"))) :op3 (m14 / mutate-01 :ARG2 (a13 / amino-acid :name (n13 / name :op1 "leucine") :xref (x4 / xref :value "PUBCHEM:857" :prob "10.872692")) :ARG3 a12) :op4 (m15 / mutate-01 :ARG2 (a14 / amino-acid :name (n14 / name :op1 "tyrosine") :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG3 a12)))))))) :ARG2 (t / tumor :quant "22" :ARG1-of (i3 / include-91 :ARG2 (t2 / tumor :quant "201") :ARG3 (p4 / percentage-entity :value "10.9")))) # ::id pmid_2354_8132.100 # ::date 2015-08-30T07:12:42 # ::file pmid_2354_8132_100.txt # ::snt Five of the PIK3CA mutants also contained another mutation in either KRAS or BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (c / contain-01 :ARG0 (m / mutate-01 :quant "5" :ARG2 (g / gene :name (n / name :op1 "PIK3CA") :xref (x2 / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")) :ARG1-of (i / include-91 :ARG2 (m2 / mutate-01 :ARG2 g))) :ARG1 (m3 / mutate-01 :ARG1 (o / or :op1 (g2 / gene :name (n2 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :mod (a / another)) :mod (a2 / also)) # ::id pmid_2354_8132.101 # ::date 2015-08-30T07:17:46 # ::file pmid_2354_8132_101.txt # ::snt Clinicopathological associations # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (a / associate-01 :mod (c / clinicopathological)) # ::id pmid_2354_8132.102 # ::date 2015-08-30T07:20:16 # ::file pmid_2354_8132_102.txt # ::snt KRAS mutations were more frequent in patients older than the median age of diagnosis (21.5% vs. 8.2%; P=0.034), whereas no statistically significant differences were found for BRAF or PIK3CA mutations regarding this parameter. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (c / contrast-01 :ARG1 (f / frequent-02 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :location (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient)) :mod (o / old :degree (m2 / more) :compared-to (a / age :mod (d / diagnose-01) :mod (m3 / median)))) :degree (m4 / more) :ARG1-of (m5 / mean-01 :ARG2 (c2 / contrast-01 :ARG1 (p3 / percentage-entity :value "21.5") :ARG2 (p4 / percentage-entity :value "8.2"))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.034")) :ARG2 (f2 / find-01 :polarity "-" :ARG1 (d2 / differ-02 :ARG1 (o2 / or :op1 (m6 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (m7 / mutate-01 :ARG1 (g3 / gene :name (n3 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :ARG3 (p6 / parameter :mod (t / this)) :ARG1-of (s / significant-02 :manner (s2 / statistics))) :ARG0-of (r / regard-01))) # ::id pmid_2354_8132.103 # ::date 2015-08-30T13:14:08 # ::file pmid_2354_8132_103.txt # ::snt BRAF and PIK3CA mutations were more frequent in the colon than in the sigmoid or rectum: 20.8% vs. 1.6% vs. 0.0% (P=0.000) for BRAF and 23.4% vs. 12.1% vs. 5.4% (P=0.011) for PIK3CA mutations (Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 15, 2015 (f / frequent-02 :ARG1 (a / and :op1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (m2 / mutate-01 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003")))) :degree (m3 / more) :location (c / colon) :compared-to (o / or :op1 (s / sigmoid) :op2 (r / rectum)) :ARG1-of (m4 / mean-01 :ARG2 (a2 / and :op1 (m5 / mutate-01 :ARG1 g :quant (p / percentage-entity :value "20.8") :location c :compared-to (m6 / mutate-01 :ARG1 g :quant (p2 / percentage-entity :value "1.6") :location s) :compared-to (m7 / mutate-01 :ARG1 g :quant (p3 / percentage-entity :value "0.0") :location r) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.000")) :op2 (m8 / mutate-01 :ARG1 g2 :quant (p5 / percentage-entity :value "23.4") :location c :compared-to (m9 / mutate-01 :ARG1 "2" :quant (p6 / percentage-entity :value "12.1") :location s) :compared-to (m10 / mutate-01 :ARG1 g2 :quant (p7 / percentage-entity :value "5.4") :location r) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.011")))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3"))) # ::id pmid_2354_8132.104 # ::date 2015-08-30T13:31:52 # ::file pmid_2354_8132_104.txt # ::snt Although the frequency of KRAS mutations is higher in sigmoid and rectum, the difference is not statistically significant. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (s / significant-02 :polarity "-" :ARG1 (d / differ-02) :manner (s2 / statistics) :concession (h / high-02 :ARG1 (f / frequent-02 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))) :location (a / and :op1 (s3 / sigmoid) :op2 (r / rectum)) :degree (m2 / more))) # ::id pmid_2354_8132.105 # ::date 2015-08-30T13:44:03 # ::file pmid_2354_8132_105.txt # ::snt No significant differences were found between genders regarding KRAS, BRAF, or PIK3CA mutation frequencies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (f / find-01 :polarity "-" :ARG1 (d / differ-02 :ARG1 (g / gender) :ARG3 (f2 / frequent-02 :ARG1 (o / or :op1 (m / mutate-01 :ARG1 (g2 / gene :name (n / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (m2 / mutate-01 :ARG1 (g3 / gene :name (n2 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op3 (m3 / mutate-01 :ARG1 (g4 / gene :name (n3 / name :op1 "PIK3CA") :xref (x / xref :value "UNIPROT:PK3CA_HUMAN" :prob "1.003"))))) :ARG1-of (s / significant-02))) # ::id pmid_2384_5441.1 # ::date 2015-06-24T12:39:12 # ::file pmid_2384_5441_1.txt # ::snt A Genetic Progression Model of BrafV600E-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention (PMID:23845441) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (r / reveal-01 :ARG0 (m / model :mod (p / progress-01 :mod (g / genetic)) :topic (c / create-01 :ARG1 (t3 / tumor :mod (i2 / intestine)) :ARG2-of (i3 / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))) :ARG1 (t / target-01 :purpose (i / intervene-01 :ARG1 (t2 / therapy))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID23845441"))) # ::id pmid_2384_5441.52 # ::date 2015-06-24T12:41:09 # ::file pmid_2384_5441_52.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 25, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2384_5441.53 # ::date 2015-06-24T12:53:56 # ::file pmid_2384_5441_53.txt # ::snt BRAFV600E Initiates a Serrated Pathway to Intestinal Tumorigenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (i / initiate-01 :ARG0 (e / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1 (p / pathway :ARG1-of (s / serrate-01) :destination (c / create-01 :ARG1 (t / tumor :mod (i2 / intestine))))) # ::id pmid_2384_5441.54 # ::date 2015-06-24T13:04:20 # ::file pmid_2384_5441_54.txt # ::snt To examine the effect of BrafV600E in the intestine, we created a Braf knockin allele, which can be activated by Cre, leading to the production of the V637E mutant Braf protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / create-01 :ARG0 (w / we) :ARG1 (a / allele :mod (g / gene :name (n / name :op1 "Braf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG1-of (k / knock-in-00) :ARG1-of (a2 / activate-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Cre") :xref (x3 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")) :ARG1-of (p / possible-01) :ARG0-of (l / lead-03 :ARG2 (p3 / produce-01 :ARG0 a2 :ARG1 (e4 / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))))) :purpose (e / examine-01 :ARG0 w :ARG1 (a3 / affect-01 :ARG0 (g2 / gene :name (n4 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG1 (i / intestine)))) # ::id pmid_2384_5441.55 # ::date 2015-06-24T14:14:39 # ::file pmid_2384_5441_55.txt # ::snt BrafV637E in mouse exon 18 is at the orthologous position of the human BRAFV600E mutation affecting exon 15. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (b / be-located-at-91 :ARG1 (g / gene :name (n / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :location (e / exon :mod "18" :mod (m2 / mouse)) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG2 (p / position :mod (o / orthologous) :compared-to (g2 / gene :name (n2 / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "V600E") :mod (h / human) :ARG0-of (a / affect-01 :ARG1 (e2 / exon :mod "15")) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) # ::id pmid_2384_5441.56 # ::date 2015-06-24T14:22:21 # ::file pmid_2384_5441_56.txt # ::snt In the absence of Cre, a Lox-Stop-Lox cassette located in intron 17 prevents expression of the mutant allele (Figures 1A–1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 2, 2015 (p / prevent-01 :ARG0 (c3 / cassette :name (n / name :op1 "Lox-Stop-Lox") :location (i / intron :mod "17")) :ARG1 (e / express-03 :ARG1 (a / allele :ARG2-of (m / mutate-01))) :ARG1-of (c2 / cause-01 :ARG0 (a2 / absent-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "1A") :op2 (f2 / figure :mod "1D")))) # ::id pmid_2384_5441.57 # ::date 2015-06-24T14:29:24 # ::file pmid_2384_5441_57.txt # ::snt To direct mutant Braf expression to the intestine, we used Villin-Cre (Vil-Cre) mice in which Cre is broadly expressed in epithelia of the small and large intestine (Madison et al., 2002). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (m / mouse :mod (m3 / macro-molecular-complex :part (p5 / protein :name (n / name :op1 "Villin") :xref (x2 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352")) :part (e4 / enzyme :name (n5 / name :op1 "Cre") :xref (x1 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :location-of (e / express-03 :ARG2 e4 :ARG3 (e2 / epithelium :part-of (a / and :op1 (i / intestine :mod (s / small)) :op2 (i2 / intestine :mod (l / large)))) :ARG1-of (b / broad-02))) :ARG2 (d / direct-01 :ARG0 w :ARG1 (e3 / express-03 :ARG2 (e5 / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG2 (i3 / intestine)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n4 / name :op1 "Madison")) :op2 (p4 / person :mod (o / other)) :time (d3 / date-entity :year "2002"))))) # ::id pmid_2384_5441.58 # ::date 2015-06-25T10:29:56 # ::file pmid_2384_5441_58.txt # ::snt In Vil-Cre;BrafLSL-V637E/+ mice the stop cassette at the Braf locus is excised specifically in the intestine but not in other organs (Figure 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c3 / contrast-01 :ARG1 (e / excise-01 :ARG1 (c / cassette :ARG2-of (s / stop-01)) :ARG2 (l / locus :mod (g / gene :name (n / name :op1 "Braf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :location (i / intestine) :ARG1-of (s2 / specific-02)) :ARG2 (e2 / excise-01 :polarity "-" :ARG1 c :ARG2 l :location (o / organ :mod (o2 / other))) :location (m / mouse :mod (m3 / macro-molecular-complex :part (p / protein :name (n2 / name :op1 "Villin") :xref (x3 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352")) :part (e4 / enzyme :name (n4 / name :op1 "Cre") :xref (x1 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :mod (g2 / gene :name (n3 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "LSL-V637E/+") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1E"))) # ::id pmid_2384_5441.59 # ::date 2015-06-25T10:44:45 # ::file pmid_2384_5441_59.txt # ::snt The murine BrafLSL-V637E allele is a knockin allele and is thus expressed from the endogenous Braf locus at physiologic levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / allele :mod (g / gene :name (n / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "LSL-V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :domain (a2 / allele :ARG1-of (k / knock-in-00) :ARG0-of (c / cause-01 :ARG1 (e / express-03 :ARG1 "a" :ARG3 (l / locus :mod (g2 / gene :name (n2 / name :op1 "Braf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (e2 / endogenous)) :location (l2 / level :mod (p / physiologic))))) :mod (o / organism :name (n3 / name :op1 "Muridae"))) # ::id pmid_2384_5441.60 # ::date 2015-06-25T11:04:52 # ::file pmid_2384_5441_60.txt # ::snt All Vil-Cre;BrafLSL-V637E/+ animals developed lifelong persistent generalized crypt hyperplasia affecting nearly every crypt, leading to significantly elongated and thickened small and large intestines (Figures 1F–1P; Figure S1A available online). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / develop-01 :ARG1 (a / animal :mod (a2 / all) :mod (m2 / macro-molecular-complex :part (p / protein :name (n / name :op1 "Villin") :xref (x2 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352")) :part (e4 / enzyme :name (n4 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :mod (g / gene :name (n2 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "LSL-V637E/+") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG2 (h / hyperplasia :mod (c / crypt) :ARG1-of (g2 / generalize-01) :duration (l / lifelong) :ARG0-of (a3 / affect-01 :ARG1 (c2 / crypt :mod (e / every :mod (n3 / near)))) :ARG0-of (l2 / lead-03 :ARG2 (a4 / and :op1 (e2 / elongate-01 :ARG1 (a5 / and :op1 (i / intestine :mod (s / small)) :op2 (i2 / intestine :mod (l3 / large)))) :op2 (t / thicken-01 :ARG1 a5) :ARG1-of (s2 / significant-02))) :ARG1-of (p2 / persist-01)) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (v / value-interval :op1 (f / figure :mod "1F") :op2 (f2 / figure :mod "1P")) :op2 (f3 / figure :mod "S1A" :ARG2-of (a7 / available-02 :medium (o / online)))))) # ::id pmid_2384_5441.61 # ::date 2015-06-25T11:31:52 # ::file pmid_2384_5441_61.txt # ::snt Endoscopically and histologically, villi in the small intestine (SI) had a thickened and deformed appearance and were often branched (Figures 1I–1L). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 2, 2015 (a / and :op1 (h / have-03 :ARG0 (v / villus :part-of (i / intestine :mod (s / small))) :ARG1 (a2 / appear-01 :ARG1 (a3 / and :op1 (t / thicken-01) :op2 (d / deform-01)))) :op2 (b / branch-01 :frequency (o / often)) :mod (e / endoscopic) :mod (h2 / histologic) :ARG1-of (d2 / describe-01 :ARG0 (v2 / value-interval :op1 (f / figure :mod "1I") :op2 (f2 / figure :mod "1L")))) # ::id pmid_2384_5441.62 # ::date 2015-06-25T11:44:49 # ::file pmid_2384_5441_62.txt # ::snt Changes in the large intestine (LI) included crypt hyperplasia and mucosal protrusions resembling villous structures that replaced the normal crypt pattern (Figures 1M–1P). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / include-01 :ARG1 (a / and :op1 (h / hyperplasia :mod (c2 / crypt)) :op2 (p / protrude-01 :ARG2 (m / mucus) :ARG1-of (r / resemble-01 :ARG2 (s / structure :mod (v / villus) :ARG2-of (r2 / replace-01 :ARG1 (p2 / pattern-01 :ARG1 (c3 / crypt :ARG1-of (n / normal-02)))))))) :ARG2 (c / change-01 :ARG1 (i2 / intestine :mod (l / large))) :ARG1-of (d / describe-01 :ARG0 (v2 / value-interval :op1 (f / figure :mod "1M") :op2 (f2 / figure :mod "1P")))) # ::id pmid_2384_5441.63 # ::date 2015-06-27T03:51:45 # ::file pmid_2384_5441_63.txt # ::snt This generalized hyperplasia was characterized by focal serrated epithelial formations, which had cytomorphologic features of human microvesicular or goblet cell-rich hyperplastic (serrated) polyps (Figures 1Q–1T and S1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / characterize-01 :ARG1 (h / hyperplasia :mod (t / this) :ARG1-of (g / generalize-01)) :ARG2 (f / form-01 :ARG1 (e / epithelium :ARG1-of (s / serrate-01 :ARG2 (f2 / focus))) :ARG0-of (h2 / have-03 :ARG1 (f3 / feature :mod (c2 / cytomorphologic) :poss (o / or :op1 (p / polyp :mod (m / microvesicular) :mod (h3 / human)) :op2 (p3 / polyp :mod (h5 / hyperplastic) :mod (r / rich :mod (c3 / cell :name (n / name :op1 "goblet" :op2 "cell")))))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (v / value-interval :op1 (f4 / figure :mod "1Q") :op2 (f5 / figure :mod "1T")) :op2 (f6 / figure :mod "S1B")))) # ::id pmid_2384_5441.64 # ::date 2015-06-27T05:24:21 # ::file pmid_2384_5441_64.txt # ::snt Both types were present in the LI, whereas microvesicular hyperplasia was predominant in the SI. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG1 (p / present-02 :ARG1 (t / type-03 :mod (b / both)) :ARG2 (i / intestine :mod (l / large))) :ARG2 (p2 / predominate-01 :ARG1 (h / hyperplasia :mod (m / microvesicular)) :location (i2 / intestine :mod (s / small)))) # ::id pmid_2384_5441.65 # ::date 2015-06-27T05:29:40 # ::file pmid_2384_5441_65.txt # ::snt Because of this resemblance to human serrated hyperplasia (Figure S1B), we refer to the histology in the mouse as murine serrated hyperplasia (mSH). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (r / refer-01 :ARG0 (w / we) :ARG1 (h / histology :location (m / mouse)) :ARG2 (m2 / medical-condition :name (n2 / name :op1 "hyperplasia") :ARG1-of (s / serrate-01) :mod (o / organism :name (n / name :op1 "Muridae"))) :ARG0-of (c / cause-01 :ARG1 (r2 / resemble-01 :ARG2 (m3 / medical-condition :name (n3 / name :op1 "hyperplasia") :mod (h4 / human) :ARG1-of s) :mod (t / this)))) # ::id pmid_2384_5441.66 # ::date 2015-06-27T05:57:20 # ::file pmid_2384_5441_66.txt # ::snt Like in human serrated hyperplastic polyps, there was a mild increase in the number of proliferating cells in mSH as compared to wild-type mucosa (Figures S1C and S1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (i / increase-01 :ARG1 (n / number :quant-of (c / cell :ARG0-of (p / proliferate-01) :location (m4 / medical-condition :name (n2 / name :op1 "mSH")))) :degree (m / mild) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "S1C") :op2 (f2 / figure :mod "S1D"))) :ARG1-of (r / resemble-01 :ARG2 (p2 / polyp :mod (h / hyperplastic) :ARG1-of (s / serrate-01) :mod (h2 / human))) :ARG1-of (c2 / compare-01 :ARG2 (m3 / mucosa :mod (w / wild-type)))) # ::id pmid_2384_5441.67 # ::date 2015-06-27T06:18:51 # ::file pmid_2384_5441_67.txt # ::snt Ki67-positive cells were present in the mid and/or upper crypt in Vil-Cre;BrafLSL-V637E/+ intestines but were restricted to the lower crypt in wild-type intestines (Figure S1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (p4 / present-02 :ARG1 (c2 / cell :mod (p / protein :name (n / name :op1 "Ki67") :xref (x3 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653")) :mod (p2 / positive)) :ARG2 (a / and-or :op1 (c3 / crypt :mod (m / mid)) :op2 (c4 / crypt :mod (u / upper)) :part-of (i / intestine :mod (g / gene :name (n3 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "LSL-V637E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (m4 / macro-molecular-complex :part (p3 / protein :name (n2 / name :op1 "Villin") :xref (x1 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352")) :part (e2 / enzyme :name (n4 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")))))) :ARG2 (r / restrict-01 :ARG1 c2 :location (c5 / crypt :ARG1-of (l / low-04 :degree (m3 / more)) :part-of (i2 / intestine :mod (w / wild-type)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S1C"))) # ::id pmid_2384_5441.68 # ::date 2015-06-27T07:22:54 # ::file pmid_2384_5441_68.txt # ::snt Hyperproliferation seems to be the underlying mechanism of the hyperplastic changes because apoptosis was not reduced in Vil-Cre;BrafLSL-V637E/+ intestines as compared to wild-type mucosa (Figures S1E and S1F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / seem-01 :ARG1 (m / mechanism :ARG0-of (u / underlie-01 :ARG1 (c / change-01 :mod (h2 / hyperplastic))) :domain (h / hyperproliferate-01)) :ARG1-of (c2 / cause-01 :ARG0 (r / reduce-01 :polarity "-" :ARG1 (a / apoptosis) :location (i / intestine :mod (m4 / macro-molecular-complex :part (p / protein :name (n / name :op1 "Villin") :xref (x2 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352")) :part (e2 / enzyme :name (n3 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :mod (g / gene :name (n2 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "LSL-V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG1-of (c3 / compare-01 :ARG2 (m3 / mucosa :mod (w / wild-type))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "S1E") :op2 (f2 / figure :mod "S1F")))) # ::id pmid_2384_5441.69 # ::date 2015-06-27T07:51:34 # ::file pmid_2384_5441_69.txt # ::snt We also intercrossed LSL-BrafV600E mice with Lgr5-EGFP-IRES-CreERT2 knockin mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / intercross-00 :ARG0 (w / we) :ARG1 (m / mouse :mod (m5 / molecular-physical-entity :name (n / name :op1 "LSL") :xref (x1 / xref :value "PUBCHEM:62524" :prob "11.787919")) :mod (g / gene :name (n2 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG2 (m3 / mouse :ARG1-of (k / knock-in-00) :mod (m4 / molecular-physical-entity :name (n3 / name :op1 "Lgr5-EGFP-IRES-CreERT2"))) :mod (a / also)) # ::id pmid_2384_5441.70 # ::date 2015-06-27T09:01:35 # ::file pmid_2384_5441_70.txt # ::snt Tamoxifen-inducible Lgr5-Cre allowed stochastic activation of mutant Braf in a part of the intestinal stem cells, thereby inducing hyperplastic polyps in nonhyperplastic surrounding mucosa (Figure S1G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / allow-01 :ARG0 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "Lgr5") :xref (x2 / xref :value "UNIPROT:LGR5_HUMAN" :prob "0.603")) :part (e2 / enzyme :name (n2 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")) :ARG2-of (i / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "tamoxifen") :xref (x3 / xref :value "PUBCHEM:2733526" :prob "14.823483")) :ARG1-of (p3 / possible-01))) :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "Braf") :ARG1-of (m2 / mutate-01) :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (s2 / stochastic)) :location (p4 / part :part-of (c / cell :mod (s3 / stem) :source (i2 / intestine))) :ARG0-of (c2 / cause-01 :ARG1 (i3 / induce-01 :ARG2 (p5 / polyp :mod (h / hyperplastic)) :location (m3 / mucosa :ARG1-of (s4 / surround-01) :mod (h2 / hyperplastic :polarity "-")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S1G"))) # ::id pmid_2384_5441.71 # ::date 2015-06-27T09:22:48 # ::file pmid_2384_5441_71.txt # ::snt BRAF mutations have been observed in human serrated polyps occurring sporadically or in serrated polyposis syndrome and we show here that BRAFV600E is indeed the underlying initiating event that is sufficient to induce lifelong sustained hyperplasia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / and :op1 (o / observe-01 :ARG1 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :location (o2 / or :op1 (p / polyp :mod (h / human) :ARG1-of (s / serrate-01) :frequency (s2 / sporadic)) :op2 (s3 / syndrome :mod (p2 / polyposis :ARG1-of s)))) :op2 (s4 / show-01 :ARG0 (w / we) :ARG1 (e / event :ARG0-of (i / initiate-01) :ARG0-of (u / underlie-01) :domain (e2 / enzyme :name (n2 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG0-of (s5 / suffice-01 :ARG1 (i2 / induce-01 :ARG2 (h2 / hyperplasia :duration (l / lifelong) :ARG1-of (s6 / sustain-01)))) :mod (i3 / indeed)) :location (h3 / here))) # ::id pmid_2384_5441.72 # ::date 2015-06-27T09:42:14 # ::file pmid_2384_5441_72.txt # ::snt BRAFV600E Induced Serrated Tumorigenesis Progresses through a Hyperplasia/Adenoma/Carcinoma Sequence # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (p / progress-01 :ARG1 (c2 / create-01 :ARG1 (t / tumor) :ARG1-of (s / serrate-01) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :instrument (s2 / slash :op1 (s3 / sequence :mod (m3 / medical-condition :name (n3 / name :op1 "hyperplasia"))) :op2 (s4 / sequence :mod (m2 / medical-condition :name (n2 / name :op1 "adenoma"))) :op3 (s5 / sequence :mod (c / carcinoma)))) # ::id pmid_2384_5441.73 # ::date 2015-06-27T09:52:06 # ::file pmid_2384_5441_73.txt # ::snt To investigate whether mSH progresses to dysplasia, we aged Vil-Cre;BrafLSL-V637E/+mice up to 18 months and sacrificed them at various time points. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (a2 / age-01 :ARG0 (w / we) :ARG1 (m / mice :mod (m2 / macro-molecular-complex :part (p / protein :name (n / name :op1 "Villin") :xref (x2 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352")) :part (e2 / enzyme :name (n2 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :mod (g / gene :name (n3 / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "LSL-V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :time (u / up-to :op1 (t / temporal-quantity :quant "18" :unit (m4 / month)))) :op2 (s / sacrifice-01 :ARG0 w :ARG1 m :time (p3 / point :mod (t2 / time) :mod (v / various))) :purpose (i / investigate-01 :ARG0 w :ARG1 (p4 / progress-01 :mode "interrogative" :ARG1 (m6 / medical-condition :name (n4 / name :op1 "mSH")) :ARG4 (m7 / medical-condition :name (n5 / name :op1 "dysplasia"))))) # ::id pmid_2384_5441.74 # ::date 2015-06-27T10:07:10 # ::file pmid_2384_5441_74.txt # ::snt Hyperplasia to dysplasia progression was often observed at a young age (2–3 months), at which time some animals already developed macroscopic tumors (>2 mm) with dysplasia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 4, 2015 (o / observe-01 :ARG1 (p / progress-01 :ARG3 (h / hyperplasia) :ARG4 (d / dysplasia)) :time (a / age-01 :ARG2 (y / young) :ARG1-of (m / mean-01 :ARG2 (t / temporal-quantity :quant (v / value-interval :op1 "2" :op2 "3") :unit (m2 / month))) :time-of (d2 / develop-01 :ARG1 (a2 / animal :mod (s / some)) :ARG2 (t2 / tumor :mod (m3 / macroscopic) :quant (m4 / more-than :op1 (a3 / area-quantity :quant "2" :unit (m5 / millimeter))) :accompanier d) :time (a4 / already))) :frequency (o2 / often)) # ::id pmid_2384_5441.75 # ::date 2015-06-27T10:38:58 # ::file pmid_2384_5441_75.txt # ::snt At 10 months, virtually all mice had such dysplastic lesions, often large numbers (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 4, 2015 (h / have-03 :ARG0 (m / mouse :mod (a / all) :mod (v / virtual)) :ARG1 (l / lesion :mod (d / dysplastic) :quant (n / number :mod (l2 / large)) :frequency (o / often) :mod (s / such)) :age (t / temporal-quantity :quant "10" :unit (m2 / month)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2384_5441.76 # ::date 2015-06-27T10:48:33 # ::file pmid_2384_5441_76.txt # ::snt Histologically, BrafV637E-induced dysplastic lesions had features of human traditional serrated adenomas (TSAs), including crypt elongation and a serrated eosinophilic adenomatous epithelium (Figures 2B–2E and S1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (h / have-03 :ARG0 (l / lesion :mod (d / dysplastic) :ARG2-of (i / induce-01 :ARG0 (e4 / enzyme :name (n / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :ARG1 (f / feature :ARG2-of (i2 / include-91 :ARG1 (a2 / and :op1 (e / elongate-01 :ARG1 (c / crypt)) :op2 (e2 / epithelium :mod (e3 / eosinophilic) :ARG1-of "s" :mod (m2 / medical-condition :name (n2 / name :op1 "adenoma"))))) :poss (m3 / medical-condition :name (n3 / name :op1 "adenoma") :ARG1-of (s / serrate-01) :mod (t / traditional) :mod (h2 / human))) :manner (h3 / histologic) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (v / value-interval :op1 (f2 / figure :mod "2B") :op2 (f3 / figure :mod "2E")) :op2 (f4 / figure :mod "S1B")))) # ::id pmid_2384_5441.77 # ::date 2015-06-27T12:48:12 # ::file pmid_2384_5441_77.txt # ::snt Although both TSAs and SSAs are associated with mutant BRAF in humans, we did not observe SSA in our model. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (h / have-concession-91 :ARG1 (o / observe-01 :polarity "-" :ARG0 (w / we) :ARG1 (m4 / medical-condition :name (n3 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma")) :location (m / model :poss w)) :ARG2 (a / associate-01 :ARG1 (a2 / and :op1 (m3 / medical-condition :name (n2 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma")) :op2 m4) :ARG2 (g / gene :name (n4 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location (h2 / human))) # ::id pmid_2384_5441.78 # ::date 2015-06-27T12:54:43 # ::file pmid_2384_5441_78.txt # ::snt A possible reason is that mouse tumors were predominantly in the SI (only five of 95 tumors were in the large intestine), where the specific morphologic features of human colonic SSAs might not develop. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / cause-01 :ARG0 (b / be-located-at-91 :ARG1 (t / tumor :mod (m / mouse)) :ARG2 (i / intestine :mod (s / small) :ARG1-of (d / develop-01 :polarity "-" :ARG2 (f / feature :ARG1-of (s2 / specific-02) :mod (m3 / morphologic) :poss (m4 / medical-condition :name (n2 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma") :mod (h / human) :mod (c2 / colon))) :ARG1-of (p3 / possible-01))) :ARG1-of (p2 / predominate-01) :ARG1-of (m2 / mean-01 :ARG2 (b2 / be-located-at-91 :ARG1 (t2 / tumor :quant "5" :ARG1-of (i3 / include-91 :ARG2 (t3 / tumor :quant "95")) :mod (o / only)) :ARG2 (i2 / intestine :mod (l / large))))) :ARG1-of (p / possible-01)) # ::id pmid_2384_5441.79 # ::date 2015-06-27T13:23:40 # ::file pmid_2384_5441_79.txt # ::snt To avoid misleading nomenclature by drawing inadequate morphologic parallels between murine SI lesions and human LI tumors, we refer to dysplastic lesions as “murine serrated adenoma with dysplasia” (mSA) or more specifically as mSA with low-grade dysplasia (mSA-LGD) or high-grade dysplasia (mSA-HGD). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (r / refer-01 :ARG0 (w / we) :ARG1 (l / lesion :mod (d / dysplastic)) :ARG2 (o / or :op1 (m / medical-condition :name (n3 / name :op1 "adenoma") :ARG1-of (s / serrate-01) :mod (o3 / organism :name (n2 / name :op1 "Muridae")) :prep-with (d2 / dysplasia)) :op2 (o2 / or :op1 (m2 / medical-condition :name (n4 / name :op1 "adenoma") :ARG0-of (h4 / have-03 :ARG1 (d3 / dysplasia :degree (g / grade :ARG1-of (l2 / low-04))))) :op2 (m3 / medical-condition :name (n5 / name :op1 "adenoma") :ARG0-of (h3 / have-03 :ARG1 (d4 / dysplasia :degree (g2 / grade :ARG1-of (h / high-02)))) :ARG1-of (s3 / specific-02 :degree (m8 / more))))) :purpose (a2 / avoid-01 :ARG0 w :ARG1 (n / nomenclature :ARG0-of (m7 / mislead-02)) :manner (d5 / draw-01 :ARG1 (p / parallel-01 :ARG1 (a4 / and :op1 (l3 / lesion :mod (i / intestine :mod (s2 / small)) :mod o3)) :mod (m6 / morphologic) :mod (a3 / adequate :polarity "-" :op2 (t / tumor :mod (h2 / human) :mod (i2 / intestine :mod (l4 / large)))))))) # ::id pmid_2384_5441.80 # ::date 2015-06-27T13:55:24 # ::file pmid_2384_5441_80.txt # ::snt Macroscopically, BrafV637E-induced neoplasia resembled human BRAF mutant colonic tumors, which frequently show a nonpolypoid sessile growth pattern (Figure S2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / resemble-01 :ARG1 (n4 / neoplasia :ARG2-of (i / induce-01 :ARG0 (e2 / enzyme :name (n / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :ARG2 (t2 / tumor :mod (h / human) :mod (g / gene :name (n2 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (c / colon) :ARG0-of (s / show-01 :ARG1 (p / pattern :mod (g3 / grow-01 :ARG1 (s2 / sessile :mod (p2 / polypoid :polarity "-")))) :ARG1-of (f2 / frequent-02))) :manner (m3 / macroscopic) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S2A"))) # ::id pmid_2384_5441.81 # ::date 2015-06-27T14:05:26 # ::file pmid_2384_5441_81.txt # ::snt Proliferation rates were increased on average 2.4-fold in mSA-LGD and 9.1-fold in mSA-HGD as compared to hyperplasia (Figures S2B–2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (i / increase-01 :ARG1 (r / rate :degree-of (p / proliferate-01)) :ARG2 (a / and :op1 (p2 / product-of :op1 "2.4" :location (d2 / disease :name (n / name :op1 "mSA-LGD"))) :op1 (p3 / product-of :op1 "9.1" :location (d3 / disease :name (n2 / name :op1 "mSA-HGD"))) :ARG2-of (a2 / average-01)) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "S2B") :op2 (f2 / figure :mod "2D"))) :ARG1-of (c / compare-01 :ARG2 (h / hyperplasia))) # ::id pmid_2384_5441.82 # ::date 2015-06-27T14:19:12 # ::file pmid_2384_5441_82.txt # ::snt Like human BRAF mutant tumors, mouse mSAs frequently showed abundant mucin production and stained positive for Alcian blue (Figure S2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (s / show-01 :ARG0 (d2 / disease :name (n3 / name :op1 "mSA") :mod (m3 / mouse)) :ARG1 (p / produce-01 :ARG1 (m2 / mucin) :mod (a2 / abundant)) :ARG1-of (f2 / frequent-02)) :op2 (s2 / stain-01 :ARG1 d2 :ARG2 (s3 / small-molecule :name (n / name :op1 "Alcian" :op2 "blue") :xref (x1 / xref :value "PUBCHEM:16211091" :prob "10.575867")) :mod (p2 / positive)) :ARG1-of (r / resemble-01 :ARG2 (t / tumor :mod (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m4 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (h / human))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S2E"))) # ::id pmid_2384_5441.83 # ::date 2015-06-27T14:26:59 # ::file pmid_2384_5441_83.txt # ::snt In a subset of mice (n = 5) dysplasia progressed to invasive carcinomas: 8.3% (1/12) of Vil-Cre;BrafLSL-V637E/+ mice younger than 10 months and 13.8% (4/29) of mice older 10 months had cancers (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / progress-01 :ARG1 (d / dysplasia) :ARG4 (c / carcinoma :ARG0-of (i / invade-01)) :location (s / subset :ARG1-of (i2 / include-91 :ARG2 (m / mouse)) :ord (o / ordinal-entity :value "5")) :ARG1-of (m2 / mean-01 :ARG2 (h / have-03 :ARG0 (a / and :op1 (m3 / mouse :quant "1" :ARG1-of (i3 / include-91 :ARG2 (m4 / mouse :quant "12" :mod (g / gene :name (n3 / name :op1 "Braf") :ARG2-of (m6 / mutate-01 :value "LSL-V637E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (y / young :degree (m7 / more) :compared-to (t / temporal-quantity :quant "10" :unit (m9 / month))) :mod (m11 / macro-molecular-complex :part (p3 / protein :name (n / name :op1 "Villin") :xref (x1 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352")) :part (e2 / enzyme :name (n2 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")))) :ARG3 (p2 / percentage-entity :value "8.3"))) :op2 (m8 / mouse :quant "4" :ARG1-of (i4 / include-91 :ARG2 (m10 / mouse :quant "29" :mod g :mod (o2 / old :degree m7 :compared-to t) :mod m11) :ARG3 (p5 / percentage-entity :value "13.8")))) :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2384_5441.84 # ::date 2015-06-28T07:03:52 # ::file pmid_2384_5441_84.txt # ::snt Two of these cancers were low-grade tumors (well and moderately differentiated), and three were high-grade cancers (poorly or undifferentiated; glandular structures in less than 50% of the tumor). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (t / tumor :mod (g / grade :ARG1-of (l / low-04)) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (d / differentiate-01 :ARG1 t :ARG1-of (g2 / good-02)) :op2 (d2 / differentiate-01 :ARG1 t :ARG1-of (m2 / moderate-03)))) :domain (d5 / disease :quant "2" :wiki "Cancer" :name (n / name :op1 "cancer") :ARG1-of (i / include-91 :ARG2 (d6 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :mod (t4 / this))) :op2 (d7 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :domain (d8 / disease :quant "3" :wiki "Cancer" :name (n4 / name :op1 "cancer") :ARG1-of i) :mod (g3 / grade :ARG1-of (h / high-02)) :ARG1-of (m3 / mean-01 :ARG2 (o / or :op1 (d3 / differentiate-01 :ARG1 d7 :manner (p / poor)) :op2 (d4 / differentiate-01 :polarity "-" :ARG1 d7 :ARG1-of (m4 / mean-01 :ARG2 (s / structure :mod (g4 / gland) :poss (t2 / tumor :quant (l2 / less-than :op1 (p2 / percentage-entity :value "50")) :ARG1-of (i2 / include-91 :ARG2 (t3 / tumor)))))))))) # ::id pmid_2384_5441.85 # ::date 2015-06-28T07:04:52 # ::file pmid_2384_5441_85.txt # ::snt Examples are shown in Figures 2F–2I. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 2, 2015 (s / show-01 :ARG1 (e / exemplify-01) :location (v / value-interval :op1 (f / figure :mod "2F") :op2 (f2 / figure :mod "2I"))) # ::id pmid_2384_5441.86 # ::date 2015-06-28T08:14:43 # ::file pmid_2384_5441_86.txt # ::snt Across a larger set of BrafV637E-induced cancers in p53 or p16 mutant backgrounds (Table S1 and detailed below), we found that 30% of tumors were high grade. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (t / tumor :mod (g / grade :ARG1-of (h / high-02)) :ARG1-of (i / include-91 :ARG2 (t2 / tumor) :ARG3 (p / percentage-entity :value "30"))) :location (a / across :op1 (s / set :mod (l / large :degree (m / more)) :ARG2-of (i2 / include-91 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :ARG2-of (i3 / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :location (a2 / and :op1 (b / background :mod (g3 / gene :name (n2 / name :op1 "p53") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :op2 (b2 / background :mod (g2 / gene :name (n3 / name :op1 "p16") :ARG2-of m3 :xref (x1 / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262"))))))) :ARG1-of (d / describe-01 :ARG0 (t3 / table :mod "S1")) :ARG1-of (d2 / detail-01 :location (b3 / below)))) # ::id pmid_2384_5441.87 # ::date 2015-06-28T08:33:36 # ::file pmid_2384_5441_87.txt # ::snt Collectively these results describe a mouse model of serrated intestinal cancer, which provides functional evidence for the key role of mutant Braf in tumor initiation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (d / describe-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t3 / this)) :ARG1 (m / model :mod (m2 / mouse) :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :mod (i / intestine) :ARG1-of (s / serrate-01))) :ARG0-of (p / provide-01 :ARG1 (e / evidence-01 :ARG1 (r2 / role :ARG1-of (k / key-01) :poss (g / gene :name (n / name :op1 "Braf") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :topic (i2 / initiate-01 :ARG0 g :ARG1 (t2 / tumor))) :ARG0-of (f / function-01))) :manner (c2 / collective)) # ::id pmid_2384_5441.88 # ::date 2015-06-28T08:45:17 # ::file pmid_2384_5441_88.txt # ::snt BrafV637E-Induced Murine Intestinal Tumors Are Frequently Microsatellite-Unstable # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / stable-03 :polarity "-" :ARG1 (t / tumor :mod (i / intestine) :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :mod (o / organism :name (n2 / name :op1 "Muridae"))) :ARG1-of (f / frequent-02) :mod (m3 / microsatellite)) # ::id pmid_2384_5441.89 # ::date 2015-06-28T08:54:59 # ::file pmid_2384_5441_89.txt # ::snt High level microsatellite instability (MSI-H) occurs in 50% of human BRAF mutant cancers (Rajagopalan et al., 2002). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (b / be-located-at-91 :ARG1 (s / stable-03 :polarity "-" :degree (l / level :ARG1-of (h2 / high-02)) :mod (m2 / microsatellite)) :ARG2 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (h / human) :mod (g / gene :name (n2 / name :op1 "Braf") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG1-of (i / include-91 :ARG2 (d3 / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod h :mod g) :ARG3 (p / percentage-entity :value "50"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n3 / name :op1 "Rajagopalan")) :op2 (p4 / person :mod (o2 / other))) :time (d2 / date-entity :year "2002")))) # ::id pmid_2384_5441.90 # ::date 2015-06-28T09:10:04 # ::file pmid_2384_5441_90.txt # ::snt It is however not understood at which stage MSI develops and whether BRAF mutations are cause or consequence of MSI. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (c / contrast-01 :ARG2 (u / understand-01 :polarity "-" :ARG1 (a / and :op1 (s / stage :time-of (d / develop-01 :ARG1 (s2 / stable-03 :polarity "-" :mod (m2 / microsatellite)))) :op2 (o / or :mode "interrogative" :op1 (c2 / cause-01 :ARG0 (m / mutate-01 :ARG2 (g / gene :name (n2 / name :op1 "Braf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG1 s2) :op2 (c3 / cause-01 :ARG0 s2 :ARG1 m))))) # ::id pmid_2384_5441.91 # ::date 2015-06-28T09:25:00 # ::file pmid_2384_5441_91.txt # ::snt To address this question, we assessed the MSI status in BrafV637E-induced serrated hyperplasia and neoplasia as well as in Msh2/ and Apcmin control tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (a / assess-01 :ARG0 (w / we) :ARG1 (s / status :ARG1-of (s3 / stable-03 :polarity "-" :mod (m5 / microsatellite)) :location (a2 / and :op1 (m6 / medical-condition :name (n / name :op1 "hyperplasia") :ARG1-of (s2 / serrate-01) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :op2 (m7 / medical-condition :name (n6 / name :op1 "neoplasia") :ARG1-of s2 :ARG1-of i) :op3 (t2 / tumor :mod (c / control) :mod (p / protein :name (n4 / name :op1 "Msh2") :ARG2-of (m2 / mutate-01 :mod "-/-") :xref (x2 / xref :value "UNIPROT:MSH2_HUMAN" :prob "0.603"))) :op4 (t3 / tumor :mod c :mod (p2 / protein :name (n5 / name :op1 "Apc") :ARG2-of (m3 / mutate-01 :mod "-/+" :mod (m4 / min)) :xref (x / xref :value "UNIPROT:APC_HUMAN" :prob "0.604"))))) :purpose (a3 / address-02 :ARG0 w :ARG1 (t / thing :mod (t4 / this) :ARG1-of (q / question-01)))) # ::id pmid_2384_5441.92 # ::date 2015-06-28T09:47:46 # ::file pmid_2384_5441_92.txt # ::snt A panel of eight microsatellite repeats was used for MSI typing (Figure 2J; Supplemental Experimental Procedures). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (u / use-01 :ARG1 (p / panel :consist-of (m3 / molecular-physical-entity :quant "8" :ARG1-of (r2 / repeat-01) :part-of (m / microsatellite))) :ARG2 (t / type-03 :ARG1 (s2 / stable-03 :polarity "-" :mod (m2 / microsatellite))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2J") :op2 (p2 / procedure :mod (e / experiment-01) :ARG2-of (s / supplement-01))))) # ::id pmid_2384_5441.93 # ::date 2015-06-28T09:56:26 # ::file pmid_2384_5441_93.txt # ::snt We found that all BrafV637E-induced hyperplastic polyps (13/13) were microsatellite stable (MSS) or MSI-low (MSI-L). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (s / stable-03 :ARG1 (p / polyp :quant "13" :mod (h / hyperplastic) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :mod (a2 / all) :ARG1-of (i2 / include-91 :ARG2 (p2 / polyp))) :mod (m / microsatellite))) # ::id pmid_2384_5441.94 # ::date 2015-06-28T10:06:14 # ::file pmid_2384_5441_94.txt # ::snt Contrarily, 39.4% (13/33) of BrafV637E-induced mSAs and carcinomas were MSI-H and only 6% (2/32) were MSS (Figure 2J). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (c / contrast-01 :ARG2 (a / and :op1 (h / high-02 :ARG1 (a2 / and :quant "13" :op1 (m / medical-condition :name (n3 / name :op1 "adenoma") :ARG1-of (s2 / serrate-01) :mod (o2 / organism :name (n / name :op1 "Muridae"))) :op2 (m5 / medical-condition :name (n5 / name :op1 "carcinoma")) :ARG1-of (i2 / include-91 :ARG2 (a4 / and :quant "33" :op1 (m4 / medical-condition :name (n4 / name :op1 "adenoma")) :op2 m5 :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :ARG3 (p / percentage-entity :value "39.4"))) :ARG2 (s / stable-03 :polarity "-" :mod (m3 / microsatellite))) :op2 (s3 / stable-03 :ARG1 (a3 / and :quant "2" :op1 m4 :op2 m5 :ARG1-of (i4 / include-91 :ARG2 (a5 / and :quant "32" :op1 m4 :op2 m5 :ARG2-of i) :ARG3 (p2 / percentage-entity :value "6" :mod (o / only)))) :mod m3)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2J"))) # ::id pmid_2384_5441.95 # ::date 2015-06-28T10:40:21 # ::file pmid_2384_5441_95.txt # ::snt MSI-H was observed at similar frequencies in mSAs (10/25; 40%) and carcinomas (3/8; 37.5%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (o / observe-01 :ARG1 (h / high-02 :ARG2 (s / stable-03 :polarity "-" :mod (m3 / microsatellite)) :frequency (f / frequency :ARG1-of (r / resemble-01))) :location (a / and :op1 (m / medical-condition :quant "10" :name (n2 / name :op1 "adenoma") :ARG1-of (i / include-91 :ARG2 (m2 / medical-condition :quant "25" :name (n3 / name :op1 "adenoma")) :ARG3 (p / percentage-entity :value "40")) :ARG1-of (s2 / serrate-01) :mod (o2 / organism :name (n / name :op1 "Muridae"))) :op2 (c / carcinoma :quant "3" :ARG1-of (i2 / include-91 :ARG2 (m4 / medical-condition :quant "8" :name (n4 / name :op1 "carcinoma")) :ARG3 (p2 / percentage-entity :value "37.5"))))) # ::id pmid_2384_5441.96 # ::date 2015-06-28T10:46:54 # ::file pmid_2384_5441_96.txt # ::snt Apcmin-induced adenomas were all (9/9; 100%) MSS or MSI-L. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / stable-03 :ARG1 (m3 / medical-condition :quant "9" :name (n / name :op1 "adenoma") :ARG2-of (i / induce-01 :ARG0 (g / gene :name (n3 / name :op1 "Apc") :ARG2-of (m / mutate-01 :mod "-/+" :value (m2 / min)) :xref (x / xref :value "UNIPROT:APC_HUMAN" :prob "0.604"))) :mod (a3 / all) :ARG1-of (i2 / include-91 :ARG2 (m4 / medical-condition :quant "9" :name (n2 / name :op1 "adenoma")) :ARG3 (p / percentage-entity :value "100"))) :mod (m5 / microsatellite)) # ::id pmid_2384_5441.97 # ::date 2015-06-28T11:06:45 # ::file pmid_2384_5441_97.txt # ::snt The lack of MSI-H in mSH, but its presence in all subsequent stages of tumorigenesis (mSA-LGD, mSA-HGD and carcinoma) suggests its early development during BrafV637E-initiated transformation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (c / contrast-01 :ARG1 (l / lack-01 :ARG0 (m3 / medical-condition :name (n / name :op1 "mSH")) :ARG1 (s4 / stable-03 :polarity "-" :mod (m5 / microsatellite) :ARG2-of (h / high-02))) :ARG2 (b / be-temporally-at-91 :ARG1 s4 :ARG2 (t2 / thing :ARG2-of (s2 / stage-02 :ARG1 (c2 / create-01 :ARG1 (t / tumor)) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (m6 / medical-condition :name (n2 / name :op1 "mSA-LGD")) :op2 (m7 / medical-condition :name (n4 / name :op1 "mSA-HGD")) :op3 (m2 / medical-condition :name (n5 / name :op1 "carcinoma")))) :time (s3 / subsequent))))) :ARG1 (d / develop-01 :ARG2 s4 :time (e / early) :time (t4 / transform-01 :ARG1-of (i / initiate-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m4 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))))) # ::id pmid_2384_5441.98 # ::date 2015-06-28T11:18:33 # ::file pmid_2384_5441_98.txt # ::snt P53 Tumor Suppression Inhibits Invasion and Metastasis but Does Not Affect Tumor Initiation in BrafV637E-Induced Tumorigenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (h / have-concession-91 :ARG1 (i / inhibit-01 :ARG0 (s / suppress-01 :ARG0 (p / protein :name (n / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1 (t / tumor)) :ARG1 (a2 / and :op2 (i2 / invade-01) :op2 (m / metastasize-101))) :ARG2 (a / affect-01 :polarity "-" :ARG0 s :ARG2 (i3 / initiate-01 :ARG1 (c / create-01 :ARG1 (t2 / tumor) :ARG2-of (i4 / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))))) # ::id pmid_2384_5441.99 # ::date 2015-06-28T11:27:15 # ::file pmid_2384_5441_99.txt # ::snt The long latency and low penetrance of cancer development might be explained by the ability of constitutive MAPK signaling to activate anti-oncogenic programs, most notably the p16INK4a/Rb and p19ARF/p53 pathways (Palmero et al., 1998; Lin et al., 1998). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (e / explain-01 :ARG0 (c / capable-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "MAPK") :ARG0-of (s / signal-07) :mod (c2 / constitutive)) :ARG2 (a / activate-01 :ARG0 p3 :ARG1 (p4 / program :ARG0-of (o / oppose-01 :ARG1 (o2 / oncogene)) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (p5 / pathway :name (n3 / name :op1 "p16INK4a/Rb")) :op2 (p6 / pathway :name (n4 / name :op1 "p19ARF/p53"))) :ARG1-of (n5 / notable-04 :degree (m / most)))))) :ARG1 (d / develop-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")) :mod (l / latent :ARG1-of (l2 / long-03)) :ARG1-of (p2 / penetrate-01 :ARG1-of (l3 / low-04)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n6 / name :op1 "Palmero")) :op2 (p9 / person :mod (o3 / other))) :time (d4 / date-entity :year "1998")) :op1 (p10 / publication-91 :ARG0 (a5 / and :op1 (p11 / person :name (n7 / name :op1 "Lin")) :op2 p9) :time d4)))) # ::id pmid_2384_5441.100 # ::date 2015-06-26T01:28:13 # ::file pmid_2384_5441_100.txt # ::snt To investigate the role of p53 in BrafV637E-induced intestinal tumorigenesis, we used p53LSL-R172H/+ knockin mice, expressing the equivalent of the dominant-negative human TP53R175H conditionally (Olive et al., 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (m / mouse :location-of (k / knock-in-00 :ARG1 (p / protein :name (n / name :op1 "p53") :ARG2-of (m2 / mutate-01 :value "LSL-R172H") :xref (x3 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG3-of (e / express-03 :ARG2 (e2 / equal-01 :ARG1 (g / gene :name (n4 / name :op1 "TP53") :ARG2-of (m3 / mutate-01 :value "R175H" :mod "-/-") :mod (h / human) :ARG0-of (d3 / dominate-01) :xref (x2 / xref :value "UNIPROT:P53_HUMAN" :prob "1.003"))) :manner (c / conditional))) :ARG2 (i / investigate-01 :ARG0 w :ARG1 (r / role :poss (p3 / protein :name (n3 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :topic (c2 / create-01 :ARG1 (t / tumor :mod (i2 / intestine)) :ARG2-of (i3 / induce-01 :ARG0 (e3 / enzyme :name (n5 / name :op1 "Braf") :ARG2-of (m4 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a / and :op1 (p5 / person :name (n6 / name :op1 "Olive")) :op2 (p6 / person :mod (o / other))) :time (d2 / date-entity :year "2004")))) # ::id pmid_2384_5441.101 # ::date 2015-06-26T02:48:09 # ::file pmid_2384_5441_101.txt # ::snt We intercrossed them with Vil-Cre;BrafLSL-V637E/+ mice, aged the different double- and triple-transgenic cohorts, and monitored mice for tumor development (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (a / and :op1 (i / intercross-00 :ARG0 (w / we) :ARG1 (a2 / and :op1 (t / they) :op2 (m / mouse :mod (e / enzyme :name (n / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "LSL-V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (e2 / enzyme :name (n2 / name :op1 "Cre") :ARG2-of (e3 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "Villin") :xref (x2 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352"))) :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))))) :op2 (a3 / age-01 :ARG0 w :ARG1 (a4 / and :op1 (c / cohort :mod (p / product-of :op1 "2" :op2 (t2 / transgenesis))) :op2 (c2 / cohort :mod (p2 / product-of :op1 "3" :op2 t2)) :ARG1-of (d / differ-02))) :op2 (m3 / monitor-01 :ARG0 w :ARG1 a2 :ARG2 (d2 / develop-02 :ARG1 (t3 / tumor))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2384_5441.102 # ::date 2015-06-26T05:05:05 # ::file pmid_2384_5441_102.txt # ::snt We found that the average number of mSAs per mouse was similar in Vil-Cre;BrafLSL-V637E/+ and Vil-Cre;BrafLSL-V637E/+;p53LSL-R172H/+ animals (2.3 and 1.8, respectively; Figure 3B; Table S2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (r / resemble-01 :ARG1 (r2 / rate-entity-91 :ARG1 (n / number-01 :ARG1 (d / disease :name (n2 / name :op1 "mSA")) :ARG2 "2.3" :ARG1-of (a / average-01)) :ARG2 (m / mouse) :location (a2 / animal :mod (e / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "LSL-V637E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (e2 / enzyme :name (n4 / name :op1 "Cre") :ARG2-of (e3 / express-03 :ARG1 (g / gene :name (n5 / name :op1 "Villin") :xref (x / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352"))) :xref (x1 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")))) :ARG2 (r3 / rate-entity-91 :ARG1 (n6 / number-01 :ARG1 d :ARG2 "1.8" :ARG1-of a) :ARG2 m :location (a3 / animal :mod e2 :mod e :mod (p / protein :name (n7 / name :op1 "p53") :ARG2-of (m3 / mutate-01 :value "LSL-R172H") :xref (x3 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "3B") :op2 (t / table :mod "S2")))) # ::id pmid_2384_5441.103 # ::date 2015-06-26T09:08:32 # ::file pmid_2384_5441_103.txt # ::snt Likewise, the proportion of mice developing mSAs did not differ between groups (82.9% and 82.8%, respectively, Table S2), suggesting that the p53 pathway does not restrain dysplasia initiation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / differ-02 :polarity "-" :ARG1 (p / proportion-01 :ARG1 (m / mouse :ARG1-of (d2 / develop-01 :ARG2 (d3 / disease :name (n / name :op1 "mSA"))))) :quant (a / and :op1 (p2 / percentage-entity :value "82.9") :op2 (p3 / percentage-entity :value "82.8")) :ARG1-of (d4 / describe-01 :ARG0 (t / table :mod "S2")) :ARG0-of (s / suggest-01 :ARG1 (r / restrain-01 :polarity "-" :ARG0 (p4 / pathway :name (n2 / name :op1 "p53")) :ARG1 (i / initiate-01 :ARG1 (d5 / dysplasia)))) :ARG1-of (r2 / resemble-01) :location (g / group)) # ::id pmid_2384_5441.104 # ::date 2015-06-26T09:36:21 # ::file pmid_2384_5441_104.txt # ::snt In sharp contrast, invasive cancers were found considerably more frequently in Vil-Cre;BrafV637E/+;p53LSL-R172H/+ mice (Figure 3B; Table S3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG2 (f / find-01 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG0-of (i / invade-01)) :location (m / mouse :mod (e / enzyme :name (n2 / name :op1 "Cre") :ARG2-of (e2 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "Villin") :xref (x2 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352"))) :xref (x1 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")) :mod (e3 / enzyme :name (n4 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (p / protein :name (n5 / name :op1 "p53") :ARG2-of (m3 / mutate-01 :value "LSL-R172H") :xref (x3 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG1-of (f2 / frequent-02 :degree (m4 / more :degree (c2 / considerable)))) :degree (s / sharp) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f3 / figure :mod "3B") :op2 (t / table :mod "S3")))) # ::id pmid_2384_5441.105 # ::date 2015-06-26T09:55:51 # ::file pmid_2384_5441_105.txt # ::snt Fifty-six percent of Vil-Cre;BrafLSL-V637E/+; p53LSL-R172H/+ animals at an age of 10–20 months had carcinomas, as compared to 13.8% of mice in the Vil-Cre;BrafLSL-V637E/+ cohort (p = 0.002, χ2 test). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-03 :ARG0 (a / animal :mod (e / enzyme :name (n / name :op1 "Cre") :ARG2-of (e2 / express-03 :ARG1 (g / gene :name (n2 / name :op1 "Villin") :xref (x2 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352"))) :xref (x1 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")) :mod (e3 / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "LSL-V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (p / protein :name (n4 / name :op1 "p53") :ARG2-of (m2 / mutate-01 :value "LSL-R172H") :xref (x3 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1-of (i / include-91 :ARG2 (a2 / animal :mod e :mod e3 :mod p) :ARG3 (p2 / percentage-entity :value "56")) :age (t / temporal-quantity :quant (v / value-interval :op1 "10" :op2 "20") :unit (m3 / month))) :ARG1 (c / carcinoma) :compared-to (h2 / have-03 :ARG0 (m4 / mouse :location (c2 / cohort :mod e :mod e3) :ARG1-of (i2 / include-91 :ARG2 (m5 / mouse :location c2) :ARG3 (p3 / percentage-entity :value "13.8"))) :ARG1 c) :ARG1-of (s / statistical-test-91 :ARG2 "0.002" :ARG4 (t2 / test :name (n5 / name :op1 "χ2")))) # ::id pmid_2384_5441.106 # ::date 2015-06-26T14:00:30 # ::file pmid_2384_5441_106.txt # ::snt The average number of cancers was 5.2 times higher in the Vil-Cre;BrafLSL-V637E/+;p53LSL-R172H/+ cohort (p = 0.007; Mann-Whitney rank sum test). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (n / number-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")) :ARG1-of (a / average-01) :ARG1-of (h / high-02 :degree (m / more) :degree (p / product-of :op1 "5.2")) :location (c / cohort :mod (e / enzyme :name (n3 / name :op1 "Cre") :ARG2-of (e2 / express-03 :ARG1 (g / gene :name (n4 / name :op1 "Villin") :xref (x3 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.352"))) :xref (x2 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")) :mod (e3 / enzyme :name (n5 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "LSL-V637") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (p2 / protein :name (n6 / name :op1 "p53") :ARG2-of (m3 / mutate-01 :value "LSL-R172H") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG1-of (s / statistical-test-91 :ARG2 "0.007" :ARG4 (t / test :name (n7 / name :op1 "Mann-Whitney" :op2 "rank" :op3 "sum" :op4 "test")))) # ::id pmid_2384_5441.107 # ::date 2015-06-26T14:28:15 # ::file pmid_2384_5441_107.txt # ::snt Some animals had more than one synchronous cancer and 25% (3/12) of mice with cancer had metastases to local lymph nodes, pancreas, or lungs (Figures 3C and 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (h / have-03 :ARG0 (a2 / animal :quant (s / some)) :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod (s2 / synchrony) :quant (m / more-than :op1 "1"))) :op2 (h2 / have-03 :ARG0 (m2 / mouse :quant "3" :ARG1-of (i / include-91 :ARG2 (m3 / mouse :quant "12") :ARG3 (p / percentage-entity :value "25")) :ARG0-of (h3 / have-03 :ARG1 d)) :ARG1 (m4 / metastasize-101 :ARG1 d :ARG2 (o / or :op1 (n2 / node :mod (l / lymph) :ARG1-of (l2 / local-02)) :op2 (p2 / pancreas) :op3 (l3 / lung)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3C") :op2 (f2 / figure :mod "3D")))) # ::id pmid_2384_5441.108 # ::date 2015-06-26T14:55:24 # ::file pmid_2384_5441_108.txt # ::snt All together, these data show that p53 does not affect early stages of BrafV637E-induced tumorigenesis but plays an important role in invasiveness control. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (d / data :mod (t / this)) :ARG1 (c / contrast-01 :ARG1 (a / affect-01 :polarity "-" :ARG0 (p / protein :name (n / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :ARG1 (t3 / thing :ARG2-of (s2 / stage-02 :ARG1 (c3 / create-01 :ARG1 (t2 / tumor) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :time (e2 / early)))) :ARG2 (p2 / play-02 :ARG0 p :ARG1 (c2 / control-01 :ARG1 (i2 / invade-01) :mod (i3 / important)))) :ARG2-of (s3 / sum-up-01)) # ::id pmid_2384_5441.109 # ::date 2015-06-26T15:06:03 # ::file pmid_2384_5441_109.txt # ::snt Activation of p53 Tumor Suppression during Advanced, but Not Early Tumorigenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (a / activate-01 :ARG1 (s / suppress-01 :ARG1 (t / tumor :mod (p / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :time (c / contrast-01 :ARG1 (c2 / create-01 :ARG1 (t2 / tumor) :ARG1-of (a2 / advance-01)) :ARG2 (c3 / create-01 :ARG1 (t3 / tumor) :time (e / early :polarity "-")))) # ::id pmid_2384_5441.110 # ::date 2015-06-26T15:10:42 # ::file pmid_2384_5441_110.txt # ::snt We next examined at which stage of tumorigenesis the p53 pathway becomes activated (Figures 3E–3N). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (e / examine-01 :ARG0 (w / we) :ARG1 (t2 / thing :ARG2-of (s / stage-02 :ARG1 (c / create-01 :ARG1 (t / tumor))) :time-of (b / become-01 :ARG1 (p / pathway :name (n / name :op1 "p53")) :ARG2 (a / activate-01 :ARG1 p))) :time (n2 / next) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure :mod "3E") :op2 (f2 / figure :mod "3N")))) # ::id pmid_2384_5441.111 # ::date 2015-06-26T15:19:24 # ::file pmid_2384_5441_111.txt # ::snt We performed immunohistochemistry for p53 and its target gene p21 in wild-type as well as Braf mutant hyperplasia and neoplasia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / perform-01 :ARG0 (w / we) :ARG1 (i / immunohistochemistry) :beneficiary (a / and :op1 (p2 / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :op2 (g / gene :name (n2 / name :op1 "p21") :ARG1-of (t / target-01) :poss p2 :xref (x2 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002"))) :location (a2 / and :op1 (h / hyperplasia :mod (w2 / wild-type)) :op2 (h2 / hyperplasia :ARG2-of (m / mutate-01 :ARG0 (g2 / gene :name (n3 / name :op1 "Braf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :op3 (n4 / neoplasia :mod w2) :op4 (n5 / neoplasia :ARG2-of m))) # ::id pmid_2384_5441.112 # ::date 2015-06-26T15:30:42 # ::file pmid_2384_5441_112.txt # ::snt Immunoreactivity for p53 was negative in all wild-type intestines (n = 21), all BrafV637E-induced mSHs (n = 43), and most mSAs-LGD (Figures 3F–3H and 3N). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (n / negative-01 :ARG1 (a / and :op1 (i2 / intestine :mod (w / wild-type) :mod (a2 / all) :ARG1-of (n3 / number-01 :ARG2 "21")) :op2 (m / medical-condition :name (n4 / name :op1 "mSH") :ARG2-of (i3 / induce-01 :ARG0 (e / enzyme :name (n5 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG1-of (n6 / number-01 :ARG2 "43") :mod a2) :op3 (d2 / disease :name (n7 / name :op1 "mSA-LGD") :quant (m4 / most))) :ARG2 (i / immunoreact-00 :ARG1 (p / protein :name (n2 / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (v / value-interval :op1 (f / figure :mod "3F") :op2 (f2 / figure :mod "3H")) :op2 (f3 / figure :mod "3N")))) # ::id pmid_2384_5441.113 # ::date 2015-06-26T15:52:49 # ::file pmid_2384_5441_113.txt # ::snt Only 5/37 mSAs-LGD were p53-positive (example in Figure 3I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (p / positive :topic (p2 / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :domain (d / disease :quant "5" :name (n2 / name :op1 "mSA-LGD") :ARG1-of (i / include-91 :ARG2 (d2 / disease :quant "37" :name (n3 / name :op1 "mSA-LGD")))) :mod (o / only) :ARG0-of (e / exemplify-01 :location (f / figure :mod "3I"))) # ::id pmid_2384_5441.114 # ::date 2015-06-26T15:57:40 # ::file pmid_2384_5441_114.txt # ::snt We detected however marked p53 expression in 97% (28/29) of mSAs-HGD (Figures 3L and 3N). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (h / have-concession-91 :ARG2 (d / detect-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :degree (m / mark-01)) :location (d2 / disease :quant "28" :name (n2 / name :op1 "mSA-HGD") :ARG1-of (i / include-91 :ARG2 (d3 / disease :quant "29" :name (n3 / name :op1 "mSA-HGD")) :ARG3 (p2 / percentage-entity :value "97")))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "3L") :op2 (f2 / figure :mod "3N")))) # ::id pmid_2384_5441.115 # ::date 2015-06-26T16:05:44 # ::file pmid_2384_5441_115.txt # ::snt There was a strong concordance of p53 and p21 immunoreactivity in all samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 29, 2016 (r / resemble-01 :ARG1 (i / immunoreact-00 :ARG1 (p / protein :name (n / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG2 (i2 / immunoreact-00 :ARG1 (p2 / protein :name (n2 / name :op1 "p21") :xref (x / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002"))) :location (t / thing :mod (a / all) :ARG1-of (s / sample-01)) :degree (s2 / strong)) # ::id pmid_2384_5441.116 # ::date 2015-06-26T16:17:20 # ::file pmid_2384_5441_116.txt # ::snt Similar to p53, p21 IHC was negative in all wild-type intestines (n = 21), all BrafV637E-induced mSHs (n = 15), and most (10/11) mSAs-LGD but was present in the majority (8/9; 89%) of mSAs-HGD (Figures 3G, 3J, 3M, and 3N). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / contrast-01 :ARG1 (n / negative-01 :ARG1 (a / and :op1 (i2 / intestine :mod (w / wild-type) :mod (a2 / all) :ARG1-of (n3 / number-01 :ARG2 "21")) :op2 (d / disease :name (n4 / name :op1 "mSH") :ARG2-of (i3 / induce-01 :ARG0 (e / enzyme :name (n5 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG1-of (n6 / number-01 :ARG2 "15") :mod a2) :op3 (m4 / medical-condition :quant "10" :name (n7 / name :op1 "mSA-LGD") :ARG1-of (i4 / include-91 :ARG2 (m5 / medical-condition :quant "11" :name (n8 / name :op1 "mSA-LGD")) :ARG3 (m2 / most)))) :ARG2 (i / immunohistochemistry :mod (p / protein :name (n2 / name :op1 "p21") :xref (x2 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")))) :ARG2 (p4 / present-02 :ARG1 i :ARG2 (m6 / medical-condition :quant "8" :name (n9 / name :op1 "mSA-HGD") :ARG1-of (i5 / include-91 :ARG2 (m7 / medical-condition :quant "9" :name (n10 / name :op1 "mSA-HGD")) :ARG3 (a3 / and :op1 (m3 / majority) :op2 (p2 / percentage-entity :value "89"))))) :ARG1-of (r / resemble-01 :ARG2 (p3 / protein :name (n11 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG1-of (d6 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "3G") :op2 (f2 / figure :mod "3J") :op3 (f3 / figure :mod "3M") :op4 (f4 / figure :mod "3N")))) # ::id pmid_2384_5441.117 # ::date 2015-06-26T16:40:12 # ::file pmid_2384_5441_117.txt # ::snt These data suggest selective activation of p53 tumor suppression during advanced but not early stages of tumor evolution. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (a / activate-01 :ARG1 (s2 / suppress-01 :ARG1 (t2 / tumor :mod (p / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :ARG0-of (s3 / select-01) :time (c / contrast-01 :ARG1 (t3 / thing :ARG2-of (s4 / stage-02 :ARG1 (e / evolve-01 :ARG1 t2) :ARG1-of (a2 / advance-01))) :ARG2 (t4 / thing :ARG2-of (s5 / stage-02 :ARG1 e :time (e2 / early :polarity "-")))))) # ::id pmid_2384_5441.118 # ::date 2015-06-26T16:47:50 # ::file pmid_2384_5441_118.txt # ::snt To investigate the mechanism of p53 activation, we first stained for the DNA damage marker γH2AX. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (s / stain-01 :ARG0 (w / we) :purpose (m / marker :name (n / name :op1 "γH2AX") :mod (d / damage-01 :ARG1 (n2 / nucleic-acid :name (n4 / name :op1 "DNA")))) :time (f / first) :purpose (i / investigate-01 :ARG0 w :ARG1 (m2 / mechanism :poss (a / activate-01 :ARG1 (p / protein :name (n3 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))))) # ::id pmid_2384_5441.119 # ::date 2015-06-26T17:34:07 # ::file pmid_2384_5441_119.txt # ::snt Oncogene-induced DNA damage can activate p53 via ARF-independent pathways (Sherr and McCormick, 2002). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 2, 2015 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (d / damage-01 :ARG1 (n5 / nucleic-acid :name (n6 / name :op1 "DNA")) :ARG2-of (i / induce-01 :ARG0 (o / oncogene))) :ARG1 (p2 / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :instrument (p3 / pathway :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 (p4 / protein :name (n2 / name :op1 "ARF") :xref (x1 / xref :value "UNIPROT:ARF_HUMAN" :prob "1.002"))))) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and :op1 (p6 / person :name (n3 / name :op1 "Sherr")) :op2 (p7 / person :name (n4 / name :op1 "McCormick"))) :time (d5 / date-entity :year "2002")))) # ::id pmid_2384_5441.120 # ::date 2015-06-26T17:42:20 # ::file pmid_2384_5441_120.txt # ::snt All mSHs (n = 20) or mSAs-LGD (n = 12) were γH2AX-negative (Figure 3K), and only three of 17 mSAs-HGD (all p53/p21-positive) showed evidence for activation of the DNA damage response. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / and :op1 (n / negative-01 :ARG1 (o / or :op1 (m / medical-condition :name (n3 / name :op1 "mSH") :ARG1-of (n4 / number-01 :ARG2 "20")) :op2 (m4 / medical-condition :name (n5 / name :op1 "mSA-LGD") :ARG1-of (n6 / number-01 :ARG2 "12")) :mod (a2 / all)) :ARG2 (p4 / protein :name (n2 / name :op1 "γH2AX") :xref (x2 / xref :value "UNIPROT:H2AX_HUMAN" :prob "0.692")) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3K"))) :op2 (s / show-01 :ARG0 (m3 / medical-condition :quant "3" :name (n7 / name :op1 "mSA-HGD") :ARG1-of (i / include-91 :ARG2 (m2 / medical-condition :quant "17" :name (n8 / name :op1 "mSA-HGD") :mod (p / positive :topic (s2 / slash :op1 (p2 / protein :name (n9 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :op2 (p3 / protein :name (n10 / name :op1 "p21") :xref (x1 / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")))) :mod a2)) :mod (o2 / only)) :ARG1 (e / evidence-01 :ARG1 (a3 / activate-01 :ARG1 (r / respond-01 :ARG2 (d6 / damage-01 :ARG1 (n11 / nucleic-acid :name (n12 / name :op1 "DNA")))))))) # ::id pmid_2384_5441.121 # ::date 2015-06-26T17:55:25 # ::file pmid_2384_5441_121.txt # ::snt In contrast, p19Arf expression increased substantially during tumor progression: average normalized p19Arf mRNA levels were similar in BrafV637E-induced mSHs (0.7) and wild-type mucosa (1.0), but were increased 9.9-, 32.3-, and 39.4-fold in mSAs-LGD, mSAs-HGD, and carcinomas, respectively (Figure 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (i / increase-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "p19Arf") :xref (x1 / xref :value "UNIPROT:CD2A2_HUMAN" :prob "0.652"))) :degree (s / substantial) :time (p2 / progress-01 :ARG1 (t / tumor)) :ARG1-of (m / mean-01 :ARG2 (c2 / contrast-01 :ARG1 (r / resemble-01 :ARG1 (l / level :quant-of (n8 / nucleic-acid :name (n2 / name :op1 "mRNA")) :mod p :ARG1-of (n3 / normalize-01) :ARG1-of (a / average-04)) :location (a2 / and :op1 (m6 / medical-condition :quant "0.7" :name (n4 / name :op1 "mSH") :ARG2-of (i2 / induce-01 :ARG0 (e2 / enzyme :name (n5 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :op2 (m3 / mucosa :quant "1.0" :mod (w / wild-type)))) :ARG2 (a3 / and :op1 (i3 / increase-01 :ARG1 l :ARG2 (p3 / product-of :op1 "9.9") :location (m4 / medical-condition :name (n6 / name :op1 "mSA-LGD"))) :op2 (i4 / increase-01 :ARG1 l :ARG2 (p4 / product-of :op1 "32.3") :location (m5 / medical-condition :name (n7 / name :op1 "mSA-HGD"))) :op3 (i5 / increase-01 :ARG1 l :ARG2 (p5 / product-of :op1 "39.4") :location (c3 / carcinoma)))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "3E"))) # ::id pmid_2384_5441.122 # ::date 2015-06-26T21:39:48 # ::file pmid_2384_5441_122.txt # ::snt We conclude that p53 is activated mainly via p19Arf in advanced BrafV637E-iduced tumorigenesis, explaining its late stage specific function. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (c / conclude-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "p19Arf") :xref (x2 / xref :value "UNIPROT:CD2A2_HUMAN" :prob "0.652")) :ARG1 (p2 / protein :name (n3 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :mod (m / main) :time (c2 / create-01 :ARG1 (t / tumor) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n4 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG1-of (a2 / advance-01)) :ARG0-of (e2 / explain-01 :ARG1 (f / function-01 :ARG0 p2 :ARG1-of (s / specific-02 :ARG2 (t2 / thing :ARG2-of (s2 / stage-02 :ARG1 c2))) :time (l / late))))) # ::id pmid_2384_5441.123 # ::date 2015-06-26T21:49:50 # ::file pmid_2384_5441_123.txt # ::snt Selective Pressure for p53 Inactivation Develops at Advanced Stages of Tumor Evolution # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (d / develop-01 :ARG2 (p / pressure-01 :ARG1 (a / activate-01 :polarity "-" :ARG1 (p2 / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG0-of (s / select-01)) :time (s2 / stage :subevent-of (e / evolve-01 :ARG1 (t / tumor)) :ARG1-of (a2 / advance-01))) # ::id pmid_2384_5441.124 # ::date 2015-06-26T21:54:23 # ::file pmid_2384_5441_124.txt # ::snt To examine whether p53 mutations occur spontaneously during BrafV637E-induced intestinal tumorigenesis, we next sequenced p53 in Braf mutant tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (s / sequence-01 :ARG0 (w / we) :ARG1 (p / protein :name (n / name :op1 "p53") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :location (t / tumor :ARG0-of (m / mutate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Braf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :time (n3 / next) :purpose (e2 / examine-01 :ARG0 w :ARG1 (m2 / mutate-01 :mode "interrogative" :ARG1 p :manner (s2 / spontaneous) :time (c / create-01 :ARG1 (t2 / tumor :mod (i / intestine)) :ARG2-of (i2 / induce-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "V637E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))))) # ::id pmid_2384_5441.125 # ::date 2015-06-26T22:01:37 # ::file pmid_2384_5441_125.txt # ::snt Whereas mSAs (n = 17) did not have p53 mutations, we identified a missense mutation (S152R; equivalent of human T155A) in one of the two carcinomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (i / identify-01 :ARG0 (w / we) :ARG1 (m / mutate-01 :value "S152R" :mod (m2 / missense) :ARG1-of (e / equal-01 :ARG2 (m3 / mutate-01 :value "T155A" :mod (h / human)))) :location (c / carcinoma :quant "1" :ARG1-of (i2 / include-91 :ARG2 (c2 / carcinoma :quant "2"))) :ARG1-of (c3 / contrast-01 :ARG2 (h2 / have-03 :polarity "-" :ARG0 (d / disease :name (n / name :op1 "mSA") :ARG1-of (n2 / number-01 :ARG2 "17")) :ARG1 (m4 / mutate-01 :ARG1 (p / protein :name (n3 / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))))) # ::id pmid_2384_5441.126 # ::date 2015-06-26T22:09:26 # ::file pmid_2384_5441_126.txt # ::snt S152R leads to stabilization of nonfunctional p53, as evidenced by loss of p21 expression in cancer cells (Figures 3O–3Q). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 2, 2015 (l / lead-03 :ARG0 (m / mutate-01 :value "S152R") :ARG2 (s / stabilize-01 :ARG1 (p / protein :name (n / name :op1 "p53") :ARG0-of (f / function-01 :polarity "-") :xref (x1 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG1-of (e / evidence-01 :ARG0 (l2 / lose-02 :ARG1 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "p21") :xref (x / xref :value "UNIPROT:CDN1A_HUMAN" :prob "1.002")) :ARG3 (c / cell :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))))) :ARG1-of (d2 / describe-01 :ARG0 (v / value-interval :op1 (f2 / figure :mod "3O") :op2 (f3 / figure :mod "3Q")))) # ::id pmid_2384_5441.127 # ::date 2015-06-26T22:15:08 # ::file pmid_2384_5441_127.txt # ::snt In the second cancer, p53 expression was lost whereas the surrounding dysplasia, which gave rise to the cancer, was p53-positive (Figures 3R and 3S). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (c / contrast-01 :ARG1 (l / lose-02 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")))) :ARG2 (p2 / positive :topic p :domain (d / dysplasia :ARG1-of (s / surround-01) :ARG0-of (g / give-01 :ARG1 (a / arise-02 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))) :location (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ord (o / ordinal-entity :value "2")) :ARG1-of (d4 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3R") :op2 (f2 / figure :mod "3S")))) # ::id pmid_2384_5441.128 # ::date 2015-06-26T22:23:49 # ::file pmid_2384_5441_128.txt # ::snt These results suggest late stage specific selective pressure to inactivate p53, further supporting the importance of p53 for invasiveness control. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p / pressure-01 :ARG2 (a / activate-01 :polarity "-" :ARG1 (p2 / protein :name (n / name :op1 "p53") :xref (x / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :ARG0-of (s2 / select-01) :ARG1-of (s3 / specific-02) :time (s4 / stage :mod (l / late))) :ARG0-of (s5 / support-01 :ARG1 (i / important :domain p2 :purpose (c / control-01 :ARG1 (i2 / invade-01))) :mod (f / further))) # ::id pmid_2384_5441.129 # ::date 2015-06-26T22:30:17 # ::file pmid_2384_5441_129.txt # ::snt Inactivation of p16 Promotes Advanced Phases of BrafV637E-Induced Intestinal Tumorigenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (p / promote-01 :ARG0 (a / activate-01 :polarity "-" :ARG1 (p2 / protein :name (n / name :op1 "p16") :xref (x / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262"))) :ARG1 (p3 / phase :subevent-of (c / create-01 :ARG1 (t / tumor :mod (i / intestine)) :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :ARG1-of (a2 / advance-01))) # ::id pmid_2384_5441.130 # ::date 2015-06-26T22:42:10 # ::file pmid_2384_5441_130.txt # ::snt To examine the role of p16Ink4a, we first analyzed p16Ink4a expression in Braf mutant healthy and neoplastic intestines (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / analyze-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (g / gene :name (n / name :op1 "p16Ink4a") :xref (x1 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :ARG3 (a2 / and :op1 (i / intestine :mod (n2 / neoplasm)) :op2 (i2 / intestine :mod (h / health)) :ARG0-of (m / mutate-01 :ARG2 (g2 / gene :name (n3 / name :op1 "Braf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))) :time (f / first) :purpose (e3 / examine-01 :ARG0 w :ARG1 (r / role :poss g)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4A"))) # ::id pmid_2384_5441.131 # ::date 2015-06-26T22:47:42 # ::file pmid_2384_5441_131.txt # ::snt Whereas p16Ink4a expression was similar in Braf mutant mSH and WT mucosa, there was a marked upregulation of p16Ink4a expression in Braf mutant neoplasia. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / upregulate-01 :ARG1 (e / express-03 :ARG2 (g / gene :name (n / name :op1 "p16Ink4a") :xref (x1 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691"))) :location (n2 / neoplasia :ARG0-of (m / mutate-01 :ARG2 (g2 / gene :name (n3 / name :op1 "Braf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :degree (m2 / marked) :ARG1-of (c / contrast-01 :ARG2 (r / resemble-01 :ARG1 e :location (a / and :op1 (m4 / medical-condition :name (n4 / name :op1 "mSH") :ARG0-of m) :op2 (m3 / mucosa :mod (w / wild-type)))))) # ::id pmid_2384_5441.132 # ::date 2015-06-26T22:56:52 # ::file pmid_2384_5441_132.txt # ::snt This effect was less pronounced in mSAs-LGD than in mSAs-HGD, in which p16Ink4a was induced on average 100-fold (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (p / pronounced-02 :ARG1 (t / thing :ARG2-of (a / affect-01) :mod (t2 / this)) :location (d / disease :name (n / name :op1 "mSA-LGD")) :degree (l / less) :compared-to (d2 / disease :name (n2 / name :op1 "mSA-HGD") :location-of (p2 / pronounced-02 :ARG1 t) :location-of (i / induce-01 :ARG2 (g / gene :name (n3 / name :op1 "p16Ink4a") :xref (x / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :quant (p4 / product-of :op1 "100" :ARG1-of (a2 / average-01)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id pmid_2384_5441.133 # ::date 2015-06-30T00:26:23 # ::file pmid_2384_5441_133.txt # ::snt Thus, similarly to BrafV637E-induced Arf/p53 activation, substantial p16Ink4a activation is only triggered at advanced stages of tumorigenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (i / infer-01 :ARG1 (t / trigger-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "p16Ink4a") :xref (x1 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :mod (s / substantial)) :mod (o / only) :ARG1-of (r / resemble-01 :ARG2 (a3 / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "Arf/p53")) :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))) :time (t3 / thing :ARG2-of (s2 / stage-02 :ARG1 (c / create-01 :ARG1 (t2 / tumor)) :ARG1-of (a2 / advance-01))))) # ::id pmid_2384_5441.134 # ::date 2015-06-30T00:50:25 # ::file pmid_2384_5441_134.txt # ::snt This is consistent with observations in humans, where p16 was upregulated in BRAF mutant premalignant lesions (SSAs and TSAs) but not in hyperplasia (Kriegl et al., 2011). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (c / consistent-01 :ARG1 (t / this) :ARG2 (o / observe-01 :location (h / human :location-of (c2 / contrast-01 :ARG1 (u / upregulate-01 :ARG1 (g / gene :name (n / name :op1 "p16") :xref (x1 / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262")) :condition (l / lesion :mod (p / premalignant) :mod (g2 / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (m4 / medical-condition :name (n4 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma")) :op2 (m3 / medical-condition :name (n5 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma")))))) :ARG2 (u2 / upregulate-01 :polarity "-" :ARG1 g :condition (h2 / hyperplasia))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n3 / name :op1 "Kriegl")) :op2 (p4 / person :mod (o2 / other))) :time (d / date-entity :year "2011")))) # ::id pmid_2384_5441.135 # ::date 2015-06-30T01:01:26 # ::file pmid_2384_5441_135.txt # ::snt To investigate whether p16Ink4a inactivation occurs spontaneously in BrafV637E-induced tumors, we performed comparative genomic hybridization, sequencing, and methylation analysis of the cdkn2a locus. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (p / perform-01 :ARG0 (w / we) :ARG1 (a / and :op1 (h / hybridize-01 :ARG1 (l / locus :ARG0-of (c2 / contain-01 :ARG1 (g2 / gene :name (n / name :op1 "CDKN2A") :xref (x1 / xref :value "UNIPROT:CD2A1_HUMAN" :prob "1.002")))) :mod (g / genome) :ARG0-of (c / compare-01)) :op2 (s / sequence :mod g2) :op3 (a2 / analyze-01 :ARG1 g2 :mod (m / methylate-01))) :purpose (i / investigate-01 :ARG0 w :ARG1 (a3 / activate-01 :polarity "-" :mode "interrogative" :ARG1 (g4 / gene :name (n2 / name :op1 "p16Ink4a") :xref (x / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :mod (s2 / spontaneous) :location (t / tumor :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))))) # ::id pmid_2384_5441.136 # ::date 2015-06-30T01:13:43 # ::file pmid_2384_5441_136.txt # ::snt We did not identify Cdkn2a mutations or copy number alterations in any of the 12 TSAs and eight carcinomas analyzed (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Dec 9, 2015 (i / identify-01 :polarity "-" :ARG0 (w / we) :ARG1 (o / or :op1 (m / mutate-01 :ARG2 (g / gene :name (n / name :op1 "Cdkn2a") :xref (x / xref :value "UNIPROT:CD2A1_HUMAN" :prob "0.602"))) :op2 (a / alter-01 :ARG1 (n2 / number :quant-of (t2 / thing :ARG2-of (c / copy-01))))) :location (a2 / and :op1 (m2 / medical-condition :name (n3 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma")) :op2 (c2 / carcinoma :quant "8") :mod (a3 / any) :ARG1-of (a4 / analyze-01)) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s / show-01 :polarity "-")))) # ::id pmid_2384_5441.137 # ::date 2015-06-30T01:19:31 # ::file pmid_2384_5441_137.txt # ::snt In a subset of BrafV637E-induced mSAs-HGD and carcinomas, however, we found partial CpG island methylation in the p16Ink4a (but not p19Arf) promoter (Figure S3), similar to observations in humans (Kriegl et al., 2011). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 3, 2015 (h / have-concession-91 :ARG1 (c2 / contrast-01 :ARG1 (f / find-01 :ARG0 (w / we) :ARG1 (m / methylate-01 :ARG1 (d2 / dna-sequence :name (n / name :op1 "CpG" :op2 "island") :part-of (m2 / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (g2 / gene :name (n2 / name :op1 "p16Ink4a") :xref (x1 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691"))))) :degree (p / part))) :ARG2 (f2 / find-01 :polarity "-" :ARG0 w :ARG1 (m4 / methylate-01 :ARG1 (d3 / dna-sequence :name (n4 / name :op1 "CpG" :op2 "island") :part-of (m3 / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (g3 / gene :name (n3 / name :op1 "p19Arf") :xref (x / xref :value "UNIPROT:CD2A2_HUMAN" :prob "0.652"))))) :degree p)) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "S3")) :location (s / subset :ARG1-of (i2 / include-91 :ARG2 (a / and :op1 (d6 / disease :name (n7 / name :op1 "mSA-HGD")) :op2 (c3 / carcinoma) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n5 / name :op1 "Braf") :ARG2-of (m6 / mutate-01 :value "V637E") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))))) :ARG2-of (r2 / resemble-01 :ARG1 (o / observe-01 :location (h2 / human)))) :ARG1-of (d5 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a2 / and :op1 (p7 / person :name (n6 / name :op1 "Kriegl")) :op2 (p8 / person :mod (o2 / other))) :time (d / date-entity :year "2011")))) # ::id pmid_2384_5441.138 # ::date 2015-06-30T01:42:46 # ::file pmid_2384_5441_138.txt # ::snt To study the effect of p16Ink4a inactivation in vivo, we used p16Ink4a mice, which have a point mutation that is silent in the p19Arf reading frame but introduces a stop codon in p16Ink4a (Krimpenfort et al., 2001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (u2 / use-01 :ARG0 (w / we) :ARG1 (m / mouse :mod (g / gene :name (n / name :op1 "p16Ink4a*") :xref (x2 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.601")) :location-of (m2 / mutate-01 :mod (p / point) :mod (s / silent) :location (f / frame :topic (r / read-01) :mod (g3 / gene :name (n2 / name :op1 "p19Arf") :xref (x / xref :value "UNIPROT:CD2A2_HUMAN" :prob "0.652"))) :ARG1-of (c / contrast-01 :ARG2 (i / introduce-02 :ARG0 m2 :ARG1 (c2 / codon :mod (s2 / stop)) :ARG2 "g2")))) :ARG2 (s3 / study-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (a2 / activate-01 :polarity "-" :ARG1 (g2 / gene :name (n5 / name :op1 "p16Ink4a") :xref (x1 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691"))) :manner (i2 / in-vivo))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n4 / name :op1 "Krimpenfort")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2001")))) # ::id pmid_2384_5441.139 # ::date 2015-06-30T02:36:36 # ::file pmid_2384_5441_139.txt # ::snt Vil-Cre;BrafLSL-V637E/+ mice with heterozygous or homozygous mutation of p16Ink4a(Vil-Cre;BrafLSL-V637E/+;p16Ink4a) were aged and sacrificed at different time points to assess tumor incidence and latency (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op1 (a2 / age-01 :ARG1 (m / mouse :location-of (o / or :op1 (m2 / mutate-01 :ARG2 (g2 / gene :name (n / name :op1 "p16Ink4a") :xref (x2 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :mod (h / heterozygous)) :op2 (m3 / mutate-01 :ARG2 g2 :mod (h2 / homozygous))) :mod (g / gene :name (n2 / name :op1 "Braf") :ARG2-of (m4 / mutate-01 :value "LSL-V637E/+") :xref (x4 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG1-of (d3 / describe-01 :ARG2 (m5 / mouse :mod g :mod (g3 / gene :name (n4 / name :op1 "p16Ink4a") :ARG2-of (m6 / mutate-01) :xref (x1 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :mod "e")) :mod (e / enzyme :name (n3 / name :op1 "Cre") :ARG2-of (e2 / express-03 :ARG1 (g4 / gene :name (n5 / name :op1 "Vil") :xref (x / xref :value "UNIPROT:VILI_HUMAN" :prob "0.602"))) :xref (x3 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202")))) :op2 (s / sacrifice-01 :ARG1 m :time (p2 / point :ARG1-of (d / differ-02)) :purpose (a3 / assess-01 :ARG1 (a4 / and :op1 (i / incidence) :op2 (l / latency) :mod (t / tumor)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id pmid_2384_5441.140 # ::date 2015-06-30T02:53:37 # ::file pmid_2384_5441_140.txt # ::snt We observed 1.3-fold increased numbers of mSAs in Vil-Cre;BrafLSL-V637E/+;p16Ink4a animals as compared to Vil-Cre;BrafLSL-V637E/+ mice, but this was statistically not significant (Figure 4C; Table S4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c / contrast-01 :ARG1 (o / observe-01 :ARG0 (w / we) :ARG1 (n / number :quant-of (d2 / disease :name (n6 / name :op1 "mSA")) :ARG1-of (i / increase-01 :ARG2 (p / product-of :op1 "1.3") :location (a / animal :mod "g" :mod (g2 / gene :name (n4 / name :op1 "p16Ink4a") :ARG2-of (m4 / mutate-01) :xref (x1 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :mod (e / enzyme :name (n3 / name :op1 "Cre") :ARG2-of (e2 / express-03 :ARG1 (g3 / gene :name (n5 / name :op1 "Vil") :xref (x / xref :value "UNIPROT:VILI_HUMAN" :prob "0.602"))) :xref (x2 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :compared-to (m2 / mouse :mod (g / gene :name (n2 / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+") :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod e)))) :ARG2 (s / significant-02 :polarity "-" :ARG1 n :manner (s2 / statistic)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (t / table :mod "S4") :op2 (f / figure :mod "4C")))) # ::id pmid_2384_5441.141 # ::date 2015-06-30T03:05:03 # ::file pmid_2384_5441_141.txt # ::snt In contrast, carcinoma development was significantly increased in Vil-Cre;BrafLSL-V637E/+;p16Ink4 mice, which had on average 6.4 times as many cancers as Vil-Cre;BrafLSL-V637E/+;p16Ink4a+/+ mice (p < 0.001; Figure 4C; Table S5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (c / contrast-01 :ARG2 (i / increase-01 :ARG1 (d / develop-01 :ARG2 (c2 / carcinoma)) :ARG2 (s / significant-02) :location (m / mouse :mod (g / gene :name (n / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+") :xref (x4 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG0-of (h / have-03 :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :quant (p / product-of :op1 "6.4" :ARG1-of (a / average-01)) :compared-to (m2 / mouse :mod g :mod (g2 / gene :name (n3 / name :op1 "p16Ink4a") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :mod "e"))) :mod (g3 / gene :name (n4 / name :op1 "p16Ink4a") :ARG2-of (m5 / mutate-01) :xref (x1 / xref :value "UNIPROT:R9S252_HUMAN" :prob "0.691")) :mod (e / enzyme :name (n2 / name :op1 "Cre") :ARG2-of (e2 / express-03 :ARG1 (g4 / gene :name (n5 / name :op1 "Vil") :xref (x / xref :value "UNIPROT:VILI_HUMAN" :prob "0.602"))) :xref (x3 / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than :op1 "0.001"))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (t / table :mod "S5") :op2 (f / figure :mod "4C")))) # ::id pmid_2384_5441.142 # ::date 2015-06-30T03:13:11 # ::file pmid_2384_5441_142.txt # ::snt Many of the mice developed multiple synchronous carcinomas and, in some animals (3/24), these tumors were metastatic. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 16, 2015 (a / and :op1 (d / develop-01 :ARG1 (m / mouse :quant (m2 / many)) :ARG2 (c / carcinoma :quant (m3 / multiple) :ARG1-of (s / synchronous-02))) :op2 (m4 / metastasize-101 :ARG1 (t / tumor :mod (t2 / this)) :location (a2 / animal :quant (s2 / some :ARG1-of (m5 / mean-01 :ARG2 (a3 / animal :quant "3" :ARG1-of (i / include-91 :ARG2 (a4 / animal :quant "24")))))))) # ::id pmid_2384_5441.143 # ::date 2015-06-30T03:21:04 # ::file pmid_2384_5441_143.txt # ::snt All together, these results show that Arf/p53 and p16 exert independent critical tumor-suppressive effects, which are mainly operative at advanced stages of BrafV637E-induced intestinal tumorigenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (e / exert-01 :ARG0 (a / and :op1 (p / pathway :name (n / name :op1 "Arf/p53")) :op2 (p2 / protein :name (n2 / name :op1 "p16") :xref (x / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262"))) :ARG1 (a2 / affect-01 :ARG0 a :ARG2 (s2 / suppress-01 :ARG1 (t3 / tumor)) :ARG1-of (c / critical-02) :ARG0-of (d / depend-01 :polarity "-") :ARG0-of (o / operate-01 :manner (m / main) :time (t5 / thing :ARG2-of (s3 / stage-02 :ARG1 (c2 / create-01 :ARG1 (t4 / tumor :mod (i / intestine)) :ARG2-of (i2 / induce-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :ARG1-of (a3 / advance-01)))))) :manner (t6 / together :mod (a4 / all))) # ::id pmid_2384_5441.144 # ::date 2015-06-30T04:00:06 # ::file pmid_2384_5441_144.txt # ::snt Intensification of Map Kinase Signaling during Dysplasia Progression # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / intensify-01 :ARG1 (s / signal-07 :ARG0 (p2 / pathway :name (n / name :op1 "Map" :op2 "Kinase"))) :time (p / progress-01 :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia")))) # ::id pmid_2384_5441.145 # ::date 2015-06-30T04:04:54 # ::file pmid_2384_5441_145.txt # ::snt Because Braf-induced Mapk signaling does not seem to engage intrinsic tumor suppression in early tumorigenesis, we next assessed the MAPK pathway activity at different stages of tumor evolution. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Dec 22, 2015 (a / assess-01 :ARG0 (w / we) :ARG1 (a2 / activity-06 :ARG0 (p2 / pathway :name (n3 / name :op1 "Mapk"))) :time (n2 / next) :ARG1-of (c / cause-01 :ARG0 (s2 / seem-01 :polarity "-" :ARG1 (e2 / engage-01 :ARG0 (s3 / signal-07 :ARG0 p2 :ARG2-of (i / induce-01 :ARG0 (e4 / enzyme :name (n / name :op1 "Braf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :ARG1 (s4 / suppress-01 :ARG1 "t" :mod (i2 / intrinsic)) :ARG2 (c2 / create-01 :ARG1 "t" :time (e3 / early))))) :time (t2 / thing :ARG2-of (s / stage-02 :ARG1 (e / evolve-01 :ARG1 (t / tumor)) :ARG1-of (d / differ-02)))) # ::id pmid_2384_5441.146 # ::date 2015-06-30T04:11:43 # ::file pmid_2384_5441_146.txt # ::snt Unexpectedly, phospho-p42/p44 MAPK (pErk) protein levels were only slightly increased in BrafV637E-induced mSH as compared to wild-type mucosa but were highly induced in mSAs and carcinomas (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (e3 / enzyme :name (n2 / name :op1 "p42/p44" :op2 "MAPK") :ARG3-of (p3 / phosphorylate-01) :ARG1-of (m5 / mean-01 :ARG2 (e4 / enzyme :name (n3 / name :op1 "Erk") :ARG3-of p3 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))))) :ARG2 (s / slight :mod (o / only)) :location (d2 / disease :name (n4 / name :op1 "mSH") :ARG2-of (i2 / induce-01 :ARG0 (e2 / enzyme :name (n / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :compared-to (m3 / mucosa :mod (w / wild-type))) :ARG2 (i3 / induce-01 :ARG2 l :ARG1-of (h / high-02) :location (a / and :op1 (m / medical-condition :name (n5 / name :op1 "mSA")) :op2 (c2 / carcinoma))) :ARG1-of (e / expect-01 :polarity "-") :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id pmid_2384_5441.147 # ::date 2015-06-30T04:20:54 # ::file pmid_2384_5441_147.txt # ::snt Immunohistochemistry revealed that in wild-type mucosa and BrafV637E-induced mSH, pErk reactivity was mostly confined to the lower parts of the crypts (Figures 5B and 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r2 / reveal-01 :ARG0 (i / immunohistochemistry) :ARG1 (c / confine-01 :ARG1 (r / react-01 :ARG0 (e / enzyme :name (n / name :op1 "Erk") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603"))) :ARG2 (p3 / part :ARG1-of (l / low-04 :ARG2 (c2 / crypt) :degree (m / more))) :degree (m2 / most) :location (a / and :op1 (m3 / mucosa :mod (w / wild-type)) :op2 (m4 / medical-condition :name (n3 / name :op1 "mSH") :ARG2-of (i2 / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m5 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "5B") :op2 (f2 / figure :mod "5C")))) # ::id pmid_2384_5441.148 # ::date 2015-06-30T04:27:57 # ::file pmid_2384_5441_148.txt # ::snt In mSAs-LGD, few scattered pERK-positive cells were occasionally additionally detected in dysplastic areas (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / detect-01 :ARG1 (c / cell :quant (f / few) :ARG1-of (s / scatter-01) :mod (p / positive :topic (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :time (o / occasional) :manner (a / additional) :location (a2 / area :mod (m2 / medical-condition :name (n2 / name :op1 "dysplasia"))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "5D")) :condition (m3 / medical-condition :name (n3 / name :op1 "mSAs-LGD"))) # ::id pmid_2384_5441.149 # ::date 2015-06-30T04:32:11 # ::file pmid_2384_5441_149.txt # ::snt mSAs-HGD and carcinomas, however, stained uniformly positive for pErk (Figures 5E–5G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (s / stain-01 :ARG1 (a / and :op1 (d2 / disease :name (n2 / name :op1 "mSA-HGD")) :op2 (m / medical-condition :name (n3 / name :op1 "carcinoma"))) :manner (p / positive :ARG1-of (u / uniform-02) :topic (e / enzyme :name (n / name :op1 "Erk") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "5E") :op2 (f2 / figure :mod "5F") :op3 (f3 / figure :mod "5G")))) # ::id pmid_2384_5441.150 # ::date 2015-06-30T04:42:42 # ::file pmid_2384_5441_150.txt # ::snt Compared to wild-type mucosa, the number of pERK-positive cells per gland was increased 1.4-, 2.4-, and 6.6-fold in mSH, mSAs-LGD, and mSAs-HGD, respectively (Figure S4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a3 / and :op1 (i / increase-01 :ARG1 (r / rate-entity-91 :ARG1 (n / number :quant-of (c / cell :mod (p / positive :topic (e / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))))) :ARG2 (g / gland)) :ARG2 (p4 / product-of :op1 "1.4") :location (m2 / medical-condition :name (n3 / name :op1 "mSH"))) :op2 (i2 / increase-01 :ARG1 r :ARG2 (p5 / product-of :op1 "2.4") :location (m / medical-condition :name (n4 / name :op1 "mSAs-LGD"))) :op3 (i3 / increase-01 :ARG1 r :ARG2 (p6 / product-of :op1 "6.6") :location (m3 / medical-condition :name (n5 / name :op1 "mSAs-HGD"))) :compared-to (m4 / mucosa :mod (w / wild-type)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S4A")) :manner (r2 / respective)) # ::id pmid_2384_5441.151 # ::date 2015-06-30T04:53:46 # ::file pmid_2384_5441_151.txt # ::snt To assess the functional relevance of these observations, we examined expression of a panel of 15 Erk target genes (Pratilas et al., 2009) using qRT-PCR (Figure 5H) or immunohistochemistry (Figure S4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (e2 / examine-01 :ARG0 (w / we) :ARG1 (e3 / express-03 :ARG1 (p / panel :consist-of (g / gene :quant "15" :ARG1-of (t / target-01 :ARG0 (p6 / protein-family :name (n / name :op1 "Erk")))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n2 / name :op1 "Pratilas")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2009"))))) :manner (u / use-01 :ARG1 (o2 / or :op1 (r2 / react-01 :ARG0 (p5 / polymerase) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5H")) :mod (c / chain) :mod (r3 / real-time) :mod (q / quantitative) :subevent (t3 / transcribe-01 :ARG1-of (r4 / reverse-01))) :op2 (i / immunohistochemistry :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "S4"))))) :purpose (a2 / assess-01 :ARG0 w :ARG1 (r / relevance :mod (f3 / function) :poss (o3 / observe-01 :mod (t2 / this))))) # ::id pmid_2384_5441.152 # ::date 2015-06-30T05:14:01 # ::file pmid_2384_5441_152.txt # ::snt The panel of markers includes a number of effectors of Ras/Raf-induced transformation, such as the ETS family members Etv4 and Etv5 or cMyc and Ccnd1, and genes involved in the feedback regulation of Mek/Erk signaling, such as Dusp4, Dusp6, Spry2, and Spry4. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / include-91 :ARG1 (a / and :op1 (n2 / number :quant-of (e / effector :ARG0-of (t / transform-01 :ARG2-of (i2 / induce-01 :ARG0 (s / slash :op1 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x8 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e3 / enzyme :name (n4 / name :op1 "Raf") :xref (x7 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))) :example (o / or :op1 (a2 / and :op1 (g8 / gene :name (n5 / name :op1 "Etv4") :xref (x6 / xref :value "UNIPROT:ETV4_HUMAN" :prob "0.603")) :op2 (g9 / gene :name (n6 / name :op1 "Etv5") :xref (x5 / xref :value "UNIPROT:ETV5_HUMAN" :prob "0.603")) :mod (m2 / member :ARG1-of (i4 / include-91 :ARG2 (p3 / protein-family :name (n9 / name :op1 "ETS"))))) :op2 (g / gene :name (n7 / name :op1 "cMyc") :xref (x9 / xref :value "UNIPROT:Q16158_HUMAN" :prob "0.631")) :op3 (g2 / gene :name (n8 / name :op1 "Ccnd1") :xref (x4 / xref :value "UNIPROT:CCND1_HUMAN" :prob "0.604"))))) :op2 (g3 / gene :ARG1-of (i3 / involve-01 :ARG2 (r / regulate-01 :ARG1 (s2 / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Mek/Erk"))) :mod (f2 / feedback))) :example (a3 / and :op1 (g4 / gene :name (n10 / name :op1 "Dusp4") :xref (x3 / xref :value "UNIPROT:DUS4_HUMAN" :prob "0.602")) :op2 (g5 / gene :name (n11 / name :op1 "Dusp6") :xref (x2 / xref :value "UNIPROT:DUS6_HUMAN" :prob "0.602")) :op3 (g6 / gene :name (n12 / name :op1 "Spry2") :xref (x1 / xref :value "UNIPROT:SPY2_HUMAN" :prob "0.682")) :op4 (g7 / gene :name (n13 / name :op1 "Spry4") :xref (x / xref :value "UNIPROT:SPY4_HUMAN" :prob "0.682"))))) :ARG2 (p2 / panel :consist-of (m / marker))) # ::id pmid_2384_5441.153 # ::date 2015-06-30T05:28:47 # ::file pmid_2384_5441_153.txt # ::snt We found that the transcriptional output of the Erk pathway was only slightly induced in BrafV637E-dependent mSH and mSAs-LGD (average fold-change across target genes: 1.1 and 3.4, respectively) but was strongly upregulated in mSAs-HGD and carcinomas (average fold-change across target genes: 13.0 and 12.6, respectively). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (i / induce-01 :ARG2 (o2 / output :ARG1-of (t / transcribe-01 :ARG0 (p / pathway :name (n / name :op1 "Erk")))) :degree (s / slight :mod (o / only) :ARG1-of (m5 / mean-01 :ARG2 (c3 / change-01 :ARG1 (g2 / gene :ARG1-of (t2 / target-01)) :ARG1-of (a3 / average-04) :mod (f2 / fold) :quant (a4 / and :op1 (p2 / product-of :op1 "1.1") :op2 (p4 / product-of :op1 "3.4") :mod (r / respective))))) :location (a / and :op1 (m7 / medical-condition :name (n3 / name :op1 "mSH")) :op2 (m / medical-condition :name (n4 / name :op1 "mSAs-LGD")) :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))) :ARG2 (u / upregulate-01 :ARG1 o2 :degree (s2 / strong :ARG1-of (m6 / mean-01 :ARG2 (c4 / change-01 :ARG1 g2 :ARG1-of a3 :mod f2 :quant (a5 / and :op1 (p3 / product-of :op1 "13.0") :op2 (p5 / product-of :op1 "12.6") :mod r)))) :location (a2 / and :op1 (m2 / medical-condition :name (n5 / name :op1 "mSAs-HGD")) :op2 (m8 / medical-condition :name (n6 / name :op1 "carcinoma")))))) # ::id pmid_2384_5441.154 # ::date 2015-06-30T05:39:08 # ::file pmid_2384_5441_154.txt # ::snt The extent of induction varied between markers and was highest for Fosl1 (60-fold induction in BrafV637E-induced mSAs-HGD). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (a / and :op1 (v / vary-01 :ARG1 (e / extent :extent-of (i / induce-01)) :ARG0-of (d / depend-01 :ARG1 (m2 / marker))) :op2 (h / high-02 :ARG1 e :degree (m / most) :condition (p / protein :name (n / name :op1 "Fosl1") :xref (x / xref :value "UNIPROT:FOSL1_HUMAN" :prob "0.603")) :ARG1-of (m3 / mean-01 :ARG2 (i2 / induce-01 :degree (p2 / product-of :op1 "60") :location (m6 / medical-condition :name (n3 / name :op1 "mSAs-HGD") :ARG2-of (i3 / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m5 / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))))))) # ::id pmid_2384_5441.155 # ::date 2015-06-30T05:44:29 # ::file pmid_2384_5441_155.txt # ::snt Wnt Pathway Activation during Dysplasia Progression # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "Wnt")) :time (p2 / progress-01 :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia")))) # ::id pmid_2384_5441.156 # ::date 2015-06-30T05:46:00 # ::file pmid_2384_5441_156.txt # ::snt To examine the role of the Wnt pathway in BrafV637E-induced tumorigenesis, we first analyzed the expression of ten different Wnt target genes in a total of 78 samples (Figures 6A and S5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 19, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG1 (g / gene :quant "10" :ARG1-of (d / differ-02) :ARG0-of (t / target-01 :ARG1 (p / pathway :name (n / name :op1 "Wnt")))) :ARG3 (t4 / thing :ARG1-of (s / sample-01) :ARG1-of (t2 / total-01 :ARG2 "78"))) :time (f / first) :purpose (e2 / examine-01 :ARG0 w :ARG1 (p2 / play-08 :ARG0 p :ARG1 (c / create-01 :ARG1 (t3 / tumor) :ARG2-of (i / induce-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "6A") :op2 (f3 / figure :mod "S5")))) # ::id pmid_2384_5441.157 # ::date 2015-06-30T05:51:07 # ::file pmid_2384_5441_157.txt # ::snt We found that Wnt target gene expression was similar in wild-type mucosa and BrafV637E-induced mSH but was upregulated in a large number of BrafV637E-induced mSAs-HGD (and occasionally in mSAs-LGD) to similar levels as in Apcmin-induced tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (r2 / resemble-01 :ARG1 (e / express-03 :ARG1 (g / gene :ARG0-of (t / target-01 :ARG1 (p / protein :name (n2 / name :op1 "Wnt") :xref (x1 / xref :value "UNIPROT:WNT1_HUMAN" :prob "0.202")))) :ARG3 (m / mucosa :mod (w2 / wild-type))) :ARG2 (e2 / express-03 :ARG1 g :ARG3 (m6 / medical-condition :name (n5 / name :op1 "mSH") :ARG2-of (i / induce-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "V637E") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))))) :ARG2 (u / upregulate-01 :ARG1 e :location (a / and :op1 (n / number :mod (l / large) :quant-of (m2 / medical-condition :name (n6 / name :op1 "mSAs-HGD") :ARG2-of i)) :op2 (m4 / medical-condition :name (n7 / name :op1 "mSAs-LGD") :manner (o / occasional))) :degree (l2 / level :ARG1-of (r3 / resemble-01 :ARG2 (l3 / level :location (t2 / tumor :ARG2-of (i2 / induce-01 :ARG0 (g3 / gene :name (n4 / name :op1 "Apcmin")))))))))) # ::id pmid_2384_5441.158 # ::date 2015-06-30T06:12:11 # ::file pmid_2384_5441_158.txt # ::snt Immunohistochemical staining of beta-catenin (Ctnnb1), a key effector of Wnt pathway activation, was performed to further confirm these observations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p / perform-01 :ARG1 (s / stain-01 :ARG1 (p2 / protein :name (n / name :op1 "beta-catenin") :ARG1-of (e2 / encode-01 :ARG0 (g / gene :name (n3 / name :op1 "Ctnnb1") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.603"))) :mod (e / effector :ARG1-of (k / key-02) :ARG0-of (a / activate-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "Wnt")))) :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.703")) :mod (i / immunohistochemistry)) :purpose (c2 / confirm-01 :ARG1 (o / observe-01 :mod (t / this)) :degree (f / further))) # ::id pmid_2384_5441.159 # ::date 2015-06-30T06:16:59 # ::file pmid_2384_5441_159.txt # ::snt As in wild-type mucosa, there was no evidence for nuclear β-catenin accumulation in mSHs (n = 42) and the majority of mSAs-LGD (14/15). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (e3 / evidence-01 :polarity "-" :ARG1 (a / accumulate-01 :ARG0 (n2 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :ARG1 (p / protein :name (n / name :op1 "β-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263"))) :location (a2 / and :op1 (m9 / medical-condition :name (n3 / name :op1 "mSH") :ARG1-of (m7 / mean-01 :ARG2 (e2 / equal-01 :ARG1 m9 :ARG2 "42"))) :op2 (m / medical-condition :name (n4 / name :op1 "mSAs-LGD") :quant (m2 / majority :ARG1-of (m4 / mean-01 :ARG2 (m3 / medical-condition :quant "14" :name (n5 / name :op1 "mSAs-LGD") :ARG1-of (i / include-91 :ARG2 (m5 / medical-condition :quant "15" :name (n6 / name :op1 "mSAs-LGD")))))))) :ARG1-of (s2 / same-01 :ARG2 (m6 / mucosa :mod (w / wild-type)))) # ::id pmid_2384_5441.160 # ::date 2015-06-30T06:28:05 # ::file pmid_2384_5441_160.txt # ::snt In contrast, there was diffuse or focal nuclear β-catenin accumulation in a substantial part of mSAs-HGD (8/14) and carcinomas (2/4) (Figures 6B–6F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (a / accumulate-01 :ARG0 (n / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :ARG1 (p / protein :name (n2 / name :op1 "β-catenin") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")) :mod (o / or :op1 (d / diffuse-01) :op2 (f / focus)) :location (a2 / and :op1 (p2 / part :ARG1-of (m2 / mean-01 :ARG2 (m / medical-condition :quant "8" :name (n4 / name :op1 "mSAs-HGD") :ARG1-of (i / include-91 :ARG2 (m3 / medical-condition :quant "14" :name (n5 / name :op1 "mSAs-HGD"))))) :quant-of (m6 / medical-condition :name (n3 / name :op1 "mSAs-HGD"))) :op2 (p3 / part :quant-of (c2 / carcinoma) :ARG1-of (m5 / mean-01 :ARG2 (c3 / carcinoma :quant "2" :ARG1-of (i2 / include-91 :ARG2 (c4 / carcinoma :quant "4"))))) :mod (s / substantial))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "6B") :op2 (f3 / figure :mod "6C") :op3 (f4 / figure :mod "6D") :op4 (f5 / figure :mod "6E") :op5 (f6 / figure :mod "6F")))) # ::id pmid_2384_5441.161 # ::date 2015-06-30T06:34:28 # ::file pmid_2384_5441_161.txt # ::snt To analyze the mechanisms of Wnt pathway activation, we performed whole-exome sequencing of 20 Braf mutant tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 16, 2015 (p / perform-01 :ARG0 (w / we) :ARG1 (s / sequence :mod (e / exome :mod (w2 / whole))) :location (t / tumor :quant "20" :mod (g / gene :name (n / name :op1 "Braf") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :purpose (a / analyze-01 :ARG0 w :ARG1 (m2 / mechanism :ARG0-of (a2 / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "Wnt")))))) # ::id pmid_2384_5441.162 # ::date 2015-06-30T06:38:41 # ::file pmid_2384_5441_162.txt # ::snt We identified a number of mutations in known Wnt pathway genes (Table S6), including intracellular components of the Wnt pathway (e.g., Apc, Ctnnb1, Gsk3b, and Axin2), Wnt receptors (e.g., Lrp8 and Fzd9), or negative regulators of Wnt signaling (e.g., Lrp1b and Lrp4). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (i / identify-01 :ARG0 (w / we) :ARG1 (n / number :quant-of (m / mutate-01 :ARG1 (g / gene :ARG1-of (k / know-01) :mod (p / pathway :name (n2 / name :op1 "Wnt")) :ARG1-of (d / describe-01 :ARG0 (t / table :mod "S6")) :ARG2-of (i2 / include-01 :ARG1 (o2 / or :op1 (c / component :mod (i3 / intracellular) :part-of p :example (a2 / and :op1 (p2 / protein :name (n3 / name :op1 "Apc") :xref (x4 / xref :value "UNIPROT:APC_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n4 / name :op1 "Ctnnb1") :xref (x5 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.603")) :op3 (e / enzyme :name (n5 / name :op1 "Gsk3b") :xref (x6 / xref :value "UNIPROT:GSK3B_HUMAN" :prob "0.603")) :op4 (p4 / protein :name (n6 / name :op1 "Axin2") :xref (x1 / xref :value "UNIPROT:AXIN2_HUMAN" :prob "0.683")))) :op2 (r2 / receptor :mod p :example (a3 / and :op1 (p5 / protein :name (n7 / name :op1 "Lrp8") :xref (x7 / xref :value "UNIPROT:LRP8_HUMAN" :prob "0.603")) :op2 (p6 / protein :name (n8 / name :op1 "Fzd9") :xref (x2 / xref :value "UNIPROT:FZD9_HUMAN" :prob "0.603")))) :op3 (g10 / gene :example (a / and :op1 (p7 / protein :name (n10 / name :op1 "Lrp1b") :xref (x3 / xref :value "UNIPROT:LRP1B_HUMAN" :prob "0.603")) :op2 (p8 / protein :name (n11 / name :op1 "Lrp4") :xref (x / xref :value "UNIPROT:LRP4_HUMAN" :prob "0.603"))) :ARG2-of (d2 / downregulate-01 :ARG1 (s / signal-07 :ARG0 p))))))))) # ::id pmid_2384_5441.163 # ::date 2015-06-30T06:45:35 # ::file pmid_2384_5441_163.txt # ::snt We then further analyzed the most frequently altered genes (Apc, Ctnnb1, and Lrp1b) in another 46 tumors and found mutations in these three genes in 21/66 samples: Apc (n = 6), Ctnnb1 (n = 9), and Lrp1b (n = 6). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (a2 / analyze-01 :ARG0 (w / we) :ARG1 (g / gene :ARG1-of (a3 / alter-01 :ARG1-of (f3 / frequent-02 :degree (m / most))) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 (g2 / gene :name (n / name :op1 "Apc") :xref (x2 / xref :value "UNIPROT:APC_HUMAN" :prob "0.604")) :op2 (g3 / gene :name (n2 / name :op1 "Ctnnb1") :xref (x1 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.603")) :op3 (g4 / gene :name (n3 / name :op1 "Lrp1b") :xref (x / xref :value "UNIPROT:LRP1B_HUMAN" :prob "0.603"))))) :time (t / then) :degree (f / further) :location (t2 / tumor :quant "46" :mod (a5 / another))) :op2 (f2 / find-01 :ARG0 w :ARG1 (m3 / mutate-01 :ARG1 (a7 / and :op1 g2 :op2 g3 :op3 g4 :ARG1-of (s / sample-01 :quant "21" :ARG1-of (i / include-91 :ARG2 (t3 / thing :quant "66" :ARG1-of (s2 / sample-01))) :ARG1-of (m4 / mean-01 :ARG2 (a6 / and :op1 (s3 / sample-01 :quant "6" :ARG1 g2) :op2 (s4 / sample-01 :quant "9" :ARG1 g3) :op3 (s5 / sample-01 :quant "6" :ARG1 g4)))))))) # ::id pmid_2384_5441.164 # ::date 2015-06-30T08:45:39 # ::file pmid_2384_5441_164.txt # ::snt Wnt pathway mutations frequently occurred in high-grade dysplasia, suggesting an early requirement during tumorigenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (f / frequent-02 :ARG1 (m / mutate-01 :ARG1 (p / pathway :name (n / name :op1 "Wnt"))) :location (m2 / medical-condition :name (n2 / name :op1 "dysplasia") :mod (g / grade :ARG1-of (h / high-02))) :ARG0-of (s / suggest-01 :ARG1 (r / require-01 :ARG1 m :time (e / early) :time (c / create-01 :ARG1 (t / tumor))))) # ::id pmid_2384_5441.165 # ::date 2015-06-30T08:52:04 # ::file pmid_2384_5441_165.txt # ::snt Only missense, nonsense, essential splice site mutations or frameshift-causing indels were observed (no silent mutations), suggesting a strong enrichment for functionally relevant events. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 16, 2015 (o / observe-01 :ARG1 (o2 / or :op1 (m / mutate-01 :mod (m2 / missense)) :op2 (m3 / mutate-01 :mod (n / nonsense)) :op3 (m4 / mutate-01 :ARG0-of (s / splice-01 :ARG1 (s2 / site)) :mod (e / essential)) :op4 (i / indel :ARG0-of (c / cause-01 :ARG1 (f / frameshift))) :ARG1-of (m5 / mean-01 :ARG2 (m6 / mutate-01 :polarity "-" :mod (s3 / silent)))) :mod (o3 / only) :ARG0-of (s4 / suggest-01 :ARG1 (e2 / enrich-01 :ARG1 (e3 / event :ARG1-of (r / relevant-01 :manner (f2 / functional))) :ARG1-of (s5 / strong-02)))) # ::id pmid_2384_5441.166 # ::date 2015-06-30T10:07:51 # ::file pmid_2384_5441_166.txt # ::snt For example, Apc mutations were mostly nonsense or frameshift mutations, whereas Ctnnb1 mutations were recurrent activating mutations at specific positions that have also been described in humans (e.g., T141I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG1 (o / or :op1 (m / mutate-01 :mod (n / nonsense)) :op2 (m2 / mutate-01 :mod (f / frameshift)) :quant (m3 / most) :domain (m4 / mutate-01 :ARG1 (g / gene :name (n2 / name :op1 "Apc") :xref (x1 / xref :value "UNIPROT:APC_HUMAN" :prob "0.604")))) :ARG2 (m6 / mutate-01 :location (p / position :ARG1-of (s / specific-02)) :ARG0-of (a / activate-01 :frequency (r / recurrent)) :domain (m5 / mutate-01 :ARG1 (g2 / gene :name (n3 / name :op1 "Ctnnb1") :xref (x / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.603"))) :example (m7 / mutate-01 :value "T141I") :ARG1-of (d / describe-01 :mod (a2 / also) :condition (h / human))) :ARG0-of (e / exemplify-01)) # ::id pmid_2384_5441.167 # ::date 2015-06-30T10:14:37 # ::file pmid_2384_5441_167.txt # ::snt Missense mutations in Lrp1b, a negative regulator of Wnt signaling, have been found earlier in Braf mutant human melanoma (Nikolaev et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (f / find-01 :ARG1 (m2 / mutate-01 :ARG1 (g / gene :name (n / name :op1 "Lrp1b") :ARG2-of (d2 / downregulate-01 :ARG1 (s / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "Wnt")))) :xref (x1 / xref :value "UNIPROT:LRP1B_HUMAN" :prob "0.603")) :mod (m3 / missense)) :time (e / early :degree (m / more)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n4 / name :op1 "Nikolaev")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2012"))) :location (m6 / medical-condition :name (n5 / name :op1 "melanoma") :mod (h / human) :mod (g2 / gene :name (n3 / name :op1 "Braf") :ARG2-of (m5 / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) # ::id pmid_2384_5441.168 # ::date 2015-06-30T10:18:55 # ::file pmid_2384_5441_168.txt # ::snt All together, these results provide strong evidence for an important role of Wnt pathway activation during early dysplasia progression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (p / provide-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG1 (e / evidence-01 :ARG1 (r2 / role :poss (a / activate-01 :ARG1 (p2 / pathway :name (n / name :op1 "Wnt"))) :mod (i / important) :time (p3 / progress-01 :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia")) :time (e2 / early))) :ARG1-of (s / strong-02)) :manner (t3 / together :mod (a2 / all))) # ::id pmid_2384_5441.169 # ::date 2015-06-30T10:24:37 # ::file pmid_2384_5441_169.txt # ::snt It is worth noting that in some tumors with strong Wnt target gene expression, no mutations in Wnt pathway genes were found, suggesting additional unidentified mechanisms. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (w / worth-02 :ARG2 (n2 / note-01 :ARG1 (f / find-01 :polarity "-" :ARG1 (m / mutate-01 :ARG2 "g") :location (t / tumor :quant (s / some) :mod (e / express-03 :ARG1 (g / gene :ARG0-of (t2 / target-01 :ARG1 (p / pathway :name (n / name :op1 "Wnt")))) :ARG1-of (s2 / strong-02))) :ARG0-of (s3 / suggest-01 :ARG1 (m2 / mechanism :mod (a / additional) :ARG1-of (i / identify-01 :polarity "-")))))) # ::id pmid_2384_5441.170 # ::date 2015-06-30T10:25:12 # ::file pmid_2384_5441_170.txt # ::snt Large-Scale Drug Screening Identifies Targetable Nodes in Braf-Induced Tumorigenesis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 16, 2015 (i / identify-01 :ARG0 (s / screen-01 :ARG1 (d / drug) :mod (s2 / scale :mod (l / large))) :ARG1 (n / node :ARG1-of (t / target-01 :ARG1-of (p / possible-01))) :location (c / create-01 :ARG1 (t2 / tumor) :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))) # ::id pmid_2384_5441.171 # ::date 2015-06-29T14:06:12 # ::file pmid_2384_5441_171.txt # ::snt To test the sensitivity of BrafLSL-V637E/+-induced intestinal cancer cell lines to Braf inhibition we performed short-term proliferation assays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / perform-01 :ARG0 (w / we) :ARG1 (a / assay-01 :ARG1 (p2 / proliferate-01 :ARG1-of (s3 / short-07))) :purpose (t / test-01 :ARG0 w :ARG1 (s2 / sensitive-03 :ARG0 (c / cell-line :ARG2-of (i / induce-01 :ARG0 (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Braf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "Cancer") :mod (i2 / intestine))) :ARG1 (g / gene :name (n2 / name :op1 "Braf") :ARG2-of (m / mutate-01 :value "LSL-V637E/+") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))))) # ::id pmid_2384_5441.172 # ::date 2015-06-29T14:19:17 # ::file pmid_2384_5441_172.txt # ::snt Overall, only minor growth inhibition was observed for Braf mutant mouse and human colorectal cancer cell lines treated with 5 μM PLX4720, a selective inhibitor of mutant Braf (Figures 7A and 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (o / observe-01 :ARG1 (i2 / inhibit-01 :ARG1 (g / grow-01) :mod (o2 / only) :beneficiary (a / and :op1 (m2 / mouse :mod (e / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :op2 (c / cell-line :mod (h / human) :ARG1-of (t2 / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "PLX4720") :quant (c4 / concentration-quantity :quant "5" :unit (m4 / micromolar)) :ARG0-of (i3 / inhibit-01 :ARG1 e :mod (s2 / selective)) :xref (x1 / xref :value "PUBCHEM:24180719" :prob "18.572987"))) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer")))) :ARG1-of (m / minor-01)) :mod (o3 / overall) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7B")))) # ::id pmid_2384_5441.173 # ::date 2015-06-29T14:30:09 # ::file pmid_2384_5441_173.txt # ::snt Braf inhibition was proposed to cause feedback activation of the epidermal growth factor receptor (EGFR) in human BRAF mutant CRCs (Prahallad et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / propose-01 :ARG1 (c / cause-01 :ARG0 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Braf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG1 (a / activate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.703")) :destination-of (f / feedback) :location (d / disease :name (n / name :op1 "colorectal" :op2 "cancer") :mod (h / human) :mod (g / gene :name (n6 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n7 / name :op1 "Prahallad")) :op2 (p4 / person :mod (o / other))) :time (d3 / date-entity :year "2012")))) # ::id pmid_2384_5441.174 # ::date 2015-06-29T14:38:11 # ::file pmid_2384_5441_174.txt # ::snt We therefore treated mouse and human BRAF mutant cell lines with the EGFR small molecule kinase inhibitor, Gefitinib, alone or in combination with PLX4720. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (t2 / treat-04 :ARG0 (w / we) :ARG1 (a / and :op1 (c / cell-line :mod (m / mouse) :mod (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (c2 / cell-line :mod (h / human) :mod g)) :ARG2 (a2 / and :op1 (s / small-molecule :name (n3 / name :op1 "Gefitinib") :ARG0-of (i2 / inhibit-01 :ARG1 (k / kinase :name (n6 / name :op1 "EGFR") :xref (x1 / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004"))) :mod (a4 / alone) :xref (x3 / xref :value "PUBCHEM:123631" :prob "16.963549")) :op2 (c3 / combine-01 :ARG1 s :ARG2 (s2 / small-molecule :name (n4 / name :op1 "PLX4720") :xref (x2 / xref :value "PUBCHEM:24180719" :prob "18.572987")))) :ARG1-of (c4 / cause-01)) # ::id pmid_2384_5441.175 # ::date 2015-06-29T14:45:49 # ::file pmid_2384_5441_175.txt # ::snt As expected, Gefitinib and PLX4720 synergized in-growth inhibition (Figures 7A and 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (s / synergize-01 :ARG0 (a / and :op1 (s2 / small-molecule :name (n / name :op1 "Gefitinib") :xref (x1 / xref :value "PUBCHEM:123631" :prob "16.963549")) :op2 (s3 / small-molecule :name (n2 / name :op1 "PLX4720") :xref (x / xref :value "PUBCHEM:24180719" :prob "18.572987"))) :ARG2 (i / inhibit-01 :ARG1 (g / grow-in-00)) :ARG1-of (e / expect-01) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7B")))) # ::id pmid_2384_5441.176 # ::date 2015-06-29T14:49:37 # ::file pmid_2384_5441_176.txt # ::snt The murine intestinal cancer cell line MouseT1 (from a Vil-Cre;BrafLSL-V637E/+;p53LSL-R172H/+ mouse), had similar sensitivity to combinatorial PLX4720/Gefitinib treatment as HT-29 (WiDr), one of the three human cell lines tested by Prahallad and colleagues (Figures 7A and 7B; inhibition of proliferation by 60%–70%). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-03 :ARG0 (c / cell-line :wiki "-" :name (n2 / name :op1 "MouseT1") :mod (o / organism :wiki "Muridae" :name (n / name :op1 "Muridae")) :source (m / mouse :mod (m2 / macro-molecular-complex :part (p3 / protein :wiki "Villin" :name (n3 / name :op1 "Vil") :xref (x1 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.602")) :part (e2 / enzyme :wiki "Cre_recombinase" :name (n4 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :mod (e / enzyme :wiki "-" :name (n5 / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (p5 / protein :wiki "P53" :name (n6 / name :op1 "p53") :ARG2-of (m4 / mutate-01 :value "LSL-R172H/+") :xref (x3 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001"))) :mod (d / disease :wiki "Cancer" :name (n12 / name :op1 "cancer") :mod (i / intestine))) :ARG1 (s / sensitive-03 :ARG0 c :ARG1 (t / treat-04 :ARG2 (c3 / combine-01 :ARG1 (s2 / small-molecule :wiki "-" :name (n7 / name :op1 "PLX4720") :xref (x5 / xref :value "PUBCHEM:24180719" :prob "18.572987")) :ARG2 (s3 / small-molecule :wiki "Gefitinib" :name (n8 / name :op1 "Gefitinib") :xref (x4 / xref :value "PUBCHEM:123631" :prob "16.963549")))) :ARG1-of (r2 / resemble-01 :ARG2 (c4 / cell-line :wiki "-" :name (n9 / name :op1 "HT-29") :ARG2-of (i4 / include-91 :ARG1 (c7 / cell-line :wiki "-" :name (n11 / name :op1 "WiDr"))) :ARG1-of (i2 / include-91 :ARG2 (c5 / cell-line :quant "3" :mod (h2 / human) :ARG1-of (t2 / test-01 :ARG0 (a2 / and :op1 (p6 / person :wiki "-" :name (n10 / name :op1 "Prahallad")) :op2 (c6 / colleague)))))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "7A") :op2 (f2 / figure :mod "7B") :op3 (i3 / inhibit-01 :ARG1 (p7 / proliferate-01))) :ARG2 (v / value-interval :op1 (p / percentage-entity :value "60") :op2 (p2 / percentage-entity :value "70")))) # ::id pmid_2384_5441.177 # ::date 2015-06-29T14:53:29 # ::file pmid_2384_5441_177.txt # ::snt It seems, however, that the effectiveness of PLX4720/Gefitinib varies considerably among human cancers: in three of five tested human cell lines the effects were rather modest (growth inhibition by 25%–40%; Figure 7A and data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (h / have-concession-91 :ARG1 (s3 / seem-01 :ARG1 (v / vary-01 :ARG1 (e / effective-04 :ARG0 (a / and :op1 (s / small-molecule :name (n / name :op1 "PLX4720") :xref (x1 / xref :value "PUBCHEM:24180719" :prob "18.572987")) :op2 (s2 / small-molecule :name (n2 / name :op1 "Gefitinib") :xref (x / xref :value "PUBCHEM:123631" :prob "16.963549")))) :manner (c / considerable) :ARG1-of (m2 / mean-01 :ARG2 (m / modest :domain (a3 / affect-01) :location (c3 / cell-line :quant "3" :ARG1-of (i2 / include-91 :ARG2 (c4 / cell-line :quant "5" :ARG1-of (t2 / test-01) :mod (h2 / human)))) :degree (r / rather))) :location (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :mod h2))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (i3 / inhibit-01 :ARG1 (g / grow-01)) :op2 (f / figure :mod "7A") :op3 (d2 / data :ARG1-of (s4 / show-01 :polarity "-"))) :ARG2 (v2 / value-interval :op1 (p / percentage-entity :value "25") :op2 (p2 / percentage-entity :value "40")))) # ::id pmid_2384_5441.178 # ::date 2015-06-30T02:54:09 # ::file pmid_2384_5441_178.txt # ::snt We next performed long-term (14 days) clonogenic assays and again found that although PLX4720 and Gefitinib synergized in-growth inhibition, most of the treated cell lines retained variable levels of colony-forming capacity (Figure 7C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (a / and :op1 (p / perform-01 :ARG0 (w / we) :ARG1 (a2 / assay-01 :ARG1 (c / clonogenic) :duration (l / long-03 :ARG1-of (m2 / mean-01 :ARG2 (t / temporal-quantity :quant "14" :unit (d / day))))) :time (n / next)) :op2 (f / find-01 :ARG0 w :ARG1 (h / have-concession-91 :ARG1 (r / retain-01 :ARG0 (c2 / cell-line :quant (m / most) :ARG1-of (i3 / include-91 :ARG2 (c3 / cell-line :ARG1-of (t2 / treat-04)))) :ARG1 (l2 / level :ARG1-of (v / vary-01) :degree-of (c4 / capable-01 :ARG1 c2 :ARG2 (f2 / form-01 :ARG1 (c5 / colony))))) :ARG2 (s / synergize-01 :ARG0 (a4 / and :op1 (s2 / small-molecule :name (n2 / name :op1 "PLX4720") :xref (x1 / xref :value "PUBCHEM:24180719" :prob "18.572987")) :op2 (s3 / small-molecule :name (n3 / name :op1 "Gefitinib") :xref (x / xref :value "PUBCHEM:123631" :prob "16.963549"))) :ARG2 (i / inhibit-01 :ARG1 (g / grow-in-00)))) :mod (a3 / again)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "7C"))) # ::id pmid_2384_5441.179 # ::date 2015-06-30T03:12:17 # ::file pmid_2384_5441_179.txt # ::snt To identify alternative drugs with effectiveness across cell lines, we performed high-throughput drug screening. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (p / perform-01 :ARG0 (w / we) :ARG1 (s / screen-01 :ARG1 (d / drug) :manner (t / throughput :ARG1-of (h / high-02))) :purpose (i / identify-01 :ARG0 w :ARG1 (d2 / drug :mod (a / alternative) :ARG0-of (e / effective-04 :ARG1 (a2 / across :op1 (c / cell-line)))))) # ::id pmid_2384_5441.180 # ::date 2015-06-30T03:15:42 # ::file pmid_2384_5441_180.txt # ::snt We tested a large set of compounds inhibiting a broad range of molecules, pathways, and biologic processes (Figure 7B; Table S7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (s / set :mod (l / large) :consist-of (c / compound) :ARG0-of (i / inhibit-01 :ARG1 (a / and :op1 (m / molecule) :op2 (p / pathway) :op3 (p2 / process-01 :ARG1 (b2 / biology)) :ARG1-of (r / range-01 :ARG1-of (b / broad-02))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "7B") :op2 (t2 / table :mod "S7")))) # ::id pmid_2384_5441.181 # ::date 2015-06-30T03:39:19 # ::file pmid_2384_5441_181.txt # ::snt All compounds were tested alone or in combination with PLX4720 and for each cell line we performed 100 different short-term (6 day) sensitivity assays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (a / and :op1 (t2 / test-01 :ARG1 (c / compound :mod (a2 / all)) :manner (o / or :op1 (a3 / alone) :op2 (c2 / combine-01 :ARG1 c :ARG2 (s / small-molecule :name (n / name :op1 "PLX4720") :xref (x / xref :value "PUBCHEM:24180719" :prob "18.572987"))))) :op2 (p / perform-01 :ARG0 (w / we) :ARG1 (a4 / assay-01 :quant "100" :ARG1 (s2 / sensitive-03) :ARG1-of (d2 / differ-02) :ARG1-of (s4 / short-07 :ARG1-of (m / mean-01 :ARG2 (t / temporal-quantity :quant "6" :unit (d / day))))) :beneficiary (c3 / cell-line :mod (e / each)))) # ::id pmid_2384_5441.182 # ::date 2015-06-30T04:07:04 # ::file pmid_2384_5441_182.txt # ::snt These screens revealed several treatment approaches that were highly effective (Figure 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / reveal-01 :ARG0 (s / screen-01 :mod (t / this)) :ARG1 (a / approach-02 :ARG2 (t2 / treat-04) :quant (s2 / several) :ARG1-of (e / effective-04 :ARG1-of (h / high-02))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7B"))) # ::id pmid_2384_5441.183 # ::date 2015-06-30T04:11:23 # ::file pmid_2384_5441_183.txt # ::snt PD0325901, a Mek inhibitor, was the most effective single compound across cell lines in the short-term assays (Figure 7B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / compound :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7B")) :ARG1-of (s4 / single-02) :ARG1-of (e2 / effective-04 :mod (m / most) :time (a / assay-01 :ARG1-of (s2 / short-07)) :location (a2 / across :op1 (c2 / cell-line))) :domain (s / small-molecule :name (n2 / name :op1 "PD0325901") :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987"))) # ::id pmid_2384_5441.184 # ::date 2015-06-30T04:18:37 # ::file pmid_2384_5441_184.txt # ::snt In the long-term clonogenic assay, it induced complete inhibition of colony-forming capacity in five of six cell lines and partial inhibition in the remaining line RKO (Figure 7C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (i / induce-01 :ARG0 (i3 / it) :ARG2 (a / and :op1 (i2 / inhibit-01 :ARG1 (c / capable-01 :ARG2 (f / form-01 :ARG1 (c2 / colony))) :ARG1-of (c3 / complete-01) :location (c4 / cell-line :quant "5" :ARG1-of (i4 / include-91 :ARG2 (c5 / cell-line :quant "6")))) :op2 (i5 / inhibit-01 :location (c6 / cell-line :name (n / name :op1 "RKO") :ARG1-of (r / remain-01)) :degree (p / part))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "7C")) :time (a2 / assay-01 :ARG1 (c7 / clonogenic) :duration (l / long-03))) # ::id pmid_2384_5441.185 # ::date 2015-06-30T04:25:17 # ::file pmid_2384_5441_185.txt # ::snt The PI3K inhibitor GDC0941 was not effective as a single agent, but induced potent inhibition in combination with PLX4720 across cell lines (Figures 7B and 7C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (e / effective-04 :polarity "-" :ARG0 (s / small-molecule :name (n / name :op1 "GDC0941") :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"))) :xref (x1 / xref :value "PUBCHEM:17755052" :prob "18.349844")) :manner (a / agent :ARG1-of (s2 / single-02))) :ARG2 (i3 / induce-01 :ARG0 s :ARG2 (i4 / inhibit-01 :mod (p / potent)) :manner (c2 / combine-01 :ARG1 s :ARG2 (s3 / small-molecule :name (n3 / name :op1 "PLX4720") :xref (x / xref :value "PUBCHEM:24180719" :prob "18.572987"))) :location (a2 / across :op1 (c3 / cell-line))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "7B") :op2 (f2 / figure :mod "7C")))) # ::id pmid_2384_5441.186 # ::date 2015-06-30T04:30:36 # ::file pmid_2384_5441_186.txt # ::snt Some other drug combinations strongly inhibited selected cell lines, although they were not broadly effective across tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / have-concession-91 :ARG1 (i / inhibit-01 :ARG0 (c / combine-01 :ARG1 (d / drug) :mod (s / some) :mod (o / other)) :ARG1 (c2 / cell-line :ARG1-of (s3 / select-01)) :ARG1-of (s2 / strong-02)) :ARG2 (e / effective-04 :polarity "-" :ARG0 c :ARG1 (a / across :op1 (t / tumor)) :ARG1-of (b / broad-02))) # ::id pmid_2384_5441.187 # ::date 2015-06-30T04:34:51 # ::file pmid_2384_5441_187.txt # ::snt For example, the combination of PLX4720 plus the kinase inhibitor VX-680 was the most potent drug combination for the treatment of RKO, a highly resistant cell line to most other drugs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c2 / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "PLX4720") :xref (x1 / xref :value "PUBCHEM:24180719" :prob "18.572987")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "VX-680") :ARG0-of (i / inhibit-01 :ARG1 (k / kinase)) :xref (x / xref :value "PUBCHEM:5494449" :prob "16.102781")) :domain (c / combine-01 :mod (d / drug) :mod (p / potent :degree (m / most)) :ARG2-of (t2 / treat-04 :ARG1 (c3 / cell-line :name (n3 / name :op1 "RKO") :ARG0-of (r / resist-01 :ARG1 (d2 / drug :mod (o / other) :mod m) :ARG1-of (h / high-02))))) :ARG1-of (e / exemplify-01)) # ::id pmid_2384_5441.188 # ::date 2015-06-30T05:16:25 # ::file pmid_2384_5441_188.txt # ::snt This shows the power of systematic drug screening to identify patient-specific treatment approaches even for highly resistant tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (t / this) :ARG1 (p / power :poss (s3 / screen-01 :ARG1 (d / drug :mod (s2 / systematic)) :ARG2 (i / identify-01 :ARG1 (a / approach-02 :ARG1-of (s4 / specific-02 :ARG2 (t2 / treat-04 :ARG1 (p2 / patient)))) :beneficiary (t3 / tumor :ARG0-of (r / resist-01 :ARG1-of (h / high-02)) :mod (e / even)))))) # ::id pmid_2384_5441.189 # ::date 2015-06-30T05:22:53 # ::file pmid_2384_5441_189.txt # ::snt Another example is the combination of the Chk1/2 inhibitor AZD-7762 plus PLX4720, which was very effective in MouseT1, HT-29, LS411N, and COLO-205 and could potentially be a broadly effective alternative first-line or second-line combination. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (a / and :op1 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "AZD-7762") :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Chk1/2"))) :xref (x1 / xref :value "PUBCHEM:11152667" :prob "19.183332")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PLX4720") :xref (x / xref :value "PUBCHEM:24180719" :prob "18.572987")) :ARG1-of (e3 / exemplify-01 :mod (a2 / another)) :ARG0-of (e / effective-04 :ARG1 (a3 / and :op1 (c2 / cell-line :name (n4 / name :op1 "MouseT1")) :op2 (c3 / cell-line :name (n5 / name :op1 "HT-29")) :op3 (c4 / cell-line :name (n6 / name :op1 "LS411N")) :op4 (c5 / cell-line :name (n7 / name :op1 "COLO-205"))) :degree (v / very))) :op2 (p2 / possible-01 :ARG1 (o / or :op1 (c6 / combine-01 :mod (a4 / alternative) :mod (l / line :ord (o2 / ordinal-entity :value "1"))) :op2 (c7 / combine-01 :mod a4 :mod (l2 / line :ord (o3 / ordinal-entity :value "2"))) :ARG1-of (e4 / effective-04 :ARG1-of (b / broad-02)) :domain c) :mod (p3 / potential))) # ::id pmid_2384_5441.190 # ::date 2015-06-30T05:34:36 # ::file pmid_2384_5441_190.txt # ::snt In Vivo Validation of Mek and Combinatorial Braf/PI3K Inhibition # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (a / and :op1 (v / validate-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :manner (i / in-vivo)) :op2 (i4 / inhibit-01 :ARG1 (c / combine-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Braf") :xref (x2 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG2 (e3 / enzyme :name (n3 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))))) # ::id pmid_2384_5441.191 # ::date 2015-06-30T05:38:16 # ::file pmid_2384_5441_191.txt # ::snt To study the effectiveness of broadly effective drug combinations in vivo, we first transplanted mouse and human cell lines subcutaneously (s.c.) into immunodeficient Nod Scid IL12R-gamma null (NSG) mice and assessed their response to PD0325901. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (t / transplant-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (c / cell-line :mod (m / mouse)) :op2 (c2 / cell-line :mod (h / human))) :ARG2 (o / organism :name (n / name :op1 "NSG" :op2 "mouse") :mod (i / immunodeficient)) :time (f / first) :manner (s / subcutaneous)) :op2 (a3 / assess-01 :ARG0 w :ARG1 (r / respond-01 :ARG0 a2 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")))) :purpose (s3 / study-01 :ARG0 w :ARG1 (e / effective-04 :ARG0 (c3 / combine-01 :mod (d / drug) :manner (i2 / in-vivo) :ARG0-of (e2 / effective-04 :ARG1-of (b / broad-02)))))) # ::id pmid_2384_5441.192 # ::date 2015-06-30T06:09:30 # ::file pmid_2384_5441_192.txt # ::snt Treatment was started 7–14 days after s.c. injection of cells as soon as tumors were palpable. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (s / start-01 :ARG1 (t2 / treat-04) :time (a / after :op1 (i / inject-01 :ARG1 (c / cell) :manner (s2 / subcutaneous) :time (a2 / as-soon-as :op1 (p / palpable :domain (t4 / tumor)))) :quant (v / value-interval :op1 (t3 / temporal-quantity :quant "7" :unit (d2 / day)) :op2 (t / temporal-quantity :quant "14" :unit (d / day))))) # ::id pmid_2384_5441.193 # ::date 2015-06-30T06:16:30 # ::file pmid_2384_5441_193.txt # ::snt Animals were given PD0325901 or vehicle by oral gavage for 13–15 days. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (g / give-01 :ARG1 (o / or :op1 (s / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :op2 (v / vehicle)) :ARG2 (a / animal) :manner (g2 / gavage :mod (o2 / oral)) :duration (v2 / value-interval :op1 (t2 / temporal-quantity :quant "13" :unit (d2 / day)) :op2 (t / temporal-quantity :quant "15" :unit (d / day)))) # ::id pmid_2384_5441.194 # ::date 2015-06-30T06:23:23 # ::file pmid_2384_5441_194.txt # ::snt PD0325901 was highly effective, causing regression of tumors from all tested cell lines (Figure 7D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (e / effective-04 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1-of (h / high-02) :ARG0-of (c / cause-01 :ARG1 (r / regress-01 :ARG1 (t / tumor :source (c2 / cell-line :ARG1-of (t2 / test-01) :mod (a / all))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7D"))) # ::id pmid_2384_5441.195 # ::date 2015-06-30T06:25:48 # ::file pmid_2384_5441_195.txt # ::snt Figures S6A and S6B show that after 13–15 days of PD0325901 treatment there was complete inhibition of ERK phosphorylation in surviving tumor cells and that only very few scattered Ki67-positive cancer cells could still be observed in the necrotic tumor mass. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / show-01 :ARG0 (a / and :op1 (f / figure :mod "S6A") :op2 (f2 / figure :mod "S6B")) :ARG1 (a2 / and :op1 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (c / complete-01) :time (a3 / after :op1 (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD0325901") :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987"))) :quant (v / value-interval :op1 (t3 / temporal-quantity :quant "13" :unit (d3 / day)) :op2 (t / temporal-quantity :quant "15" :unit (d / day)))) :location (c2 / cell :mod (t4 / tumor) :ARG0-of (s3 / survive-01))) :op2 (p3 / possible-01 :ARG1 (o / observe-01 :ARG1 (c3 / cell :mod (p4 / protein :name (n4 / name :op1 "Ki67") :mod (p2 / positive) :xref (x1 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653")) :ARG1-of (s4 / scatter-01) :quant (f3 / few :mod (o2 / only)) :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :location (m / mass-01 :ARG0 (t5 / tumor) :mod (n5 / necrosis)) :mod (s5 / still))))) # ::id pmid_2384_5441.196 # ::date 2015-06-30T06:26:09 # ::file pmid_2384_5441_196.txt # ::snt We next performed orthotopic transplantation of mouse and human Braf mutant cancer cell lines into the cecum of NSG mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (p / perform-01 :ARG0 (w / we) :ARG1 (t / transplant-01 :ARG0 w :ARG1 (a / and :op1 (c / cell-line :mod (g / gene :name (n4 / name :op1 "Braf") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :mod (m2 / mouse) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :op2 (c3 / cell-line :mod g :mod (h / human) :mod d)) :ARG2 (c4 / cecum :part-of (o / organism :name (n2 / name :op1 "NSG" :op2 "mouse"))) :mod (o2 / orthotopic)) :time (n3 / next)) # ::id pmid_2384_5441.197 # ::date 2015-06-30T06:30:19 # ::file pmid_2384_5441_197.txt # ::snt Fourteen days later, treatment was started with either vehicle or PD0325901. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (s / start-01 :ARG1 (t2 / treat-04 :ARG2 (o / or :op1 (v / vehicle) :op2 (s2 / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")))) :time (l3 / late :degree (m3 / more :quant (t / temporal-quantity :quant "14" :unit (d / day))))) # ::id pmid_2384_5441.198 # ::date 2015-06-30T06:33:31 # ::file pmid_2384_5441_198.txt # ::snt Mice were sacrificed after 17 days of treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (s / sacrifice-01 :ARG1 (m / mouse) :time (a / after :op1 (t2 / treat-01) :quant (t / temporal-quantity :quant "17" :unit (d / day)))) # ::id pmid_2384_5441.199 # ::date 2015-06-30T06:34:40 # ::file pmid_2384_5441_199.txt # ::snt Figures S6C–S6E show that vehicle-treated mice developed large tumors, which metastasized to local lymph nodes and the peritoneum, causing hemorrhagic ascites. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (v / value-interval :op1 (f / figure :mod "S6C") :op2 (f2 / figure :mod "S6E")) :ARG1 (d / develop-01 :ARG1 (m / mouse :ARG1-of (t / treat-04 :ARG2 (v2 / vehicle))) :ARG2 (t2 / tumor :mod (l / large) :ARG1-of (m2 / metastasize-101 :ARG2 (a / and :op1 (n / node :mod (l2 / lymph) :ARG1-of (l3 / local-02)) :op2 (p / peritoneum)) :ARG0-of (c / cause-01 :ARG1 (a2 / ascite :mod (h / hemorrhagic))))))) # ::id pmid_2384_5441.200 # ::date 2015-06-30T06:41:12 # ::file pmid_2384_5441_200.txt # ::snt In contrast, in the PD0325901-treated group, tumors were either not detectable or small (maximum 0.01 cm3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (c / contrast-01 :ARG2 (o / or :op1 (d / detect-01 :ARG1 (t / tumor) :ARG1-of (p / possible-01 :polarity "-")) :op2 (s / small :domain (t2 / tumor :ARG1-of (m / mean-01 :ARG2 (m2 / maximum :op1 (v / volume-quantity :quant "0.01" :unit (c2 / cubic-centimeter)))))) :location (g / group :ARG1-of (t3 / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")))))) # ::id pmid_2384_5441.201 # ::date 2015-06-30T06:51:27 # ::file pmid_2384_5441_201.txt # ::snt To examine the effect of PD0325901 on proliferation in endogenous BrafV637E-induced tumors, we performed short-term treatments (5 days) of Vil-Cre;BrafLSL-V637E/+ mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / perform-01 :ARG0 (w / we) :ARG1 (t2 / treat-04 :ARG1 (m7 / mouse :mod (m / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "Vil") :xref (x2 / xref :value "UNIPROT:VILI_HUMAN" :prob "0.602")) :part (e4 / enzyme :name (n2 / name :op1 "Cre") :xref (x / xref :value "UNIPROT:ATF6B_HUMAN" :prob "0.202"))) :mod (e / enzyme :name (n3 / name :op1 "Braf") :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+") :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :ARG1-of (s3 / short-07 :ARG1-of (m2 / mean-01 :ARG2 (t / temporal-quantity :quant "5" :unit (d / day))))) :purpose (e2 / examine-01 :ARG0 w :ARG1 (a2 / affect-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "PD0325901") :xref (x4 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (p4 / proliferate-01 :ARG0 (t3 / tumor :ARG2-of (i / induce-01 :ARG0 (e3 / enzyme :name (n5 / name :op1 "Braf") :ARG2-of (m4 / mutate-01 :value "V637E") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671"))) :mod (m5 / monocot)))))) # ::id pmid_2384_5441.202 # ::date 2015-06-30T07:00:07 # ::file pmid_2384_5441_202.txt # ::snt We used animals that were more than 1 year of age and were expected to have tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (a3 / and :op1 (a / animal :age (m2 / more-than :op1 (t / temporal-quantity :quant "1" :unit (y / year)))) :op2 (e / expect-01 :ARG1 (h / have-03 :ARG0 a :ARG1 (t2 / tumor))))) # ::id pmid_2384_5441.203 # ::date 2015-06-30T07:04:03 # ::file pmid_2384_5441_203.txt # ::snt Figures S6F and S6G show that Ki67 immunoreactivity was weak in the majority of dysplastic cells in PD0325901-treated mice but was strong in tumors of vehicle-treated animals. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (s / show-01 :ARG0 (v / value-interval :op1 (f / figure :mod "S6F") :op2 (f2 / figure :mod "S6G")) :ARG1 (c / contrast-01 :ARG1 (w / weak-02 :ARG1 (i / immunoreact-00 :ARG1 (p / protein :name (n / name :op1 "Ki67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))) :location (m2 / mouse :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x1 / xref :value "PUBCHEM:9826528" :prob "18.572987")))) :location (c2 / cell :quant (m / majority) :mod (d / dysplastic))) :ARG2 (s3 / strong-02 :ARG1 i :location (a / animal :ARG1-of (t2 / treat-01 :ARG2 (v2 / vehicle)))))) # ::id pmid_2384_5441.204 # ::date 2015-06-30T07:25:24 # ::file pmid_2384_5441_204.txt # ::snt All together, these data show that Mek inhibition is effective in the treatment of Braf-induced intestinal tumors in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (s / show-01 :ARG0 (d / data :mod (t / this)) :ARG1 (e2 / effective-04 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :ARG1 (t2 / treat-04 :ARG1 (t3 / tumor :mod (i2 / intestine) :ARG2-of (i3 / induce-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Braf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")))) :manner (i4 / in-vivo))) :mod (t4 / together :mod (a / all))) # ::id pmid_2384_5441.205 # ::date 2015-06-30T07:29:14 # ::file pmid_2384_5441_205.txt # ::snt To examine the effectiveness of combinatorial Braf/PI3K inhibition in vivo we treated s.c. transplanted murine and human cell lines with a combination of PLX4720 and GDC0941 or vehicle. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (t / treat-04 :ARG0 (w / we) :ARG1 (a / and :op1 (c / cell-line :ARG1-of (t2 / transplant-01 :manner (s / subcutaneous)) :mod (o2 / organism :name (n5 / name :op1 "Muridae"))) :op2 (c2 / cell-line :mod (h / human) :ARG1-of t2)) :ARG2 (c3 / combine-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "PLX4720") :xref (x3 / xref :value "PUBCHEM:24180719" :prob "18.572987")) :ARG2 (o / or :op1 (s3 / small-molecule :name (n2 / name :op1 "GDC0941") :xref (x2 / xref :value "PUBCHEM:17755052" :prob "18.349844")) :op2 (v / vehicle))) :purpose (e / examine-01 :ARG0 w :ARG1 (e2 / effective-04 :ARG0 (i / inhibit-01 :ARG1 (c4 / combine-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Braf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG2 (e4 / enzyme :name (n4 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :manner (i2 / in-vivo))))) # ::id pmid_2384_5441.206 # ::date 2015-06-30T07:34:20 # ::file pmid_2384_5441_206.txt # ::snt Figures 7E, S6H, and S6I show that combined Braf/PI3K inhibition elicited potent growth inhibition in both models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 30, 2015 (s / show-01 :ARG0 (a / and :op1 (f / figure :mod "7E") :op2 (f2 / figure :mod "S6H") :op3 (f3 / figure :mod "S6I")) :ARG1 (e / elicit-01 :ARG0 (i / inhibit-01 :ARG1 (c / combine-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Braf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.671")) :ARG2 (e3 / enzyme :name (n2 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :ARG1 (i2 / inhibit-01 :ARG1 (g / grow-01) :mod (p / potent)) :location (m / model :mod (b / both)))) # ::id pmid_2384_5441.207 # ::date 2015-06-30T07:37:10 # ::file pmid_2384_5441_207.txt # ::snt Immunohistochemical staining revealed that proliferation was substantially inhibited in the PLX4720/GDC0941-treated group, with only few Ki67-positive cells being detectable in regressed tumor masses (Figure S6I). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (r / reveal-01 :ARG0 (s / stain-01 :mod (i / immunohistochemical)) :ARG1 (a2 / and :op1 (i2 / inhibit-01 :ARG1 (p / proliferate-01) :degree (s2 / substantial) :location (g / group :ARG1-of (t / treat-04 :ARG2 (a / and :op1 (s3 / small-molecule :name (n / name :op1 "PLX4720") :xref (x1 / xref :value "PUBCHEM:24180719" :prob "18.572987")) :op2 (s4 / small-molecule :name (n2 / name :op1 "GDC0941") :xref (x2 / xref :value "PUBCHEM:17755052" :prob "18.349844")))))) :op2 (p2 / possible-01 :ARG1 (d / detect-01 :ARG1 (c2 / cell :quant (f2 / few :mod (o / only)) :mod (p4 / protein :name (n3 / name :op1 "Ki67") :mod (p3 / positive) :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.653"))) :location (m / mass-01 :ARG0 (t2 / tumor) :ARG1-of (r2 / regress-01))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "S6I"))) # ::id pmid_2384_5441.208 # ::date 2015-06-30T07:43:50 # ::file pmid_2384_5441_208.txt # ::snt These data mirror the in vitro effectiveness of these treatments in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (m / mirror-01 :ARG1 (d / data :mod (t / this)) :ARG2 (e / effective-04 :ARG0 (t2 / treat-04 :manner (i2 / in-vivo) :mod t) :manner (i / in-vitro))) # ::id pmid_2423_8212.1 # ::date 2015-08-25T08:45:27 # ::file pmid_2423_8212_1.txt # ::snt Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts (PMID:24238212) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / result-01 :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "Mek") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243"))) :ARG2 (a3 / and :op1 (a / activity-06 :ARG1-of (m / mark-01) :ARG0-of (o / oppose-01 :ARG1 (m4 / melanosphere :ARG1-of (d / derive-01 :ARG2 (p / person :ARG1-of (h / have-org-role-91 :ARG2 (p2 / patient)))) :mod (m6 / medical-condition :name (n2 / name :op1 "melanoma") :ARG1-of (m3 / metastasize-101)))) :ARG0-of (c / counter-01 :ARG1 (t / tumor))) :op2 (x / xenograft :ARG1-of (g / generate-01 :ARG0 (m5 / melanosphere)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID24238212"))) # ::id pmid_2423_8212.94 # ::date 2015-08-25T08:47:15 # ::file pmid_2423_8212_94.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2423_8212.95 # ::date 2015-08-25T08:48:26 # ::file pmid_2423_8212_95.txt # ::snt Melanospheres isolated from metastatic melanoma tumors possess stem cell properties, are highly tumorigenic in vivo and recapitulate the patient tumor # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (a / and :op1 (p / possess-01 :ARG0 (m3 / melanosphere :ARG1-of (i / isolate-01 :ARG2 (t / tumor :ARG1-of (m2 / metastasize-101) :mod (m / medical-condition :name (n / name :op1 "melanoma"))))) :ARG1 (p2 / property :mod (c2 / cell :mod (s / stem)))) :op2 (c3 / cause-01 :ARG0 m3 :ARG1 (t2 / tumor) :degree (h / high) :manner (i2 / in-vivo)) :op3 (r / recapitulate-01 :ARG0 m3 :ARG1 (t3 / tumor :mod (p3 / person :ARG1-of (h2 / have-org-role-91 :ARG2 (p4 / patient)))))) # ::id pmid_2423_8212.96 # ::date 2015-08-25T09:11:20 # ::file pmid_2423_8212_96.txt # ::snt Ten patient-derived metastatic melanoma specimens were enzymatically dissociated and tumor cells were cultured in selective conditions for CSC (tumor spheres), as previously described [41-44]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (a / and :op1 (d / dissociate-01 :ARG1 (s / specimen :quant "10" :ARG1-of (m2 / metastasize-101) :ARG1-of (d2 / derive-01 :ARG2 (p / person :ARG1-of (h / have-org-role-91 :ARG2 (p2 / patient)))) :mod (m4 / medical-condition :name (n2 / name :op1 "melanoma"))) :manner (e / enzyme)) :op2 (c / culture-01 :ARG1 (c2 / cell :mod (t / tumor)) :manner (c3 / condition :ARG0-of (s2 / select-01)) :purpose (c4 / cell :mod (s3 / stem) :ARG1-of (m3 / mean-01 :ARG2 (s4 / sphere :mod t)) :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :ARG1-of (d3 / describe-01 :time (p3 / previous)) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 (v / value-interval :op1 "41" :op2 "44"))))) # ::id pmid_2423_8212.97 # ::date 2015-08-25T09:34:20 # ::file pmid_2423_8212_97.txt # ::snt Following prolonged culture, we obtained exponentially growing “melanospheres” with efficiency of 80% (Figure 1A left). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (o / obtain-01 :ARG0 (w / we) :ARG1 (m / melanosphere :ARG1-of (g / grow-01 :manner (e / exponential)) :ARG1-of (e2 / efficient-01 :degree (p / percentage-entity :value "80"))) :ARG1-of (f / follow-01 :ARG2 (c2 / culture-01 :ARG1-of (p2 / prolong-01))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1A" :ARG1-of (l / left-20)))) # ::id pmid_2423_8212.98 # ::date 2015-08-25T09:54:23 # ::file pmid_2423_8212_98.txt # ::snt The same cells cultured in conditions specific for the growth of melanocytes generated monolayers of tumor cells whose morphology resembled differentiated cells, suggesting the capacity of melanospheres to differentiate in vitro (Figure 1A right). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (g / generate-01 :ARG0 (c / cell :ARG1-of (c2 / culture-01 :manner (c3 / condition :ARG1-of (s2 / specific-02 :ARG2 (g2 / grow-01 :ARG1 (m4 / melanocyte))))) :ARG1-of (s4 / same-01)) :ARG1 (m / monolayer :consist-of (c5 / cell :ARG0-of (h / have-03 :ARG1 (m2 / morphology :ARG1-of (r / resemble-01 :ARG2 (c6 / cell :ARG1-of (d / differentiate-101))))) :mod (t / tumor))) :ARG0-of (s3 / suggest-01 :ARG1 (c7 / capable-01 :ARG1 (m3 / melanosphere) :ARG2 (d2 / differentiate-101 :manner (i / in-vitro)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1A" :ARG1-of (r2 / right-04)))) # ::id pmid_2423_8212.99 # ::date 2015-08-25T10:10:12 # ::file pmid_2423_8212_99.txt # ::snt We next investigated the expression of antigens that have been previously associated with MIC. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (a / antigen :ARG1-of (a2 / associate-01 :ARG2 (c / cell :ARG0-of (i2 / initiate-01 :ARG1 (m / medical-condition :name (n2 / name :op1 "melanoma")))) :time (p / previous)))) :time (n / next)) # ::id pmid_2423_8212.100 # ::date 2015-08-25T10:17:06 # ::file pmid_2423_8212_100.txt # ::snt Melanospheres did not express CD133, CD20, CD24, ABCB5 or CD271 (Additional file 1: Figure S1A-B), while p-glycoprotein was detectable at low levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG1 (e / express-03 :polarity "-" :ARG2 (o / or :op1 (p / protein :name (n / name :op1 "CD133") :xref (x4 / xref :value "UNIPROT:PROM1_HUMAN" :prob "1.002")) :op2 (p2 / protein :name (n2 / name :op1 "CD20") :xref (x / xref :value "UNIPROT:CD20_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "CD24") :xref (x1 / xref :value "UNIPROT:CD24_HUMAN" :prob "1.003")) :op4 (p4 / protein :name (n4 / name :op1 "ABCB5") :xref (x2 / xref :value "UNIPROT:ABCB5_HUMAN" :prob "1.003")) :op5 (p5 / protein :name (n5 / name :op1 "CD271") :xref (x3 / xref :value "UNIPROT:TNR16_HUMAN" :prob "1.003"))) :ARG3 (m / melanosphere) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "1" :ARG1-of (a / add-02) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (f2 / figure :mod "S1A") :op2 (f3 / figure :mod "S1B")))))) :ARG2 (d2 / detect-01 :ARG1 (g / glycoprotein :ARG3-of (p8 / phosphorylate-01) :quant (l / level :ARG1-of (l2 / low-04))) :ARG1-of (p6 / possible-01))) # ::id pmid_2423_8212.101 # ::date 2015-08-25T10:37:58 # ::file pmid_2423_8212_101.txt # ::snt They expressed stem cell-related markers as c-Kit, Cripto, CD146, CD44 and CD166 (Additional file 1: Figure S1A) in agreement with previous reports on cell line-derived melanospheres [38]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / express-03 :ARG2 (m / marker :ARG1-of (r / relate-01 :ARG2 (c / cell :mod (s / stem))) :ARG1-of (e2 / exemplify-01 :ARG0 (a / and :op1 (e3 / enzyme :name (n / name :op1 "c-Kit") :xref (x1 / xref :value "UNIPROT:SCF_HUMAN" :prob "0.233")) :op2 (p2 / protein :name (n2 / name :op1 "Cripto") :xref (x / xref :value "UNIPROT:TDGF1_HUMAN" :prob "0.603")) :op3 (p3 / protein :name (n3 / name :op1 "CD146") :xref (x2 / xref :value "UNIPROT:MUC18_HUMAN" :prob "1.002")) :op4 (p4 / protein :name (n4 / name :op1 "CD44") :xref (x3 / xref :value "UNIPROT:CD44_HUMAN" :prob "1.004")) :op5 (p5 / protein :name (n5 / name :op1 "CD166") :xref (x4 / xref :value "UNIPROT:CD166_HUMAN" :prob "1.003"))) :ARG1-of (d3 / describe-01 :ARG0 (f / file :mod "1" :ARG1-of (a3 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (f2 / figure :mod "S1A")))))) :ARG3 (t / they) :ARG0-of (a2 / agree-01 :ARG2 (t2 / thing :time (p6 / previous) :ARG1-of (r2 / report-01 :topic (m3 / melanosphere :ARG1-of (d / derive-01 :ARG2 (c3 / cell-line)))))) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 "38")))) # ::id pmid_2423_8212.102 # ::date 2015-08-25T10:50:08 # ::file pmid_2423_8212_102.txt # ::snt Finally, embryonic stem cell markers Nanog and Oct-4 were detected at the RNA level in all samples analyzed (Additional file 1: Figure S1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (d / detect-01 :ARG1 (a / and :op1 (m / marker :wiki "Homeobox_protein_NANOG" :name (n / name :op1 "Nanog") :mod (c / cell :mod (s / stem)) :mod (e / embryo)) :op2 (m2 / marker :wiki "Oct-4" :name (n2 / name :op1 "Oct-4") :mod c :mod e)) :location (t / thing :mod (a2 / all) :ARG1-of (a3 / analyze-01) :ARG1-of (s2 / sample-01)) :location (l / level :mod (n3 / nucleic-acid :wiki "RNA" :name (n4 / name :op1 "RNA"))) :ARG1-of (d2 / describe-01 :ARG0 (f / file :mod "1" :ARG1-of (a4 / add-02) :ARG1-of (m3 / mean-01 :ARG2 (f2 / figure :mod "S1C")))) :time (f3 / final)) # ::id pmid_2423_8212.103 # ::date 2015-08-25T10:58:38 # ::file pmid_2423_8212_103.txt # ::snt The CD44 isoform V6 was specifically restricted to melanospheres, being not expressed in differentiated cells, nor in tumor cells freshly isolated from melanosphere-derived xenografts nor in melanocytes (Additional file 1: Figure S1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (r / restrict-01 :ARG1 (i / isoform :name (n / name :op1 "V6") :mod (p / protein :name (n2 / name :op1 "CD44") :xref (x1 / xref :value "UNIPROT:CD44_HUMAN" :prob "1.004")) :ARG1-of (e / express-03 :polarity "-" :ARG3 (o / or :op1 (c2 / cell :ARG1-of (d / differentiate-101)) :op2 (c3 / cell :mod (t / tumor) :ARG1-of (i2 / isolate-01 :ARG2 (x / xenograft :ARG1-of (d2 / derive-01 :ARG2 "m3")) :ARG1-of (f / fresh-04))) :op3 (m2 / melanocyte)))) :ARG2 (m3 / melanosphere) :manner (s / specific-02) :ARG1-of (d3 / describe-01 :ARG0 (f2 / file :mod "1" :ARG1-of (a / add-02) :ARG1-of (m / mean-01 :ARG2 (f3 / figure :mod "S1D"))))) # ::id pmid_2423_8212.104 # ::date 2015-08-25T11:07:49 # ::file pmid_2423_8212_104.txt # ::snt Melanospheres could be expanded in vitro for several months and their proliferation rate was not lost with time (Additional file 2: Figure S2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (a / and :op1 (p2 / possible-01 :ARG1 (e / expand-01 :ARG1 (m3 / melanosphere) :manner (i / in-vitro) :duration (s / several :op1 (t2 / temporal-quantity :quant "1" :unit (m / month))))) :op2 (l / lose-02 :ARG0 m3 :ARG1 (r / rate :degree-of (p / proliferate-01 :ARG0 m3)) :condition (t / time)) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "2" :ARG1-of (a2 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (f2 / figure :mod "S2A"))))) # ::id pmid_2423_8212.105 # ::date 2015-08-25T11:35:04 # ::file pmid_2423_8212_105.txt # ::snt They were composed by a large (mean 42% ± 8 in all examined samples) fraction of self-renewing sphere-reforming cells (Additional file 2: Figure S2B upper left). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / compose-01 :ARG1 (t / they) :ARG2 (f / fraction-01 :ARG1 (c2 / cell :ARG0-of (r / renew-01 :ARG1 c2) :ARG0-of (r2 / reform-01 :ARG2 (s / sphere))) :mod (l / large) :ARG1-of (a2 / average-01 :ARG2 (o / or :op1 (p / percentage-entity :value "42" :ARG2-of (a3 / add-02 :ARG1 (p2 / percentage-entity :value "8"))) :op2 (p3 / percentage-entity :value "42" :ARG2-of (s2 / subtract-01 :ARG1 p2))) :location (t2 / thing :mod (a4 / all) :ARG1-of (e / examine-01) :ARG1-of (s3 / sample-01)))) :ARG1-of (d / describe-01 :ARG0 (f2 / file :mod "2" :ARG1-of (a / add-02) :ARG1-of (m / mean-01 :ARG2 (f3 / figure :mod "S2B" :ARG1-of (l2 / left-20 :mod (u / upper))))))) # ::id pmid_2423_8212.106 # ::date 2015-08-25T11:58:25 # ::file pmid_2423_8212_106.txt # ::snt Finally, secondary and tertiary spheres were formed with a similar frequency and tertiary spheres were able to proliferate indefinitely, indicating that the fraction of self-renewing cells did not decrease with passages (Additional file 2: Figure S2B upper right panel). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (a2 / and :op1 (f / form-01 :ARG1 (a / and :op1 (s / sphere :mod (s2 / secondary)) :op2 (s3 / sphere :mod (t / tertiary))) :manner (f2 / frequency :ARG1-of (r / resemble-01))) :op2 (p / possible-01 :ARG1 (p2 / proliferate-01 :ARG0 s3 :duration (d / definite :polarity "-"))) :ARG0-of (i / indicate-01 :ARG1 (d2 / decrease-01 :polarity "-" :ARG0 (f3 / fraction-01 :ARG1 (c / cell :ARG0-of (r2 / renew-01 :ARG1 c))) :condition (p3 / pass-08))) :time (f4 / final) :ARG1-of (d3 / describe-01 :ARG0 (f5 / file :mod "2" :ARG1-of (a3 / add-02) :ARG1-of (m / mean-01 :ARG2 (f6 / figure :mod "S2B" :part (p4 / panel :ARG1-of (r3 / right-04 :mod (u / upper)))))))) # ::id pmid_2423_8212.107 # ::date 2015-08-25T12:15:04 # ::file pmid_2423_8212_107.txt # ::snt The clonogenic activity was higher in melanospheres than in their differentiated counterpart (Additional file 2: Figure S2B lower panels). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (h / high-02 :ARG1 (a / activity-06 :ARG0 (m2 / melanosphere) :mod (c / clonogenic)) :compared-to (c3 / counterpart :ARG1-of (d / differentiate-101) :poss m2) :ARG1-of (d2 / describe-01 :ARG0 (f / file :mod "2" :ARG1-of (a2 / add-02) :ARG1-of (m / mean-01 :ARG2 (f2 / figure :mod "S2B" :part (p / panel :ARG1-of (l / low-04)))))) :degree (m3 / more)) # ::id pmid_2423_8212.108 # ::date 2015-08-25T12:22:39 # ::file pmid_2423_8212_108.txt # ::snt Under appropriate conditions, melanospheres generated a progeny of cells with morphology and phenotype of melanocytic, adipogenic or osteogenic cells, demonstrating multiple differentiation ability and recapitulating the plasticity of neural crest cells (Additional file 2:Figure S2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (g / generate-01 :ARG0 (m5 / melanosphere) :ARG1 (p / progeny :poss (c2 / cell :ARG0-of (h / have-03 :ARG1 (a / and :op1 (m / morphology) :op2 (p2 / phenotype) :poss (o / or :op1 (c3 / cell :mod (m2 / melanocyte)) :op2 (c4 / cell :mod (a2 / adipogenesis)) :op3 (c5 / cell :mod (o2 / osteogenesis))))))) :ARG0-of (d / demonstrate-01 :ARG1 (c6 / capable-01 :ARG1 m5 :ARG2 (d2 / differentiate-101 :mod (m3 / multiple)))) :ARG0-of (r / recapitulate-01 :ARG1 (p3 / plasticity :poss (c7 / cell :mod (c8 / crest) :mod (n2 / neural)))) :ARG1-of (d3 / describe-01 :ARG0 (f / file :mod "2" :ARG1-of (a3 / add-02) :ARG1-of (m4 / mean-01 :ARG2 (f2 / figure :mod "S2C")))) :condition (c9 / condition :ARG1-of (a4 / appropriate-02))) # ::id pmid_2423_8212.109 # ::date 2015-08-25T12:45:10 # ::file pmid_2423_8212_109.txt # ::snt Melanospheres were highly tumorigenic when injected subcutaneously in NOD Scid or Nude mice and all samples displayed tumor take of 100% down to 25000 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (a / and :op1 (c / cause-01 :ARG0 (m4 / melanosphere) :ARG1 (t / tumor) :degree (h / high) :condition (i / inject-01 :ARG1 m4 :ARG2 (o / or :op1 (m5 / mouse :name (n / name :op1 "NOD-Scid")) :op2 (m2 / mouse :mod (n3 / nude))) :manner (s / subcutaneous))) :op2 (d / display-01 :ARG0 (t2 / thing :ARG1-of (s2 / sample-01) :mod (a2 / all)) :ARG1 (t3 / take-01 :ARG1 t :quant (p / percentage-entity :value "100" :ARG1-of (m3 / mean-01 :ARG2 (c4 / cell :quant (d2 / down-to :quant "25000")))) :mod t))) # ::id pmid_2423_8212.110 # ::date 2015-08-25T13:10:19 # ::file pmid_2423_8212_110.txt # ::snt For one sample we performed a limiting dilution experiment and even as low as 5 cells readily generated a tumor within 8 weeks (Figure 1B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (a / and :op1 (p / perform-02 :ARG0 (w / we) :ARG1 (e / experiment-01 :ARG0 w :ARG1 (t3 / thing :quant "1" :ARG1-of (s / sample-01)) :ARG2 (d / dilute-01 :ARG0-of (l / limit-01)))) :op2 (g / generate-01 :ARG0 (c / cell :ARG1-of (l2 / low-04 :ARG3 "5") :mod (e2 / even)) :ARG1 (t / tumor) :manner (r / ready) :time (u / up-to :op1 (t2 / temporal-quantity :quant "8" :unit (w2 / week)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "1C")))) # ::id pmid_2423_8212.111 # ::date 2015-08-25T13:20:04 # ::file pmid_2423_8212_111.txt # ::snt In contrast, melanosphere-derived differentiated cells displayed a decreased and delayed tumor growth in vivo, and as many as 5x104 differentiated cells generated a slowly growing tumor with a 10-week delay post-injection (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (c / contrast-01 :ARG2 (a / and :op1 (d / display-01 :ARG0 (c3 / cell :ARG1-of (d4 / differentiate-101) :ARG1-of (d5 / derive-01 :ARG2 (m / melanosphere))) :ARG1 (g / grow-01 :ARG1 (t / tumor) :ARG1-of (d2 / decrease-01) :ARG1-of (d3 / delay-01)) :manner (i / in-vivo)) :op2 (g2 / generate-01 :ARG0 (c2 / cell :ARG1-of d4 :quant (a3 / as-many-as :op1 "50000")) :ARG1 (t2 / tumor :ARG1-of (g3 / grow-01 :ARG1-of (s / slow-05))) :ARG0-of (h / have-03 :ARG1 (d6 / delay-01 :ARG2 (t3 / temporal-quantity :quant "10" :unit (w / week)) :time (a2 / after :op1 (i2 / inject-01))))) :ARG1-of (d7 / describe-01 :ARG0 (f / figure :mod "1B")))) # ::id pmid_2423_8212.112 # ::date 2015-08-25T13:35:24 # ::file pmid_2423_8212_112.txt # ::snt Immunohistochemical analysis of melanosphere-derived xenografts, performed for all samples, revealed a high similarity between the xenograft and the original patient tumor in terms of morphology and expression of the melanoma-associated diagnostic antigens MART1 and S100 (Figure 1D is a representative image). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (x / xenograft :ARG1-of (d / derive-01 :ARG2 (m3 / melanosphere))) :ARG1-of (p / perform-02) :beneficiary (t / thing :ARG1-of (s / sample-01) :mod (a2 / all)) :mod (i / immunohistochemical)) :ARG1 (r2 / resemble-01 :ARG1 x :ARG2 (t2 / tumor :mod (o / original) :mod (p2 / person :ARG0-of (h2 / have-org-role-91 :ARG2 (p3 / patient)))) :ARG1-of (h / high-02) :topic (a3 / and :op1 (m / morphology) :op2 (e / express-03 :ARG2 (a4 / and :op1 (a5 / antigen :name (n2 / name :op1 "MART1") :ARG1-of (a7 / associate-01 :ARG2 (m2 / medical-condition :name (n / name :op1 "melanoma"))) :mod (d2 / diagnose-01)) :op2 (a6 / antigen :name (n3 / name :op1 "S100") :ARG1-of a7 :mod d2))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1D" :ARG1-of (r3 / represent-01 :ARG0 (i2 / image))))) # ::id pmid_2423_8212.113 # ::date 2015-08-25T13:53:32 # ::file pmid_2423_8212_113.txt # ::snt Following xenograft dissociation and re-injection we easily obtained secondary and tertiary tumors, suggesting that tumorigenic potential was not lost with passages in mice, in fact these results proved the ability of tumorigenic cells to self-renew in vivo (results not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m2 / multi-sentence :snt1 (o / obtain-01 :ARG0 (w / we) :ARG1 (a / and :op1 (t / tumor :mod (s / secondary)) :op2 (t2 / tumor :mod (t3 / tertiary))) :ARG1-of (e / easy-05) :ARG0-of (s2 / suggest-01 :ARG1 (l / lose-02 :polarity "-" :ARG1 (c / capable-01 :ARG1 (c2 / cause-01 :ARG1 (t4 / tumor))) :condition (p / pass-03 :location (m / mouse)))) :ARG1-of (f / follow-01 :ARG2 (a2 / and :op1 (d / dissociate-01 :ARG1 (x / xenograft)) :op2 (r / reinject-00 :ARG1 x)))) :snt2 (p2 / prove-01 :ARG0 (t5 / thing :ARG2-of (r2 / result-01) :ARG1-of (s3 / show-01 :polarity "-") :mod (t6 / this)) :ARG1 (c3 / capable-01 :ARG1 (c4 / cell :ARG0-of (c5 / cause-01 :ARG1 (t7 / tumor))) :ARG2 (r3 / renew-01 :ARG0 c4 :ARG1 c4 :manner (i / in-vivo))) :mod (i2 / in-fact))) # ::id pmid_2423_8212.114 # ::date 2015-08-25T14:15:06 # ::file pmid_2423_8212_114.txt # ::snt Based on these in vitro and in vivo results, we considered melanospheres as surrogate of melanoma-initiating cells (MIC) exploitable for pre-clinical experimentation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (c / consider-02 :ARG0 (w / we) :ARG1 (m2 / melanosphere) :ARG2 (s / surrogate :poss (c3 / cell :ARG0-of (i / initiate-01 :ARG1 (m / medical-condition :name (n / name :op1 "melanoma"))) :ARG1-of (e / exploit-01 :ARG2 (e2 / experiment-01 :time (b / before :op1 (c4 / clinic))) :ARG1-of (p / possible-01)))) :ARG2-of (b2 / base-02 :ARG1 (t / thing :ARG2-of (r / result-01) :manner (i2 / in-vivo) :manner (i3 / in-vitro) :mod (t2 / this)))) # ::id pmid_2423_8212.115 # ::date 2015-08-25T14:24:59 # ::file pmid_2423_8212_115.txt # ::snt Melanospheres are resistant to chemotherapeutic drugs and to most pathway inhibitors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (r / resist-01 :ARG0 (m3 / melanosphere) :ARG1 (a / and :op1 (d / drug :mod (c2 / chemotherapy)) :op2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway)) :quant (m2 / most)))) # ::id pmid_2423_8212.116 # ::date 2015-08-25T14:29:29 # ::file pmid_2423_8212_116.txt # ::snt We investigated the response of melaospheres to chemotherapeutic agents currently used in the treatment of melanoma patients. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (r / respond-01 :ARG0 (m2 / melanosphere) :ARG1 (a / agent :mod (c2 / chemotherapy) :ARG1-of (u / use-01 :ARG2 (t / treat-03 :ARG1 (p / person :ARG0-of (h / have-org-role-91 :ARG2 (p2 / patient))) :ARG2 (m / medical-condition :name (n / name :op1 "melanoma"))) :time (c3 / current))))) # ::id pmid_2423_8212.117 # ::date 2015-08-25T14:33:04 # ::file pmid_2423_8212_117.txt # ::snt Melanospheres were exposed to cisplatin, temozolomide, dacarbazine and paclitaxel for 48 hours and cell viability was assessed by MTT assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / and :op1 (e / expose-01 :ARG1 (m / melanosphere) :ARG2 (a2 / and :op1 (s / small-molecule :name (n2 / name :op1 "cisplatin") :xref (x4 / xref :value "PUBCHEM:441203" :prob "10.782021")) :op2 (s2 / small-molecule :name (n3 / name :op1 "temozolomide") :xref (x1 / xref :value "PUBCHEM:5394" :prob "17.068911")) :op3 (s3 / small-molecule :name (n4 / name :op1 "dacarbazine") :xref (x / xref :value "PUBCHEM:5281007" :prob "16.914757")) :op4 (s4 / small-molecule :name (n5 / name :op1 "paclitaxel") :xref (x3 / xref :value "PUBCHEM:4666" :prob "15.068933"))) :duration (t / temporal-quantity :quant "48" :unit (h / hour))) :op1 (a3 / assess-01 :ARG0 (a4 / assay-01 :instrument (s5 / small-molecule :name (n / name :op1 "MTT") :xref (x2 / xref :value "PUBCHEM:64965" :prob "17.320225"))) :ARG1 (v / viability :mod (c2 / cell)))) # ::id pmid_2423_8212.118 # ::date 2015-08-25T14:39:15 # ::file pmid_2423_8212_118.txt # ::snt Overall a weak cytotoxic effect (<40% in all samples and with all drugs) was observed with no therapeutic window as compared to normal melanocytes (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (o / observe-01 :ARG1 (a / affect-01 :ARG1 (t2 / thing :ARG1-of (s / sample-01) :mod (a2 / all)) :ARG2 (d2 / drug :mod a2) :ARG1-of (w / weak-02) :mod (c / cytotoxic) :ARG0-of (h / have-03 :polarity "-" :ARG1 (w2 / window :mod (t / therapy))) :degree (l / less-than :op1 (p / percentage-entity :value "40"))) :compared-to (m / melanocyte :ARG1-of (n2 / normal-02)) :mod (o2 / overall) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2423_8212.119 # ::date 2015-08-25T14:47:35 # ::file pmid_2423_8212_119.txt # ::snt Conversely, differentiated cells were extremely sensitive to cisplatin, in 3 out of 3 samples assessed (Figure 2B is a representative sample). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (s / sensitive-03 :ARG0 (c / cell :ARG1-of (d / differentiate-101)) :ARG1 (s2 / small-molecule :name (n / name :op1 "cisplatin") :xref (x / xref :value "PUBCHEM:441203" :prob "10.782021")) :degree (e / extreme) :location (t / thing :quant "3" :ARG1-of (a / assess-01) :ARG1-of (s3 / sample-01) :ARG1-of (i / include-91 :ARG2 (t2 / thing :quant "3" :ARG1-of s3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2B" :ARG0-of (r / represent-01 :ARG1 (t3 / thing :ARG1-of s3)))) :manner (c2 / converse)) # ::id pmid_2423_8212.120 # ::date 2015-08-25T14:55:50 # ::file pmid_2423_8212_120.txt # ::snt We next investigated the cytotoxic potential of a panel of 80 signaling pathway inhibitors on melanospheres derived from patient #1 and #2 and #3 encompassing inhibitors of RAS/RAF/MEK and PI3K/AKT pathways as well as tyrosine kinase receptors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (c / capable-01 :ARG1 (p / panel :consist-of (m / molecular-physical-entity :quant "80" :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / pathway :ARG0-of (s / signal-07)))) :ARG0-of (e / encompass-01 :ARG1 (a3 / and :op1 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (a2 / and :op1 (p7 / pathway :name (n2 / name :op1 "RAS/RAF/MEK")) :op2 (p8 / pathway :name (n3 / name :op1 "PI3K/AKT"))))) :op2 (p9 / protein :name (n4 / name :op1 "tyrosine" :op2 "kinase" :op3 "receptor") :xref (x / xref :value "UNIPROT:NTRK1_HUMAN" :prob "0.703"))))) :ARG2 (c2 / cytotoxic) :beneficiary (m2 / melanosphere :ARG1-of (d / derive-01 :ARG2 (a / and :op1 (p3 / person :ARG1-of (h / have-org-role-91 :ARG2 (p4 / patient)) :ord (o / ordinal-entity :value "1")) :op2 (p5 / person :ARG1-of h :ord (o2 / ordinal-entity :value "2")) :op3 (p6 / person :ARG1-of h :ord (o3 / ordinal-entity :value "3")))))) :time (n / next)) # ::id pmid_2423_8212.121 # ::date 2015-08-25T15:11:30 # ::file pmid_2423_8212_121.txt # ::snt Only inhibitors of the RAS/RAF/MEK pathway (including the MEK inhibitors PD098059 and U0126 and the Erk2 inhibitor 5-iodotubercidin) showed promising antitumor activity in terms of reduced cell viability, as measured by MTT assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (s / show-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "RAS/RAF/MEK"))) :ARG2-of (i2 / include-01 :ARG1 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "PD098059") :ARG0-of (i3 / inhibit-01 :ARG1 (p3 / protein-family :name (n5 / name :op1 "MEK")))) :op2 (s3 / small-molecule :name (n3 / name :op1 "U0126") :ARG0-of i3 :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :op3 (s4 / small-molecule :name (n4 / name :op1 "5-iodotubercidin") :ARG0-of (i4 / inhibit-01 :ARG1 (e / enzyme :name (n6 / name :op1 "Erk2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :xref (x3 / xref :value "PUBCHEM:1830" :prob "12.840892")))) :mod (o / only)) :ARG1 (a2 / activity-06 :ARG1 (o2 / oppose-01 :ARG1 (t / tumor)) :ARG0-of (p2 / promise-01) :topic (v / viability :mod (c / cell) :ARG0-of (r / reduce-01) :ARG1-of (m2 / measure-01 :ARG0 (a3 / assay-01 :instrument (s5 / small-molecule :name (n7 / name :op1 "MTT") :xref (x2 / xref :value "PUBCHEM:64965" :prob "17.320225"))))))) # ::id pmid_2423_8212.122 # ::date 2015-08-25T15:24:24 # ::file pmid_2423_8212_122.txt # ::snt The other drugs, except for the broadly toxic compound staurosporin used as positive control, were nearly unable to reduce cell viability/proliferation, although all compounds were used at doses higher than the described IC50 in order to enhance their activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (p / possible-01 :polarity "-" :ARG1 (r / reduce-01 :ARG0 (d / drug :mod (o / other) :ARG2-of (e / except-01 :ARG1 (c / compound :name (n / name :op1 "staurosporin") :mod (t / toxic :ARG1-of (b / broad-02)) :ARG1-of (u / use-01 :ARG2 (c2 / control :mod (p2 / positive)))))) :ARG1 (s / slash :op1 (v / viability :mod (c3 / cell)) :op2 (p3 / proliferate-01 :ARG0 c3))) :concession (u2 / use-01 :ARG1 (c4 / compound :mod (a / all) :ARG2-of (d2 / dose-01 :ARG1-of (h2 / high-02 :degree (m / more) :compared-to (t2 / thing :name (n2 / name :op1 "IC50") :ARG1-of (d3 / describe-01))))) :ARG2 (e2 / enhance-01 :ARG1 (a2 / activity-06 :ARG0 c4))) :mod (n3 / near)) # ::id pmid_2423_8212.123 # ::date 2015-08-25T15:36:12 # ::file pmid_2423_8212_123.txt # ::snt A similar drug response was observed for the different samples (Figure 2C shows a representative one). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (o / observe-01 :ARG1 (r / respond-01 :ARG0 (d / drug) :ARG1-of (r2 / resemble-01)) :location (t / thing :ARG1-of (s / sample-01) :ARG1-of (d2 / differ-02)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2C" :ARG0-of (s2 / show-01 :ARG1 (t2 / thing :ARG1-of (s3 / sample-01 :ARG0-of (r3 / represent-01))))))) # ::id pmid_2423_8212.124 # ::date 2015-08-30T05:03:36 # ::file pmid_2423_8212_124.txt # ::snt In line with the melanosphere sensitivity to compounds targeting the MAPK pathways, we observed the activation of this signaling pathway with high levels of phosphorylation of Erk and downstream S6 (Figure 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (o / observe-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG1 (p / pathway :ARG0-of (s / signal-07) :mod (t / this)) :mod (l / level :ARG1-of (h / high-02 :ARG2 (p2 / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "Erk") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :op2 (p4 / protein :name (n2 / name :op1 "S6") :location (d / downstream))))))) :ARG1-of (a3 / align-01 :ARG2 (s2 / sensitive-03 :ARG0 (c / cell :name (n3 / name :op1 "melanosphere")) :ARG1 (c2 / compound :ARG0-of (t2 / target-01 :ARG1 (p5 / pathway :name (n4 / name :op1 "MAPK")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2D"))) # ::id pmid_2423_8212.125 # ::date 2015-08-30T05:25:39 # ::file pmid_2423_8212_125.txt # ::snt We also found high levels of Cyclin-D and undetectable p16 (Figure 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (l / level :ARG1-of (h / high-02 :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "Cyclin-D") :xref (x1 / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.352")) :op2 (p2 / protein :name (n2 / name :op1 "p16") :ARG1-of (d / detect-01 :ARG1-of (p3 / possible-01 :polarity "-")) :xref (x / xref :value "UNIPROT:MSH6_HUMAN" :prob "0.262"))))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2D"))) # ::id pmid_2423_8212.126 # ::date 2015-08-30T05:31:28 # ::file pmid_2423_8212_126.txt # ::snt These results are in agreement with the frequent alteration of the RAS/RAF/MEK pathway and cell cycle deregulation found in melanomas. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (a / agree-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (a3 / and :op1 (a2 / alter-01 :ARG1 (p / pathway :name (n / name :op1 "RAS/RAF/MEK")) :ARG1-of (f2 / frequent-02)) :op1 (d / deregulate-01 :ARG1 (c / cycle :mod (c2 / cell))) :ARG1-of (f / find-01 :location (m / medical-condition :name (n2 / name :op1 "melanoma"))))) # ::id pmid_2423_8212.127 # ::date 2015-08-30T05:46:59 # ::file pmid_2423_8212_127.txt # ::snt Next, we analyzed DNA sequences of genes whose alterations may contribute to the abnormal pathway activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (d / dna-sequence :part-of (g / gene :poss-of (a2 / alter-01 :ARG0-of (c / contribute-01 :ARG2 (a3 / activate-01 :ARG1 (p2 / pathway) :ARG1-of (n / normal-02 :polarity "-")) :ARG1-of (p3 / possible-01))))) :time (n2 / next)) # ::id pmid_2423_8212.128 # ::date 2015-08-30T05:55:22 # ::file pmid_2423_8212_128.txt # ::snt As reported in the Additional file 3: Table S1, NRAS was never mutated in the analyzed samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (m / mutate-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "NRAS") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :location (t2 / thing :ARG1-of (a / analyze-01) :ARG1-of (s / sample-01)) :ARG1-of (r / report-01 :medium (t / table :mod "S1" :part-of (f / file :mod "3" :mod (a2 / additional)))) :time (e2 / ever)) # ::id pmid_2423_8212.129 # ::date 2015-08-30T06:00:34 # ::file pmid_2423_8212_129.txt # ::snt Instead, despite the ubiquitous Erk phosphorylation found in melanospheres, the BRAF-V600E mutation was detected in samples 1, 2 and 4, BRAF-V600K mutation was found in samples 5 and 8, while samples 3, 6 and 7 displayed wild type BRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (a / and :op1 (d / detect-01 :ARG1 (m / mutate-01 :value "V600E" :ARG2 (e / enzyme :name (n3 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :location (a2 / and :op1 (t / thing :mod "1" :ARG1-of (s / sample-01)) :op2 (t2 / thing :mod "2" :ARG1-of s) :op3 (t3 / thing :mod "4" :ARG1-of s))) :op2 (f2 / find-01 :ARG1 (m2 / mutate-01 :value "V600K" :ARG1 e) :location (a3 / and :op1 (t4 / thing :mod "5" :ARG1-of s) :op2 (t5 / thing :mod "8" :ARG1-of s))) :op3 (d2 / display-01 :ARG0 (a4 / and :op1 (t6 / thing :mod "3" :ARG1-of s) :op2 (t7 / thing :mod "6" :ARG1-of s) :op3 (t8 / thing :mod "7" :ARG1-of s)) :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "Erk") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :mod (u / ubiquity) :ARG1-of (f / find-01 :location (c / cell :name (n2 / name :op1 "melanosphere")))) :ARG1-of (i / instead-of-91)) # ::id pmid_2423_8212.130 # ::date 2015-08-30T06:14:45 # ::file pmid_2423_8212_130.txt # ::snt All samples displayed wild type PTEN. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (d / display-01 :ARG0 (t / thing :mod (a / all) :ARG1-of (s / sample-01)) :ARG1 (p / protein :name (n / name :op1 "PTEN") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) # ::id pmid_2423_8212.131 # ::date 2015-08-30T06:16:26 # ::file pmid_2423_8212_131.txt # ::snt Finally, sequence analysis of the exon 4 and 5 of GNAQ gene, whose mutations have been associated with wild type BRAF and NRAS melanomas, revealed wild type status in all samples (Additional file 3: Table S1 and Additional file 4) [45]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (a2 / and :op1 (e / exon :mod "4") :op2 (e2 / exon :mod "5") :part-of (g / gene :name (n / name :op1 "GNAQ") :poss-of (m / mutate-01 :ARG1-of (a3 / associate-01 :ARG2 (a4 / and :op1 (m2 / medical-condition :name (n2 / name :op1 "melanoma") :mod (e3 / enzyme :name (n3 / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (m3 / medical-condition :name (n4 / name :op1 "melanoma") :mod (e4 / enzyme :name (n5 / name :op1 "NRAS") :mod w :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))))) :xref (x2 / xref :value "UNIPROT:GNAQ_HUMAN" :prob "1.004"))) :mod (s / sequence)) :ARG1 (s2 / status :location (t2 / thing :mod (a5 / all) :ARG1-of (s3 / sample-01)) :mod w) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and :op1 (t / table :mod "S1" :part-of (f / file :mod "3" :mod (a7 / additional))) :op2 (f2 / file :mod "4" :mod (a8 / additional)) :op3 (p / publication :ARG1-of (c / cite-01 :ARG2 "45")))) :time (f3 / final)) # ::id pmid_2423_8212.132 # ::date 2015-08-30T06:25:58 # ::file pmid_2423_8212_132.txt # ::snt Treatment with MEK inhibitor PD0325901 results in strong antitumor activity against melanospheres # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "PD0325901") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"))) :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987"))) :ARG2 (a / activity-06 :ARG1 (c2 / counter-01 :ARG1 (c3 / cell :name (n3 / name :op1 "melanosphere"))) :ARG0-of (c / counter-01 :ARG1 (t2 / tumor)) :ARG1-of (s2 / strong-02))) # ::id pmid_2423_8212.133 # ::date 2015-08-30T06:34:52 # ::file pmid_2423_8212_133.txt # ::snt The encouraging activity of the MEK inhibitors used in the pathway inhibitor screening (see above) prompted us to study the antitumor effect of the MEK inhibitor PD0325901 on the melanospheres, based on its antitumor activity described in clinical studies [16]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (p / prompt-01 :ARG0 (a / activity-06 :ARG0 (s / small-molecule :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))) :ARG1-of (u / use-01 :ARG2 (s2 / screen-01 :ARG1 (s3 / small-molecule :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / pathway)))))) :ARG0-of (e / encourage-01) :ARG1-of (d / describe-01 :location (a2 / above))) :ARG1 (s4 / study-01 :ARG0 (w / we) :ARG1 (a3 / affect-01 :ARG0 (s5 / small-molecule :name (n2 / name :op1 "PD0325901") :ARG0-of (i3 / inhibit-01 :ARG1 p2) :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (c / cell :name (n3 / name :op1 "melanosphere")) :ARG2 (c2 / counter-01 :ARG1 (t / tumor))) :ARG1-of (b / base-02 :ARG2 (a4 / activity-06 :ARG0 s5 :ARG1 c2 :ARG1-of (d2 / describe-01 :medium (s6 / study-01 :mod (c3 / clinic) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "16"))))))))) # ::id pmid_2423_8212.134 # ::date 2015-08-30T06:48:29 # ::file pmid_2423_8212_134.txt # ::snt Following 3 day-exposure to PD0325901, at doses comparable with those achieved in vivo, both wild type and mutated-BRAF cells displayed decreased proliferation/viability, with mutated-BRAF samples being more sensitive to the drug (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / display-01 :ARG0 (a / and :op1 (c / cell :mod (e2 / enzyme :name (n / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (c2 / cell :mod (e3 / enzyme :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1 (a4 / and :op1 (o / or :op1 (p / proliferate-01) :op2 (v / viability) :ARG1-of (d2 / decrease-01)) :op2 (s2 / sensitive-03 :ARG0 (s3 / sample-01 :mod e3) :ARG1 "s" :degree (m2 / more))) :time (a2 / after :op1 (e / expose-01 :ARG1 a :ARG2 (s / small-molecule :name (n3 / name :op1 "PD0325901") :quant (d4 / dose :ARG1-of (c3 / comparable-03 :ARG2 (d5 / dose :ARG1-of (a3 / achieve-01 :manner (i / in-vivo))))) :ARG2-of (d8 / dose-01) :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :duration (t / temporal-quantity :quant "3" :unit (d3 / day)))) :ARG1-of (d7 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2423_8212.135 # ::date 2015-08-30T06:58:03 # ::file pmid_2423_8212_135.txt # ::snt In order to distinguish the cytostatic from the cytotoxic effect and to unravel the molecular mechanisms of PD0325901 antitumor activity against malenospheres, we first performed cell cycle analysis of control and treated samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (p / perform-02 :ARG0 (w / we) :ARG1 (a / analyze-01 :ARG1 (a2 / and :op1 (t3 / thing :mod (c3 / control) :ARG1-of (s2 / sample-01)) :op2 (t4 / thing :ARG1-of (t / treat-04) :ARG1-of s2)) :mod (c / cycle :mod (c2 / cell))) :purpose (a3 / and :op1 (d / distinguish-01 :ARG0 w :ARG1 (a4 / affect-01 :ARG2 (c4 / cytostasis)) :ARG2 (a5 / affect-01 :ARG2 (c5 / cytotoxicity))) :op2 (u / unravel-01 :ARG0 w :ARG1 (m / mechanism :mod (m2 / molecule) :poss (a6 / activity-06 :ARG0 (s3 / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (c6 / counter-01 :ARG1 (t2 / tumor)) :ARG0-of (c7 / counter-01 :ARG1 (c8 / cell :name (n2 / name :op1 "melanosphere"))))))) :time (f / first)) # ::id pmid_2423_8212.136 # ::date 2015-08-30T09:42:21 # ::file pmid_2423_8212_136.txt # ::snt After short exposure (2 days), PD0325901 greatly affected cell cycle progression by determining accumulation of cells in the G1 phase, both in the wild type and mutated-BRAF samples (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901") :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (p / progress-01 :ARG1 (c / cycle :mod (c2 / cell))) :ARG2 (d / determine-01 :ARG0 s :ARG1 (a2 / accumulate-01 :ARG1 (c3 / cell) :time (e2 / event :name (n4 / name :op1 "G1" :op2 "phase"))) :location (a3 / and :op1 (t2 / thing :mod (e3 / enzyme :name (n2 / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (s2 / sample-01)) :op2 (t3 / thing :mod (e4 / enzyme :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of s2))) :manner (g / great) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3B")) :time (a4 / after :op1 (e / expose-01 :ARG1-of (s4 / short-07)) :duration (t / temporal-quantity :quant "2" :unit (d3 / day)))) # ::id pmid_2423_8212.137 # ::date 2015-08-30T09:54:58 # ::file pmid_2423_8212_137.txt # ::snt At the molecular level, together with a striking decrease in Cyclin D levels which is in line with the observed cell cycle arrest, treated samples displayed a decline in Erk and S6 phosphorylation, thus, proving MEK signaling inhibition by PD0325901 (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / display-01 :ARG0 (t2 / thing :ARG1-of (t / treat-04) :ARG1-of (s / sample-01)) :ARG1 (a5 / and :op1 (d2 / decline-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Erk") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :op2 (p3 / protein :name (n2 / name :op1 "S6"))))) :op2 (d3 / decrease-01 :ARG1 (l2 / level :quant-of (p6 / protein :name (n5 / name :op1 "Cyclin" :op2 "D") :xref (x / xref :value "UNIPROT:PCNA_HUMAN" :prob "0.352"))) :ARG1-of (s4 / strike-04) :ARG1-of (a3 / align-01 :ARG2 (a4 / arrest-02 :ARG1 (c2 / cycle :mod (c3 / cell)) :ARG1-of (o / observe-01))))) :ARG0-of (c / cause-01 :ARG1 (p4 / prove-01 :ARG1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "PD0325901") :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (s3 / signal-07 :ARG0 (p5 / pathway :name (n4 / name :op1 "MEK")))))) :location (l / level :mod (m / molecule)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "3C"))) # ::id pmid_2423_8212.138 # ::date 2015-08-30T10:07:11 # ::file pmid_2423_8212_138.txt # ::snt Given that PD0325901 may induce apoptosis in melanoma cell lines, we investigated whether a similar mechanism could account for the reduced number of viable cells in PD0325901-treated melanosphere samples [17]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (a / account-01 :ARG0 (m / mechanism :ARG1-of (r / resemble-01)) :ARG1 (n / number-01 :ARG1 (c / cell :mod (v / viable)) :ARG1-of (r2 / reduce-01) :location (s / sample-01 :ARG1 (c2 / cell :name (n2 / name :op1 "melanosphere")) :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987"))))))) :ARG1-of (c3 / cause-01 :ARG0 (p / possible-01 :ARG1 (i2 / induce-01 :ARG0 s2 :ARG2 (a2 / apoptosis) :location (c4 / cell-line :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma")))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 "17")))) # ::id pmid_2423_8212.139 # ::date 2015-08-30T10:14:34 # ::file pmid_2423_8212_139.txt # ::snt Indeed, PD0325901-treated mutant-BRAF melanospheres contained a high fraction of apoptotic annexin V-positive cells compared to control samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contain-01 :ARG0 (c2 / cell :name (n / name :op1 "melanosphere") :mod (e / enzyme :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "PD0335901")))) :ARG1 (f / fraction :ARG1-of (h / high-02) :quant-of (c3 / cell :mod (p / positive :mod (p2 / protein :name (n4 / name :op1 "annexin" :op2 "V") :xref (x / xref :value "UNIPROT:ANXA5_HUMAN" :prob "0.702"))) :mod (a / apoptosis)) :compared-to (t2 / thing :mod (c4 / control) :ARG1-of (s2 / sample-01))) :mod (i / indeed)) # ::id pmid_2423_8212.140 # ::date 2015-08-30T10:21:09 # ::file pmid_2423_8212_140.txt # ::snt In contrast, PD0325901 treated wild type-BRAF melanospheres did not show such a dramatic increase (Figure 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c3 / contrast-01 :ARG2 (s / show-01 :polarity "-" :ARG0 (c / cell :name (n / name :op1 "melanosphere") :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x1 / xref :value "PUBCHEM:9826528" :prob "18.572987"))) :mod (e / enzyme :name (n3 / name :op1 "BRAF") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG1 (i / increase-01 :ARG2 (d / dramatic))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3D"))) # ::id pmid_2423_8212.141 # ::date 2015-08-30T10:24:42 # ::file pmid_2423_8212_141.txt # ::snt Importantly, we found that both wild type and mutated-BRAF melanoma differentiated cells, were exquisitely sensitive to the drug, as indicated by the high fraction of sub-diploid cells detected in treated samples stained with Propidium Iodide (Figure 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (s / sensitive-03 :ARG0 (a / and :op1 (c / cell :ARG1-of (d / differentiate-01) :mod (m2 / medical-condition :name (n / name :op1 "melanoma")) :mod (e2 / enzyme :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (c2 / cell :ARG1-of d :mod m2 :mod (w2 / wild-type))) :ARG1 (d3 / drug) :manner (e / exquisite) :ARG1-of (i / indicate-01 :ARG0 (f2 / fraction :ARG1-of (h / high-02) :quant-of (c3 / cell :mod (s2 / sub-diploid) :ARG1-of (d4 / detect-01 :location (t2 / thing :ARG1-of (t / treat-04) :ARG1-of (s4 / stain-01 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "Propidium" :op2 "Iodide") :xref (x1 / xref :value "PUBCHEM:104981" :prob "12.372932"))) :ARG1-of (s3 / sample-01))))))) :mod (i2 / important) :ARG1-of (d5 / describe-01 :ARG0 (f3 / figure :mod "3E"))) # ::id pmid_2423_8212.142 # ::date 2015-08-30T10:33:51 # ::file pmid_2423_8212_142.txt # ::snt This additional apoptosis assay confirmed that, at the level of melanospheres, only mutated-BRAF cells rapidly underwent PD0325901-induced apoptosis, while apoptotic hypodiploid DNA-cells were almost absent in the treated wild type-BRAF cells (Figure 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / confirm-01 :ARG0 (a / assay-01 :ARG1 (a2 / apoptosis) :mod (a3 / additional) :mod (t / this)) :ARG1 (c3 / contrast-01 :ARG1 (u / undergo-28 :ARG1 (c2 / cell :mod (e2 / enzyme :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (o / only)) :ARG2 (a4 / apoptosis :ARG2-of (i / induce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987")))) :manner (r / rapid)) :ARG2 (a5 / absent-01 :ARG1 (c4 / cell :mod (h / hypodiploid) :mod (a6 / apoptosis) :mod (n5 / nucleic-acid :name (n6 / name :op1 "DNA"))) :ARG2 (c5 / cell :mod (e / enzyme :name (n3 / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :ARG1-of (t2 / treat-04)) :degree (a7 / almost)) :location (l / level :mod (c6 / cell :name (n4 / name :op1 "melanosphere")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3E"))) # ::id pmid_2423_8212.143 # ::date 2015-08-30T10:41:43 # ::file pmid_2423_8212_143.txt # ::snt These results indicate that PD0325901 exerted strong cytotoxic activity against mutant-BRAF melanospheres, and a strong cytostatic activity against wild type-BRAF melanospheres, where cytotoxicity played a minor role. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (e / exert-01 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901") :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (a / and :op1 (a2 / activity-06 :ARG1 (c / cytotoxicity) :ARG1-of (s2 / strong-02) :ARG0-of (c3 / counter-01 :ARG1 (c2 / cell :name (n2 / name :op1 "melanosphere") :mod (e2 / enzyme :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))))) :op2 (a3 / activity-06 :ARG1 (c4 / cytostasis) :ARG0-of (c5 / counter-01 :ARG1 (c6 / cell :name (n4 / name :op1 "melanosphere") :mod (e3 / enzyme :name (n5 / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :location-of (p / play-02 :ARG0 (c7 / cytotoxicity) :ARG1 (r2 / role :ARG1-of (m2 / minor-01))))) :ARG1-of s2)))) # ::id pmid_2423_8212.144 # ::date 2015-08-30T10:48:50 # ::file pmid_2423_8212_144.txt # ::snt In contrast, differentiated melanoma cells were efficiently killed by PD0325901, regardless BRAF status (Figure 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c3 / contrast-01 :ARG2 (k / kill-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x1 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (c / cell :ARG1-of (d / differentiate-01) :mod (m / medical-condition :name (n / name :op1 "melanoma"))) :ARG2-of (e / efficient-01) :concession (s2 / status :mod (e2 / enzyme :name (n3 / name :op1 "BRAF") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3E"))) # ::id pmid_2423_8212.145 # ::date 2015-08-30T10:55:28 # ::file pmid_2423_8212_145.txt # ::snt Treatment with MEK inhibitor PD0325901 results in strong antitumor activity in melanosphere-derived xenografts # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "PD0325901") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"))) :xref (x1 / xref :value "PUBCHEM:9826528" :prob "18.572987"))) :ARG2 (a / activity-06 :ARG1 (c / counter-01 :ARG1 (t2 / tumor)) :ARG1-of (s2 / strong-02) :location (x / xenograft :ARG1-of (d / derive-01 :ARG2 (c2 / cell :name (n3 / name :op1 "melanosphere")))))) # ::id pmid_2423_8212.146 # ::date 2015-08-30T10:58:12 # ::file pmid_2423_8212_146.txt # ::snt We investigated the activity of PD0325901 against melanosphere-generated subcutaneous xenografts. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / activity-06 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901") :xref (x1 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG0-of (c / counter-01 :ARG1 (x / xenograft :mod (s2 / subcutaneous) :ARG1-of (g / generate-01 :ARG2 (c2 / cell :name (n2 / name :op1 "melanosphere"))))))) # ::id pmid_2423_8212.147 # ::date 2015-08-30T13:05:46 # ::file pmid_2423_8212_147.txt # ::snt Doses of 25 or 12.5 mg/Kg were investigated in order to define a well tolerated dose with reduced toxicity and maximum antitumor activity, as the optimal doses and schedules for antitumor activity in the absence of toxicity was not previously determined in cancer patients. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (i / investigate-01 :ARG1 (d / dose :quant (c / concentration-quantity :quant (o / or :op1 "25" :op2 "12.5") :unit (m / milligram-per-kilogram))) :purpose (d2 / define-01 :ARG1 (d3 / dose :ARG1-of (t / tolerate-01 :ARG1-of (w / well-09)) :ARG0-of (h2 / have-03 :ARG1 (a5 / and :op1 (t2 / toxicity :ARG1-of (r / reduce-01)) :op2 (a / activity-06 :ARG1 (c2 / counter-01 :ARG1 (t3 / tumor)) :degree (m2 / maximum)))))) :ARG1-of (c3 / cause-01 :ARG0 (d4 / determine-01 :polarity "-" :ARG1 (a2 / and :op1 (d5 / dose :mod (o2 / optimal)) :op2 (s / schedule :mod o2) :beneficiary (a3 / activity-06 :ARG1 c2)) :time (p / previous) :condition (a4 / absent-01 :ARG1 (t5 / toxicity)) :location (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient)) :mod (c5 / cancer))))) # ::id pmid_2423_8212.148 # ::date 2015-08-30T13:16:43 # ::file pmid_2423_8212_148.txt # ::snt We chose the bi-weekly treatment schedule for drug administration based on previously published results showing high systemic toxicity occurring during daily drug administration [46] and as we previously experienced similar results in mice (results not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (c / choose-01 :ARG0 (w / we) :ARG1 (s / schedule-01 :ARG0 w :ARG1 (t / treat-04) :ARG2 (a / administer-01 :ARG1 (d / drug)) :ARG3 (r / rate-entity-91 :ARG1 "1" :ARG2 (t2 / temporal-quantity :quant "2" :unit (w2 / week)))) :ARG1-of (b / base-02 :ARG2 (a3 / and :op1 (t3 / thing :ARG2-of (r2 / result-01) :ARG1-of (p4 / publish-01 :time (p / previous)) :ARG0-of (s2 / show-01 :ARG1 (t4 / toxicity :mod (s3 / systemic) :time (a2 / administer-01 :ARG1 d :frequency (r3 / rate-entity-91 :ARG3 (t5 / temporal-quantity :quant "1" :unit (d2 / day)))))) :ARG1-of (h / high-02) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "46")))) :op2 (e2 / experience-01 :ARG0 w :ARG1 (t6 / thing :ARG2-of (r4 / result-01) :ARG1-of (r5 / resemble-01) :location (m / mouse) :ARG1-of (s4 / show-01 :polarity "-")) :time p)))) # ::id pmid_2423_8212.149 # ::date 2015-08-30T13:32:39 # ::file pmid_2423_8212_149.txt # ::snt PD0325901 administration, by oral gavage, caused a striking reduction in tumor growth at both drug doses, displaying stronger activity for the higher dose (Figure 4A and Additional file 5: Figure S3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (c / cause-01 :ARG0 (a / administer-01 :ARG1 (s / small-molecule :name (n / name :op1 "PD0325901") :xref (x / xref :value "PUBCHEM:9826528" :prob "18.572987")) :medium (m / mouth) :ARG0-of (d3 / display-01 :ARG1 (a2 / activity-06 :ARG0 (d4 / dose :ARG1-of (h / high-02 :degree "m2")) :ARG1-of (s3 / strong-02 :degree (m2 / more))))) :ARG1 (r / reduce-01 :ARG1 (g / grow-01 :ARG1 (t / tumor) :condition (d / dose-01 :ARG1 (d2 / drug) :mod (b / both))) :ARG1-of (s2 / strike-04)) :ARG1-of (d5 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "S3A" :part-of (f3 / file :mod "5" :mod (a4 / additional)))))) # ::id pmid_2423_8212.150 # ::date 2015-08-30T13:42:57 # ::file pmid_2423_8212_150.txt # ::snt Importantly, treated mice did not exhibit signs of toxicity under this treatment schedule. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (e / exhibit-01 :polarity "-" :ARG0 (m / mouse :ARG1-of (t / treat-04)) :ARG1 (s / signal-07 :ARG1 (t2 / toxicity)) :condition (s2 / schedule-01 :ARG1 (t3 / treat-04) :mod (t4 / this)) :mod (i / important)) # ::id pmid_2423_8212.151 # ::date 2015-08-30T13:44:41 # ::file pmid_2423_8212_151.txt # ::snt Immunoblot analysis of xenografts displayed markedly reduced levels of Erk and downstream S6 phosphorylation in treated tumors, indicating that PD0325901 levels reached in vivo were sufficient to achieve almost complete Erk inactivation and that the effects observed on tumors were caused by specific PD0325901 activity (Additional file 5: Figure S3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (d / display-01 :ARG0 (a / analyze-01 :ARG1 (x / xenograft) :mod (i / immunoblot-01)) :ARG1 (l / level :degree-of (p2 / phosphorylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "Erk") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :op2 (p3 / protein :name (n2 / name :op1 "S6") :location (d2 / downstream)))) :ARG1-of (r / reduce-01 :ARG2 (m / marked)) :location (t / tumor :ARG1-of (t2 / treat-04))) :ARG0-of (i2 / indicate-01 :ARG1 (a6 / and :op1 (s2 / suffice-01 :ARG0 (l2 / level :quant-of (s / small-molecule :name (n3 / name :op1 "PD0325901") :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1-of (r2 / reach-01 :manner (i3 / in-vivo))) :ARG1 (a2 / achieve-01 :ARG0 l2 :ARG1 (a4 / activate-01 :polarity "-" :ARG1 e :ARG1-of (c / complete-02 :degree (a5 / almost))))) :op2 (c2 / cause-01 :ARG0 (a8 / activity-06 :ARG0 s :ARG1-of (s3 / specific-02)) :ARG1 (a7 / affect-01 :ARG1-of (o / observe-01 :location (t3 / tumor)))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "S3B" :part-of (f2 / file :mod "5" :mod (a9 / additional))))) # ::id pmid_2423_8212.152 # ::date 2015-08-30T13:56:51 # ::file pmid_2423_8212_152.txt # ::snt Immunohistochemistry analysis of xenografts revealed decreased proliferation rates for treated tumors (lower Ki-67 expression in comparison with control tumors) and reduced activation of the Mek/Erk pathway (lower Erk phosphorylation) (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (x / xenograft) :mod (i / immunohistochemistry)) :ARG1 (a2 / and :op1 (r2 / rate :degree-of (p / proliferate-01 :ARG0 (t / tumor :ARG1-of (t2 / treat-04))) :ARG1-of (d / decrease-01) :ARG1-of (m2 / mean-01 :ARG2 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "Ki-67") :xref (x1 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.632")) :ARG1-of (l / low-04 :degree (m / more) :ARG1-of (c / compare-01 :ARG2 (t3 / tumor :mod (c2 / control))))))) :op2 (a3 / activate-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "Mek/Erk")) :ARG1-of (r3 / reduce-01) :ARG1-of (m3 / mean-01 :ARG2 (p4 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk") :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "0.603")) :ARG1-of (l2 / low-04 :degree m))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id pmid_2423_8212.153 # ::date 2015-08-30T15:22:02 # ::file pmid_2423_8212_153.txt # ::snt In addition, staining with murine CD34 antibody demonstrated a strong inhibitory effect of PD0325901 on tumor vascularization, as control tumors contained large vessels, while treated tumors displayed drastically compromised vasculature composed by minuscule vessels (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a2 / and :op2 (d / demonstrate-01 :ARG0 (s / stain-01 :ARG2 (a3 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n / name :op1 "CD34") :mod (o / organism :name (n3 / name :op1 "Muridae")) :xref (x / xref :value "UNIPROT:CD34_HUMAN" :prob "1.003"))))) :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "PD0325901") :xref (x1 / xref :value "PUBCHEM:9826528" :prob "18.572987")) :ARG1 (v / vascularize-01 :ARG1 (t / tumor)) :ARG2 (i / inhibit-01) :ARG1-of (s3 / strong-02) :ARG1-of (c / cause-01 :ARG0 (c7 / contrast-01 :ARG1 (c3 / contain-01 :ARG0 (t2 / tumor :mod (c4 / control)) :ARG1 (v2 / vessel :mod (l / large))) :ARG2 (d2 / display-01 :ARG0 (t3 / tumor :ARG1-of (t4 / treat-04)) :ARG1 (v3 / vasculature :ARG1-of (c5 / compromise-02 :manner (d3 / drastic)) :ARG1-of (c6 / compose-01 :ARG2 (v4 / vessel :mod (m / minuscule))))))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id pmid_2423_8212.154 # ::date 2015-08-30T15:35:30 # ::file pmid_2423_8212_154.txt # ::snt A decrease of tumor vascularization appeared also by macroscopic observation of the tumors (Additional file 5: Figure S3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / appear-01 :ARG1 (d / decrease-01 :ARG1 (v / vascularize-01 :ARG1 (t / tumor))) :mod (a2 / also) :manner (o / observe-01 :ARG1 t :mod (m / macroscopy)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "S3A" :part-of (f2 / file :mod "5" :mod (a3 / additional))))) # ::id pmid_2423_8212.155 # ::date 2015-08-30T15:38:14 # ::file pmid_2423_8212_155.txt # ::snt Importantly, similar results were obtained when xenografts were generated by wild type-BRAF melanospheres indicating that this strategy might constitute a potentially exploitable therapeutic approach both for mutated-BRAF and wild type-BRAF melanoma patients (Figure 4C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (o / obtain-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :time (g / generate-01 :ARG0 (c / cell :wiki "-" :name (n / name :op1 "melanosphere") :mod (e3 / enzyme :wiki "-" :name (n2 / name :op1 "BRAF") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :ARG1 (x / xenograft)) :ARG0-of (i / indicate-01 :ARG1 (p / possible-01 :ARG1 (c2 / constitute-01 :ARG0 (s / strategy :mod (t2 / this)) :ARG1 (a / approach-02 :ARG1-of (e / exploit-01 :ARG1-of (p2 / possible-01) :manner (p5 / potential)) :mod (t3 / therapy) :beneficiary (a4 / and :op1 (p3 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p6 / patient)) :mod (m2 / medical-condition :wiki "Melanoma" :name (n3 / name :op1 "melanoma") :mod (e2 / enzyme :wiki "-" :name (n4 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (p4 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 p6) :mod (m3 / medical-condition :wiki "Melanoma" :name (n5 / name :op1 "melanoma") :mod e3))))))) :mod (i2 / important) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "4C") :op2 (f3 / figure :mod "4D")))) # ::id pmid_2423_8212.156 # ::date 2015-08-30T15:46:34 # ::file pmid_2423_8212_156.txt # ::snt Immunoblot analysis showed that VEGF levels were lower in treated-melanospheres (Figure 4E) and immunohistochemistry analysis showed that PD0325901-treated xenografts expressed reduced levels of VEGF in comparison with control tumors (Figure 4F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Sep 12, 2015 (a / and :op1 (s / show-01 :ARG0 (a2 / analyze-01 :mod (i / immunoblot-01)) :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "VEGF") :xref (x1 / xref :value "UNIPROT:VEGFA_HUMAN" :prob "1.003")) :ARG1-of (l2 / low-04 :degree (m / more)) :location (c / cell :name (n2 / name :op1 "melanosphere") :ARG1-of (t / treat-04)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4E")))) :op2 (s2 / show-01 :ARG0 (a3 / analyze-01 :mod (i2 / immunohistochemistry)) :ARG1 (e / express-03 :ARG2 (l3 / level :quant-of p :ARG1-of (r / reduce-01) :ARG1-of (c2 / compare-01 :ARG2 (t3 / tumor :mod (c3 / control)))) :ARG3 (x / xenograft :ARG1-of (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "PD0325901") :xref (x2 / xref :value "PUBCHEM:9826528" :prob "18.572987")))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4F"))))) # ::id pmid_2423_8212.157 # ::date 2015-08-30T16:36:39 # ::file pmid_2423_8212_157.txt # ::snt These results were obtained both for mutated BRAF and wild type BRAF melanospheres and xenografts and suggest that Mek inhibition might determine, together with a direct cytotoxic/cytostatic effect on tumor cells, a reduction of the tumor cell-dependent pro-angiogenic activity in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (o / obtain-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :beneficiary (a2 / and :op1 (a3 / and :op1 (c / cell :name (n / name :op1 "melanosphere") :mod (e2 / enzyme :name (n2 / name :op1 "BRAF") :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (c2 / cell :name (n3 / name :op1 "melanosphere") :mod (e / enzyme :name (n4 / name :op1 "BRAF") :mod (w / wild-type) :xref (x3 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op2 (x / xenograft))) :op2 (s / suggest-01 :ARG0 t :ARG1 (p / possible-01 :ARG1 (d / determine-01 :ARG0 (i / inhibit-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "Mek") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.243")) :ARG1-of (a4 / accompany-01 :ARG0 (a5 / affect-01 :ARG1 (c5 / cell :mod (t3 / tumor)) :ARG2 (o2 / or :op1 (c3 / cytotoxicity) :op2 (c4 / cytostasis)) :ARG1-of (d2 / direct-02)))) :ARG1 (r2 / reduce-01 :ARG1 (a6 / activity-06 :ARG0-of (d3 / depend-01 :ARG1 c5) :manner (i2 / in-vivo) :ARG0-of (f / favor-01 :ARG1 (a7 / angiogenesis)))))))) # ::id pmid_2456_8222.1 # ::date 2015-08-25T10:59:34 # ::file pmid_2456_8222_1.txt # ::snt Targeting the prohibitin scaffold-CRAF kinase interaction in RAS-ERK-driven pancreatic ductal adenocarcinoma (PMID:24568222) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (t / target-01 :ARG1 (i / interact-01 :ARG0 (p5 / protein :name (n3 / name :op1 "prohibitin") :mod (s / scaffold) :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "0.702")) :ARG1 (k / kinase :name (n / name :op1 "CRAF") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :location (a / adenocarcinoma :ARG1-of (d2 / drive-02 :ARG0 (p / pathway :name (n4 / name :op1 "RAS-ERK"))) :mod (d4 / duct :part-of (p2 / pancreas)))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID24568222"))) # ::id pmid_2456_8222.9 # ::date 2015-08-25T11:25:48 # ::file pmid_2456_8222_9.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2456_8222.10 # ::date 2015-08-25T11:28:27 # ::file pmid_2456_8222_10.txt # ::snt The level of PHB expression was crucial for maintenance of oncogenic ERK-driven pancreatic tumorigenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / crucial :domain (l / level :mod (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")))) :purpose (m / maintain-01 :ARG1 (c4 / create-01 :ARG1 (t / tumor :mod (p / pancreas)) :ARG1-of (d / drive-02 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer)) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))) # ::id pmid_2456_8222.11 # ::date 2015-08-25T11:40:48 # ::file pmid_2456_8222_11.txt # ::snt Additionally, rocaglamide (RocA), a small molecular inhibitor, selectively bound to PHB with nanomolar affinity to disrupt the PHB-CRAF interaction by altering its localization to the plasma membrane. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / and :op2 (b / bind-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "rocaglamide") :ARG1-of (m2 / mean-01 :ARG2 (s4 / small-molecule :ARG0-of (i / inhibit-01))) :xref (x3 / xref :value "PUBCHEM:331783" :prob "18.013371")) :ARG2 (p2 / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :mod (s / selective) :manner (a2 / affinity :prep-to (d / disrupt-01 :ARG0 (r / rocaglamide) :ARG1 (i2 / interact-01 :ARG0 p2 :ARG1 (e / enzyme :name (n4 / name :op1 "CRAF") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :manner (a3 / alter-01 :ARG0 s3 :ARG1 (b2 / be-located-at-91 :ARG1 i2 :ARG2 (m3 / membrane :mod (p / plasma) :xref (x2 / xref :value "GO:0016020" :prob "0.8"))))) :mod (n3 / nanomolar)))) # ::id pmid_2456_8222.12 # ::date 2015-08-25T12:07:46 # ::file pmid_2456_8222_12.txt # ::snt Consequently, there was an impairment of oncogenic RAS-ERK signaling, thereby blocking in vitro and in vivo growth and metastasis of pancreatic cancer cells that were addicted to RAS-ERK signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (c / cause-01 :ARG1 (i / impair-01 :ARG1 (s / signal-07 :ARG0 (p2 / pathway :name (n / name :op1 "RAS-ERK") :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer))) :ARG0-of (c4 / cause-01 :ARG1 (b / block-01 :ARG1 (a / and :op1 (g / grow-01 :ARG1 (c5 / cell :mod (c6 / cancer) :mod (p / pancreas) :ARG1-of (a3 / addict-01 :ARG2 s)) :manner (a2 / and :op1 (i2 / in-vitro) :op2 (i3 / in-vivo))) :op2 (m / metastasize-101 :ARG1 c5))))))) # ::id pmid_2456_8222.13 # ::date 2015-08-25T12:31:03 # ::file pmid_2456_8222_13.txt # ::snt More importantly, RocA treatment resulted in a significant increase of the lifespan of tumor-bearing mice without any detectable toxicity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (r / result-01 :ARG1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "rocaglamide") :xref (x / xref :value "PUBCHEM:331783" :prob "18.013371"))) :ARG2 (i / increase-01 :ARG1 (l / lifespan :duration-of (l3 / live-01 :ARG0 (m / mouse :ARG0-of (b / bear-01 :ARG1 (t3 / tumor))))) :ARG1-of (s / significant-02)) :mod (i2 / important :degree (m2 / more)) :manner (t2 / toxicity :polarity "-" :ARG1-of (d3 / detect-01 :ARG1-of (p / possible-01)))) # ::id pmid_2456_8222.39 # ::date 2015-08-25T12:45:48 # ::file pmid_2456_8222_39.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 25, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2456_8222.40 # ::date 2015-08-25T12:57:36 # ::file pmid_2456_8222_40.txt # ::snt Expression and localization of PHB in pancreatic cancer cells and tissue # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (a / and :op1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :op2 (b / be-located-at-91 :ARG1 p2 :ARG2 (a2 / and :op1 (c / cell :mod (p / pancreas) :mod (c2 / cancer)) :op2 (t / tissue :mod p :mod c2)))) # ::id pmid_2456_8222.41 # ::date 2015-08-25T13:04:03 # ::file pmid_2456_8222_41.txt # ::snt To investigate the role of PHB in pancreatic cancer cells, we first chose two human pancreatic cancer cell lines, AsPC-1 (high malignancy) and Capan-2 (low malignancy). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 31, 2015 (c / choose-01 :ARG0 (w / we) :ARG1 (c2 / cell-line :quant "2" :mod (c3 / cancer) :mod (p / pancreas) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (c4 / cell-line :name (n / name :op1 "AsPC-1") :ARG0-of (h3 / have-03 :ARG1 (m2 / malignancy :ARG1-of (h2 / high-02)))) :op1 (c5 / cell-line :name (n2 / name :op1 "Capan-2") :ARG0-of (h4 / have-03 :ARG1 (m3 / malignancy :ARG1-of (l / low-04)))))) :part-of (h / human)) :purpose (i / investigate-01 :ARG0 w :ARG1 (r / role :poss (p2 / protein :name (n3 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :location (c6 / cell :mod (p3 / pancreas) :mod (c7 / cancer)))) :ord (o2 / ordinal-entity :value "1")) # ::id pmid_2456_8222.42 # ::date 2015-08-25T20:29:15 # ::file pmid_2456_8222_42.txt # ::snt Interestingly, AsPC-1 cells grew as single cells (Figure 1A, left), whereas Capan-2 cells exhibited tiny islands of densely packed cells (Figure 1A, right). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG1 (g / grow-01 :ARG1 (c2 / cell-line :name (n / name :op1 "AsPC-1")) :ARG4 (c3 / cell :ARG1-of (s / single-02)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A" :ARG1-of (l / left-20)))) :ARG2 (e / exhibit-01 :ARG0 (c4 / cell-line :name (n2 / name :op1 "Capan-2")) :ARG1 (i / island :mod (t / tiny) :consist-of (c6 / cell :ARG2-of (p / pack-01 :manner (d2 / dense)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "1A" :ARG1-of (r / right-04)))) :ARG2-of (i2 / interest-01)) # ::id pmid_2456_8222.43 # ::date 2015-08-25T20:37:43 # ::file pmid_2456_8222_43.txt # ::snt Additionally, AsPC-1 cells exhibited much higher growth and migration capacities than those of Capan-2 cells (Additional file 1: Figure S1A,B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / and :op2 (e / exhibit-01 :ARG0 (c / cell-line :name (n / name :op1 "AsPC-1")) :ARG1 (a2 / and :op1 (g / grow-01 :ARG1-of (h / high-02 :degree (m / more :quant (m2 / much)))) :op2 (c2 / capable-01 :ARG2 (m3 / migrate-01) :ARG1-of (h2 / high-02))) :compared-to (c3 / cell-line :name (n2 / name :op1 "Capan-2"))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "1" :mod (a3 / additional) :part (a4 / and :op1 (f2 / figure :mod "S1A") :op2 (f3 / figure :mod "S1B"))))) # ::id pmid_2456_8222.44 # ::date 2015-08-25T20:49:06 # ::file pmid_2456_8222_44.txt # ::snt RT-PCR showed a difference in PHB mRNA expression levels, revealing higher expression in AsPC-1 cells than that in Capan-2 cells (Figure 1B and Additional file 1: Figure S2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (t / thing :name (n / name :op1 "RT-PCR")) :ARG1 (d / differ-02 :ARG1 (l / level :degree-of (e / express-03 :ARG2 (n4 / nucleic-acid :name (n6 / name :op1 "RNA") :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))))))) :ARG0-of (r2 / reveal-01 :ARG1 (e2 / express-03 :ARG3 (c / cell-line :name (n3 / name :op1 "AsPC-1")) :ARG1-of (h / high-02 :degree (m2 / more) :compared-to (e3 / express-03 :ARG3 (c2 / cell-line :name (n5 / name :op1 "Capan-2")))))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1B") :op2 (f2 / file :mod (a2 / additional) :part (f3 / figure :mod "S2A"))))) # ::id pmid_2456_8222.45 # ::date 2015-08-25T21:03:16 # ::file pmid_2456_8222_45.txt # ::snt In agreement with RT-PCR data, immunoblot analysis also demonstrated high expression of PHB protein in AsPC-1 cells, but little expression in Capan-2 cells (Figure 1C and Additional file 1: Figure S2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (d / demonstrate-01 :ARG0 (a / analyze-01 :mod (i / immunoblot-01)) :ARG1 (c2 / contrast-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG3 (c / cell-line :name (n2 / name :op1 "AsPC-1")) :ARG1-of (h / high-02)) :ARG2 (e2 / express-03 :ARG3 (c3 / cell-line :name (n3 / name :op1 "Capan-2")) :mod (l / little))) :mod (a2 / also) :ARG1-of (a3 / agree-01 :ARG2 (d2 / data :mod (t / thing :name (n4 / name :op1 "RT-PCR")))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "1C") :op2 (f2 / file :mod (a5 / additional) :part (f3 / figure :mod "S2B"))))) # ::id pmid_2456_8222.46 # ::date 2015-08-25T21:13:36 # ::file pmid_2456_8222_46.txt # ::snt Intriguingly, localization of PHB in AsPC-1 cells was mainly in the plasma membrane and cytosol, whereas its localization was in Capan-2 cells (Figure 1D,E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (c2 / contrast-01 :ARG1 (b / be-located-at-91 :ARG1 "p2" :ARG2 (a / and :op1 (m / membrane :mod (p / plasma) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :op2 (c / cytosol :xref (x1 / xref :value "GO:0005829" :prob "0.8")) :part-of (c3 / cell-line :name (n2 / name :op1 "AsPC-1"))) :mod (m2 / main) :ARG0-of (i / intrigue-01) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1D") :op2 (f2 / figure :mod "1E")))) :ARG2 (b3 / be-located-at-91 :ARG1 (p2 / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG2 (c4 / cell-line :name (n3 / name :op1 "Capan-2")))) # ::id pmid_2456_8222.47 # ::date 2015-08-25T21:23:22 # ::file pmid_2456_8222_47.txt # ::snt This result indicated that the observed phenotypes may correlate with the expression and localization of PHB protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p / possible-01 :ARG1 (c / correlate-01 :ARG1 (p2 / phenotype :ARG1-of (o / observe-01)) :ARG2 (a / and :op1 (e / express-03 :ARG2 (p3 / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :op2 (b / be-located-at-91 :ARG1 p3))))) # ::id pmid_2456_8222.48 # ::date 2015-08-25T21:27:03 # ::file pmid_2456_8222_48.txt # ::snt Therefore, AsPC-1 cells were chosen to investigate the biological properties of PHB in pancreatic cancer both in vitro and in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (c / cause-01 :ARG1 (c2 / choose-01 :ARG1 (c3 / cell-line :name (n / name :op1 "AsPC-1")) :purpose (i / investigate-01 :ARG1 (p / property :mod (b / biological) :poss (p2 / protein :name (n2 / name :op1 "PHB") :topic (c4 / cancer :mod (p3 / pancreas)) :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :manner (a / and :op1 (i2 / in-vitro) :op2 (i3 / in-vivo) :mod (b2 / both))))) # ::id pmid_2456_8222.49 # ::date 2015-08-25T21:41:35 # ::file pmid_2456_8222_49.txt # ::snt We next assessed PHB expression in pancreatic tissue. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (a / assess-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG3 (t / tissue :mod (p2 / pancreas))) :time (n / next)) # ::id pmid_2456_8222.50 # ::date 2015-08-26T09:48:50 # ::file pmid_2456_8222_50.txt # ::snt PHB protein was weakly expressed in 63.6% of normal pancreas samples (n = 11) (Figure 1F,G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG3 (s / sample :ARG1-of (i / include-91 :ARG2 (s2 / sample :quant "11" :mod (p3 / pancreas) :ARG1-of (n2 / normal-02)) :ARG3 (p / percentage-entity :value "63.6"))) :degree (w / weak-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1F" :mod "1G"))) # ::id pmid_2456_8222.51 # ::date 2015-08-26T09:58:17 # ::file pmid_2456_8222_51.txt # ::snt However, PHB protein was strongly expressed in 58.7% of PDAC samples (n = 46) (Figure 1F,G and Additional file 1: Figure S3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (c / contrast-01 :ARG2 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG3 (s2 / sample :ARG1-of (i / include-91 :ARG2 (s3 / sample :quant "46" :mod (a / adenocarcinoma :mod (d3 / duct :part-of (p3 / pancreas)))) :ARG3 (p / percentage-entity :value "58.7"))) :ARG1-of (s / strong-02)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1F" :mod "1G") :op2 (f2 / file :mod "1" :mod (a3 / additional) :part (f3 / figure :mod "S3"))))) # ::id pmid_2456_8222.52 # ::date 2015-08-26T10:06:49 # ::file pmid_2456_8222_52.txt # ::snt Taken together, these results show that PHB, which becomes more pronounced with pancreatic cancer malignancy, may serve as a therapeutic target in pancreatic cancer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01) :ARG1-of (t2 / take-04 :mod (t3 / together)) :mod (t6 / this)) :ARG1 (p / possible-01 :ARG1 (s2 / serve-01 :ARG0 (p2 / protein :name (n2 / name :op1 "PHB") :ARG1-of (b / become-01 :ARG2 (p4 / pronounced-02 :degree (m2 / more) :condition (m3 / malignant-02 :ARG1 (p5 / pancreas) :ARG2 (c2 / cancer)))) :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG2 (t4 / target-01 :ARG1 p2 :mod (t5 / therapy) :condition (c / cancer :mod (p3 / pancreas)))))) # ::id pmid_2456_8222.53 # ::date 2015-08-26T10:18:51 # ::file pmid_2456_8222_53.txt # ::snt PHB is indispensable for EGF-induced ERK activation in pancreatic cancer cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / indispensable-01 :ARG1 (p2 / protein :name (n3 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG2 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :ARG2-of (i2 / induce-01 :ARG0 (p4 / protein :name (n4 / name :op1 "EGF") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004"))) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :location (c / cell :mod (c2 / cancer :mod (p3 / pancreas))))) # ::id pmid_2456_8222.54 # ::date 2015-08-26T10:25:01 # ::file pmid_2456_8222_54.txt # ::snt The duration of ERK activity is a crucial factor in diverse biological processes that determine cell fate decisions [18]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (f / factor :mod (c / crucial) :domain (d / duration :duration-of (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :topic (p2 / process-01 :mod (b / biological) :mod (d2 / diverse) :ARG0-of (d3 / determine-01 :ARG1 (d4 / decide-01 :ARG1 (f2 / fate-01 :ARG1 (c2 / cell))))) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "18")))) # ::id pmid_2456_8222.55 # ::date 2015-08-26T10:33:57 # ::file pmid_2456_8222_55.txt # ::snt ERK is phosphorylated and activated by MEK in response to growth factor stimulation, and then activated ERK phosphorylates and activates nuclear targets to up-regulate immediate-early genes [19]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a6 / and :op1 (a / and :op1 (p3 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2 (e / enzyme :name (n4 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op2 (a2 / activate-01 :ARG0 e :ARG1 e3) :ARG2-of (r / respond-01 :ARG1 (s / stimulate-01 :ARG0 (p / protein :name (n5 / name :op1 "growth-factor") :xref (x3 / xref :value "UNIPROT:MT3_HUMAN" :prob "0.282"))))) :op2 (a4 / and :op1 (p2 / phosphorylate-01 :ARG1 (m / molecular-physical-entity :ARG1-of (t / target-01) :mod (n3 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8"))) :ARG2 (e4 / enzyme :name (n2 / name :op1 "ERK") :ARG1-of (a3 / activate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op2 (a5 / activate-01 :ARG0 e4 :ARG1 m) :purpose (u2 / upregulate-01 :ARG1 (g2 / gene :mod (e2 / early :mod (i / immediate))) :ARG2 e4) :time (t2 / then)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "19")))) # ::id pmid_2456_8222.56 # ::date 2015-08-26T11:10:16 # ::file pmid_2456_8222_56.txt # ::snt Therefore, we determined the expression levels of p-ERK1/2 in AsPC-1 and Capan-2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (c / cause-01 :ARG1 (d / determine-01 :ARG0 (w / we) :ARG1 (l / level :degree-of (e / express-03 :ARG2 (e2 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)) :ARG3 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "AsPC-1")) :op2 (c3 / cell-line :name (n3 / name :op1 "Capan-2"))))))) # ::id pmid_2456_8222.57 # ::date 2015-08-26T11:19:44 # ::file pmid_2456_8222_57.txt # ::snt Intriguingly, the phosphorylation status of ERK2 was much higher than that of ERK1 in AsPC-1 cells, and this phenomenon was completely converse in Capan-2 cells (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / and :op1 (h / high-02 :ARG1 (s / status :mod (p / phosphorylate-01 :ARG1 (e / enzyme :name (n5 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :degree (m / more :quant (m2 / much)) :compared-to (s2 / status :location (c / cell-line :name (n3 / name :op1 "AsPC-1")) :mod (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003"))))) :op2 (c5 / converse :domain (p3 / phenomenon :mod (t / this)) :ARG1-of (c3 / complete-02) :location (c4 / cell-line :name (n4 / name :op1 "Capan-2"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A")) :ARG0-of (i / intrigue-01)) # ::id pmid_2456_8222.58 # ::date 2015-08-26T11:30:03 # ::file pmid_2456_8222_58.txt # ::snt This observation suggests distinct roles of ERK1 and ERK2 in the regulation of cell behavior in AsPC-1 and Capan-2 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / suggest-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (r / roles :mod (d / distinct) :topic (r2 / regulate-01 :ARG1 (b / behave-01 :ARG0 (c / cell) :location (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "AsPC-1")) :op2 (c3 / cell-line :name (n4 / name :op1 "Capan-2"))))) :poss (a / and :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))))) # ::id pmid_2456_8222.59 # ::date 2015-08-26T11:35:06 # ::file pmid_2456_8222_59.txt # ::snt To test whether PHB is required for the ERK pathway, we validated a siRNA against PHB (siPHB) in AsPC-1 and Panc-1 cells by quantitative real-time PCR. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (v / validate-01 :ARG0 (w / we) :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "siRNA") :ARG0-of (o / oppose-01 :ARG1 "p")) :location (a / and :op1 (c / cell-line :name (n4 / name :op1 "AsPC-1")) :op2 (c2 / cell-line :name (n5 / name :op1 "Panc-1"))) :manner (r / react-01 :ARG0 (p2 / polymerase) :mod (q / quantitative) :mod (r2 / real-time) :ARG1-of (c3 / chain-01)) :purpose (t2 / test-01 :ARG0 w :ARG1 (r3 / require-01 :mode "interrogative" :ARG0 (p3 / pathway :name (n7 / name :op1 "ERK")) :ARG1 (p / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))))) # ::id pmid_2456_8222.60 # ::date 2015-08-26T12:32:44 # ::file pmid_2456_8222_60.txt # ::snt The results showed that siPHB reduced the PHB mRNA level by about 80% compared with that using control siRNA (siCon) (Additional file 1: Figure S4A,B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01)) :ARG1 (r2 / reduce-01 :ARG0 (n4 / nucleic-acid :name (n6 / name :op1 "siRNA") :mod "p2") :ARG1 (l / level :quant-of (n2 / nucleic-acid :name (n5 / name :op1 "mRNA") :mod (p2 / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")))) :ARG2 (a / about :quant (p / percentage-entity :value "80" :compared-to (l2 / level :condition (u / use-01 :ARG1 (n7 / nucleic-acid :name (n3 / name :op1 "siRNA") :ARG0-of (c / control-01))))))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod (a2 / additional) :part (f2 / figure :mod "S4A" :mod "S4B")))) # ::id pmid_2456_8222.61 # ::date 2015-08-26T12:42:57 # ::file pmid_2456_8222_61.txt # ::snt Furthermore, we checked the phosphorylation status of ERK1/2 in siPHB-transfected AsPC-1 and Panc-1 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (a2 / and :op2 (c / check-01 :ARG0 (w / we) :ARG1 (s / status :mod (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "AsPC-1") :ARG1-of (t / transfect-01 :ARG2 (n5 / nucleic-acid :name (n6 / name :op1 "siRNA") :mod (p3 / protein :name (n4 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))))) :op2 (c3 / cell-line :name (n3 / name :op1 "Panc-1") :ARG1-of t)))))) # ::id pmid_2456_8222.62 # ::date 2015-08-26T12:57:26 # ::file pmid_2456_8222_62.txt # ::snt As expected, stimulation of AsPC-1 cells with epidermal growth factor (EGF) caused an increase of ERK1/2 phosphorylation (Figure 2B,C), whereas silencing of PHB expression strongly suppressed the EGF-induced phosphorylation of ERK (Figure 2B,C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c3 / contrast-01 :ARG1 (c / cause-01 :ARG0 (s / stimulate-01 :ARG1 (c2 / cell-line :name (n / name :op1 "AsPC-1")) :ARG2 (p / protein :name (n2 / name :op1 "epidermal" :op2 "growth" :op3 "factor") :xref (x2 / xref :value "UNIPROT:EGF_HUMAN" :prob "0.703"))) :ARG1 (i / increase-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B" :mod "2C"))) :ARG2 (s2 / suppress-01 :ARG0 (s3 / silence-01 :ARG1 (e / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "PHB") :xref (x1 / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")))) :ARG1 (p5 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG2-of (i2 / induce-01 :ARG0 p)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2B" :mod "2C")) :ARG1-of (s4 / strong-02)) :ARG1-of (e2 / expect-01)) # ::id pmid_2456_8222.63 # ::date 2015-08-26T13:11:40 # ::file pmid_2456_8222_63.txt # ::snt This finding suggested specific involvement of PHB in the RAS-RAF-ERK pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / suggest-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (i / involve-01 :ARG1 (p / protein :name (n / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG2 (p2 / pathway :name (n2 / name :op1 "RAS-RAF-ERK")) :ARG1-of (s2 / specific-02))) # ::id pmid_2456_8222.64 # ::date 2015-08-26T08:19:14 # ::file pmid_2456_8222_64.txt # ::snt Moreover, a similar result was obtained in Panc-1 cells (Figure 2B), indicating general inhibition of ERK activation by PHB depletion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (o / obtain-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :location (c / cell-line :name (n / name :op1 "Panc-1")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B")) :ARG0-of (i / indicate-01 :ARG1 (i2 / inhibit-01 :ARG0 (d2 / deplete-01 :ARG2 (p2 / protein :name (n3 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (g / general-02))))) # ::id pmid_2456_8222.65 # ::date 2015-08-26T08:28:51 # ::file pmid_2456_8222_65.txt # ::snt Thus, these results clearly indicate that PHB is required for EGF-induced ERK1/2 activation in pancreatic cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (c / cause-01 :ARG1 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (r2 / require-01 :ARG0 (a / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2") :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n3 / name :op1 "EGF") :xref (x / xref :value "UNIPROT:EGF_HUMAN" :prob "1.004")))) :location (c2 / cell :mod (c4 / cancer :mod (p3 / pancreas)))) :ARG1 (p / protein :name (n / name :op1 "PHB") :xref (x1 / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :ARG1-of (c3 / clear-06))) # ::id pmid_2456_8222.66 # ::date 2015-08-26T08:33:22 # ::file pmid_2456_8222_66.txt # ::snt RocA disrupts the ERK pathway by targeting the CRAF-PHB interaction in AsPC-1 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 28, 2015 (d / disrupt-01 :ARG0 (s / small-molecule :name (n / name :op1 "RocA")) :ARG1 (p / pathway :name (n2 / name :op1 "ERK")) :manner (t / target-01 :ARG0 s :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n3 / name :op1 "CRAF") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1 (p2 / protein :name (n4 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :location (c / cell-line :name (n5 / name :op1 "AsPC-1"))))) # ::id pmid_2456_8222.67 # ::date 2015-08-26T09:12:55 # ::file pmid_2456_8222_67.txt # ::snt The oncogenic RAS-ERK pathway is a key node for cellular proliferation signals and has been the focus of substantial drug discovery efforts in many cancers [20-23]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 21, 2016 (a / and :op1 (k / key-02 :ARG1 (n / node :domain (p / pathway :name (n2 / name :op1 "RAS-ERK") :ARG0-of (c / cause-01 :ARG1 (c2 / cancer)))) :ARG2 (s / signal-07 :ARG1 (p2 / proliferate-01 :ARG0 (c3 / cell)))) :op2 (f / focus-01 :ARG1 (e / effort-01 :ARG1 (d / discover-01 :ARG1 (d2 / drug)) :degree (s2 / substantial)) :ARG2 p :location (c4 / cancer :quant (m / many))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 (v / value-interval :op1 "20" :op2 "23"))))) # ::id pmid_2456_8222.68 # ::date 2015-08-26T09:31:03 # ::file pmid_2456_8222_68.txt # ::snt A previous study has indicated that RocA suppresses the ERK pathway in leukemic cells [24]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (i / indicate-01 :ARG0 (s / study-01 :time (p2 / previous)) :ARG1 (s2 / suppress-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "RocA")) :ARG1 (p3 / pathway :name (n3 / name :op1 "ERK")) :location (c / cell :mod (l / leukemia))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "24")))) # ::id pmid_2456_8222.69 # ::date 2015-08-26T09:40:36 # ::file pmid_2456_8222_69.txt # ::snt To confirm that the anti-tumor effect of RocA is indeed caused by suppression of the ERK pathway, we examined the effect of RocA on ERK activity in AsPC-1 cells (Figure 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / examine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "RocA")) :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :location (c / cell-line :name (n3 / name :op1 "AsPC-1"))) :purpose (c2 / confirm-01 :ARG0 w :ARG1 (c3 / cause-01 :ARG0 (s / suppress-01 :ARG1 (p2 / pathway :name (n4 / name :op1 "ERK"))) :ARG1 (a3 / affect-01 :ARG0 s2 :ARG2 (t / tumor :ARG1-of (c4 / counter-01 :ARG0 s2))) :mod (i / indeed))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3E"))) # ::id pmid_2456_8222.70 # ::date 2015-08-26T09:52:55 # ::file pmid_2456_8222_70.txt # ::snt The results showed significant dose-dependent inhibition of the phosphorylation status of ERK1/2 (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01)) :ARG1 (i / inhibit-01 :ARG1 (s3 / status :mod (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")))) :ARG0-of (d / depend-01 :ARG1 (d2 / dose-01)) :ARG1-of (s2 / significant-02)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2456_8222.71 # ::date 2015-08-26T10:03:35 # ::file pmid_2456_8222_71.txt # ::snt Importantly, RocA showed very strong time-dependent suppression of ERK1/2 activities (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 28, 2015 (s / show-01 :ARG0 (s4 / small-molecule :name (n / name :op1 "RocA")) :ARG1 (s2 / suppress-01 :ARG1 (a / activity-06 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2"))) :ARG0-of (d / depend-01 :ARG1 (t / time)) :ARG1-of (s3 / strong-02 :degree (v / very))) :mod (i / important) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2456_8222.72 # ::date 2015-08-26T10:16:11 # ::file pmid_2456_8222_72.txt # ::snt PHB was previously shown to be required for membrane association and activation of CRAF [15]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / show-01 :ARG1 (p / protein :name (n / name :op1 "PHB") :ARG1-of (r / require-01 :ARG0 (a / and :op1 (a2 / associate-01 :ARG1 (m / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :op2 (a3 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "CRAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))) :xref (x1 / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 "15"))) :time (p3 / previous)) # ::id pmid_2456_8222.73 # ::date 2015-08-26T10:19:57 # ::file pmid_2456_8222_73.txt # ::snt Therefore, we examined whether RocA affects PHB-CRAF membrane association in AsPC-1 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (c / cause-01 :ARG1 (e / examine-01 :ARG0 (w / we) :ARG1 (a / affect-01 :mode "interrogative" :ARG0 (s / small-molecule :name (n / name :op1 "RocA")) :ARG1 (a2 / associate-01 :ARG1 (m2 / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :ARG2 (m3 / macro-molecular-complex :part (p / protein :name (n2 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :part (e2 / enzyme :name (n3 / name :op1 "CRAF") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :location (c2 / cell-line :name (n4 / name :op1 "AsPC-1")))))) # ::id pmid_2456_8222.74 # ::date 2015-08-26T10:32:39 # ::file pmid_2456_8222_74.txt # ::snt To this end, cell membrane and cytosol fractions were prepared from AsPC-1 cells treated with Roc-A or DMSO to analyze the localization of PHB and CRAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (p / prepare-01 :ARG1 (a / and :op1 (m / membrane :mod (c / cell) :xref (x3 / xref :value "GO:0016020" :prob "0.8")) :op2 (f / fraction-01 :location (c2 / cytosol :xref (x2 / xref :value "GO:0005829" :prob "0.8")))) :ARG2 (c3 / cell-line :name (n / name :op1 "AsPC-1") :ARG1-of (t / treat-04 :ARG2 (o / or :op1 (s / small-molecule :name (n2 / name :op1 "Roc-A")) :op2 (s2 / small-molecule :name (n3 / name :op1 "DMSO") :xref (x4 / xref :value "PUBCHEM:679" :prob "16.740406"))))) :purpose (a2 / analyze-01 :ARG1 (b / be-located-at-91 :ARG1 (a3 / and :op1 (p2 / protein :name (n4 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :op2 (e / enzyme :name (n5 / name :op1 "CRAF") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))) :purpose (t2 / this)) # ::id pmid_2456_8222.75 # ::date 2015-08-26T11:02:18 # ::file pmid_2456_8222_75.txt # ::snt Immunoblot analysis showed significant reduction of CRAF, particularly phosphorylated CRAF (pSer338), in the membrane fraction after RocA treatment (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (i / immunoblot-01)) :ARG1 (r / reduce-01 :ARG1 (e / enzyme :name (n / name :op1 "CRAF") :ARG2-of (i2 / include-01 :ARG1 (a2 / amino-acid :mod "338" :name (n2 / name :op1 "serine") :ARG3-of (p / phosphorylate-01) :mod (p2 / particular) :part-of e :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1-of (s2 / significant-02) :location (f / fraction-01 :ARG1 (m / membrane :xref (x1 / xref :value "GO:0016020" :prob "0.8")))) :time (a3 / after :op1 (t / treat-04 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "RocA")))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3C"))) # ::id pmid_2456_8222.76 # ::date 2015-08-26T11:10:43 # ::file pmid_2456_8222_76.txt # ::snt Notably, RocA also significantly reduced the levels of PHB in the membrane fraction, indicating that binding of RocA to PHB may also interfere with PHB membrane association. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (r / reduce-01 :ARG0 (s / small-molecule :name (n / name :op1 "RocA")) :ARG1 (l / level :quant-of (p / protein :name (n2 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :mod (a / also) :ARG1-of (s2 / significant-02) :location (f / fraction-01 :ARG1 (m / membrane :xref (x1 / xref :value "GO:0016020" :prob "0.8"))) :ARG0-of (i / indicate-01 :ARG1 (p2 / possible-01 :ARG1 (i2 / interfere-01 :ARG0 (b / bind-01 :ARG1 s :ARG2 p) :ARG1 (a2 / associate-01 :ARG1 (m2 / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :ARG2 p) :mod a))) :ARG1-of (n3 / notable-04)) # ::id pmid_2456_8222.77 # ::date 2015-08-26T11:24:03 # ::file pmid_2456_8222_77.txt # ::snt However, RocA did not influence membrane localization of RAS (Figure 3C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (c / contrast-01 :ARG2 (i / influence-01 :polarity "-" :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA")) :ARG1 (b / be-located-at-91 :ARG1 (p2 / protein-family :name (n3 / name :op1 "RAS")) :ARG2 (m / membrane :xref (x / xref :value "GO:0016020" :prob "0.8")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3C"))) # ::id pmid_2456_8222.78 # ::date 2015-08-26T11:53:04 # ::file pmid_2456_8222_78.txt # ::snt Indeed, immunoprecipitation analysis suggested that RocA substantially decreased the amounts of total CRAF bound to PHB in AsPC-1 cells (Figure 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (s / suggest-01 :ARG0 (a / analyze-01 :ARG1 (i / immunoprecipitate-01)) :ARG1 (d / decrease-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA")) :ARG1 (a2 / amount-01 :ARG1 (e / enzyme :name (n2 / name :op1 "CRAF") :mod (t / total) :ARG1-of (b / bind-01 :ARG2 (p / protein :name (n3 / name :op1 "PHB") :xref (x1 / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :location (c / cell-line :name (n4 / name :op1 "AsPC-1"))) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :manner (s3 / substantial)) :mod (i2 / indeed) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3D"))) # ::id pmid_2456_8222.79 # ::date 2015-08-26T12:11:01 # ::file pmid_2456_8222_79.txt # ::snt Notably, confocal microscopic analysis showed that treatment of AsPC-1 cells with 100 nM RocA for 4 h led to a loss of plasma membrane localization and random redistribution of PHB (Figure 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (s / show-01 :ARG0 (a / analyze-01 :mod (m / microscopy :mod (c / confocal))) :ARG1 (l / lead-03 :ARG0 (t / treat-04 :ARG1 (c2 / cell-line :name (n / name :op1 "AsPC-1")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA") :quant (c3 / concentration-quantity :quant "100" :unit (n3 / nanomolar))) :duration (t2 / temporal-quantity :quant "4" :unit (h / hour))) :ARG1 (a2 / and :op1 (l2 / lose-02 :ARG1 (b / be-located-at-91 :ARG1 "p2" :ARG2 (m2 / membrane :mod (p / plasma) :xref (x1 / xref :value "GO:0016020" :prob "0.8")))) :op2 (r / redistribute-01 :ARG1 (p2 / protein :name (n4 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :manner (r2 / random)))) :ARG1-of (n5 / notable-04) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3E"))) # ::id pmid_2456_8222.80 # ::date 2015-08-26T12:59:34 # ::file pmid_2456_8222_80.txt # ::snt This observation indicates that inhibition of the PHB-CRAF interaction by RocA leads to the loss of spatial organization of PHB in AsPC-1 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (i / indicate-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (l / lead-03 :ARG0 (i2 / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "RocA")) :ARG1 (i3 / interact-01 :ARG0 (p / protein :name (n / name :op1 "PHB") :xref (x1 / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n2 / name :op1 "CRAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :ARG1 (l2 / lose-02 :ARG1 (o2 / organize-01 :ARG1 p :mod (s2 / space) :location (c / cell-line :name (n4 / name :op1 "AsPC-1")))))) # ::id pmid_2456_8222.81 # ::date 2015-08-26T13:04:26 # ::file pmid_2456_8222_81.txt # ::snt Collectively, these results further demonstrate that RocA blocks the RAS-CRAF-ERK signaling pathway by disruption of the PHB-CRAF interaction in pancreatic cancer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (d2 / demonstrate-01 :ARG0 (r / result-01 :mod (t / this)) :ARG1 (b / block-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA")) :ARG1 (p / pathway :name (n3 / name :op1 "RAS-CRAF-ERK") :ARG0-of (s2 / signal-07)) :manner (d3 / disrupt-01 :ARG0 s :ARG1 (i / interact-01 :ARG0 (p2 / protein :name (n4 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG1 (e / enzyme :name (n5 / name :op1 "CRAF") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :location (c / cancer :mod (p3 / pancreas)))) :degree (f / further) :mod (c2 / collective)) # ::id pmid_2456_8222.82 # ::date 2015-08-26T13:10:46 # ::file pmid_2456_8222_82.txt # ::snt RocA mimics the effect of PHB knockdown on epithelial-mesenchymal transition (EMT) markers and reverses the EMT phenotype in AsPC-1 cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (a / and :op1 (m / mimic-01 :ARG0 (s / small-molecule :name (n / name :op1 "RocA")) :ARG1 (a2 / affect-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n2 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :ARG1 (m2 / marker :mod (t / transition-01 :ARG2 (c / cell :mod (m3 / mesenchyme)) :ARG3 (c3 / cell :mod (e / epithelium)))))) :op1 (r / reverse-01 :ARG0 s :ARG1 (p2 / phenotype :mod t) :location (c2 / cell-line :name (n4 / name :op1 "AsPC-1")))) # ::id pmid_2456_8222.83 # ::date 2015-08-26T13:16:58 # ::file pmid_2456_8222_83.txt # ::snt The oncogenic RAS-RAF-ERK pathway confers epithelial cells with critical motile and invasive capacities during carcinoma progression, often by promotion of EMT [25,26]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (c / confer-02 :ARG0 (p / pathway :name (n / name :op1 "PAS-RAF-ERK") :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer))) :ARG1 (a / and :op1 (c8 / capable-01 :ARG1 "c4" :ARG2 (m / motile :ARG1-of (c5 / critical-02))) :op1 (c10 / capable-01 :ARG1 "c4" :ARG2 (i / invade-01 :ARG0 "c4"))) :ARG2 (c4 / cell :mod (e / epithelium)) :time (p2 / progress-01 :ARG1 (c7 / carcinoma)) :manner (p3 / promote-01 :ARG1 (t / transition-01 :ARG2 (c6 / cell :mod (m2 / mesenchyme)) :ARG3 (c11 / cell :mod (e2 / epithelium))) :frequency (o / often)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c9 / cite-01 :ARG2 (a2 / and :op1 "25" :op2 "26"))))) # ::id pmid_2456_8222.84 # ::date 2015-08-27T10:57:28 # ::file pmid_2456_8222_84.txt # ::snt To further investigate the role of PHB in EMT, the effects of PHB siRNA and RocA on EMT markers were assayed in AsPC-1 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / assay-01 :ARG1 (a3 / affect-01 :ARG0 (a4 / and :op1 (n4 / nucleic-acid :name (n / name :op1 "siRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")))) :op2 (s / small-molecule :name (n3 / name :op1 "RocA"))) :ARG1 (m / marker :mod (t / transition-01 :ARG2 (c / cell :mod (m2 / mesenchyme)) :ARG3 (c2 / cell :mod (e2 / epithelium))))) :location (c3 / cell-line :name (n5 / name :op1 "AsPC-1")) :purpose (i / investigate-01 :ARG1 (r2 / role :topic t :poss p) :degree (f / further))) # ::id pmid_2456_8222.85 # ::date 2015-08-27T11:03:51 # ::file pmid_2456_8222_85.txt # ::snt First, we detected EMT markers in AsPC-1 and Capan-2 cells (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (d / detect-01 :ARG0 (w / we) :ARG1 (m / marker :mod (t / transition-01 :ARG2 (c / cell :mod (m2 / mesenchyme)) :ARG3 (c2 / cell :mod (e / epithelium)))) :location (a / and :op1 (c3 / cell-line :name (n2 / name :op1 "AsPC-1")) :op2 (c4 / cell-line :name (n3 / name :op1 "Capan-2"))) :time (f / first) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4A"))) # ::id pmid_2456_8222.86 # ::date 2015-08-27T11:06:44 # ::file pmid_2456_8222_86.txt # ::snt Knockdown of PHB in AsPC-1 cells by siRNA resulted in upregulation of E-cadherin and β-catenin and downregulation of vimentin (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / result-01 :ARG1 (k / knock-down-02 :ARG0 (n7 / nucleic-acid :name (n / name :op1 "siRNA")) :ARG1 (p / protein :name (n2 / name :op1 "PHB") :xref (x3 / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :location (c / cell-line :name (n3 / name :op1 "AsPC-1"))) :ARG2 (a / and :op1 (u / upregulate-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n4 / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n5 / name :op1 "β-catenin") :xref (x2 / xref :value "UNIPROT:CTNB1_HUMAN" :prob "0.263")))) :op2 (d / downregulate-01 :ARG1 (p4 / protein :name (n6 / name :op1 "vimentin") :xref (x1 / xref :value "UNIPROT:VIME_HUMAN" :prob "0.702")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id pmid_2456_8222.87 # ::date 2015-08-27T11:14:15 # ::file pmid_2456_8222_87.txt # ::snt Similar to the effect of PHB knockdown, treatment of AsPC-1 cells with RocA showed the same results (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (s / show-01 :ARG0 (t / treat-04 :ARG1 (c / cell-line :name (n / name :op1 "AsPC-1")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA"))) :ARG1 (r2 / result-01 :ARG1-of (s3 / same-01)) :ARG1-of (r3 / resemble-01 :ARG2 (a / affect-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n3 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id pmid_2456_8222.88 # ::date 2015-08-27T11:20:02 # ::file pmid_2456_8222_88.txt # ::snt Activated ERK2 directly phosphorylates Snail, leading to nuclear accumulation, reduced ubiquitylation, and an increased protein half-life of Snail, and then promotion of breast cancer cell invasion and migration in vitro and metastasis in vivo[27]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Snail") :xref (x / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :ARG2 (e / enzyme :name (n2 / name :op1 "ERK2") :ARG1-of (a / activate-01) :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG0-of (l / lead-03 :ARG2 (a2 / and :op1 (a3 / accumulate-01 :mod (n4 / nucleus :xref (x4 / xref :value "GO:0005634" :prob "0.8"))) :op2 (p3 / protein :name (n5 / name :op1 "Ubiquitin") :ARG1-of (r / reduce-01) :xref (x1 / xref :value "UNIPROT:RL40_HUMAN" :prob "1.002")) :op3 (p4 / protein :name (n6 / name :op1 "Snail") :ARG0-of (l2 / live-01 :degree (h / half)) :ARG1-of (i / increase-01) :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212")) :op4 (p5 / promote-01 :ARG1 (a4 / and :op1 (a5 / and :op1 (i2 / invade-01 :ARG0 (c / cell :mod (c2 / cancer :mod (b / breast)))) :op2 (m / migrate-01) :manner (i3 / in-vitro)) :op2 (m2 / metastasize-101 :manner (i4 / in-vivo))) :time (t / then)))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 "27"))) :ARG1-of (d / direct-02)) # ::id pmid_2456_8222.89 # ::date 2015-08-27T11:32:31 # ::file pmid_2456_8222_89.txt # ::snt Another study has shown clear increases of ZEB1 and ZEB2 protein levels by ERK2 but not ERK1 [28]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (s / show-01 :ARG0 (s2 / study-01 :mod (a / another)) :ARG1 (c / contrast-01 :ARG1 (i / increase-01 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :ARG1 (a2 / and :op1 (l / level :quant-of (p / protein :name (n / name :op1 "ZEB1") :xref (x2 / xref :value "UNIPROT:ZEB1_HUMAN" :prob "1.003"))) :op2 (l2 / level :quant-of (p2 / protein :name (n2 / name :op1 "ZEB2") :xref (x / xref :value "UNIPROT:ZEB2_HUMAN" :prob "1.003")))) :ARG1-of (c2 / clear-06)) :ARG2 (i2 / increase-01 :polarity "-" :ARG0 (e2 / enzyme :name (n4 / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :ARG1 a2)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "28")))) # ::id pmid_2456_8222.90 # ::date 2015-08-27T11:42:18 # ::file pmid_2456_8222_90.txt # ::snt To further investigate the molecular basis of ERK-regulated EMT, we detected the levels of Snail1, ZEB1, and transcription factors known to regulate EMT which act downstream of ERK1/2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (d / detect-01 :ARG0 (w / we) :ARG1 (a / and :op1 (l / level :quant-of (p / protein :name (n / name :op1 "Snail") :xref (x1 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.212"))) :op2 (l2 / level :quant-of (p2 / protein :name (n2 / name :op1 "ZEB1") :xref (x / xref :value "UNIPROT:ZEB1_HUMAN" :prob "1.003"))) :op3 (l3 / level :quant-of (f / factor :ARG0-of (t / transcribe-01 :ARG2 (c / cell :mod (m2 / mesenchyme)) :ARG3 (c2 / cell :mod (e / epithelium))) :ARG0-of (r / regulate-01 :ARG1 (t2 / transition-01) :ARG1-of (k / know-01)) :ARG0-of (a2 / act-02 :location (r2 / relative-position :op1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")) :direction (d2 / downstream)))))) :purpose (i / investigate-01 :ARG0 w :ARG1 (b2 / base-02 :ARG1 (t3 / transition-01 :ARG2 c :ARG3 c2 :ARG1-of (r3 / regulate-01 :ARG0 (p3 / protein-family :name (n6 / name :op1 "ERK")))) :ARG2 (m / molecule)) :degree (f2 / further))) # ::id pmid_2456_8222.91 # ::date 2015-08-27T11:54:19 # ::file pmid_2456_8222_91.txt # ::snt Interestingly, we observed similar results in PHB-silenced and RocA-treated AsPC-1 cells (Figure 4B,C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (r / result-01 :ARG2 (c / cell-line :name (n2 / name :op1 "ASPC-1") :ARG1-of (t / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "RocA"))) :location-of (p / protein :name (n / name :op1 "PHB") :ARG1-of (s / silence-01) :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :ARG1-of (r3 / resemble-01)) :ARG2-of (i / interest-01) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "4B") :op2 (f2 / figure :mod "4C")))) # ::id pmid_2456_8222.92 # ::date 2015-08-27T11:59:31 # ::file pmid_2456_8222_92.txt # ::snt AsPC-1 cells lacking PHB expression showed defective migration (Figure 4D), indicating that the formation of clusters is the consequence of reduced motility of cells that lack high levels of PHB. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / show-01 :ARG0 (c / cell-line :name (n / name :op1 "ASPC-1") :ARG0-of (l / lack-01 :ARG1 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))))) :ARG1 (m / migrate-01 :mod (d / defective)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4D")) :ARG0-of (i / indicate-01 :ARG1 (c3 / cause-01 :ARG0 (m2 / motility :ARG1-of (r / reduce-01) :mod (c2 / cell) :ARG0-of (l2 / lack-01 :ARG1 (l3 / level :ARG1-of (h / high-02) :quant-of p))) :ARG1 (f2 / form-01 :ARG1 (c4 / cluster))))) # ::id pmid_2456_8222.93 # ::date 2015-08-27T12:06:24 # ::file pmid_2456_8222_93.txt # ::snt Notably, AsPC-1 cells treated with RocA formed cell clusters similar to those formed by cells with reduced PHB expression (Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (f / form-01 :ARG0 (c / cell-line :wiki "-" :name (n / name :op1 "AsPC-1") :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :wiki "-" :name (n2 / name :op1 "RocA")))) :ARG1 (c2 / cluster :ARG1-of (r2 / resemble-01 :ARG2 (c5 / cluster :ARG1-of (f2 / form-01 :ARG0 (c4 / cell :ARG3-of (e / express-03 :ARG2 (p / protein :wiki "Prohibitin" :name (n3 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG1-of (r3 / reduce-01)))))) :consist-of (c3 / cell)) :ARG1-of (n4 / notable-04) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "4D"))) # ::id pmid_2456_8222.94 # ::date 2015-08-27T12:12:10 # ::file pmid_2456_8222_94.txt # ::snt Taken together, RocA mimics the effect of PHB knockdown on EMT marker expression and reverses the EMT phenotype in AsPC-1 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (a2 / and :op1 (m / mimic-01 :ARG0 (s / small-molecule :name (n / name :op1 "RocA")) :ARG1 (a / affect-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n2 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :ARG1 (e2 / express-03 :ARG2 (m2 / marker :mod (t / transition-01 :ARG2 (c / cell :mod (m3 / mesenchyme)) :ARG3 (c2 / cell :mod (e / epithelium))))))) :op2 (r / reverse-01 :ARG0 s :ARG1 (p2 / phenotype :mod t) :location (c3 / cell-line :name (n4 / name :op1 "AsPC-1"))) :ARG1-of (t2 / take-01 :manner (t3 / together))) # ::id pmid_2456_8222.95 # ::date 2015-08-27T12:19:04 # ::file pmid_2456_8222_95.txt # ::snt RocA selectively diminishes the viability of PHB-dependent pancreatic cancer cells in vitro and inhibits their migration in vitro and in vivo # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / and :op1 (d2 / diminish-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA")) :ARG1 (v / viable :domain (c / cell :mod (c2 / cancer :mod (p / pancreas)) :ARG0-of (d3 / depend-01 :ARG1 (p2 / protein :name (n3 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003"))) :mod (i / in-vitro))) :manner (s2 / selective)) :op2 (i2 / inhibit-01 :ARG0 s :ARG1 (a2 / and :op1 (m / migrate-01 :ARG0 c :mod (i3 / in-vitro)) :op2 (m2 / migrate-01 :ARG0 c :mod (i4 / in-vivo))))) # ::id pmid_2456_8222.96 # ::date 2015-08-27T12:26:12 # ::file pmid_2456_8222_96.txt # ::snt To characterize the action of RocA on pancreatic cancer cell growth, AsPC-1 and Panc-1 cells were treated with RocA (100 nM) or DMSO for 16 h and then applied to CCK-8 assays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (a / and :op1 (t / treat-04 :ARG1 (a2 / and :op1 (c / cell-line :name (n2 / name :op1 "AsPC-1")) :op2 (c2 / cell-line :name (n3 / name :op1 "Panc-1"))) :ARG2 (o / or :op1 (s / small-molecule :name (n4 / name :op1 "RocA") :quant (c3 / concentration-quantity :quant "100" :unit (n6 / nanomolar))) :op2 (s2 / small-molecule :name (n5 / name :op1 "DMSO") :xref (x / xref :value "PUBCHEM:679" :prob "16.740406"))) :duration (t2 / temporal-quantity :quant "16" :unit (h / hour))) :op2 (a3 / apply-02 :ARG1 a2 :ARG2 (a4 / assay-01 :mod (t4 / thing :name (n7 / name :op1 "CCK-8"))) :time (t3 / then)) :purpose (c4 / characterize-01 :ARG1 (a5 / act-02 :ARG0 (s3 / small-molecule :name (n8 / name :op1 "RocA")) :ARG1 (g / grow-01 :ARG1 (c5 / cell :mod (c6 / cancer :mod (p / pancreas))))))) # ::id pmid_2456_8222.97 # ::date 2015-08-27T12:41:23 # ::file pmid_2456_8222_97.txt # ::snt RocA markedly impaired the growth of AsPC-1 and Panc-1 cells without affecting Hs 578Bst or L02 cells as controls (Figure 5A,B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (i / impair-01 :ARG0 (s / small-molecule :name (n / name :op1 "RocA")) :ARG1 (g / grow-01 :ARG1 (a / and :op1 (c / cell-line :name (n2 / name :op1 "ASPC-1")) :op2 (c2 / cell-line :name (n3 / name :op1 "Panc-1")))) :manner (m / marked) :ARG0-of (a2 / affect-01 :polarity "-" :ARG1 (o / or :op1 (c3 / cell-line :name (n4 / name :op1 "Hs" :op2 "578Bst")) :op2 (c4 / cell-line :name (n5 / name :op1 "L02"))) :ARG0-of (c5 / control-01)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "5A") :op2 (f2 / figure :mod "5B")))) # ::id pmid_2456_8222.98 # ::date 2015-08-27T12:49:25 # ::file pmid_2456_8222_98.txt # ::snt Interestingly, Capan-2 cells did not show any detectable toxicity in the presence of RocA (Additional file 1: Figure S5), suggesting deficient expression of PHB in Capan-2 cells may rescue the effects of RocA. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / show-01 :polarity "-" :ARG0 (c / cell-line :name (n / name :op1 "Capan-2")) :ARG1 (t / toxicity :ARG1-of (d2 / detect-01 :ARG1-of (p / possible-01)) :mod (a3 / any)) :condition (p2 / present-02 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "RocA"))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "S5" :location (f2 / file :mod "1" :ARG1-of (a / add-02)))) :ARG0-of (s3 / suggest-01 :ARG1 (p3 / possible-01 :ARG1 (r / rescue-01 :ARG0 (e / express-03 :ARG2 (p4 / protein :name (n3 / name :op1 "PHB") :xref (x / xref :value "UNIPROT:PHB_HUMAN" :prob "1.003")) :ARG3 c :mod (d / deficient)) :ARG1 (a2 / affect-01 :ARG0 s2)))) :ARG2-of (i / interest-01)) # ::id pmid_2456_8222.99 # ::date 2015-08-27T12:56:19 # ::file pmid_2456_8222_99.txt # ::snt Additionally, RocA impaired the migration of AsPC-1 and Panc-1 cells (Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (i / impair-01 :ARG0 (s / small-molecule :name (n / name :op1 "RocA")) :ARG1 (m / migrate-01 :ARG0 (a / and :op1 (c / cell-line :name (n2 / name :op1 "AsPC-1")) :op2 (c2 / cell-line :name (n3 / name :op1 "Panc-1")))) :ARG1-of (a2 / add-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id pmid_2456_8222.100 # ::date 2015-08-27T12:58:16 # ::file pmid_2456_8222_100.txt # ::snt To investigate the effect of RocA on metastasis, we established an orthotopic xenograft model in mice using AsPC-1 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 28, 2015 (e / establish-01 :ARG0 (w / we) :ARG1 (m / model :mod (x / xenograft) :mod (o / orthotopic) :location (m2 / mouse)) :instrument (c / cell-line :name (n / name :op1 "AsPC-1")) :purpose (i / investigate-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA")) :ARG1 (m3 / metastasize-101)))) # ::id pmid_2456_8222.101 # ::date 2015-08-27T13:02:36 # ::file pmid_2456_8222_101.txt # ::snt At 1 week after orthotopic implantation of AsPC-1 cells into severe combined immunodeficient (SCID) mice, RocA (5 mg/kg body weight) was administrated via intraperitoneal injection daily for 3 weeks. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / administrate-01 :ARG1 (s / small-molecule :name (n / name :op1 "RocA") :quant (c3 / concentration-quantity :quant "5" :unit (m2 / milligram-per-kilogram))) :frequency (t3 / temporal-quantity :quant "1" :unit (d / day)) :duration (t2 / temporal-quantity :quant "3" :unit (w2 / week)) :time (a2 / after :op1 (i3 / implant-01 :ARG1 (c / cell-line :name (n2 / name :op1 "AsPC-1")) :ARG2 (m3 / mouse :mod (i4 / immunodeficient) :ARG1-of (c2 / combine-01 :degree (s2 / severe))) :mod (o / orthotopic)) :quant (t / temporal-quantity :quant "1" :unit (w / week))) :manner (i / inject-01 :ARG1 s :ARG2 (b / body :ARG1-of (w3 / weight-01)) :mod (i2 / intraperitoneal))) # ::id pmid_2456_8222.102 # ::date 2015-08-27T13:19:34 # ::file pmid_2456_8222_102.txt # ::snt As a result, treatment with RocA significantly suppressed cancer metastasis to the lung and liver in mice (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / suppress-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA"))) :ARG1 (m / metastasize-101 :ARG1 (c / cancer) :ARG2 (a / and :op1 (l / lung) :op2 (l2 / liver))) :ARG1-of (s3 / significant-02) :location (m2 / mouse) :ARG2-of (r / result-01) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id pmid_2456_8222.103 # ::date 2015-08-27T13:22:46 # ::file pmid_2456_8222_103.txt # ::snt Histological analysis of the lung and liver revealed that dissemination of cancer cells was absent in tissue sections from RocA-treated mice, but an abundance of cancer cells were observed in vehicle-treated mice (Figure 5D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (c3 / contrast-01 :ARG1 (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (a2 / and :op1 (l / lung) :op2 (l2 / liver)) :mod (h / histologic)) :ARG1 (a3 / absent-01 :ARG1 (d2 / disseminate-01 :ARG1 (c / cell :mod (c2 / cancer))) :ARG2 (s / section-01 :ARG1 (t / tissue) :ARG3 (m / mouse :ARG1-of (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA"))))))) :ARG2 (o / observe-01 :ARG1 (a4 / abound-01 :ARG1 c) :location (m2 / mouse :ARG1-of (t3 / treat-04 :ARG2 (v / vehicle)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5D"))) # ::id pmid_2456_8222.104 # ::date 2015-08-27T13:30:49 # ::file pmid_2456_8222_104.txt # ::snt Comparison of the survival curve of RocA-treated mice with that of vehicle-treated mice showed that RocA treatment significantly prolonged the survival of tumor-bearing mice (Additional file 1: Figure S6A,B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / show-01 :ARG0 (c / compare-01 :ARG1 (c2 / curve :mod (s2 / survive-01 :ARG0 (m / mouse :ARG1-of (t / treat-04 :ARG2 (s3 / small-molecule :name (n / name :op1 "RocA")))))) :ARG2 (c3 / curve :mod (s6 / survive-01 :ARG0 (m2 / mouse :ARG1-of (t3 / treat-04 :ARG2 (v / vehicle)))))) :ARG1 (p / prolong-01 :ARG0 t :ARG1 (s5 / survive-01 :ARG0 (m3 / mouse :ARG0-of (b / bear-01 :ARG1 (t4 / tumor)))) :ARG1-of (s4 / significant-02)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "S6A") :op2 (f2 / figure :mod "S6B") :location (f3 / file :mod "1" :ARG1-of (a2 / add-02))))) # ::id pmid_2456_8222.105 # ::date 2015-08-27T13:37:57 # ::file pmid_2456_8222_105.txt # ::snt Taken together, RocA impairs the migration of pancreatic cancer cells in vitro and in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (i / impair-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA")) :ARG1 (a / and :op1 (m / migrate-01 :ARG0 (c / cell :mod (c2 / cancer :mod (p / pancreas))) :manner (i2 / in-vitro)) :op2 (m2 / migrate-01 :ARG0 c :manner (i3 / in-vivo))) :ARG1-of (t / take-01 :manner (t2 / together))) # ::id pmid_2456_8222.106 # ::date 2015-08-27T13:41:15 # ::file pmid_2456_8222_106.txt # ::snt RocA suppresses in vivo growth of tumor xenografts # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (s / suppress-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA")) :ARG1 (g / grow-01 :ARG1 (x / xenograft :mod (t / tumor))) :manner (i / in-vivo)) # ::id pmid_2456_8222.107 # ::date 2015-08-27T13:43:12 # ::file pmid_2456_8222_107.txt # ::snt To further evaluate the anti-tumor activity of RocA, we administered RocA to SCID mice bearing subcutaneous AsPC-1 tumor cell xenografts and monitored the tumor growth rate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (a2 / and :op1 (a / administer-01 :ARG0 (w / we) :ARG1 (s / small-molecule :name (n / name :op1 "RocA")) :ARG2 (m / mouse :mod (i / immunodeficient) :ARG1-of (c / combine-01 :degree (s3 / severe)) :ARG0-of (b / bear-01 :ARG1 (x / xenograft :mod (c2 / cell-line :name (n2 / name :op1 "AsPC-1") :mod (t / tumor)) :mod (s2 / subcutaneous))))) :op2 (m2 / monitor-01 :ARG0 w :ARG1 (r / rate :mod (g2 / grow-01 :ARG1 t))) :purpose (e / evaluate-01 :ARG0 w :ARG1 (a3 / activity-06 :ARG0 s :ARG0-of (c3 / counter-01 :ARG1 t)) :degree (f / further))) # ::id pmid_2456_8222.108 # ::date 2015-08-27T13:55:01 # ::file pmid_2456_8222_108.txt # ::snt RocA was administrated by intraperitoneal injection once per day. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / administrate-01 :ARG1 (s / small-molecule :name (n / name :op1 "RocA")) :frequency (r / rate-entity-91 :ARG1 "1" :ARG2 (t / temporal-quantity :quant "1" :unit (d / day))) :manner (i / inject-01 :ARG1 s :mod (i2 / intraperitoneal))) # ::id pmid_2456_8222.109 # ::date 2015-08-27T14:02:33 # ::file pmid_2456_8222_109.txt # ::snt As a result, RocA significantly suppressed tumor growth compared with that in the control group. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / suppress-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA")) :ARG1 (g / grow-01 :ARG1 (t / tumor)) :ARG1-of (s3 / significant-02) :ARG2-of (r / result-01) :compared-to (g3 / grow-01 :ARG1 t :location (g2 / group :mod (c / control)))) # ::id pmid_2456_8222.110 # ::date 2015-08-27T14:04:28 # ::file pmid_2456_8222_110.txt # ::snt Tumor volumes in the RocA-treated group were 37 ± 8% of those in the control group (Figure 6A,B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (e / equal-01 :ARG1 (v / volume :quant-of (t / tumor) :location (g / group :ARG1-of (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "RocA"))))) :ARG2 (v3 / value-interval :op1 (p4 / product-of :op1 (p2 / percentage-entity :value "37" :ARG2-of (s2 / subtract-01 :ARG1 (p / percentage-entity :value "8"))) :op2 (v2 / volume :location (g2 / group :mod (c / control)) :quant-of t)) :op2 (p5 / product-of :op1 (p3 / percentage-entity :value "37" :ARG2-of (a / add-02 :ARG1 p)) :op2 v2)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "6A") :op2 (f2 / figure :mod "6B")))) # ::id pmid_2456_8222.111 # ::date 2015-08-28T05:32:37 # ::file pmid_2456_8222_111.txt # ::snt Intriguingly, RocA treatment neither caused any loss of body weight nor exhibited apparent signs of toxicity in mice during the treatments (Figure 6C), suggesting that RocA is generally well tolerated in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (a / and :op1 (c / cause-01 :polarity "-" :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "RocA"))) :ARG1 (l / lose-02 :ARG1 (w / weight-01 :ARG1 (b / body)) :mod (a2 / any))) :op2 (e / exhibit-01 :polarity "-" :ARG0 t :ARG1 (s2 / signal-07 :ARG1 (t2 / toxicity) :ARG1-of (a3 / appear-02)) :location (m / mouse)) :time (t3 / treat-04) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C")) :ARG0-of (s3 / suggest-01 :ARG1 (t4 / tolerate-01 :ARG1 s :ARG1-of (w2 / well-09 :ARG1-of (g / general-02)) :manner (i / in-vivo))) :ARG0-of (i2 / intrigue-01)) # ::id pmid_2456_8222.112 # ::date 2015-08-28T05:41:04 # ::file pmid_2456_8222_112.txt # ::snt Moreover, although RocA-treated mice eventually died from the pancreatic tumors, treatment with RocA significantly extended their lifespan compared with that of vehicle treatment (Figure 6D,E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (a / and :op2 (h / have-concession-91 :ARG1 (e2 / extend-01 :ARG0 "t" :ARG1 (l / lifespan :poss "m") :ARG1-of (s2 / significant-02) :compared-to (l2 / lifespan :poss (m2 / mouse :ARG1-of (t4 / treat-04 :ARG2 (v / vehicle))))) :ARG2 (d / die-01 :ARG1 (m / mouse :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "RocA")))) :time (e / eventual) :ARG1-of (c / cause-01 :ARG0 (t2 / tumor :mod (p / pancreas))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "6D") :op2 (f2 / figure :mod "6E")))) # ::id pmid_2456_8222.113 # ::date 2015-08-28T05:48:21 # ::file pmid_2456_8222_113.txt # ::snt Next, we investigated the effect of RocA on cell proliferation in vivo by hematoxylin and eosin (H&E) staining and examining Ki-67 and cyclin D1 expression in tumor tissues harvested from vehicle- and RocA-treated mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (i3 / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "RocA")) :ARG1 (p / proliferate-01 :ARG0 (c / cell) :manner (i2 / in-vivo))) :manner (a6 / and :op1 (s2 / stain-01 :ARG0 w :ARG2 (a2 / and :op1 (s3 / small-molecule :name (n2 / name :op1 "hematoxylin") :xref (x2 / xref :value "PUBCHEM:10603" :prob "16.740406")) :op2 (s4 / small-molecule :name (n3 / name :op1 "eosin") :xref (x3 / xref :value "PUBCHEM:11048" :prob "9.837358")))) :op2 (e2 / examine-01 :ARG0 w :ARG1 (a4 / and :op1 (e / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "Ki-67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.632")) :ARG3 (t / tissue :mod (t2 / tumor) :ARG1-of (h / harvest-01 :source (a5 / and :op1 (m3 / mouse :ARG1-of (t3 / treat-04 :ARG2 s)) :op2 (m4 / mouse :ARG1-of (t4 / treat-04 :ARG2 (v / vehicle))))))) :op2 (e3 / express-03 :ARG2 (p3 / protein :name (n5 / name :op1 "cyclin" :op2 "D1") :xref (x1 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")) :ARG3 t)))) :time (n6 / next)) # ::id pmid_2456_8222.114 # ::date 2015-08-28T05:57:10 # ::file pmid_2456_8222_114.txt # ::snt H&E staining showed a compact mass of epithelial cells in vehicle-treated mice, whereas RocA-treated tumors exhibited loose epithelial cell aggregates with a higher number of interspersed mesenchymal cells (Figure 6F, left). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (c3 / contrast-01 :ARG1 (s / show-01 :ARG0 (s2 / stain-01 :ARG2 (a / and :op1 (s4 / small-molecule :name (n / name :op1 "hematoxylin") :xref (x1 / xref :value "PUBCHEM:10603" :prob "16.740406")) :op2 (s5 / small-molecule :name (n2 / name :op1 "eosin") :xref (x / xref :value "PUBCHEM:11048" :prob "9.837358")))) :ARG1 (m4 / mass-01 :ARG0 (c2 / cell :mod (e / epithelium)) :location (m5 / mouse :ARG1-of (t / treat-04 :ARG2 (v / vehicle))) :ARG1-of (c / compact-01))) :ARG2 (e2 / exhibit-01 :ARG0 (t2 / tumor :ARG1-of (t3 / treat-04 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "RocA")))) :ARG1 (a2 / aggregate-01 :ARG1 (c4 / cell) :ARG1-of (l / loose-04) :ARG0-of (h2 / have-03 :ARG1 (n4 / number :ARG1-of (h / high-02 :degree (m / more)) :quant-of (c5 / cell :mod (m6 / mesenchymal) :ARG1-of (i / intersperse-01)))) :mod e)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6F" :ARG1-of (l2 / left-20)))) # ::id pmid_2456_8222.115 # ::date 2015-08-28T06:13:45 # ::file pmid_2456_8222_115.txt # ::snt In addition, RocA treatment resulted in a 3.2-fold decrease of Ki-67-positive cells in tumor sections from RocA-treated mice compared with that in vehicle-treated mice (Figure 6F, middle and 6G, upper). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (a2 / and :op2 (r / result-01 :ARG1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "RocA"))) :ARG2 (d / decrease-01 :ARG1 (c / cell :mod (p2 / positive :mod (p3 / protein :name (n2 / name :op1 "Ki-67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.632")))) :ARG2 (p / product-of :op1 "3.2") :location (s2 / section-01 :ARG1 (t2 / tumor) :ARG3 (m / mouse :ARG1-of t)) :compared-to (d3 / decrease-01 :location (m2 / mouse :ARG1-of (t4 / treat-04 :ARG2 (v / vehicle))))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "6F" :direction (m3 / middle)) :op2 (f2 / figure :mod "6G" :direction (u / upper)))))) # ::id pmid_2456_8222.116 # ::date 2015-08-28T06:23:56 # ::file pmid_2456_8222_116.txt # ::snt Furthermore, we found a 4.1-fold decrease of cyclin D1-positive cells in tumor sections from RocA-treated mice relative to that in vehicle-treated mice (Figure 6F, right and 6G, lower). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (a / and :op2 (f / find-01 :ARG0 (w / we) :ARG1 (d / decrease-01 :ARG1 (c / cell :mod (p2 / positive :mod (p3 / protein :name (n / name :op1 "cyclin" :op2 "D1") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")))) :ARG2 (p / product-of :op1 "4.1") :location (s / section-01 :ARG1 (t / tumor) :ARG3 (m2 / mouse :ARG1-of (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA"))))) :ARG1-of (r / relative-05 :ARG3 (d3 / decrease-01 :location (m3 / mouse :ARG1-of (t4 / treat-04 :ARG2 (v / vehicle))))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "6F" :ARG1-of (r2 / right-04)) :op2 (f3 / figure :mod "6G" :ARG1-of (l / low-04 :degree (m / more)))))) # ::id pmid_2456_8222.117 # ::date 2015-08-28T06:28:45 # ::file pmid_2456_8222_117.txt # ::snt Therefore, RocA is a potent small molecule that suppresses the growth of AsPC-1 cell-derived tumors in vivo. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (c / cause-01 :ARG1 (m / molecule :mod (s / small) :mod (p / potent) :domain (s2 / small-molecule :name (n / name :op1 "RocA")) :ARG0-of (s3 / suppress-01 :ARG1 (g / grow-01 :ARG1 (t / tumor :mod (i / in-vivo) :ARG1-of (d / derive-01 :ARG2 (c2 / cell-line :name (n2 / name :op1 "AsPC-1")))))))) # ::id pmid_2464_2271.1 # ::date 2015-08-07T08:32:05 # ::file pmid_2464_2271_1.txt # ::snt Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation (PMID:24642271) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / switch-01 :ARG0 (r / rearrange-01 :ARG1 (p7 / protein-family :name (n2 / name :op1 "ETS")) :mod (d3 / disease :wiki "Prostate_cancer" :name (n5 / name :op1 "prostate" :op2 "cancer"))) :ARG1 (p2 / program :mod (e / express-03 :ARG1 (g2 / gene) :ARG3 (c / cell :ARG0-of (m / migrate-01)))) :ARG2 (r3 / regulate-01 :ARG1 (p4 / pathway :name (n4 / name :op1 "PI3K/AKT"))) :ARG3 (r2 / regulate-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "RAS/ERK"))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG8 "PMID24642271"))) # ::id pmid_2464_2271.8 # ::date 2015-08-08T12:49:06 # ::file pmid_2464_2271_8.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Aug 8, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2464_2271.9 # ::date 2015-08-08T13:41:18 # ::file pmid_2464_2271_9.txt # ::snt We find that oncogenic ETS expression negatively correlates with RAS and RAF mutations in prostate tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (f / find-01 :ARG0 (w / we) :ARG1 (c / correlate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n / name :op1 "ETS") :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :ARG2 (m / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n3 / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op2 (g2 / gene :name (n4 / name :op1 "RAF") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")))) :ARG2-of (n5 / negative-01) :location (t / tumor :mod (p / prostate)))) # ::id pmid_2464_2271.10 # ::date 2015-08-08T13:52:38 # ::file pmid_2464_2271_10.txt # ::snt Furthermore, the oncogenic ETS transcription factors only increased cell migration in the absence of RAS/ERK activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 24, 2015 (a / and :op2 (i / increase-01 :ARG0 (p / protein-family :name (n / name :op1 "ETS" :op2 "transcription" :op3 "factor") :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :ARG1 (m / migrate-01 :ARG0 (c / cell)) :mod (o / only) :condition (a2 / absent-01 :ARG1 (a3 / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "RAS/ERK")))))) # ::id pmid_2464_2271.11 # ::date 2015-08-08T23:49:25 # ::file pmid_2464_2271_11.txt # ::snt In contrast to RAS/ERK, it has been reported that oncogenic ETS expression positively correlates with PI3K/AKT activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (r / report-01 :ARG1 (c2 / correlate-01 :ARG1 (e / express-03 :ARG2 (p4 / protein :name (n2 / name :op1 "ETS") :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :ARG2 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "PI3K/AKT"))) :manner (p2 / positive))) :ARG2 (p3 / pathway :name (n3 / name :op1 "RAS/ERK"))) # ::id pmid_2464_2271.12 # ::date 2015-08-08T23:52:16 # ::file pmid_2464_2271_12.txt # ::snt We identified a mechanistic explanation for this finding by showing that oncogenic ETS proteins required AKT signaling to activate a cell migration gene expression program through ETS/AP-1 binding sequences. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / identify-01 :ARG0 (w / we) :ARG1 (e / explain-01 :ARG1 (t / thing :mod (t2 / this) :ARG1-of (f / find-01)) :mod (m2 / mechanistic)) :manner (s / show-01 :ARG0 w :ARG1 (r / require-01 :ARG0 (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG1 (p2 / program :mod (e2 / express-03 :ARG1 (g / gene) :ARG3 (c2 / cell :ARG0-of (m / migrate-01)))) :instrument (p4 / protein-segment :name (n3 / name :op1 "ETS/AP-1") :ARG2-of (b / bind-01))) :ARG1 (s2 / signal-07 :ARG0 (p3 / pathway :name (n4 / name :op1 "AKT")))))) # ::id pmid_2464_2271.13 # ::date 2015-08-09T00:02:43 # ::file pmid_2464_2271_13.txt # ::snt Levels of pAKT correlated with the ability of oncogenic ETS proteins to increase cell migration, but this process did not require mTORC1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / correlate-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG2 (c2 / capable-01 :ARG1 (p2 / protein :name (n2 / name :op1 "ETS") :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG2 (i / increase-01 :ARG0 p2 :ARG1 (m / migrate-01 :ARG0 (c4 / cell)))) :ARG1-of (c5 / contrast-01 :ARG2 (r / require-01 :polarity "-" :ARG0 (p3 / process :mod (t / this)) :ARG1 (m2 / macro-molecular-complex :name (n4 / name :op1 "mTORC1"))))) # ::id pmid_2464_2271.48 # ::date 2015-08-09T00:13:03 # ::file pmid_2464_2271_48.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2464_2271.49 # ::date 2015-08-09T00:13:53 # ::file pmid_2464_2271_49.txt # ::snt Oncogenic ETS gene rearrangement occurs in tumors lacking RAS/ERK mutations # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / rearrange-01 :ARG1 (g / gene :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :ARG0-of (e / encode-01 :ARG1 (p2 / protein-family :name (n / name :op1 "ETS")))) :location (t / tumor :ARG0-of (l / lack-01 :ARG1 (m / mutate-01 :ARG1 (p / pathway :name (n3 / name :op1 "RAS/ERK")))))) # ::id pmid_2464_2271.50 # ::date 2015-08-09T00:15:42 # ::file pmid_2464_2271_50.txt # ::snt If oncogenic ETS gene rearrangements replace RAS/ERK activation, we predict that RAS/ERK mutations will occur only in ETS rearrangement negative tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / predict-01 :ARG0 (w / we) :ARG1 (m / mutate-01 :ARG1 (p2 / pathway :name (n / name :op1 "RAS/ERK")) :location (t / tumor :mod (r / rearrange-01 :polarity "-" :ARG1 (g / gene :ARG0-of (e / encode-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "ETS"))) :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))) :mod (o / only))) :condition (r2 / replace-01 :ARG1 (a / activate-01 :ARG1 p2) :ARG2 (r3 / rearrange-01 :ARG1 g))) # ::id pmid_2464_2271.51 # ::date 2015-08-09T00:22:36 # ::file pmid_2464_2271_51.txt # ::snt To test this hypothesis, we examined the results of three recently published studies [6,22,23] that both sequence exons and identify chromosome rearrangements in prostate tumors (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (e / examine-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (s2 / sequence-01 :ARG0 (b / both) :ARG1 (e2 / exon)) :op2 (i / identify-01 :ARG0 b :ARG1 (r3 / rearrange-01 :ARG1 (c2 / chromosome :xref (x / xref :value "GO:0005694" :prob "0.8")) :location (t4 / tumor :mod (p2 / prostate)))) :ARG2-of (r / result-01 :ARG1 (s / study-01 :quant "3" :ARG1-of (p / publish-01 :time (r2 / recent)) :ARG1-of (c / cite-01 :ARG2 (a / and :op1 "6" :op2 "22" :op3 "23"))))) :purpose (t3 / test-01 :ARG0 w :ARG1 (t / thing :ARG1-of (h / hypothesize-01) :mod (t6 / this))) :ARG1-of (d / describe-01 :ARG0 (t5 / table :mod "1"))) # ::id pmid_2464_2271.52 # ::date 2015-08-09T00:55:20 # ::file pmid_2464_2271_52.txt # ::snt Together these studies examine 266 prostate tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (e / examine-01 :ARG0 (s / study-01 :mod (t / this) :mod (t3 / together)) :ARG1 (t2 / tumor :quant "266" :mod (p / prostate))) # ::id pmid_2464_2271.53 # ::date 2015-08-09T00:56:38 # ::file pmid_2464_2271_53.txt # ::snt One-half (133) have ERG or ETV1 chromosome rearrangements. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (h / have-03 :ARG0 (t / thing :quant "133" :ARG1-of (i / include-91 :ARG2 (t2 / thing) :ARG3 "1/2")) :ARG1 (r / rearrange-01 :ARG1 (o / or :op1 (c / chromosome :mod (g / gene :name (n / name :op1 "ERG") :xref (x1 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :xref (x2 / xref :value "GO:0005694" :prob "0.8")) :op2 (c2 / chromosome :mod (g2 / gene :name (n2 / name :op1 "ETV1") :xref (x / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :xref (x3 / xref :value "GO:0005694" :prob "0.8"))))) # ::id pmid_2464_2271.54 # ::date 2015-08-09T01:07:18 # ::file pmid_2464_2271_54.txt # ::snt We searched for either gene fusions, or point mutations in canonical RAS/ERK pathway genes (RAS, RAF, MEK, and ERK encoding genes). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / search-01 :ARG0 (w / we) :ARG2 (o / or :op1 (f / fuse-01 :ARG1 (g / gene :mod (p2 / pathway :name (n5 / name :op1 "RAS/ERK") :mod (c / canonical)) :ARG1-of (m2 / mean-01 :ARG2 (g2 / gene :ARG0-of (e5 / encode-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "RAS") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op2 (e2 / enzyme :name (n2 / name :op1 "RAF") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :op3 (e3 / enzyme :name (n3 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op4 (e4 / enzyme :name (n4 / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))))))) :op2 (m / mutate-01 :ARG1 g :mod (p / point)))) # ::id pmid_2464_2271.55 # ::date 2015-08-09T01:14:37 # ::file pmid_2464_2271_55.txt # ::snt Eight tumors had such aberrations, and all eight were negative for oncogenic ETS rearrangements. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / and :op1 (h / have-03 :ARG0 (t / tumor :quant "8") :ARG1 (a2 / aberration :mod (s / such))) :op2 (n / negative-01 :ARG1 (t2 / tumor :ARG1-of (i / include-91 :ARG2 t :ARG3 (a3 / all))) :ARG2 (r / rearrange-01 :ARG1 (g / gene :name (n2 / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))))) # ::id pmid_2464_2271.56 # ::date 2015-08-09T01:19:56 # ::file pmid_2464_2271_56.txt # ::snt This indicates that, while genomic alterations in RAS/ERK pathway components are rare in prostate cancer, there is a statistically significant (P = 0.007; Fisher’s exact test) mutual exclusivity of these alterations and ETS rearrangements. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (i / indicate-01 :ARG0 (t / this) :ARG1 (s / significant-02 :ARG1 (e / exclusive-02 :ARG0 "a3" :ARG2 (r / rearrange-01 :ARG1 (g / gene :name (n2 / name :op1 "ETS") :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :manner (m / mutual)) :mod (s2 / statistics) :concession (r2 / rare-02 :ARG1 (a3 / alter-01 :ARG1 (c / component :mod (p2 / pathway :name (n3 / name :op1 "RAS/ERK"))) :mod (g2 / genome)) :location (d2 / disease :wiki "Prostate_cancer" :name (n5 / name :op1 "prostate" :op2 "cancer"))) :ARG1-of (s3 / statistical-test-91 :ARG2 "0.007" :ARG4 (t2 / thing :name (n / name :op1 "Fisher’s" :op2 "exact" :op3 "test"))))) # ::id pmid_2464_2271.57 # ::date 2015-08-09T01:40:18 # ::file pmid_2464_2271_57.txt # ::snt It has been previously reported that PI3K/AKT activation via PTEN deletion positively correlates with ETS gene rearrangements [16,20]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 28, 2015 (r / report-01 :ARG1 (c / correlate-01 :ARG1 (a / activate-01 :ARG1 (p3 / pathway :name (n / name :op1 "PI3K/AKT")) :manner (d / delete-01 :ARG1 (p4 / protein :name (n2 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004")))) :ARG2 (r2 / rearrange-01 :ARG1 (g / gene :ARG0-of (e / encode-01 :ARG1 (p6 / protein-family :name (n3 / name :op1 "ETS"))))) :manner (p2 / positive)) :time (p / previous) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 "16" :op2 "20"))))) # ::id pmid_2464_2271.58 # ::date 2015-08-09T01:48:03 # ::file pmid_2464_2271_58.txt # ::snt A search for PTEN loss in these 266 tumors (Table 1) confirms these findings and indicates that PTEN loss is more than twice as likely in tumors with ETS gene rearrangements than in those without (P = 0.0008; Fisher’s exact test). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 14, 2015 (a / and :op1 (c / confirm-01 :ARG0 (s / search-01 :ARG1 (t / tumor :quant "266" :mod (t2 / this)) :ARG2 (l / lose-02 :ARG1 (p / protein :name (n / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :ARG1-of (d / describe-01 :ARG0 (t3 / table :mod "1"))) :ARG1 (t4 / thing :mod t2 :ARG1-of (f / find-01))) :op2 (i / indicate-01 :ARG0 s :ARG1 (l2 / likely-01 :ARG1 (l3 / lose-02 :ARG1 p :location (t5 / tumor :mod (r / rearrange-01 :ARG1 (g / gene :ARG0-of (e / encode-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "ETS"))))))) :degree (m / more-than :op1 (p2 / product-of :op1 "2" :op2 (t6 / tumor :mod (r2 / rearrange-01 :polarity "-" :ARG1 g)))) :ARG1-of (s2 / statistical-test-91 :ARG2 "0.0008" :ARG4 (t7 / thing :name (n3 / name :op1 "Fisher’s" :op2 "exact" :op3 "test")))))) # ::id pmid_2464_2271.59 # ::date 2015-08-09T02:08:28 # ::file pmid_2464_2271_59.txt # ::snt In conclusion, ERG and ETV1 gene rearrangements positively correlate with PTEN loss and negatively correlate with RAS/ERK mutations in tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / conclude-01 :ARG1 (a / and :op1 (c2 / correlate-01 :ARG1 (r / rearrange-01 :ARG1 (a2 / and :op1 (g / gene :name (n / name :op1 "ERG") :xref (x2 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :op2 (g2 / gene :name (n2 / name :op1 "ETV1") :xref (x1 / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")))) :ARG2 (l / lose-02 :ARG1 (p2 / protein :name (n4 / name :op1 "PTEN") :xref (x / xref :value "UNIPROT:PTEN_HUMAN" :prob "1.004"))) :manner (p / positive)) :op2 (c3 / correlate-01 :ARG1 r :ARG2 (m / mutate-01 :ARG1 (p3 / pathway :name (n5 / name :op1 "RAS/ERK"))) :ARG2-of (n3 / negative-01)) :location (t / tumor))) # ::id pmid_2464_2271.60 # ::date 2015-08-09T02:13:31 # ::file pmid_2464_2271_60.txt # ::snt Prostate cancer cell lines as models of oncogenic ETS function # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / model-01 :ARG1 (f / function-01 :ARG0 (p / protein :name (n / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :location (c2 / cell-line :mod (d2 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer")))) # ::id pmid_2464_2271.61 # ::date 2015-08-09T02:21:44 # ::file pmid_2464_2271_61.txt # ::snt To test the effect of RAS/ERK signaling and PI3K/AKT signaling on oncogenic ETS function in prostate cell lines, we must first determine which cell lines have these characteristics. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 28, 2015 (o / obligate-01 :ARG1 (w / we) :ARG2 (d / determine-01 :ARG0 w :ARG1 (c4 / cell-line :mod (a3 / amr-unknown) :ARG0-of (h / have-03 :ARG1 (t2 / thing :mod (t3 / this) :ARG2-of (c3 / characteristic-02)))) :ord (o2 / ordinal-entity :value "1")) :purpose (t / test-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "RAS/ERK"))) :op2 (s2 / signal-07 :ARG0 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT")))) :ARG1 (f / function-01 :ARG0 (g / gene :name (n3 / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :location (c2 / cell-line :source (p3 / prostate)))))) # ::id pmid_2464_2271.62 # ::date 2015-08-09T02:33:40 # ::file pmid_2464_2271_62.txt # ::snt Although some prostate cancer cell lines, such as VCaP (ERG) and LNCaP (ETV1) are reported to have oncogenic ETS gene rearrangements [11,14], the full extent of oncogenic ETS protein expression, including fusion-independent expression, in commonly used prostate cancer cell lines has not been determined. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / determine-01 :polarity "-" :ARG1 (e / extent :degree-of (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG3 (c2 / cell-line :mod d2 :ARG1-of (u / use-01 :mod (c3 / common))) :ARG2-of (i / include-91 :ARG1 (e3 / express-03 :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 (f2 / fuse-01))))) :ARG1-of (f / full-09)) :concession (r / report-01 :ARG1 (h / have-03 :ARG0 (c4 / cell-line :mod (s / some) :example (a / and :op1 (c5 / cell-line :name (n4 / name :op1 "VCaP") :mod (g / gene :name (n6 / name :op1 "ERG") :xref (x1 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003"))) :op2 (c6 / cell-line :name (n5 / name :op1 "LNCaP") :mod (g2 / gene :name (n7 / name :op1 "ETV1") :xref (x / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")))) :mod (d4 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer"))) :ARG1 (r2 / rearrange-01 :ARG1 (g3 / gene :ARG0-of c :ARG0-of (e4 / encode-01 :ARG1 (p4 / protein-family :name (n8 / name :op1 "ETS")))))) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 (a2 / and :op1 "11" :op2 "14")))))) # ::id pmid_2464_2271.63 # ::date 2015-08-09T03:41:50 # ::file pmid_2464_2271_63.txt # ::snt To identify the expression level of the four oncogenic ETS proteins, we first tested available antibodies using purified recombinant proteins (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 28, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (a / antibody :ARG2-of (a2 / available-02)) :ord (o / ordinal-entity :value "1") :manner (u / use-01 :ARG0 w :ARG1 (p / protein :ARG1-of (p2 / purify-01) :ARG3-of (r / recombine-01))) :purpose (i / identify-01 :ARG0 w :ARG1 (l / level :degree-of (e / express-03 :ARG2 (p3 / protein :quant "4" :name (n / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_2464_2271.64 # ::date 2015-08-09T03:49:20 # ::file pmid_2464_2271_64.txt # ::snt We identified antibodies to ERG, ETV1, ETV4, and ETV5 that could detect each protein at femtomolar levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (i / identify-01 :ARG0 (w / we) :ARG1 (a / antibody :ARG0-of (c / counter-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "ERG") :xref (x3 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "ETV1") :xref (x / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "ETV4") :xref (x2 / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")) :op4 (p4 / protein :name (n4 / name :op1 "ETV5") :xref (x1 / xref :value "UNIPROT:ETV5_HUMAN" :prob "1.003")))) :ARG0-of (d / detect-01 :ARG1 (p6 / protein :mod (e / each) :quant (l / level :mod (f / femtomolar))) :ARG1-of (p5 / possible-01)))) # ::id pmid_2464_2271.65 # ::date 2015-08-09T04:02:33 # ::file pmid_2464_2271_65.txt # ::snt Because ETV1, ETV4, and ETV5 are homologous proteins, the sensitivity and specificity of these antibodies were compared. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (c / compare-01 :ARG1 (a / and :op1 (s / sensitive-03 :ARG0 (a2 / antibody :mod (t / this))) :op2 (s2 / specific-02 :ARG1 a2)) :ARG1-of (c2 / cause-01 :ARG0 (p / protein :mod (h / homologous) :domain (a3 / and :op1 (p2 / protein :name (n / name :op1 "ETV1") :xref (x / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n2 / name :op1 "ETV4") :xref (x2 / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n3 / name :op1 "ETV5") :xref (x1 / xref :value "UNIPROT:ETV5_HUMAN" :prob "1.003")))))) # ::id pmid_2464_2271.66 # ::date 2015-08-09T04:05:16 # ::file pmid_2464_2271_66.txt # ::snt ETV1 and ETV4 antibodies were specific, but the ETV5 antibody recognized ETV4 and ETV5 equally. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (c / contrast-01 :ARG1 (s / specific-02 :ARG1 (a / and :op1 (a2 / antibody :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n / name :op1 "ETV1") :xref (x2 / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")))) :op2 (a3 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p2 / protein :name (n2 / name :op1 "ETV4") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")))))) :ARG2 (r / recognize-02 :ARG0 (a4 / antibody :ARG0-of (c4 / counter-01 :ARG1 (p3 / protein :name (n3 / name :op1 "ETV5") :xref (x1 / xref :value "UNIPROT:ETV5_HUMAN" :prob "1.003")))) :ARG1 (a5 / and :op1 p2 :op2 p3) :manner (e / equal-01))) # ::id pmid_2464_2271.67 # ::date 2015-08-09T05:16:30 # ::file pmid_2464_2271_67.txt # ::snt We then examined oncogenic ETS protein levels, along with phosphorylated ERK (pERK: RAS/ERK pathway) and phosphorylated AKT (pAKT: PI3K/AKT pathway) levels in six prostate cancer cell lines (Figure 1B and Additional file 1: Figure S1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e2 / examine-01 :ARG0 (w / we) :ARG1 (a / and :op1 (l / level :quant-of (p / protein :name (n4 / name :op1 "ETS") :ARG0-of (c2 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :op2 (l2 / level :quant-of (p3 / pathway :name (n5 / name :op1 "ERK") :ARG3-of (p4 / phosphorylate-01) :ARG1-of (m / mean-01 :ARG2 (p5 / pathway :name (n6 / name :op1 "RAS/ERK"))))) :op3 (l3 / level :quant-of (p6 / pathway :name (n7 / name :op1 "AKT") :ARG3-of p4 :ARG1-of (m2 / mean-01 :ARG2 (p7 / pathway :name (n8 / name :op1 "PI3K/AKT"))))) :location (c / cell-line :quant "6" :mod (d / disease :wiki "Prostate_cancer" :name (n / name :op1 "prostate" :op2 "cancer")))) :time (t / then) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "S1A" :location (f3 / file :mod "1" :ARG1-of (a3 / add-02)))))) # ::id pmid_2464_2271.68 # ::date 2015-08-09T13:29:31 # ::file pmid_2464_2271_68.txt # ::snt DU145 cells, which have a KRAS gene rearrangement [24], did not have high levels of any oncogenic ETS protein, or pAKT, but did have pERK, consistent with the small fraction of prostate cancers with RAS/ERK pathway mutations (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (h / have-03 :polarity "-" :ARG0 (c2 / cell-line :name (n2 / name :op1 "DU145") :ARG0-of (h3 / have-03 :ARG1 (r / rearrange-01 :ARG1 (g / gene :name (n5 / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "24"))))) :ARG1 (o / or :op1 (l / level :quant-of (p / protein :name (n / name :op1 "ETS") :mod (a / any) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x3 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :op2 (l2 / level :quant-of (e / enzyme :name (n4 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG1-of (h2 / high-02))) :ARG2 (h4 / have-03 :ARG0 c2 :ARG1 (e2 / enzyme :name (n6 / name :op1 "ERK") :ARG3-of p2 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :ARG1-of (c5 / consistent-01 :ARG2 (f / fraction :mod (s / small) :quant-of (d5 / disease :wiki "Prostate_cancer" :name (n9 / name :op1 "prostate" :op2 "cancer") :ARG0-of (h5 / have-03 :ARG1 (m / mutate-01 :ARG1 (p5 / pathway :name (n8 / name :op1 "RAS/ERK")))))))) :ARG1-of (d4 / describe-01 :ARG0 (t / table :mod "1"))) # ::id pmid_2464_2271.69 # ::date 2015-08-09T13:40:22 # ::file pmid_2464_2271_69.txt # ::snt Of the remaining five prostate cancer cell lines, four had high expression of a single oncogenic protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / express-03 :ARG2 (p2 / protein :ARG1-of (s / single-02) :ARG0-of (c3 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))) :ARG3 (c / cell-line :quant "4" :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant "5" :ARG1-of (r / remain-01) :mod (d3 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer"))))) :ARG1-of (h / high-02)) # ::id pmid_2464_2271.70 # ::date 2015-08-09T13:44:13 # ::file pmid_2464_2271_70.txt # ::snt These included ERG in VCaP, consistent with a TMRPSS2/ERG rearrangement [11], ETV1 in MDA-PCa-2B, consistent with an ETV1 gene rearrangement [14], and ETV4 in PC3, consistent with high ETV4 mRNA [25]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / include-91 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "ERG") :location (c / cell-line :name (n4 / name :op1 "VCaP")) :ARG1-of (c4 / consistent-01 :ARG2 (r / rearrange-01 :ARG1 (g / gene :name (n7 / name :op1 "TMRPSS2/ERG"))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "11")))) :xref (x4 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :op2 (p2 / protein :name (n2 / name :op1 "ETV1") :location (c2 / cell-line :name (n5 / name :op1 "MDA-PCa-2B")) :ARG1-of (c6 / consistent-01 :ARG2 (r2 / rearrange-01 :ARG1 (g2 / gene :name (n8 / name :op1 "ETV1") :xref (x2 / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003"))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c7 / cite-01 :ARG2 "14")))) :xref (x1 / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "ETV4") :location (c3 / cell-line :name (n6 / name :op1 "PC3")) :ARG1-of (c8 / consistent-01 :ARG2 (n11 / nucleic-acid :name (n9 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p7 / protein :name (n10 / name :op1 "ETV4") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003"))) :ARG1-of (h / high-02)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c9 / cite-01 :ARG2 "25")))) :xref (x3 / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003"))) :ARG2 (t / this)) # ::id pmid_2464_2271.71 # ::date 2015-08-09T13:53:46 # ::file pmid_2464_2271_71.txt # ::snt ETV4 protein was also present at high levels in CWR22Rv1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 9, 2015 (p / present-02 :ARG1 (p2 / protein :name (n / name :op1 "ETV4") :quant (l / level :ARG1-of (h / high-02)) :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")) :ARG2 (c / cell-line :name (n2 / name :op1 "CWR22Rv1")) :mod (a / also)) # ::id pmid_2464_2271.72 # ::date 2015-08-09T13:55:13 # ::file pmid_2464_2271_72.txt # ::snt Of the four lines with high oncogenic ETS protein expression, all had high levels of pAKT, but only one (CWR22Rv1) had high levels of pERK, consistent with the analysis of prostate tumors in Table 1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (h / have-03 :ARG0 (c2 / cell-line :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant "4" :ARG3-of (e / express-03 :ARG2 (p / protein :name (n / name :op1 "ETS") :ARG0-of (c4 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG1-of (h2 / high-02))) :ARG3 (a / all))) :ARG1 (l / level :quant-of (e2 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1-of h2)) :ARG2 (h3 / have-03 :ARG0 (c5 / cell-line :quant "1" :mod (o / only) :ARG1-of (m / mean-01 :ARG2 (c6 / cell-line :name (n4 / name :op1 "CWR22Rv1"))) :ARG1-of (i2 / include-91 :ARG2 c3)) :ARG1 (l2 / level :ARG1-of h2 :quant-of (e3 / enzyme :name (n5 / name :op1 "ERK") :ARG3-of p2 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1-of (c7 / consistent-01 :ARG2 (a2 / analyze-01 :ARG1 (t / tumor :mod (p3 / prostate)) :location (t2 / table :mod "1")))) # ::id pmid_2464_2271.73 # ::date 2015-08-09T14:01:34 # ::file pmid_2464_2271_73.txt # ::snt Surprisingly, despite an ETV1 gene rearrangement [14], and high ETV1 mRNA levels [25], ETV1 protein was not observed in LNCaP cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 28, 2015 (o / observe-01 :polarity "-" :ARG1 (p / protein :name (n / name :op1 "ETV1") :xref (x1 / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :location (c / cell-line :name (n2 / name :op1 "LNCaP")) :concession (a / and :op1 (r / rearrange-01 :ARG1 (g / gene :name (n3 / name :op1 "ETV1") :xref (x / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "14")))) :op2 (l / level :ARG1-of (h / high-02) :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 g)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "25"))))) :ARG0-of (s / surprise-01)) # ::id pmid_2464_2271.74 # ::date 2015-08-09T14:05:59 # ::file pmid_2464_2271_74.txt # ::snt However, this is consistent with results from Vitari et al. who showed low ETV1 protein levels in LNCaP cells due to proteasomal targeting by the COP1 E3 ubiquitin ligase [26]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 18, 2015 (c / contrast-01 :ARG2 (c2 / consistent-01 :ARG1 (t / this) :ARG2 (t2 / thing :ARG2-of (r / result-01 :ARG1 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Vitari")) :op2 (p3 / person :mod (o / other)) :ARG0-of (s / show-01 :ARG1 (l / level :ARG1-of (l2 / low-04 :ARG1-of (c4 / cause-01 :ARG0 (t3 / target-01 :ARG0 (e / enzyme :name (n4 / name :op1 "COP1" :op2 "E3" :op3 "ubiquitin" :op4 "ligase")) :ARG1 (m / macro-molecular-complex :name (n5 / name :op1 "proteasome"))))) :quant-of (p4 / protein :name (n2 / name :op1 "ETV1") :xref (x / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :location (c3 / cell-line :name (n3 / name :op1 "LNCaP"))))))))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c5 / cite-01 :ARG2 "26")))) # ::id pmid_2464_2271.75 # ::date 2015-08-09T14:17:15 # ::file pmid_2464_2271_75.txt # ::snt Long exposures could identify pERK, pAKT, and some ETS proteins at low levels in immunoblots from most cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / possible-01 :ARG1 (i / identify-01 :ARG0 (e3 / expose-01 :ARG1-of (l3 / long-03)) :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p3 / phosphorylate-01) :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "AKT") :ARG3-of p3 :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op3 (p2 / protein :name (n3 / name :op1 "ETS") :mod (s / some) :xref (x1 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :quant (l / level :ARG1-of (l2 / low-04))) :location (i2 / immunoblot-01 :ARG2 (c / cell-line :quant (m / most))))) # ::id pmid_2464_2271.76 # ::date 2015-08-10T16:25:15 # ::file pmid_2464_2271_76.txt # ::snt To more quantitatively establish the “high-level” threshold shown in Figure 1B, ETS proteins in cell extracts were compared with purified standards (Additional file 1: Figure S1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / compare-01 :ARG1 (p / protein-family :name (n / name :op1 "ETS") :location (e / extract-01 :ARG1 (c2 / cell))) :ARG2 (s / standard-02 :ARG1-of (p2 / purify-01)) :purpose (e2 / establish-01 :ARG1 (t / threshold :mod (l / level :ARG1-of (h / high-02)) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "1B"))) :manner (q / quantitative :degree (m / more))) :ARG1-of (d / describe-01 :ARG0 (f2 / file :mod "1" :ARG1-of (a / add-02) :part (f3 / figure :mod "S1B")))) # ::id pmid_2464_2271.77 # ::date 2015-08-10T17:02:28 # ::file pmid_2464_2271_77.txt # ::snt All “high-level” expression for ETS proteins exceeded 50,000 proteins per cell, and was highest at 330,000 proteins per cell for ERG in VCaP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (e / exceed-01 :ARG0 (e2 / express-03 :ARG2 (p / protein-family :name (n / name :op1 "ETS")) :mod (l / level :ARG1-of (h / high-02)) :mod (a2 / all)) :ARG1 (r / rate-entity-91 :ARG1 (p2 / protein :quant "50000") :ARG2 (c / cell))) :op2 (h2 / high-02 :ARG1 (e3 / express-03 :ARG1 (g / gene :name (n2 / name :op1 "ERG") :xref (x / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :ARG2 p :ARG3 (c2 / cell-line :name (n3 / name :op1 "VCaP"))) :ARG2 (r2 / rate-entity-91 :ARG1 (p3 / protein :quant "330000") :ARG2 c) :degree (m / most))) # ::id pmid_2464_2271.78 # ::date 2015-08-10T17:28:10 # ::file pmid_2464_2271_78.txt # ::snt Low-level ETS expression was 10,000 proteins per cell (ETV4 in DU145) or less (Additional file 1: Figure S1B and data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / express-03 :ARG2 (p / protein-family :name (n / name :op1 "ETS")) :mod (l / level :ARG1-of (l2 / low-04)) :quant (o / or :op1 (r / rate-entity-91 :ARG1 (p2 / protein :quant "10000") :ARG2 (c / cell)) :op2 (l3 / less-than :op1 r)) :ARG1-of (m / mean-01 :ARG2 (e2 / express-03 :ARG1 (p3 / protein :name (n2 / name :op1 "ETV4") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")) :ARG3 (c2 / cell-line :name (n3 / name :op1 "DU145")))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / file :mod "1" :ARG1-of (a2 / add-02) :part (f2 / figure :mod "S1B")) :op1 (d2 / data :ARG1-of (s / show-01 :polarity "-"))))) # ::id pmid_2464_2271.79 # ::date 2015-08-11T01:50:25 # ::file pmid_2464_2271_79.txt # ::snt It is possible that oncogenic ETS expression and signaling pathway activation could influence each other. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (p / possible-01 :ARG1 (p2 / possible-01 :ARG1 (a / and :op1 (i / influence-01 :ARG0 (e / express-03 :ARG2 (p3 / protein :name (n / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :ARG1 (a2 / activate-01 :ARG1 (p4 / pathway :ARG0-of (s / signal-07)))) :op2 (i2 / influence-01 :ARG0 a2 :ARG1 e)))) # ::id pmid_2464_2271.80 # ::date 2015-08-11T01:57:10 # ::file pmid_2464_2271_80.txt # ::snt To test this, RWPE-1 (RWPE) cells derived from normal prostate [27] or variations of this line that express either Ki-RAS (RWPE-KRAS, also known as RWPE-2) or ERG (RWPE-ERG) were compared. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / compare-01 :ARG1 (c2 / cell-line :name (n / name :op1 "RWPE-1") :ARG1-of (d / derive-01 :ARG2 (p / prostate :ARG1-of (n2 / normal-02))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "27")))) :ARG2 (o / or :op1 (v / vary-01 :ARG1 c2 :ARG3-of (e / express-03 :ARG2 (e4 / enzyme :name (n4 / name :op1 "Ki-RAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.653"))) :ARG1-of (k / know-02 :ARG2 (c4 / cell-line :name (n5 / name :op1 "RWPE-2")) :mod (a / also))) :op2 (v2 / vary-01 :ARG1 c2 :ARG3-of (e2 / express-03 :ARG2 (p4 / protein :name (n3 / name :op1 "ERG") :xref (x1 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")))) :mod (e3 / either)) :purpose (t / test-01 :ARG1 (t2 / this))) # ::id pmid_2464_2271.81 # ::date 2015-08-11T02:27:33 # ::file pmid_2464_2271_81.txt # ::snt ERG levels in RWPE-ERG cells were similar to VCaP cells (Additional file 1: Figure S1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / resemble-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "ERG") :xref (x / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :location (c / cell-line :name (n2 / name :op1 "RWPE-ERG"))) :ARG2 (l2 / level :quant-of p :location (c2 / cell-line :name (n3 / name :op1 "VCaP"))) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "1" :ARG1-of (a / add-02) :part (f2 / figure :mod "S1C")))) # ::id pmid_2464_2271.82 # ::date 2015-08-11T02:35:58 # ::file pmid_2464_2271_82.txt # ::snt None of the oncogenic ETS were expressed at high levels in RWPE or RWPE-KRAS cells, and only ERG was expressed in RWPE-ERG cells (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 14, 2015 (a / and :op1 (e / express-03 :ARG2 (i / include-91 :ARG1 (n / none) :ARG2 (p / protein :name (n2 / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :ARG3 (o2 / or :op1 (c2 / cell-line :name (n4 / name :op1 "RWPE")) :op2 (c3 / cell-line :name (n6 / name :op1 "RWPE-KRAS"))) :quant (l / level :ARG1-of (h / high-02))) :op2 (e2 / express-03 :ARG2 (p2 / protein :name (n5 / name :op1 "ERG") :xref (x / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :ARG3 (c4 / cell-line :name (n7 / name :op1 "RWPE-ERG")) :mod (o3 / only)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id pmid_2464_2271.83 # ::date 2015-08-11T02:51:39 # ::file pmid_2464_2271_83.txt # ::snt As expected, KRAS increased both pERK and pAKT levels (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / increase-01 :ARG0 (e / enzyme :name (n / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1 (a / and :op1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :op2 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of p :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :ARG1-of (e4 / expect-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id pmid_2464_2271.84 # ::date 2015-08-11T03:02:30 # ::file pmid_2464_2271_84.txt # ::snt Interestingly, over-expression of ERG also resulted in activation of AKT and a small increase in pERK (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "ERG") :xref (x1 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003"))) :ARG2 (a / and :op1 (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op2 (i / increase-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :degree (s / small))) :mod (a3 / also) :ARG2-of (i2 / interest-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id pmid_2464_2271.85 # ::date 2015-08-11T03:12:42 # ::file pmid_2464_2271_85.txt # ::snt In other cell types, the RAS/ERK pathway activates ETV1, ETV4, and ETV5 expression [28]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (a / activate-01 :ARG0 (p / pathway :name (n / name :op1 "RAS/ERK")) :ARG1 (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "ETV1") :xref (x / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n3 / name :op1 "ETV4") :xref (x1 / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")) :op3 (p4 / protein :name (n4 / name :op1 "ETV5") :xref (x2 / xref :value "UNIPROT:ETV5_HUMAN" :prob "1.003")))) :location (t / type :mod (c / cell) :mod (o / other)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "28")))) # ::id pmid_2464_2271.86 # ::date 2015-08-11T03:17:33 # ::file pmid_2464_2271_86.txt # ::snt Therefore, high ETV4 expression in CWR22Rv1 cells could be the result of ERK activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (p / possible-01 :ARG1 (r / result-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "ETV4") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")) :ARG3 (c2 / cell-line :name (n3 / name :op1 "CWR22Rv1")) :ARG1-of (h / high-02))))) # ::id pmid_2464_2271.87 # ::date 2015-08-11T03:23:36 # ::file pmid_2464_2271_87.txt # ::snt To test this, CWR22Rv1 and DU145 cells were treated with the MEK inhibitor U0126 for 24 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "CWR22Rv1")) :op2 (c2 / cell-line :name (n2 / name :op1 "DU145"))) :ARG2 (s / small-molecule :name (n3 / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"))) :xref (x / xref :value "PUBCHEM:3006531" :prob "17.656696")) :duration (t2 / temporal-quantity :quant "24" :unit (h / hour)) :purpose (t3 / test-01 :ARG1 (t4 / this))) # ::id pmid_2464_2271.88 # ::date 2015-08-11T03:29:53 # ::file pmid_2464_2271_88.txt # ::snt In both cell lines, U0126 decreased pERK levels, but did not alter levels of ETV4 (Figure 1C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (d / decrease-01 :ARG0 (s / small-molecule :name (n / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1 (l / level :quant-of (e / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG2 (a / alter-01 :polarity "-" :ARG0 s :ARG1 (l2 / level :quant-of (p2 / protein :name (n3 / name :op1 "ETV4") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")))) :location (c2 / cell-line :mod (b / both)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id pmid_2464_2271.89 # ::date 2015-08-11T03:37:05 # ::file pmid_2464_2271_89.txt # ::snt Therefore, RAS/ERK activation does not drive oncogenic ETS expression in prostate cancer cell lines, however in at least one context (ERG in RWPE) an oncogenic ETS could induce the phosphorylation of both AKT and, to a lesser degree, ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (h / have-concession-91 :ARG1 (d / drive-02 :polarity "-" :ARG0 (a / activate-01 :ARG0 (p / pathway :name (n / name :op1 "RAS/ERK"))) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "ETS") :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG3 (c3 / cell-line :mod (d3 / disease :wiki "Prostate_cancer" :name (n4 / name :op1 "prostate" :op2 "cancer"))))) :ARG2 (p4 / possible-01 :ARG1 (i / induce-01 :ARG0 (p5 / protein :quant "1" :name (n5 / name :op1 "ETS") :ARG0-of c2 :xref (x3 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG2 (a2 / and :op1 (p6 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "AKT") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op2 (p7 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n7 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")) :degree (l / less :degree (m / more))))) :location (c4 / context :quant (a3 / at-least :op1 "1") :ARG1-of (m2 / mean-01 :ARG2 (e4 / express-03 :ARG2 (p8 / protein :name (n8 / name :op1 "ERG") :xref (x4 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :ARG3 (c5 / cell-line :name (n9 / name :op1 "RWPE")))))))) # ::id pmid_2464_2271.90 # ::date 2015-08-11T04:04:50 # ::file pmid_2464_2271_90.txt # ::snt Oncogenic ETS proteins and KRAS drive prostate cell migration, but not synergistically # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / contrast-01 :ARG1 (d / drive-02 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "ETS") :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :op2 (e / enzyme :name (n3 / name :op1 "KRAS") :ARG0-of c2 :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1 (m / migrate-01 :ARG0 (c3 / cell :mod (p2 / prostate)))) :ARG2 (d3 / drive-02 :polarity "-" :ARG0 a :ARG1 m :manner (s / synergistical))) # ::id pmid_2464_2271.91 # ::date 2015-08-11T04:31:25 # ::file pmid_2464_2271_91.txt # ::snt We next tested the role of signaling pathways in the ability of oncogenic ETS proteins to drive cell migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (r / role :poss (p / pathway :ARG0-of (s / signal-07)) :topic (c / capable-01 :ARG1 (p2 / protein :name (n / name :op1 "ETS") :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG2 (d2 / drive-02 :ARG0 p2 :ARG1 (m / migrate-01 :ARG0 (c3 / cell))))) :time (n3 / next)) # ::id pmid_2464_2271.92 # ::date 2015-08-11T04:36:13 # ::file pmid_2464_2271_92.txt # ::snt Because cancer derived cell lines have many mutations and copy number alterations that affect cellular phenotypes, we used the RWPE-ERG and RWPE-KRAS cell lines to compare the ability of oncogenic ETS and RAS signaling to promote cell migration in the same cellular background. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / cause-01 :ARG0 (h / have-03 :ARG0 (c2 / cell-line :ARG1-of (d / derive-01 :ARG2 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :ARG1 (a / and :op1 (m / mutate-01 :ARG2 c2 :quant (m2 / many)) :op2 (a2 / alter-01 :ARG1 (n2 / number-01 :ARG1 (c3 / copy-01 :ARG1 c2))) :ARG0-of (a3 / affect-01 :ARG1 (p / phenotype :mod (c4 / cell))))) :ARG1 (u / use-01 :ARG0 (w / we) :ARG1 (a4 / and :op1 (c5 / cell-line :name (n3 / name :op1 "RWPE-ERG")) :op2 (c6 / cell-line :name (n4 / name :op1 "RWPE-KRAS"))) :ARG2 (c7 / compare-01 :ARG0 w :ARG1 (c8 / capable-01 :ARG1 (s / signal-07 :ARG0 (a5 / and :op1 (p2 / protein :name (n5 / name :op1 "ETS") :ARG0-of (c9 / cause-01 :ARG1 d2) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :op2 (e / enzyme :name (n6 / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")))) :ARG2 (p3 / promote-01 :ARG0 a5 :ARG1 (m3 / migrate-01 :ARG0 (c10 / cell))))) :location (b / background :mod (c11 / cell) :ARG1-of (s2 / same-01)))) # ::id pmid_2464_2271.93 # ::date 2015-08-11T04:58:36 # ::file pmid_2464_2271_93.txt # ::snt RWPE-ERG and RWPE-KRAS cells migrated 5- and 10-fold more than RWPE cells (Figure 2A and Additional file 2: Figure S2), indicating that both ERG and KRAS induce cell migration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (m / migrate-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "RWPE-ERG")) :op2 (c2 / cell-line :name (n2 / name :op1 "RWPE-KRAS"))) :degree (m2 / more-than :op1 (a2 / and :op1 (p / product-of :op1 "5") :op2 (p2 / product-of :op1 "10") :compared-to (c3 / cell-line :name (n3 / name :op1 "RWPE")))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "2A") :op2 (f2 / file :mod "2" :ARG1-of (a4 / add-02) :part (f3 / figure :mod "S2")))) :ARG0-of (i / indicate-01 :ARG1 (i2 / induce-01 :ARG0 (a5 / and :op1 (p3 / protein :name (n4 / name :op1 "ERG") :xref (x / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :op2 (e / enzyme :name (n5 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG2 (m3 / migrate-01 :ARG0 (c4 / cell))))) # ::id pmid_2464_2271.94 # ::date 2015-08-11T05:19:48 # ::file pmid_2464_2271_94.txt # ::snt Similar to our previous findings [15], overexpression of oncogenic ETS proteins ETV1, ETV5, and ERG, but not other ETS proteins (FLI1 and SPDEF), promoted RWPE cell migration (Figure 2B and Additional file 2: Figure S2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (p / promote-01 :ARG0 (o / overexpress-01 :ARG1 (p2 / protein :name (n / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (p3 / protein :name (n3 / name :op1 "ETV1") :xref (x2 / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :op2 (p4 / protein :name (n4 / name :op1 "ETV5") :xref (x4 / xref :value "UNIPROT:ETV5_HUMAN" :prob "1.003")) :op3 (p5 / protein :name (n5 / name :op1 "ERG") :xref (x5 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")))) :xref (x1 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG1-of (c2 / contrast-01 :ARG2 (o2 / overexpress-01 :ARG1 (p6 / protein :name (n6 / name :op1 "ETS") :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (p7 / protein :name (n7 / name :op1 "FLI1") :xref (x / xref :value "UNIPROT:FLI1_HUMAN" :prob "1.003")) :op2 (p8 / protein :name (n8 / name :op1 "SPDEF") :xref (x6 / xref :value "UNIPROT:SPDEF_HUMAN" :prob "1.003")))) :mod (o3 / other) :xref (x3 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))))) :ARG1 (m3 / migrate-01 :ARG0 (c3 / cell-line :name (n9 / name :op1 "RWPE"))) :ARG1-of (r / resemble-01 :ARG2 (t / thing :ARG1-of (f / find-01 :ARG0 (w / we)) :time (p9 / previous) :ARG1-of (d2 / describe-01 :ARG0 (p10 / publication :ARG1-of (c4 / cite-01 :ARG2 "15"))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "2B") :op2 (f3 / file :mod "2" :ARG1-of (a4 / add-02) :part (f4 / figure :mod "S2"))))) # ::id pmid_2464_2271.95 # ::date 2015-08-11T05:47:02 # ::file pmid_2464_2271_95.txt # ::snt In contrast, when the same ETS proteins were over-expressed in RWPE-KRAS cells, none of the oncogenic ETS proteins induced additional cell migration (Figure 2C and Additional file 2: Figure S2), suggesting that these ETS proteins and KRAS were functioning to activate the same pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / contrast-01 :ARG2 (i / induce-01 :ARG0 (i2 / include-91 :ARG2 (p / protein :name (n / name :op1 "ETS") :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG3 (n3 / none)) :ARG2 (m / migrate-01 :ARG0 (c3 / cell) :ARG1-of (a / add-02)) :time (o / overexpress-01 :ARG1 (p2 / protein :name (n4 / name :op1 "ETS") :ARG1-of (s / same-01) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :location (c4 / cell-line :name (n5 / name :op1 "RWPE-KRAS"))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2C") :op2 (f2 / file :mod "2" :part (f3 / figure :mod "S2")))) :ARG0-of (s2 / suggest-01 :ARG1 (f4 / function-01 :ARG0 (a3 / and :op1 p2 :op2 (e / enzyme :name (n6 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1 (a4 / activate-01 :ARG0 a3 :ARG1 (p3 / pathway :ARG1-of s)))))) # ::id pmid_2464_2271.96 # ::date 2015-08-11T06:04:53 # ::file pmid_2464_2271_96.txt # ::snt These findings are consistent with our model that oncogenic ETS proteins can mimic RAS activation in cell lines lacking RAS activity, and are distinct from ETS proteins expressed in normal prostate. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / consistent-01 :ARG1 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG2 (m / model-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p / possible-01 :ARG1 (m2 / mimic-01 :ARG0 (p2 / protein :name (n / name :op1 "ETS") :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "RAS") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")))) :location (c3 / cell-line :ARG0-of (l / lack-01 :ARG1 (a3 / activity-06 :ARG0 e)))) :op2 (d2 / distinct :domain p2 :compared-to (p3 / protein :name (n4 / name :op1 "ETS") :ARG2-of (e2 / express-03 :ARG3 (p4 / prostate :ARG1-of (n5 / normal-02))) :xref (x1 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")))))) # ::id pmid_2464_2271.97 # ::date 2015-08-11T06:16:41 # ::file pmid_2464_2271_97.txt # ::snt A role for the PI3K/AKT pathway in oncogenic ETS function # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (r / role :poss (p / pathway :wiki "Akt/PKB_signaling_pathway" :name (n / name :op1 "PI3K/AKT")) :topic (f / function-01 :ARG0 (p2 / protein :wiki "ETS_transcription_factor_family" :name (n2 / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")))) # ::id pmid_2464_2271.98 # ::date 2015-08-11T06:20:56 # ::file pmid_2464_2271_98.txt # ::snt To identify signaling pathways required for the oncogenic function of ETS factors, a microarray analysis of ETV4 knockdown in PC3 prostate cancer cells [25] was compared to the Connectivity Map database [29] that contains microarray data of PC3 cells treated with 1309 small molecules, including many signaling pathway inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / compare-01 :ARG1 (a / analyze-01 :ARG1 (k / knock-down-02 :ARG1 (g / gene :name (n / name :op1 "ETV4") :xref (x1 / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")) :location (c2 / cell-line :name (n2 / name :op1 "PC3") :mod (d / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer")))) :mod (m / microarray) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "25")))) :ARG2 (d3 / database :name (n4 / name :op1 "Connectivity" :op2 "Map") :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "29"))) :ARG0-of (c5 / contain-01 :ARG1 (d5 / data :mod m :topic (c6 / cell-line :name (n5 / name :op1 "PC3") :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :quant "1309" :ARG2-of (i / include-91 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p4 / pathway :ARG0-of (s2 / signal-07))) :quant (m3 / many))))))))) :purpose (i3 / identify-01 :ARG1 (p5 / pathway :ARG0-of s2 :ARG1-of (r / require-01 :ARG0 (f / function-01 :ARG0 (f2 / factor :mod (p6 / protein :name (n6 / name :op1 "ETS") :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :ARG0-of (c7 / cause-01 :ARG1 (d6 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")))))))) # ::id pmid_2464_2271.99 # ::date 2015-08-11T06:48:24 # ::file pmid_2464_2271_99.txt # ::snt Similarities between the gene expression profile of a signaling pathway inhibitor and ETV4 knockdown would predict a role for that pathway in oncogenic ETS function. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (p / predict-01 :ARG0 (r / resemble-01 :ARG1 (p2 / profile-01 :ARG0 (e / express-03 :ARG1 (g / gene)) :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / pathway :ARG0-of (s / signal-07))))) :ARG2 (k / knock-down-02 :ARG1 (g2 / gene :name (n / name :op1 "ETV4") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003")))) :ARG1 (r2 / role :poss p3 :topic (f / function-01 :ARG0 (p4 / protein :name (n2 / name :op1 "ETS") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))))) # ::id pmid_2464_2271.100 # ::date 2015-08-11T07:09:12 # ::file pmid_2464_2271_100.txt # ::snt The top two, and three of the top five small molecules that induced gene expression changes most similar to ETV4 knockdown were inhibitors of either PI3K or mTOR, a downstream effector of PI3K (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / molecular-physical-entity :domain (a / and :op1 (s / small-molecule :quant "2" :ARG0-of (t / top-02)) :op2 (s2 / small-molecule :quant "3" :ARG1-of (i / include-91 :ARG2 (s3 / small-molecule :quant "5" :ARG0-of t))) :ARG0-of (i2 / induce-01 :ARG2 (c / change-01 :ARG1 (e / express-03 :ARG1 (g / gene)) :ARG1-of (r / resemble-01 :ARG2 (k / knock-down-02 :ARG1 (g2 / gene :name (n / name :op1 "ETV4") :xref (x / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003"))) :degree (m2 / most))))) :ARG0-of (i3 / inhibit-01 :ARG1 (o / or :op1 (p2 / protein-family :name (n2 / name :op1 "PI3K")) :op2 (p / protein :name (n3 / name :op1 "mTOR") :mod (e3 / effector :poss p2 :location (d / downstream)) :xref (x1 / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")) :mod (e4 / either))) :ARG1-of (d2 / describe-01 :ARG0 (t2 / table :mod "2"))) # ::id pmid_2464_2271.101 # ::date 2015-08-11T07:37:29 # ::file pmid_2464_2271_101.txt # ::snt These data suggest that in PC3 cells, PI3K and ETV4 activate a similar gene expression program. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (d / data :mod (t / this)) :ARG1 (a / activate-01 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op2 (p / protein :name (n2 / name :op1 "ETV4") :xref (x1 / xref :value "UNIPROT:ETV4_HUMAN" :prob "1.003"))) :ARG1 (p2 / program-01 :ARG1 (e2 / express-03 :ARG1 (g / gene)) :ARG1-of (r / resemble-01)) :location (c / cell-line :name (n3 / name :op1 "PC3")))) # ::id pmid_2464_2271.102 # ::date 2015-08-11T07:48:58 # ::file pmid_2464_2271_102.txt # ::snt To test if the PI3K pathway is required for an oncogenic ETS protein to promote the cell migration phenotype, RWPE-ERG and RWPE-KRAS cells were treated with the PI3K inhibitor, LY294002. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (t / treat-04 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "RWPE-ERG")) :op2 (c2 / cell-line :name (n2 / name :op1 "RWPE-KRAS"))) :ARG2 (s / small-molecule :name (n3 / name :op1 "LY294002") :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :xref (x2 / xref :value "PUBCHEM:3973" :prob "18.86067")) :purpose (t2 / test-01 :ARG1 (r / require-01 :mode "interrogative" :ARG0 (p / promote-01 :ARG0 (p2 / protein :name (n5 / name :op1 "ETS") :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :ARG1 (p3 / phenotype :mod (m / migrate-01 :ARG0 (c4 / cell)))) :ARG1 (p4 / pathway :name (n7 / name :op1 "PI3K"))))) # ::id pmid_2464_2271.103 # ::date 2015-08-11T08:02:28 # ::file pmid_2464_2271_103.txt # ::snt LY294002 reduced AKT phosphorylation in both lines, consistent with PI3K inhibition (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (r / reduce-01 :ARG0 (s / small-molecule :name (n / name :op1 "LY294002") :xref (x2 / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (p / phosphorylate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :location (c / cell-line :mod (b / both)) :ARG1-of (c2 / consistent-01 :ARG2 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2464_2271.104 # ::date 2015-08-11T08:10:13 # ::file pmid_2464_2271_104.txt # ::snt Strikingly, PI3K inhibition completely abrogated cell migration induced by ERG, but not cell migration induced by KRAS (Figure 3B and Additional file 2: Figure S2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / contrast-01 :ARG1 (a / abrogate-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1 (m / migrate-01 :ARG0 (c2 / cell) :ARG2-of (i2 / induce-01 :ARG0 (p / protein :name (n2 / name :op1 "ERG") :xref (x2 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")))) :ARG1-of (c3 / complete-01)) :ARG2 (a2 / abrogate-01 :polarity "-" :ARG0 i :ARG1 (m2 / migrate-01 :ARG0 c2 :ARG2-of (i3 / induce-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))))) :ARG1-of (s / strike-04) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3B") :op2 (f2 / file :mod "2" :ARG1-of (a4 / add-02) :part (f3 / figure :mod "S2"))))) # ::id pmid_2464_2271.105 # ::date 2015-08-11T08:21:52 # ::file pmid_2464_2271_105.txt # ::snt In fact RWPE-KRAS cells actually migrated more when PI3K was inhibited. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (m / migrate-01 :ARG0 (c / cell-line :name (n / name :op1 "RWPE-KRAS")) :degree (m2 / more) :time (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1-of (a / actual-02) :mod (i2 / in-fact)) # ::id pmid_2464_2271.106 # ::date 2015-08-11T08:31:42 # ::file pmid_2464_2271_106.txt # ::snt This increased migration may be due to relief of RAF inhibition by AKT [9], as RWPE-KRAS cells had higher pMEK levels after treatment by LY294002 (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Aug 11, 2015 (c / cause-01 :ARG0 (h / have-03 :ARG0 (c2 / cell-line :name (n / name :op1 "RWPE-KRAS")) :ARG1 (l / level :quant-of (e / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (h2 / high-02 :degree (m / more))) :time (a / after :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "LY294002") :xref (x3 / xref :value "PUBCHEM:3973" :prob "18.86067"))))) :ARG1 (p2 / possible-01 :ARG1 (c3 / cause-01 :ARG0 (r / relieve-01 :ARG1 (i / inhibit-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :ARG1 (e3 / enzyme :name (n5 / name :op1 "RAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")))) :ARG1 (m2 / migrate-01 :ARG1-of (i2 / increase-01) :mod (t2 / this))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "9")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2464_2271.107 # ::date 2015-08-10T06:30:53 # ::file pmid_2464_2271_107.txt # ::snt To confirm the role of PI3K, a second PI3K inhibitor, ZSTK474, was also tested (Figures 3A and 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (t3 / test-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474") :ARG1-of (m / mean-01 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 "p") :ord (o / ordinal-entity :value "2"))) :xref (x / xref :value "PUBCHEM:11647372" :prob "18.167522")) :mod (a / also) :purpose (c / confirm-01 :ARG1 (r / role :poss (p / pathway :name (n2 / name :op1 "PI3K")))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B")))) # ::id pmid_2464_2271.108 # ::date 2015-08-10T09:08:31 # ::file pmid_2464_2271_108.txt # ::snt Like LY294002, ZSTK474 significantly reduced migration of RWPE-ERG cells, but not RWPE-KRAS cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "ZSTK474") :xref (x1 / xref :value "PUBCHEM:11647372" :prob "18.167522")) :ARG1 (m / migrate-01 :ARG0 (c2 / cell-line :name (n3 / name :op1 "RWPE-ERG"))) :ARG1-of (r2 / resemble-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "LY294002") :xref (x / xref :value "PUBCHEM:3973" :prob "18.86067"))) :ARG1-of (s3 / significant-02)) :ARG2 (r3 / reduce-01 :polarity "-" :ARG0 s :ARG1 (m2 / migrate-01 :ARG0 (c3 / cell-line :name (n4 / name :op1 "RWPE-KRAS"))))) # ::id pmid_2464_2271.109 # ::date 2015-08-10T09:13:11 # ::file pmid_2464_2271_109.txt # ::snt Cell migration induced by other oncogenic ETS factors, ETV1, and ETV5, was also abrogated by PI3K inhibition (Figure 3C and Additional file 2: Figure S2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / abrogate-01 :ARG1 (m / migrate-01 :ARG0 (c2 / cell) :ARG2-of (i / induce-01 :ARG0 (f / factor :mod (p4 / protein :name (n / name :op1 "ETS") :xref (x2 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :mod (o / other) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (p2 / protein :name (n3 / name :op1 "ETV1") :xref (x / xref :value "UNIPROT:ETV1_HUMAN" :prob "1.003")) :op2 (p / protein :name (n2 / name :op1 "ETV5") :xref (x3 / xref :value "UNIPROT:ETV5_HUMAN" :prob "1.003")))) :ARG0-of (c3 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))))) :ARG2 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :mod (a3 / also) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "3C") :op2 (f3 / file :mod "2" :mod (a5 / additional) :location-of (f4 / figure :mod "S2"))))) # ::id pmid_2464_2271.110 # ::date 2015-08-11T02:15:34 # ::file pmid_2464_2271_110.txt # ::snt A second cell migration assay, the scratch assay, confirmed that PI3K inhibition reduced migration caused by ERG expression, but not migration caused by KRAS (Figure 3D and Additional file 3: Figure S3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / confirm-01 :ARG0 (a3 / assay-01 :ARG1 (m2 / migrate-01 :ARG0 (c2 / cell)) :ARG1-of (m3 / mean-01 :ARG2 (a4 / assay-01 :mod (s / scratch-02))) :ord (o / ordinal-entity :value "2")) :ARG1 (c3 / contrast-01 :ARG1 (r2 / reduce-01 :ARG0 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1 (m4 / migrate-01 :ARG1-of (c4 / cause-01 :ARG0 (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "ERG") :xref (x2 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")))))) :ARG2 (r / reduce-01 :polarity "-" :ARG0 i :ARG1 (m5 / migrate-01 :ARG1-of (c6 / cause-01 :ARG0 (g / gene :name (n3 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "3D") :op2 (f2 / file :mod "3" :location-of (f3 / figure :mod "S3"))))) # ::id pmid_2464_2271.111 # ::date 2015-08-10T15:51:18 # ::file pmid_2464_2271_111.txt # ::snt An AKT inhibitor had a similar effect (Figure 3D and Additional file 3: Figure S3), indicating that PI3K is functioning via AKT activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (a / affect-02 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 "e")) :ARG0-of (i2 / indicate-01 :ARG1 (f / function-01 :ARG0 (p / pathway :name (n2 / name :op1 "PI3K")) :instrument (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))))) :ARG1-of (r / resemble-01) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "3D") :op2 (f3 / file :mod "3" :mod (a4 / additional) :part-of (f4 / figure :mod "S3"))))) # ::id pmid_2464_2271.112 # ::date 2015-08-10T16:04:45 # ::file pmid_2464_2271_112.txt # ::snt These results indicate that overexpression of an oncogenic ETS gene can switch the control of prostate cell migration from the RAS/ERK pathway to the PI3K/AKT pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p2 / possible-01 :ARG1 (s / switch-01 :ARG0 (o / overexpress-01 :ARG1 (g / gene :name (n2 / name :op1 "ETS") :ARG0-of (c4 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :ARG1 (c / control-01 :ARG1 (m / migrate-01 :ARG1 (c3 / cell :source (p3 / prostate)))) :ARG2 (p5 / pathway :name (n4 / name :op1 "PI3K/AKT")) :ARG3 (p4 / pathway :name (n3 / name :op1 "RAS/ERK"))))) # ::id pmid_2464_2271.113 # ::date 2015-08-10T16:13:59 # ::file pmid_2464_2271_113.txt # ::snt We next tested if the PI3K pathway was regulating the ability of ERG to activate the transcription of RAS- and ERG-responsive target genes near enhancers that are co-occupied by ETS and AP-1 proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (r / regulate-01 :mode "interrogative" :ARG0 (p / pathway :name (n3 / name :op1 "PI3K")) :ARG1 (c / capable-01 :ARG1 (p2 / protein :name (n4 / name :op1 "ERG") :xref (x1 / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")) :ARG2 (a / activate-01 :ARG0 p2 :ARG1 (t2 / transcribe-01 :ARG1 (a2 / and :op1 (g / gene :ARG0-of (r2 / responsive-02 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (g2 / gene :ARG0-of (r3 / responsive-02 :ARG1 p2)) :ARG1-of (t3 / target-01))) :ARG1-of (n6 / near-01 :ARG2 (m / molecular-physical-entity :ARG0-of (e3 / enhance-01) :ARG1-of (o / occupy-01 :ARG0 (a3 / and :op1 (p3 / protein :name (n7 / name :op1 "ETS") :xref (x2 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :op2 (p4 / protein :name (n8 / name :op1 "AP-1") :xref (x / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))))))))) :time (n2 / next)) # ::id pmid_2464_2271.114 # ::date 2015-08-10T16:27:15 # ::file pmid_2464_2271_114.txt # ::snt The expression levels of two such genes, ARHGAP29, and SMAD3, were measured by quantitative reverse transcription PCR (qRT-PCR) (Figure 4A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / measure-01 :ARG1 (l / level :degree-of (e / express-03 :ARG1 (a2 / and :quant "2" :op1 (g / gene :name (n2 / name :op1 "ARHGAP29") :xref (x1 / xref :value "UNIPROT:RHG29_HUMAN" :prob "1.002")) :op2 (g2 / gene :name (n3 / name :op1 "SMAD3") :xref (x / xref :value "UNIPROT:SMAD3_HUMAN" :prob "1.003")) :mod (s / such)))) :ARG2 (r / react-01 :ARG0 (p / polymerase) :ARG1-of (c / chain-01)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B")))) # ::id pmid_2464_2271.115 # ::date 2015-08-11T03:08:33 # ::file pmid_2464_2271_115.txt # ::snt Both ARHGAP29 and SMAD3 have roles in cell migration and/or cell morphology [30,31], are direct targets of oncogenic ETS proteins and AP-1 by ChIP-seq [15], and are activated by KRAS and oncogenic ETS expression (Figure 4A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / and :op1 (h / have-03 :ARG0 (a4 / and :op1 (g2 / gene :name (n2 / name :op1 "ARHGAP29") :xref (x2 / xref :value "UNIPROT:RHG29_HUMAN" :prob "1.002")) :op2 (g / gene :name (n / name :op1 "SMAD3") :xref (x5 / xref :value "UNIPROT:SMAD3_HUMAN" :prob "1.003"))) :ARG1 (r / role :topic (o / or :op1 (m / migrate-01 :ARG0 (c / cell)) :op2 (m2 / morphology :mod c))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 (a6 / and :op1 "30" :op2 "31"))))) :op2 (t / target-01 :ARG0 (a7 / and :op1 (p2 / protein :name (n3 / name :op1 "ETS") :xref (x3 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")) :op2 (p3 / protein :name (n4 / name :op1 "AP-1") :xref (x4 / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652")) :ARG0-of (c4 / cause-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))) :ARG1 a4 :ARG2 (t2 / thing :name (n5 / name :op1 "ChIP-seq")) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "15"))) :ARG1-of (d3 / direct-02)) :op3 (a3 / activate-01 :ARG0 (a8 / and :op1 (e / express-03 :ARG1 (g3 / gene :name (n7 / name :op1 "KRAS") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :op2 (e2 / express-03 :ARG1 (g4 / gene :name (n6 / name :op1 "ETS") :ARG0-of c4 :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")))) :ARG1 a4) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4b")))) # ::id pmid_2464_2271.116 # ::date 2015-08-11T02:28:11 # ::file pmid_2464_2271_116.txt # ::snt Similar to the cell migration phenotype, the activation of both genes was significantly attenuated by PI3K inhibition in RWPE-ERG cells, but not in RWPE-KRAS cells (Figure 4A and B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c5 / contrast-01 :ARG1 (a4 / attenuate-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))) :ARG1 (a2 / activate-01 :ARG1 (g / gene :mod (b / both))) :ARG1-of (s / significant-02) :location (c2 / cell-line :name (n2 / name :op1 "RWPE-ERG"))) :ARG2 (a5 / attenuate-01 :polarity "-" :ARG0 i :ARG1 a2 :location (c / cell-line :name (n3 / name :op1 "RWPE-KRAS"))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B"))) :ARG1-of (r / resemble-01 :ARG2 (p2 / phenotype :mod (m / migrate-01 :ARG0 (c4 / cell))))) # ::id pmid_2464_2271.117 # ::date 2015-08-10T13:36:55 # ::file pmid_2464_2271_117.txt # ::snt Therefore cell migration changes are consistent with changes in the expression of these two oncogenic ETS target genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c6 / cause-01 :ARG1 (c / consistent-01 :ARG1 (c2 / change-01 :ARG1 (m / migrate-01 :ARG0 (c3 / cell))) :ARG2 (c4 / change-01 :ARG1 (e / express-03 :ARG1 (g / gene :quant "2" :mod (t / this) :ARG1-of (t2 / target-01 :ARG0 (p / protein :name (n / name :op1 "ETS") :ARG0-of (c7 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")))))))) # ::id pmid_2464_2271.118 # ::date 2015-08-10T14:10:50 # ::file pmid_2464_2271_118.txt # ::snt These results indicate that the PI3K/AKT pathway functions through ERG to regulate expression of cell migration genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (f / function-01 :ARG0 (p / pathway :name (n / name :op1 "PI3K/AKT")) :ARG1 (r2 / regulate-01 :ARG0 p :ARG1 (e / express-03 :ARG1 (g / gene :mod (m / migrate-01 :ARG0 (c2 / cell))))) :instrument (p2 / protein :name (n2 / name :op1 "ERG") :xref (x / xref :value "UNIPROT:ERG_HUMAN" :prob "1.003")))) # ::id pmid_2464_2271.119 # ::date 2015-08-10T14:26:21 # ::file pmid_2464_2271_119.txt # ::snt We next used a reporter assay to test if these gene expression changes were mediated by the ETS/AP-1 binding sequences we found in the enhancers of oncogenic ETS target genes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (a / assay-01 :ARG1 (g / gene :ARG0-of (r / report-01))) :ARG2 (t / test-01 :ARG0 w :ARG1 (m / mediate-01 :mode "interrogative" :ARG0 (p / protein-segment :name (n2 / name :op1 "ETS/AP-1") :ARG2-of (b2 / bind-01) :ARG1-of (f / find-01 :ARG0 w :location (m2 / molecular-physical-entity :ARG0-of (e2 / enhance-01 :ARG1 (g2 / gene :ARG1-of (t4 / target-01 :ARG0 (p4 / protein :name (n3 / name :op1 "ETS") :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")))))))) :ARG1 (c / change-01 :ARG1 (e / express-03 :ARG1 g2)))) :time (n / next)) # ::id pmid_2464_2271.120 # ::date 2015-08-10T14:32:21 # ::file pmid_2464_2271_120.txt # ::snt Three copies of an ETS/AP-1 consensus sequence were cloned upstream of a minimal promoter driving firefly luciferase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / clone-01 :ARG1 (c2 / copy-01 :quant "3" :ARG1 (p2 / protein-segment :name (n / name :op1 "ETS/AP-1") :mod (c3 / consensus))) :direction (u / upstream :op1 (m2 / molecular-physical-entity :ARG1-of (m / minimal-02) :ARG0-of (p / promote-01) :ARG0-of (d / drive-02 :ARG1 (e / enzyme :name (n2 / name :op1 "firefly" :op2 "luciferase")))))) # ::id pmid_2464_2271.121 # ::date 2015-08-10T06:43:55 # ::file pmid_2464_2271_121.txt # ::snt Luciferase expression from this vector was higher when the ERK pathway was active, indicating that this pathway regulates the reporter construct (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (h2 / high-02 :ARG1 (e2 / express-03 :ARG2 (l / luciferase) :ARG3 (v / vector :mod (t / this))) :degree (m / more) :time (a / activity-06 :ARG0 (p / pathway :name (n / name :op1 "ERK"))) :ARG0-of (i / indicate-01 :ARG1 (r / regulate-01 :ARG0 p :ARG1 (c / construct-01 :ARG0 (g / gene :ARG0-of (r2 / report-01))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id pmid_2464_2271.122 # ::date 2015-08-10T06:52:01 # ::file pmid_2464_2271_122.txt # ::snt Point mutations in either the ETS or AP-1 binding sequences completely eliminated luciferase expression indicating that both binding sites are required for activity (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (e / eliminate-01 :ARG0 (m / mutate-01 :ARG1 (o / or :op1 (d2 / dna-sequence :ARG2-of (b2 / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "ETS") :xref (x / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262")))) :op2 (p4 / protein-segment :ARG2-of (b / bind-01 :ARG1 (p3 / protein :name (n2 / name :op1 "AP-1") :xref (x1 / xref :value "UNIPROT:JUN_HUMAN" :prob "0.652"))))) :mod (p / point)) :ARG1 (e2 / express-03 :ARG2 (l / luciferase)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C")) :ARG1-of (c / complete-02) :ARG0-of (i / indicate-01 :ARG1 (r / require-01 :ARG0 (a / activity-06 :ARG0 o) :ARG1 o))) # ::id pmid_2464_2271.123 # ::date 2015-08-11T02:02:21 # ::file pmid_2464_2271_123.txt # ::snt The PI3K inhibitor, LY294002, caused a significant decrease in the activity of this reporter in RWPE-ERG cells (Figure 4D), but significantly increased activity in RWPE-KRAS cells (Figure 4E), consistent with the cell migration findings. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (c2 / cause-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "LY294002") :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "PI3K"))) :xref (x / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (d / decrease-01 :ARG1 (a / activity-06 :ARG0 (g / gene :ARG0-of (r / report-01) :mod (t / this)) :location (c5 / cell-line :name (n3 / name :op1 "RWPE-ERG"))) :ARG1-of (s / significant-02)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "4D"))) :ARG2 (i / increase-01 :ARG0 s3 :ARG1 (a2 / activity-06 :ARG0 g :location (c6 / cell-line :name (n4 / name :op1 "RWPE-KRAS"))) :ARG1-of (c3 / consistent-01 :ARG2 (f / find-01 :ARG1 (m / migrate-01 :ARG0 (c4 / cell)))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "4E")) :ARG1-of s)) # ::id pmid_2464_2271.124 # ::date 2015-08-10T14:54:42 # ::file pmid_2464_2271_124.txt # ::snt Therefore, the PI3K pathway can alter the expression of cell migration genes via ETS/AP-1 sites. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / cause-01 :ARG1 (p / possible-01 :ARG1 (a / alter-01 :ARG0 (p2 / pathway :name (n / name :op1 "PI3K")) :ARG1 (e / express-03 :ARG1 (g / gene :mod (m / migrate-01 :ARG0 (c2 / cell)))) :instrument (p3 / protein-segment :name (n2 / name :op1 "ETS/AP-1"))))) # ::id pmid_2464_2271.125 # ::date 2015-08-10T14:28:13 # ::file pmid_2464_2271_125.txt # ::snt The role of AKT in oncogenic ETS function is not via mTORC1 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / role :poss (e / enzyme :name (n / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :topic (f / function-01 :ARG0 (g / gene :name (n2 / name :op1 "ETS") :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))) :instrument (m2 / macro-molecular-complex :polarity "-" :name (n3 / name :op1 "mTORC1"))) # ::id pmid_2464_2271.126 # ::date 2015-08-10T14:31:32 # ::file pmid_2464_2271_126.txt # ::snt PI3K/AKT signaling has a number of cellular functions including the activation of the mTOR-containing complexes mTORC1 and mTORC2 [8]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (f2 / function-01 :ARG0 (s / signal-07 :ARG0 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT"))) :ARG1 (c / cell) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 "8"))) :ARG1-of (i / include-91 :ARG2 (a / activate-01 :ARG0 p2 :ARG1 (a2 / and :op1 (m2 / macro-molecular-complex :name (n3 / name :op1 "mTORC1")) :op2 (m3 / macro-molecular-complex :name (n4 / name :op1 "mTORC2")) :ARG0-of (c2 / contain-01 :ARG1 (p / protein :name (n / name :op1 "mTOR") :xref (x / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")))))) :quant (n5 / number)) # ::id pmid_2464_2271.127 # ::date 2015-08-10T08:01:38 # ::file pmid_2464_2271_127.txt # ::snt mTORC1 includes the Raptor protein and regulates gene expression via translational control. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (a / and :op1 (i2 / include-91 :ARG1 (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC1")) :ARG2 (p2 / protein :name (n / name :op1 "Raptor") :xref (x / xref :value "UNIPROT:RPTOR_HUMAN" :prob "1.002"))) :op2 (r / regulate-01 :ARG0 m2 :ARG1 (e / express-03 :ARG1 (g / gene)) :instrument (c / control-01 :ARG1 (t / translate-02)))) # ::id pmid_2464_2271.128 # ::date 2015-08-10T08:35:16 # ::file pmid_2464_2271_128.txt # ::snt mTORC2 includes the Rictor protein and provides positive feedback by phosphorylating and activating AKT. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (a / and :op1 (i / include-91 :ARG1 (m2 / macro-molecular-complex :name (n / name :op1 "mTORC2")) :ARG2 (p5 / protein :name (n2 / name :op1 "Rictor") :xref (x / xref :value "UNIPROT:RICTR_HUMAN" :prob "0.602"))) :op2 (p / provide-01 :ARG0 m2 :ARG1 (f / feedback :mod (p2 / positive)) :manner (a2 / and :op1 (p3 / phosphorylate-01 :ARG1 "p4" :ARG2 m2) :op2 (a3 / activate-01 :ARG0 m2 :ARG1 (p4 / pathway :name (n3 / name :op1 "AKT")))))) # ::id pmid_2464_2271.129 # ::date 2015-08-10T08:58:28 # ::file pmid_2464_2271_129.txt # ::snt To test the role of mTOR-containing complexes in oncogenic ETS function, shRNAs were used to knockdown mTOR, Raptor, and Rictor, in RWPE-ERG cells (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (u / use-01 :ARG1 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA")) :ARG2 (k / knock-down-02 :ARG1 (a / and :op1 "m" :op2 (p2 / protein :name (n6 / name :op1 "Raptor") :xref (x / xref :value "UNIPROT:RPTOR_HUMAN" :prob "1.002")) :op3 (p3 / protein :name (n7 / name :op1 "Rictor") :xref (x1 / xref :value "UNIPROT:RICTR_HUMAN" :prob "0.602")) :location (c3 / cell-line :name (n4 / name :op1 "RWPE-ERG")))) :purpose (t / test-01 :ARG1 (r / role :poss (m / macro-molecular-complex :ARG0-of (c / contain-01 :ARG1 (p / protein :name (n / name :op1 "mTOR") :xref (x3 / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")))) :topic (f / function-01 :ARG0 (g / gene :name (n2 / name :op1 "ETS") :ARG0-of (c4 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :xref (x2 / xref :value "UNIPROT:ETS1_HUMAN" :prob "0.262"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "5A"))) # ::id pmid_2464_2271.130 # ::date 2015-08-10T16:40:03 # ::file pmid_2464_2271_130.txt # ::snt Loss of Raptor resulted in an increase in cell migration, indicating that mTORC1 is not required for the ability of PI3K/AKT to promote cell migration (Figure 5B and Additional file 2: Figure S2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (r / result-01 :ARG1 (l / lose-02 :ARG1 (p2 / protein :name (n2 / name :op1 "Raptor") :xref (x / xref :value "UNIPROT:RPTOR_HUMAN" :prob "1.002"))) :ARG2 (i / increase-01 :ARG1 (m / migrate-01 :ARG0 (c / cell))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "5B") :op2 (f2 / file :mod "2" :part (f3 / figure :mod "S2")))) :ARG0-of (i2 / indicate-01 :ARG1 (r2 / require-01 :polarity "-" :ARG0 (c3 / capable-01 :ARG1 (p5 / pathway :name (n4 / name :op1 "PI3K/AKT")) :ARG2 (p4 / promote-01 :ARG0 p5 :ARG1 m)) :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "mTORC1"))))) # ::id pmid_2464_2271.131 # ::date 2015-08-10T14:44:02 # ::file pmid_2464_2271_131.txt # ::snt Loss of mTOR had little effect on RWPE-ERG migration, while loss of Rictor decreased migration (Figure 5B and Additional file 2: Figure S2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 13, 2015 (c / contrast-01 :ARG1 (a2 / affect-01 :ARG0 (l2 / lose-02 :ARG1 (p / protein :name (n2 / name :op1 "mTOR") :xref (x1 / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004"))) :ARG1 (m2 / migrate-01 :ARG0 (c2 / cell-line :name (n / name :op1 "RWPE-ERG"))) :degree (l / little)) :ARG2 (d2 / decrease-01 :ARG0 (l3 / lose-02 :ARG1 (p2 / protein :name (n3 / name :op1 "Rictor") :xref (x / xref :value "UNIPROT:RICTR_HUMAN" :prob "0.602"))) :ARG1 m2) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "5B") :op2 (f2 / file :mod "2" :location-of (f3 / figure :mod "S2"))))) # ::id pmid_2464_2271.132 # ::date 2015-08-10T14:53:58 # ::file pmid_2464_2271_132.txt # ::snt Because the major role of the Rictor-containing mTORC2 complex is thought to be the phosphorylation of AKT, we hypothesized that these results were due to changes in AKT phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 18, 2015 (c / cause-01 :ARG0 (t / think-01 :ARG1 (r / role :mod (m / major) :poss (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC2") :ARG0-of (c2 / contain-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Rictor") :xref (x / xref :value "UNIPROT:RICTR_HUMAN" :prob "0.602")))) :domain (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))))) :ARG1 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (c3 / cause-01 :ARG0 (c4 / change-01 :ARG1 p) :ARG1 (t2 / thing :ARG2-of (r2 / result-01) :mod (t3 / this))))) # ::id pmid_2464_2271.133 # ::date 2015-08-10T13:23:58 # ::file pmid_2464_2271_133.txt # ::snt Consistent with previous findings [32-34], Raptor knockdown increased AKT phosphorylation, and Rictor knockdown decreased AKT phosphorylation (Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (a / and :op1 (i / increase-01 :ARG0 (k / knock-down-02 :ARG1 (p3 / protein :name (n2 / name :op1 "Raptor") :xref (x / xref :value "UNIPROT:RPTOR_HUMAN" :prob "1.002"))) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "AKT") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :op2 (d2 / decrease-01 :ARG0 (k2 / knock-down-02 :ARG1 (p4 / protein :name (n3 / name :op1 "Rictor") :xref (x2 / xref :value "UNIPROT:RICTR_HUMAN" :prob "0.602"))) :ARG1 p) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C")) :ARG1-of (c / consistent-01 :ARG2 (t / thing :ARG1-of (f2 / find-01 :time (p2 / previous)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 "32" :op2 "34"))))))) # ::id pmid_2464_2271.134 # ::date 2015-08-10T15:06:02 # ::file pmid_2464_2271_134.txt # ::snt Therefore, the effect of mTOR containing complexes on RWPE-ERG cell migration can be explained indirectly by changes to pAKT levels, rather than by a direct role. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Aug 24, 2015 (c / cause-01 :ARG1 (p / possible-01 :ARG1 (e / explain-01 :ARG0 (c6 / change-01 :ARG1 (l / level :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p5 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :ARG1-of (i / instead-of-91 :ARG2 (r / role :ARG1-of (d2 / direct-02)))) :ARG1 (a / affect-01 :ARG0 (m3 / macro-molecular-complex :ARG0-of (c4 / contain-01 :ARG1 (p3 / protein :name (n / name :op1 "mTOR") :xref (x / xref :value "UNIPROT:MTOR_HUMAN" :prob "1.004")))) :ARG1 (m2 / migrate-01 :ARG0 (c3 / cell-line :name (n2 / name :op1 "RWPE-ERG")))) :ARG1-of (d / direct-02 :polarity "-")))) # ::id pmid_2465_1010.1 # ::date 2015-02-09T09:42:41 # ::file pmid_2465_1010_1.txt # ::snt Dragging Ras Back in the Ring (PMID:24651010) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 31, 2015 (p / publication-91 :ARG1 (d / drag-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (r / ring) :direction (b / back)) :ARG8 "PMID24651010") # ::id pmid_2465_1010.2 # ::date 2015-02-10T04:25:26 # ::file pmid_2465_1010_2.txt # ::snt Ras proteins play a major role in human cancers but have not yielded to therapeutic attack. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (p / play-08 :ARG0 (p2 / protein-family :name (n / name :op1 "Ras")) :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :mod (h / human)) :ARG1-of (m / major-02)) :ARG2 (y / yield-02 :polarity "-" :ARG0 p2 :ARG2 (a / attack-01 :ARG0 (t / therapy) :ARG1 p2))) # ::id pmid_2465_1010.3 # ::date 2015-02-10T13:22:39 # ::file pmid_2465_1010_3.txt # ::snt Ras-driven cancers are among the most difficult to treat and often excluded from therapies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 13, 2015 (a / and :op1 (i / include-91 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG1-of (d2 / drive-02 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ARG2-of (t / treat-03 :manner (d4 / difficult :degree (m / most))))) :op2 (e2 / exclude-01 :ARG1 d :ARG2 (t2 / therapy) :frequency (o / often))) # ::id pmid_2465_1010.4 # ::date 2015-02-10T14:22:33 # ::file pmid_2465_1010_4.txt # ::snt The Ras proteins have been termed “undruggable,” based on failures from an era in which understanding of signaling transduction, feedback loops, redundancy, tumor heterogeneity, and Ras’ oncogenic role was poor. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (t / term-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG3 (p / possible-01 :polarity "-" :ARG1 (d / drug-01 :ARG1 e)) :ARG1-of (b / base-02 :ARG2 (f / fail-01 :time (e2 / era :time-of (p2 / poor :domain (u / understand-01 :ARG1 (a / and :op1 (t2 / transduce-01 :ARG1 (s / signal-07)) :op2 (l / loop :mod (f2 / feedback)) :op3 (r / redundancy) :op4 (h / heterogeneous :domain (t3 / tumor)) :op5 (c / cause-01 :ARG0 e :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))))))) # ::id pmid_2465_1010.5 # ::date 2015-02-10T15:36:53 # ::file pmid_2465_1010_5.txt # ::snt Structures of Ras oncoproteins bound to their effectors or regulators are unsolved, and it is unknown precisely how Ras proteins activate their downstream targets. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (s / solve-01 :polarity "-" :ARG1 (s2 / structure :consist-of (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :ARG1-of (b / bind-01 :ARG2 (o2 / or :op1 (e2 / effector :poss e) :op2 (m / molecular-physical-entity :ARG0-of (r / regulate-01 :ARG1 e)))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (k / know-01 :polarity "-" :ARG1 (t / thing :manner-of (a2 / activate-01 :ARG0 (p2 / protein-family :name (n2 / name :op1 "Ras")) :ARG1 (m2 / molecular-physical-entity :ARG1-of (t2 / target-01 :ARG0 p2) :location (d / downstream)))) :manner (p / precise))) # ::id pmid_2465_1010.6 # ::date 2015-02-10T22:50:20 # ::file pmid_2465_1010_6.txt # ::snt These knowledge gaps have impaired development of therapeutic strategies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Mar 17, 2015 (i / impair-01 :ARG0 (g / gap :mod (t2 / this) :topic (k / know-03)) :ARG1 (d / develop-02 :ARG1 (s / strategy :mod (t / therapy)))) # ::id pmid_2465_1010.7 # ::date 2015-02-10T22:58:33 # ::file pmid_2465_1010_7.txt # ::snt A better understanding of Ras biology and biochemistry, coupled with new ways of targeting undruggable proteins, is likely to lead to new ways of defeating Ras-driven cancers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (l / likely-01 :ARG1 (l2 / lead-03 :ARG0 (u / understand-01 :ARG1 (a / and :op1 (b / biology :mod (p3 / protein-family :name (n / name :op1 "Ras"))) :op2 (b2 / biochemistry :mod p3)) :ARG1-of (c / couple-01 :ARG2 (w2 / way :ARG1-of (n4 / new-01) :manner-of (t / target-01 :ARG1 (p / protein :ARG1-of (d4 / drug-01 :ARG1-of (p2 / possible-01 :polarity "-")))))) :ARG1-of (g / good-02 :degree (m / more))) :ARG2 (w / way :ARG1-of (n2 / new-01) :manner-of (d / defeat-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ARG1-of (d3 / drive-02 :ARG0 p3)))))) # ::id pmid_2465_1010.8 # ::date 2015-02-10T23:12:32 # ::file pmid_2465_1010_8.txt # ::snt Main Text # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 10, 2015 (t / text :mod (m / main)) # ::id pmid_2465_1010.9 # ::date 2015-02-10T23:14:13 # ::file pmid_2465_1010_9.txt # ::snt Fifty years have passed since the transforming power of Ras genes was first recognized. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 31, 2015 (p / pass-03 :ARG1 (t / temporal-quantity :quant "50" :unit (y / year)) :time (s / since :op1 (r / recognize-02 :ARG1 (p2 / possible-01 :ARG1 (t2 / transform-01 :ARG0 (g / gene :wiki "-" :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ord (o / ordinal-entity :value "1")))) # ::id pmid_2465_1010.10 # ::date 2015-02-11T03:01:29 # ::file pmid_2465_1010_10.txt # ::snt Harvey sarcoma virus, Kirsten sarcoma virus, and Rasheed sarcoma virus contain Ras genes (so named for their role in forming rat sarcomas; reviewed in Barbacid, 1987; Karnoub and Weinberg, 2008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contain-01 :ARG0 (a / and :op1 (v / virus :name (n2 / name :op1 "Harvey" :op2 "sarcoma" :op3 "virus")) :op2 (v2 / virus :name (n3 / name :op1 "Kirsten" :op2 "sarcoma" :op3 "virus")) :op3 (v3 / virus :name (n4 / name :op1 "Rasheed" :op2 "sarcoma" :op3 "virus"))) :ARG1 (g / gene :name (n / name :op1 "Ras") :ARG1-of (n5 / name-01 :ARG1-of (c2 / cause-01 :ARG0 (p6 / play-08 :ARG0 g :ARG1 (f / form-01 :ARG1 (s / sarcoma :mod (r / rat)))))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (r2 / review-02 :ARG2 (a2 / and :op1 (p / publication-91 :ARG0 (p3 / person :name (n6 / name :op1 "Barbacid")) :time (d / date-entity :year "1987")) :op2 (p2 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n7 / name :op1 "Karnoub")) :op2 (p5 / person :name (n8 / name :op1 "Weinberg"))) :time (d2 / date-entity :year "2008"))))) # ::id pmid_2465_1010.11 # ::date 2015-02-11T03:47:55 # ::file pmid_2465_1010_11.txt # ::snt These retroviruses initiated tumors efficiently and, using temperature-sensitive mutants, were shown to be necessary for tumor maintenance (Shih et al., 1979). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 13, 2015 (a / and :op1 (i / initiate-01 :ARG0 (r / retrovirus :mod (t / this)) :ARG1 (t2 / tumor) :ARG2-of (e / efficient-01 :ARG1 r)) :op2 (s / show-01 :ARG1 (n / need-01 :ARG0 (m / maintain-01 :ARG1 t2) :ARG1 r) :manner (u / use-01 :ARG1 (v / virus :ARG2-of (m2 / mutate-01) :ARG0-of (s2 / sensitive-03 :ARG1 (t3 / temperature))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n2 / name :op1 "Shih")) :op2 (p3 / person :mod (o / other))) :time (d2 / date-entity :year "1979")))) # ::id pmid_2465_1010.12 # ::date 2015-02-11T04:14:45 # ::file pmid_2465_1010_12.txt # ::snt They formed part of a fascinating collection of retroviruses that was assembled in the 1970s, each able to transform cells in culture and in avian and rodent models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 13, 2015 (i / include-91 :ARG1 (t / they) :ARG2 (c / collection :ARG0-of (f2 / fascinate-01) :consist-of (r / retrovirus :ARG0-of (t2 / transform-01 :ARG1 (c2 / cell :source (a2 / and :op1 (c3 / culture) :op2 (m / model :mod (b / bird)) :op3 (m2 / model :mod (r2 / rodent)))) :ARG1-of (p2 / possible-01)) :mod (e / each)) :ARG1-of (a / assemble-02 :time (d / date-entity :decade "1970")))) # ::id pmid_2465_1010.13 # ::date 2015-02-11T04:48:49 # ::file pmid_2465_1010_13.txt # ::snt These experiments were, essentially, unbiased screens for genes that cause cancer; the nature of the proteins that the genes encoded was completely unknown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (m / multi-sentence :snt1 (s / screen-01 :ARG0 (e / experiment-01 :mod (t / this)) :ARG2 (g / gene :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :ARG1-of (b / bias-01 :polarity "-") :mod (e2 / essential)) :snt2 (k / know-01 :polarity "-" :ARG1 (n2 / nature :mod (p / protein :ARG1-of (e3 / encode-01 :ARG0 (g2 / gene)))) :ARG1-of (c2 / complete-02))) # ::id pmid_2465_1010.14 # ::date 2015-02-11T05:08:05 # ::file pmid_2465_1010_14.txt # ::snt Remarkably, the majority of these viruses encoded proteins that were later identified as components of the tyrosine kinase-Ras signaling pathway (Vogt, 2012), even though the biochemical nature of these proteins was unknown, and tyrosine kinase activity had not been discovered (Eckhart et al., 1979). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (e / encode-01 :ARG0 (v / virus :ARG1-of (i / include-91 :ARG2 (v2 / virus :mod (t / this)) :ARG3 (m / majority))) :ARG1 (p / protein :ARG1-of (i2 / identify-01 :ARG2 (c / component :part-of (p2 / pathway :name (n / name :op1 "tyrosine" :op2 "kinase-Ras") :ARG0-of (s / signal-07))) :time (l / late :degree (m2 / more)) :ARG1-of (h / have-concession-91 :ARG2 (a / and :op1 (k / know-01 :polarity "-" :ARG1 (n2 / nature :mod (b / biochemical) :poss p)) :op2 (d / discover-01 :polarity "-" :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n3 / name :op1 "tyrosine" :op2 "kinase") :xref (x / xref :value "UNIPROT:FER_HUMAN" :prob "0.392"))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n4 / name :op1 "Eckhart")) :op2 (p6 / person :mod (o / other))) :time (d4 / date-entity :year "1979")))))) :ARG1-of (r / remarkable-02) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n5 / name :op1 "Vogt"))) :time (d5 / date-entity :year "2012")))) # ::id pmid_2465_1010.15 # ::date 2015-02-11T06:42:30 # ::file pmid_2465_1010_15.txt # ::snt Of the hundreds of mutant proteins now known to contribute to cancer that could have been identified in these assays, including those involved in DNA repair, cellular metabolism, RNA splicing, and the other hallmarks of cancer (Hanahan and Weinberg, 2011), those in the tyrosine kinase-Ras pathway stand out as the major drivers and have been the richest source of targets of successful cancer therapies (Abl, epidermal growth factor receptor [EGFR], Her2/neu, B-Raf, Kit, ALK, etc.). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op1 (s / stand-out-06 :ARG1 (p / protein :location (p2 / pathway :name (n / name :op1 "tyrosine" :op2 "kinase-Ras")) :ARG1-of (i / include-91 :ARG2 (p4 / protein :ARG2-of (m2 / mutate-01) :quant (m3 / multiple :op1 "100") :ARG0-of (c2 / contribute-01 :ARG2 "d2" :ARG1-of (k / know-01 :time (n9 / now))) :ARG1-of (i2 / identify-01 :ARG0 (a3 / assay-01 :mod (t4 / this)) :ARG1-of (p5 / possible-01)) :ARG2-of (i3 / include-91 :ARG1 (a4 / and :op1 (p6 / protein :ARG1-of (i4 / involve-01 :ARG2 (a5 / and :op1 (r / repair-01 :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n13 / name :op1 "DNA"))) :op2 (m4 / metabolism :mod (c3 / cell)) :op3 (s5 / splice-01 :ARG1 (n14 / nucleic-acid :name (n15 / name :op1 "RNA"))) :op4 (h / hallmark :mod (o / other) :mod "d2"))))))) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a6 / and :op1 (p8 / person :name (n10 / name :op1 "Hanahan")) :op2 (p9 / person :name (n11 / name :op1 "Weinberg"))) :time (d5 / date-entity :year "2011"))))) :ARG1-of (c / cause-01 :ARG0 (d / drive-02 :ARG0 p :ARG1-of (m / major-02)))) :op2 (s2 / source-02 :ARG0 p :ARG1 (t / thing :ARG1-of (t2 / target-01 :ARG0 (t3 / therapy :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")) :ARG0-of (s3 / succeed-01)) :example (a2 / and :op1 (p10 / protein :name (n3 / name :op1 "Abl") :xref (x2 / xref :value "UNIPROT:ABL1_HUMAN" :prob "0.603")) :op2 (e / enzyme :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor") :xref (x4 / xref :value "UNIPROT:EGFR_HUMAN" :prob "0.703")) :op3 (p3 / protein :name (n5 / name :op1 "Her2/neu")) :op4 (e2 / enzyme :name (n6 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")) :op5 (e5 / enzyme :name (n7 / name :op1 "Kit") :xref (x / xref :value "UNIPROT:Q14708_HUMAN" :prob "0.671")) :op6 (e6 / enzyme :name (n8 / name :op1 "ALK") :xref (x3 / xref :value "UNIPROT:ALK_HUMAN" :prob "1.003")) :op7 (e3 / et-cetera)))) :mod (r3 / rich :degree (m5 / most)))) # ::id pmid_2465_1010.16 # ::date 2015-02-11T11:09:35 # ::file pmid_2465_1010_16.txt # ::snt These successes can therefore be attributed to the central, dominant role of this pathway in cancer, as well as the fortuitous abundance of druggable targets. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 13, 2015 (i / infer-01 :ARG1 (p / possible-01 :ARG1 (a / attribute-01 :ARG1 (s / succeed-01 :mod (t / this)) :ARG2 (a2 / and :op1 (p2 / play-08 :ARG0 (p3 / pathway :mod t) :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")) :ARG0-of (d2 / dominate-01) :mod (c / central)) :op2 (t2 / thing :ARG1-of (t3 / target-01) :mod (a3 / abundance :mod (f / fortuity)) :ARG1-of (d3 / drug-01 :ARG1-of (p4 / possible-01))))))) # ::id pmid_2465_1010.17 # ::date 2015-02-11T11:55:47 # ::file pmid_2465_1010_17.txt # ::snt However, specific therapies have not been developed for mutant Ras proteins themselves or for the cancers that they drive. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (h / have-concession-91 :ARG1 (d / develop-02 :polarity "-" :ARG1 (t / therapy :ARG1-of (s / specific-02)) :ARG3 (o / or :op1 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :ARG1-of (d3 / drive-02 :ARG0 e))))) # ::id pmid_2465_1010.18 # ::date 2015-02-11T12:06:32 # ::file pmid_2465_1010_18.txt # ::snt Worse yet, tumors driven by Ras genes are excluded from treatment with other targeted therapies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (b / bad-05 :ARG1 (e / exclude-01 :ARG1 (t / tumor :ARG1-of (d / drive-02 :ARG0 (g / gene :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (t2 / treat-03 :ARG2 t :ARG3 (t3 / therapy :mod (o / other) :ARG2-of (t4 / target-01)))) :degree (m / more) :mod (y / yet)) # ::id pmid_2465_1010.19 # ::date 2015-02-11T12:14:27 # ::file pmid_2465_1010_19.txt # ::snt Early efforts to block Ras cancers by preventing Ras farnesylation, once thought to be an essential posttranslational modification for Ras activity, were thwarted by the unexpected presence of a backup system (geranylgeranyltransferase) that restored activity of K-Ras and N-Ras after farnesyltransferase treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 21, 2016 (t / thwart-01 :ARG0 (p / present-02 :ARG1 (e2 / enzyme :name (n / name :op1 "geranylgeranyltransferase") :ARG0-of (b / back-up-04) :ARG0-of (r / restore-01 :ARG1 (a / activity-06 :ARG0 (a2 / and :op1 (e3 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x3 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e4 / enzyme :name (n3 / name :op1 "N-Ras") :xref (x2 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")))) :time (a3 / after :op1 (t2 / treat-04 :ARG1 (e5 / enzyme :name (n4 / name :op1 "farnesyltransferase") :xref (x1 / xref :value "UNIPROT:GGPPS_HUMAN" :prob "0.382"))))) :xref (x4 / xref :value "UNIPROT:FPPS_HUMAN" :prob "0.352")) :ARG1-of (e / expect-01 :polarity "-")) :ARG1 (e6 / effort-01 :ARG1 (b2 / block-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer") :ARG1-of (c / cause-01 :ARG0 (e8 / enzyme :name (n6 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG3 (p2 / prevent-01 :ARG1 (f / farnesylate-01 :ARG1 e8 :ARG1-of (t3 / think-01 :ARG2 (m / modify-01 :ARG1 (a5 / activity-06 :ARG0 e8) :time (a4 / after :op1 (t4 / translate-02)) :mod (e9 / essential)) :time (o / once))))) :mod (e7 / early))) # ::id pmid_2465_1010.20 # ::date 2015-02-11T12:38:20 # ::file pmid_2465_1010_20.txt # ::snt Likewise, efforts to kill Ras cancers by blocking one of Ras’ major downstream effectors, Raf kinase (Figure 1), ran into the unexpected discovery that, in Ras-transformed cells, Raf inhibitors activate the pathway rather than inhibit it (see below and discussion in Holderfield et al., 2013 and Lito et al., 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 21, 2016 (r / run-07 :ARG0 (e / effort-01 :ARG1 (k / kill-01 :ARG1 (d6 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ARG1-of (c2 / cause-01 :ARG0 (e2 / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2 (b / block-01 :ARG1 (k2 / kinase :name (n2 / name :op1 "Raf") :ARG1-of (i / include-91 :ARG2 (e4 / effector :location (d2 / downstream) :ARG1-of (m / major-02) :poss e2)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1")) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))) :ARG1 (d / discover-01 :ARG1 (a / activate-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 k2)) :ARG1 (p / pathway) :ARG1-of (i3 / instead-of-91 :ARG2 (i4 / inhibit-01 :ARG1 p)) :location (c3 / cell :ARG2-of (t / transform-01 :ARG0 e2))) :ARG1-of (e3 / expect-01 :polarity "-")) :manner (l / likewise) :ARG1-of (s / see-01 :location (b2 / below)) :ARG1-of (d4 / discuss-01 :ARG0 (a2 / and :op1 (p2 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n4 / name :op1 "Holderfield")) :op2 (p5 / person :mod (o / other))) :time (d5 / date-entity :year "2013")) :op2 (p3 / publication-91 :ARG0 (p6 / person :name (n5 / name :op1 "Lito")) :time d5)))) # ::id pmid_2465_1010.21 # ::date 2015-02-11T13:01:03 # ::file pmid_2465_1010_21.txt # ::snt MAP kinase kinase (MEK) inhibitors and phosphatidylinositol 3-kinase (PI3K) inhibitors have not yet shown significant clinical activity in Ras cancers, for reasons relating to feedback loops and poor therapeutic windows, among other issues discussed below. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :polarity "-" :ARG1 (a2 / activity-06 :ARG0 (a / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MAP" :op2 "kinase" :op3 "kinase")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "phosphatidylinositol" :op2 "3-kinase"))))) :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :ARG1-of (c3 / cause-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :mod (c / clinic) :ARG1-of (s2 / significant-02)) :time (y / yet) :ARG1-of (c4 / cause-01 :ARG0 (r / reason :ARG1-of (r2 / relate-01 :ARG2 (a3 / and :op1 (l / loop :mod (f / feedback)) :op2 (w / window :mod (t / therapy) :mod (p2 / poor)) :ARG1-of (i3 / include-91 :ARG2 (i4 / issue-02 :mod (o / other)) :ARG1-of (d / discuss-01 :location (b / below)))))))) # ::id pmid_2465_1010.22 # ::date 2015-02-11T13:23:40 # ::file pmid_2465_1010_22.txt # ::snt A convergence of urgent unmet clinical needs and advances in drug discovery has energized new efforts to target Ras cancers within academic centers and in the biopharmaceutical industry. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (e / energize-01 :ARG0 (c / converge-01 :ARG0 (n / need-01 :ARG1-of (m / meet-01 :polarity "-") :mod (u / urgent) :mod (c2 / clinical)) :ARG1 (a / advance-01 :ARG1 (d / discover-01 :ARG1 (d2 / drug)))) :ARG1 (e2 / effort-01 :ARG1 (t / target-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :ARG1-of (c4 / cause-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :location (a2 / and :op1 (c5 / center :mod (a3 / academia)) :op2 (i / industry :mod (b / biopharmaceutical)))) :ARG1-of (n2 / new-01))) # ::id pmid_2465_1010.23 # ::date 2015-02-11T13:35:19 # ::file pmid_2465_1010_23.txt # ::snt To catalyze these renewed efforts, the National Cancer Institute recently launched a national Ras program at Frederick National Laboratory for Cancer (see http://webdefence.global.blackspider.com/urlwrap/?q=AXicY2Rn8FrCwHB9AQNDUU6liXmKXnFRmV5uYmZOcn5eSVF-jl5yfi5DiaGJuaeHSY6Bgam5mRFDUlJiSmJRYqlDcQpEPqOkpMBKXz8osdg5FagrMUcvvyidAQIA65QdsA&Z), whose goal is to fill critical knowledge gaps that are essential to target Ras cancers effectively and to engage the research community toward solving the Ras problem. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 25, 2016 (l / launch-01 :ARG0 (r / research-institute :name (n / name :op1 "National" :op2 "Cancer" :op3 "Institute")) :ARG1 (p / program :mod (n2 / nation) :topic (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :purpose (a / and :op1 (f2 / fill-01 :ARG1 (g / gap :topic (k / know-03 :mod (e3 / essential) :purpose (t2 / target-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer") :ARG1-of (c4 / cause-01 :ARG0 e2)) :ARG1-of (e4 / effective-04))) :ARG1-of (c2 / critical-02))) :op2 (e5 / engage-01 :ARG1 (c5 / community :ARG0-of (r4 / research-01)) :ARG2 (s / solve-01 :ARG0 c5 :ARG1 (p2 / problem :topic e2))))) :time (r2 / recent) :purpose (c / catalyze-01 :ARG0 r :ARG1 (e / effort-01 :ARG1-of (r3 / renew-01) :mod (t / this))) :location (f / facility :name (n4 / name :op1 "Frederick" :op2 "National" :op3 "Laboratory" :op4 "for" :op5 "Cancer")) :ARG1-of (s2 / see-01 :ARG0 (y / you) :medium (u / url-entity :value "http://webdefence.global.blackspider.com/urlwrap/?q=AXicY2Rn8FrCwHB9AQNDUU6liXmKXnFRmV5uYmZOcn5eSVF-jl5yfi5DiaGJuaeHSY6Bgam5mRFDUlJiSmJRYqlDcQpEPqOkpMBKXz8osdg5FagrMUcvvyidAQIA65QdsA&Z"))) # ::id pmid_2465_1010.24 # ::date 2015-02-11T13:53:05 # ::file pmid_2465_1010_24.txt # ::snt Here, we will discuss some of these knowledge gaps, as well as recent advances and the challenges that lie ahead. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 31, 2015 (d / discuss-01 :ARG0 (w / we) :ARG1 (a / and :op1 (g / gap :ARG1-of (i / include-91 :ARG2 (g2 / gap :topic (k / know-03) :mod (t / this))) :mod (s / some)) :op2 (a2 / advance-01 :time (r / recent)) :op3 (c / challenge-01 :ARG1-of (l / lie-07 :ARG2 (a3 / ahead)))) :medium (h / here)) # ::id pmid_2465_1010.25 # ::date 2015-02-11T13:57:41 # ::file pmid_2465_1010_25.txt # ::snt Ras Mutations in Cancer # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m / mutate-01 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :location (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) # ::id pmid_2465_1010.26 # ::date 2015-02-11T14:03:22 # ::file pmid_2465_1010_26.txt # ::snt Ras genes were the first oncogenes identified in human cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (o / oncogene :ARG1-of (i / identify-01 :location (c / cell :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :mod (h / human)))) :ord (o2 / ordinal-entity :value "1") :domain (g / gene :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) # ::id pmid_2465_1010.27 # ::date 2015-02-11T14:10:56 # ::file pmid_2465_1010_27.txt # ::snt In a series of classic experiments, the groups of Weinberg, Cooper, Barbacid, and Wigler independently identified the transforming genes from T24/EJ bladder carcinoma cells as H-Ras (Der et al., 1982; Parada et al., 1982; Santos et al., 1982; Taparowsky et al., 1982). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 13, 2015 (i / identify-01 :ARG0 (a / and :op1 (g / group :ARG1-of (l / lead-02 :ARG0 (p / person :name (n / name :op1 "Weinberg")))) :op2 (g2 / group :ARG1-of (l2 / lead-02 :ARG0 (p2 / person :name (n2 / name :op1 "Cooper")))) :op3 (g3 / group :ARG1-of (l3 / lead-02 :ARG0 (p3 / person :name (n3 / name :op1 "Barbacid")))) :op4 (g4 / group :ARG1-of (l4 / lead-02 :ARG0 (p4 / person :name (n4 / name :op1 "Wigler"))))) :ARG1 (g5 / gene :ARG0-of (t / transform-01) :part-of (c2 / cell-line :name (n5 / name :op1 "T24/EJ") :mod (c3 / carcinoma :mod (b / bladder)))) :ARG2 (e2 / enzyme :name (n6 / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :manner (s / series :consist-of (e / experiment-01 :mod (c / classic))) :ARG0-of (d3 / depend-01 :polarity "-") :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p5 / publication-91 :ARG0 (a3 / and :op1 (p9 / person :name (n7 / name :op1 "Der")) :op2 (p10 / person :mod (o / other))) :time (d2 / date-entity :year "1982")) :op2 (p6 / publication-91 :ARG0 (a4 / and :op1 (p11 / person :name (n8 / name :op1 "Parada")) :op2 p10) :time d2) :op3 (p7 / publication-91 :ARG0 (a5 / and :op1 (p12 / person :name (n9 / name :op1 "Santos")) :op2 p10) :time d2) :op4 (p8 / publication-91 :ARG0 (a6 / and :op1 (p13 / person :name (n10 / name :op1 "Taparowsky")) :op2 p10) :time d2)))) # ::id pmid_2465_1010.28 # ::date 2015-02-11T14:34:09 # ::file pmid_2465_1010_28.txt # ::snt More than 30 years later, Ras genes are well established as the most frequently mutated oncogenes in human cancer (Table 1), though H-Ras itself is rarely one of them. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e3 / establish-01 :ARG1 (g / gene :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (o / oncogene :ARG1-of (m2 / mutate-01 :ARG1-of (f / frequent-02 :degree (m3 / most))) :location (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :mod (h / human))) :mod (w / well) :time (l / late :op1 (m / more-than :op1 (t / temporal-quantity :quant "30" :unit (y / year)))) :concession (i / include-91 :ARG1 (g2 / gene :name (n2 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG2 g :ARG1-of (r / rare-02)) :ARG1-of (d / describe-01 :ARG0 (t2 / table :mod "1"))) # ::id pmid_2465_1010.29 # ::date 2015-02-10T00:38:54 # ::file pmid_2465_1010_29.txt # ::snt Although these numbers are, by now, painfully familiar, they underscore major gaps in our knowledge of Ras biology. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (u / underscore-01 :ARG0 (n2 / number :mod (t / this)) :ARG1 (g / gap :ARG1-of (m / major-02) :topic (k / know-03 :ARG0 (w / we) :ARG1 (b / biology :mod (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :concession (f / familiarize-01 :ARG1 n2 :degree (p / pain-01) :time (b2 / by :op1 (n / now)))) # ::id pmid_2465_1010.30 # ::date 2015-02-10T00:40:36 # ::file pmid_2465_1010_30.txt # ::snt Most obviously, we do not understand why K-Ras mutation is much more frequent in human cancer than N-Ras or H-Ras, even though each of these is a powerful transforming gene in model systems, and all forms are expressed widely in adult tissues and in tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (u2 / understand-01 :polarity "-" :ARG0 (w / we) :ARG1 (t / thing :ARG0-of (c / cause-01 :ARG1 (f / frequent-02 :ARG1 (m3 / mutate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :degree (m / more :quant (m2 / much)) :location (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :mod (h / human)) :compared-to (o3 / or :op1 (m5 / mutate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))) :op2 (m7 / mutate-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))))))) :ARG1-of (o / obvious-01 :degree (m4 / most)) :concession (a2 / and :op1 (g / gene :domain (a / and :op1 e3 :op2 e4 :op3 e5) :ARG0-of (t2 / transform-01) :location (s / system :mod (m6 / model)) :ARG1-of (p / powerful-02)) :op2 (e / express-03 :ARG1 (f2 / form :mod (a3 / all)) :ARG3 (a4 / and :op1 (t3 / tissue :mod (a5 / adult)) :op2 (t4 / tumor)) :ARG1-of (w2 / wide-02)))) # ::id pmid_2465_1010.31 # ::date 2015-02-10T00:43:28 # ::file pmid_2465_1010_31.txt # ::snt A simple explanation for the high frequency of K-Ras mutations, relative to H-Ras and N-Ras, is that the K-Ras protein has unique properties that favor oncogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (e3 / explain-01 :ARG0 (p / property :mod (u / unique) :poss (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG0-of (f / favor-01 :ARG1 (c / create-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))) :ARG1 (f2 / frequent-02 :ARG1 (m / mutate-01 :ARG1 e) :ARG1-of (h / high-02) :compared-to (a2 / and :op1 (m2 / mutate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :op2 (m3 / mutate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))))) :ARG1-of (s / simple-02)) # ::id pmid_2465_1010.32 # ::date 2015-02-10T00:44:03 # ::file pmid_2465_1010_32.txt # ::snt At first sight, this seems unlikely because the Ras proteins are highly conserved, especially in their effector-binding regions where they are actually identical. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (s / seem-01 :ARG1 (l / likely-01 :polarity "-" :ARG1 (t / thing :mod (t2 / this))) :ARG1-of (c / cause-01 :ARG0 (c2 / conserve-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "Ras")) :ARG1-of (h / high-02) :location (p / protein-segment :ARG1-of (b / bind-01 :ARG2 (e / effector)) :part-of p2 :ARG1-of (i / identical-01 :ARG1-of (a / actual-02)) :degree (e4 / especially)))) :time (s2 / see-01 :ord (o / ordinal-entity :value "1"))) # ::id pmid_2465_1010.33 # ::date 2015-02-10T00:46:36 # ::file pmid_2465_1010_33.txt # ::snt However, K-Ras, but not N-Ras or H-Ras, confers stem-like properties on certain cell types (Quinlan and Settleman, 2009). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c4 / contrast-01 :ARG2 (c / confer-02 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1 (p / property :ARG1-of (r / resemble-01 :ARG2 (p5 / property :poss (c5 / cell :mod (s / stem))))) :ARG2 (t / type-03 :ARG1 (c2 / cell) :mod (c3 / certain)) :ARG1-of (c6 / contrast-01 :ARG0 (c7 / confer-02 :polarity "-" :ARG0 (o / or :op1 (e3 / enzyme :name (n3 / name :op1 "N-Ras") :xref (x / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :ARG1 p :ARG2 t)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n4 / name :op1 "Quinlan")) :op2 (p4 / person :name (n5 / name :op1 "Settleman"))) :time (d / date-entity :year "2009"))))) # ::id pmid_2465_1010.34 # ::date 2015-02-10T00:47:09 # ::file pmid_2465_1010_34.txt # ::snt K-Ras-4B, the most highly expressed splice variant of K-Ras, binds calmodulin; H-Ras and N- Ras do not (Villalonga et al., 2001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras-4B") :mod (v2 / variant :ARG1-of (e5 / express-03 :ARG1-of (h / high-02 :degree (m2 / most)) :compared-to "r") :ARG2-of (r / result-01 :ARG1 (s / splice-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) :xref (x3 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :ARG2 (p / protein :name (n5 / name :op1 "calmodulin") :xref (x5 / xref :value "UNIPROT:CALM_HUMAN" :prob "0.703"))) :snt2 (b2 / bind-01 :polarity "-" :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e3 / enzyme :name (n3 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))) :ARG2 (p5 / protein :name (n7 / name :op1 "calmodulin") :xref (x4 / xref :value "UNIPROT:CALM_HUMAN" :prob "0.703"))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n6 / name :op1 "Villalonga")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2001")))) # ::id pmid_2465_1010.35 # ::date 2015-02-10T00:47:51 # ::file pmid_2465_1010_35.txt # ::snt We believe that this unique property of K-Ras-4B confers stem-like properties to cells expressing oncogenic K-Ras-4B proteins (M. Wang and F.M., unpublished data). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (b / believe-01 :ARG0 (w / we) :ARG1 (c / confer-02 :ARG0 (p / property :mod (t / this) :mod (u / unique) :poss (e / enzyme :name (n / name :op1 "K-Ras-4B") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263"))) :ARG1 (p2 / property :ARG1-of (r / resemble-01 :ARG2 (p6 / property :poss (c5 / cell :mod (s / stem))))) :ARG2 (c2 / cell :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "K-Ras-4B") :ARG0-of (c3 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263"))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (p3 / publish-01 :polarity "-" :ARG0 (a / and :op1 (p4 / person :name (n3 / name :op1 "M." :op2 "Wang")) :op2 (p5 / person :name (n4 / name :op1 "F.M."))))))) # ::id pmid_2465_1010.36 # ::date 2015-02-10T00:48:23 # ::file pmid_2465_1010_36.txt # ::snt Analysis of human syndromes caused by germline mutations in H-Ras or K-Ras supports the idea that K-Ras is a stronger oncogene. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 13, 2015 (s / support-01 :ARG0 (a / analyze-01 :ARG1 (s2 / syndrome :mod (h / human) :ARG1-of (c / cause-01 :ARG0 (m / mutate-01 :ARG1 (g / germline) :location (o / or :op1 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))))) :ARG1 (i / idea :mod (o2 / oncogene :domain e2 :compared-to e :ARG1-of (s3 / strong-02 :degree (m2 / more))))) # ::id pmid_2465_1010.37 # ::date 2015-02-10T00:48:49 # ::file pmid_2465_1010_37.txt # ::snt Unexpectedly, humans can tolerate germline-activating mutations in H-Ras—the same activating mutations that drive somatic mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (p / possible-01 :ARG1 (t / tolerate-01 :ARG0 (h / human) :ARG1 (m / mutate-01 :ARG0-of (a / activate-01 :ARG1 (g / germline)) :location (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG1-of (s2 / same-01 :ARG2 (m2 / mutate-01 :ARG0 (d / drive-02 :ARG1 (m3 / mutate-01 :mod (s / somatic))) :ARG0-of (a2 / activate-01))))) :ARG1-of (e2 / expect-01 :polarity "-")) # ::id pmid_2465_1010.38 # ::date 2015-02-10T00:49:16 # ::file pmid_2465_1010_38.txt # ::snt Costello syndrome, which is characterized by germline H-Ras mutations, is associated with a broad spectrum of developmental abnormalities and a high risk for rhabdomyosarcomas and neuroblastomas (reviewed in Rauen, 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / associate-01 :ARG1 (d2 / disease :name (n2 / name :op1 "Costello" :op2 "syndrome") :ARG1-of (c / characterize-01 :ARG2 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :location (g2 / germline)))) :ARG2 (a3 / and :op1 (a2 / abnormality :quant (s / spectrum :ARG1-of (b / broad-02)) :mod (g / growth)) :op2 (r / risk-01 :ARG2 (a4 / and :op1 (m2 / medical-condition :name (n3 / name :op1 "rhabdomyosarcoma")) :op2 (m3 / medical-condition :name (n4 / name :op1 "neuroblastoma"))) :ARG1-of (h / high-02))) :ARG1-of (r2 / review-02 :ARG2 (p2 / publication-91 :ARG0 (p3 / person :name (n5 / name :op1 "Rauen")) :time (d / date-entity :year "2013")))) # ::id pmid_2465_1010.39 # ::date 2015-02-10T00:52:57 # ::file pmid_2465_1010_39.txt # ::snt It is puzzling that these individuals do not succumb to malignancies associated with sporadic H-Ras mutations (Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 18, 2015 (p / puzzle-01 :ARG0 (s / succumb-01 :polarity "-" :ARG0 (i / individual :mod (t / this)) :ARG1 (m / malignancy :ARG1-of (a / associate-01 :ARG2 (m2 / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :time (s2 / sporadic))))) :ARG1-of (d / describe-01 :ARG0 (t2 / table :mod "1"))) # ::id pmid_2465_1010.40 # ::date 2015-02-10T00:53:50 # ::file pmid_2465_1010_40.txt # ::snt Although fully activating alleles of H-Ras can be tolerated, fully activated alleles of K-Ras may not. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :polarity "-" :ARG1 (t / tolerate-01 :ARG1 (a / allele :ARG1-of (a2 / activate-01 :degree (f / full)) :mod (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :concession (p2 / possible-01 :ARG1 (t2 / tolerate-01 :ARG1 (a3 / allele :ARG0-of (a4 / activate-01 :manner f) :mod (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))))) # ::id pmid_2465_1010.41 # ::date 2015-02-10T00:54:21 # ::file pmid_2465_1010_41.txt # ::snt Variant alleles of K-Ras that account for a small fraction of Noonan’s syndrome and cardiofaciocutaneous syndrome are weakly activated relative to their sporadic oncogenic counterparts (Schubbert et al., 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / activate-01 :ARG1 (a2 / allele :mod (v2 / variant) :mod (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG0-of (a3 / account-01 :ARG1 (a4 / and :op1 (d2 / disease :name (n2 / name :op1 "Noonan’s" :op2 "syndrome")) :op2 (d3 / disease :name (n3 / name :op1 "cardiofaciocutaneous" :op2 "syndrome")) :quant (f / fraction :mod (s / small))))) :ARG1-of (w / weak-02) :compared-to (c / counterpart :mod (s2 / sporadic) :poss v2 :ARG0-of (c2 / cause-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG0 (a5 / and :op1 (p2 / person :name (n4 / name :op1 "Schubbert")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2007")))) # ::id pmid_2465_1010.42 # ::date 2015-02-10T00:54:57 # ::file pmid_2465_1010_42.txt # ::snt Further support for the idea that K-Ras has functions distinct from H-Ras and N-Ras comes from analyses of the roles of Ras genes in development. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 17, 2015 (s / support-01 :ARG0 (a / analyze-01 :ARG1 (r / role :mod (g / gene :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (d / develop-02)) :ARG1 (i / idea :mod (f2 / function-01 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :mod (d2 / distinct :compared-to (a2 / and :op1 (f3 / function-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :xref (x3 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :op2 (f4 / function-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "N-Ras") :xref (x2 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))))))) :degree (f / further)) # ::id pmid_2465_1010.43 # ::date 2015-02-10T00:55:23 # ::file pmid_2465_1010_43.txt # ::snt Mice that lack K-Ras die during embryogenesis, whereas mice lacking H-Ras and/or N-Ras are viable (Johnson et al., 1997). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c2 / contrast-01 :ARG1 (d2 / die-01 :ARG1 (m / mouse :ARG0-of (l / lack-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :time (c / create-01 :ARG1 (e3 / embryo))) :ARG2 (v / viable :domain (m2 / mouse :ARG0-of (l2 / lack-01 :ARG1 (a / and-or :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e4 / enzyme :name (n3 / name :op1 "N-Ras") :xref (x / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n4 / name :op1 "Johnson")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "1997")))) # ::id pmid_2465_1010.44 # ::date 2015-02-10T00:55:46 # ::file pmid_2465_1010_44.txt # ::snt However, replacing K-Ras with H-Ras at the K-Ras genomic locus allows mice to develop, suggesting that differential regulation of K-Ras and H-Ras gene expression determines their relative importance in development rather than the properties of the proteins themselves (Potenza et al., 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (h / have-concession-91 :ARG1 (a / allow-01 :ARG0 (r / replace-01 :ARG1 (g2 / gene :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2 (g3 / gene :name (n2 / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :location (l / locus :mod (g / genomic) :ARG0-of (c2 / contain-01 :ARG1 g2))) :ARG1 (d2 / develop-01 :ARG1 (m / mouse)) :ARG0-of (s / suggest-01 :ARG1 (d3 / determine-01 :ARG0 (r2 / regulate-01 :ARG1 (e3 / express-03 :ARG1 (a2 / and :op1 g2 :op2 g3)) :mod (d4 / differential)) :ARG1 (i / important :ARG1-of (r3 / relative-05) :poss a2 :purpose (d5 / develop-01)) :ARG1-of (i2 / instead-of-91 :ARG2 (p2 / property :poss a2))))) :ARG1-of (d6 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n3 / name :op1 "Potenza")) :op2 (p / person :mod (o / other))) :time (d / date-entity :year "2005")))) # ::id pmid_2465_1010.45 # ::date 2015-02-10T00:56:22 # ::file pmid_2465_1010_45.txt # ::snt Furthermore, Balmain and colleagues discovered that these H-Ras knock-in mice develop tumors in response to carcinogens at normal frequencies, except that they are now driven by H-Ras instead of K-Ras (To et al., 2008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / and :op2 (d2 / discover-01 :ARG0 (a2 / and :op1 (p / person :name (n3 / name :op1 "Balmain")) :op2 (c / colleague :poss p)) :ARG1 (d3 / develop-01 :ARG1 (m / mouse :ARG3-of (e4 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :mod (t2 / this)) :ARG2 (t / tumor) :ARG2-of (r / respond-01 :ARG1 (c3 / carcinogen)) :frequency (n4 / normal-02) :ARG1-of (e3 / except-01 :ARG2 (d4 / drive-02 :ARG0 e :ARG1 c3 :time (n5 / now) :ARG1-of (i / instead-of-91 :ARG2 (d5 / drive-02 :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1 c3)))))) :ARG1-of (d6 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n6 / name :op1 "To")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2008")))) # ::id pmid_2465_1010.46 # ::date 2015-02-10T00:57:10 # ::file pmid_2465_1010_46.txt # ::snt These data argue strongly that the locus is critical and that the specific Ras paralog encoded at that locus does not affect the frequency at which tumors arise. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / argue-01 :ARG0 (d / data :mod (t / this)) :ARG1 (a2 / and :op1 (c / critical-02 :ARG1 (l / locus)) :op2 (a3 / affect-01 :polarity "-" :ARG0 (p / paralog :mod (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (s2 / specific-02) :ARG1-of (e2 / encode-01 :location l)) :ARG1 (h / have-frequency-91 :ARG1 (a4 / arise-02 :ARG1 (t3 / tumor))))) :ARG1-of (s / strong-02)) # ::id pmid_2465_1010.47 # ::date 2015-02-10T00:57:37 # ::file pmid_2465_1010_47.txt # ::snt Equally important, they find that K-Ras-4A, not K-Ras-4B, is necessary for lung tumor initiation, although K-Ras-4B is much more highly expressed during progression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (f / find-01 :ARG0 (t / they) :ARG1 (n2 / need-01 :ARG1 (e / enzyme :name (n3 / name :op1 "K-Ras-4A") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :purpose (i2 / initiate-01 :ARG1 (t2 / tumor :mod (l / lung))) :concession (e4 / express-03 :ARG2 "e2" :ARG1-of (h / high-02 :degree (m / more :quant (m2 / much))) :time (p / progress-01 :ARG1 t2)) :ARG1-of (c / contrast-01 :ARG2 (n / need-01 :polarity "-" :ARG1 (e2 / enzyme :name (n4 / name :op1 "K-Ras-4B") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :purpose i2))) :mod (i3 / important :degree (e3 / equal))) # ::id pmid_2465_1010.48 # ::date 2015-02-10T00:58:05 # ::file pmid_2465_1010_48.txt # ::snt This supports the idea that K-Ras-4B is the more important target in established tumors but raises the concern that K-Ras-4A may have an important role in minor stem-like populations of established tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 20, 2016 (c / contrast-01 :ARG1 (s / support-01 :ARG0 (t / thing :mod (t2 / this)) :ARG1 (i / idea :mod (t3 / target-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras-4B") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :mod (i2 / important :degree (m / more) :location (t4 / tumor :ARG1-of (e2 / establish-01)))))) :ARG2 (r3 / raise-01 :ARG0 t :ARG1 (c2 / concern-01 :ARG0 (p / possible-01 :ARG1 (r2 / role :poss (e3 / enzyme :name (n2 / name :op1 "K-Ras-4A") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :mod (i3 / important) :topic (p2 / population :ARG1-of (m2 / minor-01) :ARG1-of (c3 / consist-01 :ARG2 (c4 / cell :ARG1-of (r / resemble-01 :ARG2 (c5 / cell :mod (s2 / stem))))) :part-of t4)))))) # ::id pmid_2465_1010.49 # ::date 2015-02-10T00:59:25 # ::file pmid_2465_1010_49.txt # ::snt These findings point toward an urgent need to validate K-Ras-4A and K-Ras-4B as drug targets, a major issue that has not yet been addressed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 31, 2015 (p / point-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG2 (n / need-01 :ARG1 (v / validate-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "K-Ras-4A") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :op2 (e2 / enzyme :name (n3 / name :op1 "K-Ras-4B") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :ARG1-of (t3 / target-01 :ARG0 (d / drug)))) :mod (u / urgent) :ARG0-of (i / issue-02 :ARG1-of (m / major-02) :ARG1-of (a2 / address-02 :polarity "-" :time (y / yet))))) # ::id pmid_2465_1010.50 # ::date 2015-02-10T00:59:44 # ::file pmid_2465_1010_50.txt # ::snt Different frequencies of K-Ras, N-Ras, and H-Ras mutations in human tumors may also reflect differences in gene expression resulting from differential codon usage; rare codons limit K-Ras expression and thus allow more efficient oncogenesis by preventing oncogene-induced senescence (Lampson et al., 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m / multi-sentence :snt1 (p / possible-01 :ARG1 (r / reflect-01 :ARG1 (h / have-frequency-91 :ARG1 (m2 / mutate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x3 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras") :xref (x2 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")) :op3 (e3 / enzyme :name (n3 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))) :ARG1-of (d3 / differ-02) :location (t / tumor :mod (h2 / human))) :ARG2 (d4 / differ-02 :ARG1 (e4 / express-03 :ARG1 (g / gene)) :ARG2-of (r3 / result-01 :ARG1 (u / use-01 :ARG1 (c / codon) :mod (d5 / differential))))) :mod (a3 / also)) :snt2 (a2 / and :op1 (l / limit-01 :ARG0 (d7 / dna-sequence :name (n7 / name :op1 "codon") :ARG1-of (r2 / rare-02)) :ARG1 (e5 / express-03 :ARG1 (e7 / enzyme :name (n8 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :op2 (a4 / allow-01 :ARG0 d7 :ARG1 (e6 / efficient-01 :ARG2 (o / originate-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :degree (m3 / more)) :mod (t2 / thus) :manner (p2 / prevent-01 :ARG0 d7 :ARG1 (s / senescence :ARG2-of (i / induce-01 :ARG0 (o2 / oncogene)))))) :ARG1-of (d6 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a5 / and :op1 (p4 / person :name (n4 / name :op1 "Lampson")) :op2 (p5 / person :mod (o3 / other))) :time (d2 / date-entity :year "2013")))) # ::id pmid_2465_1010.51 # ::date 2015-02-10T01:01:43 # ::file pmid_2465_1010_51.txt # ::snt In addition, different rates of DNA repair have been reported for the K-Ras gene relative to N-Ras and H-Ras (Feng et al., 2002). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op2 (r / report-01 :ARG1 (d2 / differ-02 :ARG1 (g / gene :name (n / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2 (a2 / and :op1 (g2 / gene :name (n2 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (g3 / gene :name (n3 / name :op1 "N-Ras") :xref (x / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))) :ARG3 (r2 / rate :mod (r3 / repair-01 :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n4 / name :op1 "Feng")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2002")))) # ::id pmid_2465_1010.52 # ::date 2015-02-09T08:42:31 # ::file pmid_2465_1010_52.txt # ::snt The underlying reasons for different frequencies of specific activating mutations are not well understood either. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (u / understand-01 :polarity "-" :ARG1 (r / reason :ARG0-of (u2 / underlie-01 :ARG1 (h2 / have-frequency-91 :ARG1 (m2 / mutate-01 :ARG1-of (s / specific-02) :ARG0-of (a2 / activate-01)) :ARG1-of (d2 / differ-02)))) :mod (e / either) :ARG1-of (w / well-09)) # ::id pmid_2465_1010.53 # ::date 2015-02-11T22:40:35 # ::file pmid_2465_1010_53.txt # ::snt Some of these differences reflect different mutagenic insults to the genome; the G12C mutation, for example, is a hallmark of exposure to tobacco smoke and, accordingly, is the most common mutation in K-Ras in lung cancer (reviewed in Prior et al., 2012; Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (e / exemplify-01 :ARG0 (a / and :op1 (c / characteristic-02 :ARG1 (e2 / expose-01 :ARG2 (s2 / smoke-02 :ARG1 (t4 / tobacco))) :ARG2 (m4 / mutate-01 :value "G12C" :ARG2 (e3 / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :op2 (m3 / mutate-01 :ARG2 e3 :mod (c2 / common :degree (m5 / most)) :manner (a2 / accordingly) :location (d3 / disease :wiki "Lung_cancer" :name (n5 / name :op1 "lung" :op2 "cancer")))) :ARG1 (r / reflect-01 :ARG1 (t / thing :quant (s / some) :ARG1-of (i / include-91 :ARG2 (t2 / thing :ARG1-of (d / differ-02 :mod (t3 / this))))) :ARG2 (i2 / insult-01 :ARG1 (g / genome) :ARG1-of (d2 / differ-02) :ARG0-of (g2 / generate-01 :ARG1 (m2 / mutate-01 :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))))) :ARG1-of (r2 / review-02 :ARG2 (p / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n2 / name :op1 "Prior")) :op2 (p3 / person :mod (o / other))) :time (d5 / date-entity :year "2012") :part (t5 / table :mod "2")))) # ::id pmid_2465_1010.54 # ::date 2015-02-09T12:26:15 # ::file pmid_2465_1010_54.txt # ::snt Other differences in frequency may reflect different biological properties of mutant proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (p / possible-01 :ARG1 (r / reflect-01 :ARG1 (d2 / differ-02 :ARG3 (f / frequency) :mod (o / other)) :ARG2 (p2 / property :ARG1-of (h / have-03 :ARG0 (p3 / protein :ARG2-of (m / mutate-01))) :ARG1-of (d / differ-02) :mod (b / biology)))) # ::id pmid_2465_1010.55 # ::date 2015-02-12T08:34:10 # ::file pmid_2465_1010_55.txt # ::snt For example, G12C and G12V K-Ras mutations in lung adenocarcinoma preferentially activate the RalGDS pathway, whereas G12D prefers the Raf/mitogen-activated protein kinase (MAPK) and PI3K pathways (Ihle et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (a / activate-01 :ARG0 (a2 / and :op1 (m / mutate-01 :value "G12C" :ARG2 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m2 / mutate-01 :value "G12V" :ARG2 e2) :location (a4 / adenocarcinoma :mod (l2 / lung))) :ARG1 (p3 / pathway :name (n / name :op1 "RalGDS")) :ARG1-of (p2 / prefer-01) :ARG1-of (c / contrast-01 :ARG2 (p / prefer-01 :ARG0 (m3 / mutate-01 :value "G12D" :ARG2 e2) :ARG1 (a3 / and :op1 (p4 / pathway :name (n3 / name :op1 "Raf/MAPK")) :op2 (p7 / pathway :name (n6 / name :op1 "PI3K")))) :ARG0-of (e3 / exemplify-01)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a7 / and :op1 (p8 / person :name (n7 / name :op1 "Ihle")) :op2 (p9 / person :mod (o / other))) :time (d2 / date-entity :year "2012")))) # ::id pmid_2465_1010.56 # ::date 2015-02-10T00:12:53 # ::file pmid_2465_1010_56.txt # ::snt In addition, mutations at codon 61 have a more profound effect on intrinsic GTPase when these Ras proteins are bound to Raf kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (a / and :op2 (a2 / affect-01 :ARG0 (m / mutate-01 :ARG1 (c2 / codon :mod "61" :part-of (e3 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1 (e2 / enzyme :name (n2 / name :op1 "GTPase") :mod (i / intrinsic) :xref (x2 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :mod (p / profound :degree (m2 / more)) :condition (b / bind-01 :ARG1 e3 :ARG2 (k / kinase :name (n6 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))))) # ::id pmid_2465_1010.57 # ::date 2015-02-10T00:34:41 # ::file pmid_2465_1010_57.txt # ::snt This may drive a stronger signal through this effector pathway and account for higher frequency of N-Ras position 61 mutations in melanoma, a disease frequently driven by hyperactivation of Raf kinase through B-Raf mutations (Buhrman et al., 2010). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (p / possible-01 :ARG1 (a / and :op1 (d3 / drive-02 :ARG0 (t / this) :ARG1 (s / signal-07 :ARG0 (p4 / pathway :mod (e / effector)) :ARG1-of (s2 / strong-02 :degree (m / more)))) :op2 (a3 / account-01 :ARG0 t :ARG1 (h / have-frequency-91 :ARG1 (m2 / mutate-01 :value "61" :ARG2 (e2 / enzyme :name (n / name :op1 "N-Ras") :xref (x2 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")) :location (m3 / medical-condition :name (n5 / name :op1 "melanoma") :ARG1-of (d5 / drive-02 :ARG0 (h4 / hyperactivate-00 :ARG0 (m6 / mutate-01 :ARG2 (e3 / enzyme :name (n6 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :ARG1 (k4 / kinase :name (n7 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG1-of (f / frequent-02)))) :ARG1-of (h2 / high-02 :degree (m5 / more))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n2 / name :op1 "Buhrman")) :op2 (p5 / person :mod (o / other))) :time (d2 / date-entity :year "2010")))) # ::id pmid_2465_1010.58 # ::date 2015-02-13T14:33:15 # ::file pmid_2465_1010_58.txt # ::snt From a clinical viewpoint, lung adenocarcinomas driven by K-Ras mutations at G12C and G12V have a worse outcome than G12D, possibly because these mutations engage different downstream effectors as described above (Figure 1; Ihle et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Apr 29, 2015 (h / have-03 :ARG0 (a / adenocarcinoma :mod (l / lung) :ARG1-of (d4 / drive-02 :ARG0 (a2 / and :op1 (m2 / mutate-01 :value "G12C" :ARG2 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :op2 (m3 / mutate-01 :value "G12V" :ARG2 e)))) :ARG1 (o / outcome :ARG1-of (b / bad-07 :degree (m / more) :compared-to (m4 / mutate-01 :value "G12D" :ARG2 e))) :ARG1-of (c3 / cause-01 :ARG0 (e2 / engage-01 :ARG0 a2 :ARG1 (e3 / effector :location (d / downstream) :ARG1-of (d2 / differ-02))) :ARG1-of (p / possible-01)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a4 / and :op1 (p3 / person :name (n2 / name :op1 "Ihle")) :op2 (p4 / person :mod (o2 / other))) :time (d5 / date-entity :year "2012") :part (f / figure :mod "1")) :medium (a3 / above)) :ARG1-of (v2 / view-02 :mod (c2 / clinic))) # ::id pmid_2465_1010.59 # ::date 2015-02-10T11:18:06 # ::file pmid_2465_1010_59.txt # ::snt As MEK and PI3K inhibitors are tested in the clinic, it will be important to ask whether Ras alleles respond differently to these treatments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / important :domain (a / ask-01 :ARG1 (r / respond-01 :mode "interrogative" :ARG0 (e3 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (t / treat-03 :ARG1 e3 :mod (t2 / this)) :ARG1-of (d / differ-02))) :ARG1-of (c / cause-01 :ARG0 (t3 / test-01 :ARG1 (a3 / and :op1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "PI3K"))))) :location (c2 / clinic)))) # ::id pmid_2465_1010.60 # ::date 2015-02-10T22:37:25 # ::file pmid_2465_1010_60.txt # ::snt Patients suffering from cancers driven by any of these Ras mutations are excluded from treatment with cetuximab (colorectal cancer) or erlotinib (lung adenocarcinoma) because these treatments are ineffective for cancers with these Ras mutations and may even increase rates of progression. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (e / exclude-01 :ARG1 (p / patient :ARG0-of (s / suffer-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer") :ARG1-of (d / drive-02 :ARG0 (m / mutate-01 :ARG1 (e5 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :mod (a6 / any :ARG1-of (i3 / include-91)) :mod (t2 / this)))))) :ARG2 (o / or :op1 (t / treat-03 :ARG1 p :ARG3 (s2 / small-molecule :name (n / name :op1 "cetuximab") :condition (d2 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colorectal" :op2 "cancer")) :xref (x2 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :op2 (t5 / treat-03 :ARG1 p :ARG3 (s3 / small-molecule :name (n2 / name :op1 "erlotinib") :condition (m2 / medical-condition :name (n7 / name :op1 "adenocarcinoma") :mod (l / lung)) :xref (x1 / xref :value "PUBCHEM:176870" :prob "16.13064")))) :ARG1-of (c5 / cause-01 :ARG0 (a3 / and :op1 (e2 / effective-04 :polarity "-" :ARG0 o :condition (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer") :ARG1-of (c6 / cause-01 :ARG0 (m3 / mutate-01)))) :op2 (p2 / possible-01 :ARG1 (i2 / increase-01 :ARG0 o :ARG1 (r2 / rate :degree-of (p4 / progress-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))) :mod (e4 / even)))))) # ::id pmid_2465_1010.61 # ::date 2015-02-10T22:46:40 # ::file pmid_2465_1010_61.txt # ::snt Likewise, malignant melanomas with mutant N-Ras are excluded from treatment with vemurafenib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (e / exclude-01 :ARG1 (m4 / medical-condition :name (n3 / name :op1 "melanoma") :ARG2-of (m2 / malignant-02) :ARG0-of (h / have-03 :ARG1 (e2 / enzyme :name (n2 / name :op1 "N-Ras") :ARG2-of (m3 / mutate-01) :xref (x / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")))) :ARG2 (t / treat-03 :ARG1 m4 :ARG3 (s / small-molecule :name (n / name :op1 "vemurafenib") :xref (x1 / xref :value "PUBCHEM:42611257" :prob "17.762056"))) :manner (l / likewise)) # ::id pmid_2465_1010.62 # ::date 2015-02-10T23:30:04 # ::file pmid_2465_1010_62.txt # ::snt However, surprisingly, K-Ras-G13D-bearing colorectal cancers may show clinical benefit when treated with cetuximab. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c4 / contrast-01 :ARG2 (p / possible-01 :ARG1 (s2 / show-01 :ARG0 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal" :op2 "cancer") :ARG0-of (b2 / bear-01 :ARG1 (e / enzyme :name (n2 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2-of (m2 / mutate-01 :value "G13D"))) :ARG1 (b / benefit-01 :ARG0 (t / treat-03 :ARG1 d :ARG3 (s / small-molecule :name (n / name :op1 "cetuximab") :xref (x1 / xref :value "PUBCHEM:56842117" :prob "9.083761"))) :mod (c2 / clinic))) :ARG0-of (s3 / surprise-01))) # ::id pmid_2465_1010.63 # ::date 2015-02-11T02:01:28 # ::file pmid_2465_1010_63.txt # ::snt This result challenges our understanding of how these Ras mutations actually function in clinical situations (De Roock et al., 2010). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / challenge-01 :ARG0 (t4 / thing :ARG2-of (r2 / result-01) :mod (t6 / this)) :ARG1 (u / understand-01 :ARG0 (w / we) :ARG1 (t / thing :manner-of (f / function-01 :ARG0 (m2 / mutate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :mod (t3 / this)) :ARG1-of (a / actual-02) :condition (s / situation :mod (c2 / clinic))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n2 / name :op1 "De" :op2 "Roock")) :op2 (p3 / person :mod (o / other) :time (d2 / date-entity :year "2010")))))) # ::id pmid_2465_1010.64 # ::date 2015-02-11T07:43:35 # ::file pmid_2465_1010_64.txt # ::snt Even the prototypic oncogenes of Harvey and Kirsten sarcoma viruses are not fully understood; each has a codon 12 mutation, but each also carries a mutation of alanine 59 to threonine, which becomes phosphorylated by guanosine triphosphate (GTP). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (m / multi-sentence :snt1 (u / understand-01 :polarity "-" :ARG1 (a / and :op1 (g3 / gene :part-of (v / virus :name (n / name :op1 "Harvey" :op2 "Sarcoma" :op3 "Virus"))) :op2 (g4 / gene :part-of (v2 / virus :name (n2 / name :op1 "Kirsten" :op2 "Sarcoma" :op3 "Virus"))) :mod (p / prototypic) :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :mod (e / even)) :degree (f / full)) :snt2 (c3 / contrast-01 :ARG1 (m2 / mutate-01 :ARG1 (c5 / codon :mod "12" :part-of (o / oncogene :mod (e2 / each)))) :ARG2 (c4 / carry-01 :ARG0 e2 :ARG1 (m3 / mutate-01 :ARG2 (a4 / amino-acid :name (n8 / name :op1 "threonine") :ARG1-of (p2 / phosphorylate-01 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "guanosine" :op2 "triphosphate") :xref (x / xref :value "PUBCHEM:6830" :prob "10.866265"))) :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252")) :ARG3 (a3 / amino-acid :mod "59" :name (n7 / name :op1 "alanine") :xref (x2 / xref :value "PUBCHEM:602" :prob "10.089661"))) :mod (a5 / also)))) # ::id pmid_2465_1010.65 # ::date 2015-02-12T11:09:01 # ::file pmid_2465_1010_65.txt # ::snt This must have helped Scolnick and colleagues (Shih et al., 1979) identify Ras’ crucial guanosine diphosphate (GDP)/GTP properties; without covalent phosphorylation, association with these nucleotides would have been very hard to detect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a3 / and :op1 (i / infer-01 :ARG1 (h / help-01 :ARG0 (t / this) :ARG1 (i2 / identify-01 :ARG0 "a" :ARG1 (c3 / characteristic-02 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (s / slash :op1 (n5 / nucleotide :name (n3 / name :op1 "guanosine" :op2 "diphosphate")) :op2 (s2 / small-molecule :name (n4 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :mod (c4 / crucial))) :ARG2 (a / and :op1 (p2 / person :name (n / name :op1 "Scolnick")) :op2 (c / colleague))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a4 / and :op1 (p4 / person :name (n7 / name :op1 "Shih")) :op2 (p5 / person :mod (o / other))) :time (d3 / date-entity :year "1979")))) :op2 (h2 / hard-02 :ARG1 (d2 / detect-01 :ARG1 (a2 / associate-01 :ARG0 e :ARG2 s)) :degree (v / very) :condition (p3 / phosphorylate-01 :polarity "-" :ARG1 e :mod (c5 / covalent)))) # ::id pmid_2465_1010.66 # ::date 2015-02-11T07:44:04 # ::file pmid_2465_1010_66.txt # ::snt However, how phosphorylation at threonine 59 contributes to Ras’ potent oncogenicity is unclear. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-concession-91 :ARG1 (c / clear-06 :polarity "-" :ARG1 (t / thing :ARG1-of (c2 / contribute-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod "59" :name (n2 / name :op1 "threonine") :part-of "e" :xref (x1 / xref :value "PUBCHEM:205" :prob "11.848252"))) :ARG2 (c3 / cause-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")) :mod (p3 / potent)))))) # ::id pmid_2465_1010.67 # ::date 2015-02-11T09:13:24 # ::file pmid_2465_1010_67.txt # ::snt This A59T mutation inhibits Ras-Raf interaction (Shirouzu et al., 1994) and is extremely rare in human cancer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (i / inhibit-01 :ARG0 (m / mutate-01 :value "A59T" :mod (t / this)) :ARG1 (i2 / interact-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1 (e2 / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and :op1 (p2 / person :name (n3 / name :op1 "Shirouzu")) :op2 (p3 / person :mod (o / other))) :time (d2 / date-entity :year "1994")))) :op2 (r / rare-02 :ARG1 m :degree (e / extreme) :location (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (h / human)))) # ::id pmid_2465_1010.68 # ::date 2015-02-11T11:04:46 # ::file pmid_2465_1010_68.txt # ::snt These anecdotes simply remind us that after 50 years, we still have a lot to learn about the biological and biochemical functions of Ras proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (r / remind-01 :ARG0 (a / anecdote :mod (t / this)) :ARG1 (n / need-01 :ARG0 (w3 / we) :ARG1 (l / learn-01 :ARG0 w3 :ARG1 (a2 / and :op1 (f2 / function-01 :ARG0 (p / protein-family :name (n3 / name :op1 "Ras")) :mod (b / biology)) :op2 (f / function-01 :ARG0 p :mod (b2 / biochemical))) :quant (l2 / lot)) :mod (s2 / still) :time (a3 / after :op1 (t2 / temporal-quantity :quant "50" :unit (y / year)))) :ARG2 (w / we) :ARG1-of (s / simple-02)) # ::id pmid_2465_1010.69 # ::date 2015-02-13T07:47:56 # ::file pmid_2465_1010_69.txt # ::snt Although K-Ras has emerged as by far the major Ras gene mutated in human cancer, it is surprising that other activating mutations in other members of the Ras superfamily, such as R-Ras or Rap proteins, occur very rarely. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (s / surprise-01 :ARG0 (m / mutate-01 :ARG0-of (a / activate-01) :ARG1-of (r / rare-02 :degree (v / very)) :location (m2 / member :mod (o3 / other) :ARG1-of (i / include-91 :ARG2 (p / protein-family :name (n / name :op1 "Ras"))) :example (o2 / or :op1 (e3 / enzyme :name (n6 / name :op1 "R-Ras") :xref (x2 / xref :value "UNIPROT:RRAS_HUMAN" :prob "0.593")) :op2 (e4 / enzyme :name (n7 / name :op1 "Rap") :xref (x1 / xref :value "UNIPROT:AMRP_HUMAN" :prob "0.602")))) :mod (o / other)) :concession (e / emerge-02 :ARG0 (g2 / gene :name (n2 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1 (g / gene :name (n3 / name :op1 "Ras") :ARG1-of (m3 / major-02) :ARG1-of (m4 / mutate-01) :location (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (h / human)) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :degree (b / by-far))) # ::id pmid_2465_1010.70 # ::date 2015-02-09T08:46:03 # ::file pmid_2465_1010_70.txt # ::snt This is surprising because these proteins share identical or near-identical effector-binding regions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / surprise-01 :ARG0 (t / this) :ARG1-of (c / cause-01 :ARG0 (s2 / share-01 :ARG0 (p / protein :mod (t2 / this)) :ARG1 (o / or :op1 (r / region :ARG0-of (b / bind-01 :ARG1 (e / effector)) :ARG1-of (i / identical-01)) :op1 (r2 / region :ARG0-of b :ARG1-of (i2 / identical-01 :degree (n / near))))))) # ::id pmid_2465_1010.71 # ::date 2015-02-09T08:52:20 # ::file pmid_2465_1010_71.txt # ::snt However, only H-Ras, N-Ras, and K-Ras are capable of binding and activating Raf kinases, and this unique property may well account for their predominance as human oncogenes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jun 21, 2015 (a / and :op1 (h2 / have-concession-91 :ARG2 (p / possible-01 :ARG1 (c2 / capable-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")) :op3 (e3 / enzyme :name (n3 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :mod (o / only)) :ARG2 (a3 / and :op1 (b / bind-01 :ARG0 a2 :ARG1 (k / kinase :name (n4 / name :op1 "RAF") :xref (x3 / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003"))) :op2 (a4 / activate-01 :ARG0 a2 :ARG1 k))))) :op2 (p3 / possible-01 :ARG1 (a5 / account-01 :ARG0 (p5 / property :mod (u / unique) :mod (t / this)) :ARG1 (p4 / predominate-01 :ARG1 a2 :manner (o2 / oncogene :mod (h / human))) :mod (w / well)))) # ::id pmid_2465_1010.72 # ::date 2015-02-09T23:50:07 # ::file pmid_2465_1010_72.txt # ::snt In contrast, the closely related R-Ras proteins bind and activate PI3Ks but are rarely mutated in human cancer (Rodriguez-Viciana et al., 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (c3 / contrast-01 :ARG1 (a / and :op1 (b / bind-01 :ARG0 (e / enzyme :name (n2 / name :op1 "R-Ras") :ARG1-of (r / relate-01 :ARG1-of (c2 / close-10)) :xref (x / xref :value "UNIPROT:RRAS_HUMAN" :prob "0.593")) :ARG1 (p4 / protein-family :name (n4 / name :op1 "PI3K"))) :op2 (a2 / activate-01 :ARG0 e :ARG1 p4)) :ARG2 (m / mutate-01 :ARG1 e :location (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :mod (h / human)) :ARG1-of (r2 / rare-02))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n5 / name :op1 "Rodriguez-Viciana")) :op2 (p2 / person :mod (o / other))) :time (d / date-entity :year "2004")))) # ::id pmid_2465_1010.73 # ::date 2015-02-10T00:32:30 # ::file pmid_2465_1010_73.txt # ::snt Activating mutations in Ras genes, coupled with a long history of Ras biology, implicate these mutant Ras proteins as major drivers in many cancers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / implicate-01 :ARG0 (a / activate-01 :ARG0 (e3 / enzyme) :ARG1 (m2 / mutate-01 :ARG1 (g / gene :mod "p")) :ARG1-of (c / couple-01 :ARG2 (h / history :topic (b / biology :mod (p / protein-family :name (n / name :op1 "Ras"))) :ARG1-of (l / long-03)))) :ARG2 (d2 / drive-02 :ARG0 m2 :ARG1-of (m3 / major-02) :location (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :quant (m4 / many)))) # ::id pmid_2465_1010.74 # ::date 2015-02-10T00:39:05 # ::file pmid_2465_1010_74.txt # ::snt Loss of the Ras GTPase-activating protein (GAP) neurofibromin inculpates hyperactive wild-type Ras proteins as drivers in many more cancers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 5, 2015 (i / inculpate-00 :ARG0 (l / lose-02 :ARG1 (a / activate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "neurofibromin") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")) :ARG1 (p / protein :name (n / name :op1 "Ras" :op2 "GTPase") :xref (x2 / xref :value "UNIPROT:RB40L_HUMAN" :prob "0.322")))) :ARG1 (e / enzyme :name (n3 / name :op1 "Ras") :mod (w / wild-type :mod (h / hyperactive)) :ARG0-of (d3 / drive-02 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (m / more :mod (m2 / many)))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) # ::id pmid_2465_1010.75 # ::date 2015-02-10T07:24:40 # ::file pmid_2465_1010_75.txt # ::snt Somatic loss of neurofibromin expression by mutation, deletion, or by other means occurs in about 14% glioblastoma, 13%–14% melanoma, 8%–10% lung adenocarcinoma, and at single-digit frequency in most other cancers (E.A. Collisson, personal communication). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (l / lose-02 :ARG1 (e / express-03 :ARG2 (p3 / protein :name (n / name :op1 "neurofibromin") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")) :manner (o2 / or :op1 (m / mutate-01) :op2 (d / delete-01) :op3 (m2 / means :mod (o / other))) :location (a2 / and :op1 (m4 / medical-condition :name (n4 / name :op1 "glioblastoma") :mod (p2 / percentage-entity :value "14")) :op2 (m6 / medical-condition :name (n2 / name :op1 "melanoma") :mod (p5 / percentage-entity :value (b / between :op1 "13" :op2 "14"))) :op3 (m5 / medical-condition :name (n3 / name :op1 "adenocarcinoma") :mod (p6 / percentage-entity :value (b2 / between :op1 "8" :op2 "10")) :mod (l2 / lung)) :op4 (d6 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :mod (o3 / other :degree (m3 / most)) :frequency (d2 / digit :ARG1-of (s2 / single-02))))) :mod (s / somatic) :ARG1-of (d5 / describe-01 :ARG0 (c2 / communicate-01 :ARG0 (p / person :name (n5 / name :op1 "E.A." :op2 "Collisson")) :ARG1-of (p4 / personal-02)))) # ::id pmid_2465_1010.76 # ::date 2015-02-10T07:54:08 # ::file pmid_2465_1010_76.txt # ::snt Neurofibromin must now be considered as a major tumor suppressor, along with p53 and phosphatase and tensin homolog, in human cancers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (o2 / obligate-01 :ARG2 (c / consider-01 :ARG1 (a / and :op1 (p2 / protein :name (n / name :op1 "Neurofibromin") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n2 / name :op1 "p53") :xref (x2 / xref :value "UNIPROT:A0A0C4KX50_HUMAN" :prob "1.001")) :op3 (e / enzyme :name (n3 / name :op1 "phosphatase") :xref (x1 / xref :value "UNIPROT:Q59GM9_HUMAN" :prob "0.291")) :op4 (p / protein :name (n5 / name :op1 "tensin" :op2 "homolog") :xref (x3 / xref :value "UNIPROT:TENS1_HUMAN" :prob "0.232")) :ARG0-of (s / suppress-01 :ARG1 (t / tumor) :ARG1-of (m / major-02) :location (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :mod (h / human)))) :time (n4 / now))) # ::id pmid_2465_1010.77 # ::date 2015-02-10T08:01:09 # ::file pmid_2465_1010_77.txt # ::snt Loss of neurofibromin is usually mutually exclusive with Ras mutation and receptor tyrosine kinase (RTK) activation, suggesting that these genetic events represent different ways of activating similar pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (s2 / suggest-01 :ARG0 (e2 / exclusive-02 :ARG0 (l / lose-02 :ARG1 (p / protein :name (n2 / name :op1 "neurofibromin") :xref (x2 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703"))) :ARG2 (a2 / and :op1 (m2 / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (a3 / activate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase") :xref (x / xref :value "UNIPROT:MERTK_HUMAN" :prob "0.392")))) :manner (m / mutual) :mod (u / usual)) :ARG1 (r / represent-01 :ARG0 (e4 / event :mod (g / gene) :mod (t / this)) :ARG1 (w / way :manner-of (a / activate-01 :ARG0 e4 :ARG1 (p3 / pathway :ARG1-of (r2 / resemble-01))) :ARG1-of (d / differ-02)))) # ::id pmid_2465_1010.78 # ::date 2015-02-11T13:50:37 # ::file pmid_2465_1010_78.txt # ::snt However, the precise consequences of losing neurofibromin are not entirely clear. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG2 (c3 / clear-06 :polarity "-" :ARG1 (c / consequence :mod (p2 / precise) :ARG1-of (c2 / cause-01 :ARG0 (l / lose-02 :ARG1 (p / protein :name (n / name :op1 "neurofibromin") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703"))))) :degree (e / entire))) # ::id pmid_2465_1010.79 # ::date 2015-02-11T13:57:11 # ::file pmid_2465_1010_79.txt # ::snt Levels of Ras-GTP are high in cells lacking neurofibromin, but which forms of hyperactive wild-type Ras proteins are most important to the malignant phenotype is a more difficult question. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (c / contrast-01 :ARG1 (h / high-02 :ARG1 (l / level :mod (m3 / macro-molecular-complex :part (s / small-molecule :name (n4 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")) :part "e")) :location (c2 / cell :ARG0-of (l2 / lack-01 :ARG1 (p / protein :polarity "-" :name (n2 / name :op1 "neurofibromin") :xref (x1 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703"))))) :ARG2 (i2 / important :mode "interrogative" :domain (f / form :mod (e / enzyme :name (n / name :op1 "Ras") :mod (w / wild-type) :mod (h2 / hyperactive) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :beneficiary (p4 / phenotype :ARG1-of (m2 / malignant-02)) :degree (m5 / most) :ARG1-of (q / question-01 :mod (d / difficult :degree (m / more))) :degree (m4 / most))) # ::id pmid_2465_1010.80 # ::date 2015-02-11T20:29:37 # ::file pmid_2465_1010_80.txt # ::snt Perhaps elevated H-Ras, N-Ras, K-Ras-4A, and K-Ras-4B all contribute to some extent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 2, 2015 (p / possible-01 :ARG1 (c / contribute-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras") :xref (x3 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")) :op3 (e3 / enzyme :name (n3 / name :op1 "K-Ras-4A") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :op4 (e4 / enzyme :name (n4 / name :op1 "K-Ras-4B") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :ARG1-of (e5 / elevate-01) :mod (a2 / all)) :degree (e6 / extent :mod (s2 / some)))) # ::id pmid_2465_1010.81 # ::date 2015-02-11T20:36:08 # ::file pmid_2465_1010_81.txt # ::snt However, neurofibromin is also a GAP for R-Ras proteins, and hyperactivation of these proteins can also contribute to the malignant phenotype because R-Ras proteins activate p110α, p110γ, and p110δ isoforms of PI3Ks (Marte et al., 1997; Huang et al., 2004). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h2 / have-concession-91 :ARG2 (a / and :op1 (p2 / protein :name (n / name :op1 "GAP") :domain (p / protein :name (n2 / name :op1 "neurofibromin") :mod (a2 / also) :xref (x3 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")) :beneficiary (e2 / enzyme :name (n3 / name :op1 "R-Ras") :xref (x1 / xref :value "UNIPROT:RRAS_HUMAN" :prob "0.593")) :mod (a8 / also) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :op2 (p3 / possible-01 :ARG1 (c2 / contribute-01 :ARG0 (a3 / activate-01 :ARG1 "a5" :degree (h3 / hyper)) :ARG2 (p4 / phenotype :ARG1-of (m2 / malignant-02)) :mod a8) :ARG1-of (c3 / cause-01 :ARG0 (a4 / activate-01 :ARG0 e2 :ARG1 (i / include-91 :ARG1 (a5 / and :op1 (i2 / isoform :name (n4 / name :op1 "p110α")) :op2 (i3 / isoform :name (n5 / name :op1 "p110γ")) :op3 (i4 / isoform :name (n6 / name :op1 "p110δ")) :mod (e / enzyme :name (n7 / name :op1 "PI3K") :xref (x2 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))))))) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and :op1 (p6 / publication-91 :ARG0 (a9 / and :op1 (p5 / person :name (n9 / name :op1 "Marte")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "1997")) :op2 (p7 / publication-91 :ARG0 (a7 / and :op1 (p9 / person :name (n10 / name :op1 "Huang")) :op2 (p10 / person :mod (o2 / other))) :time (d2 / date-entity :year "2004"))))) # ::id pmid_2465_1010.82 # ::date 2015-02-10T14:32:38 # ::file pmid_2465_1010_82.txt # ::snt Recently, Legius and colleagues (Brems et al., 2007) discovered mutations in the Sprouty-related protein, SPRED1, in a form of neurofibromatosis type I (NF1) in which the neurofibromin gene is wild-type. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d2 / discover-01 :ARG0 (a / and :op1 (p / person :name (n / name :op1 "Legius")) :op2 (c / colleague) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and :op1 (p6 / person :name (n6 / name :op1 "Brems")) :op2 (p7 / person :mod (o2 / other))) :time (d / date-entity :year "2007")))) :ARG1 (m / mutate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "SPRED1") :ARG1-of (r2 / relate-01 :ARG2 (p3 / protein :name (n3 / name :op1 "Sprouty"))) :xref (x1 / xref :value "UNIPROT:SPRE1_HUMAN" :prob "1.003")) :location (f / form :mod (d4 / disease :name (n4 / name :op1 "neurofibromatosis" :op2 "type" :op3 "I") :location-of (g / gene :ARG0-of (e / encode-01 :ARG1 (p4 / protein :name (n5 / name :op1 "neurofibromin") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703"))) :mod (w / wild-type))))) :time (r / recent)) # ::id pmid_2465_1010.83 # ::date 2015-02-10T14:33:54 # ::file pmid_2465_1010_83.txt # ::snt This disease is now called Legius syndrome (Brems et al., 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 14, 2015 (c / call-01 :ARG1 (d2 / disease :mod (t / this)) :ARG2 (n / name :op1 "Legius" :op2 "syndrome") :time (n2 / now) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n3 / name :op1 "Brems")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2007")))) # ::id pmid_2465_1010.84 # ::date 2015-02-10T14:41:06 # ::file pmid_2465_1010_84.txt # ::snt SPRED1 has a well-established pedigree as a negative regulator of the Raf/MAPK pathway, though the mechanism has been unclear. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (h / have-03 :ARG0 (p / protein :name (n / name :op1 "SPRED1") :ARG2-of (d / downregulate-01 :ARG1 (p3 / pathway :name (n2 / name :op1 "Raf/MAPK"))) :xref (x / xref :value "UNIPROT:SPRE1_HUMAN" :prob "1.003")) :ARG1 (p2 / pedigree :ARG1-of (e / establish-01 :ARG1-of (w / well-09))) :concession (c / clear-06 :polarity "-" :ARG1 (m2 / mechanism))) # ::id pmid_2465_1010.85 # ::date 2015-02-10T14:46:29 # ::file pmid_2465_1010_85.txt # ::snt However, the fact that loss of neurofibromin is, to a significant extent, phenocopied by loss of SPRED1, supports the idea that NF1 is a disease of hyperactive Ras and that the major function of neurofibromin is to turn Ras off. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (h2 / have-concession-91 :ARG1 (s / support-01 :ARG0 (p / phenocopy-00 :ARG0 (l / lose-01 :ARG1 (p2 / protein :name (n2 / name :op1 "SPRED1") :xref (x1 / xref :value "UNIPROT:SPRE1_HUMAN" :prob "1.003"))) :ARG1 (l2 / lose-02 :ARG1 (p3 / protein :name (n3 / name :op1 "neurofibromin") :xref (x2 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703"))) :ARG1-of (s2 / significant-02)) :ARG1 (i / idea :topic (a / and :op1 (d / disease :ARG1-of (c2 / cause-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (a2 / activity-06 :degree (h / hyper)) :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :domain (d2 / disease :name (n4 / name :op1 "NF1"))) :op1 (f / function-01 :ARG0 p3 :ARG1 (t / turn-off-07 :ARG0 p3 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (m / major-02)))))) # ::id pmid_2465_1010.86 # ::date 2015-02-10T14:46:48 # ::file pmid_2465_1010_86.txt # ::snt The neurofibromin protein itself is over 2,800 amino acids in length, and the GAP domain only accounts for about 300 amino acids, raising the possibility that neurofibromin has other functions that are not directly related to negative regulation of Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a2 / and :op1 (l / long-03 :ARG1 (p / protein :name (n2 / name :op1 "neurofibromin") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")) :ARG2 (a3 / amino-acid :quant (o / over :op1 "2800"))) :op2 (a4 / account-01 :ARG0 (p2 / protein-segment :name (n3 / name :op1 "GAP" :op2 "domain")) :ARG1 (a5 / amino-acid :quant (a / about :op1 "300")) :mod (o3 / only)) :ARG0-of (r / raise-01 :ARG1 (p3 / possible-01 :ARG1 (f / function-01 :ARG0 p :ARG1 (o2 / other :ARG1-of (r2 / relate-01 :polarity "-" :ARG2 (d4 / downregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (d / direct-02))))))) # ::id pmid_2465_1010.87 # ::date 2015-02-10T14:47:04 # ::file pmid_2465_1010_87.txt # ::snt Most attempts to identify additional functions have failed, however, and it seems most likely that neurofibromin senses an unidentified cellular metabolite and downregulates Ras accordingly, just as p120 Ras-GAP senses phosphotyrosine residues, and downregulates Ras when it binds to these residues on activated receptors in the plasma membrane (reviewed in Bos et al., 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (h / have-concession-91 :ARG1 (f / fail-01 :ARG1 (a2 / attempt-01 :ARG1 (i2 / identify-01 :ARG1 (f2 / function-01 :mod (a3 / additional))) :quant (m2 / most)))) :op2 (l / likely-01 :ARG1 (s / seem-01 :ARG1 (a4 / and :op1 (s2 / sense-01 :ARG0 (p / protein :name (n2 / name :op1 "neurofibromin") :xref (x2 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")) :ARG1 (m4 / metabolite :mod (c2 / cell) :ARG1-of (i / identify-01 :polarity "-"))) :op2 (d2 / downregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 p :manner (a5 / accordingly)) :ARG1-of (r / resemble-01 :ARG2 (a7 / and :op1 (s3 / sense-01 :ARG0 (p2 / protein :name (n3 / name :op1 "p120" :op2 "Ras-GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.313")) :ARG1 (r2 / residue :mod (a6 / amino-acid :name (n4 / name :op1 "threonine") :ARG3-of (p3 / phosphorylate-01) :xref (x4 / xref :value "PUBCHEM:205" :prob "11.848252")))) :op2 (d3 / downregulate-01 :ARG1 e :ARG2 p2 :time (b / bind-01 :ARG1 p2 :ARG2 r2 :ARG3 (r3 / receptor :ARG1-of (a8 / activate-01)) :location (m3 / membrane :part-of (p4 / plasma) :xref (x3 / xref :value "GO:0016020" :prob "0.8"))))) :mod (j / just)))) :degree (m / most)) :ARG1-of (r4 / review-02 :ARG2 (p5 / publication-91 :ARG0 (a9 / and :op1 (p6 / person :name (n5 / name :op1 "Bos")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "2007")))) # ::id pmid_2465_1010.88 # ::date 2015-02-11T10:42:28 # ::file pmid_2465_1010_88.txt # ::snt Whatever neurofibromin senses (if this model is correct) is likely to be conserved between S. cerevisiae and humans because the S. cerevisiae IRA1 and IRA2 proteins look very much like neurofibromin. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (l / likely-01 :ARG1 (c / conserve-01 :ARG1 (t / thing :ARG1-of (s / sense-01 :ARG0 (p / protein :name (n / name :op1 "neurofibromin") :xref (x2 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")))) :location (b / between :op1 (o / organism :name (n2 / name :op1 "S." :op2 "cerevisiae")) :op2 (h / human))) :condition (c2 / correct-02 :ARG1 (m2 / model :mod (t2 / this))) :ARG1-of (c3 / cause-01 :ARG0 (r / resemble-01 :ARG1 (a / and :op1 (p2 / protein :name (n3 / name :op1 "IRA1") :mod o :xref (x / xref :value "UNIPROT:TBL1R_HUMAN" :prob "1.002")) :op2 (p3 / protein :name (n4 / name :op1 "IRA2") :mod o :xref (x1 / xref :value "UNIPROT:IRAK2_HUMAN" :prob "0.312"))) :ARG2 p :degree (m / much :degree (v / very))))) # ::id pmid_2465_1010.89 # ::date 2015-02-11T11:20:33 # ::file pmid_2465_1010_89.txt # ::snt Unfortunately, the complete lack of any recognizable domains or motifs outside the GAP domain and a SEC14 domain has not helped in identifying what these proteins recognize. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (h / help-01 :polarity "-" :ARG0 (l / lack-01 :ARG1 (o / or :op1 (d / domain :mod (a / any)) :op2 (m / motif :mod a) :ARG1-of (r / recognize-02 :ARG1-of (p / possible-01))) :ARG1-of (c / complete-02) :location (o2 / outside :op1 (a2 / and :op1 (p2 / protein-segment :name (n / name :op1 "GAP" :op2 "domain")) :op2 (p4 / protein-segment :name (n2 / name :op1 "SEC14" :op2 "domain"))))) :ARG1 (i / identify-01 :ARG1 (t / thing :ARG1-of (r2 / recognize-02 :ARG0 (p3 / protein :mod (t2 / this))))) :ARG2-of (f / fortunate-01 :polarity "-")) # ::id pmid_2465_1010.90 # ::date 2015-02-11T11:28:02 # ::file pmid_2465_1010_90.txt # ::snt By comparing proteins that bind to wild-type SPRED1 versus mutants from Legius syndrome, we found that neurofibromin binds directly to SPRED proteins, via their EVH1 domains, and that SPRED proteins bring neurofibromin to the plasma membrane (Stowe et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (a2 / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "neurofibromin") :xref (x2 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")) :ARG2 (p2 / protein :name (n2 / name :op1 "SPRED") :xref (x / xref :value "UNIPROT:SPRE1_HUMAN" :prob "0.333")) :ARG3 (a / and :op1 (p10 / protein-segment :name (n3 / name :op1 "EVH1" :op2 "domain") :part-of p) :op1 (p3 / protein-segment :name (n7 / name :op1 "EVH1" :op2 "domain") :part-of p2)) :ARG1-of (d2 / direct-02)) :op2 (b2 / bring-01 :ARG0 p2 :ARG1 p :ARG2 (m / membrane :part-of (p4 / plasma) :xref (x3 / xref :value "GO:0016020" :prob "0.8")))) :manner (c / compare-01 :ARG1 (p5 / protein :ARG1-of (b3 / bind-01 :ARG2 (p6 / protein :name (n4 / name :op1 "SPRED1") :mod (w2 / wild-type) :xref (x1 / xref :value "UNIPROT:SPRE1_HUMAN" :prob "1.003")))) :ARG2 (p11 / protein :ARG2-of (m2 / mutate-01) :source (d5 / disease :name (n5 / name :op1 "Legius" :op2 "syndrome")))) :ARG1-of (d6 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a3 / and :op1 (p8 / person :name (n6 / name :op1 "Stowe")) :op2 (p9 / person :mod (o / other))) :time (d / date-entity :year "2012")))) # ::id pmid_2465_1010.91 # ::date 2015-02-11T12:22:22 # ::file pmid_2465_1010_91.txt # ::snt SPRED proteins also bind to c-Kit, and perhaps to other RTKs, suggesting that neurofibromin regulates Ras locally in response to specific receptor signaling, rather than simply suppressing Ras throughout the plasma membrane. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (b / bind-01 :ARG1 (p2 / protein :name (n2 / name :op1 "SPRED") :xref (x2 / xref :value "UNIPROT:SPRE1_HUMAN" :prob "0.333")) :ARG2 (a / and :op1 (e2 / enzyme :name (n3 / name :op1 "c-Kit") :xref (x1 / xref :value "UNIPROT:SCF_HUMAN" :prob "0.233")) :op2 (e3 / enzyme :name (n4 / name :op1 "RTK") :mod (o / other) :ARG1-of (p / possible-01) :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262"))) :mod (a2 / also) :ARG0-of (s / suggest-01 :ARG1 (r / regulate-01 :ARG0 (p4 / protein :name (n5 / name :op1 "neurofibromin") :xref (x4 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")) :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (l / local-02) :ARG2-of (r2 / respond-01 :ARG1 (s2 / signal-07 :ARG0 (r3 / receptor :ARG1-of (s3 / specific-02)))) :ARG1-of (i / instead-of-91 :ARG2 (s4 / suppress-01 :ARG0 p4 :ARG1 e :location (m / membrane :part-of (p5 / plasma) :xref (x5 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (s5 / simple-02)))))) # ::id pmid_2465_1010.92 # ::date 2015-02-11T12:35:28 # ::file pmid_2465_1010_92.txt # ::snt In this case, loss of neurofibromin may lead to local activation of Ras that is coupled to specific receptors, suggesting that inhibitors of these receptors might reverse the effects of neurofibromin loss. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (p / possible-01 :ARG1 (l / lead-03 :ARG0 (l2 / lose-02 :ARG1 (p2 / protein :name (n2 / name :op1 "neurofibromin") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703"))) :ARG2 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (l3 / local-02) :ARG1-of (c / couple-01 :ARG2 (r / receptor :ARG1-of (s / specific-02)))) :ARG0-of (s2 / suggest-01 :ARG1 (p3 / possible-01 :ARG1 (r2 / reverse-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 r)) :ARG1 (a2 / affect-01 :ARG0 l2))))) :prep-in (c2 / case-04 :ARG1 (t / this))) # ::id pmid_2465_1010.93 # ::date 2015-02-11T12:47:31 # ::file pmid_2465_1010_93.txt # ::snt The recent Cancer Genome Atlas analysis of mutations in lung cancer revealed an intriguing overlap between neurofibromin loss and Met amplification, suggesting a functional connection that merits further investigation (E.A. Collisson, personal communication). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / reveal-01 :ARG0 (a / analyze-01 :ARG0 (t / thing :name (n3 / name :op1 "Cancer" :op2 "Genome" :op3 "Atlas")) :ARG1 (m / mutate-01 :ARG0 (d2 / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung" :op2 "cancer"))) :time (r2 / recent)) :ARG1 (o / overlap-01 :ARG0 (l / lose-02 :ARG1 (p2 / protein :name (n4 / name :op1 "neurofibromin") :xref (x / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703"))) :ARG1 (a2 / amplify-01 :ARG1 (p3 / protein :name (n5 / name :op1 "Met") :xref (x1 / xref :value "UNIPROT:MET_HUMAN" :prob "0.604"))) :ARG0-of (i2 / intrigue-01)) :ARG0-of (s / suggest-01 :ARG1 (c / connect-01 :ARG0-of (f / function-01) :ARG0-of (m2 / merit-01 :ARG1 (i / investigate-01 :ARG1 c :degree (f2 / further))))) :ARG1-of (c2 / communicate-01 :ARG0 (p4 / person :name (n / name :op1 "E.A" :op2 "Collisson")) :ARG1-of (p / personal-02))) # ::id pmid_2465_1010.94 # ::date 2015-02-10T14:47:37 # ::file pmid_2465_1010_94.txt # ::snt Validation of Ras as a Target # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 14, 2015 (v / validate-01 :ARG1 (t / target-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) # ::id pmid_2465_1010.95 # ::date 2015-02-10T14:50:45 # ::file pmid_2465_1010_95.txt # ::snt Ras oncogenes can certainly initiate cancer in model organisms and probably do so in humans. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op1 (p / possible-01 :ARG1 (i / initiate-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (c2 / cause-01 :ARG1 "d") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")) :location (o2 / organism :mod (m / model))) :mod (c / certain)) :op2 (p2 / probable :domain (i2 / initiate-01 :ARG0 e :ARG1 d :location (h / human)))) # ::id pmid_2465_1010.96 # ::date 2015-02-10T14:58:06 # ::file pmid_2465_1010_96.txt # ::snt However, their role in maintaining tumors is less clear. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (h / have-concession-91 :ARG1 (c / clear-06 :ARG1 (r / role :poss (t / they) :topic (m / maintain-01 :ARG1 (t2 / tumor))) :degree (l / less))) # ::id pmid_2465_1010.97 # ::date 2015-02-10T15:05:31 # ::file pmid_2465_1010_97.txt # ::snt There is significant evidence that supports K-Ras as a continued candidate for direct therapeutic targeting, dating back to the classic studies of temperature-sensitive mutants of Ras, by Scolnick, Lowy, and colleagues and including microinjection studies with antibodies that block Ras activity (Kung et al., 1986) or block specific mutant alleles of Ras (Feramisco et al., 1985). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (e3 / evidence-01 :ARG1-of (s / significant-02) :ARG0-of (s2 / support-01 :ARG1 (c / candidate :purpose (t / target-01 :ARG0 (t2 / therapy) :ARG1-of (d3 / direct-02)) :ARG1-of (c2 / continue-01) :domain (e / enzyme :name (n / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :ARG1-of (d4 / date-01 :ARG2 (s3 / study-01 :ARG0 (a / and :op1 (p / person :name (n3 / name :op1 "Scolnick")) :op2 (p2 / person :name (n4 / name :op1 "Lowy")) :op3 (c3 / colleague)) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01) :ARG0-of (s4 / sensitive-03 :ARG1 (t3 / temperature)) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :mod (c4 / classic)) :direction (b / back)) :ARG2-of (i / include-01 :ARG1 (s5 / study-01 :ARG1 (i2 / inject-01 :mod (m3 / micro)) :instrument (o / or :op1 (a2 / antibody :ARG0-of (b2 / block-01 :ARG1 (a3 / activity-06 :ARG0 (e4 / enzyme :name (n5 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and :op1 (p4 / person :name (n6 / name :op1 "Kung")) :op2 (p5 / person :mod (o2 / other))) :time (d / date-entity :year "1986"))))) :op2 (a5 / antibody :ARG0-of (b3 / block-01 :ARG1 (a6 / allele :mod e4 :ARG2-of (m2 / mutate-01) :ARG1-of (s6 / specific-02)) :ARG1-of (d6 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a7 / and :op1 (p7 / person :name (n7 / name :op1 "Feramisco")) :op2 (p8 / person :mod o2)) :time (d2 / date-entity :year "1985"))))))))) # ::id pmid_2465_1010.98 # ::date 2015-02-10T15:05:59 # ::file pmid_2465_1010_98.txt # ::snt Ablation of K-Ras in mouse models of lung adenocarcinoma (Fisher et al., 2001) or pancreas cancer (Ying et al., 2012) led to dramatic tumor regression, just as ablation of H-Ras leads to tumor regression in mouse models of melanoma (Chin et al., 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (l / lead-03 :ARG0 (a / ablate-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :location (o / or :op1 (m / model :mod (m2 / mouse) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n2 / name :op1 "Fisher")) :op2 (p4 / person :mod (o2 / other))) :time (d / date-entity :year "2001"))) :topic (m6 / medical-condition :name (n6 / name :op1 "lung" :op2 "adenocarcinoma"))) :op2 (m3 / model :mod m2 :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a4 / and :op1 (p6 / person :name (n4 / name :op1 "Ying")) :op2 (p7 / person :mod o2)) :time (d2 / date-entity :year "2012"))) :topic (d9 / disease :name (n7 / name :op1 "pancreas" :op2 "cancer"))))) :ARG2 (r / regress-01 :ARG1 (t / tumor) :degree (d6 / dramatic)) :ARG1-of (r2 / resemble-01 :ARG2 (l3 / lead-03 :ARG0 (a5 / ablate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :ARG2 (r3 / regress-01 :ARG1 (t2 / tumor) :location (m4 / model :mod (m5 / mouse) :topic (m7 / medical-condition :name (n8 / name :op1 "melanoma")))) :ARG1-of (d7 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a6 / and :op1 (p9 / person :name (n5 / name :op1 "Chin")) :op2 (p10 / person :mod o2)) :time (d3 / date-entity :year "1999")))))) # ::id pmid_2465_1010.99 # ::date 2015-02-10T15:06:14 # ::file pmid_2465_1010_99.txt # ::snt On the other hand, K-Ras knockdown in human cell lines resulted in a spectrum of responses, revealing a range of K-Ras dependencies (Singh et al., 2009). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (c / contrast-01 :ARG2 (r / result-01 :ARG1 (k / knock-down-02 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :location (c2 / cell-line :mod (h / human))) :ARG2 (t / thing :ARG2-of (r2 / respond-01) :quant (s / spectrum) :ARG0-of (r3 / reveal-01 :ARG1 (r4 / range-01 :ARG1 (d2 / depend-01 :ARG1 e))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n2 / name :op1 "Singh")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2009")))) # ::id pmid_2465_1010.100 # ::date 2015-02-10T15:17:50 # ::file pmid_2465_1010_100.txt # ::snt Assessment of Ras dependency in 3D culture systems suggests that this assay system is a more stringent measure of Ras dependency. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / suggest-01 :ARG0 (a / assess-01 :ARG1 (d / depend-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :location (s2 / system :mod (c / culture :mod (d2 / dimension :quant "3")))) :ARG1 (m / measure-01 :ARG0 (s3 / system :mod (t / this) :instrument-of (a2 / assay-01)) :ARG1 d :mod (s4 / stringent :degree (m2 / more)))) # ::id pmid_2465_1010.101 # ::date 2015-02-10T15:25:13 # ::file pmid_2465_1010_101.txt # ::snt These studies raise the question of what is the most relevant system to measure this essential parameter and, in general, responses to candidate therapeutics targeting K-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (r / raise-01 :ARG0 (t / thing :ARG1-of (s / study-01) :mod (t2 / this)) :ARG1 (q / question-01 :ARG1 (s2 / system :ARG1-of (r2 / relevant-01 :ARG2 (m2 / measure-01 :ARG1 (a / and :op1 (p / parameter :mod (e2 / essential) :mod t2) :op2 (t3 / thing :ARG2-of (r3 / respond-01 :ARG1 (t4 / therapeutics :mod (c / candidate) :ARG0-of (t5 / target-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))) :ARG1-of (g / general-02))))) :degree (m / most))))) # ::id pmid_2465_1010.102 # ::date 2015-02-10T15:25:42 # ::file pmid_2465_1010_102.txt # ::snt Furthermore, the degree to which Ras genes are knocked down may be critical. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jun 26, 2015 (a / and :op2 (p / possible-01 :ARG1 (c / critical-02 :ARG1 (d2 / degree :degree-of (k / knock-down-02 :ARG1 (g / gene :ARG0-of (e2 / encode-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))))) # ::id pmid_2465_1010.103 # ::date 2015-02-10T15:31:03 # ::file pmid_2465_1010_103.txt # ::snt Genetic ablation is obviously different than small interfering RNA- or small hairpin RNA (shRNA)-mediated knockdown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 12, 2015 (d / differ-02 :ARG1 (a / ablate-01 :ARG1 (g / gene)) :ARG2 (k / knock-down-02 :ARG1-of (m / mediate-01 :ARG0 (o / or :op1 (n3 / nucleic-acid :name (n2 / name :op1 "small" :op2 "interfering" :op3 "RNA")) :op2 (n4 / nucleic-acid :name (n / name :op1 "small" :op2 "hairpin" :op3 "RNA"))))) :ARG1-of (o2 / obvious-01)) # ::id pmid_2465_1010.104 # ::date 2015-02-10T15:31:29 # ::file pmid_2465_1010_104.txt # ::snt It is also clear that knocking down activated Ras can lead to hyperactivation of upstream pathways, such as EGFR signaling (Young et al., 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c / clear-06 :ARG1 (p / possible-01 :ARG1 (l / lead-03 :ARG0 (k / knock-down-02 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 (a3 / activate-01 :ARG0 k :ARG1 (p2 / pathway :location (u / upstream) :example (s / signal-07 :ARG0 (e2 / enzyme :name (n2 / name :op1 "EGFR") :xref (x / xref :value "UNIPROT:EGFR_HUMAN" :prob "1.004")))) :degree (h / hyper)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and :op1 (p4 / person :name (n3 / name :op1 "Young")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2013"))))) :mod (a / also)) # ::id pmid_2465_1010.105 # ::date 2015-02-10T15:31:50 # ::file pmid_2465_1010_105.txt # ::snt Presumably, these pathways are suppressed in cells with activated Ras and rebound when the suppressor is removed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 14, 2015 (a / and :op1 (s / suppress-01 :ARG1 (p / pathway :mod (t / this)) :location (c / cell :ARG0-of (c2 / contain-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (a2 / activate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :op2 (r / rebound-01 :ARG1 p :time (r2 / remove-01 :ARG1 (m / molecular-physical-entity :ARG0-of s))) :ARG1-of (p2 / presume-01)) # ::id pmid_2465_1010.106 # ::date 2015-02-10T15:36:31 # ::file pmid_2465_1010_106.txt # ::snt Although this rebound effect may not be sufficient to sustain a malignant phenotype, it may offset proapoptotic effects associated with oncogene inactivation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 28, 2015 (h / have-concession-91 :ARG1 (p3 / possible-01 :ARG1 (o / offset-01 :ARG0 "a" :ARG1 (a2 / affect-01 :ARG2 (f / favor-01 :ARG1 (a5 / apoptosis)) :ARG1-of (a3 / associate-01 :ARG2 (a4 / activate-01 :polarity "-" :ARG1 (o2 / oncogene)))))) :ARG2 (p / possible-01 :ARG1 (s / suffice-01 :polarity "-" :ARG0 (a / affect-01 :ARG2 (r / rebound-01) :mod (t / this)) :purpose (s2 / sustain-01 :ARG0 a :ARG1 (p2 / phenotype :ARG2-of (m / malignant-02)))))) # ::id pmid_2465_1010.107 # ::date 2015-02-14T09:30:14 # ::file pmid_2465_1010_107.txt # ::snt Do K-Ras Therapies Have to Be Allele Specific? # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (o / obligate-01 :mode "interrogative" :ARG2 (s / specific-02 :ARG1 (t / therapy :mod (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG2 (a / allele))) # ::id pmid_2465_1010.108 # ::date 2015-02-14T10:05:25 # ::file pmid_2465_1010_108.txt # ::snt The most specific way to block oncogenic Ras would be to target the activating substitution itself. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (w / way :ARG1-of (s2 / specific-02 :degree (m / most)) :manner-of (b / block-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :domain (t / target-01 :ARG1 (s / substitute-01 :ARG0-of (a / activate-01)))) # ::id pmid_2465_1010.109 # ::date 2015-02-14T10:20:14 # ::file pmid_2465_1010_109.txt # ::snt The first example was recently published by Shokat and colleagues, who identified electrophilic compounds that react covalently with cysteine-12 in G12C mutant K-Ras (Ostrem et al., 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 16, 2015 (p / publish-01 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Shokat")) :op2 (c / colleague) :ARG0-of (i / identify-01 :ARG1 (c2 / compound :mod (e2 / electrophile) :ARG0-of (r2 / react-01 :ARG1 (a2 / amino-acid :mod "12" :name (n2 / name :op1 "cysteine") :xref (x1 / xref :value "PUBCHEM:594" :prob "11.272514")) :manner (c3 / covalent) :location (e3 / enzyme :name (n3 / name :op1 "K-Ras") :ARG2-of (m / mutate-01 :value "G12C") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))))) :ARG1 (e / exemplify-01 :ord (o / ordinal-entity :value "1")) :time (r / recent) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n4 / name :op1 "Ostrem")) :op2 (p5 / person :mod (o2 / other))) :time (d2 / date-entity :year "2013")))) # ::id pmid_2465_1010.110 # ::date 2015-02-14T10:55:47 # ::file pmid_2465_1010_110.txt # ::snt These compounds interact selectively with the GDP form of K-Ras-G12C protein (Figure 2) and bind at a pocket near switch 2 that had not been apparent from analysis of crystal structures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (a / and :op1 (i / interact-01 :ARG0 (c / compound :mod (t / this)) :ARG1 (m2 / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "K-Ras") :ARG2-of (m / mutate-01 :value "G12C") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :part (s2 / small-molecule :name (n2 / name :op1 "GDP") :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :manner (s / selective) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2"))) :op2 (b / bind-01 :ARG1 c :location (p / pocket :ARG1-of (n3 / near-02 :ARG2 (s3 / switch :mod "2")) :ARG1-of (a2 / appear-01 :polarity "-" :manner (a3 / analyze-01 :ARG1 (s4 / structure :poss (c2 / crystal))))))) # ::id pmid_2465_1010.111 # ::date 2015-02-14T13:41:13 # ::file pmid_2465_1010_111.txt # ::snt A similar approach led to the identification of a GDP analog that covalently and specifically binds G12C and renders this oncogenic protein inactive (Lim et al., 2014). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (l / lead-03 :ARG0 (a / approach-02 :ARG1-of (r / resemble-01)) :ARG1 (i / identify-01 :ARG1 (s / small-molecule :name (n / name :op1 "GDP") :mod (a2 / analog) :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "G12C") :ARG0-of (c2 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (c / covalent) :ARG1-of (s2 / specific-02)) :ARG0-of (d3 / deactivate-01 :ARG1 e) :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and :op1 (p / person :name (n3 / name :op1 "Lim")) :op2 (p2 / person :mod (o / other))) :time (d2 / date-entity :year "2014")))) # ::id pmid_2465_1010.112 # ::date 2015-02-14T14:00:23 # ::file pmid_2465_1010_112.txt # ::snt Perhaps other compounds could be identified that interact specifically with the G12D and G13D mutant forms using similar strategies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (i / identify-01 :ARG1 (c / compound :mod (o / other) :ARG0-of (i2 / interact-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (m / mutate-01 :value "G12D") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (m2 / mutate-01 :value "G13D") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (s / specific-02))) :ARG2-of (u / use-01 :ARG1 (s2 / strategy :ARG1-of (r / resemble-01))))) # ::id pmid_2465_1010.113 # ::date 2015-02-14T14:14:28 # ::file pmid_2465_1010_113.txt # ::snt These brilliant experiments remind us that these proteins are in dynamic and flexible states that might present more opportunities for small molecule attack than was previously realized. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / remind-01 :ARG0 (e / experiment-01 :mod (t / this) :ARG1-of (b / brilliant-01)) :ARG1 (p / possible-01 :ARG1 (p2 / present-01 :ARG0 (s / state :mod (d / dynamic) :ARG1-of (f / flexible-03) :poss (p3 / protein :mod (t2 / this))) :ARG1 (o / opportunity :mod (a / attack-01 :ARG0 (m / molecule :mod (s2 / small))) :quant (m2 / more-than :op1 (r2 / realize-01 :time (p4 / previous)))))) :ARG2 (w / we)) # ::id pmid_2465_1010.114 # ::date 2015-02-14T15:08:58 # ::file pmid_2465_1010_114.txt # ::snt Indeed, it is well established that Ras-GTP exists in two states, only one of which is active and each with distinct binding properties for effectors, GAPs, and nucleotide (Geyer et al., 1996; Liao et al., 2008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (e / establish-01 :ARG1 (e2 / exist-01 :ARG1 (m / macro-molecular-complex :part (e4 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part (s3 / small-molecule :name (n4 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG2 (s / state :quant "2" :ARG2-of (i / include-91 :ARG1 (s2 / state :quant "1" :mod (o / only) :ARG0-of (a / activity-06))) :poss-of (p / property :mod (b / bind-01 :ARG1 (a2 / and :op1 (e3 / effector) :op2 (p2 / protein :name (n / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :op3 (n2 / nucleotide))) :mod (d / distinct)))) :mod (i2 / indeed) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p3 / publication-91 :ARG0 (a4 / and :op1 (p4 / person :name (n5 / name :op1 "Geyer")) :op2 (p5 / person :mod (o2 / other))) :time (d3 / date-entity :year "1996")) :op2 (p6 / publication-91 :ARG0 (a5 / and :op1 (p7 / person :name (n6 / name :op1 "Liao")) :op2 (p8 / person :mod (o3 / other))) :time (d4 / date-entity :year "2008")))) :degree (w / well)) # ::id pmid_2465_1010.115 # ::date 2015-02-15T03:20:28 # ::file pmid_2465_1010_115.txt # ::snt The idea of targeting the GDP-bound form of an oncogenic mutant seems counterintuitive because we often think of oncogenic mutants as being locked in their GTP-bound states, signaling persistently downstream. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / seem-01 :ARG1 (i3 / intuitive :polarity "-" :domain (i2 / idea :mod (t / target-01 :ARG1 (m2 / macro-molecular-complex :part (e / enzyme :ARG1-of (m / mutate-01) :ARG0-of (c3 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :part (s2 / small-molecule :name (n / name :op1 "GDP") :xref (x / xref :value "PUBCHEM:8977" :prob "14.712257")))))) :ARG1-of (c2 / cause-01 :ARG0 (t2 / think-01 :ARG0 (w / we) :ARG1 e :ARG2 (a / and :op1 (l / lock-01 :ARG1 e :ARG3 (m3 / macro-molecular-complex :part e :part (s4 / small-molecule :name (n2 / name :op1 "GTP") :ARG2-of (b2 / bind-01) :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :op2 (s5 / signal-07 :ARG0 e :location (d / downstream) :ARG1-of (p / persist-01))) :frequency (o / often)))) # ::id pmid_2465_1010.116 # ::date 2015-02-15T05:57:59 # ::file pmid_2465_1010_116.txt # ::snt However, codon 12 mutants retain measurable intrinsic GTPase activity, even though they are all refractory to GAP-mediated GTPase stimulation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (r / retain-01 :ARG0 (e2 / enzyme :part (c / codon :mod "12" :ARG2-of (m / mutate-01))) :ARG1 (a / activity-06 :ARG0 (e / enzyme :wiki "GTPase" :name (n / name :op1 "GTPase") :xref (x1 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :mod (i / intrinsic) :ARG1-of (m2 / measure-01 :ARG1-of (p / possible-01)))) :ARG2 (r2 / refractory :prep-to (s / stimulate-01 :ARG1 e :ARG1-of (m3 / mediate-01 :ARG0 (p2 / protein :wiki "GTPase-activating_protein" :name (n2 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))) :domain (e3 / enzyme :mod (a2 / all) :part c))) # ::id pmid_2465_1010.117 # ::date 2015-02-15T11:21:58 # ::file pmid_2465_1010_117.txt # ::snt Although GTP hydrolysis rates are slow, the GDP off rates are also slow, and indeed, oncogenic mutants often exist with similar levels of GTP and GDP: if intrinsic GTPase and GDP off rates were identical, Ras proteins would be 50% GTP bound and 50% GDP bound. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (a / and :op1 (h / have-concession-91 :ARG1 (s / slow-05 :ARG1 (r / rate :degree-of (s2 / small-molecule :wiki "Guanosine_diphosphate" :name (n / name :op1 "GDP") :ARG1-of (d / deactivate-01) :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :mod (a2 / also)) :ARG2 (s3 / slow-05 :ARG1 (r2 / rate :degree-of (h2 / hydrolyze-01 :ARG1 (s4 / small-molecule :wiki "Guanosine_triphosphate" :name (n2 / name :op1 "GTP") :xref (x7 / xref :value "PUBCHEM:6830" :prob "15.470645")))))) :op2 (r3 / resemble-01 :ARG1 (l / level :degree-of (s9 / small-molecule :wiki "Guanosine_triphosphate" :name (n11 / name :op1 "GTP") :part-of (e2 / enzyme :ARG2-of (m2 / mutate-01) :ARG0-of (c / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n12 / name :op1 "cancer")))) :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG2 (l2 / level :degree-of (s5 / small-molecule :wiki "Guanosine_diphosphate" :name (n3 / name :op1 "GDP") :part-of e2 :xref (x6 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :frequency (o / often) :mod (i4 / indeed))) :snt2 (h3 / have-condition-91 :ARG1 (i2 / include-91 :ARG1 (a3 / and :op1 (e5 / enzyme :ARG1-of (b2 / bind-01 :ARG2 (s7 / small-molecule :wiki "Guanosine_triphosphate" :name (n9 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :quant (p / percentage-entity :value "50") :mod (p3 / protein-family :wiki "Ras_subfamily" :name (n7 / name :op1 "Ras"))) :op2 (e6 / enzyme :ARG1-of (b / bind-01 :ARG2 (s8 / small-molecule :wiki "Guanosine_diphosphate" :name (n10 / name :op1 "GDP") :xref (x2 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :quant p :mod p3)) :ARG2 (e4 / enzyme :mod p3)) :ARG2 (i / identical-01 :ARG1 (r4 / rate :degree-of (e / enzyme :wiki "GTPase" :name (n4 / name :op1 "GTPase") :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :mod (i5 / intrinsic)) :ARG2 (r5 / rate :degree-of (s6 / small-molecule :wiki "Guanosine_diphosphate" :name (n5 / name :op1 "GDP") :ARG1-of (d2 / deactivate-01) :xref (x5 / xref :value "PUBCHEM:8977" :prob "14.712257")) :mod i5)))) # ::id pmid_2465_1010.118 # ::date 2015-02-15T12:27:12 # ::file pmid_2465_1010_118.txt # ::snt This presents an opportunity for targeting the GDP-bound state and trapping it in the off state and so preventing recharging with GTP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 16, 2015 (p / present-01 :ARG0 (t3 / this) :ARG1 (o / opportunity :mod (t / target-01 :ARG1 (m / macro-molecular-complex :part (s / small-molecule :name (n / name :op1 "GDP") :ARG1-of (b2 / bind-01) :xref (x / xref :value "PUBCHEM:8977" :prob "14.712257")))) :mod (t2 / trap-01 :ARG1 m :ARG2 (d / deactivate-01 :ARG1 m) :purpose (p2 / prevent-01 :ARG1 (r / recharge-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645"))))))) # ::id pmid_2465_1010.119 # ::date 2015-02-15T12:58:24 # ::file pmid_2465_1010_119.txt # ::snt As an alternative to targeting specific Ras mutants, such as G12C, compounds could be developed that target individual Ras isoforms but do not discriminate between wild-type and mutant Ras proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (p / possible-01 :ARG1 (d / develop-02 :ARG1 (c / compound :ARG0-of (t / target-01 :ARG1 (i / isoform :mod (e / enzyme :name (n / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :mod (i2 / individual)) :ARG1-of (c2 / contrast-01 :ARG2 (d2 / discriminate-01 :polarity "-" :ARG0 c :ARG1 (b / between :op1 (e3 / enzyme :name (n3 / name :op1 "Ras") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 "e2"))))) :ARG4 (a / alternative :prep-to (t2 / target-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01) :ARG1-of (s / specific-02) :example (e6 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "G12C") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) # ::id pmid_2465_1010.120 # ::date 2015-02-15T13:29:14 # ::file pmid_2465_1010_120.txt # ::snt This could be achieved by targeting specific hypervariable regions at the C terminus where the Ras proteins differ most widely (Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / possible-01 :ARG1 (a / achieve-01 :ARG1 (t / this) :manner (t2 / target-01 :ARG1 (r / region :ARG1-of (s / specific-02) :ARG1-of (v / vary-01 :degree (h / hyper)) :location-of (d / differ-02 :ARG1 (p3 / protein-family :name (n2 / name :op1 "Ras")) :degree (w / wide :degree (m / most))) :part-of (p2 / protein-segment :name (n / name :op1 "C" :op2 "terminus"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3"))) # ::id pmid_2465_1010.121 # ::date 2015-02-15T13:47:52 # ::file pmid_2465_1010_121.txt # ::snt The C-terminal hypervariable region of K-Ras-4B is very different from the hypervariable regions of other Ras proteins and is involved in the specific interaction of K-Ras-4B with calmodulin (Lopez-Alcalá et al., 2008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / and :op1 (d / differ-02 :ARG1 (r2 / region :mod (h / hypervariable) :part-of (p / protein-segment :name (n / name :op1 "C-terminus") :part-of (e / enzyme :name (n2 / name :op1 "K-Ras-4B") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")))) :ARG2 (r / region :mod h :part-of (e2 / enzyme :name (n3 / name :op1 "Ras") :mod (o / other) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :degree (v / very)) :op2 (i / involve-01 :ARG1 r2 :ARG2 (i2 / interact-01 :ARG0 e :ARG1 (p5 / protein :name (n5 / name :op1 "calmodulin") :xref (x2 / xref :value "UNIPROT:CALM_HUMAN" :prob "0.703")) :ARG1-of (s / specific-02))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n4 / name :op1 "Lopez-Alcalá")) :op2 (p4 / person :mod (o2 / other))) :time (d3 / date-entity :year "2008")))) # ::id pmid_2465_1010.122 # ::date 2015-02-15T14:04:48 # ::file pmid_2465_1010_122.txt # ::snt Because K-Ras-4B seems to be the major form of K-Ras in established tumors, these specific biochemical properties may afford unique opportunities for therapeutic attack. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jul 30, 2015 (c / cause-01 :ARG0 (s / seem-01 :ARG1 (f / form :mod (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1-of (m / major-02) :domain (e2 / enzyme :name (n2 / name :op1 "K-Ras-4B") :xref (x1 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :location (t / tumor :ARG1-of (e3 / establish-01)))) :ARG1 (p / possible-01 :ARG1 (a / afford-02 :ARG0 (p2 / property :mod (t2 / this) :ARG1-of (s2 / specific-02) :mod (b / biochemical)) :ARG1 (o / opportunity :mod (u / unique) :mod (a2 / attack-01 :ARG0 (t3 / therapy)))))) # ::id pmid_2465_1010.123 # ::date 2015-02-15T14:18:44 # ::file pmid_2465_1010_123.txt # ::snt Mouse models suggest that such compounds would be well tolerated because animals lacking any single isoform of Ras are viable (A. Balmain, personal communication). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Nov 5, 2015 (s / suggest-01 :ARG0 (m / model :mod (m2 / mouse)) :ARG1 (t / tolerate-01 :ARG1 (c / compound :mod (s2 / such)) :manner (w / well-09)) :ARG1-of (c2 / cause-01 :ARG0 (v / viable :domain (a / animal :ARG0-of (l / lack-01 :ARG1 (i / isoform :ARG1-of (s3 / single-02) :mod (a2 / any) :mod (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) :ARG1-of (c3 / communicate-01 :ARG0 (p / person :name (n2 / name :op1 "A." :op2 "Balmain")) :ARG1-of (p2 / personal-02))) # ::id pmid_2465_1010.124 # ::date 2015-02-15T14:30:27 # ::file pmid_2465_1010_124.txt # ::snt Targeting GDP/GTP Binding and Exchange # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 17, 2015 (t / target-01 :ARG1 (a / and :op1 (b / bind-01 :ARG2 (s3 / slash :op1 (s / small-molecule :wiki "Guanosine_diphosphate" :name (n / name :op1 "GDP") :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257")) :op2 (s2 / small-molecule :wiki "Guanosine_triphosphate" :name (n2 / name :op1 "GTP") :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645")))) :op2 (e / exchange-01 :ARG1 s :ARG3 s2))) # ::id pmid_2465_1010.125 # ::date 2015-02-15T14:36:54 # ::file pmid_2465_1010_125.txt # ::snt Ras proteins bind GDP and GTP with picomolar affinity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (b / bind-01 :ARG1 (p2 / protein-family :name (n / name :op1 "Ras")) :ARG2 (a2 / and :op1 (s / small-molecule :name (n2 / name :op1 "GDP") :mod (a / affinity :mod (p / picomolar)) :xref (x1 / xref :value "PUBCHEM:8977" :prob "14.712257")) :op2 (s2 / small-molecule :name (n3 / name :op1 "GTP") :mod a :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645")))) # ::id pmid_2465_1010.126 # ::date 2015-02-15T14:46:57 # ::file pmid_2465_1010_126.txt # ::snt It is generally accepted that oncogenic Ras proteins cannot be attacked with nucleotide analogs because high GTP concentrations make competition impossible. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / accept-01 :ARG1 (p / possible-01 :polarity "-" :ARG1 (a2 / attack-01 :ARG0 (a3 / analog :mod (n2 / nucleotide)) :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (c3 / cause-01 :ARG0 (m / make-02 :ARG0 (c4 / concentrate-02 :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG1-of (h / high-02)) :ARG1 (p2 / possible-01 :polarity "-" :ARG1 (c5 / compete-01))))) :ARG1-of (g / general-02)) # ::id pmid_2465_1010.127 # ::date 2015-02-15T15:04:14 # ::file pmid_2465_1010_127.txt # ::snt The high affinity for GTP is also considered a barrier, though it is easy to imagine that analogs could be developed with equally high affinity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (h / have-concession-91 :ARG1 (c / consider-01 :ARG1 (b / barrier :domain (a / affinity :ARG1-of (h2 / high-02) :topic (s / small-molecule :name (n / name :op1 "GTP") :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645")))) :mod (a4 / also)) :ARG2 (e / easy-05 :ARG1 (i / imagine-01 :ARG1 (p / possible-01 :ARG1 (d / develop-02 :ARG1 (a2 / analog :poss-of (a3 / affinity :ARG1-of (h3 / high-02 :degree (e2 / equal))))))))) # ::id pmid_2465_1010.128 # ::date 2015-02-15T15:15:28 # ::file pmid_2465_1010_128.txt # ::snt This approach to targeting Ras has therefore been abandoned. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Feb 15, 2015 (c / cause-01 :ARG1 (a / abandon-01 :ARG1 (a2 / approach-02 :ARG1 (t2 / target-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :mod (t / this)))) # ::id pmid_2465_1010.129 # ::date 2015-02-15T15:19:36 # ::file pmid_2465_1010_129.txt # ::snt However, Ras proteins in their GTP state exist in complexes with effectors (Raf kinases, RalGDS, PI3K, other Ras-binding proteins), as well as regulators (GAPs and guanine nucleotide exchange factors [GEFs]). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (h / have-concession-91 :ARG1 (a3 / and :op1 (e / exist-01 :ARG1 (p7 / protein-family :name (n / name :op1 "Ras") :ARG1-of (b / bind-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :location (m / macro-molecular-complex :part (e3 / effector :example (a / and :op1 (p6 / protein-family :name (n3 / name :op1 "Raf")) :op2 (p4 / protein :name (n5 / name :op1 "RalGDS") :xref (x3 / xref :value "UNIPROT:GNDS_HUMAN" :prob "1.003")) :op3 (e5 / enzyme :name (n4 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op4 (p / protein :mod (o / other) :ARG1-of (b2 / bind-01 :ARG2 (p5 / protein-family :name (n6 / name :op1 "Ras")))))))) :op2 (e2 / exist-01 :ARG1 p7 :location (m3 / macro-molecular-complex :part (m2 / molecular-physical-entity :ARG0-of (r / regulate-01) :example (a2 / and :op1 (p2 / protein :name (n7 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :op2 (p3 / protein :name (n8 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor") :xref (x2 / xref :value "UNIPROT:PKHG5_HUMAN" :prob "0.393")))))))) # ::id pmid_2465_1010.130 # ::date 2015-02-15T15:40:43 # ::file pmid_2465_1010_130.txt # ::snt The effects of most of these proteins on nucleotide binding have not been measured. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 16, 2015 (m / measure-01 :polarity "-" :ARG1 (e / effect-03 :ARG0 (p / protein :ARG1-of (i / include-91 :ARG2 (p2 / protein :mod (t / this)) :ARG3 (m2 / most))) :ARG1 (b / bind-01 :ARG1 (n / nucleotide)))) # ::id pmid_2465_1010.131 # ::date 2015-02-15T15:51:08 # ::file pmid_2465_1010_131.txt # ::snt GEFs, of course, greatly reduce the affinity for nucleotides, allowing GDP to be released rapidly and replaced by GTP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 17, 2015 (r / reduce-01 :ARG0 (p / protein :name (n / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (a / affinity :topic (n2 / nucleotide)) :mod (o / of-course) :degree (g / great) :ARG0-of (a2 / allow-01 :ARG1 (a3 / and :op1 (r2 / release-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "GDP") :xref (x2 / xref :value "PUBCHEM:8977" :prob "14.712257")) :manner (r3 / rapid)) :op2 (r4 / replace-01 :ARG1 s :ARG2 (s2 / small-molecule :name (n4 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")))))) # ::id pmid_2465_1010.132 # ::date 2015-02-15T15:57:55 # ::file pmid_2465_1010_132.txt # ::snt Although oncogenic mutants do not need GEFs to put them in the active state, they are still sensitive to GEF-mediated exchange and cycle through a complex state in which nucleotide-free Ras protein is bound to the GEF; this may provide a potential opportunity for a mutant-specific nucleotide analog to bind. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-concession-91 :ARG1 (a2 / and :op1 (s / sensitive-03 :ARG0 "e" :ARG1 (e2 / exchange-01 :ARG1-of (m2 / mediate-01 :ARG0 "p")) :mod (s2 / still)) :op2 (c3 / cycle-02 :ARG1 "e" :path (m4 / macro-molecular-complex :part (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n4 / nucleotide)) :ARG1-of (b / bind-01 :ARG2 "p") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG0-of (p2 / provide-01 :ARG1 (o / opportunity :mod (b2 / bind-01 :ARG1 (a3 / analog :mod (n5 / nucleotide) :ARG1-of (s3 / specific-02 :ARG2 (m3 / mutate-01)))) :mod (p4 / potential)) :ARG1-of (p3 / possible-01))) :ARG2 (n / need-01 :polarity "-" :ARG0 (e / enzyme :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :ARG2-of (m / mutate-01)) :ARG1 (a / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 e))) # ::id pmid_2465_1010.133 # ::date 2015-02-15T15:58:26 # ::file pmid_2465_1010_133.txt # ::snt In support of this, we noted many years ago that antibodies directed against specific codon 12 mutants were effective at reversing transformation in cells, as cited above, yet these antibodies do not bind to nucleotide-loaded Ras (Clark et al., 1985). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (n / note-01 :ARG0 (w / we) :ARG1 (h / have-concession-91 :ARG1 (b2 / bind-01 :polarity "-" :ARG1 "a" :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG1-of (l / load-01 :ARG2 (n4 / nucleotide)) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 (e / effective-04 :ARG0 (a / antibody :ARG1-of (d / direct-01 :ARG2 (a2 / against :op1 (e3 / enzyme :part (c / codon :mod "12" :ARG2-of (m2 / mutate-01)) :ARG1-of (s / specific-02))))) :ARG1 (r / reverse-01 :ARG0 a :ARG1 (t2 / transform-01 :ARG1 (c2 / cell))))) :time (b / before :op1 (n2 / now) :quant (m / many :op1 (t / temporal-quantity :quant "1" :unit (y / year)))) :ARG0-of (s2 / support-01 :ARG1 (t3 / this)) :ARG1-of (c3 / cite-01 :medium (a3 / above)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a4 / and :op1 (p2 / person :name (n5 / name :op1 "Clark")) :op2 (p3 / person :mod (o / other))) :time (d3 / date-entity :year "1985")))) # ::id pmid_2465_1010.134 # ::date 2015-02-18T04:08:59 # ::file pmid_2465_1010_134.txt # ::snt We therefore speculate that oncogenic Ras exists in a nucleotide-free state frequently enough to make it vulnerable to attack. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (s / speculate-01 :ARG0 (w / we) :ARG1 (e2 / exist-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :mod (v / vulnerable) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (s2 / state :ARG1-of (f / free-04 :ARG2 (n2 / nucleotide))) :ARG1-of (f2 / frequent-02 :degree (e3 / enough)) :ARG0-of (m / make-02 :ARG1 (v2 / vulnerable :domain e :prep-to (a / attack-01)))) :ARG1-of (i / infer-01)) # ::id pmid_2465_1010.135 # ::date 2015-02-18T04:36:13 # ::file pmid_2465_1010_135.txt # ::snt Whether oncogenic Ras proteins are regulated at all by Sos and other GEFs has been surprisingly difficult to determine definitively, partly because there are many types of GEFs in mammalian cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (d / difficult :domain (d2 / determine-01 :ARG1 (r / regulate-01 :mode "interrogative" :ARG0 (a3 / and :op1 (p / protein :name (n2 / name :op1 "Sos") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203")) :op2 (p2 / protein :name (n3 / name :op1 "GEF") :mod (o / other) :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002"))) :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :degree (a2 / at-all)) :manner (d3 / definitive)) :ARG0-of (s / surprise-01) :ARG1-of (c3 / cause-01 :ARG0 (t / type-03 :ARG1 p2 :quant (m / many) :location (c4 / cell :mod (m2 / mammal))) :degree (p3 / part))) # ::id pmid_2465_1010.136 # ::date 2015-02-18T06:13:33 # ::file pmid_2465_1010_136.txt # ::snt Furthermore, GEFs such as Sos have allosteric sites for Ras binding as well as sites for GDP/GTP exchange, and it is hard to measure GTP loading on individual Ras isoforms in cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (a / and :op2 (a2 / and :op1 (h / have-03 :ARG0 (p / protein :name (n3 / name :op1 "GEF") :example (p2 / protein :name (n4 / name :op1 "Sos") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203")) :xref (x2 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (a4 / and :op1 (s2 / site :mod (a3 / allosteric) :purpose (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :op2 (s3 / site :purpose (e2 / exchange-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x4 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG2 (s4 / small-molecule :name (n5 / name :op1 "GDP") :xref (x3 / xref :value "PUBCHEM:8977" :prob "14.712257")))))) :op2 (h2 / hard-02 :ARG1 (m / measure-01 :ARG1 (l / load-01 :ARG1 (i / isoform :mod e :mod (i2 / individual)) :ARG2 s) :location (c / cell))))) # ::id pmid_2465_1010.137 # ::date 2015-02-18T06:30:21 # ::file pmid_2465_1010_137.txt # ::snt However, it is clear that mutant Ras proteins are not 100% GTP bound, and GEFs could increase the fraction of Ras-GTP to some extent. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri May 29, 2015 (h / have-concession-91 :ARG1 (a / and :op1 (c / clear-06 :ARG1 (b / bind-01 :polarity "-" :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")) :extent (p3 / percentage-entity :value "100"))) :op2 (p4 / possible-01 :ARG1 (i / increase-01 :ARG0 (p5 / protein :name (n3 / name :op1 "GEF") :xref (x1 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (f / fraction :mod (m2 / macro-molecular-complex :part e :part s)) :ARG2 (s3 / some))))) # ::id pmid_2465_1010.138 # ::date 2015-02-18T06:42:54 # ::file pmid_2465_1010_138.txt # ::snt However, targeting Sos or other GEFs for treating mutant Ras cancers does not appear an attractive proposition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-concession-91 :ARG1 (a / appear-02 :polarity "-" :ARG1 (t / target-01 :ARG1 (o / or :op1 (p / protein :name (n2 / name :op1 "Sos") :xref (x2 / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203")) :op2 (p2 / protein :name (n3 / name :op1 "GEF") :mod (o2 / other) :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002"))) :purpose (t2 / treat-03 :ARG2 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :location-of (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG1-of (p3 / propose-01 :ARG0-of (a2 / attract-01))))) # ::id pmid_2465_1010.139 # ::date 2015-02-18T06:54:25 # ::file pmid_2465_1010_139.txt # ::snt Oncogenic mutants may or may not depend on GEFs, to some degree, but wild-type Ras proteins most certainly do. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c / contrast-01 :ARG1 (o / or :op1 (p / possible-01 :ARG1 (d / depend-01 :ARG0 (p2 / protein :ARG2-of (m / mutate-01 :ARG0-of (c2 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))) :ARG1 (p3 / protein :name (n2 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")))) :op2 (p4 / possible-01 :polarity "-" :ARG1 d) :degree (s / some)) :ARG2 (d2 / depend-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 p3 :mod (c4 / certain :degree (m2 / most)))) # ::id pmid_2465_1010.140 # ::date 2015-02-18T07:05:45 # ::file pmid_2465_1010_140.txt # ::snt For these reasons, recent efforts to target mutant Ras that led to compounds that bind at the Sos-binding site may seem disappointing (Maurer et al., 2012; Sun et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 21, 2016 (p / possible-01 :ARG1 (s / seem-01 :ARG1 (d3 / disappoint-01 :ARG0 (e2 / effort-01 :ARG1 (t / target-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (m / mutate-01) :ARG0-of (l / lead-03 :ARG2 (c / compound :ARG0-of (b / bind-01 :location (s2 / site :location-of (b2 / bind-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Sos") :xref (x / xref :value "UNIPROT:SOS1_HUMAN" :prob "0.203"))))))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :time (r / recent)))) :ARG1-of (c2 / cause-01 :ARG0 (r2 / reason :mod (t2 / this))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (p3 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n3 / name :op1 "Maurer")) :op2 (p5 / person :mod (o2 / other))) :time (d2 / date-entity :year "2012")) :op2 (p6 / publication-91 :ARG0 (a3 / and :op1 (p7 / person :name (n5 / name :op1 "Sun")) :op2 (p8 / person :mod (o / other))) :time (d / date-entity :year "2012"))))) # ::id pmid_2465_1010.141 # ::date 2015-02-18T07:20:58 # ::file pmid_2465_1010_141.txt # ::snt However, the compounds that these groups discovered could be excellent starting points toward the discovery of compounds that have selectivity for mutant forms of K-Ras or block effector interactions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (h / have-concession-91 :ARG1 (p2 / possible-01 :ARG1 (p3 / point :source-of (s / start-01) :ARG1-of (e2 / excellent-02) :domain (c / compound :ARG1-of (d / discover-01 :ARG0 (g / group :mod (t / this)))) :direction (o / or :op1 (d2 / discover-01 :ARG1 (c2 / compound :ARG0-of (s2 / select-01 :ARG1 (f / form :mod (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2-of (m / mutate-01))))) :op2 (d3 / discover-01 :ARG1 (c3 / compound :ARG0-of (b / block-01 :ARG1 (i / interact-01 :ARG0 (e3 / effector))))))))) # ::id pmid_2465_1010.142 # ::date 2015-02-18T07:42:56 # ::file pmid_2465_1010_142.txt # ::snt Restoring GTP Hydrolysis # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 18, 2015 (r / restore-01 :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x / xref :value "PUBCHEM:6830" :prob "15.470645")))) # ::id pmid_2465_1010.143 # ::date 2015-02-18T07:47:36 # ::file pmid_2465_1010_143.txt # ::snt Mutations at codons 12, 13, and 61 inhibit GAP-mediated GTP hydrolysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (i / inhibit-01 :ARG0 (m / mutate-01 :location (a / and :op1 (c / codon :mod "12") :op2 (c2 / codon :mod "13") :op3 (c3 / codon :mod "61"))) :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG1-of (m2 / mediate-01 :ARG0 (p / protein :name (n5 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003"))))) # ::id pmid_2465_1010.144 # ::date 2015-02-18T07:51:37 # ::file pmid_2465_1010_144.txt # ::snt As a result, mutant Ras proteins accumulate with elevated GTP-bound proportion. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / accumulate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (p / proportion :ARG1-of (e2 / elevate-01) :quant-of (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG1-of (b / bind-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG2-of (r / result-01)) # ::id pmid_2465_1010.145 # ::date 2015-02-18T07:56:55 # ::file pmid_2465_1010_145.txt # ::snt Trahey and McCormick discovered GAP while seeking to explain how relatively small changes in intrinsic GTPase between wild-type and mutant Ras proteins accounted for profound differences in transforming activity (Trahey and McCormick, 1987). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (d2 / discover-01 :ARG0 (a / and :op1 (p / person :name (n3 / name :op1 "Trahey")) :op2 (p2 / person :name (n4 / name :op1 "McCormick"))) :ARG1 (p3 / protein :name (n5 / name :op1 "GAP") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication-91 :ARG0 a :time (d / date-entity :year "1987"))) :time (s / seek-01 :ARG0 a :ARG1 (e3 / explain-01 :ARG0 a :ARG1 (a2 / account-01 :ARG0 (c / change-01 :ARG1 (e / enzyme :name (n / name :op1 "GTPase") :mod (i / intrinsic) :xref (x3 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :mod (s2 / small :ARG2-of (r / relative-05)) :location (e2 / enzyme :name (n2 / name :op1 "Ras") :mod (w / wild-type) :compared-to (e4 / enzyme :name (n6 / name :op1 "Ras") :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1 (d3 / differ-02 :ARG1 e2 :ARG2 e4 :ARG3 (a3 / activity-06 :ARG1 (t / transform-01) :mod (p4 / profound))))))) # ::id pmid_2465_1010.146 # ::date 2015-02-18T08:10:30 # ::file pmid_2465_1010_146.txt # ::snt Intrinsic rates of GTP hydrolysis are five orders of magnitude slower than rates catalyzed by GAPs and therefore do not contribute significantly to steady-state levels of Ras-GTP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (s3 / slow-05 :ARG1 (r / rate :mod (i / intrinsic) :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :degree (m / more :degree (o / order :quant "5" :mod (m2 / magnitude))) :compared-to (r2 / rate :degree-of (c / catalyze-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))) :ARG0-of (c2 / cause-01 :ARG1 (c3 / contribute-01 :polarity "-" :ARG0 r :ARG2 (l / level :mod (s2 / state :ARG1-of (s5 / steady-01)) :quant-of (m3 / macro-molecular-complex :part (e / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part s)) :ARG1-of (s4 / significant-02)))) # ::id pmid_2465_1010.147 # ::date 2015-02-18T08:27:42 # ::file pmid_2465_1010_147.txt # ::snt However, once Ras proteins bind effectors, GAPs can no longer interact, and intrinsic GTPase may become important in determining how long Ras and its effectors remain engaged. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (h / have-concession-91 :ARG1 (a / and :op1 (p / possible-01 :ARG1 (i / interact-01 :polarity "-" :ARG0 (p2 / protein :name (n4 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003"))) :time (n5 / no-longer)) :op2 (p3 / possible-01 :ARG1 (b / become-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "GTPase") :mod (i2 / intrinsic) :xref (x1 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :ARG2 (i3 / important :purpose (d2 / determine-01 :ARG1 (t / temporal-quantity :time-of (r / remain-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e5 / effector :poss e)) :ARG3 (e4 / engage-01 :ARG1 e5))))))) :time (b2 / bind-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "ras")) :ARG2 (e3 / effector)))) # ::id pmid_2465_1010.148 # ::date 2015-02-18T08:52:15 # ::file pmid_2465_1010_148.txt # ::snt Indeed, effector binding may well affect intrinsic GTPase activity of Ras as it does for heterotrimeric G proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (a / affect-01 :ARG0 (b / bind-01 :ARG1 (e3 / effector)) :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (e / enzyme :name (n / name :op1 "GTPase") :xref (x1 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")) :mod (i / intrinsic)) :ARG1-of (s / same-01 :ARG2 (a3 / affect-01 :ARG0 b :ARG1 (p2 / protein :name (n3 / name :op1 "G") :mod (h / heterotrimeric) :xref (x / xref :value "UNIPROT:G_CSF_HUMAN_DNA" :prob "0.601")))) :degree (w / well)) :mod (i2 / indeed)) # ::id pmid_2465_1010.149 # ::date 2015-02-18T09:01:21 # ::file pmid_2465_1010_149.txt # ::snt If indeed intrinsic GTPase limits signal output, perhaps assays for compounds that stimulate intrinsic GTPase of Ras effector complexes may merit consideration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p2 / possible-01 :ARG1 (m / merit-01 :ARG0 (a / assay-01 :ARG1 (c2 / compound :ARG0-of (s / stimulate-01 :ARG1 (a2 / act-01 :ARG0 (c3 / complex :part (e4 / effector :mod (p / protein-family :name (n2 / name :op1 "Ras")))) :ARG1 (e / enzyme :name (n / name :op1 "GTPase") :mod (i / intrinsic) :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312")))))) :ARG1 (c / consider-01)) :mod (p3 / perhaps) :condition (l / limit-01 :ARG0 e :ARG1 (o2 / output :mod (s2 / signal)) :mod (i2 / indeed))) # ::id pmid_2465_1010.150 # ::date 2015-02-18T09:18:52 # ::file pmid_2465_1010_150.txt # ::snt Mattos and colleagues recently showed that the Ras-binding domain of Raf (the RBD) has a profound effect on suppressing intrinsic hydrolysis rates of Ras Q61 mutants, but not wild-type Ras or G12V mutants (Buhrman et al., 2010). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (s / show-01 :ARG0 (a / and :op1 (p / person :name (n3 / name :op1 "Mattos")) :op2 (c / colleague :poss p)) :ARG1 (a2 / affect-01 :ARG0 (p7 / protein-segment :name (n9 / name :op1 "RBD") :part-of (e / enzyme :name (n / name :op1 "Raf") :xref (x4 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG0-of (b / bind-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1 (s2 / suppress-01 :ARG1 (r2 / rate :degree-of (h / hydrolyze-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "Q61") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :mod (i / intrinsic))) :degree (p2 / profound) :ARG1-of (c3 / contrast-01 :ARG2 (a4 / affect-01 :polarity "-" :ARG0 p7 :ARG1 (s3 / suppress-01 :polarity "-" :ARG1 (o / or :op1 (e4 / enzyme :name (n5 / name :op1 "Ras") :mod (w / wild-type) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 (e5 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "G12V") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :mod p2))) :time (r / recent) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n8 / name :op1 "Buhrman")) :op2 (p4 / person :mod (o2 / other))) :time (d / date-entity :year "2010")))) # ::id pmid_2465_1010.151 # ::date 2015-02-18T09:33:47 # ::file pmid_2465_1010_151.txt # ::snt They propose that suppression of intrinsic GTPase stabilizes Ras-Raf complexes and increases signal output to the MAPK pathway selectively; this accounts for the preference of Q61 mutants over G12 mutants in melanoma, a disease that is clearly Raf-MAPK driven (Buhrman et al., 2010). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m / multi-sentence :snt1 (p2 / propose-01 :ARG0 (t / they) :ARG1 (a / and :op1 (s / stabilize-01 :ARG0 (s2 / suppress-01 :ARG1 (e / enzyme :name (n / name :op1 "GTPase") :mod (i / intrinsic) :xref (x2 / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312"))) :ARG1 (m2 / macro-molecular-complex :part (e2 / enzyme :name (n3 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part (e3 / enzyme :name (n4 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :op2 (i2 / increase-01 :ARG0 s2 :ARG1 (o2 / output :mod (s3 / signal) :direction (p / pathway :name (n2 / name :op1 "MAPK")))) :manner (s4 / select-01))) :snt2 (a2 / account-01 :ARG0 (t2 / this) :ARG1 (p3 / prefer-01 :ARG1 (e4 / enzyme :ARG2-of (m3 / mutate-01 :value "Q61")) :ARG2 (e5 / enzyme :ARG2-of (m4 / mutate-01 :value "G12")) :location (m5 / medical-condition :name (n5 / name :op1 "melanoma") :ARG1-of (d3 / drive-02 :ARG0 (p4 / pathway :name (n6 / name :op1 "Raf-MAPK")) :ARG1-of (c / clear-06))))) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n7 / name :op1 "Buhrman")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "2010")))) # ::id pmid_2465_1010.152 # ::date 2015-02-20T00:22:10 # ::file pmid_2465_1010_152.txt # ::snt In the 1980s, several groups, including those at Cetus and Hoffmann La Roche, screened for compounds that restore GTP hydrolysis to mutant Ras, in the presence or absence of GAP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jul 14, 2015 (s2 / screen-01 :ARG0 (g / group :quant (s3 / several) :ARG2-of (i / include-01 :ARG1 (a2 / and :op1 (g2 / group :location (c / company :name (n3 / name :op1 "Cetus"))) :op2 (g3 / group :location (c2 / company :name (n4 / name :op1 "Hoffmann" :op2 "La" :op3 "Roche"))) :mod (t / that)))) :ARG2 (c3 / compound :ARG0-of (r / restore-01 :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :condition (o / or :op1 (p2 / present-02 :ARG1 (p / protein :name (n5 / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003"))) :op2 (a / absent-01 :ARG1 p)))) :time (d / date-entity :decade "1980")) # ::id pmid_2465_1010.153 # ::date 2015-02-20T00:35:36 # ::file pmid_2465_1010_153.txt # ::snt These screens failed to find compounds that increased GTPase rates. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 23, 2015 (f / fail-01 :ARG1 (s / screen-01 :mod (t / this)) :ARG2 (f2 / find-01 :ARG0 s :ARG1 (c / compound :ARG0-of (i / increase-01 :ARG1 (r / rate :degree-of (e / enzyme :name (n / name :op1 "GTPase") :xref (x / xref :value "UNIPROT:RAN_HUMAN" :prob "0.312"))))))) # ::id pmid_2465_1010.154 # ::date 2015-02-20T00:37:54 # ::file pmid_2465_1010_154.txt # ::snt Furthermore, as structures of Ras proteins emerged, mostly from Wittinghofer’s group, it became clear that codon 12 substitutions presented a steric block to GAP-mediated GTP hydrolysis that could not be overcome by a small molecule. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / and :op2 (b / become-01 :ARG2 (c / clear-06 :ARG1 (p2 / present-01 :ARG0 (s2 / substitute-01 :ARG2 (c2 / codon :mod "12")) :ARG1 (b2 / block-01 :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")) :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")))) :manner (s3 / steric) :ARG1-of (o / overcome-01 :ARG0 (s4 / small-molecule) :ARG1-of (p / possible-01 :polarity "-"))))) :ARG1-of (c3 / cause-01 :ARG0 (e2 / emerge-02 :ARG0 (s5 / structure :poss (p5 / protein-family :name (n / name :op1 "Ras"))) :source (g / group :poss (p4 / person :name (n4 / name :op1 "Wittinghofer")) :degree (m2 / most)))))) # ::id pmid_2465_1010.155 # ::date 2015-02-20T00:52:34 # ::file pmid_2465_1010_155.txt # ::snt These studies were mostly based on G12V mutations because these were the most widely used at that time. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (b / base-02 :ARG1 (s / study-01 :mod (t / this)) :ARG2 (m2 / mutate-01 :value "G12V") :degree (m / most) :ARG1-of (c / cause-01 :ARG0 (u / use-01 :ARG1 m2 :ARG1-of (w / wide-02 :degree (m3 / most)) :time (t2 / that)))) # ::id pmid_2465_1010.156 # ::date 2015-02-20T00:59:12 # ::file pmid_2465_1010_156.txt # ::snt Whether the same conclusion can be applied to other mutations such as G12D or G13D remains to be seen because structures of these proteins bound to GAP have not been solved. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 23, 2015 (r / remain-01 :ARG1 (s2 / see-01 :ARG1 (p / possible-01 :mode "interrogative" :ARG1 (a / apply-02 :ARG1 (c / conclude-01 :ARG1-of (s / same-01)) :ARG2 (m / mutate-01 :mod (o / other) :example (o2 / or :op1 (m2 / mutate-01 :value "G12D") :op2 (m3 / mutate-01 :value "G13D")))))) :ARG1-of (c2 / cause-01 :ARG0 (s3 / solve-01 :polarity "-" :ARG1 (s4 / structure :poss (p2 / protein :mod (t / this)) :ARG1-of (b / bind-01 :ARG2 (p3 / protein :name (n / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003"))))))) # ::id pmid_2465_1010.157 # ::date 2015-02-20T01:09:37 # ::file pmid_2465_1010_157.txt # ::snt The approach of restoring GTP hydrolysis to mutant proteins received a brief infusion of hope when Scheffzek and colleagues showed that G12V H-Ras could indeed hydrolyze a GTP analog diaminobenzophenone-phosphoroamidate-GTP in which the aromatic amino group mimics the catalytic effects of GAP’s arginine finger (Ahmadian et al., 1999). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (r / receive-01 :ARG0 (a / approach-02 :ARG1 (r2 / restore-01 :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG2 (p2 / protein :ARG1-of (m / mutate-01)))) :ARG1 (i / infuse-01 :ARG1 (h2 / hopeful-03) :duration (b / brief)) :time (s2 / show-01 :ARG0 (a2 / and :op1 (p3 / person :name (n3 / name :op1 "Scheffzek")) :op2 (c / colleague)) :ARG1 (p / possible-01 :ARG1 (h3 / hydrolyze-01 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "diaminobenzophenone-phosphoroamidate-GTP") :mod (a3 / analog :domain s) :location-of (m3 / mimic-01 :ARG0 (g / group :mod (a4 / aromatic) :mod (a5 / amine)) :ARG1 (e2 / effect-03 :ARG0 (f / finger :part-of (p4 / protein :name (n5 / name :op1 "GAP") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :mod (a6 / amino-acid :name (n6 / name :op1 "arginine") :xref (x2 / xref :value "PUBCHEM:232" :prob "11.348415"))) :ARG1 (c2 / catalyze-01)))) :ARG2 (e / enzyme :name (n2 / name :op1 "H-Ras") :ARG2-of (m2 / mutate-01 :value "G12V") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :mod (i2 / indeed))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a7 / and :op1 (p6 / person :name (n7 / name :op1 "Ahmadian")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "1999")))) # ::id pmid_2465_1010.158 # ::date 2015-02-20T01:32:08 # ::file pmid_2465_1010_158.txt # ::snt A small molecule that provided this local charge might therefore trick mutant Ras into GTP hydrolysis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p2 / possible-01 :ARG1 (t / trick-01 :ARG0 (s2 / small-molecule :ARG0-of (p3 / provide-01 :ARG1 (c / charge-03 :ARG1-of (l / local-02) :mod (t2 / this)))) :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :ARG1-of (i / infer-01)) # ::id pmid_2465_1010.159 # ::date 2015-02-19T22:59:47 # ::file pmid_2465_1010_159.txt # ::snt At first sight, the GTD-/GTP-binding site of Ras does not offer any room for such a molecule to bind. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (s / seem-01 :ARG1 (o2 / offer-01 :polarity "-" :ARG0 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (s2 / slash :op1 (s3 / small-molecule :name (n2 / name :op1 "GTD") :xref (x1 / xref :value "PUBCHEM:5288478" :prob "19.266134")) :op2 (s4 / small-molecule :name (n3 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645")))) :ARG1 (r / room :mod (a / any)) :purpose b) :time (s5 / see-01 :ord (o / ordinal-entity :value "1"))) # ::id pmid_2465_1010.160 # ::date 2015-02-21T23:04:58 # ::file pmid_2465_1010_160.txt # ::snt However, these issues deserve rethinking—perhaps G12D offers more possibilities for this kind of attack than G12V, for example. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c / contrast-01 :ARG2 (a / and :op1 (d / deserve-01 :ARG0 (i / issue-02 :mod (t2 / this)) :ARG1 (r / rethink-01 :ARG1 i)) :op2 (p / possible-01 :ARG1 (o / offer-01 :ARG0 (m / mutate-01 :value "G12D") :ARG1 (p2 / possibility :mod (m2 / more) :mod (a2 / attack-01 :mod (k / kind :mod (t / this))) :compared-to (m3 / mutate-01 :value "G12V"))) :example-of i))) # ::id pmid_2465_1010.161 # ::date 2015-02-22T02:28:33 # ::file pmid_2465_1010_161.txt # ::snt Targeting Ras Posttranslational Modification Pathways # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jun 16, 2015 (t / target-01 :ARG1 (p / pathway :name (n / name :op1 "Ras") :ARG1-of (m / modify-01 :time (a / after :op1 (t2 / translate-02))))) # ::id pmid_2465_1010.162 # ::date 2015-02-22T02:40:57 # ::file pmid_2465_1010_162.txt # ::snt Ras proteins are processed in several steps (reviewed in Gysin et al., 2011), including farnesylation, proteolytic cleavage at the C terminus by RCE1, and carboxymethylation by isoprenylcysteine carboxyl methyltransferase (ICMT). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (p / process-01 :ARG1 (p7 / protein-family :name (n / name :op1 "Ras")) :manner (s / step-01 :ARG4 "a2" :quant (s2 / several) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (f / farnesylate-01 :ARG1 p7) :op2 (c / cleave-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "RCE1") :xref (x1 / xref :value "UNIPROT:FACE2_HUMAN" :prob "1.002")) :ARG1 (p6 / protein-segment :name (n4 / name :op1 "C-terminus") :part-of p7) :mod (p5 / proteolytic)) :op3 (c2 / carboxymethylate-00 :ARG1 p7 :ARG2 (e3 / enzyme :name (n5 / name :op1 "isoprenylcysteine" :op2 "carboxyl" :op3 "methyltransferase") :xref (x / xref :value "UNIPROT:ICMT_HUMAN" :prob "0.692")))))) :ARG1-of (r / review-02 :ARG2 (p2 / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n2 / name :op1 "Gysin")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2011")))) # ::id pmid_2465_1010.163 # ::date 2015-02-22T03:47:03 # ::file pmid_2465_1010_163.txt # ::snt K-Ras-4A, H-Ras, and N-Ras are further processed by palmitoylation (Figure 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (p / process-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "K-Ras-4A") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op3 (e3 / enzyme :name (n3 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661"))) :manner (p2 / palmitoylate-01 :ARG1 a) :degree (f / further) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3"))) # ::id pmid_2465_1010.164 # ::date 2015-02-22T04:05:38 # ::file pmid_2465_1010_164.txt # ::snt These reactions are not only essential for plasma membrane localization but also for Raf kinase activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 27, 2015 (e / essential :purpose (a / and :op1 (b / be-located-at-91 :ARG2 (m / membrane :mod (p / plasma) :xref (x1 / xref :value "GO:0016020" :prob "0.8"))) :op2 (a2 / activate-01 :ARG1 (k / kinase :name (n / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :domain (r / react-01 :mod (t / this))) # ::id pmid_2465_1010.165 # ::date 2015-02-22T07:03:47 # ::file pmid_2465_1010_165.txt # ::snt The failure of farnesyltransferase inhibitors has been well documented. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 17, 2015 (d / document-01 :ARG1 (f / fail-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "farnesyltransferase") :xref (x / xref :value "UNIPROT:GGPPS_HUMAN" :prob "0.382"))))) :ARG1-of (w / well-09)) # ::id pmid_2465_1010.166 # ::date 2015-02-22T07:30:17 # ::file pmid_2465_1010_166.txt # ::snt By sheer bad luck, the forms of Ras that play the major roles in human cancer, K-Ras and N-Ras, can be geranylgeranylated when farnesyltransferase is inhibited, allowing newly synthesized Ras proteins to be inserted correctly in the membrane and to function normally. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (g / geranylgeranylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "K-Ras") :xref (x3 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras") :xref (x2 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")) :ARG0-of (p2 / play-08 :ARG1 (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer") :mod (h / human)) :ARG1-of (m / major-02))) :ARG1-of (c2 / cause-01 :ARG0 (l / luck :ARG1-of (b / bad-07) :mod (s / sheer))) :ARG0-of (a4 / allow-01 :ARG1 (a3 / and :op1 (i2 / insert-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (s2 / synthesize-01 :ARG1-of (n6 / new-01)) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (m2 / membrane :xref (x4 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (c3 / correct-02)) :op2 (f / function-01 :ARG0 e4 :ARG1-of (n4 / normal-02))))) :condition (i / inhibit-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "farnesyltransferase") :xref (x1 / xref :value "UNIPROT:GGPPS_HUMAN" :prob "0.382")))) # ::id pmid_2465_1010.167 # ::date 2015-02-22T08:59:39 # ::file pmid_2465_1010_167.txt # ::snt H-Ras, on the other hand, is not geranylgeranylated, suggesting that tumors driven by mutant H-Ras, such as bladder cancer or thyroid cancer, might be susceptible to farnesyltransferase inhibition. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c3 / contrast-01 :ARG2 (g / geranylgeranylate-01 :polarity "-" :ARG1 (e3 / enzyme :name (n3 / name :op1 "H-Ras") :xref (x1 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :ARG0-of (s2 / suggest-01 :ARG1 (p / possible-01 :ARG1 (s / susceptible :domain (t / tumor :ARG1-of (d / drive-02 :ARG0 (e2 / enzyme :name (n2 / name :op1 "H-Ras") :ARG2-of (m / mutate-01) :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :example (o / or :op1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (b / bladder)) :op2 (d3 / disease :wiki "Thyroid_cancer" :name (n5 / name :op1 "thyroid" :op2 "cancer")))) :prep-to (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "farnesyltransferase") :xref (x / xref :value "UNIPROT:GGPPS_HUMAN" :prob "0.382")))))))) # ::id pmid_2465_1010.168 # ::date 2015-02-22T09:56:43 # ::file pmid_2465_1010_168.txt # ::snt Targeting RCE1 or ICMT has also been evaluated, though the consequences of blocking these enzymes are difficult to predict or understand. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Feb 22, 2015 (c / contrast-01 :ARG1 (e / evaluate-01 :ARG1 (t / target-01 :ARG1 (o / or :op1 (e2 / enzyme :name (n / name :op1 "RCE1") :xref (x1 / xref :value "UNIPROT:FACE2_HUMAN" :prob "1.002")) :op2 (e3 / enzyme :name (n2 / name :op1 "ICMT") :xref (x / xref :value "UNIPROT:ICMT_HUMAN" :prob "1.003")))) :mod (a / also)) :ARG2 (d / difficult :domain (o3 / or :op1 (p / predict-01 :ARG1 (c2 / consequence :ARG1-of (c3 / cause-01 :ARG0 (b / block-01 :ARG1 o)))) :op2 (u / understand-01 :ARG1 c2)))) # ::id pmid_2465_1010.169 # ::date 2015-02-22T22:27:43 # ::file pmid_2465_1010_169.txt # ::snt For example, inhibition of either enzyme can actually lead to increased Ras-mediated tumorigenesis (Court et al., 2013; Wahlstrom et al., 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (l / lead-03 :ARG0 (i2 / inhibit-01 :ARG1 (e2 / enzyme :mod (e3 / either))) :ARG2 (c / create-01 :ARG1 (t / tumor) :ARG1-of (i / increase-01) :ARG1-of (m / mediate-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :ARG1-of (a / actual-02)) :ARG0-of (e4 / exemplify-01) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p4 / publication-91 :ARG0 (a4 / and :op1 (p2 / person :name (n2 / name :op1 "Court")) :op2 (p3 / person :mod (o2 / other))) :time (d2 / date-entity :year "2013")) :op2 (p5 / publication-91 :ARG0 (a3 / and :op1 (p6 / person :name (n3 / name :op1 "Wahlstrom")) :op2 (p7 / person :mod (o / other))) :time (d3 / date-entity :year "2007"))))) # ::id pmid_2465_1010.170 # ::date 2015-02-23T00:04:29 # ::file pmid_2465_1010_170.txt # ::snt Palmitoylation and depalmitoylation of H-Ras, K-Ras-4A, and N-Ras proteins provide dynamic aspects to membrane localization and may present therapeutic opportunities for these proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 27, 2015 (a / and :op1 (p / provide-01 :ARG0 (a2 / and :op1 (p3 / palmitoylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")) :op2 (e2 / enzyme :name (n2 / name :op1 "K-Ras-4A") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :op3 (e3 / enzyme :name (n3 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")))) :op2 (d / depalmitoylate-01 :ARG1 a3)) :ARG1 (a4 / aspect :mod (d2 / dynamic)) :ARG2 (b / be-located-at-91 :ARG1 a3 :ARG2 (m / membrane :xref (x3 / xref :value "GO:0016020" :prob "0.8")))) :op2 (p2 / possible-01 :ARG1 (p4 / present-01 :ARG0 a2 :ARG1 (o / opportunity :mod (t / therapy)) :ARG2 a3))) # ::id pmid_2465_1010.171 # ::date 2015-02-23T01:10:24 # ::file pmid_2465_1010_171.txt # ::snt Recent work demonstrated that acyl protein thioesterase 1 (APT1), which is responsible for Ras depalmitoylation, could be targeted by palmostatin B to selectively inhibit the growth of N-Ras mutant leukemia cells (Xu et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (p / possible-01 :ARG1 (t / target-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "palmostatin" :op2 "B") :xref (x3 / xref :value "PUBCHEM:45100481" :prob "12.010642")) :ARG1 (e4 / enzyme :name (n6 / name :op1 "acyl" :op2 "protein" :op3 "thioesterase" :op4 "1") :ARG0-of (r2 / responsible-01 :ARG1 (d / depalmitoylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 e4)) :xref (x / xref :value "UNIPROT:LYPA1_HUMAN" :prob "0.692")) :purpose (i / inhibit-01 :ARG0 e4 :ARG1 (g / grow-01 :ARG1 (c2 / cell :source (l / leukemia) :ARG1-of (e2 / encode-01 :ARG0 (n / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA") :part (g2 / gene :name (n4 / name :op1 "N-Ras") :ARG0-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")))))) :manner (s2 / selective))) :ARG1-of (d2 / demonstrate-01 :ARG0 (w / work-01 :time (r / recent))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and :op1 (p4 / person :name (n5 / name :op1 "Xu")) :op2 (p5 / person :mod (o / other))) :time (d4 / date-entity :year "2012")))) # ::id pmid_2465_1010.172 # ::date 2015-02-23T02:50:23 # ::file pmid_2465_1010_172.txt # ::snt In contrast, K-Ras-4B localization seemed relatively static and stable: specific localization of K-Ras-4B to plasma membranes is based on electrostatic interactions between lysine residues in the hypervariable region and phospholipids in the membrane. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c2 / cause-01 :ARG0 (b / base-02 :ARG1 (b3 / be-located-at-91 :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras-4B") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :ARG2 (m / membrane :mod (p / plasma) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (s4 / specific-02)) :ARG2 (i / interact-01 :ARG0 (r2 / residue :mod (a2 / amino-acid :name (n2 / name :op1 "lysine") :xref (x3 / xref :value "PUBCHEM:866" :prob "11.053295")) :location (r3 / region :mod (h / hypervariable))) :ARG1 (p2 / phospholipid :location (m3 / membrane :xref (x1 / xref :value "GO:0016020" :prob "0.8"))) :mod (e3 / electrostatic))) :ARG1 (s / seem-01 :ARG1 (a / and :op1 (s2 / static :ARG2-of (r / relative-05) :domain b3) :op2 (s3 / stable-03 :ARG1 b3)) :ARG2-of (c3 / contrast-01))) # ::id pmid_2465_1010.173 # ::date 2015-02-23T09:26:17 # ::file pmid_2465_1010_173.txt # ::snt However, another therapeutic opportunity has been presented by the discovery that PDE6δ acts as a solubilizing factor that modulates Ras proteins by sustaining their dynamic distribution in cellular membranes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG2 (p / present-01 :ARG0 (d / discover-01 :ARG1 (a2 / act-01 :ARG0 (p2 / protein :name (n / name :op1 "PDE6δ") :xref (x / xref :value "UNIPROT:PDE6A_HUMAN" :prob "0.292")) :ARG1 (f / factor :ARG0-of (s / solubilize-00 :ARG1 "p3") :ARG0-of (m / modulate-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "Ras")) :manner (s2 / sustain-01 :ARG0 f :ARG1 (d2 / distribute-01 :ARG1 p3 :ARG2 (m2 / membrane :location (c2 / cell) :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :manner (d3 / dynamic))))))) :ARG1 (o / opportunity :mod (t / therapy) :mod (a / another)))) # ::id pmid_2465_1010.174 # ::date 2015-02-23T10:20:29 # ::file pmid_2465_1010_174.txt # ::snt A small molecule was identified that prevents association of K-Ras-4B, and other proteins, with PDEδ and so delocalizes these proteins and inhibits downstream signaling (Zimmermann et al., 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 4, 2015 (i / identify-01 :ARG1 (s / small-molecule :ARG0-of (p / prevent-01 :ARG1 (a / associate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "K-Ras-4B") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :op2 (p3 / protein :mod (o / other))) :ARG2 (p4 / protein :name (n2 / name :op1 "PDEδ") :xref (x1 / xref :value "UNIPROT:PDE5A_HUMAN" :prob "0.252"))) :ARG0-of (c2 / cause-01 :ARG1 (a4 / and :op1 (d2 / delocalize-01 :ARG0 s :ARG1 a2) :op2 (i2 / inhibit-01 :ARG0 s :ARG1 (s2 / signal-07 :source (d / downstream))))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a5 / and :op1 (p6 / person :name (n3 / name :op1 "Zimmermann")) :op2 (p7 / person :mod (o2 / other))) :time (d4 / date-entity :year "2013")))) # ::id pmid_2465_1010.175 # ::date 2015-02-23T22:29:39 # ::file pmid_2465_1010_175.txt # ::snt Little is still known about the trafficking of Ras to and from the membrane, and there are likely to be additional factors or chaperones involved in the movement of the proteins that could serve as targets for small molecules. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (a / and :op1 (k / know-01 :ARG1 (l2 / little :topic (a2 / and :op1 (t2 / traffic-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :destination (m / membrane :xref (x2 / xref :value "GO:0016020" :prob "0.8"))) :op2 (t3 / traffic-01 :ARG1 e :source (m2 / membrane :xref (x1 / xref :value "GO:0016020" :prob "0.8"))))) :mod (s / still)) :op2 (l / likely-01 :ARG1 (i / involve-01 :ARG1 (o / or :op1 (f / factor :mod (a3 / additional)) :op2 (c / chaperone)) :ARG2 (m3 / move-01 :ARG1 (p / protein :ARG0-of (s2 / serve-01 :ARG1 (t / target-01 :ARG0 (s3 / small-molecule) :ARG1 p) :ARG1-of (p2 / possible-01))))))) # ::id pmid_2465_1010.176 # ::date 2015-02-24T00:03:46 # ::file pmid_2465_1010_176.txt # ::snt In a related study, K-Ras-4B was shown to undergo retrograde trafficking from the plasma membrane to endomembranes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG1 (u / undergo-28 :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras-4B") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "0.263")) :ARG2 (t / traffic-01 :ARG1-of (r2 / retrograde-01) :source (m / membrane :mod (p2 / plasma) :xref (x1 / xref :value "GO:0016020" :prob "0.8")) :direction (e / endomembrane))) :medium (s2 / study-01 :ARG1-of (r / relate-01))) # ::id pmid_2465_1010.177 # ::date 2015-02-24T00:42:28 # ::file pmid_2465_1010_177.txt # ::snt This may serve as an additional pathway to specifically disrupt for therapeutic benefit (Bivona et al., 2006). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / possible-01 :ARG1 (s / serve-01 :ARG0 (t / this) :ARG1 (p2 / pathway :mod (a / additional)) :purpose (d / disrupt-01 :ARG0 p2 :ARG1-of (s2 / specific-02) :purpose (b / benefit-01 :ARG0 p2 :mod (t2 / therapy)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n / name :op1 "Bivona")) :op2 (p5 / person :mod (o / other))) :time (d3 / date-entity :year "2006")))) # ::id pmid_2465_1010.178 # ::date 2015-02-24T02:00:05 # ::file pmid_2465_1010_178.txt # ::snt In addition to these processing events, several recent papers have highlighted other posttranslational modifications of K-Ras that could serve as therapeutic targets. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 2, 2016 (h / highlight-01 :ARG0 (p / paper :quant (s / several) :time (r / recent)) :ARG1 (a / and :op1 (e / event :mod (t / this) :topic (p2 / process-01)) :op2 (m / modify-01 :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :mod (o / other) :time (a2 / after :op1 (t2 / translate-02)) :ARG0-of (s2 / serve-01 :ARG1 (t3 / target-01 :ARG0 (t4 / therapy) :ARG1 m) :ARG1-of (p3 / possible-01))))) # ::id pmid_2465_1010.179 # ::date 2015-02-24T07:15:46 # ::file pmid_2465_1010_179.txt # ::snt Mono-ubiquitination at Lys147 has been shown to enhance GTP loading and effector-binding affinity of K-Ras (Sasaki et al., 2011), suggesting that targeting of ubiquitin pathway enzymes might have an effect on K-Ras activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (s / show-01 :ARG1 (e / enhance-01 :ARG0 (u / ubiquitinate-01 :quant "1" :ARG1 (a / amino-acid :mod "147" :name (n / name :op1 "lysine") :xref (x2 / xref :value "PUBCHEM:866" :prob "11.053295"))) :ARG1 (a2 / and :op1 (l / load-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :op2 (a3 / affinity :poss (e2 / enzyme :name (n3 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :topic (b / bind-01 :ARG2 (e3 / effector))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a4 / and :op1 (p2 / person :name (n4 / name :op1 "Sasaki")) :op2 (p3 / person :mod (o / other))) :time (d2 / date-entity :year "2011"))) :ARG0-of (s3 / suggest-01 :ARG1 (a5 / affect-01 :ARG0 (t / target-01 :ARG1 (e4 / enzyme :part-of (p5 / pathway :name (n5 / name :op1 "ubiquitin")))) :ARG1 (a6 / activity-06 :ARG0 e2) :ARG1-of (p4 / possible-01)))) # ::id pmid_2465_1010.180 # ::date 2015-02-24T09:47:03 # ::file pmid_2465_1010_180.txt # ::snt Acetylation of Lys104 was shown to decrease GEF-induced nucleotide exchange, leading to reduced transformation efficiency in cells, and the deacetylases SIRT2 and HDAC6 were shown to regulate the level of acetylation of K-Ras (Yang et al., 2013), suggesting that inhibitors of these enzymes might have an effect on the oncogenic potential of mutant K-Ras tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / and :op1 (s / show-01 :ARG1 (d / decrease-01 :ARG0 (a2 / acetylate-01 :ARG1 (a3 / amino-acid :mod "104" :name (n / name :op1 "lysine") :xref (x4 / xref :value "PUBCHEM:866" :prob "11.053295")) :ARG0-of (l / lead-03 :ARG2 (r / reduce-01 :ARG1 (e2 / efficient-01 :ARG2 (t / transform-01 :ARG1 (c / cell)))))) :ARG1 (e / exchange-01 :ARG1 (n2 / nucleotide) :ARG2-of (i / induce-01 :ARG0 (p / protein :name (n3 / name :op1 "GEF") :xref (x3 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")))))) :op2 (s2 / show-01 :ARG1 (r2 / regulate-01 :ARG0 (a4 / and :op1 (e4 / enzyme :name (n4 / name :op1 "SIRT2") :xref (x1 / xref :value "UNIPROT:SIR2_HUMAN" :prob "1.002")) :op2 (e5 / enzyme :name (n5 / name :op1 "HDAC6") :xref (x / xref :value "UNIPROT:HDAC6_HUMAN" :prob "1.003")) :ARG2-of (d2 / deacetylate-01 :polarity "-")) :ARG1 (l2 / level :degree-of (a5 / acetylate-01 :ARG1 (e3 / enzyme :name (n8 / name :op1 "K-Ras") :xref (x2 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))) :ARG0-of (s3 / suggest-01 :ARG1 (a7 / affect-01 :ARG0 (i2 / inhibit-01 :ARG1 a4) :ARG1 (p6 / possible-01 :ARG1 (c2 / cause-01 :ARG0 (t2 / tumor :ARG2-of (m / mutate-01) :mod e3) :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))) :ARG1-of (p5 / possible-01)))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a6 / and :op1 (p3 / person :name (n7 / name :op1 "Yang")) :op2 (p4 / person :mod (o / other))) :time (d5 / date-entity :year "2013")))) # ::id pmid_2465_1010.181 # ::date 2015-02-19T06:25:35 # ::file pmid_2465_1010_181.txt # ::snt Finally, nitrosylation of Cys118 in H-Ras has been shown to activate Ras by enhancing nucleotide dissociation, leading to higher levels of GTP-bound protein. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (s / show-01 :li "-1" :ARG1 (a / activate-01 :ARG0 (n3 / nitrosylate-01 :ARG1 (a2 / amino-acid :mod "118" :name (n6 / name :op1 "cysteine") :xref (x3 / xref :value "PUBCHEM:594" :prob "11.272514")) :location (e / enzyme :name (n / name :op1 "H-Ras") :xref (x / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631"))) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :manner (e3 / enhance-01 :ARG0 n3 :ARG1 (d / dissociate-01 :ARG1 (n4 / nucleotide)) :ARG0-of (l / lead-03 :ARG2 (l2 / level :ARG1-of (h / high-02 :degree (m / more)) :degree-of (p / protein :ARG1-of (b / bind-01 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "GTP") :xref (x2 / xref :value "PUBCHEM:6830" :prob "15.470645"))))))))) # ::id pmid_2465_1010.182 # ::date 2015-02-20T03:11:21 # ::file pmid_2465_1010_182.txt # ::snt The eNos protein was identified as a strong enhancer of nitrosylation and therefore could also be a therapeutic target to attack mutant Ras (Lim et al., 2008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (c / cause-01 :ARG0 (i / identify-01 :ARG1 (p2 / protein :name (n2 / name :op1 "eNos") :xref (x / xref :value "UNIPROT:NOS3_HUMAN" :prob "0.602")) :ARG2 (e2 / enhance-01 :ARG1 (n3 / nitrosylate-01) :ARG2 p2 :ARG1-of (s / strong-02))) :ARG1 (p / possible-01 :ARG1 (t2 / target-01 :ARG0 (t / therapy) :ARG1 p2 :mod (a3 / also) :purpose (a / attack-01 :ARG0 p2 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (m / mutate-01) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))) :ARG0-of (d2 / describe-01 :ARG1 (p3 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n4 / name :op1 "Lim")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2008")))) # ::id pmid_2465_1010.183 # ::date 2015-02-23T08:32:01 # ::file pmid_2465_1010_183.txt # ::snt Downstream Pathways and Drug Targets # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 25, 2015 (a / and :op1 (p / pathway :mod (d / downstream)) :op2 (t / target-01 :ARG0 (d2 / drug))) # ::id pmid_2465_1010.184 # ::date 2015-02-23T08:34:45 # ::file pmid_2465_1010_184.txt # ::snt When it became clear that targeting mutant Ras proteins directly was technically impossible with the tools available at that time, the search for drugs that block Ras activity moved downstream. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jul 25, 2015 (s / search-01 :ARG2 (d / drug :ARG0-of (b / block-01 :ARG1 (a / activity-06 :ARG0 "e"))) :ARG0-of (m / move-01 :ARG2 (d2 / downstream)) :time (c / clear-06 :ARG1 (p / possible-01 :polarity "-" :ARG1 (t / target-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (m2 / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (d3 / direct-02) :instrument (t3 / tool :ARG2-of (a2 / available-02 :time (t4 / time :mod (t5 / that))))) :mod (t2 / technical)))) # ::id pmid_2465_1010.185 # ::date 2015-02-23T16:17:29 # ::file pmid_2465_1010_185.txt # ::snt In the early 1990s, the MAPK pathway and the PI3K pathway were known to be downstream of Ras (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (k / know-01 :ARG1 (b / be-located-at-91 :ARG1 (a / and :op1 (p / pathway :name (n / name :op1 "MAPK")) :op2 (p2 / pathway :name (n3 / name :op1 "PI3K"))) :ARG2 (r / relative-position :op1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :direction (d3 / downstream))) :time (e / early :op1 (d / date-entity :decade "1990")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1"))) # ::id pmid_2465_1010.186 # ::date 2015-02-23T16:43:14 # ::file pmid_2465_1010_186.txt # ::snt In 1993, four groups showed that Ras binds directly to Raf kinase (Moodie et al., 1993; Van Aelst et al., 1993; Warne et al., 1993; Zhang et al., 1993), and later, activation of Raf kinase by Ras was achieved in vitro (Stokoe and McCormick, 1997). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / and :op1 (s / show-01 :ARG0 (g / group :quant "4") :ARG1 (b / bind-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (k / kinase :name (n2 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG1-of (d2 / direct-02)) :time (d / date-entity :year "1993") :ARG1-of (d3 / describe-01 :ARG0 (a5 / and :op1 (p / publication-91 :ARG0 (a4 / and :op1 (p2 / person :name (n3 / name :op1 "Moodie")) :op2 (p3 / person :mod (o / other))) :time (d4 / date-entity :year "1993")) :op2 (p4 / publication-91 :ARG0 (a6 / and :op1 (p5 / person :name (n4 / name :op1 "Van" :op2 "Aelst")) :op2 (p6 / person :mod (o2 / other))) :time d4) :op3 (p7 / publication-91 :ARG0 (a7 / and :op1 (p8 / person :name (n5 / name :op1 "Warne")) :op2 (p9 / person :mod (o3 / other))) :time d4) :op4 (p10 / publication-91 :ARG0 (a8 / and :op1 (p11 / person :name (n6 / name :op1 "Zhang")) :op2 (p12 / person :mod (o4 / other))) :time d4)))) :op2 (a2 / activate-01 :ARG0 e :ARG1 k :ARG1-of (a3 / achieve-01 :manner (i / in-vitro)) :time (l / late :degree (m / more)) :ARG1-of (d5 / describe-01 :ARG0 (p13 / publication-91 :ARG0 (a9 / and :op1 (p14 / person :name (n7 / name :op1 "Stokoe")) :op2 (p15 / person :name (n8 / name :op1 "McCormick"))) :time (d6 / date-entity :year "1997"))))) # ::id pmid_2465_1010.187 # ::date 2015-02-23T16:55:30 # ::file pmid_2465_1010_187.txt # ::snt This was unexpectedly difficult; for one thing, Raf activation by Ras required fully processed Ras in a lipid environment, and direct binding of unprocessed Ras failed to activate the kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (m / multi-sentence :snt1 (d / difficult :domain (t / this) :ARG1-of (e3 / expect-01 :polarity "-")) :snt2 (a3 / and :li "1" :op1 (r / require-01 :ARG0 (a / activate-01 :ARG0 "e2" :ARG1 (k / kinase :name (n / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG1 (p / process-01 :ARG1 "e2" :degree (f / full)) :location (e4 / environment :mod (l / lipid))) :op2 (f2 / fail-01 :ARG1 (b / bind-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (p2 / process-01 :polarity "-") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1-of (d2 / direct-02)) :ARG2 (a2 / activate-01 :ARG0 b :ARG1 k)))) # ::id pmid_2465_1010.188 # ::date 2015-02-23T17:15:35 # ::file pmid_2465_1010_188.txt # ::snt Furthermore, autophosphorylation rapidly shut down Raf kinase in vitro; we had to preincubate processed Ras with Raf in the absence of ATP before measuring Raf kinase activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a4 / and :op2 (c / cause-01 :ARG0 (s2 / shut-down-05 :ARG1 (k / kinase :name (n3 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG2 (p / phosphorylate-01 :ARG1 k :ARG2 k) :manner (r / rapid) :manner (i / in-vitro)) :ARG1 (o / obligate-01 :ARG1 (w / we) :ARG2 (p2 / preincubate-01 :ARG0 w :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (p3 / process-01) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :op2 k) :condition (a3 / absent-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "ATP") :xref (x2 / xref :value "PUBCHEM:5957" :prob "14.368295"))) :time (b / before :op1 (m2 / measure-01 :ARG0 w :ARG1 (a2 / activity-06 :ARG0 k))))))) # ::id pmid_2465_1010.189 # ::date 2015-02-23T17:19:03 # ::file pmid_2465_1010_189.txt # ::snt This autophosphorylation accounts, at least in part, for paradoxical activation of Raf kinase by Raf inhibitors, a phenomenon that was discovered 16 years later (reviewed in Holderfield et al., 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 26, 2016 (a4 / account-01 :ARG0 (p / phosphorylate-01 :mod (s / self) :mod (t3 / this)) :ARG1 (a2 / activate-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 "k")) :ARG1 (k / kinase :name (n2 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :manner (p3 / paradox)) :extent (p7 / part :mod (a / at-least)) :ARG1-of (d2 / discover-01 :mod (l / late :degree (m / more :quant (t / temporal-quantity :quant "16" :unit (y / year))))) :ARG1-of (r / review-02 :ARG2 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n3 / name :op1 "Holderfield")) :op1 (p6 / person :mod (o / other))) :time (d / date-entity :year "2013")))) # ::id pmid_2465_1010.190 # ::date 2015-02-23T19:26:24 # ::file pmid_2465_1010_190.txt # ::snt These issues complicate the development of in vitro assays for compounds that prevent Ras-dependent activation of Raf kinase, an obvious system for therapeutic intervention. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (c / complicate-01 :ARG0 (i / issue-02 :mod (t / this)) :ARG1 (d / develop-02 :ARG1 (a / assay-01 :ARG1 (c2 / compound :ARG0-of (p / prevent-01 :ARG1 (a2 / activate-01 :ARG1 (k / kinase :name (n / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :ARG0-of (d2 / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :manner (i2 / in-vitro)) :mod (s / system :ARG1-of (o / obvious-01) :ARG0-of (i3 / intervene-01 :ARG1 (t2 / therapy))))) # ::id pmid_2465_1010.191 # ::date 2015-02-23T19:37:43 # ::file pmid_2465_1010_191.txt # ::snt Direct blocking of Ras-Raf binding with small molecules does not appear to be a promising approach because the binding surface (two antiparallel β strands) offers no foothold in which a compound could bind. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jul 24, 2015 (a / appear-02 :polarity "-" :ARG1 (p2 / promise-01 :ARG2 (a2 / approach :domain (b / block-01 :ARG0 (s / small-molecule) :ARG1 (b2 / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG1-of (d / direct-02)))) :ARG1-of (c / cause-01 :ARG0 (o / offer-01 :polarity "-" :ARG0 (b4 / bind-01 :ARG3 (s2 / surface)) :ARG1 (f / foothold :location-of (p3 / possible-01 :ARG1 (b3 / bind-01 :ARG1 (c3 / compound) :ARG1-of (m / mean-01 :ARG2 (s3 / strand :quant "2" :name (n3 / name :op1 "β") :mod (a3 / antiparallel))))))))) # ::id pmid_2465_1010.192 # ::date 2015-02-23T19:52:41 # ::file pmid_2465_1010_192.txt # ::snt However, for example, preventing binding using peptides or by indirect allosteric approaches has been considered (see Wu et al., 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (h2 / have-concession-91 :ARG1 (e2 / exemplify-01 :ARG0 (c2 / consider-01 :ARG1 (p / prevent-01 :ARG1 (b / bind-01) :manner (o3 / or :op1 (u / use-01 :ARG1 (p5 / peptide)) :op2 (a / approach-02 :ARG0 (m2 / molecular-physical-entity :mod (i / indirect) :mod (a3 / allosteric))))))) :ARG1-of (s / see-01 :location (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n3 / name :op1 "Wu")) :op2 (p4 / person :mod (o2 / other))) :time (d / date-entity :year "2013")))) # ::id pmid_2465_1010.193 # ::date 2015-02-23T20:01:55 # ::file pmid_2465_1010_193.txt # ::snt The drug discovery group at Onyx Pharmaceuticals began screening for Raf kinase inhibitors in 1992 after it was able produce active c-Raf kinase in baculovirus (by coinfection with v-Src) and to reconstitute the MAPK pathway in vitro (Macdonald et al., 1993). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (b / begin-01 :ARG1 (s / screen-01 :ARG0 (g / group :part-of (c / company :name (n5 / name :op1 "Onyx" :op2 "Pharmaceuticals")) :ARG0-of (d3 / discover-01 :ARG1 (d4 / drug))) :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (k / kinase :name (n4 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :time (d / date-entity :year "1992") :time (a / after :op1 (c2 / capable-01 :ARG1 g :ARG2 (a4 / and :op1 (p / produce-01 :ARG0 g :ARG1 (e2 / enzyme :name (n2 / name :op1 "c-Raf") :ARG0-of (a2 / activity-06) :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :manner (c3 / coinfect-00 :ARG0 (e3 / enzyme :name (n7 / name :op1 "v-Src"))) :location (o / organism :name (n3 / name :op1 "baculovirus"))) :op2 (r / reconstitute-01 :ARG0 g :ARG1 (p2 / pathway :name (n / name :op1 "MAPK")) :manner (i3 / in-vitro)))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n6 / name :op1 "Macdonald")) :op2 (p5 / person :mod (o2 / other)))) :time (d5 / date-entity :year "1993"))) # ::id pmid_2465_1010.194 # ::date 2015-02-24T05:16:39 # ::file pmid_2465_1010_194.txt # ::snt It was then assumed that in cancer cells with mutant Ras, the Raf/MAPK pathway would be hyperactive and that drugs that inhibit Raf would be effective ways of treating Ras mutant cancers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (a / assume-02 :ARG1 (a2 / and :op1 (h / hyperactive :domain (p / pathway :name (n4 / name :op1 "Raf" :op2 "MAPK"))) :op2 (t / treat-04 :ARG0 (d2 / drug :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod (m / mutate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG0-of (h3 / have-03 :ARG1 "m2")) :ARG1-of (e3 / effective-04))) :location (c / cell :mod (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")) :ARG0-of (h2 / have-03 :ARG1 (m2 / mutate-01 :ARG1 e))) :time (t2 / then)) # ::id pmid_2465_1010.195 # ::date 2015-02-24T05:31:21 # ::file pmid_2465_1010_195.txt # ::snt It was also assumed that MEK and extracellular signal-regulated kinase (ERK) inhibitors would have the same effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / assume-02 :ARG1 (p / possible-01 :ARG1 (a2 / affect-01 :ARG0 (a3 / and :op1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase"))))) :ARG1-of (s / same-01))) :mod (a4 / also)) # ::id pmid_2465_1010.196 # ::date 2015-02-24T05:50:42 # ::file pmid_2465_1010_196.txt # ::snt In hindsight, most of the assumptions were incorrect: the Raf/MAPK pathway is not often hyperactive in human cancer cells with mutant Ras, as measured by steady-state levels of phospho-MEK or phospho-ERK. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (c2 / correct-02 :polarity "-" :ARG1 (a / assume-02 :quant (m / most) :example (h / hyperactive :frequency (o / often :polarity "-") :domain (p / pathway :name (n3 / name :op1 "Raf" :op2 "MAPK")) :location (c / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod (h2 / human)) :prep-with (e / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (m3 / mutate-01) :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG1-of (m2 / measure-01 :ARG2 (l / level :degree-of (o2 / or :op1 (p2 / phosphorylate-01 :ARG2 (e4 / enzyme :name (n4 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op2 (p3 / phosphorylate-01 :ARG2 (e3 / enzyme :name (n5 / name :op1 "ERK") :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003")))) :ARG1-of (s / steady-01 :mod (s2 / state)))))) :prep-in (h3 / hindsight)) # ::id pmid_2465_1010.197 # ::date 2015-02-24T05:58:51 # ::file pmid_2465_1010_197.txt # ::snt Raf inhibitors lead to paradoxical activation of Raf kinase following exposure to Raf inhibitors, especially in Ras mutant cancers (reviewed in Lito et al., 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (l / lead-03 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (k2 / kinase :name (n6 / name :op1 "Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :ARG2 (a / activate-01 :ARG1 k2 :manner (p / paradox)) :location (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (m / mutate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :mod (e2 / especially)) :ARG1-of (r / review-02 :ARG2 (p3 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n5 / name :op1 "Lito")) :op2 (p5 / person :mod (o / other))) :time (d / date-entity :year "2013"))) :time (f / follow-01 :ARG2 (e3 / expose-01 :ARG2 m2))) # ::id pmid_2465_1010.198 # ::date 2015-02-21T08:40:45 # ::file pmid_2465_1010_198.txt # ::snt MEK and ERK inhibitors do not show paradoxical activation but are generally ineffective on their own because they relieve feedback inhibition on upstream kinases, leading to activation of PI3K, among other effects (Mirzoeva et al., 2009; Corcoran et al., 2012; Turke et al., 2012; Montero-Conde et al., 2013), and because they lack a clear therapeutic window. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / contrast-01 :ARG1 (s / show-01 :polarity "-" :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (a2 / and :op1 (p11 / protein-family :name (n / name :op1 "MEK")) :op2 (p12 / protein-family :name (n2 / name :op1 "ERK"))))) :ARG1 (a / activate-01 :mod (p / paradox))) :ARG2 (e / effective-04 :polarity "-" :ARG0 m :mod (b / by-oneself) :ARG1-of (g / general-02) :ARG1-of (c2 / cause-01 :ARG0 (a5 / and :op1 (r / relieve-01 :ARG0 m :ARG1 (i2 / inhibit-01 :subevent-of (f / feedback)) :ARG2 (k / kinase :location (u / upstream)) :ARG0-of (l / lead-03 :ARG2 (a3 / activate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :ARG1-of (i3 / include-91 :ARG2 (a4 / affect-01 :mod (o / other))))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (p2 / publication-91 :ARG0 (a7 / and :op1 (p6 / person :name (n4 / name :op1 "Mirzoeva")) :op2 (p7 / person :mod (o2 / other))) :time (d3 / date-entity :year "2009")) :op2 (p3 / publication-91 :ARG0 (a8 / and :op1 (p8 / person :name (n5 / name :op1 "Corcoran")) :op2 p7) :time (d4 / date-entity :year "2012")) :op3 (p4 / publication-91 :ARG0 (a9 / and :op1 (p9 / person :name (n6 / name :op1 "Turke")) :op2 p7) :time d4) :op4 (p5 / publication-91 :ARG0 (a10 / and :op1 (p10 / person :name (n7 / name :op1 "Montero-Conde")) :op2 p7) :time (d5 / date-entity :year "2013"))))) :op2 (l2 / lack-01 :ARG0 m :ARG1 (w / window :ARG1-of (c3 / clear-06) :mod (t / therapy))))))) # ::id pmid_2465_1010.199 # ::date 2015-02-21T10:06:31 # ::file pmid_2465_1010_199.txt # ::snt MEK1/MEK2 isoforms have a high degree of amino acid identity, suggesting redundant roles in signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (i4 / identical-01 :ARG1 (s / slash :op1 (i / isoform :mod (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :op2 (i3 / isoform :mod (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :ARG2 (a / amino-acid) :ARG1-of (h / high-02) :ARG0-of (s2 / suggest-01 :ARG1 (p / play-08 :ARG0 s :ARG1 (s3 / signal-07) :mod (r / redundant)))) # ::id pmid_2465_1010.200 # ::date 2015-02-21T11:28:34 # ::file pmid_2465_1010_200.txt # ::snt The same is true for ERK1/ERK2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 4, 2015 (t / true-01 :ARG1 (t2 / thing :ARG1-of (s / same-01)) :ARG2 (s2 / slash :op1 (e / enzyme :name (n / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) # ::id pmid_2465_1010.201 # ::date 2015-02-21T12:00:31 # ::file pmid_2465_1010_201.txt # ::snt However, knocking out the gene encoding MEK1, Map2k1 (Giroux et al., 1999), or the gene encoding ERK2, Mapk1 (Hatano et al., 2003; Saba-El-Leil et al., 2003; Yao et al., 2003), is embryonic lethal, indicating a requirement for signaling from a particular isoform, at least in the context of embryogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 26, 2015 (c2 / contrast-01 :ARG2 (c / cause-01 :ARG0 (k / knock-out-03 :ARG1 (o / or :op1 (g / gene :name (n / name :op1 "Map2k1") :ARG0-of (e / encode-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003"))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p4 / person :name (n5 / name :op1 "Giroux")) :op2 (p3 / person :mod (o2 / other))) :time (d3 / date-entity :year "1999"))) :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "0.603")) :op2 (g2 / gene :name (n3 / name :op1 "Mapk1") :ARG0-of (e3 / encode-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and :op1 (p5 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n6 / name :op1 "Hatano")) :op2 p3) :time (d5 / date-entity :year "2003")) :op2 (p6 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n7 / name :op1 "Saba-El-Leil")) :op2 p3) :time d5) :op3 (p7 / publication-91 :ARG0 (a6 / and :op1 (p10 / person :name (n8 / name :op1 "Yao")) :op2 p3) :time d5))) :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :ARG1 (d / die-01 :ARG1 (e5 / embryo)) :ARG0-of (i / indicate-01 :ARG1 (r / require-01 :ARG1 (s / signal-07 :ARG0 "i2") :ARG2 (i2 / isoform :mod (p / particular)) :condition (e6 / embryogenesis :mod (a / at-least)))))) # ::id pmid_2465_1010.202 # ::date 2015-02-21T12:41:19 # ::file pmid_2465_1010_202.txt # ::snt Although Map2k2−/− (MEK2 null) and Mapk3−/− (ERK1 null) mice are viable, in vivo ablation of MEK1 in a Map2k2−/− background (Scholl et al., 2007; Blasco et al., 2011) or ERK2 in a Mapk3−/− background (Chan et al., 2013) results in apoptosis and lethality in adult mice. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 26, 2015 (h / have-concession-91 :ARG1 (r / result-01 :ARG1 (o / or :op1 (a2 / ablate-01 :ARG1 (e3 / enzyme :name (n7 / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :manner (i / in-vivo) :location (b / background :mod "g") :ARG1-of (d / describe-01 :ARG0 (a6 / and :op1 (p / publication-91 :ARG0 (a7 / and :op1 (p3 / person :name (n9 / name :op1 "Scholl")) :op2 (p4 / person :mod (o2 / other))) :time (d2 / date-entity :year "2007")) :op2 (p2 / publication-91 :ARG0 (a8 / and :op1 (p5 / person :name (n10 / name :op1 "Blasco")) :op2 p4) :time (d3 / date-entity :year "2011"))))) :op2 (a3 / ablate-01 :ARG1 (e4 / enzyme :name (n8 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")) :manner i :location (b2 / background :mod "g2") :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a9 / and :op1 (p8 / person :name (n11 / name :op1 "Chan")) :op2 p4) :time (d5 / date-entity :year "2013"))))) :ARG2 (a4 / and :op1 (a5 / apoptosis :mod "m5") :op2 (d6 / die-01 :ARG1 (m5 / mouse :mod (a10 / adult))))) :ARG2 (v / viable :domain (a / and :op1 (m / mouse :mod (g / gene :name (n / name :op1 "Map2k2−/−") :ARG1-of (e5 / express-03 :polarity "-" :ARG2 (e / enzyme :name (n3 / name :op1 "MEK2") :xref (x3 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :op2 (m2 / mouse :mod (g2 / gene :name (n2 / name :op1 "Mapk3−/−") :ARG1-of (e6 / express-03 :polarity "-" :ARG2 (e2 / enzyme :name (n5 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")))))))) # ::id pmid_2465_1010.203 # ::date 2015-02-21T13:21:26 # ::file pmid_2465_1010_203.txt # ::snt This may suggest a limited therapeutic window for any pan inhibitor of these kinases, and the clinical toxicity of potential drugs in this target class bears this out. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Mar 16, 2015 (a / and :op1 (p / possible-01 :ARG1 (s / suggest-01 :ARG0 (t / this) :ARG1 (w / window :mod (t2 / therapy) :ARG1-of (l / limit-01) :poss (m / molecular-physical-entity :mod (p2 / pan) :ARG0-of (i / inhibit-01 :ARG1 (k / kinase :mod (t3 / this))))))) :op2 (b / bear-out-05 :ARG0 (t4 / toxic :mod (c / clinic) :domain (d / drug :mod (p3 / potential) :ARG1-of (i2 / include-91 :ARG2 (c2 / class :ARG1-of (t5 / target-01))))) :ARG1 p)) # ::id pmid_2465_1010.204 # ::date 2015-02-21T22:09:03 # ::file pmid_2465_1010_204.txt # ::snt The Onyx/Bayer screen for c-Raf inhibitors led to the discovery and development of sorafenib. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 21, 2015 (l / lead-03 :ARG0 (s / screen-01 :ARG0 (s2 / slash :op1 (c / company :name (n / name :op1 "Onyx")) :op2 (c2 / company :name (n2 / name :op1 "Bayer"))) :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "C-Raf") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673"))))) :ARG2 (a / and :op1 (d / discover-01 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "sorafenib") :xref (x1 / xref :value "PUBCHEM:216239" :prob "16.740406"))) :op2 (d2 / develop-02 :ARG1 s3))) # ::id pmid_2465_1010.205 # ::date 2015-02-21T22:38:00 # ::file pmid_2465_1010_205.txt # ::snt However, it was disappointing when sorafenib failed to show clinical benefit in early clinical trials against Ras mutant cancers, and this lack of response was difficult to understand because sorafenib does indeed inhibit Raf kinase. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (h / have-concession-91 :ARG1 (a / and :op1 (d / disappoint-01 :ARG0 (s2 / show-01 :polarity "-" :ARG0 (s3 / small-molecule :wiki "Sorafenib" :name (n / name :op1 "sorafenib") :xref (x2 / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG1 (b / benefit-01 :ARG0 s3 :mod (c / clinic)) :time (t / trial-06 :mod c :time (e / early) :purpose (c2 / counter-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :mod (e2 / enzyme :wiki "Ras_subfamily" :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))))))) :op2 (d2 / difficult :domain (u / understand-01 :ARG1 (l / lack-01 :ARG1 (r / respond-01) :mod (t2 / this))) :ARG1-of (c3 / cause-01 :ARG0 (i / inhibit-01 :ARG0 s3 :ARG1 (k / kinase :wiki "RAF_kinase" :name (n3 / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :mod (i2 / indeed)))))) # ::id pmid_2465_1010.206 # ::date 2015-02-22T01:00:29 # ::file pmid_2465_1010_206.txt # ::snt Despite this, sorafenib and fluoro-sorafenib (regorafenib) have since been approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid cancer, colorectal cancer, and gastrointestinal stromal cancer. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-concession-91 :ARG1 (a / approve-01 :ARG1 (a2 / and :op1 (s2 / small-molecule :name (n / name :op1 "sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :op2 (s3 / small-molecule :name (n2 / name :op1 "fluoro-sorafenib") :ARG1-of (m / mean-01 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "regorafenib") :xref (x1 / xref :value "PUBCHEM:11167602" :prob "16.963549"))))) :ARG2 (t2 / treat-03 :ARG2 (a3 / and :op1 (c / carcinoma :mod (c2 / cell :mod (k / kidney))) :op2 (c3 / carcinoma :mod (h2 / hepatocellular)) :op3 (d / disease :wiki "Thyroid_cancer" :name (n4 / name :op1 "thyroid" :op2 "cancer")) :op4 (d2 / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal" :op2 "cancer")) :op5 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :mod (s5 / stroma :mod (g / gastrointestinal))))) :time (s / since)) :ARG2 (t / this)) # ::id pmid_2465_1010.207 # ::date 2015-02-22T01:27:11 # ::file pmid_2465_1010_207.txt # ::snt In hepatocellular carcinoma, biomarker analysis in Phase II clinical trials showed a clear correlation between levels of phospho-ERK and clinical response, suggesting that inhibition of Raf kinase is responsible for part of the clinical benefit (Abou-Alfa et al., 2006), but in the other indications, it appears likely that inhibition of vascular endothelial growth factor receptor 2 or other kinases is responsible. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (b / biomarker)) :ARG1 (c3 / correlate-01 :ARG1 (l / level :degree-of (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p2 / phosphorylate-01) :xref (x1 / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG2 (r / respond-01 :mod "c2") :ARG1-of (c4 / clear-06)) :subevent-of (t / trial-06 :mod (c2 / clinic) :mod (p / phase :ord (o / ordinal-entity :value "2"))) :ARG0-of (s2 / suggest-01 :ARG1 (r2 / responsible-01 :ARG0 (i / inhibit-01 :ARG1 (k / kinase :name (n2 / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG1 (b2 / benefit-01 :mod (c5 / clinic) :degree (p3 / part)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n3 / name :op1 "Abou-Alfa")) :op2 (p6 / person :mod (o2 / other))) :time (d2 / date-entity :year "2006"))) :condition (c6 / carcinoma :mod (h2 / hepatocellular))) :ARG2 (a3 / appear-02 :ARG1 (l2 / likely-01 :ARG1 (r3 / responsible-01 :ARG0 (i3 / inhibit-01 :ARG1 (o4 / or :op1 (e3 / enzyme :name (n4 / name :op1 "vascular" :op2 "endothelial" :op3 "growth" :op4 "factor" :op5 "receptor" :op6 "2") :xref (x / xref :value "UNIPROT:VGFR2_HUMAN" :prob "0.703")) :op2 (k3 / kinase :mod (o5 / other)))) :ARG1 b2)) :condition (i2 / indicate-101 :mod (o3 / other)))) # ::id pmid_2465_1010.208 # ::date 2015-02-22T08:58:46 # ::file pmid_2465_1010_208.txt # ::snt Hopefully, a clearer picture will emerge through analysis of exceptional responders or through deciphering mechanisms of drug resistance. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (e / emerge-01 :ARG0 (p / picture :ARG1-of (c / clear-06 :degree (m / more))) :ARG1 (o / or :op1 (a / analyze-01 :ARG1 (t / thing :ARG0-of (r / respond-01) :mod (e2 / exceptional))) :op2 (d / decipher-01 :ARG1 (m2 / mechanism :mod (r2 / resist-01 :ARG1 (d2 / drug))))) :ARG1-of (h / hopeful-03)) # ::id pmid_2465_1010.209 # ::date 2015-02-22T09:17:41 # ::file pmid_2465_1010_209.txt # ::snt Inhibitors of PI3K pathway have not yet fared much better in the clinic, also because of feedback mechanisms that activate upstream signaling, as well as poor therapeutic index. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (c / cause-01 :ARG0 (a / and :op1 (m4 / mechanism :mod (f2 / feedback) :ARG0-of (a2 / activate-01 :ARG1 (s / signal-07 :source (u / upstream))) :mod (a3 / also)) :op2 (i2 / index :mod (t / therapy) :mod (p2 / poor))) :ARG1 (f / fare-01 :polarity "-" :ARG0 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "PI3K")))) :ARG1-of (g / good-02 :degree (m / more :quant (m2 / much))) :location (c2 / clinic) :time (y / yet))) # ::id pmid_2465_1010.210 # ::date 2015-02-22T09:42:33 # ::file pmid_2465_1010_210.txt # ::snt However, the relative failure of these downstream approaches does not mean that they are not critical to Ras oncogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (c2 / contrast-01 :ARG2 (m / mean-01 :polarity "-" :ARG1 (f / fail-01 :ARG1 (a / approach-02 :mod (t / this) :mod (d / downstream)) :ARG2-of (r / relative-05)) :ARG2 (c / critical-02 :polarity "-" :ARG1 a :ARG2 (c3 / cause-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))) # ::id pmid_2465_1010.211 # ::date 2015-02-22T10:03:43 # ::file pmid_2465_1010_211.txt # ::snt Indeed, ablation of c-Raf (but not B-Raf) in mice inhibits development and delays progression of Ras-driven tumors in a lung adenocarcinoma model (Blasco et al., 2011). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Mar 13, 2015 (a / and :op1 (i / inhibit-01 :ARG0 (a2 / ablate-01 :ARG1 (e / enzyme :name (n / name :op1 "C-Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.673")) :location (m / mouse) :ARG1-of (c / contrast-01 :ARG2 (a5 / ablate-01 :polarity "-" :ARG1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :xref (x1 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))))) :ARG1 (d2 / develop-01 :ARG1 "m2" :ARG2 "t")) :op2 (d / delay-01 :ARG0 a2 :ARG1 (p / progress-01 :ARG1 (t / tumor :ARG1-of (d3 / drive-02 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))) :location (m2 / model :topic (a3 / adenocarcinoma :mod (l / lung))))) :mod (i2 / indeed) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a4 / and :op1 (p3 / person :name (n4 / name :op1 "Blasco")) :op2 (p4 / person :mod (o / other))) :time (d5 / date-entity :year "2011")))) # ::id pmid_2465_1010.212 # ::date 2015-02-22T10:22:39 # ::file pmid_2465_1010_212.txt # ::snt However, in an in vivo pancreatic cancer mouse model, B-Raf was shown to be required for tumor progression (Sobczak et al., 2008). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (c2 / contrast-01 :ARG2 (s / show-01 :ARG1 (r / require-01 :ARG0 (p / progress-01 :ARG1 (t / tumor)) :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :xref (x / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661"))) :condition (m / model :mod (m2 / mouse) :mod (i / in-vivo) :topic (d3 / disease :wiki "Pancreatic_cancer" :name (n4 / name :op1 "pancreatic" :op2 "cancer"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and :op1 (p4 / person :name (n2 / name :op1 "Sobczak")) :op2 (p5 / person :mod (o / other))) :time (d2 / date-entity :year "2008"))))) # ::id pmid_2465_1010.213 # ::date 2015-02-22T11:21:14 # ::file pmid_2465_1010_213.txt # ::snt This suggests tissue-specific signaling cascades and will require more investigation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (s / suggest-01 :ARG0 (t / this) :ARG1 (c / cascade :subevent (s2 / signal-07) :ARG1-of (s3 / specific-02 :ARG2 (t2 / tissue)))) :op2 (r / require-01 :ARG0 t :ARG1 (i / investigate-01 :degree (m / more)))) # ::id pmid_2465_1010.214 # ::date 2015-02-22T11:29:00 # ::file pmid_2465_1010_214.txt # ::snt Genetic disruption of Ras binding to PI3K-α has a similar effect. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Feb 22, 2015 (a / affect-01 :ARG0 (d / disrupt-01 :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "PI3K-α") :xref (x1 / xref :value "UNIPROT:PK3CB_HUMAN" :prob "0.253"))) :mod (g / genetic)) :ARG1-of (r / resemble-01)) # ::id pmid_2465_1010.215 # ::date 2015-02-22T11:38:20 # ::file pmid_2465_1010_215.txt # ::snt We can therefore assume that small molecules that can block downstream signaling without triggering feedback and with the correct specificity and biochemical properties may still be effective, but more work needs to be done to develop such compounds effectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (h / have-concession-91 :ARG1 (n / need-01 :ARG1 (w2 / work-01 :degree (m2 / more) :purpose (d2 / develop-02 :ARG0 "w" :ARG1 (c2 / compound :mod (s5 / such)) :ARG1-of (e2 / effective-04)))) :ARG2 (i / infer-01 :ARG1 (p / possible-01 :ARG1 (a / assume-02 :ARG0 (w / we) :ARG1 (p2 / possible-01 :ARG1 (e / effective-04 :ARG0 (m / molecule :mod (s / small) :ARG0-of (b / block-01 :ARG1 (s2 / signal-07 :source (d / downstream)) :manner (t / trigger-01 :polarity "-" :ARG0 m :ARG1 (f / feedback)) :ARG1-of (p4 / possible-01)) :ARG0-of (h2 / have-03 :ARG1 (a2 / and :op1 (s3 / specificity :ARG1-of (c / correct-02)) :op2 (p3 / property :mod (b2 / biochemical) :ARG1-of c)))) :mod (s4 / still))))))) # ::id pmid_2465_1010.216 # ::date 2015-02-22T11:58:37 # ::file pmid_2465_1010_216.txt # ::snt The third direct effector arm of Ras signaling that plays a major role in human cancer is the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (a / arm :mod (e / effector :ARG1-of (d3 / direct-02)) :poss (s / signal-07 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ord (o / ordinal-entity :value "3") :ARG0-of (p2 / play-08 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :mod (h / human)) :ARG1-of (m / major-02)) :domain (p / protein :name (n / name :op1 "RalGDS") :xref (x / xref :value "UNIPROT:GNDS_HUMAN" :prob "1.003")) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1"))) # ::id pmid_2465_1010.217 # ::date 2015-02-22T12:07:02 # ::file pmid_2465_1010_217.txt # ::snt Perhaps the best evidence of the importance of this effector pathway comes from demonstration that mice null for RalGDS have reduced skin carcinogen-induced tumor incidence, size, and progression to malignancy compared to wild-type mice (González-García et al., 2005). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (p / possible-01 :ARG1 (e / evidence-01 :ARG0 (d / demonstrate-01 :ARG1 (h / have-03 :ARG0 (m3 / mouse :mod (n3 / null :mod (p7 / protein :name (n / name :op1 "RalGDS") :xref (x / xref :value "UNIPROT:GNDS_HUMAN" :prob "1.003")))) :ARG1 (a / and :op1 (i2 / incidence :frequency-of (t / tumor :ARG2-of (i3 / induce-01 :ARG0 (c2 / carcinogen)) :mod (s / skin))) :op2 (s2 / size :mod t) :op3 (p3 / progress-01 :ARG1 t :ARG4 (m2 / malignancy)) :ARG1-of (r / reduce-01 :ARG1-of (c3 / compare-01 :ARG2 (m4 / mouse :mod (w / wild-type))))))) :ARG1 (i / important :domain (p2 / pathway :mod (e2 / effector) :mod (t2 / this))) :ARG1-of (g / good-02 :degree (m / most))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n2 / name :op1 "González-García")) :op2 (p6 / person :mod (o / other))) :time (d3 / date-entity :year "2005")))) # ::id pmid_2465_1010.218 # ::date 2015-02-22T12:30:02 # ::file pmid_2465_1010_218.txt # ::snt These data, and many others (Martin et al., 2011; Kashatus, 2013), support a role for RalGDS both in vitro and in vivo as an important effector pathway utilized by oncogenic Ras to drive tumorigenesis that could potentially be exploited for therapeutic intervention, although the absence of somatic mutations in this effector pathway makes its precise role less clear than the Raf/MAPK and PI3K pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jan 13, 2016 (s / support-01 :ARG0 (a / and :op2 (d / data :mod (t / this)) :op2 (o / other :quant (m / many)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p / publication-91 :ARG0 (a3 / and :op1 (p2 / person :name (n / name :op1 "Martin")) :op2 (p3 / person :mod (o2 / other))) :time (d3 / date-entity :year "2011")) :op2 (p4 / publication-91 :ARG0 (p5 / person :name (n2 / name :op1 "Kashatus")) :time (d4 / date-entity :year "2013"))))) :ARG1 (a6 / and :op1 (p6 / play-02 :ARG0 (p15 / pathway :name (n3 / name :op1 "RalGDS")) :ARG1 (p7 / pathway :mod (e / effector) :mod (i / important) :ARG1-of (u / utilize-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d6 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :purpose (d5 / drive-02 :ARG0 e2 :ARG1 (c3 / create-01 :ARG1 (t2 / tumor) :ARG1-of (e3 / exploit-01 :ARG2 (i4 / intervene-01 :mod (t3 / therapy)) :ARG1-of (p8 / possible-01) :mod (p9 / potential)))))) :manner (i2 / in-vitro)) :op2 (p14 / play-02 :ARG0 p15 :ARG1 p7 :manner (i3 / in-vivo))) :concession (m2 / make-02 :ARG0 (a4 / absent-01 :ARG1 (m3 / mutate-01 :mod (s2 / somatic)) :ARG2 p7) :ARG1 (p10 / play-02 :ARG0 p15 :mod (p11 / precise) :ARG1-of (c4 / clear-06 :degree (l / less) :ARG1-of (c5 / compare-01 :ARG2 (a5 / and :op1 (p12 / pathway :name (n5 / name :op1 "Raf/MAPK")) :op2 (p13 / pathway :name (n6 / name :op1 "PI3K")))))))) # ::id pmid_2465_1010.219 # ::date 2015-02-22T12:54:40 # ::file pmid_2465_1010_219.txt # ::snt On the other hand, Ral signaling is upstream of NF-κB and TBK1, both of which have been implicated as essential genes downstream of K-Ras (Neel et al., 2011; Kashatus, 2013). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (b / be-located-at-91 :ARG1 (s / signal-07 :ARG0 (p6 / protein :name (n / name :op1 "Ral") :xref (x2 / xref :value "UNIPROT:RALA_HUMAN" :prob "0.603"))) :ARG2 (r / relative-position :op1 (a / and :op1 (p7 / protein :name (n2 / name :op1 "NF-κB")) :op2 (e / enzyme :name (n3 / name :op1 "TBK1") :xref (x1 / xref :value "UNIPROT:TBK1_HUMAN" :prob "1.003")) :ARG1-of (i / implicate-01 :location (r2 / relative-position :op1 (e2 / enzyme :name (n4 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :direction (d / downstream)) :prep-as (g3 / gene :mod (e3 / essential)))) :direction (u / upstream))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n5 / name :op1 "Neel")) :op2 (p4 / person :mod (o / other))) :time (d3 / date-entity :year "2011")) :op2 (p2 / publication-91 :ARG0 (p5 / person :name (n6 / name :op1 "Kashatus")) :time (d4 / date-entity :year "2013"))))) # ::id pmid_2465_1010.220 # ::date 2015-02-22T13:26:44 # ::file pmid_2465_1010_220.txt # ::snt Other potential Ras effectors that could be important in cancer and therefore a source of potential therapeutic targets include phospholipase CE and Tiam1, a GEF that stimulates the activation of Rac (Figure 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (i / include-01 :ARG1 (a / and :op1 (p4 / phospholipase :name (n3 / name :op1 "CE")) :op2 (p7 / protein :name (n4 / name :op1 "Tiam1") :ARG1-of (m / mean-01 :ARG2 (p5 / protein :name (n5 / name :op1 "GEF") :ARG0-of (s2 / stimulate-01 :ARG1 (a2 / activate-01 :ARG1 (p6 / protein :name (n6 / name :op1 "Rac") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.603")))) :xref (x2 / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002"))) :xref (x1 / xref :value "UNIPROT:TIAM1_HUMAN" :prob "0.604"))) :ARG2 (e / effector :mod (p / potential) :mod (p8 / protein-family :name (n / name :op1 "Ras")) :mod (o / other) :mod (i2 / important :ARG1-of (p2 / possible-01) :topic (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")) :ARG0-of (c / cause-01 :ARG1 (s / source-02 :ARG0 e :ARG1 (t / target-01 :ARG0 (t2 / therapy) :ARG1 e :mod (p3 / potential)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1"))) # ::id pmid_2465_1010.221 # ::date 2015-02-22T13:44:55 # ::file pmid_2465_1010_221.txt # ::snt Rac1 is necessary for K-Ras tumor initiation, further implicating the importance of this pathway in K-Ras tumorigenesis, though not yet providing obvious therapeutic targets (Gysin et al., 2011). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 13, 2015 (n / need-01 :ARG0 (i / initiate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG1 (t / tumor)) :ARG1 (p / pathway :name (n2 / name :op1 "Rac1")) :ARG0-of (i2 / implicate-01 :ARG1 (i3 / important :domain p :topic (c / create-01 :ARG0 e :ARG1 (t2 / tumor))) :concession (p2 / provide-01 :polarity "-" :ARG0 p :ARG1 (t3 / target-01 :ARG0 (t4 / therapy) :ARG1-of (o / obvious-01)) :time (y / yet)) :mod (f / further)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and :op1 (p4 / person :name (n4 / name :op1 "Gysin")) :op2 (p5 / person :mod (o2 / other))) :time (d2 / date-entity :year "2011")))) # ::id pmid_2465_1010.222 # ::date 2015-02-23T09:53:14 # ::file pmid_2465_1010_222.txt # ::snt Likewise, cyclin D1, NF-κB, and Myc are necessary for Ras tumorigenesis; further analysis of the role of these pathways may lead to new therapeutic insights. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (m / multi-sentence :snt1 (r / require-01 :ARG0 (c / create-01 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG1 (t / tumor)) :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "cyclin" :op2 "D1") :xref (x2 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")) :op2 (p2 / protein :name (n3 / name :op1 "NF-κB")) :op3 (p3 / protein :name (n4 / name :op1 "Myc") :xref (x / xref :value "UNIPROT:MYC_HUMAN" :prob "0.604"))) :mod (l2 / likewise)) :snt2 (p4 / possible-01 :ARG1 (l / lead-03 :ARG0 (a2 / analyze-01 :ARG1 (r2 / role :topic (p5 / pathway :mod (t2 / this))) :degree (f / further)) :ARG2 (i / insight :mod (t3 / therapy) :ARG1-of (n5 / new-01))))) # ::id pmid_2465_1010.223 # ::date 2015-02-23T10:13:56 # ::file pmid_2465_1010_223.txt # ::snt For example, Puyol et al. (2010) recently demonstrated that germline or conditional deletion of Cdk4 led to senescence in lung cells expressing activated K-Ras. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d2 / demonstrate-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n2 / name :op1 "Puyol")) :op2 (p3 / person :mod (o / other))) :time (d / date-entity :year "2010")) :ARG1 (l / lead-03 :ARG0 (o2 / or :op1 (d3 / delete-01 :ARG0 (g / germline) :ARG1 (g2 / gene :name (n4 / name :op1 "Cdk4") :xref (x / xref :value "UNIPROT:CDK4_HUMAN_DNA" :prob "0.701"))) :op2 (d4 / delete-01 :ARG1 g2 :mod (c2 / conditional))) :ARG2 (s / senescence) :location (c3 / cell :ARG3-of (e4 / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "K-Ras") :ARG1-of (a2 / activate-01) :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :mod (l2 / lung))) :ARG0-of (e / exemplify-01) :time (r / recent)) # ::id pmid_2465_1010.224 # ::date 2015-02-23T10:22:39 # ::file pmid_2465_1010_224.txt # ::snt Furthermore, treatment with a Cdk4 inhibitor reduced the growth of K-Ras-driven tumors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (r / reduce-01 :ARG0 (t2 / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Cdk4") :xref (x1 / xref :value "UNIPROT:CDK4_HUMAN_DNA" :prob "0.701"))))) :ARG1 (g / grow-01 :ARG1 (t3 / tumor :ARG1-of (d / drive-02 :ARG0 (e / enzyme :name (n2 / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))))))) # ::id pmid_2465_1010.225 # ::date 2015-02-23T10:25:51 # ::file pmid_2465_1010_225.txt # ::snt Finally, unbiased shRNA screens have revealed potential targets for K-Ras cancers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Oct 23, 2015 (r / reveal-01 :li "-1" :ARG0 (s / screen-01 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA")) :ARG1-of (b / bias-01 :polarity "-")) :ARG1 (t / target-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :mod (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :mod (p / potential))) # ::id pmid_2465_1010.226 # ::date 2015-02-23T10:30:21 # ::file pmid_2465_1010_226.txt # ::snt These include STK33, TBK1, and GATA-2. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / include-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "STK33") :xref (x2 / xref :value "UNIPROT:STK33_HUMAN" :prob "1.003")) :op2 (e / enzyme :name (n2 / name :op1 "TBK1") :xref (x1 / xref :value "UNIPROT:TBK1_HUMAN" :prob "1.003")) :op3 (p3 / protein :name (n3 / name :op1 "GATA-2") :xref (x / xref :value "UNIPROT:GATA2_HUMAN" :prob "0.682"))) :ARG2 (t / this)) # ::id pmid_2465_1010.227 # ::date 2015-02-23T10:32:57 # ::file pmid_2465_1010_227.txt # ::snt So far, STK33 inhibition does not appear to be a useful approach to K-Ras cancers (Weiwer et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 6, 2015 (a / appear-02 :polarity "-" :ARG1 (a2 / approach-02 :ARG0 (i / inhibit-01 :ARG1 (p / protein :name (n3 / name :op1 "STK33") :xref (x1 / xref :value "UNIPROT:STK33_HUMAN" :prob "1.003"))) :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :mod (e / enzyme :name (n / name :op1 "K-Ras") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661"))) :ARG1-of (u / useful-05)) :time (s / so-far) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n4 / name :op1 "Weiwer")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2012")))) # ::id pmid_2465_1010.228 # ::date 2015-02-23T10:37:30 # ::file pmid_2465_1010_228.txt # ::snt TBK1 inhibitors are still being investigated: this target is of particular interest because it is part of the well-validated RalGDS pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (m / multi-sentence :snt1 (i2 / investigate-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "TBK1") :xref (x / xref :value "UNIPROT:TBK1_HUMAN" :prob "1.003")))) :mod (s / still)) :snt2 (i3 / interest-01 :ARG2 (t / thing :ARG1-of (t2 / target-01) :mod (t3 / this)) :mod (p2 / particular) :ARG1-of (c / cause-01 :ARG0 (i4 / include-91 :ARG1 t :ARG2 (p3 / pathway :name (n2 / name :op1 "RalGDS") :ARG1-of (v / validate-01 :manner (w / well))))))) # ::id pmid_2465_1010.229 # ::date 2015-02-23T10:44:03 # ::file pmid_2465_1010_229.txt # ::snt GATA2 is also of considerable interest; genetic ablation leads to tumor regression in mouse models of adenocarcinoma of the lung, and whereas this transcription factor may appear to be the least druggable of targets, its role in regulating the proteasome suggested therapeutic approaches that appear very promising (Kumar et al., 2012). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (m / multi-sentence :snt1 (i / interest-01 :ARG2 (p / protein :name (n / name :op1 "GATA2") :xref (x / xref :value "UNIPROT:GATA2_HUMAN" :prob "1.003")) :mod (a / also) :degree (c / considerable)) :snt2 (a2 / and :op1 (l / lead-03 :ARG0 (a3 / ablate-01 :mod (g / genetic)) :ARG2 (r / regress-01 :ARG1 (t / tumor) :location (m2 / model :mod (m5 / medical-condition :name (n2 / name :op1 "adenocarcinoma") :mod (l2 / lung)) :mod (m3 / mouse)))) :op2 (h / have-concession-91 :ARG1 (s / suggest-01 :ARG0 (r2 / role :poss "f" :topic (r3 / regulate-01 :ARG0 "f" :ARG1 (m4 / macro-molecular-complex :name (n3 / name :op1 "proteasome")))) :ARG1 (a5 / approach-02 :ARG2 (t6 / therapy) :ARG0-of (p4 / promise-01 :degree (v / very) :ARG1-of (a6 / appear-02)))) :ARG2 (p2 / possible-01 :ARG1 (a4 / appear-02 :ARG1 (p3 / possible-01 :ARG1 (d4 / drug-01 :ARG2 (f / factor :ARG0-of (t2 / transcribe-01) :mod (t3 / this)) :degree (l3 / least) :compared-to (t4 / thing :ARG0-of (t5 / target-01)))))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a7 / and :op1 (p6 / person :name (n4 / name :op1 "Kumar")) :op2 (p7 / person :mod (o / other))) :time (d / date-entity :year "2012")))))) # ::id pmid_2465_1010.230 # ::date 2015-02-23T12:05:35 # ::file pmid_2465_1010_230.txt # ::snt Future Prospects # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (p / prospect-02 :time (f / future)) # ::id pmid_2465_1010.231 # ::date 2015-02-23T12:06:38 # ::file pmid_2465_1010_231.txt # ::snt In this Review, we have summarized some of the challenges of targeting Ras cancers. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / summarize-01 :ARG0 (w / we) :ARG1 (t / thing :ARG1-of (i / include-91 :ARG2 (t2 / thing :ARG0-of (c / challenge-01 :ARG1 (t3 / target-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer") :mod (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :ARG3 (s2 / some))) :medium (r / review :mod (t4 / this))) # ::id pmid_2465_1010.232 # ::date 2015-02-23T12:11:47 # ::file pmid_2465_1010_232.txt # ::snt Despite the tremendous progress that has been made, we still have to learn a great deal about these cancers before we can be confident that we can treat them effectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (h / have-concession-91 :ARG1 (o / obligate-01 :ARG2 (l / learn-01 :ARG0 (w / we) :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod (t / this)) :quant (d / deal :mod (g / great)) :time (b / before :op1 (p / possible-01 :ARG1 (c2 / confident-01 :ARG1 w :ARG2 (p2 / possible-01 :ARG1 (t2 / treat-04 :ARG0 w :ARG1 d2 :ARG1-of (e / effective-04)))))) :mod (s / still))) :ARG2 (p3 / progress-01 :degree (t3 / tremendous))) # ::id pmid_2465_1010.233 # ::date 2015-02-23T12:17:12 # ::file pmid_2465_1010_233.txt # ::snt Recent experience in targeting Raf and MEK has underscored how a pathway that appeared simple and linear is extremely complex and poorly understood at the level of detail required to shut it down effectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (u / underscore-01 :ARG0 (e3 / experience-01 :ARG1 (t / target-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Raf") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :time (r / recent)) :ARG1 (t2 / thing :manner-of (a2 / and :op1 (c / complex :degree (e4 / extreme) :domain (p / pathway :ARG1-of (s / simple-02) :mod (l / linear) :ARG1-of (a3 / appear-02))) :op2 (u2 / understand-01 :ARG1 p :ARG2 (l2 / level :mod (d / detail-01 :ARG1-of (r2 / require-01 :ARG0 (s2 / shut-down-05 :ARG1 p :ARG1-of (e5 / effective-04))))) :degree (p2 / poor))))) # ::id pmid_2465_1010.234 # ::date 2015-02-23T13:53:46 # ::file pmid_2465_1010_234.txt # ::snt Nobody expected that Raf inhibitors would activate Raf kinase in Ras-transformed cells, for example, or that inhibition of downstream kinases like MEK would lead to activation of upstream signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 4, 2016 (e4 / expect-01 :polarity "-" :ARG0 (a / anybody) :ARG1 (o / or :op1 (a2 / activate-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (k / kinase :name (n / name :op1 "Raf") :xref (x2 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603"))) :ARG0-of (a3 / activate-01 :ARG1 k :location (c / cell :ARG1-of (t2 / transform-01 :ARG0 (e6 / enzyme :name (n4 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) :ARG0-of (e2 / exemplify-01)) :op2 (l / lead-03 :ARG0 (i2 / inhibit-01 :ARG1 (k2 / kinase :mod (d / downstream) :example (e3 / enzyme :name (n2 / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")))) :ARG2 (a4 / activate-01 :ARG1 (s / signal-07 :direction (u / upstream)))))) # ::id pmid_2465_1010.235 # ::date 2015-02-23T13:59:53 # ::file pmid_2465_1010_235.txt # ::snt We need a much deeper analysis of the molecular mechanisms underlying Ras regulation and effector engagement before we can expect to interfere with these mechanisms effectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (n3 / need-01 :ARG0 (w / we) :ARG1 (a / analyze-01 :ARG1 (m / mechanism :mod (m2 / molecule) :ARG0-of (u / underlie-01 :ARG1 (a2 / and :op1 (r / regulate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :op2 (e2 / engage-01 :ARG1 (e3 / effector))))) :ARG1-of (d / deep-02 :degree (m3 / more :mod (m4 / much))) :time (b / before :op1 (p / possible-01 :ARG1 (e4 / expect-01 :ARG0 w :ARG1 (i / interfere-01 :ARG0 w :ARG1 m :ARG1-of (e5 / effective-04))))))) # ::id pmid_2465_1010.236 # ::date 2015-02-23T14:05:46 # ::file pmid_2465_1010_236.txt # ::snt It seems to us more likely that these deeper insights will lead to productive approaches for intervention than to the conclusion that Ras is indeed undruggable. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (s / seem-01 :ARG1 (l / lead-03 :ARG0 (i / insight :ARG1-of (d / deep-03 :degree (m / more)) :mod (t / this)) :ARG1 (a / approach-02 :ARG1-of (p / productive-03) :purpose (i2 / intervene-01) :ARG1-of (i3 / instead-of-91 :ARG2 (c2 / conclude-01 :ARG1 (p2 / possible-01 :polarity "-" :ARG1 (d2 / drug-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :mod (i4 / indeed)))))) :ARG2 (w / we) :ARG1-of (l2 / likely-01 :degree (m2 / more))) # ::id pmid_2465_1010.237 # ::date 2015-02-23T13:42:16 # ::file pmid_2465_1010_237.txt # ::snt New technologies and insights and fresh eyes are likely to solve this problem. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / solve-01 :ARG0 (a / and :op1 (t2 / technology :ARG1-of (n / new-01)) :op2 (i / insight :ARG1-of n) :op3 (e / eye :ARG1-of (f / fresh-04))) :ARG1 (p / problem :mod (t / this)) :ARG1-of (l / likely-01)) # ::id pmid_2465_1010.238 # ::date 2015-02-23T14:12:44 # ::file pmid_2465_1010_238.txt # ::snt We are also optimistic that completely different approaches to treating cancer will contribute to eliminating Ras cancers, including new ways of knocking down/out genes using RNAi and CRISPR technologies and delivering these payloads to tumors (Davis et al., 2010), as well as new ways of deploying the immune system. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (o / optimistic :domain (w / we) :mod (a / also) :topic (c / contribute-01 :ARG0 (a2 / approach-02 :ARG1 (t / treat-04 :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :ARG1-of (d3 / differ-02 :ARG1-of (c2 / complete-02)) :ARG2-of (i / include-01 :ARG1 (a3 / and :op1 (w2 / way :ARG1-of (n4 / new-01) :manner-of (a5 / and :op1 (s / slash :op1 (k / knock-down-02 :ARG1 (g / gene) :ARG5 (u / use-01 :ARG1 (a4 / and :op1 (t2 / technology :mod (i3 / interfere-01 :ARG0 (n5 / nucleic-acid :name (n8 / name :op1 "RNA")))) :op2 (t3 / technology :mod (d8 / dna-sequence :name (n6 / name :op1 "CRISPR")))))) :op2 (k2 / knock-out-03 :ARG1 g :ARG2 u)) :op2 (d5 / deliver-01 :ARG1 (p / payload :mod (t4 / this)) :ARG2 (t5 / tumor))) :ARG1-of (d6 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a6 / and :op1 (p3 / person :name (n7 / name :op1 "Davis")) :op2 (p4 / person :mod (o2 / other))) :time (d / date-entity :year "2010")))) :op2 (w3 / way :ARG1-of n4 :manner-of (d7 / deploy-01 :ARG1 (s2 / system :ARG1-of (i2 / immune-02))))))) :ARG2 (e2 / eliminate-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :mod (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) # ::id pmid_2465_1010.239 # ::date 2015-02-24T13:50:16 # ::file pmid_2465_1010_239.txt # ::snt In this respect, it is noteworthy that anti-CTLA-4 therapy appears to be equally effective in treating melanoma driven by N-Ras or B-Raf; therefore, Ras cancers may not be excluded from these approaches as they have been from others. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Mar 9, 2016 (m / multi-sentence :snt1 (r / recommend-01 :ARG1 (n4 / note-01 :ARG1 (a / appear-02 :ARG1 (e / effective-04 :ARG0 (t / therapy :mod (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p2 / protein :name (n / name :op1 "CTLA-4") :xref (x / xref :value "UNIPROT:CTLA4_HUMAN" :prob "1.002"))))) :ARG1 (t2 / treat-04 :ARG1 (m2 / medical-condition :name (n6 / name :op1 "melanoma") :ARG1-of (d / drive-02 :ARG0 (o / or :op1 (e6 / enzyme :name (n7 / name :op1 "N-Ras") :xref (x1 / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")) :op2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :xref (x3 / xref :value "UNIPROT:Q9NY11_HUMAN" :prob "0.661")))))) :degree (e5 / equal)))) :mod (i3 / in-respect :mod (t4 / this))) :snt2 (i2 / infer-01 :ARG1 (p / possible-01 :polarity "-" :ARG1 (e7 / exclude-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer") :mod (e3 / enzyme :name (n3 / name :op1 "Ras") :xref (x2 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213"))) :ARG2 (a3 / approach-02 :mod (t3 / this)) :ARG1-of (r2 / resemble-01 :ARG2 (e8 / exclude-01 :ARG1 d4 :ARG2 (a4 / approach-02 :mod (o2 / other)))))))) # ::id pmid_2465_1010.240 # ::date 2015-02-24T14:09:30 # ::file pmid_2465_1010_240.txt # ::snt All of these considerations lead us to be optimistic about future prospects of finally delivering the knockout punch. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jul 26, 2015 (l / lead-03 :ARG0 (c2 / consider-01 :mod (t / this) :mod (a / all)) :ARG1 (w / we) :ARG2 (o / optimistic :domain w :topic (p / prospect-02 :ARG1 (d / deliver-01 :ARG1 (p2 / punch-01 :mod (k / knock-out-03)) :time (f2 / final)) :time (f / future)))) # ::id pmid_2465_1010.241 # ::date 2015-02-23T12:18:36 # ::file pmid_2465_1010_241.txt # ::snt Figure 1 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 23, 2015 (f / figure :mod "1") # ::id pmid_2465_1010.242 # ::date 2015-02-23T12:18:58 # ::file pmid_2465_1010_242.txt # ::snt Simplified View of the Ras Pathway # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 23, 2015 (v / view-02 :ARG1 (p / pathway :name (n2 / name :op1 "Ras")) :ARG1-of (s / simplify-01)) # ::id pmid_2465_1010.243 # ::date 2015-02-24T14:16:38 # ::file pmid_2465_1010_243.txt # ::snt Ras proteins are converted from their GDP state to their GTP state by GEFs, in response to upstream signals (Bos et al., 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / convert-01 :ARG0 (p2 / protein :name (n4 / name :op1 "GEF") :xref (x / xref :value "UNIPROT:S2A4R_HUMAN" :prob "1.002")) :ARG1 (p5 / protein-family :name (n / name :op1 "Ras")) :ARG2 (s4 / state :mod (s2 / small-molecule :name (n3 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645")) :mod p5) :ARG3 (s3 / state :mod (s / small-molecule :name (n2 / name :op1 "GDP") :xref (x2 / xref :value "PUBCHEM:8977" :prob "14.712257")) :poss p5) :ARG2-of (r / respond-01 :ARG1 (s5 / signal-07 :direction (u / upstream))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n5 / name :op1 "Bos")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year "2007")))) # ::id pmid_2465_1010.244 # ::date 2015-02-23T12:25:19 # ::file pmid_2465_1010_244.txt # ::snt GAPs convert Ras-GTP back to Ras-GDP. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 23, 2015 (c / convert-01 :ARG0 (p / protein :name (n / name :op1 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :ARG1 (m / macro-molecular-complex :part (e / enzyme :name (n2 / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part (s / small-molecule :name (n3 / name :op1 "GTP") :xref (x3 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG3 (m2 / macro-molecular-complex :part e :part (s2 / small-molecule :name (n4 / name :op1 "GDP") :xref (x2 / xref :value "PUBCHEM:8977" :prob "14.712257"))) :direction (b / back)) # ::id pmid_2465_1010.245 # ::date 2015-02-24T14:22:49 # ::file pmid_2465_1010_245.txt # ::snt p120 GAP does this when recruited to activated RTKs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (d / do-02 :ARG0 (p / protein :name (n / name :op1 "p120" :op2 "GAP") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.693")) :ARG1 (t / this) :time (r / recruit-01 :ARG1 p :ARG2 (e / enzyme :name (n2 / name :op1 "RTK") :ARG1-of (a / activate-01) :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")))) # ::id pmid_2465_1010.246 # ::date 2015-02-24T14:26:16 # ::file pmid_2465_1010_246.txt # ::snt The signal that directs NF1 (neurofibromin)/SPRED to inactivate Ras is not known. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 24, 2015 (k / know-01 :polarity "-" :ARG1 (s / signal-07 :ARG0-of (d / direct-01 :ARG1 (s2 / slash :op1 (p / protein :name (n2 / name :op1 "neurofibromin") :xref (x2 / xref :value "UNIPROT:NF1_HUMAN" :prob "0.703")) :op2 (p2 / protein :name (n3 / name :op1 "SPRED") :xref (x / xref :value "UNIPROT:SPRE1_HUMAN" :prob "0.333"))) :ARG2 (a / activate-01 :polarity "-" :ARG0 s2 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")))))) # ::id pmid_2465_1010.247 # ::date 2015-02-24T14:28:52 # ::file pmid_2465_1010_247.txt # ::snt Several other GAPs are capable of downregulating Ras (Bos et al., 2007). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 24, 2015 (c / capable-01 :ARG1 (p / protein :name (n2 / name :op1 "GAP") :quant (s / several) :mod (o / other) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "1.003")) :ARG2 (d2 / downregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :ARG2 p) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and :op1 (p3 / person :name (n3 / name :op1 "Bos")) :op2 (p4 / person :mod o)) :time (d / date-entity :year "2007")))) # ::id pmid_2465_1010.248 # ::date 2015-02-24T14:29:43 # ::file pmid_2465_1010_248.txt # ::snt Ras-GTP binds and activates multiple downstream effectors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 25, 2015 (a / and :op1 (b / bind-01 :ARG0 (m / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "Ras") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.213")) :part (s / small-molecule :name (n2 / name :op1 "GTP") :xref (x1 / xref :value "PUBCHEM:6830" :prob "15.470645"))) :ARG1 (e2 / effector :mod (d / downstream) :quant (m2 / multiple))) :op2 (a2 / activate-01 :ARG0 m :ARG1 e)) # ::id pmid_2465_1010.249 # ::date 2015-02-25T12:38:37 # ::file pmid_2465_1010_249.txt # ::snt The group of proteins shown on the left includes potential effectors whose significance is less well understood relative to RalGDS, Raf kinases, and PI3Ks (Gysin et al., 2011). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / include-01 :ARG2 (g / group :consist-of (p / protein) :ARG1-of (s / show-01 :location (l / left-20)) :ARG2-of (i2 / include-01 :ARG1 (e2 / effector :mod (p2 / potential) :ARG0-of (s2 / signify-01 :ARG1-of (u / understand-01 :mod (w / well :degree (l2 / less) :compared-to (a / and :op1 (p3 / protein :name (n2 / name :op1 "RalGDS") :xref (x / xref :value "UNIPROT:GNDS_HUMAN" :prob "1.003")) :op2 (p8 / protein-family :name (n3 / name :op1 "Raf")) :op3 (p7 / protein-family :name (n / name :op1 "PI3K"))))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n4 / name :op1 "Gysin")) :op2 (p6 / person :mod (o / other))) :time (d / date-entity :year "2011")))) # ::id pmid_2465_1010.250 # ::date 2015-02-26T13:01:57 # ::file pmid_2465_1010_250.txt # ::snt Protein families are represented as single proteins to simplify the schematic; in addition, feedback loops are not included. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (m / multi-sentence :snt1 (r / represent-01 :ARG0 (p / protein :ARG1-of (s / single-02)) :ARG1 (p3 / protein-family) :purpose (s2 / simplify-01 :ARG0 r :ARG1 (s3 / schematic))) :snt2 (a / and :op2 (i / include-01 :polarity "-" :ARG1 (l / loop-01 :mod (f2 / feedback))))) # ::id pmid_2465_1010.251 # ::date 2015-02-23T12:31:30 # ::file pmid_2465_1010_251.txt # ::snt Figure 2 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 23, 2015 (f / figure :mod "2") # ::id pmid_2465_1010.252 # ::date 2015-02-23T12:31:52 # ::file pmid_2465_1010_252.txt # ::snt Structure Showing Small Molecule-Directed Electrophilic Attack of K-Ras-G12C # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 26, 2015 (s / show-01 :ARG0 (s2 / structure-01) :ARG1 (a / attack-01 :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras") :ARG1-of (m / mutate-01 :value "G12C") :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :mod (e / electrophile) :ARG1-of (d / direct-01 :ARG0 (s3 / small-molecule)))) # ::id pmid_2465_1010.253 # ::date 2015-02-26T11:13:12 # ::file pmid_2465_1010_253.txt # ::snt K-Ras-G12C (Protein Data Bank 4LUC_A) is displayed in surface representation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Dec 18, 2015 (d / display-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG1-of (m / mutate-01 :value "G12C") :part-of (d2 / data-bank :name (n2 / name :op1 "4LUC_A") :mod (p / protein)) :xref (x / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")) :ARG2 (r / represent-01 :ARG2 (s / surface))) # ::id pmid_2465_1010.254 # ::date 2015-02-25T12:57:00 # ::file pmid_2465_1010_254.txt # ::snt The cocrystallized ligands, GDP and N-(1-[(2,4-dichlorophenoxy)acetyl]piperidin- 4-yl)-4-sulfanylbutanamide, are shown in stick mode. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s2 / show-01 :ARG1 (l / ligand :ARG1-of (c / cocrystallize-00) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (l2 / ligand :name (n2 / name :op1 "GDP")) :op1 (l3 / ligand :name (n3 / name :op1 "N-(1-[(2,4-dichlorophenoxy)acetyl]piperidin-4-yl)-4-sulfanylbutanamide"))))) :manner (m2 / mode :mod (s / stick))) # ::id pmid_2465_1010.255 # ::date 2015-02-25T13:22:45 # ::file pmid_2465_1010_255.txt # ::snt The location of calcium ion is shown as a green ball. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Oct 26, 2015 (s / show-01 :ARG1 (l / location :location-of (c / calcium :ARG1-of (i2 / ionize-01))) :manner (b / ball :ARG1-of (g / green-02))) # ::id pmid_2465_1010.256 # ::date 2015-02-25T13:25:59 # ::file pmid_2465_1010_256.txt # ::snt Switch 1 (28–38) and switch 2 (57–63) are highlighted by orange and red colors, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jun 18, 2015 (a2 / and :op1 (h / highlight-01 :ARG1 (s / switch :ord (o / ordinal-entity :value "1") :mod (v / value-interval :op1 "28" :op2 "38")) :manner (o2 / orange)) :op2 (h2 / highlight-01 :ARG1 (s2 / switch :ord (o3 / ordinal-entity :value "2") :mod (v2 / value-interval :op1 "57" :op2 "63")) :manner (r / red-02))) # ::id pmid_2465_1010.257 # ::date 2015-02-25T13:52:56 # ::file pmid_2465_1010_257.txt # ::snt Key ligand-interacting residue (C12, V9, V7, F78, I100, M72, Q99, and R68) positions are colored green. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (c / color-01 :ARG1 (a / and :op1 (p / position :location-of (r / residue :mod (a2 / amino-acid :mod "12" :name (n / name :op1 "cysteine") :xref (x1 / xref :value "PUBCHEM:594" :prob "11.272514")))) :op2 (p2 / position :location-of (r2 / residue :mod (a3 / amino-acid :mod "9" :name (n2 / name :op1 "valine") :xref (x / xref :value "PUBCHEM:6287" :prob "10.890044")))) :op3 (p3 / position :location-of (r3 / residue :mod (a4 / amino-acid :mod "7" :name (n3 / name :op1 "valine") :xref (x3 / xref :value "PUBCHEM:6287" :prob "10.890044")))) :op4 (p4 / position :location-of (r4 / residue :mod "78" :mod (a5 / amino-acid :name (n4 / name :op1 "phenylalanine") :xref (x2 / xref :value "PUBCHEM:994" :prob "10.46286")))) :op5 (p5 / position :location-of (r5 / residue :mod "100" :mod (a6 / amino-acid :name (n5 / name :op1 "isoleucine") :xref (x5 / xref :value "PUBCHEM:791" :prob "12.011956")))) :op6 (p6 / position :location-of (r6 / residue :mod "72" :mod (a7 / amino-acid :name (n6 / name :op1 "methionine") :xref (x4 / xref :value "PUBCHEM:876" :prob "11.787682")))) :op7 (p7 / position :location-of (r7 / residue :mod "99" :mod (a8 / amino-acid :name (n7 / name :op1 "glutamine") :xref (x7 / xref :value "PUBCHEM:738" :prob "11.972775")))) :op8 (p8 / position :location-of (r8 / residue :mod "68" :mod (a9 / amino-acid :name (n8 / name :op1 "arginine") :xref (x6 / xref :value "PUBCHEM:232" :prob "11.348415")))) :ARG0-of (i / interact-01 :ARG1 (l / ligand)) :ARG1-of (k / key-02)) :ARG2 (g / green-02 :ARG1 a)) # ::id pmid_2465_1010.258 # ::date 2015-02-25T13:59:12 # ::file pmid_2465_1010_258.txt # ::snt Position of C12 residue is shown in ball and stick (green). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / show-01 :ARG1 (p / position-01 :ARG1 (r / residue :mod (a / amino-acid :mod "12" :wiki "Cysteine" :name (n / name :op1 "cysteine") :xref (x / xref :value "PUBCHEM:594" :prob "11.272514")))) :manner (a2 / and :op1 (b / ball) :op2 (s2 / stick) :ARG1-of (g / green-02))) # ::id pmid_2465_1010.259 # ::date 2015-02-25T14:05:02 # ::file pmid_2465_1010_259.txt # ::snt Note that residues 58 and 60 are part of both switch 2 and the key ligand-interacting group (shown in blue). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (n / note-01 :ARG1 (a / and :op1 (r / residue :mod (a2 / amino-acid :mod "58")) :op2 (r2 / residue :mod (a3 / amino-acid :mod "60")) :part-of (a4 / and :op1 (s / switch :mod "2") :op2 (g / group :ARG0-of (i / interact-01 :ARG1 (l / ligand)) :ARG1-of (k / key-02)))) :ARG1-of (s2 / show-01 :manner (b / blue))) # ::id pmid_2465_1010.260 # ::date 2015-02-23T14:16:26 # ::file pmid_2465_1010_260.txt # ::snt Figure 3 # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Feb 23, 2015 (f / figure :mod "3") # ::id pmid_2465_1010.261 # ::date 2015-02-23T14:16:48 # ::file pmid_2465_1010_261.txt # ::snt Schematic Representation of the Ras Isoforms # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue May 19, 2015 (r / representation-02 :ARG1 (i / isoform :name (n2 / name :op1 "Ras")) :ARG2 (s / schematic)) # ::id pmid_2465_1010.262 # ::date 2015-02-23T14:19:16 # ::file pmid_2465_1010_262.txt # ::snt The structures of the G domain of H-Ras, N-Ras, and K-Ras have been solved and are virtually identical, but the structure of processed hypervariable regions has not been solved and is therefore depicted as a linear sequence. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Feb 26, 2015 (a / and :op1 (s / solve-01 :ARG1 (a2 / and :op1 (s2 / structure-01 :ARG1 (p / protein-segment :name (n3 / name :op1 "G" :op2 "domain") :part-of (e / enzyme :name (n / name :op1 "H-Ras") :xref (x2 / xref :value "UNIPROT:Q16046_HUMAN" :prob "0.631")))) :op2 (s3 / structure-01 :ARG1 (p2 / protein-segment :name (n4 / name :op1 "G" :op2 "domain") :part-of (e3 / enzyme :name (n5 / name :op1 "N-Ras") :xref (x / xref :value "UNIPROT:Q9UM97_HUMAN" :prob "0.661")))) :op3 (s4 / structure-01 :ARG1 (p3 / protein-segment :name (n6 / name :op1 "G" :op2 "domain") :part-of (e2 / enzyme :name (n2 / name :op1 "K-Ras") :xref (x1 / xref :value "UNIPROT:Q92668_HUMAN" :prob "0.661")))))) :op2 (i / identical-01 :ARG1 a2 :mod (v / virtual)) :ARG1-of (c / contrast-01 :ARG2 (a3 / and :op1 (s5 / solve-01 :polarity "-" :ARG1 (s6 / structure-01 :ARG1 (r / region :ARG1-of (v2 / vary-01 :degree (h / hyper)) :ARG1-of (p4 / process-01)))) :op2 (d / depict-01 :ARG1 s6 :ARG2 (s7 / sequence :mod (l / linear)))))) # ::id pmid_2465_1010.263 # ::date 2015-02-25T13:15:55 # ::file pmid_2465_1010_263.txt # ::snt Lipid modifications with farnesyl (purple) and palmitoyl (orange) chains are shown. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 1, 2016 (s / show-01 :ARG1 (m / modify-01 :ARG1 (l / lipid) :instrument (a / and :op1 (c / chain :mod (f / farnesyl) :ARG1-of (p / purple-02)) :op2 (c2 / chain :mod (p2 / palmitoyl :ARG1-of (r4 / represent-01 :ARG0 (o / orange))))))) # ::id pmid_2470_8867.1 # ::date 2015-08-26T08:04:52 # ::file pmid_2470_8867_1.txt # ::snt Met receptor-induced Grb2 or Shc signals both promote transformation of intestinal epithelial cells, albeit they are required for distinct oncogenic functions (PMID:24708867) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Nov 24, 2015 (p / promote-02 :ARG0 (s / signal-07 :ARG0 (a / and :op1 (p2 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :ARG2-of (i / induce-01 :ARG0 (r / receptor :name (n3 / name :op1 "Met")))) :ARG1 (t / transform-01 :ARG1 (c / cell :source (e / epithelium :part-of (i2 / intestine)))) :concession (r2 / require-01 :ARG0 (f / function-01 :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer)) :mod (d / distinct)) :ARG1 a) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG8 "PMID24708867"))) # ::id pmid_2470_8867.9 # ::date 2015-08-26T09:09:27 # ::file pmid_2470_8867_9.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2470_8867.10 # ::date 2015-08-26T09:39:11 # ::file pmid_2470_8867_10.txt # ::snt We show, for the first time, that constitutive activation of either Grb2 or Shc signals in IEC-6 cells, promotes morphological transformation associated with down-regulation of E-cadherin, as well as increased cell growth, loss of growth contact inhibition, anchorage-independent growth, and resistance to serum deprivation and anoikis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / show-01 :ARG0 (w / we) :ARG1 (p / promote-02 :ARG0 (a / activate-01 :ARG1 (s2 / signal-07 :ARG0 (o2 / or :op1 (p2 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))) :mod (c / constitutive) :location (c2 / cell-line :name (n3 / name :op1 "IEC-6"))) :ARG1 (a2 / and :op1 (t / transform-01 :mod (m / morphological) :ARG1-of (a3 / associate-01 :ARG2 (d / downregulate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :op2 (g / grow-01 :ARG1 (c3 / cell) :ARG1-of (i / increase-01)) :op3 (l / lose-01 :ARG1 (i2 / inhibit-01 :ARG0 (c4 / contact-01) :ARG1 (g2 / grow-01))) :op4 (g3 / grow-01 :ARG0-of (d2 / depend-01 :polarity "-" :ARG1 (a4 / anchorage))) :op5 (r / resist-01 :ARG1 (a5 / and :op1 (d3 / deprive-01 :ARG1 (s3 / serum)) :op2 (a6 / anoikis))))) :ord (o / ordinal-entity :value "1")) # ::id pmid_2470_8867.11 # ::date 2015-08-26T10:20:39 # ::file pmid_2470_8867_11.txt # ::snt Oncogenic activation of Met was revealed to induce morphological transformation, E-cadherin down-regulation, and protection against anoikis by mechanisms dependent on Grb2, while Shc was shown to be partly required for enhanced cell growth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 6, 2015 (c / contrast-01 :ARG1 (r / reveal-01 :ARG1 (i / induce-01 :ARG0 (a / activate-01 :ARG1 (p5 / protein :name (n / name :op1 "Met") :xref (x2 / xref :value "UNIPROT:MET_HUMAN" :prob "0.604")) :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer))) :ARG1 (a2 / and :op1 (t / transform-01 :mod (m / morphological)) :op2 (d / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin") :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :op3 (p2 / protect-01 :ARG2 (a3 / anoikis) :ARG3 (m2 / mechanism :ARG0-of (d2 / depend-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")))))))) :ARG2 (s / show-01 :ARG1 (r3 / require-01 :ARG0 (g / grow-01 :ARG1 (c4 / cell) :ARG1-of (e / enhance-01)) :ARG1 (p4 / protein :name (n4 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :degree (p6 / part)))) # ::id pmid_2470_8867.12 # ::date 2015-08-26T10:48:31 # ::file pmid_2470_8867_12.txt # ::snt The coupling of activated Met to the Ras/MEK/Erk and PI3K/Akt pathways, and the sustained engagement of Grb2 or Shc in IECs, was shown to trigger negative feedback, limiting the extent of activation of these pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / show-01 :ARG1 (t / trigger-01 :ARG0 (a / and :op1 (c / couple-01 :ARG1 (p / protein :name (n / name :op1 "Met") :ARG1-of (a3 / activate-01) :xref (x2 / xref :value "UNIPROT:MET_HUMAN" :prob "0.604")) :ARG2 (a2 / and :op1 (p2 / pathway :name (n2 / name :op1 "Ras/MEK/Erk")) :op2 (p3 / pathway :name (n3 / name :op1 "PI3K/Akt")))) :op2 (e / engage-01 :ARG1 (o / or :op1 (p4 / protein :name (n4 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p5 / protein :name (n5 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :ARG2 (c2 / cell :name (n6 / name :op1 "IEC")) :ARG1-of (s2 / sustain-01))) :ARG1 (f / feedback :ARG0-of (n7 / negative-03)) :ARG0-of (l / limit-01 :ARG1 (e2 / extent :extent-of (a5 / activate-01 :ARG1 (a6 / and :op1 p2 :op2 p3 :mod (t2 / this))))))) # ::id pmid_2470_8867.13 # ::date 2015-08-26T11:07:52 # ::file pmid_2470_8867_13.txt # ::snt Nonetheless, morphological alterations and E-cadherin down-regulation induced by the oncogenic Tpr-Met, and by Grb2 or Shc signals, were blocked by MEK, but not PI3K, inhibitors while the enhanced growth and resistance to anoikis induced by Tpr-Met were nearly abolished by co-treatment with both inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (h / have-concession-91 :ARG1 (c / contrast-01 :ARG1 (c2 / contrast-01 :ARG1 (b / block-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p6 / protein-family :name (n5 / name :op1 "MEK")))) :ARG1 (a / and :op1 (a2 / alter-01 :mod (m / morphological)) :op2 (d / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG2-of (i / induce-01 :ARG0 (a3 / and :op1 (p2 / protein :name (n2 / name :op1 "Tpr-Met") :ARG0-of (c3 / cause-01 :ARG1 (c4 / cancer)) :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")) :op1 (s / signal-07 :ARG0 (o / or :op1 (p3 / protein :name (n3 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p4 / protein :name (n4 / name :op1 "Shc") :xref (x2 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))))))) :ARG2 (b2 / block-01 :polarity "-" :ARG0 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p5 / protein-family :name (n6 / name :op1 "PI3K")))) :ARG1 a)) :ARG2 (a4 / abolish-01 :ARG1 (a5 / and :op1 (g / grow-01 :ARG1-of (e3 / enhance-01)) :op2 (r / resist-01 :ARG1 (a6 / anoikis :ARG2-of (i4 / induce-01 :ARG0 p2)))) :mod (n7 / near) :instrument (t / treat-04 :ARG2 (a7 / and :op1 m2 :op2 m3))))) # ::id pmid_2470_8867.95 # ::date 2015-08-26T12:14:10 # ::file pmid_2470_8867_95.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Aug 26, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2470_8867.96 # ::date 2015-08-26T12:14:48 # ::file pmid_2470_8867_96.txt # ::snt Oncogenic engagement of Grb2 or Shc signaling promotes morphological transformation in normal IECs and reduces E-cadherin expression # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (a / and :op1 (p / promote-02 :ARG0 (e / engage-01 :ARG1 (s / signal-07 :ARG0 (o / or :op1 (p2 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))) :ARG0-of (c / cause-01 :ARG1 (c2 / cancer))) :ARG1 (t / transform-01 :ARG1 (c3 / cell :name (n3 / name :op1 "IEC") :ARG1-of (n4 / normal-02)) :mod (m / morphological))) :op2 (r / reduce-01 :ARG0 e :ARG1 (e2 / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "E-cadherin") :xref (x2 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) # ::id pmid_2470_8867.97 # ::date 2015-08-26T12:23:55 # ::file pmid_2470_8867_97.txt # ::snt In contrast with many other RTKs, the ability of the Met receptor to recruit signaling proteins, and thus its biological activities, is dependent on two phospho-Tyr residues located within its C-terminus (Y1349/Y1356 in Met; Y482/Y489 in Tpr-Met [28-30]). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / contrast-01 :ARG1 (d / depend-01 :ARG0 (c2 / capable-01 :ARG1 (r / receptor :name (n / name :op1 "Met")) :ARG2 (r2 / recruit-01 :ARG0 r :ARG1 (p / protein :ARG0-of (s / signal-07))) :ARG0-of (c3 / cause-01 :ARG1 (a4 / activity-06 :ARG0 r :mod (b2 / biology)))) :ARG1 (a2 / and :op1 (r3 / residue :ARG1-of (p2 / phosphorylate-01) :location (p3 / protein-segment :name (n3 / name :op1 "C-terminus") :part-of r) :mod (s2 / slash :op1 (a / amino-acid :mod "1349" :name (n5 / name :op1 "tyrosine") :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a3 / amino-acid :mod "1356" :name (n6 / name :op1 "tyrosine") :xref (x4 / xref :value "PUBCHEM:1153" :prob "11.081481")) :part-of (p7 / protein :name (n10 / name :op1 "Met") :xref (x1 / xref :value "UNIPROT:MET_HUMAN" :prob "0.604")))) :op2 (r4 / residue :ARG1-of p2 :mod (s3 / slash :op1 (a5 / amino-acid :mod "482" :name (n4 / name :op1 "tyrosine") :xref (x5 / xref :value "PUBCHEM:1153" :prob "11.081481")) :op2 (a6 / amino-acid :mod "489" :name (n9 / name :op1 "tyrosine") :xref (x6 / xref :value "PUBCHEM:1153" :prob "11.081481")) :part-of (p4 / protein :name (n2 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 (v / value-interval :op1 "28" :op2 "30")))))) :ARG2 (e / enzyme :name (n7 / name :op1 "RTK") :quant (m / many) :mod (o / other) :xref (x2 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262"))) # ::id pmid_2470_8867.98 # ::date 2015-08-26T13:29:45 # ::file pmid_2470_8867_98.txt # ::snt This unique characteristic has been exploited to generate Met receptor variants capable of binding exclusively to a single RTK-proximal signaling protein [8]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (e / exploit-01 :ARG1 (t2 / thing :mod (u / unique) :mod (t / this) :ARG2-of (c / characteristic-02)) :ARG2 (g / generate-01 :ARG1 (v / variant :mod (r / receptor :wiki "C-Met" :name (n / name :op1 "Met")) :ARG1-of (c2 / capable-01 :ARG2 (b / bind-01 :ARG1 v :ARG2 (p / protein :ARG0-of (s / signal-07 :ARG1 (e3 / enzyme :wiki "Receptor_tyrosine_kinase" :name (n2 / name :op1 "RTK") :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")) :mod (p2 / proximal)) :ARG1-of (s2 / single-02)) :manner (e2 / exclusive-02))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG0-of (c3 / cite-01 :ARG2 "8")))) # ::id pmid_2470_8867.99 # ::date 2015-08-26T13:44:55 # ::file pmid_2470_8867_99.txt # ::snt These well-characterized docking-specific Met variants consist of the cytosolic oncogenic form of the Met receptor, Tpr-Met, in which the multi-substrate binding region has been replaced with a motif selective for the recruitment of a single signaling protein, found in other RTKs (Additional file 1 and [8]). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (c / consist-01 :ARG1 (v / variant :mod (r / receptor :name (n / name :op1 "Met") :mod (o / other)) :ARG1-of (s / specific-02 :ARG2 (d / dock-01)) :ARG1-of (c2 / characterize-01 :ARG1-of (w / well-09)) :mod (t / this)) :ARG2 (f / form :ARG0-of (c3 / cause-01 :ARG1 (c4 / cancer)) :mod (c5 / cytosol :xref (x1 / xref :value "GO:0005829" :prob "0.8")) :mod (r2 / receptor :name (n2 / name :op1 "Met")) :ARG1-of (m / mean-01 :ARG2 (r3 / receptor :name (n3 / name :op1 "Tpr-Met"))) :location-of (r4 / region :ARG1-of (b2 / bind-01) :mod (s5 / substrate :quant (m2 / multiple)) :ARG1-of (r5 / replace-01 :ARG2 (m3 / motif :ARG0-of (s2 / select-01 :ARG1 (r6 / recruit-01 :ARG1 (p / protein :ARG0-of (s3 / signal-07) :ARG1-of (s4 / single-02) :ARG1-of (f3 / find-01 :location (e / enzyme :name (n4 / name :op1 "RTK") :mod (o2 / other) :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")))))))))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / file :mod "1" :mod (a2 / additional)) :op2 (p2 / publication :ARG0-of (c6 / cite-01 :ARG2 "8"))))) # ::id pmid_2470_8867.100 # ::date 2015-08-26T14:38:58 # ::file pmid_2470_8867_100.txt # ::snt To determine whether the selective oncogenic engagement of either the Grb2 or the Shc adaptor protein was sufficient to induce transformation of IECs, we generated populations of IEC-6 cells [25] expressing Tpr-Met variants that specifically bind to either the Grb2 (TM-Grb2-IEC-6 cells) or Shc (TM-Shc1-IEC-6 and TM-Shc2-IEC-6 cells, respectively) adaptor proteins, through retroviral infection. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (g / generate-01 :ARG0 (w / we) :ARG1 (p / population :consist-of (c / cell-line :name (n / name :op1 "IEC-6") :ARG1-of (d / describe-01 :ARG0-of (c2 / cite-01 :ARG2 "25")) :ARG3-of (e / express-03 :ARG2 (v / variant :mod (p2 / protein :name (n2 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")) :ARG1-of (b / bind-01 :ARG2 (o / or :op1 (p3 / protein :name (n3 / name :op1 "Grb2") :mod (a / adaptor) :location (c3 / cell-line :name (n4 / name :op1 "TM-Grb2-IEC-6")) :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p4 / protein :name (n5 / name :op1 "Shc") :mod a :location (a3 / and :op1 (c4 / cell-line :name (n6 / name :op1 "TM-Shc1-IEC-6")) :op2 (c5 / cell-line :name (n7 / name :op1 "TM-Shc2-IEC-6"))) :xref (x2 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :instrument (i / infect-01 :mod (r / retrovirus)) :manner (s / specific-02)))))) :purpose (d2 / determine-01 :ARG0 w :ARG1 (s2 / suffice-01 :mode "interrogative" :ARG0 (e2 / engage-01 :ARG1 (o2 / or :op1 (p5 / protein :name (n8 / name :op1 "Grb2") :mod a :xref (x3 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p6 / protein :name (n9 / name :op1 "Shc") :mod a :xref (x4 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :ARG0-of (c6 / cause-01 :ARG1 (c7 / cancer)) :mod (s3 / selective)) :ARG1 (i2 / induce-01 :ARG0 e2 :ARG2 (t / transform-01 :ARG2 (c8 / cell :name (n10 / name :op1 "IEC"))))))) # ::id pmid_2470_8867.101 # ::date 2015-08-26T15:35:43 # ::file pmid_2470_8867_101.txt # ::snt For each experiment, these cells were compared with the previously characterized untransformed sham-infected IEC-6 (Control-IEC-6) cells or those transformed by unmodified Tpr-Met (Tpr-Met-IEC-6) [5]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (c / compare-01 :ARG1 (c2 / cell :mod (t / this)) :ARG2 (o / or :op1 (c5 / cell-line :name (n / name :op1 "IEC-6") :ARG1-of (c4 / characterize-01 :time (p / previous)) :ARG1-of (t2 / transform-01 :polarity "-") :ARG1-of (i / infect-01 :mod (s / sham)) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :name (n2 / name :op1 "Control-IEC-6")))) :op2 (c6 / cell :ARG1-of c4 :ARG1-of (t3 / transform-01 :ARG0 (p3 / protein :name (n3 / name :op1 "Tpr-Met") :ARG1-of (m3 / modify-01 :polarity "-") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))) :ARG1-of (m2 / mean-01 :ARG2 (c7 / cell-line :name (n4 / name :op1 "Tpr-Met-IEC-6"))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG0-of (c9 / cite-01 :ARG2 "5"))) :beneficiary (e / experiment-01 :mod (e2 / each))) # ::id pmid_2470_8867.102 # ::date 2015-08-26T16:01:38 # ::file pmid_2470_8867_102.txt # ::snt TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells were morphologically transformed to a similar extent relative to Control-IEC-6 cells, which grew in colonies and displayed typical normal epithelioid morphology (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (t / transform-01 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "TM-Grb2-IEC-6")) :op2 (c2 / cell-line :name (n2 / name :op1 "TM-Shc1-IEC-6")) :op3 (c3 / cell-line :name (n3 / name :op1 "TM-Shc2-IEC-6"))) :ARG2 (e / extent :ARG1-of (r / resemble-01) :ARG1-of (r2 / relative-05 :ARG3 (c4 / cell-line :name (n4 / name :op1 "Control-IEC-6") :ARG1-of (g / grow-01 :location (c5 / colony)) :ARG0-of (d / display-01 :ARG1 (m2 / morphology :ARG1-of (t2 / typical-02) :ARG1-of (n5 / normal-02) :ARG1-of (r3 / resemble-01 :ARG2 (e2 / epithelium))))))) :manner (m / morphological) :ARG1-of (d2 / describe-01 :ARG2 (f / figure :mod "1A"))) # ::id pmid_2470_8867.103 # ::date 2015-08-26T16:28:03 # ::file pmid_2470_8867_103.txt # ::snt Morphological changes induced in the TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells include an apparent breakdown of cell-cell contacts, cell dispersal, the acquisition of a fibroblast-like spindle-shaped morphology, and a more refractile appearance than the Control-IEC-6 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (i / include-01 :ARG1 (a2 / and :op1 (b / break-down-12 :ARG1 (c5 / contact-01 :ARG0 (c6 / cell) :ARG1 (c7 / cell)) :ARG1-of (a3 / appear-01)) :op2 (d / disperse-01 :ARG1 c6) :op3 (a4 / acquire-01 :ARG1 (m2 / morphology :ARG1-of (r / resemble-01 :ARG2 (f / fibroblast)) :ARG1-of (s / shape-01 :ARG2 (s2 / spindle)))) :op4 (a5 / appear-01 :mod (r2 / refractile :degree (m3 / more)) :compared-to (c8 / cell-line :name (n4 / name :op1 "Control-IEC-6")))) :ARG2 (c / change-01 :mod (m / morphology) :ARG2-of (i2 / induce-01 :location (a / and :op1 (c2 / cell-line :name (n / name :op1 "TM-Grb2-IEC-6")) :op2 (c3 / cell-line :name (n2 / name :op1 "TM-Shc1-IEC-6")) :op3 (c4 / cell-line :name (n3 / name :op1 "TM-Shc2-IEC-6")))))) # ::id pmid_2470_8867.104 # ::date 2015-08-26T17:03:03 # ::file pmid_2470_8867_104.txt # ::snt Cells expressing the Grb2 and Shc docking-specific oncoproteins also displayed many cell membrane protrusions typical of lamellipodia and invadopodia-like structures. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (d / display-01 :ARG0 (c / cell :ARG3-of (e / express-03 :ARG2 (a / and :op1 (p2 / protein :name (n / name :op1 "Grb2") :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer)) :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p / protein :name (n2 / name :op1 "Shc") :ARG0-of c2 :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG1-of (s / specific-02 :ARG2 (d2 / dock-01))))) :ARG1 (p3 / protrude-01 :ARG2 (m / membrane :part-of (c4 / cell) :xref (x2 / xref :value "GO:0016020" :prob "0.8")) :ARG1-of (t / typical-02 :ARG2 (a3 / and :op1 (s2 / structure :mod (l / lamellipodium)) :op2 (s3 / structure :ARG1-of (r / resemble-01 :ARG2 (i / invadopodium))))) :quant (m2 / many)) :mod (a2 / also)) # ::id pmid_2470_8867.105 # ::date 2015-08-26T22:13:53 # ::file pmid_2470_8867_105.txt # ::snt The Tpr-Met variants exhibited comparable levels of Tyr phosphorylation in IEC-6 cells, relative to their expression levels (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (e / exhibit-01 :ARG0 (v / variant :mod (p / protein :name (n / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))) :ARG1 (l / level :ARG1-of (c / comparable-03) :degree-of (p2 / phosphorylate-01 :ARG1 (a / amino-acid :name (n3 / name :op1 "tyrosine") :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481")) :location (c2 / cell-line :name (n2 / name :op1 "IEC-6"))) :ARG1-of (r / relative-05 :ARG3 (l2 / level :degree-of (e2 / express-03 :ARG2 v)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_2470_8867.106 # ::date 2015-08-26T22:51:34 # ::file pmid_2470_8867_106.txt # ::snt They also demonstrated the predicted binding selectivity [8,9,15,16,20] (Additional file 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (d / demonstrate-01 :ARG0 (t / they) :ARG1 (s / select-01 :ARG1-of (p / predict-01) :mod (b / bind-01)) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 "8" :op2 "9" :op3 "15" :op4 "16" :op5 "20"))) :op2 (f / file :mod "1" :mod (a4 / additional))))) # ::id pmid_2470_8867.107 # ::date 2015-08-27T04:13:27 # ::file pmid_2470_8867_107.txt # ::snt Since such morphological changes in epithelial cells are typically associated with down-regulation of E-cadherin, immunoblot (IB) analysis of the E-cadherin protein levels were performed [31]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (c / cause-01 :ARG0 (a / associate-01 :ARG1 (c2 / change-01 :ARG1 (c3 / cell :source (e / epithelium)) :mod (m / morphological) :mod (s / such)) :ARG2 (d / downregulate-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG1-of (t / typical-02)) :ARG1 (p2 / perform-02 :ARG2 (a2 / analyze-01 :ARG1 (l / level :quant-of p) :mod (i2 / immunoblot-01))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "31")))) # ::id pmid_2470_8867.108 # ::date 2015-08-27T10:32:19 # ::file pmid_2470_8867_108.txt # ::snt Consistent with the previous characterization of Tpr-Met-IEC-6 cells [5], also presented herein, oncogenic activation of Grb2- and especially Shc-specific signals led to a dramatic decrease in E-cadherin protein levels relative to the Control-IEC-6 cells (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (l / lead-03 :ARG0 (a / activate-01 :ARG1 (s / signal-07 :ARG1-of (s2 / specific-02 :ARG2 (a2 / and :op1 (p / protein :name (n / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n2 / name :op1 "Shc") :ARG1-of (s3 / special-02) :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))) :ARG0-of (c / cause-01 :ARG1 (c2 / cancer))) :ARG2 (d / decrease-01 :ARG1 (l2 / level :quant-of (p3 / protein :name (n3 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")) :ARG1-of (r / relative-05 :ARG2 (c3 / cell-line :name (n4 / name :op1 "Control-IEC-6")))) :manner (d2 / dramatic)) :ARG1-of (c4 / consistent-01 :ARG2 (c5 / characterize-01 :ARG1 (c6 / cell-line :name (n5 / name :op1 "Tpr-Met-IEC-6")) :time (p4 / previous) :ARG1-of (p6 / present-01 :mod (a3 / also) :medium (h / herein))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG0-of (c7 / cite-01 :ARG2 "5")))) :ARG1-of (d4 / describe-01 :ARG2 (f / figure :mod "1B"))) # ::id pmid_2470_8867.109 # ::date 2015-08-27T11:05:01 # ::file pmid_2470_8867_109.txt # ::snt Likewise, a marked reduction in E-cadherin (Cdh1) mRNA levels was observed in these cells, as determined by semi-quantitative and quantitative real-time RT–PCR analyses (Figure 1C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (o / observe-01 :ARG1 (r / reduce-01 :ARG1 (l / level :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin") :ARG1-of (m2 / mean-01 :ARG2 (p2 / protein :name (n3 / name :op1 "Cdh1") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "0.603"))) :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))) :ARG1-of (m / mark-01)) :location (c / cell :mod (t / this)) :ARG1-of (d / determine-01 :ARG0 (a / and :op1 (a2 / analyze-01 :mod (t2 / thing :name (n4 / name :op1 "RT-PCR")) :mod (q / quantitative :degree (s / semi)) :mod (r3 / real-time)) :op2 (a3 / analyze-01 :mod (q2 / quantitative) :mod r3 :mod t2))) :manner (l2 / likewise) :ARG1-of (d2 / describe-01 :ARG2 (a4 / and :op1 (f / figure :mod "1C") :op2 (f2 / figure :mod "1D")))) # ::id pmid_2470_8867.110 # ::date 2015-08-27T12:19:27 # ::file pmid_2470_8867_110.txt # ::snt Analysis of the expression profiles of E-cadherin transcriptional repressors in these IECs suggests that a combined up-regulation of Snail2, Twist1, or Twist2, but not of Snail1 or Zeb1, may partly account for the E-cadherin repression induced by oncogenic Met-dependent signaling, including that one driven by Grb2 and Shc signals (Additional file 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (a / analyze-01 :ARG1 (p / profile-01 :ARG1 (e / express-03 :ARG2 (m / molecular-physical-entity :ARG0-of (r / repress-01 :ARG1 (t / transcribe-01 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))))))) :location (c / cell :name (n2 / name :op1 "IEC") :mod (t2 / this))) :ARG1 (c2 / contrast-01 :ARG1 (p3 / possible-01 :ARG1 (a2 / account-01 :ARG0 (u / upregulate-01 :ARG1 (o / or :op1 (g / gene :name (n3 / name :op1 "Snail2") :xref (x6 / xref :value "UNIPROT:SNAI2_HUMAN" :prob "0.252")) :op2 (g2 / gene :name (n4 / name :op1 "Twist1") :xref (x5 / xref :value "UNIPROT:TWST1_HUMAN" :prob "0.602")) :op3 (g3 / gene :name (n5 / name :op1 "Twist2") :xref (x4 / xref :value "UNIPROT:TWST2_HUMAN" :prob "0.602"))) :ARG1-of (c3 / combine-01)) :ARG1 (r2 / repress-01 :ARG1 p2 :ARG2-of (i / induce-01 :ARG0 (s2 / signal-07 :ARG0-of (d / depend-01 :ARG1 (p6 / protein :name (n7 / name :op1 "Met") :xref (x7 / xref :value "UNIPROT:MET_HUMAN" :prob "0.604"))) :ARG0-of (c4 / cause-01 :ARG1 (c5 / cancer)))) :ARG2-of (i2 / include-01 :ARG1 (r3 / repress-01 :ARG1-of (d2 / drive-02 :ARG0 (s3 / signal-07 :ARG0 (a3 / and :op1 (p7 / protein :name (n8 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p8 / protein :name (n9 / name :op1 "Shc") :xref (x8 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))))))) :degree (p4 / part))) :ARG2 (a5 / account-01 :polarity "-" :ARG0 (u2 / upregulate-01 :ARG1 (o2 / or :op1 (g4 / gene :name (n10 / name :op1 "Snail1") :xref (x3 / xref :value "UNIPROT:SNAI1_HUMAN" :prob "0.252")) :op2 (g5 / gene :name (n11 / name :op1 "Zeb1") :xref (x2 / xref :value "UNIPROT:ZEB1_HUMAN" :prob "0.603"))) :ARG1-of c3) :ARG1 r2)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2" :mod (a4 / additional)))) # ::id pmid_2470_8867.111 # ::date 2015-08-27T13:11:30 # ::file pmid_2470_8867_111.txt # ::snt Overall, these results demonstrate that oncogenic activation of Grb2- and Shc-dependent signaling pathways, such as those activated by Tpr-Met, is sufficient to induce an epithelial-mesenchymal morphological-like transformation in normal IECs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (d / demonstrate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (s / suffice-01 :ARG0 (a / activate-01 :ARG1 (p / pathway :ARG0-of (s2 / signal-07 :ARG0-of (d2 / depend-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))) :example (p4 / pathway :ARG1-of (a3 / activate-01 :ARG0 (p5 / protein :name (n3 / name :op1 "Tpr-Met") :xref (x2 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :ARG0-of (c / cause-01 :ARG1 (c2 / cancer))) :ARG1 (i / induce-01 :ARG0 a :ARG2 (t3 / transform-01 :ARG1 (c3 / cell :name (n4 / name :op1 "IEC") :ARG1-of (n5 / normal-02)) :ARG1-of (r2 / resemble-01 :ARG2 (m / morphology)) :mod (e2 / epithelium :mod (m2 / mesenchyme))))) :mod (o / overall)) # ::id pmid_2470_8867.112 # ::date 2015-08-27T13:38:25 # ::file pmid_2470_8867_112.txt # ::snt Oncogenic engagement of Grb2 or Shc signaling enhances cell growth and loss of contact inhibition in IECs # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / enhance-01 :ARG0 (e2 / engage-01 :ARG1 (s / signal-07 :ARG0 (o / or :op1 (p / protein :name (n / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n2 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))) :ARG0-of (c / cause-01 :ARG1 (c2 / cancer))) :ARG1 (a2 / and :op1 (g / grow-01 :ARG1 (c3 / cell)) :op2 (l / lose-01 :ARG1 (i / inhibit-01 :ARG0 (c4 / contact-01)) :location (c5 / cell :name (n3 / name :op1 "IEC"))))) # ::id pmid_2470_8867.113 # ::date 2015-08-27T13:45:40 # ::file pmid_2470_8867_113.txt # ::snt We next tested the oncogenic growth characteristics of IEC-6 cells transformed by the Tpr-Met variants. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (t / test-01 :ARG0 (w / we) :ARG1 (c / characteristic-02 :ARG1 (c4 / cell-line :name (n / name :op1 "IEC-6") :ARG1-of (t2 / transform-01 :ARG0 (v / variant :mod (p / protein :name (n3 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :ARG2 (g / grow-01 :ARG1 c4) :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer))) :time (n2 / next)) # ::id pmid_2470_8867.114 # ::date 2015-08-27T13:58:25 # ::file pmid_2470_8867_114.txt # ::snt First, cell-counting assays were performed to determine the growth rate of each cell population. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (p / perform-02 :ARG1 (a / assay-01 :ARG1 (c / count-01 :ARG1 (c2 / cell))) :purpose (d / determine-01 :ARG1 (r / rate-01 :mod (g / grow-01 :ARG1 (p2 / population :consist-of (c3 / cell) :mod (e / each))))) :ord (o / ordinal-entity :value "1")) # ::id pmid_2470_8867.115 # ::date 2015-08-27T14:11:23 # ::file pmid_2470_8867_115.txt # ::snt The TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells displayed more rapid growth than Control-IEC-6 cells, albeit to a lesser extent than Tpr-Met-IEC-6 cells (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (d / display-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "TM-Grb2-IEC-6")) :op2 (c2 / cell-line :name (n2 / name :op1 "TM-Shc1-IEC-6")) :op3 (c3 / cell-line :name (n3 / name :op1 "TM-Shc2-IEC-6"))) :ARG1 (g / grow-01 :mod (r / rapid :degree (m / more) :compared-to (c4 / cell-line :name (n4 / name :op1 "Control-IEC-6")))) :concession (d2 / display-01 :ARG0 a :ARG1 (g2 / grow-01 :mod (r2 / rapid :degree (l / less) :compared-to (c5 / cell-line :name (n5 / name :op1 "Tpr-Met-IEC-6"))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2470_8867.116 # ::date 2015-08-27T14:27:53 # ::file pmid_2470_8867_116.txt # ::snt Notably, TM-Shc1-IEC-6 cells exhibited accelerated growth relative to TM-Grb2-IEC-6 and TM-Shc2-IEC-6 cells, between which the doubling time did not differ significantly. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (e / exhibit-01 :ARG0 (c / cell-line :name (n / name :op1 "TM-Shc1-IEC-6")) :ARG1 (g / grow-01 :ARG1-of (a / accelerate-01) :ARG1-of (r / relative-05 :ARG3 (a2 / and :op1 (c3 / cell-line :name (n3 / name :op1 "TM-Grb2-IEC-6") :ARG1-of (d / differ-02 :polarity "-" :ARG2 "c2" :ARG3 (t / time :duration-of (d2 / double-01)) :ARG1-of (s / significant-02))) :op2 (c2 / cell-line :name (n2 / name :op1 "TM-Shc2-IEC-6"))))) :ARG1-of (n4 / notable-04)) # ::id pmid_2470_8867.117 # ::date 2015-08-27T14:44:54 # ::file pmid_2470_8867_117.txt # ::snt The enhanced growth promoting activity of the TM-Shc1 relative to the TM-Shc2 correlates with the affinity of their respective Shc binding sites [8]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (c / correlate-01 :ARG1 (a / activity-06 :ARG0 (p3 / protein :name (n / name :op1 "TM-Shc1") :xref (x / xref :value "UNIPROT:CERS2_HUMAN" :prob "0.222")) :ARG1-of (e / enhance-01) :ARG0-of (p / promote-02 :ARG1 (g / grow-01)) :ARG1-of (r / relative-05 :ARG2 (p2 / protein :name (n2 / name :op1 "TM-Shc2")))) :ARG2 (a2 / affinity :poss (a3 / and :op1 (p6 / protein-segment :part-of p3) :op2 (p7 / protein-segment :part-of p2) :ARG2-of (b / bind-01 :ARG1 (p4 / protein :name (n3 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 "8")))) # ::id pmid_2470_8867.118 # ::date 2015-08-27T15:09:18 # ::file pmid_2470_8867_118.txt # ::snt Typical of untransformed cells, IEC-6 cells ceased proliferation upon the establishment of cell-cell contacts [5,25]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (c / cease-01 :ARG1 (p / proliferate-01 :ARG0 (c2 / cell-line :name (n / name :op1 "IEC-6"))) :time (e / establish-01 :ARG1 (c3 / contact-01 :ARG0 (c4 / cell) :ARG1 (c5 / cell))) :ARG1-of (t / typical-02 :ARG2 (c6 / cell :ARG1-of (t2 / transform-01 :polarity "-"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c7 / cite-01 :ARG2 (a / and :op1 "5" :op2 "25"))))) # ::id pmid_2470_8867.119 # ::date 2015-08-27T15:20:08 # ::file pmid_2470_8867_119.txt # ::snt As such, Control-IEC-6 cells formed a monolayer of well-organized epithelial cells upon reaching confluence (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (f / form-01 :ARG0 (c / cell-line :name (n / name :op1 "Control-IEC-6")) :ARG1 (l / layer :quant "1" :consist-of (c2 / cell :source (e / epithelium) :ARG1-of (o / organize-01 :ARG1-of (w / well-09)))) :prep-as (s / such) :time (r / reach-01 :ARG1 (c3 / confluence)) :ARG1-of (d / describe-01 :ARG2 (f2 / figure :mod "2B"))) # ::id pmid_2470_8867.120 # ::date 2015-08-27T15:28:37 # ::file pmid_2470_8867_120.txt # ::snt In sharp contrast, each of the oncogenic transformed IEC-6 cell populations appeared highly disorganized and grew in multiple layers at confluence (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (c / contrast-01 :ARG2 (a / and :op1 (a2 / appear-02 :ARG1 (o2 / organize-01 :polarity "-" :ARG1 (p / population :consist-of (c2 / cell-line :name (n / name :op1 "IEC-6")) :ARG0-of (c3 / cause-01 :ARG1 (c4 / cancer)) :ARG1-of (t / transform-01) :mod (e / each)) :ARG1-of (h / high-02))) :op2 (g / grow-01 :ARG1 p :manner (l / layer :quant (m / multiple)) :time (c5 / confluence))) :ARG1-of (s / sharp-02) :ARG1-of (d / describe-01 :ARG2 (f / figure :mod "2B"))) # ::id pmid_2470_8867.121 # ::date 2015-08-27T15:42:31 # ::file pmid_2470_8867_121.txt # ::snt Thus, oncogenic specific activation of Grb2- or Shc-dependent signals permits IECs to bypass contact inhibition of growth. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (i / infer-01 :ARG1 (p / permit-01 :ARG0 (a / activate-01 :ARG1 (s / signal-07 :ARG0-of (d / depend-01 :ARG1 (a2 / and :op1 (p2 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))) :ARG0-of (c / cause-01 :ARG1 (c2 / cancer)) :ARG1-of (s2 / specific-02)) :ARG1 (b / bypass-01 :ARG0 "c3" :ARG1 (i2 / inhibit-01 :ARG0 (c4 / contact-01) :ARG1 (g / grow-01))) :ARG2 (c3 / cell :name (n3 / name :op1 "IEC")))) # ::id pmid_2470_8867.122 # ::date 2015-08-27T15:53:01 # ::file pmid_2470_8867_122.txt # ::snt To validate this in a quantitative manner, focus formation assays were performed. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Aug 27, 2015 (p / perform-02 :ARG1 (a / assay-01 :ARG1 (f / form-01 :ARG1 (f2 / focus))) :purpose (v / validate-01 :ARG1 (t / this) :manner (q / quantitative))) # ::id pmid_2470_8867.123 # ::date 2015-08-27T15:57:54 # ::file pmid_2470_8867_123.txt # ::snt As expected [5], Control-IEC-6 cells failed to form foci, whereas TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells displayed strong focus-forming capacities, though less than that of Tpr-Met-IEC-6 cells (Figure 2C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Sep 13, 2015 (c / contrast-01 :ARG1 (f / fail-01 :ARG1 (c2 / cell-line :name (n / name :op1 "Control-IEC-6")) :ARG2 (f2 / form-01 :ARG0 c2 :ARG1 (f3 / focus))) :ARG2 (d / display-01 :ARG0 (a / and :op1 (c3 / cell-line :name (n2 / name :op1 "TM-Grb2-IEC-6")) :op2 (c4 / cell-line :name (n3 / name :op1 "TM-Shc1-IEC-6")) :op3 (c5 / cell-line :name (n4 / name :op1 "TM-Shc2-IEC-6"))) :ARG1 (c6 / capable-01 :ARG1 a :ARG2 (f4 / form-01 :ARG0 a :ARG1 (f5 / focus)) :ARG1-of (s / strong-02)) :concession (d2 / display-01 :ARG0 a :ARG1 (c7 / capable-01 :ARG1 a :ARG2 f4 :degree (l / less) :compared-to (c8 / cell-line :name (n5 / name :op1 "Tpr-Met-IEC-6"))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f6 / figure :mod "2C") :op2 (f7 / figure :mod "2D"))) :ARG1-of (e / expect-01 :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG0-of (c9 / cite-01 :ARG2 "5"))))) # ::id pmid_2470_8867.124 # ::date 2015-08-28T06:33:59 # ::file pmid_2470_8867_124.txt # ::snt The number and size of foci formed by the TM-Shc1-IEC-6 cells were markedly greater than those of the TM-Grb2-IEC-6 or TM-Shc2-IEC-6 cells (Figure 2C and D), likely reflecting their accelerated growth rate (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (g2 / great :domain (a3 / and :op1 (n / number :quant-of (f / focus :ARG1-of (f2 / form-01 :ARG0 (c4 / cell-line :name (n8 / name :op1 "TM-Shc1-IEC-6"))))) :op2 (s / size :poss f) :manner (m3 / marked)) :compared-to (a2 / and :op1 (n4 / number :quant-of (f3 / focus :ARG1-of (f4 / form-01 :ARG0 (o / or :op1 (c2 / cell-line :name (n2 / name :op1 "TM-Grb2-IEC-6")) :op2 (c5 / cell-line :name (n3 / name :op1 "TM-Shc2-IEC-6")))))) :op2 (s2 / size :poss f3)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f5 / figure :mod "2C") :op2 (f6 / figure :mod "2D"))) :ARG1-of (r2 / reflect-01 :ARG2 (a5 / accelerate-01 :ARG1 (r3 / rate :mod (g / grow-01 :ARG1 f))) :ARG1-of (l / likely-01) :ARG1-of (d2 / describe-01 :ARG0 (f7 / figure :mod "2A"))) :degree (m / more)) # ::id pmid_2470_8867.125 # ::date 2015-08-28T09:02:27 # ::file pmid_2470_8867_125.txt # ::snt These results indicate that the oncogenic engagement of Grb2- and Shc-dependent signals is sufficient to relieve contact inhibition of growth in IECs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 8, 2015 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (s / suffice-01 :ARG0 (e / engage-01 :ARG1 (s2 / signal-07 :ARG0-of (d / depend-01 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n2 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))) :ARG2 (c / cancer)) :ARG1 (r2 / relieve-01 :ARG0 e :ARG1 (i2 / inhibit-01 :ARG0 (c3 / contact-01) :ARG1 (g / grow-01 :location (c2 / cell :name (n3 / name :op1 "IEC"))))))) # ::id pmid_2470_8867.126 # ::date 2015-08-28T09:16:27 # ::file pmid_2470_8867_126.txt # ::snt Oncogenic engagement of Grb2 and Shc signaling induces anchorage-independent growth and anoikis resistance in IECs # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 8, 2015 (i / induce-01 :ARG0 (e / engage-01 :ARG1 (s / signal-07 :ARG1 (a / and :op1 (p / protein :name (n / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n2 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))) :ARG2 (c / cancer)) :ARG2 (a2 / and :op1 (g / grow-01 :ARG0-of (d / depend-01 :polarity "-" :ARG1 (a3 / anchorage))) :op2 (r / resist-01 :ARG1 (a4 / anoikis)) :location (c2 / cell :name (n3 / name :op1 "IEC")))) # ::id pmid_2470_8867.127 # ::date 2015-08-29T02:24:53 # ::file pmid_2470_8867_127.txt # ::snt We next verified whether the oncogenic activation of Grb2- or Shc-dependent signals is sufficient to confer to non-transformed IEC-6 cells the capacity to grow in the absence of anchorage to the extra-cellular matrix (ECM), by performing soft agar growth assays. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (v / verify-01 :ARG0 (w / we) :ARG1 (s / suffice-01 :mode "interrogative" :ARG0 (a / activate-01 :ARG1 (s2 / signal-07 :ARG0-of (d / depend-01 :ARG1 (o / or :op1 (p / protein :name (n2 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n3 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))) :ARG0-of (c5 / cause-01 :ARG1 (c6 / cancer))) :ARG1 (c2 / confer-02 :ARG0 a :ARG1 (c / capable-01 :ARG1 (c3 / cell-line :name (n4 / name :op1 "IEC-6") :ARG1-of (t / transform-01 :polarity "-")) :ARG2 (g / grow-01 :ARG1 c3 :condition (a2 / absent-01 :ARG1 (a3 / anchor-01 :location (m / matrix :mod (e / extracellular)))))) :ARG2 c3)) :time (n / next) :manner (p3 / perform-01 :ARG0 w :ARG1 (a4 / assay-01 :ARG1 (g2 / grow-01 :condition (a5 / agar :ARG1-of (s3 / soft-02)))))) # ::id pmid_2470_8867.128 # ::date 2015-08-29T02:47:46 # ::file pmid_2470_8867_128.txt # ::snt Consistent with previous findings [5], Control-IEC-6 cells failed to grow in soft agar whereas Tpr-Met-IEC-6 cells grew efficiently, forming numerous large colonies (Figure 3A–C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG1 (f2 / fail-01 :ARG1 (c8 / cell-line :name (n5 / name :op1 "IEC-6") :ARG0-of (c5 / control-01)) :ARG2 (g / grow-01 :ARG1 c8 :location (a / agar :ARG1-of (s / soft-02)))) :ARG2 (g2 / grow-01 :ARG1 (c4 / cell-line :name (n / name :op1 "Tpr-Met-IEC-6") :ARG2-of (f3 / form-01 :ARG1 (c6 / colony :mod (l / large) :quant (n4 / numerous)))) :ARG2-of (e2 / efficient-01)) :ARG1-of (c2 / consistent-01 :ARG2 (t / thing :ARG1-of (f / find-01) :time (p / previous)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 "5")))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f4 / figure :mod "3A") :op2 (f5 / figure :mod "3B") :op3 (f6 / figure :mod "3C")))) # ::id pmid_2470_8867.129 # ::date 2015-08-30T00:33:57 # ::file pmid_2470_8867_129.txt # ::snt TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells also formed colonies in soft agar, but with lower efficiencies. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (f / form-01 :ARG0 (a / and :op1 (c6 / cell-line :name (n7 / name :op1 "TM-Grb2-IEC-6")) :op2 (c7 / cell-line :name (n8 / name :op1 "TM-Shc1-IEC-6")) :op3 (c8 / cell-line :name (n9 / name :op1 "TM-Shc2-IEC-6"))) :ARG1 (c4 / colony) :location (a2 / agar :ARG1-of (s / soft-02)) :ARG1-of (c5 / contrast-01 :ARG2 (e4 / efficient-01 :ARG2 "f" :ARG1-of (l / low-04 :degree (m2 / more)))) :mod (a3 / also)) # ::id pmid_2470_8867.130 # ::date 2015-08-30T00:51:32 # ::file pmid_2470_8867_130.txt # ::snt While the three IEC-6 cell populations expressing docking-specific Tpr-Met variants formed similar numbers of colonies (Figure 3A), those produced by the TM-Shc1-IEC-6 cells were larger and displayed a different morphology from those produced by the TM-Shc2-IEC-6 and TM-Grb2-IEC-6 cells (Figure 3B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 10, 2015 (c / contrast-01 :ARG1 (f / form-01 :ARG0 (p / population :quant "3" :mod (c2 / cell-line :name (n / name :op1 "IEC-6")) :ARG3-of (e / express-03 :ARG2 (v / variant :mod (p2 / protein :name (n2 / name :op1 "Tpr-Met") :ARG1-of (s2 / specific-02 :ARG2 (d / dock-01)) :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :ARG1 (n3 / number-01 :ARG1 (c3 / colony) :ARG1-of (r / resemble-01)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3A"))) :ARG2 (p3 / produce-01 :ARG0 (c4 / cell-line :name (n4 / name :op1 "TM-Shc1-IEC-6")) :ARG1 (c6 / colony :mod (l / large :degree (m / more)) :ARG0-of (d3 / display-01 :ARG1 (m2 / morphology :ARG1-of (d4 / differ-02 :ARG2 (c7 / colony :ARG1-of (p5 / produce-01 :ARG0 (a / and :op1 (c5 / cell-line :name (n6 / name :op1 "TM-Shc2-IEC-6")) :op2 (c8 / cell-line :name (n7 / name :op1 "TM-Grb2-IEC-6"))))))))) :ARG1-of (d5 / describe-01 :ARG0 (a2 / and :op1 (f3 / figure :mod "3B") :op2 (f4 / figure :mod "3C"))))) # ::id pmid_2470_8867.131 # ::date 2015-08-30T01:11:28 # ::file pmid_2470_8867_131.txt # ::snt Colonies formed by the TM-Shc1-IEC-6 cells were composed mainly of loosely associated cells with apparently limited cell-cell contacts, similar to Tpr-Met-IEC-6 colonies (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 10, 2015 (c / compose-01 :ARG1 (c3 / colony :ARG1-of (f / form-01 :ARG0 (c2 / cell-line :name (n / name :op1 "TM-Shc1-IEC-6")))) :ARG2 (c4 / cell :ARG1-of (a / associate-01 :ARG1-of (l / loose-04)) :ARG0-of (h / have-03 :ARG1 (c5 / contact-01 :ARG0 (c6 / cell) :ARG1 (c7 / cell) :ARG1-of (l2 / limit-01)) :ARG1-of (a2 / appear-02))) :mod (m / main) :ARG1-of (r / resemble-01 :ARG2 (c9 / colony :mod (c10 / cell-line :name (n3 / name :op1 "Tpr-Met-IEC-6")))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3B"))) # ::id pmid_2470_8867.132 # ::date 2015-08-30T01:20:15 # ::file pmid_2470_8867_132.txt # ::snt By contrast, colonies produced by the TM-Grb2-IEC-6 or TM-Shc2-IEC-6 cells were compact and composed of tightly associated cells (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (c / contrast-01 :ARG2 (p / produce-01 :ARG0 (o / or :op1 (c3 / cell-line :name (n / name :op1 "TM-Grb2-IEC-6")) :op2 (c4 / cell-line :name (n2 / name :op1 "TM-Shc2-IEC-6"))) :ARG2 (c2 / colony :ARG1-of (c5 / compact-01) :ARG1-of (c6 / compose-01 :ARG2 (c7 / cell :ARG1-of (a / associate-01 :ARG1-of (t / tight-05)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2470_8867.133 # ::date 2015-08-30T01:24:53 # ::file pmid_2470_8867_133.txt # ::snt Growth in soft agar reflects not only the capacity of cells to proliferate in the absence of ECM attachment, but also to avoid anoikis, a form of apoptosis induced upon loss of matrix attachment [32]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (r / reflect-01 :ARG1 (g / grow-01 :location (a / agar :ARG1-of (s / soft-02))) :ARG2 (c / capable-01 :ARG1 (c2 / cell) :ARG2 (a2 / and :op1 (p / proliferate-01 :condition (a3 / absent-01 :ARG1 (a4 / attach-01 :ARG1 c2 :ARG2 (m3 / matrix :mod (e / extracellular))))) :op2 (a5 / avoid-01 :ARG1 (a6 / anoikis) :ARG1-of (m / mean-01 :ARG2 (f / form :mod (a7 / apoptosis :ARG2-of (i / induce-01 :condition (l / lose-02 :ARG1 (a8 / attach-01 :ARG2 (m2 / matrix)))))))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "32")))) # ::id pmid_2470_8867.134 # ::date 2015-08-30T01:43:03 # ::file pmid_2470_8867_134.txt # ::snt Anoikis assays were performed by monitoring the viability of cells seeded in the absence of serum under adherent and suspension conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 10, 2015 (p / perform-01 :ARG1 (a / assay-01 :ARG1 (a2 / anoikis)) :ARG2 (m / monitor-01 :ARG1 (v / viable :domain (c / cell :ARG2-of (s / seed-02 :condition (a3 / absent-01 :ARG1 (s2 / serum) :condition (a4 / and :op1 (a5 / adhere-01) :op2 (s3 / suspend-02)))))))) # ::id pmid_2470_8867.135 # ::date 2015-08-30T02:07:23 # ::file pmid_2470_8867_135.txt # ::snt As expected for normal IECs [33,34], Control-IEC-6 cells displayed anoikis sensitivity under suspension culture conditions (Figure 3D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 10, 2015 (d / display-01 :ARG0 (c / cell-line :name (n / name :op1 "IEC-6") :ARG0-of (c2 / control-01)) :ARG1 (s / sensitive-03 :ARG0 c :ARG1 (a / anoikis)) :condition (c3 / culture :ARG1-of (s2 / suspend-02)) :ARG1-of (e / expect-01 :topic (c4 / cell :name (n2 / name :op1 "IEC") :ARG1-of (n3 / normal-02)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 (a2 / and :op1 "33" :op2 "34"))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3D"))) # ::id pmid_2470_8867.136 # ::date 2015-08-30T02:13:33 # ::file pmid_2470_8867_136.txt # ::snt In contrast, IEC-6 cells transformed by either Tpr-Met, or the Grb2 or Shc docking-specific oncoproteins, displayed potent resistance to anoikis, with more than half surviving under non-adherent conditions. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (c / contrast-01 :ARG2 (d / display-01 :ARG0 (c2 / cell-line :wiki "-" :name (n / name :op1 "IEC-6") :ARG1-of (t / transform-01 :ARG0 (o / or :op1 (p / protein :wiki "Tpr-met_fusion_protein" :name (n2 / name :op1 "Tpr-Met") :xref (x2 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")) :op2 (o4 / or :op1 (p2 / protein :wiki "GRB2" :name (n5 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :wiki "SHC1" :name (n6 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG0-of (c5 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :mod (e / either) :ARG1-of (s / specific-02 :ARG2 (d2 / dock-01))))) :ARG1 (r / resist-01 :ARG0 c2 :ARG1 (a / anoikis) :mod (p4 / potent) :mod (s2 / survive-01 :ARG0 (c4 / cell :ARG1-of (i / include-91 :ARG2 c2 :ARG3 (m2 / more-than :op1 "1/2"))) :ARG1 (c3 / condition :ARG1-of (a2 / adhere-01 :polarity "-")))))) # ::id pmid_2470_8867.137 # ::date 2015-08-30T02:25:28 # ::file pmid_2470_8867_137.txt # ::snt Likewise, the viability of these transformed cells was significantly higher than that of Control-IEC-6 cells when seeded in the absence of serum and under adherent conditions (Figure 3E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (h / high-02 :ARG1 (v / viable :domain (c2 / cell :ARG1-of (t / transform-01) :mod (t2 / this) :ARG0-of (s / seed-01 :condition (a / and :op1 (a2 / absent-01 :ARG1 (s2 / serum)) :op2 (c5 / condition :mod (a3 / adhere-01))))) :ARG1-of (s3 / significant-02)) :compared-to (c3 / cell-line :name (n / name :op1 "IEC-6") :ARG0-of (c4 / control-01)) :manner (l / likewise) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3E")) :degree (m / more)) # ::id pmid_2470_8867.138 # ::date 2015-08-30T02:32:52 # ::file pmid_2470_8867_138.txt # ::snt Overall, these results indicate that the oncogenic engagement of signals downstream of Grb2 or Shc is sufficient to alleviate the anchorage-dependence of growth, and to reduce sensitivity to growth factor deprivation and to anoikis in IECs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Feb 24, 2016 (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (s / suffice-01 :ARG0 (e / engage-01 :ARG1 (s2 / signal-07 :ARG1 (o2 / or :op1 (p / protein :name (n / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n2 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :mod (d / downstream)) :ARG2 (c / cancer)) :ARG1 (a2 / and :op1 (a3 / alleviate-01 :ARG0 e :ARG1 (d2 / depend-01 :ARG0 (g / grow-01) :ARG1 (a4 / anchorage))) :op2 (r2 / reduce-01 :ARG0 e :ARG1 (s3 / sensitive-03 :ARG1 (a5 / and :op1 (d3 / deprive-01 :ARG1 (g2 / growth-factor)) :op2 (a6 / anoikis) :location (c2 / cell :name (n3 / name :op1 "IEC"))))))) :mod (o / overall)) # ::id pmid_2470_8867.139 # ::date 2015-08-30T02:42:15 # ::file pmid_2470_8867_139.txt # ::snt Silencing of Grb2 impairs Tpr-Met-induced morphological transformation and anoikis resistance in IECs, but reduced expression of Shc decreases cell growth # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (i2 / impair-01 :ARG0 (s / silence-01 :ARG1 (p / protein :name (n / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :ARG1 (a / and :op1 (t / transform-01 :ARG2-of (i / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))) :mod (m / morphologic)) :op2 (r / resist-01 :ARG1 (a2 / anoikis)) :location (c2 / cell :name (n3 / name :op1 "IEC")))) :ARG2 (d / decrease-01 :ARG0 (e / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG1-of (r2 / reduce-01)) :ARG1 (g / grow-01 :ARG1 (c3 / cell)))) # ::id pmid_2470_8867.140 # ::date 2015-08-30T03:03:22 # ::file pmid_2470_8867_140.txt # ::snt The above results with the docking-specific Tpr-Met-derived variants established that the oncogenic activation of either Grb2 or Shc signaling pathways was each sufficient to promote transformation of IECs, conferring upon them aberrant growth characteristics and resistance to anoikis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (e / establish-01 :ARG0 (t / thing :ARG2-of (r / result-01) :location (a / above) :accompanier (v / variant :ARG1-of (d / derive-01 :ARG2 (p / protein :name (n / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))) :ARG1-of (s / specific-02 :ARG2 (d2 / dock-01)))) :ARG1 (s2 / suffice-01 :ARG0 (a2 / activate-01 :ARG1 (o / or :op1 (p6 / pathway :name (n5 / name :op1 "Grb2")) :op2 (p7 / pathway :name (n6 / name :op1 "Shc")) :ARG0-of (s4 / signal-07)) :ARG0-of (c4 / cause-01 :ARG1 (c5 / cancer))) :ARG1 (p5 / promote-01 :ARG0 a2 :ARG1 (t2 / transform-01 :ARG1 (c / cell :name (n4 / name :op1 "IEC") :ARG2-of (c2 / confer-02 :ARG1 (a3 / and :op1 (c3 / characteristic-02 :ARG1 c :ARG2 (g / grow-01 :mod (a4 / aberrant))) :op2 (r2 / resist-01 :ARG0 c :ARG1 (a5 / anoikis))))))) :mod (e3 / each))) # ::id pmid_2470_8867.141 # ::date 2015-08-30T03:46:12 # ::file pmid_2470_8867_141.txt # ::snt We next sought to determine whether signaling pathways downstream of these adaptor proteins were required for the oncogenic potential of Met in IECs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (s / seek-01 :ARG0 (w / we) :ARG1 (d / determine-01 :ARG0 w :ARG1 (r / require-01 :mode "interrogative" :ARG0 (p3 / potential :poss (p4 / protein :name (n2 / name :op1 "Met") :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "0.604")) :location (c2 / cell :name (n3 / name :op1 "IEC")) :ARG0-of (c3 / cause-01 :ARG1 (c4 / cancer))) :ARG1 (p / pathway :ARG0-of (s2 / signal-07) :mod (d2 / downstream) :poss (p2 / protein :mod (t / this) :ARG0-of (a / adapt-01))))) :time (n / next)) # ::id pmid_2470_8867.142 # ::date 2015-08-30T04:35:55 # ::file pmid_2470_8867_142.txt # ::snt The impact of silencing the expression of Grb2 or Shc on the features of the Tpr-Met-IEC-6 cells was evaluated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / evaluate-01 :ARG1 (i / impact-01 :ARG0 (s / silence-01 :ARG1 (e2 / express-03 :ARG2 (o / or :op1 (p / protein :name (n / name :op1 "Grb2") :xref (x2 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n2 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))))) :ARG1 (f / feature-01 :ARG1 (c / cell-line :name (n3 / name :op1 "IEC-6") :ARG3-of (e3 / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "Tpr-Met") :xref (x1 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))))) # ::id pmid_2470_8867.143 # ::date 2015-08-30T04:39:21 # ::file pmid_2470_8867_143.txt # ::snt Stable populations of Tpr-Met-IEC-6 cells displaying marked and selective knockdown of Grb2 (TM-shGrb2) or Shc (TM-shShc) were generated using shRNAs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (g / generate-01 :ARG1 (p / population :mod (c / cell-line :name (n2 / name :op1 "Tpr-Met-IEC-6") :ARG1-of (m4 / mean-01 :ARG2 (a / and :op1 (c2 / cell-line :name (n5 / name :op1 "TM-shGrb2") :ARG0-of (d / display-01 :ARG1 (k / knock-down-02 :ARG1 (p3 / protein :name (n4 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :ARG2-of (m3 / mark-02) :mod (s2 / selective)))) :op2 (c3 / cell-line :name (n7 / name :op1 "TM-shShc") :ARG0-of (d2 / display-01 :ARG1 (k2 / knock-down-02 :ARG1 (p5 / protein :name (n6 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG2-of m3 :mod s2)))))) :ARG1-of (s / stable-02)) :ARG2-of (u / use-01 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "shRNA")))) # ::id pmid_2470_8867.144 # ::date 2015-08-30T04:57:14 # ::file pmid_2470_8867_144.txt # ::snt As demonstrated by IB analyses (Figure 4A), Grb2 and Shc (all ShcA isoforms) protein levels were selectively reduced by more than 60% in TM-shGrb2 and TM-shShc cell populations, respectively, compared to Tpr-Met-IEC-6 cells expressing a non-targeting shRNA (TM-shCTRL). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (r / reduce-01 :ARG1 (l / level :quant-of (a / and :op1 (p2 / protein :name (n / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p3 / protein :name (n2 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG1-of (m / mean-01 :ARG2 (i / isoform :mod (p4 / protein :name (n3 / name :op1 "ShcA") :xref (x2 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :mod (a2 / all))))) :ARG2 (m2 / more-than :op2 (p5 / percentage-entity :value "60")) :mod (s / selective) :location (p / population :mod (r2 / respective) :mod (c3 / cell-line :name (n11 / name :op1 "TM-shGrb2")) :mod (c4 / cell-line :name (n12 / name :op1 "TM-shShc"))) :compared-to (c / cell-line :name (n6 / name :op1 "Tpr-Met-IEC-6") :ARG3-of (e3 / express-03 :ARG2 (n4 / nucleic-acid :name (n9 / name :op1 "shRNA") :ARG0-of (t / target-01 :polarity "-"))) :ARG1-of (m3 / mean-01 :ARG2 (c2 / cell-line :name (n8 / name :op1 "TM-shCTRL")))) :ARG1-of (d / demonstrate-01 :ARG0 (a3 / analyze-01 :mod (i2 / immunoblot-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A")))) # ::id pmid_2470_8867.145 # ::date 2015-08-30T04:58:42 # ::file pmid_2470_8867_145.txt # ::snt Protein levels of Tpr-Met and actin remained equivalent amongst all these cell populations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (r / remain-01 :ARG1 (a / and :op1 (l / level :quant-of (p5 / protein :name (n3 / name :op1 "Tpr-Met") :xref (x1 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))) :op2 (l2 / level :quant-of (p6 / protein :name (n4 / name :op1 "actin") :xref (x / xref :value "UNIPROT:KLH17_HUMAN" :prob "0.302")))) :ARG3 (e / equal-01) :location (p4 / population :mod (c / cell) :mod (t / this) :mod (a2 / all))) # ::id pmid_2470_8867.146 # ::date 2015-08-30T05:06:31 # ::file pmid_2470_8867_146.txt # ::snt Phase contrast microscopy revealed that the TM-shGrb2 cells exhibited a partial reversal of the transformed morphology, relative to TM-shCTRL cells, characterized by a decrease in cell refractility and an increase in cell spreading (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (r / reveal-01 :ARG0 (m2 / microscopy :mod (c2 / contrast-01 :ARG1 (p / phase))) :ARG1 (e / exhibit-01 :ARG0 (c6 / cell-line :name (n4 / name :op1 "TM-shGrb2") :ARG1-of (r3 / relative-05 :ARG3 (c / cell-line :name (n / name :op1 "TM-shCTRL")))) :ARG1 (r2 / reverse-01 :ARG1 (t / transform-01 :ARG1 (m / morphology)) :degree (p2 / part) :ARG1-of (c3 / characterize-01 :ARG2 (a / and :op1 (d / decrease-01 :ARG1 (r4 / refractility :mod (c4 / cell))) :op2 (i / increase-01 :ARG1 (s / spread-02 :ARG1 c4)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B"))) # ::id pmid_2470_8867.147 # ::date 2015-08-30T05:10:33 # ::file pmid_2470_8867_147.txt # ::snt In contrast, the TM-shShc cells maintained the transformed morphology, and even adopted a slightly more elongated and spindle-shaped appearance than the control TM-shCTRL cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (a / and :op1 (m / maintain-01 :ARG0 (c3 / cell-line :name (n2 / name :op1 "TM-shShc")) :ARG1 (t / transform-01 :ARG1 (m2 / morphology))) :op2 (a2 / adopt-01 :ARG0 (c2 / cell) :ARG1 (a3 / appear-02 :ARG1-of (e3 / elongate-01) :ARG1-of (s / shape-01 :mod (s2 / spindle)) :mod (s3 / slight) :degree (m3 / more) :compared-to (c5 / cell-line :name (n3 / name :op1 "TM-shCTRL") :ARG0-of (c6 / control-01))) :mod (e2 / even)))) # ::id pmid_2470_8867.148 # ::date 2015-08-30T05:34:54 # ::file pmid_2470_8867_148.txt # ::snt Concordant with these morphological changes, E-cadherin protein levels were enhanced in TM-shGrb2 cells and reduced in TM-shShc cells, when compared to TM-shCTRL cells (Figure 4C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (a / and :op1 (e / enhance-01 :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :location (c5 / cell-line :name (n5 / name :op1 "TM-shGrb2"))) :op2 (r / reduce-01 :ARG1 l :location (c / cell-line :name (n2 / name :op1 "TM-shShc"))) :ARG1-of (a2 / accord-02 :ARG2 (c4 / change-01 :ARG1 (m / morphology) :mod (t / this))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4C") :op2 (f2 / figure :mod "4D"))) :compared-to (c2 / cell-line :name (n3 / name :op1 "TM-shCTRL"))) # ::id pmid_2470_8867.149 # ::date 2015-08-30T05:43:36 # ::file pmid_2470_8867_149.txt # ::snt Growth and survival characteristics of these cells were then evaluated in cell-count and anoikis assays, respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (e / evaluate-01 :ARG1 (c / characteristic-02 :ARG1 (c2 / cell :mod (t / this)) :ARG2 (a / and :op1 (g / grow-01 :ARG1 c2) :op2 (s / survive-01 :ARG0 c2))) :time (t2 / then) :manner (a2 / and :op1 (a5 / assay-01 :ARG1 (c3 / count-02 :ARG1 (c4 / cell))) :op2 (a3 / assay-01 :ARG1 (a4 / anoikis)) :mod (r / respective))) # ::id pmid_2470_8867.150 # ::date 2015-08-30T05:48:40 # ::file pmid_2470_8867_150.txt # ::snt While the TM-shGrb2 cells displayed similar growth capacity to TM-shCTRL cells, growth of the TM-shShc cells was observed to decrease in a time-dependent manner, reaching significant inhibition (37.67 ± 5.32%) 3 days after seeding (Figure 4E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (h / have-concession-91 :ARG1 (d2 / display-01 :ARG0 (c6 / cell-line :name (n4 / name :op1 "TM-shGrb2")) :ARG1 (c2 / capacity :domain (g / grow-01) :ARG1-of (c3 / comparable-03 :ARG2 (c / cell-line :name (n / name :op1 "TM-shCTRL"))))) :ARG2 (o / observe-01 :ARG1 (g2 / grow-01 :ARG1 (c4 / cell-line :name (n2 / name :op1 "TM-shShc")) :ARG1-of (d3 / decrease-01 :manner (d4 / depend-01 :ARG1 (t2 / time))) :ARG0-of (r2 / reach-01 :ARG1 (i / inhibit-01 :ARG1-of (s / significant-02) :mod (p5 / percentage-entity :value (v / value-interval :op1 "37.67" :op2 "5.32")) :time (a2 / after :op1 (t3 / temporal-quantity :quant "3" :unit (d5 / day) :time (a / after :op1 (s2 / seed-01)))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4E"))) # ::id pmid_2470_8867.151 # ::date 2015-08-30T06:13:53 # ::file pmid_2470_8867_151.txt # ::snt The TM-shGrb2 cells displayed enhanced anoikis sensitivity when compared to the TM-shCTRL and TM-shShc cells, between which no difference in survival in suspension was observed (Figure 4F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (d / display-01 :ARG0 (c4 / cell-line :name (n4 / name :op1 "TM-shGrb2")) :ARG1 (s / sensitive-03 :ARG0 c4 :ARG1 (a / anoikis) :ARG1-of (e2 / enhance-01)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4F")) :time (c3 / compare-01 :ARG1 c4 :ARG2 (a3 / and :op1 (c / cell-line :name (n / name :op1 "TM-shCTRL")) :op2 (c5 / cell-line :name (n5 / name :op1 "TM-shShc")) :location-of (o / observe-01 :ARG1 (d2 / differ-02 :polarity "-" :ARG3 (s2 / survive-01 :ARG1 (s3 / suspend-02))))))) # ::id pmid_2470_8867.152 # ::date 2015-08-30T06:41:00 # ::file pmid_2470_8867_152.txt # ::snt As shown in Figure 4G, no significant difference in cell viability was observed between the TM-shGrb2, TM-shShc, and TM-shCTRL cells 18 hours following seeding in the absence of serum under adherent conditions (Figure 4G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (o / observe-01 :ARG1 (d / differ-02 :polarity "-" :ARG1 (a3 / and :op1 (c5 / cell-line :name (n3 / name :op1 "TM-shGrb2")) :op2 (c6 / cell-line :name (n5 / name :op1 "TM-shCTRL")) :op3 (c7 / cell-line :name (n6 / name :op1 "TM-shShc"))) :ARG3 (v / viable :domain (c / cell)) :ARG1-of (s / significant-02)) :duration (t2 / temporal-quantity :quant "18" :unit (h2 / hour) :ARG1-of (f / follow-01 :ARG2 (s2 / seed-02 :condition (a / absent-01 :ARG1 (s3 / serum) :condition (a2 / adhere-01))))) :ARG1-of (s4 / show-01 :location (f2 / figure :mod "4G")) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "4G"))) # ::id pmid_2470_8867.153 # ::date 2015-08-30T06:51:58 # ::file pmid_2470_8867_153.txt # ::snt Together, these results suggest that signals downstream of Grb2 and Shc proteins are required for non-overlapping functions promoted by the oncogenic Met receptor in IECs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this) :mod (t3 / together)) :ARG1 (r2 / require-01 :ARG0 (f / function-01 :ARG1-of (p3 / promote-01 :ARG0 (r5 / receptor :name (n5 / name :op1 "Met")) :location (c2 / cell :name (n4 / name :op1 "IEC"))) :ARG0-of (o / overlap-01 :polarity "-")) :ARG1 (s2 / signal-07 :location (r4 / relative-position :op1 (a / and :op1 (p / protein :name (n / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p2 / protein :name (n2 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :direction (d / downstream))))) # ::id pmid_2470_8867.154 # ::date 2015-08-30T06:59:26 # ::file pmid_2470_8867_154.txt # ::snt MEK, but not PI3K inhibitors reduce IEC transformation promoted by the oncogenic engagement of Met, Grb2, or Shc signals # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / reduce-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :ARG1-of (c / contrast-01 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p6 / protein-family :name (n2 / name :op1 "PI3K")))))) :ARG1 (t2 / transform-01 :ARG1 (c2 / cell :name (n3 / name :op1 "IEC")) :ARG1-of (p2 / promote-01 :ARG0 (e2 / engage-01 :ARG1 (s / signal-07 :ARG0 (o / or :op1 (p3 / protein :name (n4 / name :op1 "Met") :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "0.604")) :op2 (p4 / protein :name (n5 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op3 (p5 / protein :name (n6 / name :op1 "Shc") :xref (x2 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))) :ARG2 (c3 / cancer))))) # ::id pmid_2470_8867.155 # ::date 2015-08-30T07:12:25 # ::file pmid_2470_8867_155.txt # ::snt The Grb2 and Shc adaptor proteins are known to couple RTKs, such as the Met receptor, to the Ras/MAPK and PI3K/Akt signaling pathways [28-30]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (k / know-02 :ARG1 (a5 / and :op1 (p3 / protein :name (n2 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p4 / protein :name (n3 / name :op1 "Shc") :xref (x2 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG0-of (a6 / adapt-01)) :ARG3 (c / couple-01 :ARG0 a5 :ARG1 (e / enzyme :name (n4 / name :op1 "RTK") :example (r2 / receptor :name (n6 / name :op1 "Met")) :xref (x1 / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")) :ARG2 (a2 / and :op1 (p6 / pathway :name (n5 / name :op1 "Ras/MAPK")) :op2 (p7 / pathway :name (n7 / name :op1 "PI3K/Akt")) :ARG0-of (s2 / signal-07))) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 "28" :op2 "30"))))) # ::id pmid_2470_8867.156 # ::date 2015-08-30T07:27:05 # ::file pmid_2470_8867_156.txt # ::snt The Ras/MAPK and PI3K/Akt pathways are important regulators of RTK-mediated epithelial cell transformation, but their actions are cell type-specific [31]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (c / contrast-01 :ARG1 (r2 / regulate-01 :ARG0 (a / and :op1 (p2 / pathway :name (n2 / name :op1 "Ras/MAPK")) :op2 (p3 / pathway :name (n3 / name :op1 "PI3K/Akt"))) :ARG1 (t / transform-01 :ARG1 (c2 / cell :part-of (e / epithelium)) :ARG1-of (m / mediate-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "RTK") :xref (x / xref :value "UNIPROT:DDR1_HUMAN" :prob "0.262")))) :mod (i / important)) :ARG2 (a2 / act-02 :ARG0 a :ARG1-of (s / specific-02 :ARG2 (t3 / type :mod (c3 / cell)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 "31")))) # ::id pmid_2470_8867.157 # ::date 2015-08-30T07:34:06 # ::file pmid_2470_8867_157.txt # ::snt To define the role of these signaling pathways in IEC transformation, we first compared their activation status in IEC-6 cells transformed by the Tpr-Met, TM-Grb2, TM-Shc1, and TM-Shc2 oncoproteins, to that one in non-transformed Control-IEC-6 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / compare-01 :ARG0 (w / we) :ARG1 (s3 / status :mod (a3 / activate-01) :location (c3 / cell-line :name (n2 / name :op1 "IEC-6") :ARG1-of (t4 / transform-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n3 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")) :op2 (p3 / protein :name (n4 / name :op1 "TM-Grb2")) :op3 (p4 / protein :name (n5 / name :op1 "TM-Shc1") :xref (x1 / xref :value "UNIPROT:CERS2_HUMAN" :prob "0.222")) :op4 (p5 / protein :name (n6 / name :op1 "TM-Shc2")) :ARG0-of (c5 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))))) :poss "p") :ARG2 (s4 / status :mod (t3 / that) :location (c4 / cell-line :name (n7 / name :op1 "Control-IEC-6") :ARG1-of (t6 / transform-01 :polarity "-")) :mod a3 :poss "p") :time (f / first) :purpose (d / define-01 :ARG0 w :ARG1 (r / role :poss (p / pathway :ARG1-of (s / signal-07) :mod (t / this)) :purpose (t2 / transform-01 :ARG1 (c2 / cell :name (n / name :op1 "IEC")))))) # ::id pmid_2470_8867.158 # ::date 2015-08-30T07:55:41 # ::file pmid_2470_8867_158.txt # ::snt The phosphorylation/activation levels of the downstream effectors of MEK and PI3K, Erk1/2 and Akt, respectively, were assessed by IB analyses of lysates prepared from serum-starved IEC-6 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (a / assess-01 :ARG1 (l / level :degree-of (s / slash :op1 (p2 / phosphorylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e3 / enzyme :name (n3 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")) :op3 (e4 / enzyme :name (n4 / name :op1 "Erk1/2")) :op4 (e5 / enzyme :name (n5 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :mod (e2 / effector :mod (d2 / downstream)) :mod (r / respective))) :op2 (a2 / activate-01 :ARG1 a3))) :manner (a4 / analyze-01 :ARG1 (l2 / lysate :ARG1-of (p / prepare-01 :ARG2 (c / cell-line :name (n6 / name :op1 "IEC-6") :ARG1-of (s2 / starve-01 :ARG2 (s3 / serum))))) :mod (i / immunoblot-01))) # ::id pmid_2470_8867.159 # ::date 2015-08-30T08:05:47 # ::file pmid_2470_8867_159.txt # ::snt Phosphorylation levels of neither Erk1/2 nor Akt were elevated in Tpr-Met-IEC-6, TM-Grb2-IEC-6, TM-Shc1-IEC-6, or TM-Shc2-IEC-6 cells, relative to Control-IEC-6 cells (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (e / elevate-01 :polarity "-" :ARG1 (l / level :degree-of (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Erk1/2")) :op2 (e3 / enzyme :name (n2 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :location (o / or :op1 (c3 / cell-line :name (n9 / name :op1 "Tpr-Met-IEC-6")) :op2 (c4 / cell-line :name (n10 / name :op1 "Tpr-Grb2-IEC-6")) :op3 (c5 / cell-line :name (n11 / name :op1 "Tpr-Shc1-IEC-6")) :op4 (c6 / cell-line :name (n12 / name :op1 "Tpr-Shc2-IEC-6")))) :ARG1-of (r / relative-05 :ARG3 (c / cell-line :name (n8 / name :op1 "Control-IEC-6"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id pmid_2470_8867.160 # ::date 2015-08-30T08:27:59 # ::file pmid_2470_8867_160.txt # ::snt Both Erk2 and Akt protein levels were comparable in all IEC-6 cell populations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Sep 11, 2015 (c / comparable-03 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "Erk2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :ARG2 (l2 / level :quant-of (p / protein :name (n2 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :mod (b / both) :location (p3 / population :mod (c2 / cell-line :name (n3 / name :op1 "IEC-6")) :mod (a / all))) # ::id pmid_2470_8867.161 # ::date 2015-08-30T08:30:54 # ::file pmid_2470_8867_161.txt # ::snt A similar trend of Erk1/2 and Akt phosphorylation was observed in cells maintained in the presence of serum (data not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (o / observe-01 :ARG1 (t / trend-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "Erk1/2")) :op2 (e2 / enzyme :name (n2 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")))) :ARG1-of (r2 / resemble-01)) :location (c / cell :ARG1-of (m / maintain-01 :condition (p2 / present-02 :ARG1 (s / serum)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data :ARG1-of (s3 / show-01 :polarity "-")))) # ::id pmid_2470_8867.162 # ::date 2015-08-30T08:36:15 # ::file pmid_2470_8867_162.txt # ::snt The lack of evidence for Erk1/2 and Akt activation in IEC-6 cells stably expressing the constitutively activated form of the Met receptor, or the Grb2 and Shc docking-specific oncoproteins, is consistent with both the Ras/MAPK and PI3K/Akt pathways being subject to negative feedback mechanisms [35]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c / consistent-01 :ARG1 (l / lack-01 :ARG1 (e / evidence-01 :ARG1 (a / activate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1/2")) :op2 (e3 / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :location (c2 / cell-line :name (n4 / name :op1 "IEC-6") :ARG3-of (e4 / express-03 :ARG2 (o2 / or :op1 (r / receptor :name (n6 / name :op1 "Met") :ARG1-of (a6 / activate-01 :mod (c5 / constitutive))) :op2 (a4 / and :op1 (p4 / protein :name (n / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p5 / protein :name (n5 / name :op1 "Shc") :xref (x2 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")) :ARG1-of (s2 / specific-02 :ARG2 (d / dock-01)) :ARG0-of (c3 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n10 / name :op1 "cancer"))))) :ARG1-of (s / stable-02)))))) :ARG2 (a5 / and :op1 (p / pathway :name (n7 / name :op1 "Ras/MAPK")) :op2 (p2 / pathway :name (n8 / name :op1 "PI3K/Akt")) :ARG1-of (s3 / subject-01 :ARG2 (m / mechanism :mod (f2 / feedback :ARG0-of (n9 / negative-03)))) :mod (b / both)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 "35")))) # ::id pmid_2470_8867.163 # ::date 2015-08-31T23:38:53 # ::file pmid_2470_8867_163.txt # ::snt It cannot be explained as merely a cell type–specific event, since similarly stable expression of these oncoproteins in fibroblasts failed to promote Erk1/2 or Akt activation [36] and unpublished observation]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p2 / possible-01 :polarity "-" :ARG1 (e / explain-01 :ARG1 (i / it) :manner (e2 / event :ARG1-of (s / specific-02 :ARG2 (t / type :mod (c / cell)) :degree (m / mere)))) :ARG1-of (c2 / cause-01 :ARG0 (f / fail-01 :ARG1 (e3 / express-03 :ARG2 (p / protein :ARG0-of (c3 / cause-01 :ARG1 (c4 / cancer)) :mod (t2 / this)) :ARG3 (f2 / fibroblast) :ARG1-of (s2 / stable-03 :ARG1-of (r / resemble-01))) :ARG2 (p3 / promote-01 :ARG0 e3 :ARG1 (a / activate-01 :ARG1 (o / or :op1 (s3 / slash :op1 (e6 / enzyme :name (n / name :op1 "Erk1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e5 / enzyme :name (n2 / name :op1 "Erk2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :op2 (e4 / enzyme :name (n3 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 "36")) :op2 (t3 / thing :ARG1-of (o2 / observe-01) :ARG1-of (p5 / publish-01 :polarity "-"))))) # ::id pmid_2470_8867.164 # ::date 2015-08-31T23:48:44 # ::file pmid_2470_8867_164.txt # ::snt We next investigated whether, even at the low levels observed, MEK or PI3K activities were implicated in the induction of transformation features in IEC-6 cells by the Tpr-Met, TM-Grb2, TM-Shc1, or TM-Shc2 oncoproteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (i2 / implicate-01 :mode "interrogative" :ARG1 (a / activity-06 :ARG0 (o / or :op1 (e / enzyme :name (n / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :op2 (e2 / enzyme :name (n3 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :ARG2 (i3 / induce-01 :ARG2 (f / feature :mod (t / transform-01 :ARG0 (o2 / or :op1 (p / protein :name (n5 / name :op1 "Tpr-Met") :xref (x3 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")) :op2 (p2 / protein :name (n6 / name :op1 "TM-Grb2")) :op3 (p3 / protein :name (n7 / name :op1 "TM-Shc1") :xref (x1 / xref :value "UNIPROT:CERS2_HUMAN" :prob "0.222")) :op4 (p4 / protein :name (n8 / name :op1 "TM-Shc2")) :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer))) :ARG1 (c / cell-line :name (n4 / name :op1 "IEC-6"))))) :condition (l / level :ARG1-of (l2 / low-04) :ARG1-of (o3 / observe-01) :mod (e3 / even))) :time (n2 / next)) # ::id pmid_2470_8867.165 # ::date 2015-08-31T23:57:07 # ::file pmid_2470_8867_165.txt # ::snt Cells were treated with vehicle (DMSO), 10 μM U0126 (a MEK1/2 inhibitor), 10 μM LY294002 (a PI3K inhibitor), or a combination of both inhibitors, and their morphology was examined by phase contrast microscopy, following 24 (Additional file 3) and 48 hours of treatment (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (t3 / treat-04 :ARG1 (c / cell) :ARG2 (o / or :op1 (v / vehicle :mod (s2 / small-molecule :name (n2 / name :op1 "DMSO") :xref (x2 / xref :value "PUBCHEM:679" :prob "16.740406"))) :op2 (s / small-molecule :name (n / name :op1 "U0126") :quant (c2 / concentration-quantity :quant "10" :unit (m / micromolar)) :ARG0-of (i2 / inhibit-01 :ARG1 (s3 / slash :op1 (e / enzyme :name (n3 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :xref (x4 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :op3 (s4 / small-molecule :name (n5 / name :op1 "LY294002") :quant c2 :ARG0-of (i3 / inhibit-01 :ARG1 (p2 / protein-family :name (n6 / name :op1 "PI3K"))) :xref (x3 / xref :value "PUBCHEM:3973" :prob "18.86067")) :op4 (c3 / combine-01 :ARG1 s :ARG2 s4 :mod (b / both)))) :op2 (e4 / examine-01 :ARG1 (m2 / morphology :poss c) :manner (m3 / microscopy :mod (c4 / contrast-01 :ARG1 (p / phase))) :time (a2 / and :op1 (a3 / after :op1 t3 :quant (t5 / temporal-quantity :quant "24" :unit (h / hour)) :ARG1-of (d / describe-01 :ARG0 (f / file :mod "3" :mod (a5 / additional)))) :op2 (a4 / after :op1 t3 :quant (t / temporal-quantity :quant "48" :unit h) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5B")))))) # ::id pmid_2470_8867.166 # ::date 2015-09-01T00:09:13 # ::file pmid_2470_8867_166.txt # ::snt Neither individual inhibitor treatment, nor the combination, had an obvious effect on the morphology of the Control-IEC-6 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :polarity "-" :ARG0 (a2 / and :op1 (t2 / treat-04 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (i2 / individual))) :op2 (c / combine-01)) :ARG1 (m / morphology :poss (c2 / cell-line :name (n / name :op1 "IEC-6") :mod (c3 / control))) :ARG1-of (o / obvious-01)) # ::id pmid_2470_8867.167 # ::date 2015-09-01T00:14:23 # ::file pmid_2470_8867_167.txt # ::snt Interestingly, the MEK1/2 inhibitor, but not the PI3K inhibitor, induced a potent reversion of the transformed morphological features of the Tpr-Met-IEC-6, TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells, observed within 24 hours of treatment (Additional file 3) and more striking in appearance after 48 hours (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c8 / contrast-01 :ARG1 (i2 / induce-01 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (s2 / slash :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x1 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG2 (r / reverse-01 :ARG1 (f / feature :mod (m / morphology) :ARG1-of (t4 / transform-01) :poss (a / and :op1 (c / cell-line :name (n3 / name :op1 "IEC-6") :ARG1-of (t3 / transform-01 :ARG0 (p2 / protein :name (n7 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")))) :op2 (c2 / cell-line :name (n4 / name :op1 "IEC-6") :ARG3-of (e4 / express-03 :ARG2 (p3 / protein :name (n8 / name :op1 "TM-Grb2")))) :op3 (c3 / cell-line :name (n5 / name :op1 "IEC-6") :ARG3-of (e5 / express-03 :ARG2 (p4 / protein :name (n9 / name :op1 "TM-Shc1") :xref (x3 / xref :value "UNIPROT:CERS2_HUMAN" :prob "0.222")))) :op4 (c4 / cell-line :name (n6 / name :op1 "IEC-6") :ARG3-of (e6 / express-03 :ARG2 (p5 / protein :name (n10 / name :op1 "TM-Shc2")))))) :mod (p / potent) :ARG1-of (o / observe-01 :time (a2 / after :op1 (t5 / treat-04) :quant (u / up-to :op1 (t / temporal-quantity :quant "24" :unit (h / hour)))) :ARG1-of (d / describe-01 :ARG0 (f2 / file :mod "3" :mod (a3 / additional)))) :ARG1-of (s3 / strike-04 :ARG2 (a4 / appear-01) :degree (m2 / more) :time (a5 / after :op1 t5 :quant (t2 / temporal-quantity :quant "48" :unit (h2 / hour))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "5B"))))) :ARG2 (i4 / induce-01 :polarity "-" :ARG0 (m4 / molecular-physical-entity :ARG0-of (i5 / inhibit-01 :ARG1 (p6 / protein-family :name (n11 / name :op1 "PI3K")))) :ARG1 r) :ARG2-of (i3 / interest-01)) # ::id pmid_2470_8867.168 # ::date 2015-09-01T00:33:10 # ::file pmid_2470_8867_168.txt # ::snt In the presence of U0126, the MEK1/2 inhibitor, either alone or in combination with the PI3K inhibitor, the formerly transformed Tpr-IEC-6 cells progressively lost their fibroblast-like spindle-shaped morphology, adopted a flatter cobblestone-like appearance, reformed apparent cell-cell contacts and grew again in colonies; much like the non-transformed Control-IEC-6 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (l / lose-02 :ARG0 (c / cell-line :name (n2 / name :op1 "IEC-6") :ARG1-of (t2 / transform-01 :ARG0 (p / protein :name (n3 / name :op1 "Tpr") :xref (x2 / xref :value "UNIPROT:Q15624_HUMAN" :prob "1.001")) :time (f / former))) :ARG1 (m / morphology :ARG1-of (r / resemble-01 :ARG2 (f2 / fibroblast)) :ARG1-of (s2 / shape-01 :ARG2 (s3 / spindle))) :manner (p2 / progress-01)) :op2 (a2 / adopt-01 :ARG0 c :ARG1 (a3 / appear-01 :ARG1 c :ARG1-of (f3 / flat-06 :degree (m2 / more)) :ARG1-of (r2 / resemble-01 :ARG2 (c4 / cobblestone)))) :op3 (r3 / reform-01 :ARG0 c :ARG1 (c5 / contact-01 :ARG0 (c6 / cell) :ARG1 (c7 / cell) :ARG1-of (a4 / appear-01))) :op4 (g / grow-02 :ARG1 c :ARG2 (c8 / colony) :mod (a5 / again)) :condition (p3 / present-02 :ARG1 (s / small-molecule :name (n / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (s4 / slash :op1 (e / enzyme :name (n4 / name :op1 "MEK1") :xref (x1 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :xref (x3 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :manner (o / or :op1 (a6 / alone) :op2 (c9 / combine-01 :ARG1 s :ARG2 (m4 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p4 / protein-family :name (n6 / name :op1 "PI3K"))))))) :ARG1-of (r4 / resemble-01 :ARG2 (c10 / cell :name (n7 / name :op1 "IEC-6") :ARG1-of (t / transform-01 :polarity "-") :mod (c11 / control)) :degree (m3 / much))) # ::id pmid_2470_8867.169 # ::date 2015-09-01T00:52:54 # ::file pmid_2470_8867_169.txt # ::snt Concordant with this restoration of epithelioid-like morphological features in IEC-6 cells transformed by the oncogenic Tpr-Met and its derived variants, treatment with U0126 also induced an increase in E-cadherin protein levels (Figure 5C and D, and Additional file 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / induce-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG2 (i2 / increase-01 :ARG1 (l / level :quant-of (p / protein :name (n2 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :mod (a / also) :ARG0-of (a2 / agree-01 :ARG2 (r / restore-02 :ARG1 (f / feature :mod (m / morphology) :ARG1-of (r2 / resemble-01 :ARG2 (e / epithelioid)) :poss (c / cell-line :name (n3 / name :op1 "IEC-6") :ARG1-of (t2 / transform-01 :ARG0 (a3 / and :op1 (p2 / protein :name (n4 / name :op1 "Tpr-Met") :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer)) :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")) :op2 (v / variant :ARG1-of (d / derive-01 :ARG0 p2)))))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "5C") :op2 (f3 / figure :mod "5D") :op3 (f4 / file :mod "3" :mod (a5 / additional))))) # ::id pmid_2470_8867.170 # ::date 2015-09-01T01:01:49 # ::file pmid_2470_8867_170.txt # ::snt By contrast, none of the inhibitor treatments affected E-cadherin protein levels in the Control-IEC-6 cells (Figure 5C and D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (a / affect-01 :polarity "-" :ARG0 (t2 / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01))) :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "E-cadherin") :xref (x / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :location (c2 / cell-line :name (n2 / name :op1 "IEC-6") :mod (c3 / control))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "5C") :op2 (f2 / figure :mod "5D")))) # ::id pmid_2470_8867.171 # ::date 2015-09-01T01:04:58 # ::file pmid_2470_8867_171.txt # ::snt Notably, reversion of the transformed phenotype and E-cadherin up-regulation were also promoted in transformed IEC-6 cell populations by treatment with 10 μM AZD6244 or PD184352, two additional pharmacological inhibitors of MEK1/2 (Figure 5B and C, and Additional file 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p / promote-01 :ARG0 (t3 / treat-04 :ARG2 (o / or :op1 (s2 / small-molecule :name (n4 / name :op1 "AZD6244") :xref (x4 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s3 / small-molecule :name (n5 / name :op1 "PD184352") :xref (x3 / xref :value "PUBCHEM:6918454" :prob "18.013371")) :quant (c2 / concentration-quantity :quant "10" :unit (m / micromolar)) :mod (s / small-molecule :quant "2" :mod (a3 / additional) :ARG0-of (i / inhibit-01 :ARG1 (s4 / slash :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x2 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n6 / name :op1 "MEK2") :xref (x / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :mod (p5 / pharmacology)))) :ARG1 (a / and :op1 (r / reverse-01 :ARG1 (p2 / phenotype :ARG1-of (t2 / transform-01))) :op2 (u / upregulate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "E-cadherin") :xref (x1 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003")))) :mod (a2 / also) :location (p4 / population :consist-of (c / cell-line :name (n3 / name :op1 "IEC-6") :ARG1-of t2)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "5B") :op2 (f2 / figure :mod "5C") :op3 (f3 / file :mod "3" :mod a3))) :ARG1-of (n7 / notable-04)) # ::id pmid_2470_8867.172 # ::date 2015-09-01T01:13:06 # ::file pmid_2470_8867_172.txt # ::snt Furthermore, these observations could not be attributed to the cytosolic localization of the Tpr-Met oncoprotein, since both the morphological transformation and the E-cadherin down-regulation induced by a cell surface-localized active chimeric colony stimulating factor 1 (CSF)-Met receptor [37], were reverted in a similar manner upon the inhibition of MEK1/2 activity, but not of PI3K activity (Additional file 3). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 7, 2015 (a7 / and :op2 (p2 / possible-01 :polarity "-" :ARG1 (a / attribute-01 :ARG1 (t / thing :ARG1-of (o / observe-01) :mod (t2 / this)) :ARG2 (b2 / be-located-at-91 :ARG1 (p / protein :name (n / name :op1 "Tpr-Met") :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer)) :xref (x5 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")) :ARG2 (c / cytosol :xref (x6 / xref :value "GO:0005829" :prob "0.8")))) :ARG1-of (c4 / cause-01 :ARG0 (c8 / contrast-01 :ARG1 (r2 / revert-01 :ARG0 (i2 / inhibit-01 :ARG1 (a4 / activity-06 :ARG0 (s2 / slash :op1 (e / enzyme :name (n4 / name :op1 "MEK1") :xref (x4 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG1 (a2 / and :op1 (t3 / transform-01 :ARG1 (m2 / morphology)) :op2 (d / downregulate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "E-cadherin") :xref (x3 / xref :value "UNIPROT:CADH1_HUMAN" :prob "1.003"))) :ARG2-of (i / induce-01 :ARG0 (p4 / protein :name (n3 / name :op1 "colony" :op2 "stimulating" :op3 "factor" :op4 "1" :op5 "Met" :op6 "receptor") :location (s / surface :part-of (c5 / cell)) :ARG1-of (a3 / activate-01) :mod (c6 / chimera) :xref (x / xref :value "UNIPROT:CSF2_HUMAN" :prob "0.353"))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c7 / cite-01 :ARG2 "37")))) :manner (m / manner :ARG1-of (r / resemble-01))) :ARG2 (r3 / revert-01 :polarity "-" :ARG0 (i3 / inhibit-01 :ARG1 (a5 / activity-06 :ARG0 (e3 / enzyme :name (n6 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :ARG1 a2 :manner m :ARG1-of (d3 / describe-01 :ARG0 (f / file :mod "3" :mod (a6 / additional)))))))) # ::id pmid_2470_8867.173 # ::date 2015-09-01T01:38:47 # ::file pmid_2470_8867_173.txt # ::snt Since Erk1/2 and Akt activities remained at basal levels in transformed IEC-6 cell populations, the efficacy of these pharmacological inhibitors was evaluated by testing their ability to suppress serum-induced Erk1/2 and Akt phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / evaluate-01 :ARG1 (e2 / efficient-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (t2 / this) :mod (p2 / pharmacology))) :manner (t3 / test-01 :ARG1 (c / capable-01 :ARG1 m :ARG2 (s2 / suppress-01 :ARG0 m :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (s4 / slash :op1 (e3 / enzyme :name (n / name :op1 "Erk1") :xref (x2 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e4 / enzyme :name (n2 / name :op1 "Erk2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :op2 (e5 / enzyme :name (n3 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG2-of (i2 / induce-01 :ARG0 (s3 / serum)))))) :ARG1-of (c2 / cause-01 :ARG0 (r / remain-01 :ARG1 (a2 / activity-06 :ARG0 a) :ARG3 (l / level :mod (b / base)) :location (p3 / population :consist-of (c3 / cell-line :name (n4 / name :op1 "IEC-6") :ARG1-of (t / transform-01)))))) # ::id pmid_2470_8867.174 # ::date 2015-09-01T01:52:42 # ::file pmid_2470_8867_174.txt # ::snt Serum-starved Tpr-Met and control IEC-6 cell populations were treated for 1 hour with DMSO or inhibitors, followed by 5 minutes of stimulation with 10% serum. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (t4 / treat-04 :ARG1 (a / and :op1 (p4 / population :consist-of (c / cell-line :name (n4 / name :op1 "IEC-6") :ARG1-of (t3 / transform-01 :ARG0 (p2 / protein :name (n / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :op2 (p3 / population :consist-of (c2 / cell-line :name (n2 / name :op1 "IEC-6")) :mod (c4 / control)) :ARG1-of (s / starve-01 :ARG2 (s2 / serum))) :ARG2 (o / or :op1 (s3 / small-molecule :name (n3 / name :op1 "DMSO") :xref (x1 / xref :value "PUBCHEM:679" :prob "16.740406")) :op2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01))) :duration (t / temporal-quantity :quant "1" :unit (h / hour)) :ARG2-of (f / follow-01 :ARG1 (s5 / stimulate-01 :ARG1 a :ARG2 (s6 / serum :quant (p / percentage-entity :value "10")) :duration (t2 / temporal-quantity :quant "5" :unit (m / minute))))) # ::id pmid_2470_8867.175 # ::date 2015-09-01T02:10:22 # ::file pmid_2470_8867_175.txt # ::snt A robust phosphorylation of Erk1/2 and Akt proteins was seen upon serum stimulation of Control-IEC-6 cells (Figure 5E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / see-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (s2 / slash :op1 (e / enzyme :name (n / name :op1 "Erk1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e2 / enzyme :name (n2 / name :op1 "Erk2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :op2 (p4 / protein-family :name (n3 / name :op1 "Akt"))) :mod (r / robust)) :time (s3 / stimulate-01 :ARG1 (c / cell-line :name (n4 / name :op1 "IEC-6") :mod (c2 / control)) :ARG2 (s4 / serum)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5E"))) # ::id pmid_2470_8867.176 # ::date 2015-09-01T02:15:14 # ::file pmid_2470_8867_176.txt # ::snt In sharp contrast, although the levels of Erk2 and Akt proteins were equivalent for each cell population, serum-induced Erk1/2 and Akt activation were severely attenuated in the Tpr-Met-IEC-6 cells (Figure 5E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (a / attenuate-01 :ARG1 (a4 / and :op1 (a2 / activate-01 :ARG1 (s2 / slash :op1 (e2 / enzyme :name (n / name :op1 "Erk1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e3 / enzyme :name (n2 / name :op1 "Erk2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603")))) :op2 (a5 / activate-01 :ARG1 (p2 / protein-family :name (n3 / name :op1 "Akt"))) :ARG2-of (i / induce-01 :ARG0 (s3 / serum))) :degree (s4 / severe) :location (c2 / cell-line :name (n4 / name :op1 "IEC-6") :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n5 / name :op1 "Tpr-Met") :xref (x2 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")))) :concession (e5 / equal-01 :ARG1 (l / level :quant-of e3) :ARG2 (l2 / level :quant-of p2) :ARG3 (p5 / population :mod (c5 / cell) :mod (e / each)))) :ARG1-of (s / sharp-02) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5E"))) # ::id pmid_2470_8867.177 # ::date 2015-09-01T02:26:41 # ::file pmid_2470_8867_177.txt # ::snt This further substantiates the conclusion that sustained activation of Met signaling pathways, such as those downstream of Grb2 and Shc, can activate negative feedback control of both the Erk1/2 and Akt pathways in IECs. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (s / substantiate-01 :ARG0 (t / this) :ARG1 (c / conclude-01 :ARG1 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (a2 / activate-01 :ARG1 (p2 / pathway :name (n / name :op1 "Met") :ARG0-of (s3 / signal-07) :example (p3 / pathway :location (r / relative-position :op1 (a3 / and :op1 (p4 / protein :name (n2 / name :op1 "Grb2") :xref (x / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604")) :op2 (p5 / protein :name (n3 / name :op1 "Shc") :xref (x1 / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603"))) :direction (d / downstream)) :mod (t2 / that))) :ARG1-of (s2 / sustain-01)) :ARG1 (c2 / control-01 :ARG1 (a4 / and :op1 (p6 / pathway :name (n5 / name :op1 "Erk1/2")) :op2 (p7 / pathway :name (n6 / name :op1 "Akt"))) :ARG2-of (n4 / negative-01) :mod (f2 / feedback)) :location (c3 / cell :name (n7 / name :op1 "IEC"))))) :degree (f / further)) # ::id pmid_2470_8867.178 # ::date 2015-09-01T02:34:56 # ::file pmid_2470_8867_178.txt # ::snt Importantly, the MEK1/2 and PI3K inhibitors were confirmed to efficiently suppress serum-induced Erk1/2 and Akt phosphorylation, respectively (Figure 5E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / confirm-01 :ARG1 (a / and :op1 (s / suppress-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (s5 / slash :op1 (e2 / enzyme :name (n3 / name :op1 "MEK1") :xref (x4 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n4 / name :op1 "MEK2") :xref (x3 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG1 (p / phosphorylate-01 :ARG1 (s3 / slash :op1 (e5 / enzyme :name (n / name :op1 "Erk1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "0.603")) :op2 (e6 / enzyme :name (n2 / name :op1 "Erk2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.603"))) :ARG2-of (i2 / induce-01 :ARG0 (s2 / serum))) :ARG2-of (e / efficient-01)) :op2 (s6 / suppress-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p6 / protein-family :name (n5 / name :op1 "PI3K")))) :ARG1 (p4 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n6 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG2-of i2) :ARG2-of e) :manner (r / respective)) :mod (i4 / important) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5E"))) # ::id pmid_2470_8867.179 # ::date 2015-09-01T02:42:49 # ::file pmid_2470_8867_179.txt # ::snt Although the potential off-target effects of these inhibitors cannot be excluded in these experiments, our results suggest that the morphological transformation induced by the oncogenic Met receptor, and driven by the constitutive activation of Grb2 and Shc signals in IECs, relies, at least in part, on the activation of the Ras/MAPK pathway, but not on PI3K signaling. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t2 / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (c5 / contrast-01 :ARG1 (r2 / rely-01 :ARG0 (t3 / transform-01 :ARG1 (m / morphology) :ARG2-of (i2 / induce-01 :ARG0 (r4 / receptor :name (n / name :op1 "Met") :ARG0-of (c / cause-01 :ARG1 (c2 / cancer)))) :ARG1-of (d / drive-02 :ARG0 (a2 / activate-01 :ARG1 (a3 / and :op1 (s2 / signal-07 :ARG0 (p3 / protein :name (n2 / name :op1 "Grb2") :xref (x1 / xref :value "UNIPROT:GRB2_HUMAN" :prob "0.604"))) :op2 (s3 / signal-07 :ARG0 (p4 / protein :name (n3 / name :op1 "Shc") :xref (x / xref :value "UNIPROT:SHC1_HUMAN" :prob "0.603")))) :mod (c3 / constitutive) :location (c4 / cell :name (n4 / name :op1 "IEC"))))) :ARG1 (a5 / activate-01 :ARG1 (p6 / pathway :name (n5 / name :op1 "Ras/MAPK"))) :degree (p5 / part :mod (a4 / at-least))) :ARG2 (r3 / rely-01 :polarity "-" :ARG0 t3 :ARG1 (s4 / signal-07 :ARG0 (p8 / pathway :name (n6 / name :op1 "PI3K"))))) :concession (p / possible-01 :polarity "-" :ARG1 (e2 / exclude-01 :ARG1 (a6 / affect-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (t / this)) :mod (p7 / potential) :mod (t4 / target :mod (o / off))) :ARG2 (e3 / experiment-01 :mod t)))) # ::id pmid_2470_8867.180 # ::date 2015-09-01T02:55:14 # ::file pmid_2470_8867_180.txt # ::snt The growth promoting effect of oncogenic Met in IECs is blocked by MEK inhibition, but anoikis sensitivity is restored by concomitant treatment with MEK and PI3K inhibitors # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG1 (b / block-01 :ARG0 (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))) :ARG1 (a / affect-01 :ARG0 (p3 / protein :name (n2 / name :op1 "Met") :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer)) :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "0.604")) :ARG1 (c4 / cell :name (n3 / name :op1 "IEC")) :ARG0-of (p2 / promote-01 :ARG1 (g / grow-01)))) :ARG2 (r / restore-02 :ARG0 (t / treat-04 :ARG2 (a3 / and :op1 (m / molecular-physical-entity :ARG0-of i) :op2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p4 / protein-family :name (n4 / name :op1 "PI3K"))))) :time (c5 / concomitant)) :ARG1 (s / sensitive-03 :ARG1 (a2 / anoikis)))) # ::id pmid_2470_8867.181 # ::date 2015-09-01T03:02:03 # ::file pmid_2470_8867_181.txt # ::snt We next investigated whether the growth capacity promoted by the oncogenic Met in IECs required MEK or PI3K activity. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (i / investigate-01 :ARG0 (w / we) :ARG1 (r / require-01 :mode "interrogative" :ARG0 (c / capable-01 :ARG1 (c4 / cell :name (n4 / name :op1 "IEC")) :ARG2 (g / grow-01) :ARG1-of (p2 / promote-01 :ARG0 (p3 / protein :name (n3 / name :op1 "Met") :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer)) :xref (x / xref :value "UNIPROT:MET_HUMAN" :prob "0.604")))) :ARG1 (o / or :op1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "MEK") :xref (x1 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))) :op2 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n5 / name :op1 "PI3K") :xref (x2 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))))) :time (n2 / next)) # ::id pmid_2470_8867.182 # ::date 2015-09-01T03:06:13 # ::file pmid_2470_8867_182.txt # ::snt Cell-count assays were performed with Tpr-Met and Control-IEC-6 cells that were treated for 24 or 48 hours with vehicle, U0126 or LY294002 inhibitor, or a combination of both inhibitors. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (p / perform-01 :ARG1 (a / assay-01 :mod (c / count-01 :ARG1 (c2 / cell))) :ARG2 (a2 / and :op1 (c3 / cell-line :wiki "-" :name (n5 / name :op1 "IEC-6") :ARG1-of (t2 / transform-01 :ARG0 (p2 / protein :wiki "Tpr-met_fusion_protein" :name (n2 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")))) :op2 (c4 / cell-line :wiki "-" :name (n3 / name :op1 "IEC-6") :mod (c6 / control)) :ARG1-of (t3 / treat-04 :ARG2 (o2 / or :op1 (v / vehicle) :op2 (s / small-molecule :wiki "U0126" :name (n / name :op1 "U0126") :ARG0-of (i / inhibit-01) :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :op3 (s2 / small-molecule :wiki "LY294002" :name (n4 / name :op1 "LY294002") :ARG0-of i :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")) :op4 (c7 / combine-01 :ARG1 s :ARG2 s2 :mod (b / both))) :duration (o / or :op1 (t4 / temporal-quantity :quant "24" :unit "h") :op2 (t / temporal-quantity :quant "48" :unit (h / hour)))))) # ::id pmid_2470_8867.183 # ::date 2015-09-01T03:14:55 # ::file pmid_2470_8867_183.txt # ::snt As anticipated, treatment with DMSO did not significantly impact cell growth, even after 48 hours. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (i / impact-01 :polarity "-" :ARG0 (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "DMSO") :xref (x / xref :value "PUBCHEM:679" :prob "16.740406"))) :ARG1 (g / grow-01 :ARG1 (c / cell)) :ARG1-of (s / significant-02) :time (a / after :quant (t / temporal-quantity :quant "48" :unit (h / hour)) :mod (e / even)) :ARG1-of (a2 / anticipate-01)) # ::id pmid_2470_8867.184 # ::date 2015-09-01T03:17:17 # ::file pmid_2470_8867_184.txt # ::snt Treatment with LY294002 exerted similar inhibitory effects upon the growth of both the Tpr-Met-transformed and control IEC-6 cells, reducing the number of cells by 44% and 36%, respectively relative to DMSO-treated cells, after 48 hours (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / exert-01 :ARG0 (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "LY294002") :xref (x2 / xref :value "PUBCHEM:3973" :prob "18.86067"))) :ARG1 (a / affect-01 :ARG1-of (r / resemble-01) :ARG0-of (i / inhibit-01)) :ARG2 (a2 / and :op1 (g / grow-01 :ARG1 (c / cell-line :name (n7 / name :op1 "IEC-6") :ARG1-of (t3 / transform-01 :ARG0 (p3 / protein :name (n2 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :op2 (g2 / grow-01 :ARG1 (c2 / cell-line :name (n3 / name :op1 "IEC-6") :mod (c5 / control))) :mod (b / both)) :ARG0-of (r2 / reduce-01 :ARG1 (n4 / number :quant-of c) :ARG2 (p / percentage-entity :value "44" :ARG1-of (r4 / relative-05 :ARG3 (c6 / cell :ARG1-of (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n6 / name :op1 "DMSO") :xref (x1 / xref :value "PUBCHEM:679" :prob "16.740406")))))) :time (a3 / after :quant (t / temporal-quantity :quant "48" :unit (h / hour)))) :ARG0-of (r3 / reduce-01 :ARG1 (n5 / number :quant-of c2) :ARG2 (p2 / percentage-entity :value "36" :ARG1-of r4) :time a3) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_2470_8867.185 # ::date 2015-09-01T03:26:40 # ::file pmid_2470_8867_185.txt # ::snt In contrast, in the presence of U0126, the growth of Tpr-Met-IEC-6 cells was significantly attenuated but not that of Control-IEC-6 cells (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (c2 / contrast-01 :ARG1 (a / attenuate-01 :ARG1 (g / grow-01 :ARG1 (c3 / cell-line :name (n2 / name :op1 "IEC-6") :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n3 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :ARG1-of (s2 / significant-02)) :ARG2 (a2 / attenuate-01 :polarity "-" :ARG1 (g2 / grow-01 :ARG1 (c4 / cell-line :name (n4 / name :op1 "IEC-6") :mod (c7 / control))) :ARG1-of s2) :condition (p2 / present-02 :ARG1 (s / small-molecule :name (n / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_2470_8867.186 # ::date 2015-09-01T04:11:44 # ::file pmid_2470_8867_186.txt # ::snt Furthermore, while co-treatment with U0126 failed to potentiate the growth inhibiting effect of LY294002 in Control-IEC-6 cells, the growth of Tpr-Met-IEC-6 cells was further reduced in a time-dependent manner upon exposure to both inhibitors (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op2 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (e2 / expose-01 :ARG1 "c3" :ARG2 (a3 / and :op1 "s" :op2 "s2" :ARG0-of (i2 / inhibit-01))) :ARG1 (g2 / grow-01 :ARG1 (c3 / cell-line :name (n4 / name :op1 "IEC-6") :ARG1-of (t2 / transform-01 :ARG0 (p2 / protein :name (n5 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :degree (f2 / further) :manner (d / depend-01 :ARG0 r :ARG1 (t / time))) :ARG2 (f / fail-01 :ARG1 (t3 / treat-04 :ARG2 (a4 / and :op1 "s2" :op2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696")))) :ARG2 (p / potentiate-01 :ARG1 (a2 / affect-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")) :ARG1 (c2 / cell-line :name (n3 / name :op1 "IEC-6") :mod (c4 / control)) :ARG0-of (i / inhibit-01 :ARG1 (g / grow-01)))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "6A"))) # ::id pmid_2470_8867.187 # ::date 2015-09-01T04:22:57 # ::file pmid_2470_8867_187.txt # ::snt The impact of inhibiting MEK1/2 or PI3K activity on the viability of Tpr-Met-IEC-6 cells in suspension was also evaluated. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / evaluate-01 :ARG1 (i / impact-01 :ARG0 (i2 / inhibit-01 :ARG1 (o / or :op1 (a2 / activity-06 :ARG0 (s / slash :op1 (e2 / enzyme :name (n / name :op1 "MEK1") :xref (x3 / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003")))) :op2 (a3 / activity-06 :ARG0 (e4 / enzyme :name (n3 / name :op1 "PI3K") :xref (x1 / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262"))))) :ARG1 (v / viability :poss (c / cell-line :name (n4 / name :op1 "IEC-6") :ARG1-of (s2 / suspend-02) :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n5 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")))))) :mod (a / also)) # ::id pmid_2470_8867.188 # ::date 2015-09-01T04:28:30 # ::file pmid_2470_8867_188.txt # ::snt In these anoikis assays, vehicle or the indicated inhibitors were added when cells were seeded and cell viability was measured 24 and 48 hours later. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (a / and :op1 (a2 / add-02 :ARG1 (o / or :op1 (v / vehicle) :op2 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01) :ARG1-of (i2 / indicate-01))) :time (s / seed-02 :ARG2 (c / cell))) :op2 (m4 / measure-01 :ARG1 (v2 / viability :mod c) :time (a3 / and :op1 (l2 / late :degree (m2 / more :quant (t2 / temporal-quantity :quant "24" :unit "h"))) :op2 (l / late :degree (m / more :quant (t / temporal-quantity :quant "48" :unit (h / hour)))))) :condition (a4 / assay-01 :mod (a5 / anoikis) :mod (t3 / this))) # ::id pmid_2470_8867.189 # ::date 2015-09-01T04:34:49 # ::file pmid_2470_8867_189.txt # ::snt Treatment with the PI3K inhibitor restored anoikis sensitivity to the Tpr-Met-IEC-6 cells in a time-dependent manner, reducing their viability by close to 45% relative to DMSO-treated cells after 48 hours (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r / restore-02 :ARG0 (t3 / treat-04 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "PI3K"))))) :ARG1 (s / sensitive-03 :ARG0 (c / cell-line :name (n2 / name :op1 "IEC-6") :ARG1-of (t5 / transform-01 :ARG0 (p2 / protein :name (n3 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201")))) :ARG1 (a / anoikis)) :manner (d / depend-01 :ARG0 "r" :ARG1 (t2 / time)) :ARG0-of (r2 / reduce-01 :ARG1 (v / viability :poss c) :ARG2 (c4 / close-11 :ARG2 (p / percentage-entity :value "45") :ARG1-of (r3 / relative-05 :ARG3 (c5 / cell :ARG1-of (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "DMSO") :xref (x1 / xref :value "PUBCHEM:679" :prob "16.740406")))))) :time (a2 / after :quant (t / temporal-quantity :quant "48" :unit (h / hour)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id pmid_2470_8867.190 # ::date 2015-09-01T04:42:15 # ::file pmid_2470_8867_190.txt # ::snt The MEK1/2 inhibitor, on the other hand, did not substantially impact the viability of the Tpr-Met-IEC-6 cells grown in suspension. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (i2 / impact-01 :polarity "-" :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (s / slash :op1 (e / enzyme :name (n / name :op1 "MEK1") :xref (x / xref :value "UNIPROT:MP2K1_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2") :xref (x2 / xref :value "UNIPROT:MP2K2_HUMAN" :prob "1.003"))))) :ARG1 (v / viability :poss (c2 / cell-line :name (n3 / name :op1 "IEC-6") :ARG1-of (g / grow-01 :manner (s3 / suspend-02)) :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n4 / name :op1 "Tpr-Met") :xref (x1 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :manner (s2 / substantial))) # ::id pmid_2470_8867.191 # ::date 2015-09-01T04:48:43 # ::file pmid_2470_8867_191.txt # ::snt Nonetheless, U0126 treatment did elicit a marked synergistic effect on LY294002-induced anoikis, reducing Tpr-Met-IEC-6 cell viability to levels well below those seen upon treatment with the PI3K inhibitor alone (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (h / have-concession-91 :ARG1 (e / elicit-01 :ARG0 (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x2 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :ARG1 (a / affect-01 :ARG1 (a2 / anoikis :ARG2-of (i2 / induce-01 :ARG0 (s4 / small-molecule :name (n2 / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")))) :ARG2 (s2 / synergize-01) :mod (m / marked)) :ARG0-of (r / reduce-01 :ARG1 (v / viability :poss (c / cell-line :name (n3 / name :op1 "IEC-6") :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n4 / name :op1 "Tpr-Met") :xref (x / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))))) :ARG4 (l / level :mod (b / below :degree (w / well) :compared-to (l2 / level :mod (t3 / that) :ARG1-of (s3 / see-01 :time (t4 / treat-04 :ARG2 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K"))) :mod (a3 / alone))))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id pmid_2470_8867.192 # ::date 2015-09-01T04:56:10 # ::file pmid_2470_8867_192.txt # ::snt These results suggest that Tpr-Met-mediated growth promoting effects observed in IECs implicate MEK-dependent mechanisms, but that the anoikis resistance involves the integration of both MEK- and PI3K-dependent signaling pathways. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Sep 7, 2015 (s2 / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (c / contrast-01 :ARG1 (i / implicate-01 :ARG0 (a / affect-01 :ARG0-of (p2 / promote-01 :ARG1 (g / grow-01)) :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n2 / name :op1 "Tpr-Met") :xref (x1 / xref :value "UNIPROT:Q15624_HUMAN" :prob "0.201"))) :ARG1-of (o / observe-01 :location (c4 / cell :name (n3 / name :op1 "IEC")))) :ARG1 (m2 / mechanism :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x2 / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343"))))) :ARG2 (i2 / involve-01 :ARG1 (i3 / integrate-01 :ARG1 (a3 / and :op1 (p / pathway :ARG0-of (d2 / depend-01 :ARG1 e)) :op2 (p4 / pathway :ARG0-of (d3 / depend-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K") :xref (x / xref :value "UNIPROT:ELAF_HUMAN" :prob "0.262")))) :ARG0-of (s / signal-07))) :ARG2 (r2 / resist-01 :ARG1 (a2 / anoikis))))) # ::id pmid_2493_9055.1 # ::date 2015-08-29T03:25:23 # ::file pmid_2493_9055_1.txt # ::snt Antitumor activity of selective MEK1/2 inhibitor AZD6244 in combination with PI3K/mTOR inhibitor BEZ235 in gefitinib-resistant NSCLC xenograft models (PMID:24939055) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (a / activity-06 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD6244") :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2"))) :ARG1-of (c2 / combine-01 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "BEZ235") :ARG0-of (i2 / inhibit-01 :ARG1 (p / pathway :name (n3 / name :op1 "PI3K/mTOR"))) :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG0-of (s3 / select-01) :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG0-of (c / counter-01 :ARG1 (t / tumor)) :location (m / model :mod (x / xenograft :mod (d / disease :name (n5 / name :op1 "NSCLC")) :ARG0-of (r / resist-01 :ARG1 (s4 / small-molecule :name (n6 / name :op1 "gefitinib") :xref (x2 / xref :value "PUBCHEM:123631" :prob "16.963549"))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID24939055"))) # ::id pmid_2493_9055.9 # ::date 2015-08-28T02:13:52 # ::file pmid_2493_9055_9.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 28, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2493_9055.10 # ::date 2015-08-28T08:48:58 # ::file pmid_2493_9055_10.txt # ::snt AZD6244 could inhibit the tumor growth of NCI-H1993, but slightly inhibit the tumor growth of NCI-1975 and NCI-H460. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (c / contrast-01 :ARG1 (p2 / possible-01 :ARG1 (i2 / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG1 (g / grow-01 :ARG0 (c3 / cell-line :name (n3 / name :op1 "NCI-H1993")) :ARG1 (t / tumor)))) :ARG2 (i / inhibit-01 :ARG1 (g2 / grow-01 :ARG0 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "NCI-1975")) :op2 (c4 / cell-line :name (n4 / name :op1 "NCI-H460"))) :ARG1 t) :manner (s2 / slight))) # ::id pmid_2493_9055.11 # ::date 2015-08-28T09:31:31 # ::file pmid_2493_9055_11.txt # ::snt Combining AZD6244 with BEZ235 markedly enhanced their antitumor effects and without any marked adverse events. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a2 / and :op1 (e / enhance-01 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG1 (a / affect-01 :ARG0 (a4 / and :op1 s :op2 s2) :ARG0-of (c2 / counter-01 :ARG1 (t / tumor))) :manner (m / marked)) :op2 (e2 / enhance-01 :ARG0 c :ARG0-of (c3 / cause-01 :polarity "-" :ARG1 (e3 / event :mod (a3 / adverse) :mod m)))) # ::id pmid_2493_9055.12 # ::date 2015-08-29T01:45:10 # ::file pmid_2493_9055_12.txt # ::snt Western blot analysis and immunohistochemical staining revealed that AZD6244 alone reduced ERK1/2 phosphorylation, angiogenesis, and tumor cell proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (r / reveal-01 :ARG0 (a / and :op1 (a2 / analyze-01 :mod (i2 / immunoblot-01)) :op2 (s2 / stain-01 :mod (i / immunohistochemical))) :ARG1 (r2 / reduce-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD6244") :mod (a5 / alone) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG1 (a3 / and :op1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))) :op2 (a4 / angiogenesis) :op3 (p2 / proliferate-01 :ARG0 (c / cell :mod (t / tumor)))))) # ::id pmid_2493_9055.13 # ::date 2015-08-28T08:56:36 # ::file pmid_2493_9055_13.txt # ::snt Moreover, MEK1/2 inhibition resulted in decreased AKT phosphorylation in NCI-H1993 tumor model. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 28, 2015 (a / and :op2 (r / result-01 :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2"))) :ARG2 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :location (m / model :mod (t / tumor) :mod (c / cell-line :name (n3 / name :op1 "NCI-H1993"))) :ARG1-of (d / decrease-01)))) # ::id pmid_2493_9055.14 # ::date 2015-08-28T09:17:42 # ::file pmid_2493_9055_14.txt # ::snt BEZ235 also inhibited AKT phosphorylation as well as their downstream molecules in all three tumor models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333")) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :op2 (m / molecule :direction (d / downstream) :location (m2 / model :quant "3" :mod (t / tumor) :mod (a2 / all)) :poss s)) :mod (a3 / also)) # ::id pmid_2493_9055.15 # ::date 2015-08-29T01:56:00 # ::file pmid_2493_9055_15.txt # ::snt The antiangiogenic effects were substantially enhanced when the agents were combined, which may due to the reduced expression of matrix metallopeptidase-9 in tumor tissues (MMP-9). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Nov 23, 2015 (e / enhance-01 :ARG0 (a2 / affect-01 :ARG0-of (c4 / counter-01 :ARG1 (a3 / angiogenesis))) :degree (s / substantial) :condition (c3 / combine-01 :ARG1 (a / agent)) :ARG1-of (c2 / cause-01 :ARG0 (e2 / express-03 :ARG2 (e3 / enzyme :name (n / name :op1 "matrix" :op2 "metallopeptidase-9") :xref (x / xref :value "UNIPROT:MMP9_HUMAN" :prob "0.352")) :ARG3 (t / tissue :source (t2 / tumor)) :ARG1-of (r / reduce-01)) :ARG1-of (p / possible-01))) # ::id pmid_2493_9055.94 # ::date 2015-08-28T08:54:36 # ::file pmid_2493_9055_94.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Aug 28, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2493_9055.95 # ::date 2015-08-29T02:00:50 # ::file pmid_2493_9055_95.txt # ::snt Effect of AZD6244 and BEZ235 on viability of gefitinib-resistant NSCLC in vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / affect-01 :ARG0 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG1 (v / viability :poss (d / disease :name (n3 / name :op1 "NSCLC") :ARG0-of (r / resist-01 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "gefitinib") :xref (x / xref :value "PUBCHEM:123631" :prob "16.963549")))) :manner (i / in-vitro))) # ::id pmid_2493_9055.96 # ::date 2015-08-29T02:05:45 # ::file pmid_2493_9055_96.txt # ::snt Before evaluating the effect of AZD6244, BEZ235 and AZD6244 plus BEZ235 treatment on gefitinib-resistant NSCLC xenograft models in nude mice, the sensitivity of cell lines to compounds was evaluated in vitro. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (e / evaluate-01 :ARG1 (s2 / sensitive-03 :ARG0 (c2 / cell-line) :ARG1 (c / compound)) :manner (i / in-vitro) :time (b / before :op1 (e2 / evaluate-01 :ARG1 (a / affect-01 :ARG0 (t / treat-04 :ARG1 (m / model :mod (x / xenograft :mod (d / disease :name (n3 / name :op1 "NSCLC"))) :ARG0-of (r / resist-01 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "gefitinib") :xref (x2 / xref :value "PUBCHEM:123631" :prob "16.963549"))) :location (m2 / mouse :mod (n5 / nude))) :ARG2 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333")) :op3 (a3 / and :op1 s :op2 s3))))))) # ::id pmid_2493_9055.97 # ::date 2015-08-29T12:25:56 # ::file pmid_2493_9055_97.txt # ::snt Cell proliferation was analyzed by MTT assay in cells treated with 0, 0.01, 0.1, 1, 10 and 100 μM of AZD6244 or BEZ235 for 72 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Feb 13, 2016 (a / analyze-01 :ARG1 (p / proliferate-01 :ARG0 (c / cell)) :instrument (a2 / assay-01 :instrument (s3 / small-molecule :name (n / name :op1 "MTT") :xref (x / xref :value "PUBCHEM:64965" :prob "17.320225"))) :location (c2 / cell :ARG1-of (t / treat-04 :ARG2 (a3 / and :op1 (c3 / concentration-quantity :quant "0" :unit "m3") :op2 (c4 / concentration-quantity :quant "0.01" :unit "m3") :op3 (c5 / concentration-quantity :quant "0.1" :unit "m3") :op4 (c6 / concentration-quantity :quant "1" :unit "m3") :op5 (c7 / concentration-quantity :quant "10" :unit (m3 / micromolar)) :op6 (c8 / concentration-quantity :quant "100" :unit m3) :quant-of (o / or :op1 (s / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n3 / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333")))) :duration (t2 / temporal-quantity :quant "72" :unit (h / hour))))) # ::id pmid_2493_9055.98 # ::date 2015-08-30T05:44:04 # ::file pmid_2493_9055_98.txt # ::snt The results showed that AZD6244 significantly suppressed the growth of NCI-H1993 with a low micromolar IC50 value of 5.6 μM (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01)) :ARG1 (s2 / suppress-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG1 (g / grow-01 :ARG1 (c / cell-line :name (n3 / name :op1 "NCI-H1993")) :ARG2 (v / value-01 :ARG1 (t2 / thing :name (n2 / name :op1 "IC50")) :ARG2 (c2 / concentration-quantity :quant "5.6" :unit (m / micromolar)) :ARG1-of (l / low-04))) :ARG1-of (s4 / significant-02)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_2493_9055.99 # ::date 2015-08-30T05:48:56 # ::file pmid_2493_9055_99.txt # ::snt Moreover, AZD6244 alone mildly inhibited cell growth with IC50 values of 37.5 μM and 26.8 μM in NCI-H1975 and NCI-H460 cells, respectively (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / and :op2 (i / inhibit-01 :ARG0 (a3 / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :mod (v / value-01 :ARG1 (t / thing :name (n2 / name :op1 "IC50")) :ARG2 (c3 / concentration-quantity :quant "37.5" :unit (m2 / micromolar)) :location (c4 / cell-line :name (n3 / name :op1 "NCI-H1975"))) :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n5 / name :op1 "AZD6244") :mod (v2 / value-01 :ARG1 t :ARG2 (c2 / concentration-quantity :quant "26.8" :unit (m3 / micromolar)) :location (c5 / cell-line :name (n4 / name :op1 "NCI-H460"))) :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :mod (a2 / alone)) :ARG1 (g / grow-01 :ARG1 (c / cell)) :manner (m / mild)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_2493_9055.100 # ::date 2015-08-30T05:55:39 # ::file pmid_2493_9055_100.txt # ::snt BEZ235 alone also suppressed the growth of three cell lines with slightly high IC50 values of 23.5, 67.8 and 16.8 μM in NCI-H1993, NCI-H1975 and NCI-H460 cells, respectively (Figure 1B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (s / suppress-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "BEZ235") :xref (x / xref :value "PUBCHEM:11977753" :prob "17.394333")) :ARG1 (g / grow-01 :ARG1 (a4 / and :op1 (c / cell-line :location (c3 / cell-line :name (n3 / name :op1 "NCI-H1993")) :mod (v / value-01 :ARG1 (t / thing :name (n2 / name :op1 "IC50")) :ARG2 (c2 / concentration-quantity :quant "23.5" :unit (m / micromolar)) :ARG1-of (h / high-04 :degree (s3 / slight)))) :op2 (c8 / cell-line :location (c7 / cell-line :name (n4 / name :op1 "NCI-H1975")) :mod (v2 / value-01 :ARG1 t :ARG2 (c4 / concentration-quantity :quant "67.8" :unit m))) :op3 (c9 / cell-line :location (c6 / cell-line :name (n5 / name :op1 "NCI-H460")) :mod (v3 / value-01 :ARG1 t :ARG2 (c5 / concentration-quantity :quant "16.8" :unit m))) :mod (a3 / alone))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B")) :mod (a / also)) # ::id pmid_2493_9055.101 # ::date 2015-08-29T03:41:13 # ::file pmid_2493_9055_101.txt # ::snt Concurrent inhibition of MEK and PI3K/mTOR has a synergistic effect on gefitinib-resistant NSCLC cell lines growth in vitro # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (a / affect-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :xref (x / xref :value "UNIPROT:M3K1_HUMAN" :prob "0.343")) :ARG1-of (c2 / concur-01 :ARG0 (i2 / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "PI3K/mTOR"))))) :ARG1 (g / grow-01 :ARG1 (c / cell-line :mod (d / disease :name (n3 / name :op1 "NSCLC")) :ARG0-of (r / resist-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "gefitinib") :xref (x1 / xref :value "PUBCHEM:123631" :prob "16.963549")))) :manner (i3 / in-vitro)) :ARG2 (s / synergize-01)) # ::id pmid_2493_9055.102 # ::date 2015-08-29T03:45:29 # ::file pmid_2493_9055_102.txt # ::snt The anti-proliferative effect of combining a MEK and PI3K/mTOR inhibitor was measured in NCI-H1993, NCI-H1975 and NCI-H460 cells by calculating the combination index (CI) according to the Chou-Talalay method [21] using a fixed dose ratio. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (m / measure-01 :ARG1 (a / affect-01 :ARG0 (c2 / combine-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK")))) :ARG2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / pathway :name (n / name :op1 "PI3K/mTOR"))))) :ARG0-of (c / counter-01 :ARG1 (p / proliferate-01))) :ARG2 (c6 / calculate-01 :ARG1 (i3 / index :mod (c7 / combine-01))) :ARG3 (u / use-01 :ARG1 (r / ratio :mod (d / dose :ARG1-of (f / fix-03))) :ARG1-of (s / say-01 :ARG0 (m4 / method :name (n6 / name :op1 "Chou-Talalay"))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG0-of (c8 / cite-01 :ARG1 "21")))) :location (a2 / and :op1 (c3 / cell-line :name (n3 / name :op1 "NCI-H1993")) :op2 (c4 / cell-line :name (n4 / name :op1 "NCI-H1975")) :op3 (c5 / cell-line :name (n5 / name :op1 "NCI-H460")))) # ::id pmid_2493_9055.103 # ::date 2015-08-30T08:08:19 # ::file pmid_2493_9055_103.txt # ::snt Both AZD6244 and BEZ235 were introduced to cell cultures at 0.25×, 0.5×, 1×, 2× and 4× their respective IC50s in NCI-H1993, NCI-H1975 and NCI-H460 cell lines for 72 h. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (i / introduce-01 :ARG1 (a / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x / xref :value "PUBCHEM:11977753" :prob "17.394333")) :mod (t / thing :name (n3 / name :op1 "IC50")) :quant (a3 / and :op1 (p / product-of :op1 "0.25" :op2 t) :op2 (p2 / product-of :op1 "0.5" :op2 t) :op3 (p3 / product-of :op1 "1" :op2 t) :op4 (p4 / product-of :op2 "2" :op2 t) :op5 (p5 / product-of :op2 "4" :op2 t) :mod (r / respective))) :ARG2 (c / culture-01 :ARG1 (c2 / cell)) :location (a2 / and :op1 (c3 / cell-line :name (n4 / name :op1 "NCI-H1993")) :op2 (c4 / cell-line :name (n5 / name :op1 "NCI-H1975")) :op3 (c5 / cell-line :name (n6 / name :op1 "NCI-H460"))) :duration (t2 / temporal-quantity :quant "72" :unit (h / hour))) # ::id pmid_2493_9055.104 # ::date 2015-08-29T02:06:48 # ::file pmid_2493_9055_104.txt # ::snt Cell growth in all cell lines was markedly decreased following combination treatment at multiple paired concentrations when compared with either single agent alone. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (d / decrease-01 :ARG1 (g / grow-01 :ARG1 (c / cell) :location (c2 / cell-line :mod (a / all))) :ARG2 (m / marked) :ARG1-of (f / follow-01 :ARG2 (t / treat-04 :ARG2 (c4 / concentrate-01 :ARG1-of (p / pair-01) :quant (m2 / multiple)) :mod (c3 / combine-01))) :ARG1-of (c5 / compare-01 :ARG2 (a2 / agent :ARG1-of (s / single-02) :mod (e / either) :mod (a3 / alone)))) # ::id pmid_2493_9055.105 # ::date 2015-08-29T02:09:58 # ::file pmid_2493_9055_105.txt # ::snt The cells viability data were processed to get the CI under the corresponding effective dose (ED) in NCI-H1993, NCI-H1975 and NCI-H460 cell lines (Figure 2) by CalcuSyn software. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (p / process-01 :ARG1 (d / data :topic (v / viability :poss (c / cell))) :purpose (g / get-03 :ARG1 (i / interval :mod (c7 / confidence)) :ARG2 (u / under :op1 (c6 / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-effective-dose-01 :ARG5 (a2 / and :op1 (c3 / cell-line :name (n4 / name :op1 "NCI-H1993")) :op2 (c4 / cell-line :name (n3 / name :op1 "NCI-H1975")) :op3 (c5 / cell-line :name (n2 / name :op1 "NCI-H460")))) :ARG1-of (c2 / correspond-01)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "2")) :instrument (s / software :name (n5 / name :op1 "CalcuSyn"))) # ::id pmid_2493_9055.106 # ::date 2015-08-30T06:03:45 # ::file pmid_2493_9055_106.txt # ::snt For the NCI-H1993 cell line the following CI value was obtained: 0.4101 (ED50). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (o / obtain-01 :ARG1 (v / value-01 :ARG1 (i / interval :mod (c / confidence)) :ARG2 "0.4101" :ARG2-of (f / follow-01) :ARG1-of (m / mean-01 :ARG2 (h / have-percentage-maximal-effective-dose-01 :ARG2 "50"))) :purpose (c2 / cell-line :name (n2 / name :op1 "NCI-H1993"))) # ::id pmid_2493_9055.107 # ::date 2015-08-30T06:07:33 # ::file pmid_2493_9055_107.txt # ::snt For NCI-H1975 and NCI-H460 cell line the CI values were 0.02052 (ED50), and 0.0440 (ED50) respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 12, 2016 (a / and :op1 (v / value-01 :ARG1 (i / interval :mod (c3 / confidence)) :ARG2 "0.02052" :purpose (c / cell-line :name (n / name :op1 "NCI-H1975")) :ARG1-of (m / mean-01 :ARG2 (h / have-percentage-maximal-effective-dose-01 :ARG2 "50"))) :op2 (v2 / value-01 :ARG1 i :ARG2 "0.0440" :purpose (c2 / cell-line :name (n2 / name :op1 "NCI-H460")) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91)) :ARG1-of m)) # ::id pmid_2493_9055.108 # ::date 2015-08-30T06:11:05 # ::file pmid_2493_9055_108.txt # ::snt The CI results suggested that AZD6244 and BEZ235 worked synergistically to produce an anti-proliferative effect in NCI-H1993, NCI-H1975 and NCI-H460 cell lines (Figures 2A-C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01 :ARG1 (i / index :mod (c5 / combine-01)))) :ARG1 (w / work-01 :ARG0 (a / and :op1 (s3 / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s4 / small-molecule :name (n3 / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG1 (p / produce-01 :ARG0 a :ARG1 (a2 / affect-01 :ARG0-of (c / counter-01 :ARG1 (p2 / proliferate-01 :location (a3 / and :op1 (c2 / cell-line :name (n4 / name :op1 "NCI-H1993")) :op2 (c3 / cell-line :name (n5 / name :op1 "NCI-H1975")) :op3 (c4 / cell-line :name (n6 / name :op1 "NCI-H460"))))))) :manner (s2 / synergistical)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B") :op3 (f3 / figure :mod "2C")))) # ::id pmid_2493_9055.109 # ::date 2015-08-29T03:00:20 # ::file pmid_2493_9055_109.txt # ::snt Tumor growth inhibition effect of MEK and PI3K/mTOR inhibitors in gefitinib-resistant NSCLC tumor models # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / affect-01 :ARG0 (a2 / and :op1 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK")))) :op2 (m3 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p / pathway :name (n3 / name :op1 "PI3K/mTOR"))))) :ARG1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG0 (t / tumor))) :location (m / model :mod (t2 / tumor :mod (d / disease :name (n / name :op1 "NSCLC"))) :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "gefitinib") :xref (x / xref :value "PUBCHEM:123631" :prob "16.963549"))))) # ::id pmid_2493_9055.110 # ::date 2015-08-29T03:05:30 # ::file pmid_2493_9055_110.txt # ::snt In order to investigate tumor growth inhibition effect of AZD6244 and/or BEZ235 in vivo, we used AZD6244, BEZ235, and AZD6244 plus BEZ235 to treat NCI-H1993, NCI-H1975 and NCI-H460 subcutaneous tumor models respectively for 3 weeks. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (u / use-01 :ARG0 (w / we) :ARG1 (a / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x / xref :value "PUBCHEM:11977753" :prob "17.394333")) :op3 (a5 / and :op1 s :op2 s2)) :ARG2 (t / treat-04 :ARG0 w :ARG1 (a2 / and :op1 (m / model :mod (t3 / tumor) :mod (c / cell-line :name (n3 / name :op1 "NCI-H1993"))) :op2 (m2 / model :mod t3 :mod (c2 / cell-line :name (n4 / name :op1 "NCI-H1975"))) :op3 (m3 / model :mod t3 :mod (c3 / cell-line :name (n5 / name :op1 "NCI-H460"))) :mod (s3 / subcutaneous)) :duration (t2 / temporal-quantity :quant "3" :unit (w2 / week)) :manner (r / respective)) :purpose (i2 / investigate-01 :ARG0 w :ARG1 (a3 / affect-01 :ARG0 (a4 / and-or :op1 s :op2 s2) :ARG1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 t3)) :manner (i3 / in-vivo)))) # ::id pmid_2493_9055.111 # ::date 2015-08-29T03:11:54 # ::file pmid_2493_9055_111.txt # ::snt As shown in Figure 3A-C, treatment with AZD6244 for 3 weeks was able to inhibit tumor growth of NCI-H1993 (T/C value 40%), but slightly inhibit tumor growth in both NCI-H1975 and NCI-H460 subcutaneous tumor models (T/C values 60% and 65%), whereas BEZ235 treatment caused an approximately 50% reduction in tumor growth in all three subcutaneous tumor models. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (c7 / contrast-01 :ARG1 (c3 / contrast-01 :ARG1 (p6 / possible-01 :ARG1 (i / inhibit-01 :ARG0 (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :ARG1 (g / grow-01 :ARG1 (t3 / tumor) :location (c2 / cell-line :name (n2 / name :op1 "NCI-H1993"))) :ARG1-of (m / mean-01 :ARG2 (v / value-01 :ARG2 (p / percentage-entity :value "40"))))) :ARG2 (i2 / inhibit-01 :ARG1 (g2 / grow-01 :ARG1 t3) :degree (s3 / slight) :location (a / and :op1 (m2 / model :mod t3 :location (c4 / cell-line :name (n3 / name :op1 "NCI-H1975"))) :op2 (m3 / model :mod t3 :location (c5 / cell-line :name (n4 / name :op1 "NCI-H460"))) :mod (s2 / subcutaneous)) :ARG1-of (m4 / mean-01 :ARG2 (a2 / and :op1 (v2 / value-01 :ARG2 (p2 / percentage-entity :value "60")) :op2 (v3 / value-01 :ARG2 (p3 / percentage-entity :value "65")))))) :ARG2 (c6 / cause-01 :ARG0 (t4 / treat-04 :ARG2 (s5 / small-molecule :name (n5 / name :op1 "BEZ235") :xref (x / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG1 (r / reduce-01 :ARG1 (g3 / grow-01 :ARG1 t3) :ARG2 (a3 / approximately :op1 (p4 / percentage-entity :value "50")) :location (m5 / model :quant "3" :mod s2 :mod t3 :mod (a4 / all)))) :ARG1-of (s6 / show-01 :ARG0 (a5 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B") :op3 (f3 / figure :mod "3C")))) # ::id pmid_2493_9055.112 # ::date 2015-08-29T12:26:42 # ::file pmid_2493_9055_112.txt # ::snt In contrast, the combined treatments with the two drugs almost completely inhibited NCI-H1993, NCI-H1975 and NCI-H460 tumor growth at the end of the 3 weeks of therapy (Figure 3A-D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (c / contrast-01 :ARG2 (i / inhibit-01 :ARG0 (t4 / treat-04 :ARG1-of (c6 / combine-01 :ARG2 (d2 / drug :quant "2"))) :ARG1 (a2 / and :op1 (g / grow-01 :ARG0 (c3 / cell-line :name (n / name :op1 "NCI-H1993")) :ARG1 (t3 / tumor)) :op2 (g2 / grow-01 :ARG0 (c4 / cell-line :name (n2 / name :op1 "NCI-H1975")) :ARG1 t3) :op3 (g3 / grow-01 :ARG0 (c5 / cell-line :name (n3 / name :op1 "NCI-H460")) :ARG1 t3)) :ARG1-of (c2 / complete-02 :degree (a / almost)) :time (e / end-01 :ARG1 (t2 / therapy :duration (t / temporal-quantity :quant "3" :unit (w / week))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "3A") :op2 (f2 / figure :mod "3B") :op3 (f3 / figure :mod "3C") :op4 (f4 / figure :mod "3D")))) # ::id pmid_2493_9055.113 # ::date 2015-08-29T02:14:32 # ::file pmid_2493_9055_113.txt # ::snt Single agent and combination treatment protocols were well tolerated by mice, with no weight loss or other signs of acute or delayed toxicity (Figure 4A-C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (t / tolerate-01 :ARG0 (m / mouse :ARG0-of (l / lose-02 :polarity "-" :ARG1 (w / weight)) :ARG0-of (s / signal-07 :ARG1 (o3 / or :op1 (t2 / toxicity :mod (a2 / acute)) :op2 (t3 / toxicity :ARG1-of (d / delay-01))) :mod (o2 / other))) :ARG1 (a / and :op1 (p / protocol :topic (t4 / treat-04 :ARG2 (a3 / agent :ARG1-of (s2 / single-02)))) :op2 (p2 / protocol :topic (t5 / treat-04 :ARG1-of (c / combine-01)))) :manner (w2 / well) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B") :op3 (f3 / figure :mod "4C")))) # ::id pmid_2493_9055.114 # ::date 2015-08-29T02:17:57 # ::file pmid_2493_9055_114.txt # ::snt Effect of MEK and PIK3/mTOR inhibitors on signaling transduction pathways in gefitinib-resistant NSCLC tumor models # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (a / affect-01 :ARG0 (a2 / and :op1 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))) :op2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "PIK3/mTOR"))))) :ARG1 (p3 / pathway :ARG2-of (t / transduce-01) :location (m4 / model :mod (t2 / tumor :mod (d / disease :name (n4 / name :op1 "NSCLC"))) :ARG0-of (r / resist-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "gefitinib") :xref (x / xref :value "PUBCHEM:123631" :prob "16.963549")))) :ARG0-of (s / signal-07))) # ::id pmid_2493_9055.115 # ::date 2015-08-29T02:56:07 # ::file pmid_2493_9055_115.txt # ::snt To assess the impact of both compounds on downstream molecules of the MEK and PI3K pathways, we used Western blot analysis to observe phosphorylation status and total protein expression in tumor tissues. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (a / analyze-01 :mod (i2 / immunoblot-01)) :ARG2 (o / observe-01 :ARG0 w :ARG1 (a2 / and :op1 (s / status :mod (p / phosphorylate-01)) :op2 (e / express-03 :ARG2 (p2 / protein) :ARG3 (t / tissue :source (t2 / tumor)) :ARG1-of (t3 / total-01)))) :purpose (a3 / assess-01 :ARG0 w :ARG1 (i / impact-01 :ARG0 (c / compound :mod (b / both)) :ARG1 (m / molecule :direction (d / downstream) :source (a4 / and :op1 (p3 / pathway :name (n2 / name :op1 "MEK")) :op2 (p4 / pathway :name (n3 / name :op1 "PI3K"))))))) # ::id pmid_2493_9055.116 # ::date 2015-08-29T14:02:27 # ::file pmid_2493_9055_116.txt # ::snt The results showed that p-MEK1/2, p-ERK1/2, p-AKT, p-S6 and p-4E-BP1 appeared to be inhibited by AZD6244 and BEZ235 combination treatment, whereas the total protein levels of MEK1/2, ERK1/2, AKT, S6 and 4E-BP1 remained unchanged in each tumor model (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (s2 / show-01 :ARG0 (t / thing :ARG2-of (r / result-01)) :ARG1 (c2 / contrast-01 :ARG1 (a / appear-01 :ARG1 (i / inhibit-01 :ARG0 (t2 / treat-04 :ARG0-of (c / combine-01 :ARG1 (s4 / small-molecule :name (n8 / name :op1 "AZD6244") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG2 (s3 / small-molecule :name (n7 / name :op1 "BEZ235") :xref (x2 / xref :value "PUBCHEM:11977753" :prob "17.394333")))) :ARG1 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "MEK1/2") :ARG3-of (p / phosphorylate-01)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG1-of p) :op3 (e3 / enzyme :name (n4 / name :op1 "AKT") :ARG1-of p :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")) :op4 (p3 / protein :name (n5 / name :op1 "S6") :ARG1-of p) :op5 (p4 / protein :name (n6 / name :op1 "4E-BP1") :ARG1-of p :xref (x1 / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002"))))) :ARG2 (r2 / remain-01 :ARG1 (a3 / and :op1 (l / level :degree-of e) :op2 (l2 / level :degree-of e2) :op3 (l3 / level :degree-of e3) :op4 (l4 / level :degree-of p3) :op5 (l5 / level :degree-of p4)) :ARG2 (m / model :mod (t3 / tumor)) :ARG3 (c3 / change-01 :polarity "-"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5"))) # ::id pmid_2493_9055.117 # ::date 2015-08-30T07:07:39 # ::file pmid_2493_9055_117.txt # ::snt Western blot analysis of downstream signals also showed treatment with AZD6244 or BEZ235 inhibited the phosphorylation of ERK1/2 or AKT in all three tumor models respectively. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 3, 2016 (s / show-01 :ARG0 (a / analyze-01 :ARG1 (s2 / signal-07 :direction (d / downstream)) :mod (i2 / immunoblot-01)) :ARG1 (i / inhibit-01 :ARG0 (t / treat-04 :ARG2 (o / or :op1 (s3 / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s4 / small-molecule :name (n3 / name :op1 "BEZ235") :xref (x2 / xref :value "PUBCHEM:11977753" :prob "17.394333")))) :ARG1 (p / phosphorylate-01 :ARG1 (o2 / or :op1 (e / enzyme :name (n4 / name :op1 "ERK1/2")) :op2 (e2 / enzyme :name (n5 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :location (m / model :quant "3" :mod (t2 / tumor) :mod (a2 / all))) :manner (r / respective)) :mod (a3 / also)) # ::id pmid_2493_9055.118 # ::date 2015-08-29T12:41:12 # ::file pmid_2493_9055_118.txt # ::snt In addition, combined treatment with AZD6244 and BEZ235 showed greater inhibition of p-ERK1/2 and p-AKT than observed in control group or mice treated with each compound alone in vivo (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (a / and :op2 (s2 / show-01 :ARG0 (t / treat-04 :ARG1-of (c / combine-01 :ARG2 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333"))))) :ARG1 (i / inhibit-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :op2 (e2 / enzyme :name (n4 / name :op1 "AKT") :ARG1-of p :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263"))) :mod (g / great :degree (m / more) :compared-to (i2 / inhibit-01 :ARG1-of (o / observe-01 :location (o2 / or :op1 (g2 / group :ARG1-of (c3 / control-01)) :op2 (m2 / mouse :ARG1-of (t2 / treat-04 :ARG2 (c4 / compound :mod (e3 / each) :mod (a4 / alone)) :manner (i3 / in-vivo))))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5"))) # ::id pmid_2493_9055.119 # ::date 2015-08-29T12:53:21 # ::file pmid_2493_9055_119.txt # ::snt Interestingly, the impact from both inhibitors on p-S6 and p-4E-BP1 levels was, alternatively, tumor model specific. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (s2 / specific-02 :ARG1 (i3 / impact-01 :ARG0 (m / molecular-physical-entity :mod (b / both) :ARG0-of (i2 / inhibit-01)) :ARG1 (a / and :op1 (l / level :quant-of (p2 / protein :name (n / name :op1 "S6") :ARG3-of (p / phosphorylate-01))) :op2 (l2 / level :quant-of (p3 / protein :name (n2 / name :op1 "4E-BP1") :ARG3-of p :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002"))))) :ARG2 (m2 / model :mod (t / tumor)) :ARG2-of (i / interest-01) :mod (a2 / alternative)) # ::id pmid_2493_9055.120 # ::date 2015-08-29T13:03:15 # ::file pmid_2493_9055_120.txt # ::snt For example, AZD6244 and BEZ235 alone and in combination markedly inhibited p-S6 and p-4E-BP1 expression levels in NCI-H1993 tumor models, compared with the minimal suppression observed in NCI-H460 tumor model (Figure 5). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG0 (a / and :op1 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :op2 (c / combine-01 :ARG1 s :ARG2 s2) :mod (a4 / alone)) :ARG1 (a3 / and :op1 (l / level :degree-of (e2 / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "S6") :ARG3-of (p / phosphorylate-01)) :ARG3 "m2")) :op2 (l2 / level :degree-of (e3 / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "4E-BP1") :ARG1-of p :ARG3-of p :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002")) :ARG3 (m2 / model :mod (t / tumor :mod (c3 / cell-line :name (n5 / name :op1 "NCI-H1993"))))))) :ARG0-of (e / exemplify-01) :manner (m / marked) :compared-to (s3 / suppress-01 :ARG1-of (o / observe-01 :location (m4 / model :mod t :mod (c2 / cell-line :name (n6 / name :op1 "NCI-H460")))) :degree (m3 / minimal)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5"))) # ::id pmid_2493_9055.121 # ::date 2015-08-30T07:35:33 # ::file pmid_2493_9055_121.txt # ::snt Neither AZD6244 nor BEZ235 alone suppressed p-S6 and p-4E-BP1 in NCI-H1975 tumor model. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (s / suppress-01 :polarity "-" :ARG0 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s3 / small-molecule :name (n / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333")) :mod (a3 / alone)) :ARG1 (a2 / and :op1 (p2 / protein :name (n4 / name :op1 "S6") :ARG3-of (p / phosphorylate-01)) :op2 (p3 / protein :name (n5 / name :op1 "4E-BP1") :ARG1-of p :xref (x / xref :value "UNIPROT:4EBP1_HUMAN" :prob "1.002"))) :location (m2 / model :mod (t / tumor) :mod (c / cell-line :name (n3 / name :op1 "NCI-H1975")))) # ::id pmid_2493_9055.122 # ::date 2015-08-30T06:58:30 # ::file pmid_2493_9055_122.txt # ::snt We also found that the expression of MMP-9 was significantly inhibited by AZD6244 and BEZ235 combination treatment, whereas the expression of MMP-2 was not affected by the treatment. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (t2 / treat-04 :ARG2 (c2 / combine-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :ARG2 (s3 / small-molecule :name (n4 / name :op1 "BEZ235") :xref (x3 / xref :value "PUBCHEM:11977753" :prob "17.394333")))) :ARG1 (e3 / express-03 :ARG2 (e4 / enzyme :name (n2 / name :op1 "MMP-9") :xref (x / xref :value "UNIPROT:MMP9_HUMAN" :prob "1.002"))) :ARG1-of (s / significant-02)) :ARG2 (a2 / affect-01 :polarity "-" :ARG0 t2 :ARG1 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "MMP-2") :xref (x1 / xref :value "UNIPROT:MMP2_HUMAN" :prob "1.002"))))) :mod (a / also)) # ::id pmid_2493_9055.123 # ::date 2015-08-30T06:28:03 # ::file pmid_2493_9055_123.txt # ::snt Effect of MEK and PIK3/mTOR inhibitors on the expressions of Ki-67 and CD31 in gefitinib-resistant NSCLC tumor models # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / affect-01 :ARG0 (a2 / and :op1 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / pathway :name (n3 / name :op1 "PIK3/mTOR"))))) :ARG1 (a3 / and :op1 (e / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "Ki-67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.632")) :ARG3 (m / model :mod (t / tumor :mod (d / disease :name (n / name :op1 "NSCLC"))) :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n6 / name :op1 "gefitinib") :xref (x2 / xref :value "PUBCHEM:123631" :prob "16.963549"))))) :op3 (e2 / express-03 :ARG1 (p3 / protein :name (n5 / name :op1 "CD31") :xref (x1 / xref :value "UNIPROT:PECA1_HUMAN" :prob "1.002")) :ARG3 m))) # ::id pmid_2493_9055.124 # ::date 2015-08-30T06:47:18 # ::file pmid_2493_9055_124.txt # ::snt To characterize the mechanism of tumor growth inhibition observed in our gefitinib-resistant NSCLC tumor models by AZD6244 and BEZ235, lung tumor tissues were assessed by evaluating Ki-67 expression using immunohistochemical analyses. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (a / assess-01 :ARG1 (t / tissue :source (t2 / tumor :part-of (l / lung))) :manner (e / evaluate-01 :ARG1 (e2 / express-03 :ARG2 (p / protein :name (n / name :op1 "Ki-67") :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.632")))) :manner (u / use-01 :ARG1 (a2 / analyze-01 :mod (i / immunohistochemical))) :purpose (c / characterize-01 :ARG1 (m / mechanism :ARG1-of (o / observe-01 :ARG0 (a3 / and :op1 (s / small-molecule :name (n3 / name :op1 "AZD6244") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n4 / name :op1 "BEZ235") :xref (x2 / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :location (m2 / model :ARG0-of (r / resist-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "gefitinib") :xref (x1 / xref :value "PUBCHEM:123631" :prob "16.963549"))) :mod (t4 / tumor :mod (d / disease :name (n5 / name :op1 "NSCLC"))) :poss (w / we))) :instrument-of (i2 / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t3 / tumor)))))) # ::id pmid_2493_9055.125 # ::date 2015-08-30T06:54:17 # ::file pmid_2493_9055_125.txt # ::snt We observed active cell proliferation in NCI-H1993 tumor model, with a 56% proliferation index (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Aug 30, 2015 (o / observe-01 :ARG0 (w / we) :ARG1 (p2 / proliferate-01 :ARG0 (c / cell) :ARG0-of (a / activity-06) :location (m / model :mod (t / tumor) :mod (c2 / cell-line :name (n / name :op1 "NCI-H199"))) :ARG1-of (i / index-01 :ARG2 (p / percentage-entity :value "56"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_2493_9055.126 # ::date 2015-08-30T06:17:34 # ::file pmid_2493_9055_126.txt # ::snt Monotherapy with AZD6244 or BEZ235 slightly decreased the percentage of Ki-67-positive proliferating tumor tissues, with proliferation indices of 42% and 39%, respectively (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (d / decrease-01 :ARG0 (m / monotherapy :instrument (a / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x2 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333")))) :ARG1 (p3 / percentage :quant-of (t / tissue :source (t2 / tumor) :ARG0-of (p5 / proliferate-01) :mod (p4 / protein :name (n3 / name :op1 "Ki-67") :mod (p6 / positive) :xref (x / xref :value "UNIPROT:KI67_HUMAN" :prob "0.632")) :ARG0-of (h / have-03 :ARG1 (a2 / and :op1 (i / index :mod p5 :mod (p / percentage-entity :value "42")) :op2 (i2 / index :mod p5 :mod (p2 / percentage-entity :value "39")))))) :degree (s2 / slight) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6A"))) # ::id pmid_2493_9055.127 # ::date 2015-08-30T06:22:05 # ::file pmid_2493_9055_127.txt # ::snt Combined treatment with AZD6244 and BEZ235 markedly decreased the percentage of Ki-67-positive proliferating tumor tissues to 10%, consistent with the marked inhibition of ERK1/2 and AKT phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (d / decrease-01 :ARG0 (t / treat-04 :ARG1-of (c2 / combine-01 :ARG2 (a2 / and :op1 (s / small-molecule :name (n3 / name :op1 "AZD6244") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n4 / name :op1 "BEZ235") :xref (x2 / xref :value "PUBCHEM:11977753" :prob "17.394333"))))) :ARG1 (p3 / percentage :quant-of (t2 / tissue :source (t3 / tumor) :ARG0-of (p4 / proliferate-01) :mod (p5 / protein :name (n5 / name :op1 "Ki-67") :mod (p7 / positive) :xref (x1 / xref :value "UNIPROT:KI67_HUMAN" :prob "0.632")))) :ARG2 (m / marked) :ARG4 (p6 / percentage-entity :value "10") :ARG1-of (c / consistent-01 :ARG2 (i / inhibit-01 :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))) :op2 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.263")))) :degree m))) # ::id pmid_2493_9055.128 # ::date 2015-08-30T07:14:35 # ::file pmid_2493_9055_128.txt # ::snt We also found the similar results in NCI-H1975 and NCI-H460 tumor models (Figure 6A).To evaluate the potential antiangiogenic mechanism of AZD6244 and BEZ235, gefitinib-resistant NSCLC tumor tissues were analyzed by immunostaining for CD31 (platelet endothelial cell adhesion molecule 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 19, 2016 (m / multi-sentence :snt1 (f / find-01 :ARG0 (w / we) :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6A")) :mod (a / also) :location (a2 / and :op1 (m2 / model :mod (t2 / tumor) :mod (c / cell-line :name (n2 / name :op1 "NCI-H1975"))) :op2 (m3 / model :mod t2 :mod (c2 / cell-line :name (n / name :op1 "NCI-H460"))))) :snt2 (a3 / analyze-01 :ARG0 (i / immunostain-01 :ARG3 (p / protein :name (n3 / name :op1 "CD31") :xref (x / xref :value "UNIPROT:PECA1_HUMAN" :prob "1.002"))) :ARG1 (t3 / tissue :source (t4 / tumor) :mod (d2 / disease :name (n4 / name :op1 "NSCLC")) :ARG0-of (r3 / resist-01 :ARG1 (s3 / small-molecule :name (n7 / name :op1 "gefitinib") :xref (x1 / xref :value "PUBCHEM:123631" :prob "16.963549")))) :purpose (e / evaluate-01 :ARG1 (m4 / mechanism :poss (a4 / and :op1 (s / small-molecule :name (n5 / name :op1 "AZD6244") :xref (x3 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n6 / name :op1 "BEZ235") :xref (x2 / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG0-of (c3 / counter-01 :ARG1 (a5 / angiogenesis :mod (p2 / potential))))))) # ::id pmid_2493_9055.129 # ::date 2015-08-29T04:34:16 # ::file pmid_2493_9055_129.txt # ::snt The results showed BEZ235 significantly decreased the vascular density of all three gefitinib-resistant NSCLC tumors, whereas AZD6244 monotherapy had only a mildly effect upon lung tumor angiogenesis. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (c / contrast-01 :ARG1 (s2 / show-01 :ARG0 (t2 / thing :ARG2-of (r / result-01)) :ARG1 (d / decrease-01 :ARG0 (s5 / small-molecule :name (n3 / name :op1 "BEZ235") :xref (x1 / xref :value "PUBCHEM:11977753" :prob "17.394333")) :ARG1 (d2 / density) :mod (v / vessel) :location (t3 / tumor :quant "3" :mod (d3 / disease :name (n / name :op1 "NSCLC")) :ARG0-of (r2 / resist-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "gefitinib") :xref (x2 / xref :value "PUBCHEM:123631" :prob "16.963549")))) :ARG1-of (s4 / significant-02))) :ARG2 (a / affect-01 :ARG0 (m2 / monotherapy :mod (s3 / small-molecule :name (n2 / name :op1 "AZD6244") :xref (x / xref :value "PUBCHEM:10127622" :prob "17.762056"))) :ARG1 (a2 / angiogenesis :mod (t / tumor :source (l / lung))) :manner (m / mild) :mod (o / only))) # ::id pmid_2493_9055.130 # ::date 2015-08-28T09:38:25 # ::file pmid_2493_9055_130.txt # ::snt The antiangiogenic effects AZD6244 and BEZ235 were markedly increased when they were combined (Figure 6B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (i / increase-01 :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x1 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235") :xref (x / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG0-of (c4 / counter-01 :ARG1 (a3 / angiogenesis))) :ARG2 (m / marked) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B")) :condition (c2 / combine-01 :ARG1 a2)) # ::id pmid_2493_9055.131 # ::date 2015-08-29T03:46:05 # ::file pmid_2493_9055_131.txt # ::snt MEK and PIK3/mTOR inhibitors had no effect on caspase-3, 8 and 9 activities in gefitinib-resistant NSCLC tumor models # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (a / affect-01 :polarity "-" :ARG0 (a2 / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p5 / protein-family :name (n / name :op1 "MEK")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "PIK3/mTOR"))))) :ARG1 (a3 / and :op1 (a4 / activity-06 :ARG0 (p2 / protein :name (n4 / name :op1 "Caspase" :op2 "3") :xref (x / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.682"))) :op2 (a5 / activity-06 :ARG0 (p3 / protein :name (n5 / name :op1 "Caspase" :op2 "8") :xref (x1 / xref :value "UNIPROT:CASP8_HUMAN" :prob "0.682"))) :op3 (a6 / activity-06 :ARG0 (p4 / protein :name (n6 / name :op1 "Caspase" :op2 "9") :xref (x2 / xref :value "UNIPROT:CASP9_HUMAN" :prob "0.682"))) :location (m3 / model :mod (t / tumor :mod (d / disease :name (n3 / name :op1 "NSCLC"))) :ARG0-of (r / resist-01 :ARG1 (s / small-molecule :name (n7 / name :op1 "gefitinib") :xref (x3 / xref :value "PUBCHEM:123631" :prob "16.963549")))))) # ::id pmid_2493_9055.132 # ::date 2015-08-29T01:44:31 # ::file pmid_2493_9055_132.txt # ::snt In order to investigate whether AZD6244 and/or BEZ235 would induce apoptosis in gefitinib-resistant NSCLC tumor models, activity of caspase-3, 8 and 9 were measured by the colorimetric assay. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (m / measure-01 :ARG0 (a / assay-01 :mod (c / colorimetric)) :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "Caspase" :op2 "3") :xref (x2 / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.682")) :op2 (p2 / protein :name (n3 / name :op1 "Caspase" :op2 "8") :xref (x / xref :value "UNIPROT:CASP8_HUMAN" :prob "0.682")) :op3 (p3 / protein :name (n4 / name :op1 "Caspase" :op2 "9") :xref (x1 / xref :value "UNIPROT:CASP9_HUMAN" :prob "0.682"))) :purpose (i / investigate-01 :ARG1 (i2 / induce-01 :mode "interrogative" :ARG0 (a3 / and-or :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x5 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s2 / small-molecule :name (n5 / name :op1 "BEZ235") :xref (x4 / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG2 (a4 / apoptosis) :location (m5 / model :mod (t / tumor :mod (d / disease :name (n6 / name :op1 "NSCLC"))) :ARG0-of (r / resist-01 :ARG1 (s3 / small-molecule :name (n7 / name :op1 "gefitinib") :xref (x3 / xref :value "PUBCHEM:123631" :prob "16.963549"))))))) # ::id pmid_2493_9055.133 # ::date 2015-08-29T03:15:43 # ::file pmid_2493_9055_133.txt # ::snt The results showed that AZD6244 and/or BEZ235 had no effect on caspase-3, 8 and 9 activities in all three gefitinib-resistant NSCLC tumor models (Figure 7). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 15, 2015 (s2 / show-01 :ARG0 (t / thing :ARG2-of (r / result-01)) :ARG1 (a / affect-01 :polarity "-" :ARG0 (a2 / and-or :op1 (s / small-molecule :name (n / name :op1 "AZD6244") :xref (x5 / xref :value "PUBCHEM:10127622" :prob "17.762056")) :op2 (s3 / small-molecule :name (n3 / name :op1 "BEZ235") :xref (x3 / xref :value "PUBCHEM:11977753" :prob "17.394333"))) :ARG1 (a3 / and :op1 (a4 / activity-06 :ARG0 (p / protein :name (n5 / name :op1 "Caspase" :op2 "3") :xref (x2 / xref :value "UNIPROT:CASP3_HUMAN" :prob "0.682"))) :op2 (a5 / activity-06 :ARG0 (p3 / protein :name (n4 / name :op1 "Caspase" :op2 "8") :xref (x1 / xref :value "UNIPROT:CASP8_HUMAN" :prob "0.682"))) :op3 (a6 / activity-06 :ARG0 (p2 / protein :name (n6 / name :op1 "Caspase" :op2 "9") :xref (x / xref :value "UNIPROT:CASP9_HUMAN" :prob "0.682"))) :location (m / model :quant "3" :mod (t2 / tumor :mod (d2 / disease :name (n2 / name :op1 "NSCLC"))) :ARG0-of (r2 / resist-01 :ARG1 (s4 / small-molecule :name (n7 / name :op1 "gefitinib") :xref (x4 / xref :value "PUBCHEM:123631" :prob "16.963549"))) :mod (a7 / all)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7"))) # ::id pmid_2540_9876.1 # ::date 2015-09-01T04:01:25 # ::file pmid_2540_9876_1.txt # ::snt Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86 (PMID:25409876) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 25, 2015 (i2 / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SPP86") :ARG0-of (i / inhibit-01 :ARG1 (k / kinase))) :ARG1 (p / proliferate-01 :ARG0 (c / cell) :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))) :mod (i3 / in-vitro)) :ARG0-of (s / select-01) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID25409876"))) # ::id pmid_2540_9876.10 # ::date 2015-09-01T04:12:07 # ::file pmid_2540_9876_10.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2540_9876.11 # ::date 2015-09-01T04:12:39 # ::file pmid_2540_9876_11.txt # ::snt SPP86 inhibited MAPK signaling and proliferation in RET/PTC1 expressing TPC1 but not 8505C or C643 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c2 / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86")) :ARG1 (a / and :op1 (s2 / signal-07 :ARG0 (p / pathway :name (n / name :op1 "MAPK"))) :op2 (p2 / proliferate-01 :ARG0 p)) :location (c / cell-line :name (n3 / name :op1 "TPC1") :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")) :ARG3-of (e / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "RET/PTC1"))))) :ARG2 (i2 / inhibit-01 :polarity "-" :ARG0 s :ARG1 a :location (o / or :op1 (c3 / cell-line :name (n6 / name :op1 "8505C")) :op2 (c4 / cell-line :name (n7 / name :op1 "C643"))))) # ::id pmid_2540_9876.12 # ::date 2015-09-01T04:57:51 # ::file pmid_2540_9876_12.txt # ::snt In TPC1 cells, the inhibition of RET phosphorylation required co-exposure to SPP86 and the focal adhesion kinase (FAK) inhibitor PF573228. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (r / require-01 :ARG0 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")))) :ARG1 (e / expose-01 :ARG2 (a / and :op1 (s / small-molecule :name (n2 / name :op1 "SPP86")) :op2 (s2 / small-molecule :name (n4 / name :op1 "PF573228") :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "focal-adhesion-kinase") :xref (x1 / xref :value "UNIPROT:FAK1_HUMAN" :prob "0.373"))) :xref (x2 / xref :value "PUBCHEM:11612883" :prob "9.633067")))) :location (c / cell-line :name (n5 / name :op1 "TPC1"))) # ::id pmid_2540_9876.13 # ::date 2015-09-01T05:21:39 # ::file pmid_2540_9876_13.txt # ::snt In MCF7 cells, SPP86 inhibited RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK signaling and estrogen receptorα (ERα) phosphorylation, and inhibited proliferation to a similar degree as tamoxifen. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a3 / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86")) :ARG1 (a2 / and :op1 (s2 / signal-07 :ARG0 (a / and :op1 (s3 / slash :op1 (e3 / enzyme :name (n9 / name :op1 "phosphatidylinositide" :op2 "3-kinase") :xref (x1 / xref :value "UNIPROT:A8MYT4_HUMAN" :prob "0.381")) :op2 (e / enzyme :name (n4 / name :op1 "Akt") :xref (x3 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :op2 (p / pathway :name (n / name :op1 "MAPK"))) :ARG2-of (i3 / induce-01 :ARG0 (p6 / protein :name (n8 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")))) :op2 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n5 / name :op1 "estrogen-receptor-α") :xref (x2 / xref :value "UNIPROT:Q9UE35_HUMAN" :prob "0.691"))))) :op2 (i2 / inhibit-01 :ARG0 s :ARG1 (p5 / proliferate-01) :degree (d / degree :ARG1-of (r / resemble-01 :ARG2 (s5 / small-molecule :name (n6 / name :op1 "tamoxifen") :xref (x4 / xref :value "PUBCHEM:2733526" :prob "14.823483"))))) :location (c / cell-line :name (n7 / name :op1 "MCF7"))) # ::id pmid_2540_9876.14 # ::date 2015-09-01T05:36:03 # ::file pmid_2540_9876_14.txt # ::snt Interestingly, SPP86 and PF573228 inhibited RET/PTC1 and GDNF- RET induced activation of Akt and MAPK signaling to a similar degree. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / and :op1 (i / inhibit-01 :ARG0 (a2 / and :op1 (s / small-molecule :name (n2 / name :op1 "SPP86")) :op2 (s2 / small-molecule :name (n3 / name :op1 "PF573228") :xref (x1 / xref :value "PUBCHEM:11612883" :prob "9.633067"))) :ARG1 (p2 / protein :name (n4 / name :op1 "RET/PTC1"))) :op2 (i2 / induce-01 :ARG0 (p3 / protein :name (n6 / name :op1 "GDNF-RET") :xref (x / xref :value "UNIPROT:GDNF_HUMAN" :prob "0.263")) :ARG2 (a3 / activate-01 :ARG1 (s3 / signal-07 :ARG0 (a4 / and :op1 (p4 / pathway :name (n7 / name :op1 "Akt")) :op2 (p / pathway :name (n8 / name :op1 "MAPK")))) :degree (d2 / degree :ARG1-of (r2 / resemble-01)))) :ARG2-of (i3 / interest-01)) # ::id pmid_2540_9876.107 # ::date 2015-09-01T05:41:00 # ::file pmid_2540_9876_107.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2540_9876.108 # ::date 2015-09-01T05:41:29 # ::file pmid_2540_9876_108.txt # ::snt We investigated the effect of SPP86 on ERK1/2 phosphorylation in thyroid cancer derived cell lines expressing the RET/PTC1 rearrangement (TPC1), BRAFV600E (8505C) or RASG13R (C643) mutations [47, 48]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Jan 15, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "SPP86")) :ARG1 (p / phosphorylate-01 :ARG1 (s2 / slash :op1 (e / enzyme :name (n4 / name :op1 "ERK1") :xref (x3 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :location (o2 / or :op1 (c5 / cell-line :name (n12 / name :op1 "TPC1") :ARG3-of (e3 / express-03 :ARG2 (r / rearrange-01 :ARG1 (p2 / protein :name (n6 / name :op1 "RET/PTC1"))))) :op2 (c4 / cell-line :name (n2 / name :op1 "8505C") :ARG3-of (e6 / express-03 :ARG2 (e4 / enzyme :name (n9 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :op3 (c2 / cell-line :name (n11 / name :op1 "C643") :ARG3-of (e7 / express-03 :ARG2 (e5 / enzyme :name (n10 / name :op1 "RAS") :ARG2-of (m4 / mutate-01 :value "G13R") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")))) :ARG1-of (d2 / derive-01 :ARG2 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :mod (t / thyroid))))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 "47" :op2 "48"))))) # ::id pmid_2540_9876.109 # ::date 2015-09-01T05:58:33 # ::file pmid_2540_9876_109.txt # ::snt These mutations have previously been shown to induce constitutive activation of the MAPK signaling pathway in these cell lines [4749]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (s / show-01 :ARG1 (i / induce-01 :ARG0 (m / mutate-01 :mod (t / this)) :ARG2 (a / activate-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK") :ARG0-of (s2 / signal-07)) :mod (c / constitutive)) :location (c2 / cell-line :mod (t2 / this))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 "47" :op2 "49")))) :time (p4 / previous)) # ::id pmid_2540_9876.110 # ::date 2015-09-01T06:04:04 # ::file pmid_2540_9876_110.txt # ::snt Since TPC1 but not 8505C and C643 cells depend predominantly on RET/PTC1 signaling for proliferation, we hypothesized that SPP86 should only inhibit the proliferation of the former. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (h / hypothesize-01 :ARG0 (w / we) :ARG1 (r / recommend-01 :ARG1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p2 / proliferate-01 :ARG0 "c3") :mod (o / only))) :ARG1-of (c / cause-01 :ARG0 (c2 / contrast-01 :ARG1 (d / depend-01 :ARG0 (c3 / cell-line :name (n2 / name :op1 "TPC1")) :ARG1 (s / signal-07 :ARG0 (p3 / protein :name (n3 / name :op1 "RET/PTC1"))) :purpose (p4 / proliferate-01 :ARG0 c3) :ARG1-of (p5 / predominate-01)) :ARG2 (d2 / depend-01 :polarity "-" :ARG0 (a / and :op1 (c4 / cell-line :name (n4 / name :op1 "8505C")) :op2 (c5 / cell-line :name (n5 / name :op1 "C643"))) :ARG1 s :purpose (p6 / proliferate-01 :ARG0 (a2 / and :op1 c4 :op2 c5)))))) # ::id pmid_2540_9876.111 # ::date 2015-09-02T22:45:56 # ::file pmid_2540_9876_111.txt # ::snt Sorafenib, which inhibits both RET and RAF family kinases, was used as an internal control in these experiments. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (u / use-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "sorafenib") :ARG0-of (i2 / inhibit-01 :ARG1 (a / and :op1 (p / protein-family :name (n3 / name :op1 "RET")) :op2 (p2 / protein-family :name (n4 / name :op1 "RAF")))) :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG2 (c / control-01 :ARG0 s :ARG1-of (i / internal-02) :location (e3 / experiment-01 :mod (t / this)))) # ::id pmid_2540_9876.112 # ::date 2015-09-02T22:53:12 # ::file pmid_2540_9876_112.txt # ::snt SPP86 inhibits MAPK pathway activation in RET/PTC1 expressing cell lines # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 2, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86")) :ARG1 (a / activate-01 :ARG1 (p2 / pathway :name (n3 / name :op1 "MAPK"))) :location (c / cell-line :ARG3-of (e / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "RET/PTC1"))))) # ::id pmid_2540_9876.113 # ::date 2015-09-02T22:56:23 # ::file pmid_2540_9876_113.txt # ::snt As previously reported [45], SPP86 effectively inhibits ERK1/2 phosphorylation in TPC1 cells expressing the RET/PTC1 rearrangement at a concentration of 1 μM (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p / phosphorylate-01 :ARG1 (s2 / slash :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))) :location (c / cell-line :name (n4 / name :op1 "TPC1") :ARG3-of (e4 / express-03 :ARG2 (r2 / rearrange-01 :ARG1 (p2 / protein :name (n5 / name :op1 "RET/PTC1")) :quant (c2 / concentration-quantity :quant "1" :unit (m / micromolar)))))) :ARG1-of (e / effective-04) :ARG1-of (r / report-01 :time (p3 / previous) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 "45")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_2540_9876.114 # ::date 2015-09-02T23:05:26 # ::file pmid_2540_9876_114.txt # ::snt In contrast, SPP86 had no effect on ERK1/2 phosphorylation in 8505C or C643 cells (Figure 1B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (c / contrast-01 :ARG2 (a / affect-01 :polarity "-" :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p / phosphorylate-01 :ARG1 (s2 / slash :op1 (e / enzyme :name (n2 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :location (o / or :op1 (c2 / cell-line :name (n4 / name :op1 "8505C")) :op2 (c3 / cell-line :name (n5 / name :op1 "C643")))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "1C")))) # ::id pmid_2540_9876.115 # ::date 2015-09-02T23:14:23 # ::file pmid_2540_9876_115.txt # ::snt Sorafenib, which targets both RET and RAF kinases, effectively inhibited ERK1/2 phosphorylation in TPC1 cells at a concentration of 0.1 μM (Figure 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "sorafenib") :quant (c2 / concentration-quantity :quant "0.1" :unit (m / micromolar)) :ARG0-of (t / target-01 :ARG1 (a / and :op1 (p3 / protein-family :name (n3 / name :op1 "RET")) :op2 (p / protein-family :name (n4 / name :op1 "RAF")))) :xref (x2 / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG1 (p2 / phosphorylate-01 :ARG1 (s2 / slash :op1 (e2 / enzyme :name (n6 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n7 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :ARG1-of (e / effective-04) :location (c / cell-line :name (n5 / name :op1 "TPC1")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_2540_9876.116 # ::date 2015-09-02T23:22:12 # ::file pmid_2540_9876_116.txt # ::snt Sorafenib (10 μM) also inhibited ERK1/2 phosphorylation in 8505C cells, and to a lesser extent in C643 cells consistent with previous reports [49] (Figure 1B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 25, 2015 (a2 / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "sorafenib") :quant (c / concentration-quantity :quant "10" :unit (m / micromolar)) :xref (x2 / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG1 (p / phosphorylate-01 :ARG1 (s2 / slash :op1 (e / enzyme :name (n2 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :location (c2 / cell-line :name (n4 / name :op1 "8505C")) :mod (a3 / also)) :op2 (i2 / inhibit-01 :ARG0 s :ARG1 p :location (c3 / cell-line :name (n5 / name :op1 "C643")) :ARG1-of (c4 / consistent-01 :ARG2 (t / thing :ARG1-of (r / report-01) :time (p2 / previous))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 "49"))) :degree (l / less :degree (m2 / more)) :compared-to c2) :ARG1-of (d3 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "1C")))) # ::id pmid_2540_9876.117 # ::date 2015-09-02T23:55:19 # ::file pmid_2540_9876_117.txt # ::snt The differential sensitivity of 8505C and C643 cells to SPP86 and sorafenib likely results from the latter’s effect on RAF signaling [49]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (l / likely-01 :ARG1 (r / result-01 :ARG1 (a3 / affect-01 :ARG0 "s3" :ARG1 (s4 / signal-07 :ARG0 (e / enzyme :name (n6 / name :op1 "RAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")))) :ARG2 (s / sensitive-03 :ARG0 (a / and :op1 (c / cell-line :name (n2 / name :op1 "8505C")) :op2 (c2 / cell-line :name (n3 / name :op1 "C643"))) :ARG1 (a2 / and :op1 (s2 / small-molecule :name (n4 / name :op1 "SPP86")) :op2 (s3 / small-molecule :name (n5 / name :op1 "sorafenib") :xref (x1 / xref :value "PUBCHEM:216239" :prob "16.740406"))) :ARG1-of (d / differ-02))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 "49")))) # ::id pmid_2540_9876.118 # ::date 2015-09-03T00:01:38 # ::file pmid_2540_9876_118.txt # ::snt Interestingly, SPP86 induced only modest inhibition of RET/PTC1 phosphorylation Tyr1062 at a concentration of 1 μM (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86") :quant (c / concentration-quantity :quant "1" :unit (m2 / micromolar))) :ARG2 (i3 / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "1062" :name (n3 / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "RET/PTC1")) :xref (x / xref :value "PUBCHEM:1153" :prob "11.081481"))) :mod (m / modest) :mod (o / only)) :ARG2-of (i2 / interest-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1D"))) # ::id pmid_2540_9876.119 # ::date 2015-09-03T00:05:54 # ::file pmid_2540_9876_119.txt # ::snt Complete inhibition required 10 μM of SPP86 (Figure 1D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (r / require-01 :ARG0 (i / inhibit-01 :ARG1-of (c / complete-02)) :ARG1 (c2 / concentration-quantity :quant "10" :unit (m / micromolar) :quant-of (s / small-molecule :name (n / name :op1 "SPP86"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1D"))) # ::id pmid_2540_9876.120 # ::date 2015-09-03T00:08:41 # ::file pmid_2540_9876_120.txt # ::snt Thus, the ability of SPP86 to abolish ERK1/2 phosphorylation at 1 μM does not strictly correlate with its inhibition of RET phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (c2 / correlate-01 :polarity "-" :ARG1 (c3 / capable-01 :ARG1 (s / small-molecule :name (n / name :op1 "SPP86") :quant (c4 / concentration-quantity :quant "1" :unit (m / micromolar))) :ARG2 (a / abolish-01 :ARG0 s :ARG1 (p / phosphorylate-01 :ARG1 (s2 / slash :op1 (e / enzyme :name (n2 / name :op1 "ERK1") :xref (x / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2") :xref (x2 / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))))) :ARG2 (i / inhibit-01 :ARG0 s :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n4 / name :op1 "RET") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")))) :mod (s3 / strict))) # ::id pmid_2540_9876.121 # ::date 2015-09-03T00:13:39 # ::file pmid_2540_9876_121.txt # ::snt Similar observations have previously been reported with the RET inhibitor RPI-1 [28]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (r2 / report-01 :ARG1 (o / observe-01 :ARG1-of (r3 / resemble-01)) :time (p / previous) :condition (i2 / inhibit-01 :ARG0 (p2 / protein :name (n / name :op1 "RPI-1") :xref (x / xref :value "UNIPROT:RPIA_HUMAN" :prob "0.252")) :ARG1 (p4 / protein :name (n2 / name :op1 "RET") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "28")))) # ::id pmid_2540_9876.122 # ::date 2015-09-03T00:18:15 # ::file pmid_2540_9876_122.txt # ::snt SPP86 also inhibited Akt phosphorylation on Ser473 at a concentration of 1.0 μM (Figure 1E and F). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86") :quant (c / concentration-quantity :quant "1.0" :unit (m / micromolar))) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "473" :name (n3 / name :op1 "serine") :part-of (e / enzyme :name (n2 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784"))) :mod (a2 / also) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "1E") :op2 (f2 / figure :mod "1F")))) # ::id pmid_2540_9876.123 # ::date 2015-09-03T00:21:27 # ::file pmid_2540_9876_123.txt # ::snt Prolonged exposure (20 h) to 0.5- 1 μM SPP86 was also associated with a decline in cyclin D1 levels in this cell line (Figure 1E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 25, 2015 (a / associate-01 :ARG1 (e / expose-01 :ARG2 (c / concentration-quantity :quant (v / value-interval :op1 "0.5" :op2 "1") :unit (m2 / micromolar) :quant-of (s / small-molecule :name (n / name :op1 "SPP86"))) :ARG1-of (p / prolong-01) :ARG1-of (m / mean-01 :ARG2 (t / temporal-quantity :quant "20" :unit (h / hour)))) :ARG2 (d / decline-01 :ARG1 (l / level :quant-of (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D1") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001"))) :location (c2 / cell-line :mod (t2 / this))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1E")) :mod (a2 / also)) # ::id pmid_2540_9876.124 # ::date 2015-09-03T00:28:11 # ::file pmid_2540_9876_124.txt # ::snt In contrast, prolonged exposure to SPP86 did not affect ERK1/2 phosphorylation or cyclin D1 expression in 8505C and C643 cells (Figure 1G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 25, 2015 (c / contrast-01 :ARG2 (a / affect-01 :polarity "-" :ARG0 (e / expose-01 :ARG2 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1-of (p2 / prolong-01)) :ARG1 (o / or :op1 (p / phosphorylate-01 :ARG1 (s2 / slash :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003")))) :op2 (e4 / express-03 :ARG2 (p4 / protein :name (n7 / name :op1 "cyclin" :op2 "D1") :xref (x2 / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")) :ARG3 (a2 / and :op1 (c2 / cell-line :name (n5 / name :op1 "8505C")) :op2 (c3 / cell-line :name (n6 / name :op1 "C643")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1G"))) # ::id pmid_2540_9876.125 # ::date 2015-09-03T00:32:37 # ::file pmid_2540_9876_125.txt # ::snt We noted however, that prolonged exposure to SPP86 (0.5- 1.0 μM) was associated with a decrease in Akt Ser473 phosphorylation in C643 in cells (Figure 1G). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (c3 / contrast-01 :ARG2 (n / note-01 :ARG0 (w / we) :ARG1 (a / associate-01 :ARG1 (e / expose-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "SPP86") :quant (c / concentration-quantity :unit (m / micromolar) :quant (v / value-interval :op1 "0.5" :op2 "1.0"))) :ARG1-of (p2 / prolong-01)) :ARG2 (d / decrease-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "473" :name (n3 / name :op1 "serine") :part-of (e2 / enzyme :name (n4 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :xref (x1 / xref :value "PUBCHEM:5951" :prob "11.218784")) :location (c2 / cell-line :name (n5 / name :op1 "C643")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1G"))) # ::id pmid_2540_9876.126 # ::date 2015-09-03T00:39:03 # ::file pmid_2540_9876_126.txt # ::snt C643 cells express wild type RET [47]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "RET") :mod (w / wild-type) :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :ARG3 (c / cell-line :name (n / name :op1 "C643")) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 "47")))) # ::id pmid_2540_9876.127 # ::date 2015-09-03T00:41:05 # ::file pmid_2540_9876_127.txt # ::snt SPP86 may thus inhibit RET- mediated Akt activation in this cell line. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (p / possible-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")))) :location (c2 / cell-line :mod (t / this))))) # ::id pmid_2540_9876.128 # ::date 2015-09-03T00:44:20 # ::file pmid_2540_9876_128.txt # ::snt These results demonstrate that unlike sorafenib, SPP86 appears to selectively inhibit RET/PTC1- activated MAPK signaling in these cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / demonstrate-01 :ARG0 (t / thing :ARG2-of (r2 / result-01)) :ARG1 (a / appear-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86")) :ARG1 (s3 / signal-07 :ARG0 (p / pathway :name (n3 / name :op1 "MAPK")) :ARG1-of (a2 / activate-01 :ARG0 (p3 / protein :name (n4 / name :op1 "RET/PTC1")))) :manner (s2 / selective) :location (c / cell-line :mod (t2 / this)) :ARG1-of (r / resemble-01 :polarity "-" :ARG2 (s4 / small-molecule :name (n5 / name :op1 "sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")))))) # ::id pmid_2540_9876.129 # ::date 2015-09-03T00:49:38 # ::file pmid_2540_9876_129.txt # ::snt We next investigated if FAK could maintain RET phosphorylation on Tyr1062 despite the inhibition of RET autophosphorylation by SPP86 [24]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (p3 / possible-01 :mode "interrogative" :ARG1 (m / maintain-01 :ARG0 (e / enzyme :name (n2 / name :op1 "FAK") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "1062" :name (n4 / name :op1 "tyrosine") :part-of (p / protein :name (n3 / name :op1 "RET") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481"))) :concession (i2 / inhibit-01 :ARG0 (s / small-molecule :name (n5 / name :op1 "SPP86")) :ARG1 (p4 / phosphorylate-01 :ARG1 p :ARG2 p)))) :time (n / next) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 "24")))) # ::id pmid_2540_9876.130 # ::date 2015-09-03T00:55:30 # ::file pmid_2540_9876_130.txt # ::snt Exposure to 2.5 μM of the FAK inhibitor PF573228 [50] alone, did not inhibit RET phosphorylation in TPC1 cells (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i2 / inhibit-01 :polarity "-" :ARG0 (e / expose-01 :ARG2 (c / concentration-quantity :quant "2.5" :unit (m / micromolar) :quant-of (s / small-molecule :name (n / name :op1 "PF573228") :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "FAK") :xref (x1 / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003"))) :mod (a / alone) :xref (x2 / xref :value "PUBCHEM:11612883" :prob "9.633067"))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 "50")))) :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :location (c3 / cell-line :name (n4 / name :op1 "TPC1"))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2540_9876.131 # ::date 2015-09-03T01:00:07 # ::file pmid_2540_9876_131.txt # ::snt In contrast, exposure to 2.5 μM of the FAK inhibitor PF573228 in combination with 1 μM SPP86 was sufficient to inhibit RET phosphorylation on Tyr1062 (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (s2 / suffice-01 :ARG0 (e / expose-01 :ARG2 (c2 / concentration-quantity :quant "2.5" :unit (m / micromolar) :quant-of (s3 / small-molecule :name (n2 / name :op1 "PF573228") :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "FAK") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003"))) :ARG1-of (c3 / combine-01 :ARG2 (c4 / concentration-quantity :quant "1" :quant-of (s / small-molecule :name (n3 / name :op1 "SPP86")) :unit m)) :xref (x2 / xref :value "PUBCHEM:11612883" :prob "9.633067")))) :ARG1 (i2 / inhibit-01 :ARG0 e :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "1062" :name (n5 / name :op1 "tyrosine") :part-of (p2 / protein :name (n4 / name :op1 "RET") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :xref (x3 / xref :value "PUBCHEM:1153" :prob "11.081481")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A")))) # ::id pmid_2540_9876.132 # ::date 2015-09-03T01:25:07 # ::file pmid_2540_9876_132.txt # ::snt Interestingly, PF273228 and SPP86 inhibited Akt and ERK1/2 phosphorylation to a similar degree (Figure 2B and C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 3, 2015 (i / inhibit-01 :ARG0 (a / and :op1 (s / small-molecule :name (n / name :op1 "PF273228")) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"))) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "Akt") :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op2 (s3 / slash :op1 (e2 / enzyme :name (n4 / name :op1 "ERK1") :xref (x1 / xref :value "UNIPROT:MK03_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK2") :xref (x / xref :value "UNIPROT:MK01_HUMAN" :prob "1.003"))))) :ARG2-of (i2 / interest-01) :degree (d / degree :ARG1-of (r / resemble-01)) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "2B") :op2 (f2 / figure :mod "2C")))) # ::id pmid_2540_9876.133 # ::date 2015-09-03T01:29:32 # ::file pmid_2540_9876_133.txt # ::snt Exposure to PF573288 but not SPP86 was associated with a reduction of FAK Tyr576 phosphorylation (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 3, 2015 (c / contrast-01 :ARG1 (a / associate-01 :ARG1 (e / expose-01 :ARG2 (s / small-molecule :name (n / name :op1 "PF573288"))) :ARG2 (r / reduce-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :mod "576" :name (n2 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n3 / name :op1 "FAK") :xref (x / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003")) :xref (x1 / xref :value "PUBCHEM:1153" :prob "11.081481"))))) :ARG2 (a3 / associate-01 :polarity "-" :ARG1 (e3 / expose-01 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "SPP86"))) :ARG2 r) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id pmid_2540_9876.134 # ::date 2015-09-03T01:33:52 # ::file pmid_2540_9876_134.txt # ::snt Neither PF273228 nor SPP86 suppressed Src phosphorylation (Figure 2D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (s / suppress-01 :polarity "-" :ARG0 (a / and :op1 (s2 / small-molecule :name (n / name :op1 "PF273228")) :op2 (s3 / small-molecule :name (n2 / name :op1 "SPP86"))) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Src") :xref (x / xref :value "UNIPROT:SRC_HUMAN" :prob "0.604"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2D"))) # ::id pmid_2540_9876.135 # ::date 2015-09-03T01:37:03 # ::file pmid_2540_9876_135.txt # ::snt SPP86 inhibited TPC1 cell proliferation more effectively than PF573228 (49% proliferation vs. 77%) but no additive effect was observed following co-exposure to both drugs (Figure 2E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 25, 2015 (c2 / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p3 / proliferate-01 :ARG0 (c / cell-line :name (n2 / name :op1 "TPC1")) :degree (p / percentage-entity :value "49")) :ARG1-of (e / effective-04 :ARG0 s :degree (m / more) :compared-to (i2 / inhibit-01 :ARG0 (s3 / small-molecule :name (n4 / name :op1 "PF573228") :xref (x / xref :value "PUBCHEM:11612883" :prob "9.633067")) :ARG1 (p4 / proliferate-01 :ARG0 c :degree (p2 / percentage-entity :value "77"))))) :ARG2 (o / observe-01 :polarity "-" :ARG1 (a / affect-01 :ARG2 (a2 / add-02)) :ARG1-of (f2 / follow-01 :ARG2 (e2 / expose-01 :ARG2 (a3 / and :op1 s :op2 s3)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2E"))) # ::id pmid_2540_9876.136 # ::date 2015-09-03T01:45:25 # ::file pmid_2540_9876_136.txt # ::snt Our observations strongly suggested that SPP86 would selectively inhibit RET- induced proliferation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (s / suggest-01 :ARG0 (o / observe-01 :ARG0 (w / we)) :ARG1 (i / inhibit-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p / proliferate-01 :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n2 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")))) :manner (s4 / select-01)) :ARG1-of (s2 / strong-02)) # ::id pmid_2540_9876.137 # ::date 2015-09-03T01:49:44 # ::file pmid_2540_9876_137.txt # ::snt We thus compared the effect of sorafenib and SPP86 on the proliferation of TPC1, 8505C and C643 cells in media containing 0.1% serum (i.e. low culture conditions). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (c / cause-01 :ARG1 (c2 / compare-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"))) :ARG1 (p2 / proliferate-01 :ARG0 (a3 / and :op1 (c3 / cell-line :name (n3 / name :op1 "TPC1")) :op2 (c4 / cell-line :name (n4 / name :op1 "8505C")) :op3 (c5 / cell-line :name (n5 / name :op1 "C643")))) :location (m / medium :ARG0-of (c6 / contain-01 :ARG1 (p / percentage-entity :value "0.1" :quant-of (s3 / serum)) :example (c7 / condition :mod (c8 / culture :ARG1-of (l / low-04)))))))) # ::id pmid_2540_9876.138 # ::date 2015-09-03T01:54:59 # ::file pmid_2540_9876_138.txt # ::snt Under these conditions, signaling pathway activation is predominantly under the control of the respective oncogenes expressed by these cell lines. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (a / activate-01 :ARG1 (p / pathway :ARG0-of (s / signal-07)) :ARG1-of (c / control-01 :ARG0 (o / oncogene :mod (r / respective) :ARG1-of (e / express-03 :ARG3 (c2 / cell-line :mod (t / this)))) :ARG1-of (p2 / predominate-01)) :condition (t2 / this)) # ::id pmid_2540_9876.139 # ::date 2015-09-03T02:03:13 # ::file pmid_2540_9876_139.txt # ::snt C643 and TPC1 cells showed marked differential sensitivity to SPP86 (IC50, 61.5 vs 1.5 μM for C643 and TPC1 cells respectively) (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / show-01 :ARG0 (a / and :op1 (c / cell-line :name (n / name :op1 "C643")) :op2 (c2 / cell-line :name (n2 / name :op1 "TPC1"))) :ARG1 (s2 / sensitive-03 :ARG0 a :ARG1 (s3 / small-molecule :name (n3 / name :op1 "SPP86")) :ARG1-of (d / differ-02) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s3 :ARG2 "50" :ARG4 (c3 / concentration-quantity :quant "61.5" :unit (m2 / micromolar)) :location c) :op2 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s3 :ARG2 "50" :ARG4 (c4 / concentration-quantity :quant "1.5" :unit m2) :location c2))) :ARG1-of (m4 / mark-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2540_9876.140 # ::date 2015-09-03T02:10:59 # ::file pmid_2540_9876_140.txt # ::snt In contrast, 8505C cells grew poorly under low serum conditions (data not shown), but their proliferation was enhanced when exposed to doses of SPP86 from 1–10 μM (Figure 3A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Sep 17, 2015 (c / contrast-01 :ARG2 (c3 / contrast-01 :ARG1 (g / grow-01 :ARG1 (c2 / cell-line :name (n / name :op1 "8505C")) :mod (p / poor) :condition (s / serum :ARG1-of (l / low-04)) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity "-")))) :ARG2 (e / enhance-01 :ARG1 (p2 / proliferate-01 :ARG0 c2) :condition (e2 / expose-01 :ARG1 c2 :ARG2 (d3 / dose-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "SPP86") :quant (c4 / concentration-quantity :quant (v / value-interval :op1 "1" :op2 "10") :unit (m / micromolar))))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "3A"))) # ::id pmid_2540_9876.141 # ::date 2015-09-03T02:18:02 # ::file pmid_2540_9876_141.txt # ::snt Under similar conditions, the IC50 values for sorafenib were 3.1 μM, 0.28 μM, and 33.3 μM for C643, TPC1 and 8505C cells respectively (Figure 3B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (a / and :op1 (h4 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 (s / small-molecule :name (n4 / name :op1 "sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG2 "50" :ARG4 (c2 / concentration-quantity :quant "3.1" :unit (m / micromolar)) :location (c / cell-line :name (n / name :op1 "C643"))) :op2 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s :ARG2 "50" :ARG4 (c4 / concentration-quantity :quant "0.28" :unit m) :location (c3 / cell-line :name (n2 / name :op1 "TPC1"))) :op3 (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG1 s :ARG2 "50" :ARG4 (c6 / concentration-quantity :quant "33.3" :unit m) :location (c5 / cell-line :name (n3 / name :op1 "8505C"))) :condition (c7 / condition :ARG1-of (r / resemble-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id pmid_2540_9876.142 # ::date 2015-08-31T13:34:35 # ::file pmid_2540_9876_142.txt # ::snt In general, low doses of SPP86 do not inhibit the activity of signaling proteins downstream of RET or other kinases that directly interact with it [45]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (i / inhibit-01 :polarity "-" :ARG0 (d / dose-01 :ARG2 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1-of (l / low-04)) :ARG1 (a / activity-06 :ARG0 (o2 / or :op1 (p / protein :ARG0-of (s2 / signal-07) :location (r / relative-position :op1 (p2 / protein :name (n2 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :direction (d2 / downstream))) :op2 (k / kinase :mod (o / other) :ARG0-of (i2 / interact-01 :ARG1 s :ARG1-of (d3 / direct-02))))) :ARG1-of (g / general-02) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 "45")))) # ::id pmid_2540_9876.143 # ::date 2015-08-31T13:34:46 # ::file pmid_2540_9876_143.txt # ::snt SPP86 thus selectively inhibited the proliferation of TPC1 cells dependent on oncogenic RET but not 8505C and C643 cells respectively dependent on oncogenic BRAF and RAS. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / cause-01 :ARG1 (c5 / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p / proliferate-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "TPC1") :ARG0-of (d / depend-01 :ARG1 (p2 / protein :name (n3 / name :op1 "RET") :ARG0-of (c3 / cause-01 :ARG1 (c4 / cancer)) :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))))) :manner (s3 / selective)) :ARG2 (i2 / inhibit-01 :polarity "-" :ARG0 s :ARG1 (a / and :op1 (c6 / cell-line :name (n4 / name :op1 "8505C")) :op2 (c7 / cell-line :name (n5 / name :op1 "C643")) :ARG0-of (d2 / depend-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n6 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (e2 / enzyme :name (n7 / name :op1 "RAS") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :ARG0-of c3)) :mod (r / respective))))) # ::id pmid_2540_9876.144 # ::date 2015-08-31T14:01:59 # ::file pmid_2540_9876_144.txt # ::snt SPP86 inhibits RET signaling in ERα positive breast cancer cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (s2 / signal-07 :ARG0 (p / protein :name (n2 / name :op1 "RET") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))) :location (c / cell :mod (c2 / cancer :mod (b / breast)) :mod (p3 / protein :name (n3 / name :op1 "ERα") :mod (p2 / positive) :xref (x / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623")))) # ::id pmid_2540_9876.145 # ::date 2015-08-31T14:03:46 # ::file pmid_2540_9876_145.txt # ::snt In addition to its role in thyroid cancers, RET has been shown to functionally interact with ERα in human breast cancer cell lines [5, 6, 51, 52]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (s / show-01 :ARG1 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "RET") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :ARG1 (p2 / protein :name (n2 / name :op1 "ERα") :xref (x / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623")) :ARG1-of (f / function-01) :location (c / cell-line :mod (h / human) :mod (c2 / cancer :mod (b / breast)))) :ARG1-of (a / add-02 :ARG2 (r / role :topic (c3 / cancer :mod (t / thyroid)) :poss p)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 (a2 / and :op1 "5" :op2 "6" :op3 "51" :op4 "52"))))) # ::id pmid_2540_9876.146 # ::date 2015-08-31T14:20:53 # ::file pmid_2540_9876_146.txt # ::snt We thus evaluated the utility of using SPP86 to interrogate RET signaling in MCF7 breast cancer cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (c / cause-01 :ARG1 (e / evaluate-01 :ARG0 (w / we) :ARG1 (u / utility :poss (u2 / use-01 :ARG0 w :ARG1 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG2 (i / interrogate-01 :ARG0 w :ARG1 (s2 / signal-07 :ARG0 (p / protein :name (n2 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))) :location (c2 / cell-line :name (n3 / name :op1 "MCF7") :mod (c3 / cancer :mod (b / breast)))))))) # ::id pmid_2540_9876.147 # ::date 2015-08-31T14:25:18 # ::file pmid_2540_9876_147.txt # ::snt Firstly, we studied the effect of SPP86 on RET- mediated ERα phosphorylation on serine residue 167 (Ser167). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (s / study-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p / phosphorylate-01 :ARG1 (r / residue :mod (a2 / amino-acid :mod "167" :name (n4 / name :op1 "serine") :xref (x2 / xref :value "PUBCHEM:5951" :prob "11.218784")) :part-of (p2 / protein :name (n2 / name :op1 "ERα") :xref (x / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623"))) :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n3 / name :op1 "RET") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))))) :time (f / first)) # ::id pmid_2540_9876.148 # ::date 2015-08-31T14:30:28 # ::file pmid_2540_9876_148.txt # ::snt Estrogen deprived and serum starved MCF7 cells were exposed to 10 ng/ml GDNF in the absence or presence of increasing does of SPP86. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (e / expose-01 :ARG1 (c / cell-line :name (n / name :op1 "MCF7") :ARG2-of (d / deprive-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "estrogen") :xref (x1 / xref :value "PUBCHEM:5757" :prob "10.921484"))) :ARG1-of (s2 / starve-01 :ARG2 (s3 / serum))) :ARG2 (p / protein :name (n3 / name :op1 "GDNF") :quant (c2 / concentration-quantity :quant "10" :unit (n4 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:GDNF_HUMAN" :prob "1.004")) :condition (o / or :op1 (a / absent-01 :ARG1 (d2 / dose-01 :ARG2 (s4 / small-molecule :name (n5 / name :op1 "SPP86")) :ARG1-of (i / increase-01))) :op2 (p2 / present-02 :ARG1 d2))) # ::id pmid_2540_9876.149 # ::date 2015-08-31T14:45:52 # ::file pmid_2540_9876_149.txt # ::snt In these experiments, SPP86 effectively inhibited GDNF/RET- induced ERα phosphorylation at a concentration of 0.1 μM (Figure 4A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86") :quant (c / concentration-quantity :quant "0.1" :unit (m / micromolar))) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "ERα") :xref (x / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623")) :ARG2-of (i2 / induce-01 :ARG0 (p3 / pathway :name (n3 / name :op1 "GDNF/RET")))) :location (e / experiment-01 :mod (t / this)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4A")) :ARG1-of (e2 / effective-04)) # ::id pmid_2540_9876.150 # ::date 2015-08-31T14:53:18 # ::file pmid_2540_9876_150.txt # ::snt Higher concentrations of SPP86, 1–10 μM, reduced ERα phosphorylation even below baseline levels. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Sep 1, 2015 (r / reduce-01 :ARG0 (c / concentrate-02 :ARG1 (s / small-molecule :name (n / name :op1 "SPP86") :quant (c2 / concentration-quantity :quant (v / value-interval :op1 "1" :op2 "10") :unit (m2 / micromolar))) :ARG1-of (h / high-02 :degree (m / more))) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "ERα") :xref (x / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623"))) :ARG2 (b / below :op1 (l / level :mod (b2 / baseline)) :mod (e / even))) # ::id pmid_2540_9876.151 # ::date 2015-08-31T14:57:44 # ::file pmid_2540_9876_151.txt # ::snt In addition, exposure of MCF7 cells to SPP86 was associated with a moderate decrease in ERα levels in these experiments (Figure 4A) We next investigated the effect of SPP86 on RET- mediated activation of these pathways in MCF7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (m / multi-sentence :snt1 (a / associate-01 :ARG1 (e / expose-01 :ARG1 (c / cell-line :name (n / name :op1 "MCF7")) :ARG2 (s / small-molecule :name (n2 / name :op1 "SPP86"))) :ARG2 (d / decrease-01 :ARG1 (l / level :quant-of (p / protein :name (n3 / name :op1 "ERα") :xref (x1 / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623"))) :ARG2 (m2 / moderate-03)) :location (e2 / experiment-01 :mod (t / this)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A")) :ARG1-of (a4 / add-02)) :snt2 (i / investigate-01 :ARG0 (w / we) :ARG1 (a2 / affect-01 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "SPP86")) :ARG1 (a3 / activate-01 :ARG1 (p3 / pathway :mod t) :ARG1-of (m3 / mediate-01 :ARG0 (p2 / protein :name (n5 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))) :location (c2 / cell-line :name (n6 / name :op1 "MCF7")))) :time (n7 / next))) # ::id pmid_2540_9876.152 # ::date 2015-08-31T15:03:30 # ::file pmid_2540_9876_152.txt # ::snt SPP86 inhibited GDNF/ RET- induced phosphorylation of Akt and its downstream signaling at concentrations as low as 0.1 μM (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG2-of (i2 / induce-01 :ARG0 (p2 / pathway :name (n3 / name :op1 "GDNF/RET")))) :op2 (s3 / signal-07 :ARG0 e :location (d / downstream))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B")) :condition (c2 / concentration-quantity :quant "0.1" :unit (m / micromolar) :ARG1-of (l / low-04))) # ::id pmid_2540_9876.153 # ::date 2015-08-31T15:17:08 # ::file pmid_2540_9876_153.txt # ::snt We noted that SPP86 inhibited phosphorylation of Akt more effectively than that of its downstream target p70S6K at this concentration. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (n / note-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG1-of (e2 / effective-04 :degree (m / more) :compared-to (t / target-01 :ARG0 s :ARG1 (e3 / enzyme :name (n4 / name :op1 "p70S6K") :xref (x1 / xref :value "UNIPROT:KS6B1_HUMAN" :prob "0.333")) :location (d / downstream))) :condition (c / concentration-quantity :mod (t2 / this)))) # ::id pmid_2540_9876.154 # ::date 2015-08-31T15:24:08 # ::file pmid_2540_9876_154.txt # ::snt Similarly, SPP86 inhibited Akt phosphorylation at markedly lower concentrations than those required to inhibit MAPK phosphorylation (0.1 vs. 1.0 μM) (Figure 4B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4B")) :ARG1-of (r2 / resemble-01) :condition (c3 / concentration-quantity :quant "0.1" :unit (m3 / micromolar) :ARG1-of (l / low-04 :degree (m / more :degree (m4 / marked)) :compared-to (c4 / concentration-quantity :quant "1.0" :unit m3 :ARG1-of (r / require-01 :ARG2 (i2 / inhibit-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MAPK") :xref (x1 / xref :value "UNIPROT:MK01_HUMAN" :prob "0.313"))))))))) # ::id pmid_2540_9876.155 # ::date 2015-08-31T15:24:58 # ::file pmid_2540_9876_155.txt # ::snt SPP86 effectively inhibited GDNF- induced RET phosphorylation Tyr1062 at a concentration of 1.0 μM. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86") :quant (c / concentration-quantity :quant "1.0" :unit (m / micromolar))) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod "1062" :name (n4 / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :xref (x2 / xref :value "PUBCHEM:1153" :prob "11.081481")) :ARG2-of (i2 / induce-01 :ARG0 (p3 / protein :name (n3 / name :op1 "GDNF") :xref (x1 / xref :value "UNIPROT:GDNF_HUMAN" :prob "1.004")))) :ARG1-of (e / effective-04)) # ::id pmid_2540_9876.156 # ::date 2015-09-01T12:41:21 # ::file pmid_2540_9876_156.txt # ::snt In contrast, FAK inhibition with PF573228 only moderately inhibited RET phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (i / inhibit-01 :ARG0 (i2 / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "PF573228") :xref (x2 / xref :value "PUBCHEM:11612883" :prob "9.633067")) :ARG1 (e / enzyme :name (n2 / name :op1 "FAK") :xref (x1 / xref :value "UNIPROT:FAK1_HUMAN" :prob "1.003"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))) :ARG1-of (m / moderate-03 :mod (o / only)))) # ::id pmid_2540_9876.157 # ::date 2015-09-01T12:46:41 # ::file pmid_2540_9876_157.txt # ::snt Co- exposure to PF573228 and SPP86 however, exerted an additive inhibitory effect on RET phosphorylation (Figure 4C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / have-concession-91 :ARG1 (e / exert-01 :ARG0 (c / coexpose-00 :ARG2 (a / and :op1 (s / small-molecule :name (n / name :op1 "PF573228") :xref (x1 / xref :value "PUBCHEM:11612883" :prob "9.633067")) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86")))) :ARG1 (a2 / affect-01 :ARG0 c :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))) :ARG2 (i / inhibit-01) :ARG1-of (a3 / add-02))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id pmid_2540_9876.158 # ::date 2015-09-01T13:02:40 # ::file pmid_2540_9876_158.txt # ::snt Both PF573228 and SPP86 inhibited GDNF- induced ERK1/2 and Akt phosphorylation (Figure 4C and Additional file 1A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (i / inhibit-01 :ARG0 (a / and :op1 (s / small-molecule :name (n / name :op1 "PF573228") :xref (x2 / xref :value "PUBCHEM:11612883" :prob "9.633067")) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"))) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n3 / name :op1 "ERK1/2")) :op2 (e2 / enzyme :name (n4 / name :op1 "Akt") :xref (x1 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203"))) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n5 / name :op1 "GDNF") :xref (x / xref :value "UNIPROT:GDNF_HUMAN" :prob "1.004")))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "4C") :op2 (f2 / file :mod "1A" :ARG1-of (a4 / add-02))))) # ::id pmid_2540_9876.159 # ::date 2015-09-01T13:07:39 # ::file pmid_2540_9876_159.txt # ::snt Prolonged exposure of MCF7 cells to SPP86 also lead to the suppression of cyclin D1 expression (Figure 4D). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (l / lead-03 :ARG0 (e / expose-01 :ARG1 (c / cell-line :name (n / name :op1 "MCF7")) :ARG2 (s / small-molecule :name (n2 / name :op1 "SPP86")) :ARG1-of (p / prolong-01)) :ARG2 (s2 / suppress-01 :ARG0 e :ARG1 (e2 / express-03 :ARG1 (p2 / protein :name (n3 / name :op1 "cyclin" :op2 "D1") :xref (x / xref :value "UNIPROT:Q9H014_HUMAN" :prob "1.001")))) :mod (a / also) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4D"))) # ::id pmid_2540_9876.160 # ::date 2015-09-01T13:12:05 # ::file pmid_2540_9876_160.txt # ::snt We next compared the effects of sorafenib and SPP86 on PI3K/Akt and MAPK pathway signaling, with a view to discriminate the direct effects of RET inhibition from those of a combined inhibition of RET and RAF. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 25, 2015 (c / compare-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "sorafenib") :xref (x1 / xref :value "PUBCHEM:216239" :prob "16.740406")) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"))) :ARG1 (s3 / signal-07 :ARG0 (a3 / and :op1 (p / pathway :name (n3 / name :op1 "PI3K/Akt")) :op2 (p2 / pathway :name (n4 / name :op1 "MAPK"))))) :purpose (d / discriminate-01 :ARG0 w :ARG1 (a5 / and :op1 (a4 / affect-01 :ARG0 (i / inhibit-01 :ARG1 (p3 / protein :name (n5 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))) :ARG1-of (d2 / direct-02)) :op2 (a6 / affect-01 :ARG0 (i2 / inhibit-01 :ARG1 (a7 / and :op1 p3 :op2 (p5 / protein-family :name (n7 / name :op1 "RAF"))) :ARG1-of (c2 / combine-01))))) :time (n8 / next)) # ::id pmid_2540_9876.161 # ::date 2015-09-01T13:23:36 # ::file pmid_2540_9876_161.txt # ::snt In these experiments, estrogen deprived and serum starved MCF7 cells were exposed to 10 ng/ml GDNF alone or in the presence of either sorafenib or SPP86. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (e / expose-01 :ARG1 (c / cell-line :name (n / name :op1 "MCF7") :ARG2-of (d / deprive-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "estrogen") :xref (x2 / xref :value "PUBCHEM:5757" :prob "10.921484"))) :ARG1-of (s2 / starve-01 :ARG2 (s3 / serum))) :ARG2 (p / protein :name (n3 / name :op1 "GDNF") :quant (c2 / concentration-quantity :quant "10" :unit (n4 / nanogram-per-milliliter)) :xref (x / xref :value "UNIPROT:GDNF_HUMAN" :prob "1.004")) :manner (o / or :op1 (a / alone) :op2 (p2 / present-02 :ARG1 (o2 / or :op1 (s4 / small-molecule :name (n5 / name :op1 "sorafenib") :xref (x1 / xref :value "PUBCHEM:216239" :prob "16.740406")) :op2 (s5 / small-molecule :name (n6 / name :op1 "SPP86"))))) :location (e2 / experiment-01 :mod (t / this))) # ::id pmid_2540_9876.162 # ::date 2015-09-01T13:33:49 # ::file pmid_2540_9876_162.txt # ::snt Analyses of the relative levels of phosphorylated Akt and ERK1/2 demonstrated that both compounds effectively block GDNF- induced RET signaling at concentrations as low as 1 μM (Figure 4E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (d / demonstrate-01 :ARG0 (a / analyze-01 :ARG1 (a2 / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "Akt") :ARG3-of (p / phosphorylate-01) :xref (x2 / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :ARG1-of (r / relative-05)) :op2 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of p) :ARG1-of r))) :ARG1 (b / block-01 :ARG0 (c / compound :mod (b2 / both) :quant (c2 / concentration-quantity :quant "1" :unit (m / micromolar) :ARG1-of (l3 / low-04))) :ARG1 (s / signal-07 :ARG0 (p2 / protein :name (n3 / name :op1 "RET") :xref (x / xref :value "UNIPROT:RET_HUMAN" :prob "1.004")) :ARG2-of (i / induce-01 :ARG0 (p3 / protein :name (n4 / name :op1 "GDNF") :xref (x1 / xref :value "UNIPROT:GDNF_HUMAN" :prob "1.004")))) :ARG1-of (e3 / effective-04)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4E"))) # ::id pmid_2540_9876.163 # ::date 2015-09-01T13:45:51 # ::file pmid_2540_9876_163.txt # ::snt We noted however, that sorafenib inhibited Akt and ERK1/2 slightly more effectively than SPP86 under these conditions (Figure 4E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (h / have-concession-91 :ARG1 (n / note-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "sorafenib") :xref (x1 / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "Akt") :xref (x / xref :value "UNIPROT:AKT1_HUMAN" :prob "0.203")) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK1/2"))) :ARG1-of (e2 / effective-04 :degree (m / more :degree (s2 / slight)) :compared-to (s3 / small-molecule :name (n4 / name :op1 "SPP86"))) :condition (c / condition :mod (t / this)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4E"))) # ::id pmid_2540_9876.164 # ::date 2015-09-01T13:52:38 # ::file pmid_2540_9876_164.txt # ::snt These differential effects on PI3K/Akt and MAPK signaling may result may stem from the fact that sorafenib and SPP86 target different kinases at low concentrations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / possible-01 :ARG1 (s / stem-01 :ARG1 (a / affect-01 :ARG1 (s2 / signal-07 :ARG0 (a2 / and :op1 (p2 / pathway :name (n / name :op1 "PI3K/Akt")) :op2 (p3 / pathway :name (n2 / name :op1 "MAPK")))) :mod (d / differential) :mod (t / this)) :ARG2 (t2 / target-01 :ARG0 (a3 / and :op1 (s3 / small-molecule :name (n3 / name :op1 "sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :op2 (s4 / small-molecule :name (n4 / name :op1 "SPP86"))) :ARG1 (k / kinase :ARG1-of (d2 / differ-02)) :condition (c / concentration-quantity :ARG1-of (l / low-04))))) # ::id pmid_2540_9876.165 # ::date 2015-09-01T14:03:25 # ::file pmid_2540_9876_165.txt # ::snt The enhanced inhibition of MAPK signaling observed with sorafenib may also result from the fact that it targets both RET and RAF family kinases [37, 45]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (p / possible-01 :ARG1 (r / result-01 :ARG1 (t / target-01 :ARG0 "s2" :ARG1 (a / and :op1 (p3 / protein-family :name (n3 / name :op1 "RET")) :op2 (p4 / protein-family :name (n4 / name :op1 "RAF")))) :ARG2 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "sorafenib") :xref (x / xref :value "PUBCHEM:216239" :prob "16.740406")) :ARG1 (s / signal-07 :ARG0 (p2 / pathway :name (n / name :op1 "MAPK"))) :ARG1-of (e / enhance-01) :ARG1-of (o / observe-01))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op2 "37" :op2 "45")))) :mod (a3 / also)) # ::id pmid_2540_9876.166 # ::date 2015-09-01T14:15:02 # ::file pmid_2540_9876_166.txt # ::snt Since these observations suggested that SPP86 disrupts ERα- RET crosstalk, we investigated the effect of SPP86 on the proliferation of MCF7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (i / investigate-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p / proliferate-01 :ARG0 (c / cell-line :name (n2 / name :op1 "MCF7")))) :ARG1-of (c2 / cause-01 :ARG0 (s2 / suggest-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (d / disrupt-01 :ARG0 s :ARG1 (c3 / crosstalk-00 :ARG1 (p2 / protein :name (n3 / name :op1 "ERα") :xref (x / xref :value "UNIPROT:ESR1_HUMAN" :prob "0.623")) :ARG2 (p3 / protein :name (n4 / name :op1 "RET") :xref (x1 / xref :value "UNIPROT:RET_HUMAN" :prob "1.004"))))))) # ::id pmid_2540_9876.167 # ::date 2015-09-01T14:22:15 # ::file pmid_2540_9876_167.txt # ::snt Estrogen deprived and serum starved cells were cultured in the presence of 1 ng/ml β- estradiol (E2) or 10 ng/ml GDNF alone and in combination in the presence of 1 μM SPP86 for 7 days. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (c / culture-01 :ARG1 (c2 / cell :ARG2-of (d / deprive-01 :ARG1 (s / small-molecule :name (n / name :op1 "estrogen") :xref (x2 / xref :value "PUBCHEM:5757" :prob "10.921484"))) :ARG1-of (s2 / starve-01 :ARG2 (s3 / serum))) :manner (a2 / and :op1 (p2 / present-02 :ARG1 (o / or :op1 (s4 / small-molecule :name (n2 / name :op1 "β-estradiol") :quant (c3 / concentration-quantity :quant "1" :unit (n3 / nanogram-per-milliliter)) :xref (x1 / xref :value "PUBCHEM:5757" :prob "13.090267")) :op2 (p / protein :name (n4 / name :op1 "GDNF") :quant (c4 / concentration-quantity :quant "10" :unit n3) :xref (x / xref :value "UNIPROT:GDNF_HUMAN" :prob "1.004"))) :mod (a / alone)) :op2 (p3 / present-02 :ARG1 (s5 / small-molecule :name (n5 / name :op1 "SPP86") :quant (c5 / concentration-quantity :quant "1" :unit (m / micromolar))) :mod (c6 / combine-01))) :duration (t / temporal-quantity :quant "7" :unit (d2 / day))) # ::id pmid_2540_9876.168 # ::date 2015-09-01T14:39:04 # ::file pmid_2540_9876_168.txt # ::snt SPP86 effectively inhibited E2 and/or GDNF- induced proliferation (p <0.05) (Figure 5A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p2 / proliferate-01 :ARG2-of (i2 / induce-01 :ARG0 (a / and-or :op1 (s2 / small-molecule :name (n2 / name :op1 "E2") :xref (x1 / xref :value "PUBCHEM:5757" :prob "13.96532")) :op2 (p / protein :name (n3 / name :op1 "GDNF") :xref (x / xref :value "UNIPROT:GDNF_HUMAN" :prob "1.004"))))) :ARG1-of (e / effective-04) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A")) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) # ::id pmid_2540_9876.169 # ::date 2015-09-01T14:47:26 # ::file pmid_2540_9876_169.txt # ::snt In contrast, SPP86 did not inhibit proliferation when MCF7 cells were co-exposed to 1 ng/ml E2 and 5 ng/insulin under similar conditions (Figure 5B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / contrast-01 :ARG2 (i / inhibit-01 :polarity "-" :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")) :ARG1 (p / proliferate-01) :condition (c2 / coexpose-00 :ARG1 (c3 / cell-line :name (n2 / name :op1 "MCF7")) :ARG2 (a / and :op1 (s2 / small-molecule :name (n3 / name :op1 "E2") :quant (c4 / concentration-quantity :quant "1" :unit (n4 / nanogram-per-milliliter)) :xref (x1 / xref :value "PUBCHEM:5757" :prob "13.96532")) :op2 (p2 / protein :name (n5 / name :op1 "insulin") :quant (c5 / concentration-quantity :quant "5" :unit n4) :xref (x / xref :value "UNIPROT:INS_HUMAN" :prob "0.703"))) :condition (c6 / condition :ARG1-of (r / resemble-01)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id pmid_2540_9876.170 # ::date 2015-09-01T14:53:57 # ::file pmid_2540_9876_170.txt # ::snt We next compared the effect of SPP86 and tamoxifen on the proliferation of MCF7 cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / compare-01 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (a2 / and :op1 (s / small-molecule :name (n / name :op1 "SPP86")) :op2 (s2 / small-molecule :name (n2 / name :op1 "tamoxifen") :xref (x / xref :value "PUBCHEM:2733526" :prob "14.823483"))) :ARG1 (p / proliferate-01 :ARG0 (c2 / cell-line :name (n3 / name :op1 "MCF7")))) :time (n4 / next)) # ::id pmid_2540_9876.171 # ::date 2015-09-01T14:56:00 # ::file pmid_2540_9876_171.txt # ::snt Estrogen deprived and serum starved cells were cultured in the presence of 1 ng/ml β- estradiol (E2) and 10 ng/ml GDNF with increasing doses of either SPP86 or tamoxifen, in medium containing 1 ng/ml β- estradiol (E2) and 10 ng/ml GDNF and incubated for 7 days. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Sep 16, 2015 (a3 / and :op1 (c / culture-01 :ARG1 (c2 / cell :ARG2-of (d / deprive-01 :ARG1 (s / small-molecule :name (n / name :op1 "estrogen") :xref (x3 / xref :value "PUBCHEM:5757" :prob "10.921484"))) :ARG1-of (s2 / starve-01 :ARG2 (s3 / serum))) :manner (a2 / and :op1 (p2 / present-02 :ARG1 (a / and :op1 (s4 / small-molecule :name (n2 / name :op1 "β-estradiol") :quant (c3 / concentration-quantity :quant "1" :unit (n3 / nanogram-per-milliliter)) :xref (x2 / xref :value "PUBCHEM:5757" :prob "13.090267")) :op2 (p / protein :name (n4 / name :op1 "GDNF") :quant (c4 / concentration-quantity :quant "10" :unit n3) :xref (x / xref :value "UNIPROT:GDNF_HUMAN" :prob "1.004")))) :op2 (d2 / dose-01 :ARG2 (o / or :op1 (s5 / small-molecule :name (n5 / name :op1 "SPP86")) :op2 (s6 / small-molecule :name (n6 / name :op1 "tamoxifen") :xref (x1 / xref :value "PUBCHEM:2733526" :prob "14.823483"))) :ARG1-of (i / increase-01))) :location (m / medium :ARG0-of (c5 / contain-01 :ARG1 a))) :op2 (i2 / incubate-01 :ARG1 c2 :duration (t / temporal-quantity :quant "7" :unit (d3 / day)))) # ::id pmid_2540_9876.172 # ::date 2015-09-01T15:08:49 # ::file pmid_2540_9876_172.txt # ::snt In these experiments, SPP86 and tamoxifen inhibited proliferation to a similar degree with IC50 values of 1.0 and 1.4 μM respectively (Figure 5C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Nov 25, 2015 (i / inhibit-01 :ARG0 (a / and :op1 (s / small-molecule :name (n / name :op1 "SPP86")) :op2 (s2 / small-molecule :name (n2 / name :op1 "tamoxifen") :xref (x / xref :value "PUBCHEM:2733526" :prob "14.823483"))) :ARG1 (p / proliferate-01) :degree (r / resemble-01 :ARG2 (a3 / and :op1 (v / value :mod (c3 / concentrate-02 :ARG1-of (e / equal-01 :ARG2 (c / concentration-quantity :quant "1.0" :unit (m / micromolar))) :mod (i2 / inhibit-01 :degree (p2 / percentage-entity :value "50")))) :op2 (v2 / value :mod (c4 / concentrate-02 :ARG1-of (e3 / equal-01 :ARG2 (c2 / concentration-quantity :quant "1.4" :unit m)) :mod i2)) :mod (r2 / respective))) :location (e2 / experiment-01 :mod (t2 / this)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id pmid_2541_3220.1 # ::date 2015-07-01T13:00:16 # ::file pmid_2541_3220_1.txt # ::snt Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses (PMID:25413220) # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "ERK")) :mod (c / constitutive) :location (a2 / and :op1 (m / medical-condition :name (n3 / name :op1 "melanoma")) :op2 (m2 / melanocyte :mod (s / skin)) :location (h / horse :ARG1-of (g / gray-02))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG8 (p3 / pmid :mod "25413220")))) # ::id pmid_2541_3220.12 # ::date 2015-07-01T13:10:39 # ::file pmid_2541_3220_12.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2541_3220.13 # ::date 2015-07-01T13:12:15 # ::file pmid_2541_3220_13.txt # ::snt We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "ERK")) :manner (c / constitutive) :location (a2 / and :op1 (t / tumor :mod (m / medical-condition :name (n8 / name :op1 "melanoma"))) :op2 (c2 / cell-line) :mod (h / horse :ARG1-of (g6 / gray-02))) :condition (o / or :op1 (a6 / absent-01 :ARG1 (m2 / mutate-01 :ARG1 (a4 / and :op1 (g / gene :name (n3 / name :op1 "BRAF") :xref (x4 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (g2 / gene :name (n4 / name :op1 "RAS") :xref (x3 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :op3 (g3 / gene :name (n5 / name :op1 "GNAQ") :xref (x2 / xref :value "UNIPROT:GNAQ_HUMAN" :prob "1.004")) :op4 (g4 / gene :name (n6 / name :op1 "GNA11") :xref (x1 / xref :value "UNIPROT:GNA11_HUMAN" :prob "1.004")) :op5 (g5 / gene :name (n7 / name :op1 "KIT") :xref (x / xref :value "UNIPROT:KIT_HUMAN" :prob "1.004"))) :ARG0-of (a3 / activate-01) :mod (s / somatic))) :op2 (a5 / alter-01 :ARG1 (e / express-03 :ARG2 (c3 / component :mod (m3 / main) :part-of p)))))) # ::id pmid_2541_3220.14 # ::date 2015-07-01T13:33:03 # ::file pmid_2541_3220_14.txt # ::snt The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Jan 12, 2016 (a / and :op1 (m / mitogenic :domain (p / pathway)) :op2 (m2 / mediate-01 :ARG0 (a2 / and :op1 (k / kinase :wiki "-" :name (n / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (k2 / kinase :wiki "C-Raf" :name (n2 / name :op1 "CRAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op3 (k3 / kinase :wiki "KRAS" :name (n3 / name :op1 "KRAS") :xref (x2 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG1 p)) # ::id pmid_2541_3220.15 # ::date 2015-07-01T13:37:00 # ::file pmid_2541_3220_15.txt # ::snt Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (f / find-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "ERK")) :ARG1-of (h / high-02) :location (m / melanocyte :mod (e / epidermis)) :mod (a2 / also)) :mod (i / important) :ARG0-of (s / suggest-01 :ARG1 (p2 / predispose-01 :ARG1 (h2 / horse :mod (t / this)) :ARG2 (m2 / melanomagenesis) :ARG1-of (g / general-02)))) # ::id pmid_2541_3220.98 # ::date 2015-07-01T13:45:00 # ::file pmid_2541_3220_98.txt # ::snt Results # ::preferred # ::annotator SDL-AMR-09 # ::save-date Wed Jul 1, 2015 (t / thing :ARG2-of (r / result-01)) # ::id pmid_2541_3220.99 # ::date 2015-07-01T13:45:37 # ::file pmid_2541_3220_99.txt # ::snt ERK1/2 activation in Grey horse melanomas # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (m / medical-condition :name (n3 / name :op1 "melanoma") :mod (h / horse :ARG1-of (g / gray-02)))) # ::id pmid_2541_3220.100 # ::date 2015-07-01T13:48:35 # ::file pmid_2541_3220_100.txt # ::snt Given the importance of the MAPK/ERK pathway activation in melanoma development, we examined the levels of the activated (phosphorylated) ERK1/2 (P-ERK1/2) in primary cutaneous melanoma tumours from Grey (n = 19) and non-Grey (n = 12) horses of different breeds from three geographic locations across Europe by indirect immunofluorescence, using an anti-MITF antibody to mark melanocytic lineage [23]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Tue Feb 2, 2016 (e / examine-01 :ARG0 (w / we) :ARG1 (l / level :mod (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01) :ARG1-of (a / activate-01)) :location (t / tumor :mod (p4 / primary) :mod (c / cutis) :location (a5 / and :op1 (h / horse :quant "19" :ARG1-of (g / gray-02)) :op2 (h2 / horse :quant "12" :ARG1-of (g3 / gray-02 :polarity "-")) :ARG1-of (b / breed-01 :ARG1-of (d2 / differ-02)) :source (l2 / location :quant "3" :mod (g2 / geography) :location (a2 / across :op1 (c2 / continent :wiki "Europe" :name (n5 / name :op1 "Europe"))))) :mod (m / medical-condition :name (n2 / name :op1 "melanoma")))) :manner (i / immunofluoresce-01 :mod (i2 / indirect)) :manner (u / use-01 :ARG0 w :ARG1 (a3 / antibody :ARG0-of (c3 / counter-01 :ARG1 (p5 / protein :name (n6 / name :op1 "MITF") :xref (x / xref :value "UNIPROT:MITF_HUMAN" :prob "1.003")))) :ARG2 (m2 / mark-02 :ARG0 w :ARG1 (l3 / lineage :mod (m3 / melanocyte))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "23")))) :ARG1-of (c5 / cause-01 :ARG0 (i3 / importance :domain (a4 / activate-01 :ARG1 (p7 / pathway :name (n7 / name :op1 "MAPK/ERK")) :purpose (d4 / develop-01 :ARG2 m))))) # ::id pmid_2541_3220.101 # ::date 2015-07-01T14:25:57 # ::file pmid_2541_3220_101.txt # ::snt All the tumours expressed nuclear and occasionally cytoplasmic P-ERK1/2, however, both signals were by far more abundant in the GHM samples (80.2% ±8.5 vs. 7.6% ±21.3 in Grey and non-grey MITF+ cells, respectively; Figure 1A, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (h / have-concession-91 :ARG1 (a3 / abundant :domain (s / signal-07 :mod (b / both) :quant (b5 / between :op1 (p / percentage-entity :value "80.2" :ARG2-of (a6 / add-02 :ARG1 (p4 / percentage-entity :value "8.5"))) :op2 (p5 / percentage-entity :value "80.2" :ARG2-of (s3 / subtract-01 :ARG1 p4)) :compared-to (s4 / signal-07 :quant (b4 / between :op1 (p2 / percentage-entity :value "7.6" :ARG2-of (a7 / add-02 :ARG1 (p6 / percentage-entity :value "21.3"))) :op2 (p7 / percentage-entity :value "7.6" :ARG2-of (s5 / subtract-01 :ARG1 p6)) :location (c3 / cell :mod "p3" :mod (o / organism :ARG1-of (g2 / gray-02 :polarity "-"))))) :location (c2 / cell :mod (p3 / protein :name (n4 / name :op1 "MITF") :xref (x / xref :value "UNIPROT:MITF_HUMAN" :prob "1.003")) :mod (o3 / organism :ARG1-of (g / gray-02))))) :degree (m / more :degree (b2 / by-far)) :location (s2 / sample-01 :ARG1 (d / disease :name (n3 / name :op1 "GHM"))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "A") :op2 (f2 / figure :mod "B") :part-of (f3 / figure :mod "1")))) :ARG2 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK1/1") :ARG3-of (p9 / phosphorylate-01) :mod (n9 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :mod (c4 / cytoplasma :frequency (o2 / occasional))) :ARG3 (t / tumor :mod (a / all)))) # ::id pmid_2541_3220.102 # ::date 2015-07-01T15:00:10 # ::file pmid_2541_3220_102.txt # ::snt Although non-grey melanomas were much more heterogeneous for the P-ERK1/2 staining than the Grey counterparts, the quantitative difference between the signals reached statistical significance (P <0.001). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / have-concession-91 :ARG1 (r / reach-01 :ARG0 (d3 / differ-02 :ARG1 (s2 / signal-07) :mod (q / quantity)) :ARG1 (s3 / significance :mod (s4 / statistics) :value (l / less-than :op1 "0.001"))) :ARG2 (h2 / heterogeneity :degree (m / more :mod (m2 / much)) :prep-for (s / stain-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :compared-to (h3 / heterogeneity :domain (m3 / medical-condition :name (n / name :op1 "melanoma") :mod (o / organism :ARG1-of (g / gray-02)))) :domain (m4 / medical-condition :name (n5 / name :op1 "melanoma") :mod (o2 / organism :ARG1-of (g2 / gray-02 :polarity "-"))))) # ::id pmid_2541_3220.103 # ::date 2015-07-01T15:15:46 # ::file pmid_2541_3220_103.txt # ::snt The total ERK1/2 signal was similarly heterogeneous in both Grey and non-grey samples (71.2 ± 17.4 vs. 50.5% ±13.0 in MITF+ cells of the respective melanoma type; Figure 1A, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (h / heterogeneity :domain (s / signal-07 :ARG0 (e / enzyme :name (n / name :op1 "ERK1/2")) :mod (t / total) :location (a2 / and :op1 (t3 / thing :ARG1-of (s2 / sample-01 :ARG2 (o / organism :ARG1-of (g / gray-02)))) :op2 (t4 / thing :ARG1-of (s3 / sample-01 :ARG2 (o2 / organism :ARG1-of (g2 / gray-02 :polarity "-")))))) :ARG1-of (r / resemble-01) :quant (b / between :op1 (p3 / percentage-entity :value "71.2" :ARG2-of (a3 / add-02 :ARG1 (p4 / percentage-entity :value "17.4"))) :op2 (p5 / percentage-entity :ARG2-of (s4 / subtract-01 :ARG1 p4)) :compared-to (s5 / signal-07 :quant (b2 / between :op1 (p / percentage-entity :value "50.5" :ARG2-of (a4 / add-02 :ARG1 (p6 / percentage-entity :value "13.0"))) :op2 (p7 / percentage-entity :ARG2-of (s6 / subtract-01 :ARG1 p6)))) :location (c / cell :mod (p2 / protein :name (n3 / name :op1 "MITF") :xref (x / xref :value "UNIPROT:MITF_HUMAN" :prob "1.003")) :source (m / medical-condition :name (n5 / name :op1 "melanoma") :ARG1-of (t2 / type-03 :mod (r2 / respective)))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "A") :op2 (f2 / figure :mod "B") :part-of (f3 / figure :mod "1"))))) # ::id pmid_2541_3220.104 # ::date 2015-07-01T15:28:09 # ::file pmid_2541_3220_104.txt # ::snt In line with the elevated P-ERK1/2 levels in the GHM tissues, high P-ERK1/2 levels were detected in two GHM cell lines, HoMel-L1 and HoMel-A1, established from a primary and metastatic melanoma tumour of a Grey Lipizzaner and Arabian horse, respectively [24]. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / detect-01 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p3 / phosphorylate-01)) :ARG1-of (h / high-02) :ARG2-of (a4 / align-01 :ARG1 (l2 / level :ARG1-of (e3 / elevate-01) :location (t2 / tissue :mod (d5 / disease :name (n7 / name :op1 "GHM"))) :quant-of e))) :location (c / cell-line :quant "2" :ARG2-of (i / include-91 :ARG1 (a / and :op1 (c2 / cell-line :name (n3 / name :op1 "HoMel-L1")) :op2 (c3 / cell-line :name (n4 / name :op1 "HoMel-A1")) :ARG1-of (e2 / establish-01 :source (a3 / and :op1 (t / tumor :mod (p / primary) :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma")) :part-of (o3 / organism :name (n5 / name :op1 "Grey" :op2 "Lipizzaner" :op3 "horse"))) :op2 (t3 / tumor :mod (m / metastasis) :mod m2 :part-of (o4 / organism :name (n6 / name :op1 "Arabian" :op2 "horse"))))))) :mod d5) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 "24")))) # ::id pmid_2541_3220.105 # ::date 2015-07-01T15:48:38 # ::file pmid_2541_3220_105.txt # ::snt The P-ERK1/2 levels were comparable to those seen in human melanoma cell lines with oncogenic BRAF or NRAS mutations, in contrast to a cell line with wild-type BRAF and NRAS (Figure 1C, D; Table 1). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c4 / comparable-03 :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :ARG2 (l2 / level :ARG1-of (s / see-01 :location (c / cell-line :mod (h / human) :mod (o / or :op1 (m2 / mutate-01 :ARG1 (e5 / enzyme :name (n3 / name :op1 "BRAF") :ARG0-of (c5 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (m3 / mutate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "NRAS") :ARG0-of c5 :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))) :ARG1-of (c2 / contrast-01 :ARG2 (c3 / cell-line :mod (e3 / enzyme :name (n5 / name :op1 "BRAF") :mod (w / wild-type) :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (e2 / enzyme :name (n6 / name :op1 "NRAS") :mod w :xref (x3 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")))) :mod (m / medical-condition :name (n7 / name :op1 "melanoma"))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (a3 / and :op1 (f / figure :mod "C") :op2 (f2 / figure :mod "D") :part-of (f3 / figure :mod "1")) :op2 (t / table :mod "1")))) # ::id pmid_2541_3220.106 # ::date 2015-07-01T16:03:07 # ::file pmid_2541_3220_106.txt # ::snt ERK1/2 was activated even in the absence of serum and serum addition had a minimal stimulatory effect on the P-ERK1/2 levels (Additional file 2: Figure S1A, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / and :op1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :concession (a7 / absent-01 :ARG1 (s / serum))) :op2 (a3 / affect-01 :ARG0 (a4 / add-02 :ARG1 s) :ARG1 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :ARG2 (s2 / stimulate-01 :ARG1-of (m / minimal-02))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "A") :op2 (f2 / figure :mod "B") :part-of (f3 / figure :mod "S1" :part-of (f4 / file :mod "2" :mod (a6 / additional)))))) # ::id pmid_2541_3220.107 # ::date 2015-07-01T17:00:17 # ::file pmid_2541_3220_107.txt # ::snt MEK/ERK module is required for growth of Grey horse melanoma cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (r / require-01 :ARG0 (g / grow-01 :ARG1 (c / cell :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma") :mod (h / horse :ARG1-of (g2 / gray-02))))) :ARG1 (m / module :mod (p / pathway :name (n / name :op1 "MEK/ERK")))) # ::id pmid_2541_3220.108 # ::date 2015-07-01T23:50:56 # ::file pmid_2541_3220_108.txt # ::snt To assess the involvement of the ERK pathway in proliferation of the GHM cells, we treated the HoMel-L1 and HoMel-A1 cell lines with U0126, a specific inhibitor of MEK1/2 and therefore ERK phosphorylation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (t / treat-04 :ARG0 (w / we) :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "HoMel-L1")) :op2 (c2 / cell-line :name (n2 / name :op1 "HoMel-A1"))) :ARG2 (s / small-molecule :name (n3 / name :op1 "U0126") :ARG1-of (m2 / mean-01 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "MEK1/2")) :ARG0-of (c4 / cause-01 :ARG1 (i3 / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 "p2")))) :ARG1-of (s2 / specific-02))) :xref (x / xref :value "PUBCHEM:3006531" :prob "17.656696")) :purpose (a3 / assess-01 :ARG0 w :ARG1 (i2 / involve-01 :ARG1 (p2 / pathway :name (n6 / name :op1 "ERK")) :ARG2 (p3 / proliferate-01 :ARG0 (c3 / cell :mod (d / disease :name (n7 / name :op1 "GHM"))))))) # ::id pmid_2541_3220.109 # ::date 2015-07-02T00:05:03 # ::file pmid_2541_3220_109.txt # ::snt Western blot analysis showed an expected decrease in P-ERK1/2 in both cell lines upon the treatment (Figure 2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 13, 2015 (s / show-01 :ARG0 (a / analyze-01 :manner (i / immunoblot-01)) :ARG1 (d / decrease-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :location (c / cell-line :mod (b2 / both)) :condition (t / treat-04 :ARG1 c) :ARG1-of (e / expect-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id pmid_2541_3220.110 # ::date 2015-07-02T00:11:39 # ::file pmid_2541_3220_110.txt # ::snt The treatment also largely reduced cell viability in both cell lines (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jul 20, 2015 (r / reduce-01 :ARG0 (t / treat-04) :ARG1 (v / viability :mod (c / cell) :location (c2 / cell-line :mod (b / both))) :ARG2 (l / large) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B")) :mod (a / also)) # ::id pmid_2541_3220.111 # ::date 2015-07-02T00:14:52 # ::file pmid_2541_3220_111.txt # ::snt As judged from the calculated IC50 values, HoMel-L1 appeared more sensitive to the MEK1/2 inhibition than HoMel-A1 (P <0.05) and at least as sensitive as the human Q61RNRAS line BL (Figure 2C). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / appear-02 :ARG1 (a2 / and :op1 (s / sensitive-03 :ARG0 (c / cell-line :name (n / name :op1 "HoMel-L1")) :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK1/2"))) :degree (m / more) :compared-to (c3 / cell-line :name (n3 / name :op1 "HoMel-A1"))) :op2 (s2 / sensitive-03 :ARG0 c :mod (a3 / at-least) :ARG1-of (e2 / equal-01) :compared-to (c5 / cell-line :name (n4 / name :op1 "BL") :mod (e3 / enzyme :name (n5 / name :op1 "NRAS") :ARG2-of (m2 / mutate-01 :value "Q61R") :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))))) :ARG2-of (j / judge-01 :ARG3 (c4 / concentration-quantity :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 "50") :ARG1-of (c2 / calculate-01))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2C")) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 "0.05"))) # ::id pmid_2541_3220.112 # ::date 2015-07-02T00:43:13 # ::file pmid_2541_3220_112.txt # ::snt Both GHM cell lines were less sensitive to the U0126 treatment than the human V600EBRAF line Mel-Ho, although, this did not reach statistical significance for HoMel-L1. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (h / have-concession-91 :ARG1 (s / sensitive-03 :ARG0 (c / cell-line :mod (d / disease :name (n / name :op1 "GHM")) :mod (b / both)) :ARG1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696"))) :degree (l / less) :compared-to (c2 / cell-line :name (n3 / name :op1 "Mel-Ho") :mod (e / enzyme :name (n4 / name :op1 "BRAF") :mod (h2 / human) :ARG2-of (m / mutate-01 :value "V600E") :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")))) :ARG2 (r / reach-01 :polarity "-" :ARG0 s :ARG1 (s3 / signify-01 :mod (s4 / statistics)) :prep-for (c3 / cell-line :name (n5 / name :op1 "HoMel-L1")))) # ::id pmid_2541_3220.113 # ::date 2015-07-02T00:55:45 # ::file pmid_2541_3220_113.txt # ::snt In contrast, cell viability of the human WTBRAF WTRAS line M5 was only weakly inhibited by the treatment (Figure 2B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (c / contrast-01 :ARG2 (i / inhibit-01 :ARG0 (t / treat-04) :ARG1 (v / viability :mod (c2 / cell) :poss (c3 / cell-line :name (n / name :op1 "M5") :mod (e / enzyme :name (n2 / name :op1 "BRAF") :mod (w2 / wild-type) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :mod (e2 / enzyme :name (n3 / name :op1 "RAS") :mod (w3 / wild-type) :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")))) :degree (w / weak-02 :mod (o / only))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id pmid_2541_3220.114 # ::date 2015-07-02T01:02:29 # ::file pmid_2541_3220_114.txt # ::snt These results demonstrate that ERK signaling is an important component for GHM cell growth; however the incomplete inhibition by U0126 suggests that additional ERK-independent mechanisms are involved. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c4 / contrast-01 :ARG1 (d / demonstrate-01 :ARG0 (t2 / thing :mod (t / this) :ARG2-of (r / result-01)) :ARG1 (c / component :mod (i / important) :domain (s / signal-07 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :purpose (g / grow-01 :ARG1 (c2 / cell :mod (d2 / disease :name (n2 / name :op1 "GHM")))))) :ARG2 (s2 / suggest-01 :ARG0 (i2 / inhibit-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "U0126") :xref (x1 / xref :value "PUBCHEM:3006531" :prob "17.656696")) :ARG1-of (c3 / complete-01 :polarity "-")) :ARG1 (i4 / involve-01 :ARG1 (m / mechanism :ARG0-of (d3 / depend-01 :polarity "-" :ARG1 e) :mod (a / additional))))) # ::id pmid_2541_3220.115 # ::date 2015-07-02T01:15:07 # ::file pmid_2541_3220_115.txt # ::snt Activation of ERK pathway in Grey horse melanoma cells is not linked to common oncogenic alterations # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (l / link-01 :polarity "-" :ARG1 (a / activate-01 :ARG1 (p / pathway :name (n / name :op1 "ERK")) :location (c / cell :mod (m / medical-condition :name (n3 / name :op1 "melanoma") :mod (h / horse :ARG1-of (g / gray-02))))) :ARG2 (a2 / alter-01 :mod (c2 / common) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))) # ::id pmid_2541_3220.116 # ::date 2015-07-02T01:18:01 # ::file pmid_2541_3220_116.txt # ::snt To test whether the constitutive ERK1/2 activation was due to the presence of oncogenic mutations commonly associated with ERK1/2 activation in melanocytic neoplasms, we screened the horse cell lines and seven additional GHM tumours for mutations in exons 11 and 15 of BRAF, the full coding regions of N-, K- and HRAS, exon 4 and 5 of GNAQ and GNA11, and exons 9–21 of KIT. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (s / screen-01 :ARG0 (w / we) :ARG1 (a / and :op1 (c / cell-line :mod (h / horse)) :op2 (t / tumor :quant "7" :mod (d / disease :name (n / name :op1 "GHM")) :mod (a2 / additional))) :ARG2 (m / mutate-01 :ARG1 (a3 / and :op1 (a4 / and :op1 (p7 / protein-segment :name (n15 / name :op1 "exon" :op2 "11")) :op2 (p2 / protein-segment :name (n2 / name :op1 "exon" :op2 "15")) :part-of (g / gene :name (n4 / name :op1 "BRAF") :xref (x6 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (r / region :ARG1-of (f / full-09) :ARG0-of (c2 / code-01) :part-of (a5 / and :op1 (g2 / gene :name (n5 / name :op1 "NRAS") :xref (x5 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op2 (g3 / gene :name (n6 / name :op1 "KRAS") :xref (x4 / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :op3 (g4 / gene :name (n7 / name :op1 "HRAS") :xref (x3 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")))) :op3 (a6 / and :op1 (p3 / protein-segment :name (n3 / name :op1 "exon" :op2 "4")) :op2 (p8 / protein-segment :name (n17 / name :op1 "exon" :op2 "5")) :part-of (a7 / and :op1 (g5 / gene :name (n10 / name :op1 "GNAQ") :xref (x2 / xref :value "UNIPROT:GNAQ_HUMAN" :prob "1.004")) :op2 (g6 / gene :name (n11 / name :op1 "GNA11") :xref (x / xref :value "UNIPROT:GNA11_HUMAN" :prob "1.004")))) :op4 (p4 / protein-segment :name (n8 / name :op1 "exon") :value (b / between :op1 "9" :op2 "21") :part-of (g7 / gene :name (n13 / name :op1 "KIT") :xref (x1 / xref :value "UNIPROT:KIT_HUMAN" :prob "1.004"))))) :purpose (t2 / test-01 :ARG0 w :ARG1 (c3 / cause-01 :mode "interrogative" :ARG0 (p / present-02 :ARG1 (m2 / mutate-01 :ARG1-of (a9 / associate-01 :ARG2 (a10 / activate-01 :ARG1 "e6" :location (n16 / neoplasm :mod (m3 / melanocyte))) :mod (c7 / common)) :ARG0-of (c5 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer"))))) :ARG1 (a8 / activate-01 :ARG1 (e6 / enzyme :name (n14 / name :op1 "ERK1/2")) :mod (c4 / constitutive))))) # ::id pmid_2541_3220.117 # ::date 2015-07-02T01:44:00 # ::file pmid_2541_3220_117.txt # ::snt In all the genes except KIT, no mutations were found, indicating the wild-type status of the genes in this melanoma type. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (i / indicate-01 :ARG0 (f / find-01 :polarity "-" :ARG1 (m / mutate-01 :ARG1 (g / gene :mod (a / all) :ARG2-of (e / except-01 :ARG1 (g2 / gene :name (n / name :op1 "KIT") :xref (x / xref :value "UNIPROT:KIT_HUMAN" :prob "1.004")))))) :ARG1 (s / status :mod (w / wild-type) :poss g :location (m2 / medical-condition :name (n3 / name :op1 "melanoma") :ARG1-of (t3 / type-03)))) # ::id pmid_2541_3220.118 # ::date 2015-07-02T01:51:43 # ::file pmid_2541_3220_118.txt # ::snt In KIT, four single nucleotide polymorphisms (SNPs) were found in exon 14, 15, 19 and 20 (11% each) in each of 4 different tumours (Table 2). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (f / find-01 :ARG1 (t4 / thing :quant "4" :name (n / name :op1 "single" :op2 "nucleotide" :op3 "polymorphism")) :location (a / and :op1 (p6 / protein-segment :name (n2 / name :op1 "exon" :op2 "14")) :op2 (p / protein-segment :name (n3 / name :op1 "exon" :op2 "15")) :op3 (p3 / protein-segment :name (n4 / name :op1 "exon" :op2 "19")) :op4 (p4 / protein-segment :name (n5 / name :op1 "exon" :op2 "20")) :value (p2 / percentage-entity :value "11" :mod (e5 / each)) :location (e6 / each :ARG1-of (i / include-91 :ARG2 (t / tumor :quant "4" :ARG1-of (d5 / differ-02)))) :part-of (g2 / gene :name (n8 / name :op1 "KIT") :xref (x / xref :value "UNIPROT:KIT_HUMAN" :prob "1.004"))) :ARG1-of (d6 / describe-01 :ARG0 (t2 / table :mod "2"))) # ::id pmid_2541_3220.119 # ::date 2015-06-30T07:13:18 # ::file pmid_2541_3220_119.txt # ::snt However, these SNPs were silent on the protein level and present in the constitutional DNA from both Grey and non-Grey horses of different breeds (Table 2), and therefore were considered as common germline polymorphisms with no link to the Grey phenotype. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG2 (a / and :op1 (s / silent :domain (d / dna-sequence :name (n / name :op1 "SNP") :mod (t2 / this)) :location (l / level :mod (p2 / protein))) :op2 (p / present-02 :ARG1 d :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "DNA") :ARG1-of (c2 / constitute-01) :source (a2 / and :op1 (h / horse :ARG1-of (g / gray-02)) :op2 (h2 / horse :ARG1-of (g2 / gray-02 :polarity "-")) :part-of (b / breed :ARG1-of (d3 / differ-02))))) :ARG1-of (d4 / describe-01 :ARG0 (t / table :mod "2")) :ARG0-of (c3 / cause-01 :ARG1 (c4 / consider-01 :ARG1 (p3 / polymorphism :mod (c5 / common) :part-of (c6 / cell-line :name (n2 / name :op1 "germline")) :ARG1-of (l2 / link-01 :polarity "-" :ARG2 (p4 / phenotype :mod h)) :domain d))))) # ::id pmid_2541_3220.120 # ::date 2015-06-30T07:13:40 # ::file pmid_2541_3220_120.txt # ::snt Another possible mechanism for a constitutive activation of the ERK pathway may involve overexpression of a component of the pathway or underexpression of its negative regulator. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Feb 5, 2016 (p / possible-01 :ARG1 (i / involve-01 :ARG0 (m / mechanism :ARG1-of (p2 / possible-01) :instrument-of (a2 / activate-01 :ARG1 (p3 / pathway :name (n / name :op1 "ERK")) :mod (c / constitutive)) :mod (a / another)) :ARG1 (o / or :op1 (o2 / overexpress-01 :ARG1 (c2 / component :part-of p3)) :op2 (u / underexpress-00 :ARG1 (m2 / molecular-physical-entity :part-of p3 :ARG2-of (d / downregulate-01)))))) # ::id pmid_2541_3220.121 # ::date 2015-06-30T07:13:54 # ::file pmid_2541_3220_121.txt # ::snt To address this possibility we compared expression levels of the key kinases and two major negative regulators of the pathway, SPROUTY2 and RKIP, in the GHM vs. human melanoma cell lines with activated ERK1/2 due to oncogenic BRAF or NRAS mutations. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (c / compare-01 :ARG0 (w / we) :ARG1 (l / level :degree-of (e / express-03 :ARG1 (a / and :op1 (k / kinase :ARG1-of (k2 / key-02)) :op2 (m4 / molecular-physical-entity :quant "2" :ARG2-of (d / downregulate-01 :ARG1 (p / pathway)) :ARG1-of (m / major-02) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "SPROUTY2") :xref (x2 / xref :value "UNIPROT:CMYA5_HUMAN" :prob "0.222")) :op2 (p3 / protein :name (n2 / name :op1 "RKIP") :xref (x3 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002"))))))) :compared-to (l2 / level :degree-of e :location (c3 / cell :mod (m5 / medical-condition :name (n4 / name :op1 "melanoma")))) :location (c2 / cell :mod (d2 / disease :name (n3 / name :op1 "GHM")))) :ARG2 (e4 / enzyme :name (n5 / name :op1 "ERK1/2") :ARG1-of (a3 / activate-01 :ARG1-of (c5 / cause-01 :ARG0 (m3 / mutate-01 :ARG1 (o / or :op1 (e5 / enzyme :name (n6 / name :op1 "BRAF") :ARG0-of (c6 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))) :xref (x / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (e6 / enzyme :name (n7 / name :op1 "NRAS") :ARG0-of c6 :xref (x1 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))))))) :purpose (a4 / address-02 :ARG0 w :ARG1 (p2 / possible-01 :mod (t / this)))) # ::id pmid_2541_3220.122 # ::date 2015-06-30T07:27:57 # ::file pmid_2541_3220_122.txt # ::snt We found no substantial differences in the levels of ERK1/2 (Figure 1C), MEK1/2, BRAF, NRAS (Figure 3A and Additional file 3: Figure S2A) between the horse and human melanoma cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Jan 14, 2016 (f / find-01 :polarity "-" :ARG0 (w / we) :ARG1 (d / differ-02 :ARG1 (a4 / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK1/2") :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1C")))) :op2 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "MEK1/2"))) :op3 (l3 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op4 (l4 / level :quant-of (e4 / enzyme :name (n4 / name :op1 "NRAS") :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f3 / figure :mod "3A") :op2 (f4 / file :ARG1-of (m / mean-01 :ARG2 (f5 / figure :mod "S2A")) :ARG1-of (a3 / add-02)))) :xref (x / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003"))) :location (c / cell :source (m4 / medical-condition :name (n5 / name :op1 "melanoma") :mod (h / horse)))) :ARG2 (a / and :op1 l :op2 l2 :op3 l3 :op4 l4 :location (c2 / cell :source (m2 / medical-condition :name (n6 / name :op1 "melanoma") :mod (h2 / human)))) :degree (s / substantial))) # ::id pmid_2541_3220.123 # ::date 2015-06-30T07:28:13 # ::file pmid_2541_3220_123.txt # ::snt The levels of SPROUTY2 and RKIP in the horse lines were not lower than those in the human lines (Figure 3A and Additional file 3: Figure S2A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (l / low-04 :polarity "-" :ARG1 (a / and :op1 (l2 / level :quant-of (e / enzyme :name (n / name :op1 "SPROUTY2") :xref (x / xref :value "UNIPROT:CMYA5_HUMAN" :prob "0.222"))) :op2 (l3 / level :quant-of (p / protein :name (n2 / name :op1 "RKIP") :xref (x1 / xref :value "UNIPROT:PEBP1_HUMAN" :prob "1.002"))) :location (l4 / line :mod (h / horse))) :degree (m / more) :compared-to (a4 / and :op1 l2 :op2 l3 :location (l6 / line :mod (h2 / human))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3A") :op2 (f2 / file :ARG1-of (m2 / mean-01 :ARG0 (f3 / figure :mod "S2A")) :ARG1-of (a3 / add-02))))) # ::id pmid_2541_3220.124 # ::date 2015-06-30T07:28:31 # ::file pmid_2541_3220_124.txt # ::snt Together, these results suggest that neither oncogenic mutations in the components of the ERK pathway nor alteration in their expression or of that of the pathway’s major negative regulators is likely to be responsible for the constitutive activation of ERK1/2 in GHM cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (s / suggest-01 :ARG0 (t / thing :ARG1-of (r / result-01) :mod (t2 / this)) :ARG1 (l / likely-01 :polarity "-" :ARG1 (r2 / responsible-01 :ARG0 (o / or :op1 (m / mutate-01 :ARG1 (c3 / component :part-of (p / pathway :name (n / name :op1 "ERK"))) :ARG0-of (c / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :op2 (a / alter-01 :ARG1 (e / express-03 :ARG2 (o2 / or :op1 c3 :op2 (m3 / molecular-physical-entity :ARG1-of (m2 / major-02) :ARG0-of (d / deregulate-01 :ARG1 p)))))) :ARG1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")) :location (c4 / cell :mod (d2 / disease :name (n3 / name :op1 "GHM"))) :mod (c5 / constitutive)))) :mod (t3 / together)) # ::id pmid_2541_3220.125 # ::date 2015-06-30T07:28:44 # ::file pmid_2541_3220_125.txt # ::snt ERK1/2 activation is BRAF, CRAF and KRAS-dependent in Grey horse melanoma cells # ::preferred # ::annotator SDL-AMR-09 # ::save-date Thu Dec 10, 2015 (d / depend-01 :ARG0 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))) :ARG1 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "BRAF") :xref (x2 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004")) :op2 (e3 / enzyme :name (n3 / name :op1 "CRAF") :xref (x1 / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")) :op3 (e4 / enzyme :name (n4 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :location (c / cell :source (m / medical-condition :name (n5 / name :op1 "melanoma") :mod (h / horse :ARG1-of (g / gray-02))))) # ::id pmid_2541_3220.126 # ::date 2015-06-30T07:40:11 # ::file pmid_2541_3220_126.txt # ::snt In order to identify upstream signaling components involved in the constitutive ERK1/2 activation in GHM cells we used specific inhibitors against RAF (L779450), RAS (farnesyl thiosalicylic acid, FTS) and PI3K/AKT (LY294002) proteins. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (u / use-01 :ARG0 (w / we) :ARG1 (a4 / and :op1 (m / molecular-physical-entity :ARG0-of (i4 / inhibit-01 :ARG1 (p / protein-family :name (n4 / name :op1 "RAF"))) :ARG1-of (m2 / mean-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "L779450")))) :op2 (m3 / molecular-physical-entity :ARG0-of (i5 / inhibit-01 :ARG1 (p3 / protein-family :name (n5 / name :op1 "RAS"))) :ARG1-of (m4 / mean-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "farnesyl" :op2 "thiosalicylic" :op3 "acid") :xref (x / xref :value "PUBCHEM:389644" :prob "11.594721")))) :op3 (m5 / molecular-physical-entity :ARG0-of (i6 / inhibit-01 :ARG1 (p2 / pathway :name (n6 / name :op1 "PI3K/AKT"))) :ARG1-of (m6 / mean-01 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "LY294002") :xref (x1 / xref :value "PUBCHEM:3973" :prob "18.86067")))) :ARG1-of (s / specific-02)) :ARG2 (i2 / identify-01 :ARG0 w :ARG1 (c / component :ARG0-of (s5 / signal-07 :direction (u2 / upstream)) :ARG1-of (i3 / involve-01 :ARG2 (a3 / activate-01 :ARG1 (e4 / enzyme :name (n7 / name :op1 "ERK1/2")) :location (c2 / cell :mod (d / disease :name (n8 / name :op1 "GHM"))) :mod (c3 / constitutive)))))) # ::id pmid_2541_3220.127 # ::date 2015-07-01T05:46:10 # ::file pmid_2541_3220_127.txt # ::snt Only the L779450 treatment was able to reduce P-ERK1/2 levels, suggesting involvement of RAF kinases in the control of ERK activation (Figure 3B and Additional file 3: Figure S2B; FTS treatment not shown). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (p2 / possible-01 :ARG1 (r / reduce-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "L779450")) :mod (o / only)) :ARG1 (l / level :quant-of (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :ARG0-of (s2 / suggest-01 :ARG1 (i / involve-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "RAF")) :ARG2 (c / control-01 :ARG1 (a / activate-01 :ARG1 (p3 / protein-family :name (n4 / name :op1 "ERK"))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3B") :op2 (f2 / file :mod "3" :ARG1-of (a4 / add-02) :ARG1-of (m / mean-01 :ARG2 (f3 / figure :mod "S2B"))) :op3 (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "FTS") :xref (x / xref :value "PUBCHEM:5469318" :prob "18.86067")) :ARG1-of (s4 / show-01 :polarity "-"))))) # ::id pmid_2541_3220.128 # ::date 2015-07-01T06:05:39 # ::file pmid_2541_3220_128.txt # ::snt The treatment attenuated cell growth in both cell lines (Figure 3C, D) to the levels comparable to those attained by the U0126 treatment, supporting a role of RAF kinases in GHM cell growth through ERK1/2 activation. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (a / attenuate-01 :ARG0 (t / treat-04 :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "3C") :op2 (f2 / figure :mod "3D"))) :ARG0-of (s2 / support-01 :ARG1 (r / role :poss (p / protein-family :name (n2 / name :op1 "RAF")) :beneficiary (g2 / grow-01 :ARG1 (c4 / cell :mod (d2 / disease :name (n3 / name :op1 "GHM"))))) :manner (a4 / activate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "ERK1/2"))))) :ARG1 (g / grow-01 :ARG1 (c / cell)) :location (c2 / cell-line :mod (b / both)) :destination (l / level :ARG1-of (c3 / comparable-03 :ARG2 (l2 / level :ARG1-of (a3 / attain-01 :ARG0 (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :xref (x / xref :value "PUBCHEM:3006531" :prob "17.656696")))))))) # ::id pmid_2541_3220.129 # ::date 2015-07-01T07:31:32 # ::file pmid_2541_3220_129.txt # ::snt We also examined the contribution of individual RAF isoforms on ERK1/2 activation by RNA silencing (siRNA). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (e2 / examine-01 :ARG0 (w / we) :ARG1 (c / contribute-01 :ARG0 (i / isoform :mod (e / enzyme :name (n / name :op1 "RAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "1.003")) :mod (i2 / individual)) :ARG2 (a / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"))) :manner (s / silence-01 :ARG1 (n4 / nucleic-acid :name (n3 / name :op1 "siRNA")))) :mod (a2 / also)) # ::id pmid_2541_3220.130 # ::date 2015-07-01T07:46:12 # ::file pmid_2541_3220_130.txt # ::snt While no considerable reduction in ERK1/2 activation was achieved by ARAF depletion, BRAF and CRAF silencing each reduced the level of ERK1/2 phosphorylation (Figure 4A-E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (c / contrast-01 :ARG1 (a / achieve-01 :polarity "-" :ARG1 (r / reduce-01 :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))) :mod (c2 / considerable)) :manner (d / deplete-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ARAF") :xref (x2 / xref :value "UNIPROT:ARAF_HUMAN" :prob "1.004")))) :ARG2 (r2 / reduce-01 :ARG0 (a3 / and :op1 (s / silence-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "BRAF") :xref (x1 / xref :value "UNIPROT:BRAF_HUMAN" :prob "1.004"))) :op2 (s2 / silence-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "CRAF") :xref (x / xref :value "UNIPROT:RAF1_HUMAN" :prob "0.603")))) :ARG1 (l / level :quant-of (p / phosphorylate-01 :ARG1 e))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B") :op3 (f3 / figure :mod "4C") :op4 (f4 / figure :mod "4D") :op5 (f5 / figure :mod "4E")))) # ::id pmid_2541_3220.131 # ::date 2015-07-01T09:23:26 # ::file pmid_2541_3220_131.txt # ::snt Since RAS kinases are known upstream activators of wild-type RAF kinases, the failure of the FTS treatment to affect the P-ERK1/2 levels was somewhat unexpected. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / cause-01 :ARG0 (m / molecular-physical-entity :ARG0-of (a2 / activate-01 :ARG1 (p2 / protein-family :name (n4 / name :op1 "RAF") :mod (w / wild-type)) :direction (u / upstream)) :domain (k2 / kinase :name (n3 / name :op1 "RAS") :xref (x / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263")) :ARG1-of (k / know-01)) :ARG1 (e3 / expect-01 :polarity "-" :ARG1 (f / fail-01 :ARG1 (t3 / treat-04 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "FTS") :xref (x1 / xref :value "PUBCHEM:5469318" :prob "18.86067"))) :ARG2 (a3 / affect-01 :ARG0 t3 :ARG1 (l / level :quant-of (e4 / enzyme :name (n6 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))))) :degree (s / somewhat))) # ::id pmid_2541_3220.132 # ::date 2015-07-01T09:41:37 # ::file pmid_2541_3220_132.txt # ::snt We therefore decided to directly manipulate the levels of RAS kinases by siRNA-based approach to address their potential contribution to the ERK1/2 pathway in GHM cells. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 16, 2016 (c / cause-01 :ARG1 (d / decide-01 :ARG0 (w / we) :ARG1 (m / manipulate-01 :ARG0 w :ARG1 (l / level :quant-of (p3 / protein-family :name (n2 / name :op1 "RAS"))) :manner (a / approach-02 :ARG1-of (b / base-02 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "siRNA")))) :purpose (a2 / address-02 :ARG0 w :ARG1 (c2 / contribute-01 :ARG0 l :ARG2 (p2 / pathway :name (n3 / name :op1 "ERK1/2") :location (c3 / cell :mod (d3 / disease :name (n4 / name :op1 "GHM")))) :mod (p / potential))) :ARG1-of (d2 / direct-02)))) # ::id pmid_2541_3220.133 # ::date 2015-07-01T09:55:17 # ::file pmid_2541_3220_133.txt # ::snt The initial experiment with combined depletion of NRAS, HRAS and KRAS indicated their involvement in the signaling (Figure 5B, C left panels). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sat Jan 30, 2016 (i / indicate-01 :ARG0 (e / experiment-01 :ARG1 (d / deplete-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "NRAS") :xref (x2 / xref :value "UNIPROT:RASN_HUMAN" :prob "1.003")) :op2 (e3 / enzyme :name (n2 / name :op1 "HRAS") :xref (x1 / xref :value "UNIPROT:RASH_HUMAN" :prob "1.003")) :op3 (e4 / enzyme :name (n3 / name :op1 "KRAS") :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003"))) :ARG3-of (c / combine-01)) :mod (i2 / initial)) :ARG1 (i3 / involve-01 :ARG1 a :ARG2 (s / signal-07)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "5B") :op2 (f2 / figure :mod "5C") :location (p / panel :ARG1-of (l / left-20))))) # ::id pmid_2541_3220.134 # ::date 2015-07-01T10:07:58 # ::file pmid_2541_3220_134.txt # ::snt Further investigation of individual contribution of the RAS isoforms indicated KRAS as major RAS activator of the ERK signaling in these cells (Figure 5B-E). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Jan 4, 2016 (i / indicate-01 :ARG0 (i2 / investigate-01 :ARG2 (c / contribute-01 :ARG0 (i4 / isoform :mod (e3 / enzyme :name (n3 / name :op1 "RAS") :xref (x1 / xref :value "UNIPROT:RASA1_HUMAN" :prob "0.263"))) :mod (i3 / individual)) :degree (f / further)) :ARG1 (e4 / enzyme :name (n4 / name :op1 "KRAS") :ARG0-of (a2 / activate-01 :ARG1 (s / signal-07 :ARG0 (p / protein-family :name (n / name :op1 "ERK")) :location (c2 / cell :mod (t / this))) :topic e3 :ARG1-of (m / major-02)) :xref (x / xref :value "UNIPROT:RASK_HUMAN" :prob "1.003")) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "5B") :op2 (f3 / figure :mod "5C") :op3 (f4 / figure :mod "5D") :op4 (f5 / figure :mod "5E")))) # ::id pmid_2541_3220.135 # ::date 2015-07-01T10:38:20 # ::file pmid_2541_3220_135.txt # ::snt ERK pathway is activated already in skin melanocytes of Grey horses # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (a / activate-01 :ARG1 (p / pathway :name (n2 / name :op1 "ERK")) :time (a2 / already) :location (m / melanocyte :part-of (s / skin) :poss (h / horse :ARG1-of (g / gray-02)))) # ::id pmid_2541_3220.136 # ::date 2015-07-01T10:41:47 # ::file pmid_2541_3220_136.txt # ::snt The absence of the oncogenic mutations commonly linked to the activation of the ERK pathway in melanomas, the strong association of the Grey mutation with the melanoma predisposition [17] and the notion that the Grey mutation has an effect throughout melanocyte development [18], prompted us to test if the ERK pathway was already activated at the level of normal skin melanocytes in Grey horses. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Mon Dec 21, 2015 (p / prompt-02 :ARG0 (a / and :op1 (a2 / absent-01 :ARG1 (m / mutate-01 :ARG0-of (c2 / cause-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :ARG1-of (l / link-01 :ARG2 (a3 / activate-01 :ARG1 (p2 / pathway :wiki "MAPK/ERK_pathway" :name (n3 / name :op1 "ERK")) :location (m5 / medical-condition :wiki "Melanoma" :name (n7 / name :op1 "melanoma"))) :degree (c6 / common)))) :op2 (a4 / associate-01 :ARG1 (m3 / mutate-01 :mod (o / organism :ARG1-of (g / gray-02))) :ARG2 (p3 / predispose-01 :ARG2 m5) :ARG1-of (s / strong-02) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c / cite-01 :ARG2 "17")))) :op3 (n / notion :topic (a5 / affect-01 :ARG0 m3 :time (d2 / develop-02 :ARG1 (m2 / melanocyte)) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c7 / cite-01 :ARG2 "18")))))) :ARG1 (w / we) :ARG2 (t / test-01 :ARG0 w :ARG2 (a6 / activate-01 :mode "interrogative" :ARG1 p2 :time (a7 / already) :location (m4 / melanocyte :part-of (s2 / skin :ARG1-of (n6 / normal-02)) :location (h / horse :ARG1-of g))))) # ::id pmid_2541_3220.137 # ::date 2015-07-01T11:17:21 # ::file pmid_2541_3220_137.txt # ::snt We analyzed expression of both phosphorylated and total ERK1/2 in skin samples from Grey (n =9) vs. non-grey horses (n =12) of different breeds from the same and different geographic locations, as was done for the melanoma samples. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (a / analyze-01 :ARG0 (w / we) :ARG1 (e / express-03 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :op2 (e3 / enzyme :name (n2 / name :op1 "ERK1/2") :mod (t / total))) :location (s / sample-01 :ARG1 (s2 / skin) :ARG2 (a3 / and :op1 (h / horse :quant "9" :ARG1-of (g / gray-02)) :op2 (h2 / horse :quant "12" :ARG1-of (g2 / gray-02 :polarity "-")) :mod (b / breed :ARG1-of (d / differ-02) :source (a4 / and :op1 (l / location :mod (g3 / geographic :ARG1-of (s3 / same-01))) :op2 (l2 / location :mod (g4 / geographic :ARG1-of d))))))) :ARG2-of (r / resemble-01 :ARG1 (d3 / do-02 :ARG2 (s4 / sample-01 :ARG1 (m / medical-condition :name (n3 / name :op1 "melanoma")))))) # ::id pmid_2541_3220.138 # ::date 2015-07-01T12:15:52 # ::file pmid_2541_3220_138.txt # ::snt A high percentage of MITF+ epidermal melanocytes positive for the P-ERK1/2 was detected in all Grey horse skins (75.8% ±10.0) in sharp contrast to non-grey horse skins, where the phosphorylated ERK was absent (Figure 6A, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Jan 17, 2016 (d / detect-01 :ARG1 (p / percentage :ARG1-of (h / high-02) :quant-of (m2 / melanocyte :part-of (e / epidermis) :mod (p2 / protein :name (n2 / name :op1 "MITF+") :xref (x1 / xref :value "UNIPROT:MITF_HUMAN" :prob "0.672")) :mod (p3 / positive :mod (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p4 / phosphorylate-01)))) :ARG1-of (m / mean-01 :quant (p5 / percentage-entity :value "75.8" :ARG2-of (a2 / add-02 :ARG1 (p6 / percentage-entity :value "10.0")) :ARG2-of (s2 / subtract-01 :ARG1 (p7 / percentage-entity :value "10.0"))))) :location (s / skin :part-of (h2 / horse :ARG1-of (g / gray-02)) :mod (a / all)) :ARG1-of (c2 / contrast-01 :ARG2 (s4 / skin :part-of (h3 / horse :ARG1-of (g2 / gray-02 :polarity "-")) :location-of (e3 / enzyme :name (n4 / name :op1 "ERK") :ARG1-of (a3 / absent-01) :ARG3-of p4 :xref (x / xref :value "UNIPROT:EPHB2_HUMAN" :prob "1.003"))) :ARG1-of (s3 / sharp-02)) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "6A") :op2 (f2 / figure :mod "6B")))) # ::id pmid_2541_3220.139 # ::date 2015-07-01T13:32:37 # ::file pmid_2541_3220_139.txt # ::snt The activated ERK1/2 was detected both in the cytoplasm and the nucleus in Grey melanocytes. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (d / detect-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG1-of (a / activate-01)) :location (a2 / and :op1 (c / cytoplasm :xref (x / xref :value "GO:0005737" :prob "0.8")) :op2 (n2 / nucleus :xref (x1 / xref :value "GO:0005634" :prob "0.8")) :part-of (m / melanocyte :mod (o / organism :ARG1-of (g / gray-02))))) # ::id pmid_2541_3220.140 # ::date 2015-07-01T13:35:33 # ::file pmid_2541_3220_140.txt # ::snt Percentage of the total ERK1/2 positive cells was 99.5% ±0.5 in Grey and 77.1% ±11.3 in non-grey skins (Figure 6A, B). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (a / and :op1 (p3 / percentage-entity :value "99.5" :ARG2-of (a2 / add-02 :ARG1 (p4 / percentage-entity :value "0.5")) :ARG2-of (s / subtract-01 :ARG1 (p5 / percentage-entity :value "0.5")) :location (s2 / skin :ARG1-of (g / gray-02))) :op2 (p6 / percentage-entity :value "77.1" :ARG2-of (a3 / add-02 :ARG1 (p7 / percentage-entity :value "11.3")) :ARG2-of (s3 / subtract-01 :ARG1 (p8 / percentage-entity :value "11.3")) :location (s4 / skin :ARG1-of (g2 / gray-02 :polarity "-"))) :domain (p9 / percentage :quant-of (c / cell :mod (p10 / positive :mod (e / enzyme :name (n / name :op1 "ERK1/2") :mod (t / total))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "6A") :op2 (f2 / figure :mod "6B")))) # ::id pmid_2541_3220.141 # ::date 2015-07-01T14:01:03 # ::file pmid_2541_3220_141.txt # ::snt Interestingly, keratinocytes from Grey but not non-grey horses were also positive for P-ERK1/2 (Figure 6A). # ::preferred # ::annotator SDL-AMR-09 # ::save-date Fri Nov 6, 2015 (c / contrast-01 :ARG1 (p / positive :mod (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)) :domain (k2 / keratinocyte :source (h / horse :ARG1-of (g / gray-02))) :mod (a / also)) :ARG2 (p3 / positive :polarity "-" :mod e :domain (k / keratinocyte :source (h2 / horse :ARG1-of (g2 / gray-02 :polarity "-")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A")) :ARG0-of (i / interest-01)) # ::id pmid_2541_3220.142 # ::date 2015-07-01T23:34:49 # ::file pmid_2541_3220_142.txt # ::snt The staining pattern of both P-ERK1/2 and ERK1/2 was highly reproducible in samples coming from different studs and prepared in different laboratories. # ::preferred # ::annotator SDL-AMR-09 # ::save-date Sun Dec 20, 2015 (r / reproduce-01 :ARG1 (p2 / pattern :topic (s / stain-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p3 / phosphorylate-01)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))))) :ARG1-of (p / possible-01) :ARG1-of (h / high-02) :location (t / thing :ARG1-of (p4 / prepare-01 :location (l / laboratory :ARG1-of "d")) :ARG1-of (s2 / sample-01 :ARG2 (s3 / stud :ARG1-of (d / differ-02)))))